AN IMPROVED DOS-RESISTANT ID-BASED PASSWORD AUTHENTICATION SCHEME WITHOUT USING SMART CARD

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Efficient Lattice (H)IBE in the Standard Model

Eﬃcient Lattice(H)IBE in the Standard ModelShweta Agrawal1,Dan Boneh2 ,and Xavier Boyen31University of Texas,Austin2Stanford University3Universit´e de Li`e ge,BelgiumAbstract.We construct an eﬃcient identity based encryption systembased on the standard learning with errors(LWE)problem.Our securityproof holds in the standard model.The key step in the constructionis a family of lattices for which there are two distinct trapdoors forﬁnding short vectors.One trapdoor enables the real system to generateshort vectors in all lattices in the family.The other trapdoor enables thesimulator to generate short vectors for all lattices in the family exceptfor one.We extend this basic technique to an adaptively-secure IBE anda Hierarchical IBE.1IntroductionIdentity-Based Encryption(IBE)provides a public-key encryption mechanism where a public key is an arbitrary string such as an email address or a telephone number.The corresponding private key can only be generated by a Private-Key Generator(PKG)who has knowledge of a master secret.Identity-based encryption wasﬁrst proposed by Shamir[28],however,it is only recently that practical implementations were proposed.Boneh and Franklin[8]deﬁne a secu-rity model for identity-based encryption and give a construction based on the Bilinear Diﬃe-Hellman(BDH)problem.Cocks[13]describes a construction us-ing quadratic residues modulo a composite(see also[9])and Gentry et al.[16] give a construction using lattices.The security of all these systems requires cryp-tographic hash functions that are modeled as random oracles.For pairing-based systems,the structure of pairing groups enabled several secure IBE systems in the standard model[11,6,7,31,17,32].For systems based on quadratic residuosity it is still not known how to build a secure IBE in the standard model.In this paper we focus on lattice-based IBE.Cash et al.[12],Peikert[24]and Agrawal et al.[3]recently showed how to construct secure IBE in the standard model from the learning with errors(LWE)problem[27].Their constructions view an identity as a sequence of bits and then assign a matrix to each bit.The resulting systems,while quite elegant,are considerably less eﬃcient than the underlying random-oracle system of[16]on which they are built.A full version of this paper is available at[1].Supported by NSF and the Packard Foundation.1.1Our ResultsWe construct a lattice-based IBE in the standard model whose performance is comparable to the performance of the random-oracle system from[16].In particular,we process identities as one chunk rather than bit-by-bit resulting in lattices whose dimension is similar to those in the random oracle system.Lattices in our system are built from two parts called“right”and“left”lattices.A trapdoor for the left lattice is used as the master secret in the real system and enables one to generate private keys for all identities.A trapdoor for the right lattice is only used in the proof of selective security and enables the simulator to generate private keys for all identities except for one.We use a“low norm”randomization matrix R to ensure that an attacker cannot distinguish between the real world and a simulation.In pairing-based IBE systems one uses large groups G and therefore identities can be encoded as integers in the range1...|G|.In contrast,lattice systems are typically deﬁned over a relatively smallﬁeld Z q and consequently encoding identities as integers in1...q would result in too few identities for the system.Instead,we represent identities as matrices in Z n×nq for some n.More precisely,we represent identities as elements in Z n q(for a total of q n identities)and thenuse an encoding function H:Z n q→Z n×nq to map identities to matrices.Oursecurity proof requires that for all id1=id2the matrix H(id1)−H(id2)∈Z n×nqis invertible.We present an encoding function H that has this property and expect this encoding to be useful in other lattice-based constructions.A similar function H was developed by Cramer and Damgard[14]in an entirely diﬀerent context.Full IBE.In the full version of the paper[1]we show that our base construction extends to an adaptively-secure IBE using a lattice analog of the Waters IBE[31]. Our base construction requires that the underlyingﬁeld Z q satisfy q>Q where Q is the number of private key queries issued by the adversary.This requirement can be relaxed using the framework of Boyen[10].Hierarchical IBE(HIBE).In the full version of the paper[1]we show how to extend our base IBE to an HIBE using the basis delegation technique from[12, 24].The construction assigns a matrix to each level of the hierarchy and the resulting lattice dimension is linear in the recipient identity’s depth.Since we do not process identities bit-by-bit we obtain an eﬃcient HIBE where the lattice dimension is much smaller than in[12,24].We note that a recent result of[2]uses a diﬀerent basis delegation mechanism to construct an improved HIBE where the lattice dimension isﬁxed for the entire hierarchy.2PreliminariesNotation.Throughout the paper we say that a function :R≥0→R≥0is neg-ligible if (n)is smaller than all polynomial fractions for suﬃciently large n. We say that an event happens with overwhelming probability if it happens with2probability at least1− (n)for some negligible function .We say that integer vectors v1,...,v n∈Z m are Z q-linearly independent if they are linearly indepen-dent when reduced modulo q.2.1IBE and Hierarchical IBERecall that an Identity-Based Encryption system(IBE)consists of four algo-rithms[28,8]:Setup,Extract,Encrypt,Decrypt.The Setup algorithm generates system parameters,denoted by PP,and a master key MK.The Extract algorithm uses the master key to extract a private key corresponding to a given identity. The encryption algorithm encrypts messages for a given identity(using the sys-tem parameters)and the decryption algorithm decrypts ciphertexts using the private key.In a Hierarchical IBE[20,18],identities are vectors,and there is aﬁfth algo-rithm called Derive.A vector of dimension represents an identity at depth . Algorithm Derive takes as input an identity id=(I1,...,I )at depth and the private key SK id| −1of the parent identity id| −1=(I1,...,I −1)at depth −1≥0.It outputs the private key SK id for identity id.We sometimes refer to the master key as the private key at depth0,given which the algorithm Derive performs the same function as Extract.The Setup algorithm in an HIBE scheme takes the maximum depth of the hierarchy as input.Selective and Adaptive ID Security.The standard IBE security model of[8]de-ﬁnes the indistinguishability of ciphertexts under an adaptive chosen-ciphertext and chosen-identity attack(IND-ID-CCA2).A weaker notion of IBE security given by Canetti,Halevi,and Katz[11]forces the adversary to announce ahead of time the public key it will target,which is known as a selective-identity attack (IND-sID-CCA2).As with regular public-key encryption,we can deny the adversary the ability to ask decryption queries(for the target identity),which leads to the weaker notions of indistinguishability of ciphertexts under an adaptive chosen-identity chosen-plaintext attack(IND-ID-CPA)and under a selective-identity chosen-plaintext attack(IND-sID-CPA)respectively.Security Game.We deﬁne IBE and HIBE selective security using a game that captures a strong privacy property called indistinguishable from random which means that the challenge ciphertext is indistinguishable from a random element in the ciphertext space.This property implies both semantic security and recip-ient anonymity,and also implies that the ciphertext hides the public parame-ters(PP)used to create it.This can make the IBE more resistant to subpoenas since an observer cannot tell from the ciphertext which authority holds the cor-responding master secret.For a security parameterλ,we let Mλdenote the message space and let Cλdenote the ciphertext space.The game,for a hierarchy of maximum depth d,proceeds as follows.Init:The adversary is given the maximum depth of the hierarchy d and outputs),k≤d.a target identity id∗=(I∗1, (I)k3Setup:The challenger runs Setup(1λ,1d)(where d=1for IBE)and gives the adversary the resulting system parameters PP.It keeps the master key MK to itself.Phase1:The adversary issues queries q1,...,q m where the i-th query q i is a query on id i,where id i=(I1,...,I u)for some u≤d.We require that id i is not a preﬁx of id∗,(i.e.,it is not the case that u≤k and I i=I∗i for all i=1,...,u).The challenger responds by running algorithm Extract to obtain a private key d i for the public key id i.It sends d i to the adversary.All queries may be made adaptively,that is,the adversary may ask q i with knowledge of the challenger’s responses to q1,...,q i−1.Challenge:Once the adversary decides that Phase1is over it outputs a plain-text M∈Mλon which it wishes to be challenged.The challenger picks a random bit r∈{0,1}and a random ciphertext C∈Cλ.If r=0it sets the challenge ciphertext to C∗:=Encrypt(PP,id∗,M).If r=1it sets the chal-lenge ciphertext to C∗:=C.It sends C∗as the challenge to the adversary. Phase2:The adversary issues additional adaptive queries q m+1,...,q n where q i is a private-key extraction query on id i,where id i is not a preﬁx of id∗.The challenger responds as in Phase1.Guess:Finally,the adversary outputs a guess r ∈{0,1}and wins if r=r . We refer to such an adversary A as an INDr–sID-CPA adversary.We deﬁne the advantage of the adversary A in attacking an IBE or HIBE scheme E asAdv d,E,A(λ)=Pr[r=r ]−1/2The probability is over the random bits used by the challenger and the adversary. Deﬁnition1.We say that an IBE or a depth d HIBE system E is selective-identity,indistinguishable from random if for all INDr–sID-CPA PPT adversaries A we have that Adv d,E,A(λ)is a negligible function.We abbreviate this by saying that E is INDr–sID-CPA secure for depth d.2.2Statistical distanceLet X and Y be two random variables taking values in someﬁnite setΩ.Deﬁne the statistical distance,denoted∆(X;Y),as∆(X;Y):=12s∈ΩPr[X=s]−Pr[Y=s]We say that X isδ-uniform overΩif∆(X;UΩ)≤δwhere UΩis a uniform random variable overΩ.Let X(λ)and Y(λ)be ensembles of random variables.We say that X and Y are statistically close if d(λ):=∆(X(λ);Y(λ))is a negligible function ofλ.42.3Integer LatticesLet B=b1...b m∈R m×m be an m×m matrix whose columns are linearlyindependent vectors b1,...,b m∈R m.The m-dimensional full-rank latticeΛgenerated by B is the set,Λ=L(B)=y∈R m s.t.∃s∈Z m,y=B s=mi=1s i b iHere,we are interested in integer lattices,i.e,when L is contained in Z m.Deﬁnition2.For q prime,A∈Z n×mqand u∈Z n q,deﬁne:Λq(A):=e∈Z m s.t.∃s∈Z n q where A s=e(mod q)Λ⊥q(A):=e∈Z m s.t.A e=0(mod q)Λu q(A):=e∈Z m s.t.A e=u(mod q)Observe that if t∈Λu q(A)thenΛu q(A)=Λ⊥q(A)+t and henceΛu q(A)is a shift ofΛ⊥q(A).2.4The Gram-Schmidt Norm of a BasisLet S be a set of vectors S={s1,...,s k}in R m.We use the following notation:– S denotes the L2length of the longest vector in S,i.e. S :=max i s i for1≤i≤k.–˜S:={˜s1,...,˜s k}⊂R m denotes the Gram-Schmidt orthogonalization of the vectors s1,...,s k taken in that order.We refer to S as the Gram-Schmidt norm of S.Micciancio and Goldwassser[22]showed that a full-rank set S in a latticeΛcan be converted into a basis T forΛwith an equally low Gram-Schmidt norm. Lemma1([22,Lemma7.1]).LetΛbe an m-dimensional lattice.There is a deterministic polynomial-time algorithm that,given an arbitrary basis ofΛand a full-rank set S={s1,...,s m}inΛ,returns a basis T ofΛsatisfyingT ≤ S and T ≤ S √m/2Ajtai[4]showed how to sample an essentially uniform matrix A∈Z n×mq with an associated basis S A ofΛ⊥q(A)with low Gram-Schmidt norm.We use an improved sampling algorithm from Alwen and Peikert[5].The following follows from Theorem3.2of[5]takingδ:=1/3.5Theorem 1.Let q ≥3be odd and m := 6n log q .There is a probabilistic polynomial-time algorithm TrapGen (q,n )that outputs apair (A ∈Z n ×m q ,S ∈Z m ×m )such that A is statistically close to a uniform matrix in Z n ×m q and S is a basis for Λ⊥q (A )satisfyingS≤O ( n log q )and S ≤O (n log q )with all but negligible probability in n .We will also need the following simple lemma about the eﬀect of matrix multiplication on the Gram-Schmidt norm.Lemma 2.Let R be a matrix in R ×m and S ={s 1,...,s k }⊂R m a linearly independent set.Let S R :={Rs 1,...,Rs k }.ThenS R ≤max 1≤i ≤k R ˜s i Proof.We show that for all i =1,...,k the i -th Gram-Schmidt vector of S R has L 2norm less than R ˜s i .This will prove the lemma.For i ∈{1,...,k }let V :=span R (Rs 1,...,Rs i −1).Set v :=s i −˜s i .Then v ∈span R (s 1,...,s i −1)and therefore Rv ∈V .Let u be the projection of R ˜s i on V and let z :=R ˜s i −u .Then z is orthogonal to V andRs i =Rv +R ˜s i =Rv +u +z =(Rv +u )+z .By construction,Rv +u ∈V and hence,since z is orthogonal to V ,this z must be the i -th Gram-Schmidt vector of S R .Since z is the projection of R ˜s i on V ⊥we obtain that z ≤ R ˜s i .Hence,for all i =1,...,k the i -th Gram-Schmidt vector of S R has L 2norm less than R ˜s i which proves the lemma.2.5Discrete GaussiansLet L be a subset of Z m .For any vector c ∈R m and any positive parameter σ∈R >0,deﬁne:ρσ,c (x )=exp −π x −c 2σ2 :a Gaussian-shaped function on R m with center cand parameter σ,ρσ,c (L )= x ∈L ρσ,c (x ):the (always converging)sum of ρσ,c over L ,D L,σ,c :the discrete Gaussian distribution over L with parameters σand c ,∀y ∈L ,D L,σ,c (y )=ρσ,c (y )ρσ,c (L )We abbreviate ρσ,0and D L,σ,0as ρσand D L,σ.We write ρto denote ρ1.The distribution D L,σ,c will most often be deﬁned over the lattice L =Λ⊥q (A )for amatrix A ∈Z n ×m q or over a coset L =t +Λ⊥q (A )where t ∈Z m .6Properties.The following lemma from [24]captures standard properties of these distributions.The ﬁrst two properties follow from Lemma 4.4of [23]and Corol-lary 3.16of [27]respectively (using Lemma 3.1from [16]to bound the smoothing parameter).We state in property (2)a stronger version of Regev’s Corollary 3.16found in [2].The last two properties are algorithms from [16].Lemma 3.Let q ≥2and let A be a matrix in Z n ×m q with m >n .Let T A be a basis for Λ⊥q (A )and σ≥ T A ω(√log m ).Then for c ∈Rm and u ∈Z n q :1.Pr x ∼D Λ⊥q (A ),σ: x >√m σ ≤negl(n ).2.A set of O (m log m )samples from D Λ⊥q (A ),σcontains a full rank set in Z m ,except with negligible probability.3.There is a PPT algorithm SampleGaussian (A,T A ,σ,c )that returns x ∈Λ⊥q (A )drawn from a distribution statistically close to D Λ,σ,c .4.There is a PPT algorithm SamplePre (A,T A ,u,σ)that returns x ∈Λu q (A )sampled from a distribution statistically close to D Λu q (A ),σ.Recall that if Λu q (A )is not empty then Λu q (A )=t +Λ⊥q (A )for some t ∈Λu q (A ).Algorithm SamplePre (A,T A ,u,σ)works by calling SampleGaussian (A,T A ,σ,t )and subtracts t from the result.2.6The L WE hardness assumptionSecurity of all our constructions reduces to the LWE (learning with errors)prob-lem,a classic hard problem on lattices deﬁned by Regev [27].Deﬁnition 3.Consider a prime q ,a positive integer n ,and a distribution χover Z q ,all public.An (Z q ,n,χ)-LWE problem instance consists of access to an unspeciﬁed challenge oracle O ,being,either,a noisy pseudo-random sampler O s carrying some constant random secret key s ∈Z n q ,or,a truly random sampler O $,whose behaviors are respectively as follows:O s :outputs samples of the form (u i ,v i )= u i ,u T i s +x i ∈Z n q ×Z q ,where,s ∈Z n q is a uniformly distributed persistent value invariant across invocations,x i ∈Z q is a fresh sample from χ,and u i is uniform in Z n q .O $:outputs truly uniform random samples from Z n q ×Z q .The (Z q ,n,χ)-LWE problem allows repeated queries to the challenge oracleO .We say that an algorithm A decides the (Z q ,n,χ)-LWE problem if Pr[A O s =1]−Pr[A O $=1] is non-negligible for a random s ∈Z n q .Regev [27]shows that for certain noise distributions χ,denoted Ψα,the LWE problem is as hard as the worst-case SIVP and GapSVP under a quantum reduction (see also [25]).Deﬁnition 4.Consider a real parameter α=α(n )∈(0,1)and a prime q .Denote by T =R /Z the group of reals [0,1)with addition modulo 1.Denote7by Ψαthe distribution over T of a normal variable with mean 0and standard deviation α/√2πthen reduced modulo 1.Denote by x = x +12 the nearest integer to the real x ∈R .We denote by Ψαthe discrete distribution over Z q of the random variable q X mod q where the random variable X ∈T has distribution Ψα.Theorem 2([27]).If there exists an eﬃcient,possibly quantum,algorithm for deciding the (Z q ,n,Ψα)-LWE problem for q >2√n/αthen there exists an eﬃ-cient quantum algorithm for approximating the SIVP and GapSVP problems,to within ˜O(n/α)factors in the 2norm,in the worst case.If we assume the hardness of approximating the SIVP or GapSVP problems in lattices of dimension n to within approximation factors that are polynomial in n ,then it follows from Lemma 2that deciding the LWE problem is hard when n/αis polynomial in n .3Randomness ExtractionWe will need the following lemma which follows directly from a generalization of the left over hash lemma due to Dodis et al.[15].Lemma 4.Suppose that m >(n +1)log 2q +ω(log n )and that q is prime.LetA,B be matrices chosen uniformly in Z n ×m q and let R be an m ×m matrix chosen uniformly in {1,−1}m ×m mod q .Then,for all vectors w in Z m q ,the distribution(A,AR,R w )is statistically close to the distribution (A,B,R w ).To prove the lemma recall that for a prime q the family of hash functionsh A :Z m q →Z n q for A ∈Z n ×m q deﬁned by h A (x )=A x is universal.Therefore,when the columns of R are sampled independently and have suﬃcient entropy,the left over hash lemma (e.g.as stated in [29,Theorem 8.38])shows that the distributions (A,AR )and (A,B )are statistically close.A generalization by Dodis et al.[15](Lemma 2.2b and 2.4)shows that the same holds even if some small amount of information about R is leaked.In our case R w is leaked which is precisely the settings of Dodis et al.We provide the complete proof of Lemma 4in the full version of the paper [1].3.1Random Subset SumsWe will also need the following simple lemma.Lemma 5.Let R be an m ×m matrix chosen at random from {−1,1}m ×m .Then for all vectors u ∈R m we havePr Ru > u √m ·ω( log m ) <negl(m ).8Proof.Let r ∈{−1,1}m be a row vector of the matrix R .Then r ·u can be written as r u = m i =1x i where x i =r i u i .We know that E [x i ]=0and that x i ∈[−u i ,u i ]for all i =1,...,m .Then,by the Hoeﬀding bound [19,Theorem 2]we obtain thatPr |r ·u |> u ω( ) <negl(m )The lemma now follows since an m -vector whose entries are less than some bound B has L 2norm less than √mB . 4Sampling AlgorithmsLet A and B be matrices in Z n ×m q and let R be a matrix in {−1,1}m ×m .Our construction makes use of matrices of the form F =(A |AR +B )∈Z n ×2m q and we will need to sample short vectors in Λu q (F )for some u in Z n q .We show thatthis can be done using either a trapdoor for Λ⊥q (A )or a trapdoor Λ⊥q (B ).Moreprecisely,we deﬁne two algorithms:1.SampleLeft takes a basis for Λ⊥q (A )(the left side of F )and outputs a shortvector e ∈Λu q (F ).2.SampleRight takes a basis for Λ⊥q (B )(the right side of F )and outputs ashort vector e ∈Λu q (F ).We will show that,with appropriate parameters,the distributions on e produced by these two algorithms are statistically indistinguishable.4.1Algorithm SampleLeftAlgorithm SampleLeft (A,M 1,T A ,u,σ):Inputs:a rank n matrix A in Z n ×m q and a matrix M 1in Z n ×m 1q ,a “short”basis T A of Λ⊥q (A )and a vector u ∈Z n q ,a gaussian parameter σ> T A ·ω( log(m +m 1)).(1)Output:Let F 1:=(A |M 1).The algorithm outputs a vector e ∈Z m +m 1sampled from a distribution statistically close to D Λu q (F 1),σ.In particular,e ∈Λu q (F 1).The algorithm appears in Theorem 3.4in [12]and also in the signing algo-rithm in [24].For completeness,we brieﬂy review the algorithm.1.sample a random vector e 2∈Z m 1distributed statistically close to D Z m 1,σ,2.run e 1R ←SamplePre (A,T A ,y,σ)where y =u −(M 1·e 2)∈Z n q ,note that Λy q (A )is not empty since A is rank n ,3.output e ←(e 1,e 2)∈Z m +m 19Clearly (A |M 1)·e =u mod q and hence e ∈Λu q (F 1).Theorem 3.4in [12]shows that the vector e is sampled from a distribution statistically close to D Λu q (F 1),σ.Peikert’s basis extension method [24]gives an alternate way to view this.Given the basis T A of Λ⊥q (A )Peikert shows how to build a basis T F 1of Λ⊥q (F 1)with the same Gram-Schmidt norm as T A .Then calling SamplePre (F 1,T F 1,u,σ)generates a vector e sampled from a distribution close to D Λu q (F 1),σ.We summa-rize this in the following theorem.Theorem 3.Let q >2,m >2n log q and σ> T A·ω( 1.Then Algorithm SampleLeft (A,M 1,T A ,u,σ)taking inputs as in (1),outputs a vector e ∈Z m +m 1distributed statistically close to D Λu q (F 1),σwhere F 1:=(A |M 1).4.2Algorithm SampleRightAlgorithm SampleRight (A,B,R,T B ,u,σ).Inputs:matrices A,B in Z n ×m q where B is rank n ,a uniform random matrix R ∈{−1,1}m ×m ,a basis T B of Λ⊥q (B )and a vector u ∈Z n q ,a parameter σ> T B ·√m ·ω(log m ).(2)Output:Let F 2:=(A |AR +B ).The algorithm outputs a vector e ∈Z 2m sampled from a distribution statistically close to D Λu q (F 2),σ.In particular,e ∈Λu q (F 2).The algorithm uses the basis growth method of Peikert [24,Sec.3.3]and works in three steps:1.First,it constructs a set T F 2of 2m linearly independent vectors in Λ⊥q (F 2)such that T F 2 < T B·√m ·ω( log m )<σ/ω( log m )with overwhelming probability over the choice of R .2.Next,if needed it uses Lemma 1to convert T F 2into a basis T F 2of Λ⊥q (F 2)with the same Gram-Schmidt norm as T F 2.3.Finally,it invokes SamplePre (F 2,T F 2,u,σ)to generate a vector e ∈Λu q (F 2).Since σ> T F 2 ω(√log m )w.h.p,this e is distributed as D Λu q (F 2),σ,as re-quired.Step 1is the only step that needs explaining.Let T B ={b 1,...,b m }∈Z m ×mbe the given basis of Λ⊥q (B ).We construct the 2m vectors in Λ⊥q (F 2)as follows:1.for i =1,...,m set t i :=(−Rb i |b i )∈Z 2m and view it as a column vector;then clearly F 2·t i =B b i =0mod q and therefore t i is in Λ⊥q (F 2).2.for i =1,...,m let w i be the i -th column of the identity matrix I m .Let u i be an arbitrary vector in Z m satisfying Aw i +Bu i =0mod q .This u i exists since B is rank n .Set t i +m to be t i +m := w i −Ru i u i∈Z 2mThen F 2·t i +m =Aw i +Bu i =0mod q and hence,t i +m ∈Λ⊥q (F 2).10We show that T F2:={t1,...,t2m}are linearly independent in Z2m.First,ob-serve that theﬁrst m vectors are linearly independent and span the linear space V of vectors of the form(−Rx|x)where x∈Z m q.For all i>m,the vector t i isthe sum of the unit vector(w i|0m)plus a vector in V.It follows that T F2is alinearly independent set.This also means that for i>m the i-th Gram-Schmidt vector of T F2cannot be longer than(w i|0m)and therefore has norm at most1.Hence,to boundT F2 it suﬃces to bound the Gram-Schmidt norm of theﬁrstm vectors{t1,...,t m}.Let W∈Z2m×m be the matrix(−R |I m) .Then t i=W b i for i=1,...,m. Since R is uniform in{−1,1}m×m we know by Lemma5that for all vectors x∈R m we have w.h.pW x ≤ R x + x ≤ x √m·ω(log m)+ x ≤ x√m·ω(log m)Now,since t i=W b i for i=1,...,m,applying Lemma2to the matrix W gives a bound on the Gram-Schmidt norm of{t1,...,t m}(and hence also onT F2):T F2 ≤max1≤i≤mW˜b i ≤max1≤i≤m˜b i ·√m·ω(log m)≤ T B ·√m·ω()Thus,we built2m linearly independent vectors inΛ⊥q(F2)that w.h.p.have a short Gram-Schmidt norm as required for Step1.This completes the description of algorithm SampleRight.We summarize this in the following theorem. Theorem4.Let q>2,m>n andσ> T B ·√m·ω(log m).Then Algo-rithm,SampleRight(A,B,R,T B,u,σ)taking inputs as in(2),with R uniform in{1,−1}m×m,outputs a vector e∈Z2m distributed statistically close to DΛuq (F2),σwhere F2:=(A|AR+B).5Encoding Identities as MatricesOur construction uses an encoding function H:Z n q→Z n×nq to map identities inZ n q to matrices in Z n×nq .Our proof of security requires that the map H satisfya strong notion of injectivity,namely that,for any two distinct inputs id1and id2,the diﬀerence between the outputs H(id1)and H(id2)is never singular,i.e., det(H(id1)−H(id2))=0.Deﬁnition5.Let q be a prime and n a positive integer.We say that a function H:Z n q→Z n×nqis an encoding with full-rank diﬀerences(FRD)if:1.for all distinct u,v∈Z n q,the matrix H(u)−H(v)∈Z n×nq is full rank;and2.H is computable in polynomial time(in n log q).Clearly the function H must be injective since otherwise,if u=v satisﬁes H(u)=H(v),then H(u)−H(v)is not full-rank and hence H cannot be FRD.11The function H in Deﬁnition5has domain of size q n which is the largest possible for a function satisfying condition1of Deﬁnition5.Indeed,if H had domain larger than q n then its image is also larger than q n.But then,by pigeon-hole,there are two distinct inputs u,v such that the matrices H(u)and H(v) have the sameﬁrst row and therefore H(u)−H(v)is not full rank.It follows that our deﬁnition of FRD,which has domain of size of q n,is the largest possible. An Explicit FRD Construction.We construct an injective FRD encoding for the exponential-size domain id∈Z n q.A similar construction is described in[14].Our strategy is to construct an additive subgroup G of Z n×nq of size q n suchthat all non-zero matrices in G are full-rank.Since for all distinct A,B∈G the diﬀerence A−B is also in G,it follows that A−B is full-rank.While our primary interest is theﬁniteﬁeld Z q we describe the construction for an arbitraryﬁeld F.For a polynomial g∈F[X]of degree less than n deﬁne coeﬀs(g)∈F n to be the n-vector of coeﬃcients of g(written as a row-vector).If g is of degree less than n−1we pad the coeﬃcients vector with zeroes on the right to make it an n-vector.For example,for n=6we have coeﬀs(x3+2x+3)= (3,2,0,1,0,0)∈F6.Let f be some polynomial of degree n in F[X]that is irreducible.Recall that for a polynomial g∈F[X]the polynomial g mod f has degree less than n and therefore coeﬀs(g mod f)is a vector in F n.Now,for an input u=(u0,u1,...,u n−1)∈F n deﬁne the polynomial g u(X)= n−1i=0u i x i∈F[X].Deﬁne H(u)asH(u):=coeﬀs(g u)coeﬀs(X·g u mod f)coeﬀs(X2·g u mod f)...coeﬀs(X n−1·g u mod f)∈F n×n(3)This completes the construction.Since for all primes q and integers n>1there are(many)irreducible polynomials in Z q[X]of degree n,the construction can accommodate any pair of q and n.The following theorem proves that the function H in(3)is an FRD.The proof,given in[14],is based on the observation that the matrix H(u) corre-sponds to multiplication by a constant in the numberﬁeld K=F[X]/(f)and is therefore invertible when the matrix is non-zero.We note that similar matrix encodings of ring multiplication were previously used in[26,21].Theorem5.Let F be aﬁeld and f a polynomial in F[X].If f is irreducible in F[X]then the function H deﬁned in(3)is an encoding with full-rank diﬀerences (or FRD encoding).12。

tpo36听力题目解析

Conversation 1 (1)Lecture1 (2)Lecture 2 (4)答案： (6)Conversation 2 (6)Lecture3 (8)Lecture4 (10)答案： (12)Conversation 11.What do the speakers mainly discuss?O Methods that the professor uses to challenge her studentsO Reasons that the student turned in his paper a week late .O The two parts of an assignment for a writing class.O Seldom discussed aspects of a famous poet's work.2.What reason does the professor give for wanting to meet with the student?O She wants to compliment him on the work he has done so far.O She is concerned that the student is not reading a wide enough variety of poetry. O She wants to lend him a book of poetry.O She routinely meets individually with her students.3.What does the student like about Pablo Neruda's poems in the book Elemental Odes?O That Neruda challenged himself by limiting the theme of all the poems to fruits and vegetables O That the poems have been written in many different styles.O How Neruda focuses on color to make his poems more memorable.O How Neruda describes common objects in unexpected ways.4.Why does the student mention the meter called iambic pentameter?O To point out that his poem is longer than The Lemon.O To explain how he approached the composition of his poem.O To explain what he liked most about Neruda's poem The LemonO To distinguish Neruda's poetry from that of other poets.5.What does the professor mean when she says this:O Neruda was an extraordinary writer.O Neruda should not have won a Nobel Prize.O It is surprising that Neruda's poems are not more popularO It is unfortunate that Neruda did not win a Nobel Prize.Lecture16.What aspects of snowflakes does the professor mainly discuss? Click on 2 answers.O How they develop into complex structures.O How they are affected by the presence of ozone.O The challenges researchers face in studying them.O The function of their quasi-liquid layer.7.What does the professor say about the role of water vapor in snowflake formation?O Too much water vapor prevents the initial dinner plate from forming.O Water vapor's role in snowflake formation is not completely understood.O Water vapor molecules in snowflakes attract ice particles from the air.O Water vapor is necessary for snowflakes to be able to form branches.8.What factor helps explain why no two snowflakes are alike?O They all freeze at different rates.O They all form in slightly different air temperatures.O They all begin with a different number of water moleculesO They all follow different paths through clouds.9.How do molecules in the quasi-liquid layer differ from those in other parts of the snowflake?O They are not held in place as tightly as other molecules.O They react with ozone to keep the layer from completely freezing.O They prevent ice crystals from forming additional branches.O They are thinner than other molecules.10.What does the professor imply about ice crystals with a large number of branches? O They help block harmful radiation from the Sun.O They form as a result of complex reactions with ozone.O They contribute to a reduction in ground-level ozone.O They have a thinner quasi-liquid layer than ice crystals with fewer branches 11.What can be inferred about the professor when he says this:O He doubts that the students have understood his explanation.O He does not think that bricks are an ideal illustration of his point.O He is not sure that the information he has just given is accurate.O He thinks that the similarities between liquid and bricks are surprising Lecture 212.What is the lecture mainly about?O The discovery of a previously unknown trace metal.O The role trace metals play in carbon cycling.O Ways that living organisms rid themselves of trace metals.O Ways that zinc interacts with carbon dioxide.13.What does the professor imply about the conversation of carbon dioxide molecules in plants?O It is an unusually complex chemical process.O It only takes place in full sunlight.O It proceeds slowly when cadmium is present.O It is regulated by an enzyme that may contain zinc.14.According to the professor, why is it surprising that many marine plants areable to survive near the surface of oceans?O Weather conditions near the surface disrupt certain life processes.O The salt content of surface waters is constantly changing.O Surface waters contain low quantities of zinc.O Surface waters absorb large amounts of carbon dioxide.15.A ccording to the professor, what important function do diatoms serve?O They alter cadmium so it is less toxic to humans.O They help cycle zinc in places where it is scarce.O They distribute carbon throughout the ocean.O They remove cadium from the ocean floor.16.What point does the professor make when she talks about cadmium being poisonous to humans?O That cadmium and zinc can serve a similar function in plant enzymes.O That both cadmium and zinc are rare in plant enzymes.O That most trace metals are poisonous to humans.O That cadmium does not serve any biological purpose.17.The professor states that the discovery of an enzyme containing cadmium is important. What are two reasons that this discovery is important? Click on 2 answers.O It may lead to the discovery of new enzymes that use other trace metals.O It may explain the ocean's increased levels of carbon dioxide.O It may explain the scarcity of some elements in the ocean.O It may help scientists better understand global warming.答案：1.c2.D3. D4.B5. D6.AD7.A8.D9.A10.B11.C12.B13.D14.C15.C16.A17.ADConversation 21.Why does the woman go to talk to the man?O To find out how the store pays artists for their work.O To purchase some ceramic coffee mugs.O To find out if the store sells objects made by students.O To ask about the advantages and disadvantages of consignment sales2.What is the main reason that the woman cannot display her ceramic bowls in the campus store?O Her bowls are too expensive.O There is not enough room for her display case.O The store gets merchandise only from approved suppliers. O There is little demand on campus for ceramic bowls.3.According to the conversation, what is a reason that the woman wants to sell her bowls?O To earn enough money to buy a second display case. O To fulfill a requirement of one of her courses.O To impress her studio art professor.O To gain experience that could help in her future career.4.What is the woman's attitude toward selling items at the Emporium?O She is eager to display her work to the public there.O She is encouraged because the Emporium specializes in selling ceramics.O She is worried because she does not fully understand the consignment process.O She is worried that she might not make much money.5.What concerns does the woman initially express about selling items at the craft fair? Click on 2 answers.O Whether doing so would interfere with her studies.O Whether customers would appreciate her artistryO Whether she could afford the fee charged to sellers.O Whether she would be able to transport her items to the fair.Lecture36.What is the main purpose of the lecture?O To familiarize students with the Mayan civilization in the Classic Period.O To prepare students for an archaeology project about the Mayan civilization.O To provide evidence for a point made in a previous class about the Mayan civilization O To call into question a common view about the decline of ancient Mayan civilization.7.Why does the professor discuss Lamanai in detail?O To present findings about one Mayan settlement from the Postclassic period.O To describe the physical layout of the first Mayan settlements in Central America.O To criticize the excavation methods used there during the 1970s.O To note how the size of a typical Mayan settlement varied throughout its history.8.What is one of the features that gives Lamanai special archaeological significance?O It was the first Mayan site in Belize to be excavated in modern times.O It was occupied by two distinct cultural groups during the Classic period.O It was continuously occupied by the Maya longer than any other site.O It had an economic structure that was distinct from that of other Mayan cities9.Why does the professor say that it would require lots of funding to uncover the stone structures that she discusses?O Because there are so many of them.O Because very few archaeologists are given access to them. O Because they arelocated on so many different islands.O Because of difficult weather conditions in the region.10.According to the professor, what can be inferred from the ceramic artifactsfound on the island? O The island was the source of most of the pottery used at Lamanai.O Much of Lamanai's population relocated to the island during the Postclassicperiod. O The Mayan trading network remained strong during the Postclassicperiod.O The Maya developed new technological capabilities on the island.11.Why does the student say this:O To request that the professor repeat the point she just made.O To express his doubt about the period of time being discussed.OTo disagree with the professor's interpretation of the evidence about Lamanai. OTo find out if he correctly understands the professor's point.Lecture412.What is the main purpose of the lecture?O To explain how musicians can perform successfully in theaters and concert halls with poor acoustics.O To explain how the design of theaters and concert halls has changed over time.O To discuss design factors that affect sound in a room.O To discuss a method to measure the reverberation time of a room.13.According to the lecture, what were Sabine's contributions to architectural acoustics? Click on 2 a nswers.O He founded the field of architectural acoustics.O He developed an important formula for measuring a room’s reverberation time. O H e renewed architects ’ interest in ancient theaters.O He provided support for using established architectural principles in the design of concert halls.14.According to the professor, what is likely to happen if a room has a very long reverberation time?O Performers will have to make an effort to be louder.O Sound will not be scattered in all directions.O Older sounds will interfere with the perception of new sounds.O Only people in the center of the room will be able to hear clearly.15.Why does the professor mention a piano recital?O To illustrate that different kinds of performances require rooms with different reverberation times.O To demonstrate that the size of the instrument can affect its acoustic properties.O To cite a type of performance suitable for rectangular concert hall.O To exemplify that the reverberation time of a room is related to its size.16.According to the professor, what purpose do wall decorations in older concert halls serve?O They make sound in the hall reverberate longer.O They distribute the sound more evenly in the hall.O They make large halls look smaller and more intimate.O They distuise structural changes made to improve sound quality.17.Why does the professor say this:O To find out if students have understood his point.O To indicate that he will conclude the lecture soon.O To introduce a factor contradicting his previous statement. O To add emphasis to his previous statement.答案：1.C2.B3.B4.D5.AD6.D7.A8.C9.A10.C11D12.C13.AB14.C15.AD16.B17.D。

蛋白及多肽药物干粉吸入剂研究新进展_周洁雨

蛋白及多肽药物干粉吸入剂研究新进展周洁雨, 张兰, 毛世瑞*(沈阳药科大学药学院, 辽宁沈阳 110016)摘要: 为成功设计蛋白及多肽类药物物理混合型干粉吸入剂提供理论和实践依据, 本文综述和阐明了干粉吸入剂常用载体, 药物微粉化制备技术, 影响干粉吸入剂肺部沉积的处方工艺因素, 包括载体性质、药物载体比例、混合顺序、混合方法和混合时间、药物载体相互作用, 以及粉体学性质包括粒径大小和形态、密度、粉体流动性、带电性、分散性、吸湿性对肺部沉积率的影响。

依据上述讨论和粉末分散的机制, 提出了增加干粉吸入剂肺部沉积率的策略, 包括加入载体细粉、加入黏附力控制物质和对药物微粉再加工等。

因此, 设计肺部沉积率高的蛋白及多肽药物的物理混合型干粉吸入剂需系统地研究药物与载体相互作用, 阐明处方工艺及粉体学性质的影响。

关键词: 蛋白质及多肽类药物; 干粉吸入剂; 载体; 肺部沉积率中图分类号: R943 文献标识码:A 文章编号: 0513-4870 (2015) 07-0814-10Recent progress of dry powder inhalation of proteins and peptidesZHOU Jie-yu, ZHANG Lan, MAO Shi-rui*(School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China)Abstract: To provide theoretical and practical basis for the successful formulation design of physically-mixed inhalation dry powder of proteins and peptides, related references were collected, analyzed and summarized. Inthis review drug micronization technology and commonly used carriers for inhalation dry powder preparationwere introduced. For proteins and peptides, supercritical fluid technology and spray-drying are more suitablebecause of their capabilities of keeping drug activity. Being approved by U. S. Food and Drug Administration,lactose has been extensively used as carriers in many inhalation products. Formulation and process factors influencing drug deposition in the lung, including carrier properties, drug-carrier ratio, blending order, mixingmethods, mixing time and the interaction between drug and carrier, were elucidated. The size, shape and surface properties of carries all influence the interaction between drug and carrier. Besides, influence of micromeritic properties of the dry powder, such as particle size, shape, density, flowability, charge, dispersibilityand hygroscopicity, on drug deposition in the lung was elaborated. Among these particle size plays the mostcrucial role in particle deposition in the lung. Moreover, based on the mechanisms of powder dispersity, somestrategies to improve drug lung deposition were put forward, such as adding carrier fines, adding adhesive- controlling materials and reprocessing micronized drug. In order to design physically-mixed inhalation drypowder for proteins and peptides with high lung deposition, it is essential to study drug-carriers interactions systematically and illustrate the potential influence of formulation, process parameters and micromeritic properties of the powder.Key words: protein and peptide; dry powder inhalation; carrier; lung deposition收稿日期: 2015-03-13; 修回日期: 2015-04-23.*通讯作者 Tel / Fax: 86-24-23986358, E-mail: maoshirui@因蛋白及多肽类大分子药物膜通透性差且对酶敏感, 所以一直以来这类药物在临床上以注射给药为主。

DERSIMELAGON 产品说明书

488 Scientific AbstractsSystemic sclerosis, myositis and related syndromes - aetiology, pathogenesis and animal modelsPOS0467 DERSIMELAGON, A NOVEL ORAL MELANOCORTIN1 RECEPTOR AGONIST, DEMONSTRATES DISEASE-MODIFYING EFFECTS IN PRECLINICAL MODELS OFSYSTEMIC SCLEROSISM. Kondo1, T. Suzuki1, Y. Kawano1, S. Kojima2, M. Miyashiro1, A. Matsumoto1, G. Kania3, P. Blyszczuk3, R. Ross4, P. Mulipa4, F. Del Galdo4, Y. Zhang5, J. H. W. Distler5. 1Mitsubishi T anabe Pharma Corporation, Research Unit/Immunology & Inflammation, Souyaku Innovative Research Division, Y okohama, Japan;2Mitsubishi T anabe Pharma Corporation, Discovery T echnology Laboratories, Souyaku Innovative Research Division, Y okohama, Japan;3University Hospital Zurich, University of Zurich, Center of Experimental Rheumatology, Department of Rheumatology, Schlieren, Switzerland;4University of Leeds, Leeds Instituteof Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, Leeds, United Kingdom;5Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Department of Internal Medicine 3—Rheumatology and Immunology, Erlangen, GermanyBackground: Activation of melanocortin 1 receptor (MC1R) is known to have broad anti-inflammatory and anti-fibrotic effects. The bleomycin (BLM)-induced skin fibrosis murine model is well-established for systemic sclerosis (SSc). α-mel-anocyte-stimulating hormone, an endogenous ligand of MC1R, inhibits skin fibro-sis and MC1R knock-out enhances skin fibrosis in this model. These pieces of evidence suggest that MC1R agonism has potential in the treatment of SSc. Objectives: Dersimelagon phosphate (MT-7117) is an investigational small molecule that is an orally administered, selective agonist for MC1R. The purpose of this study is to investigate the potential of MT-7117 as a therapeutic agent for SSc by evaluat-ing its efficacy and mechanism of action in complementary preclinical models. The expression and distribution of MC1R in the skin of SSc patients was investigated. Methods: The effects of MT-7117 on skin fibrosis and lung inflammation were eval-uated in BLM-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum pro-tein profiling were performed to investigate the mechanism of action of MT-7117 in the BLM-induced SSc models. The effect of MT-7117 on TGF-β-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in skin samples from SSc patients were performed. Results: Prophylactic treatment with MT-7117 (≥0.3 mg/kg/day p.o.) significantly inhibited the increase in collagen content of the skin, the serum level of sur-factant protein D, and the weight of the lungs from BLM-induced skin fibrosis and lung inflammation model. Therapeutic treatment with MT-7117 (≥3 mg/kg/ day p.o.) significantly suppressed skin thickening and the numbers of myofi-broblasts in pre-established BLM-induced skin fibrosis model. Gene array anal-ysis using the BLM-induced SSc model demonstrated changes in numerous categories related to macrophages, monocytes, and neutrophils, followed by endothelial cell-related categories after treatment with MT-7117. In the analy-sis that focused on biological functions, categories of inflammatory response, activation of antigen-presenting cells, angiogenesis, atherosclerosis, vascu-logenesis, and vaso-occlusion were suppressed by MT-7117. In the analysis that focused on molecular signaling pathways, triggering receptor expressed on myeloid cells-1, IL-6, and oncostatin M involved in inflammation, and perox-isome proliferator-activated receptor that is related to fibrosis were all affected by MT-7117. Serum protein profiling using BLM-induced SSc model revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cys-tatin C, growth and differentiation factor-15 and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by sup-pressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA ele-vation in vitro. Immunohistochemical analyses showed that MC1R positivity was observed in 40 of 50 diffuse cutaneous SSc patients. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibro-blasts, and epidermis (keratinocytes) in the skin of SSc patients. Conclusion: MT-7117 demonstrates disease-modifying effects in preclinical mod-els of SSc. Investigations of its mechanism of action and target expression anal-yses indicate that MT-7117 exerts its positive effects by affecting the pathologies of inflammation, vascular dysfunction, and fibrosis through inflammatory cells, endothelial cells, and fibroblasts. In view of its potent beneficial impact on all these three main pathologies of SSc, MT-7117 is a potential therapeutic agent for the treatment of clinically challenging SSc, which has diverse and difficult to treat symp-toms. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress. Disclosure of Interests: Masahiro Kondo Employee of: Mitsubishi Tanabe Pharma Corporation, Tsuyoshi Suzuki Employee of: Mitsubishi Tanabe Pharma Corporation, Yuko Kawano Employee of: Mitsubishi Tanabe Pharma Corpora-tion, Shinji Kojima Employee of: Mitsubishi Tanabe Pharma Corporation, Masa-hiko Miyashiro Employee of: Mitsubishi Tanabe Pharma Corporation, Atsuhiro Matsumoto Employee of: Mitsubishi Tanabe Pharma Corporation, Gabriela Kania: None declared, Przemyslaw Blyszczuk: None declared, rebecca ross:None declared, Panji Mulipa: None declared, Francesco Del Galdo Grant/ research support from: Prof. F. Del Galdo received fees and research supportfrom Abbvie, AstraZeneca, Boehringer-Ingelheim, Capella, Chemomab, Kymab, Janssen and Mitsubishi-Tanabe., Yun Zhang: None declared, Jörg H.W. DistlerGrant/research support from: Prof. J.H.W. Distler received consulting fees, lec-ture fees, and/or honoraria from Actelion, Active Biotech, Anamar, ARXX, aTyr,Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, Sanofi-Aventis, RedX, RuiYi and UCB. J. H. W.Distler is stock owner of 4D Science and Scientific head of FibroCure.DOI: 10.1136/annrheumdis-2022-eular.29POS0468 EXTRACELLULAR VESICLES FROM SERUM OFMYOSITIS PATIENTS AS CIRCULATING BIOMARKERSAND DISEASE MEDIATORSS. Kivity1,2, H. Kravitz3, C. Cohen3, D. Margoulis3, M. Amar3, G. Kazimirsky3,D. Ozeri4, A. Dori5, C. Brodie3. 1Meir Medical Center, Rheumatology Unit, KefarSava, Israel;2T el Aviv University, Sackler faculty of Medicine, T el Aviv-Y afo, Israel;3Bar-Ilan University, The Mina and Everard Goodman Faculty of Life Sciences,Ramat Gan, Israel;4T el-HaShomer The Sheba Medical Center, ZabludowiczCenter for Autoimmune Disease, Ramat Gan, Israel;5T el-HaShomer The ShebaMedical Center, Department of Neurology, T alpiot Medical Leadership Program,Sackler Faculty of Medicine, T el Aviv University, Ramat Gan, IsraelBackground: Inflammatory myopathies (IM) are a heterogeneous group of disor-ders characterized by autoimmune inflammatory destruction of skeletal muscles.It is many times associated with lung, skin and joint involvement. Identifying bio-markers that can differentiate IM from other muscle disorders may elucidate the pathophysiology of IM, guide novel therapies, monitor disease activity/responseto treatments and predict prognosis. Exosomes are membrane-bound nanove-sicles with diameters of 30-150 nm that contain multiple proteins, nucleic acid,lipids and other molecules in a tissue- and cell-specific manner. Exosomes are secreted by a large variety of cells, play major roles in cell-cell interactions, andhave recently emerged as circulating biomarkers in a variety of pathological con-ditions, including several autoimmune diseases.Objectives: To characterize exosomes from serum of IM patients, analyze pro-tein expression and study their potential mediators of disease pathologies.Methods: Serum was collected from patients suffering from IM(n=5) and from patients suffering from Becker (BMD) and Duchenne (DMD) muscular dystro-phies (n=6). Exosomes were isolated by Exoquick precipitation and analyzedfor size distribution and by nanoparticle tracking analysis (NTA) and by Westernblot for exosome markers. The effects of the isolated EVs on human satellitecell proliferation and differentiation and macrophage activation were examined. Results: Exosomes from IM patients decreased human satellite cell proliferation (51%, P<0.01) and inhibited their myogenic differentiation as indicated by lower fusionindex (24% inhibition, P<0.01) and expression of myosin heavy chain (72% inhibi-tion, P<0.001). Similar results were obtained also with exosomes derived from DMDand BMD patients; however, their inhibitory effect were more pronounced on MyoG expression. T reatment of macrophages with exosomes from IM patients significantly increased the expression of IL-10 (3-fold, P<0.001), compared to exosomes of healthy controls and DMD patients. Another significant difference was in the expression of sig-naling molecules: Thus, exosomes from BMD patients increased the phosphorylationof Erk and p38, whereas a smaller effect was induced by IM exosomes.Conclusion: Exosomes from IM patients decrease satellite cell proliferationand myogenic differentiation compared to healthy exosomes. In addition, these exosomes increased the expression of IL-10 in macrophages. These effects areunique to exosomes of IM patients compared to muscular dystrophies. These promising results suggest that serum exosomes should be further investigatedas a novel biomarker with potential therapeutic implications.Disclosure of Interests: Shaye Kivity Speakers bureau: BI, Abbvie, Lilly, Pfizer, Janssen, Neopharm, Grant/research support from: Sobi, Haya Kravitz: None declared, Coral Cohen: None declared, Darya Margoulis: None declared, MosheAmar: None declared, Gila Kazimirsky: None declared, David Ozeri Speakers bureau: Neopharm, Consultant of: Abbvie, Amir Dori Grant/research supportfrom: Biogen, Chaya Brodie Grant/research support from: Biogen.DOI: 10.1136/annrheumdis-2022-eular.63POS0469 ENDOTHELIAL TO MESENCHYMAL TRANSITIONAND SENESCENCE ARE PART OF THE FIBROTICPATHOGENESIS IN SYSTEMIC SCLEROSISY. H. Chiu1,2, J. Spierings1, J. M. Van Laar1, J. De Vries-Bouwstra3, M. VanDijk4, R. Goldschmeding4. 1University Medical Center Utrecht, Departmentof Rheumatology and Clinical Immunology, Utrecht, Netherlands;2T ri-ServiceGeneral Hospital, Division of Rheumatology/Immunology/Allergy, T aipei, T aiwan, Republic of China;3Leiden University Medical Center, The Department of on December 24, 2023 by guest. Protected by copyright./ Ann Rheum Dis: first published as 10.1136/annrheumdis-2022-eular.29 on 23 May 2022. Downloaded from。

临床药师参与1例心衰终末期合并利尿剂抵抗患者容量管理的体会

临床药师参与1例心衰终末期合并利尿剂抵抗患者容量管理的体会杨　贤1，兰　希2，严思敏1，王文晓3，葛卫红1（1.南京大学医学院附属鼓楼医院药学部，江苏南京 210008；2.南京大学医学院附属鼓楼医院心内科，江苏南京 210008；3.青岛大学附属医院药学部，山东青岛 266000）[摘要]　1例72岁男性患者，因“反复胸痛7年，胸闷气喘3年，加重1个月”入院，入院诊断为慢性心功能不全急性失代偿，陈旧性广泛前壁心肌梗死，冠状动脉支架植入后，急性肾功能不全。

临床药师评估后，认为患者存在容量超负荷并且合并利尿剂抵抗，建议将托拉塞米注射液由静脉滴注改为静脉持续输注。

同时联合小剂量多巴胺改善肾血流。

后患者存在低钠血症，药师建议加用托伐普坦片（15 mg ，qd ）纠正电解质紊乱。

出院前患者心衰症状好转，体质量较入院时有明显下降，血钠、血钾均恢复至正常范围。

[关键词]　临床药师；心力衰竭；容量管理；利尿剂抵抗；电解质；药学监护[中图分类号]　R969.4 [文献标识码]　A [文章编号]　1672 – 8157(2021)01 – 0017 – 04Experience of clinical pharmacists participating in the capacity management of a heart failure patient with diuretic resistanceYANG Xian 1, LAN Xi 2, YAN Si-min 1, WANG Wen-xiao 3, GE Wei-hong 1(1. Department of Pharmacy, Nanjing Drum TowerHospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; 2. Department of Cardiology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; 3. Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao 266000, China )[ABSTRACT]　One 72-year-old male patient was hospitalized because of repeated chest pain for 7 years, chest tightness andasthma for 3 years and aggravation for 1 month. The patient was diagnosed as acute decompensation for chronic heart failure, old extensive anterior myocardial infarction, post coronary stent implantation and acute renal insufficiency. After evaluation by the clinical pharmacist, the patient was considered to have capacity overload and diuretic resistance. Pharmacist suggested to use torasemide injection by continuously intravenous infusion instead of intravenous drip. At the same time, small doses of dopamine was also suggested to be used combined with torasemide to improve renal blood flow. And then tolvaptan tablets (15 mg, qd) were also advised to be given to him for correcting electrolyte turbulence. The patient's symptoms of heart failure improved, the body weight decreased significantly compared with that of admission, and the level of blood sodium and blood potassium all returned to the normal range before discharge.[KEY WORDS]　Clinical pharmacist; Heart failure; Capacity management; Diuretic resistance; Electrolyte; Pharmaceutical care·临床药师园地·[通信作者]　葛卫红，女，主任药师，研究方向：临床药学。

基于身份的远程相互认证改进方案

An improved ID-based remote authentication
scheme
作者：王亚飞
作者机构：平顶山学院,河南平顶山467000
出版物刊名：河南城建学院学报
页码： 55-57页
年卷期： 2011年第2期
主题词：基于身份冒充攻击椭圆曲线密码
摘要：通过对一种基于椭圆曲线密码和身份的远程相互认证方案进行分析,发现该方案不能够抵抗假冒攻击。

针对该问题,提出了一种改进的基于身份的远程相互认证方案。

利用服务器的公钥对登录信息进行加解密操作,并增加一个时间间隔,不仅保持了原方案的安全性,还能够有效地抵抗假冒攻击。

中医英语试题及答案

中医英语试题及答案一、选择题1. What is the concept of Yin-Yang theory in Traditional Chinese Medicine (TCM)?a) The concept of genetic materialb) The concept of balance and harmonyc) The concept of Western diagnosisd) The concept of pharmaceutical drugs答案：b) The concept of balance and harmony2. Which of the following is not considered a pillar in TCM diagnosis?a) Inspectionb) Palpationc) Auscultation and olfactiond) Lab testing答案：d) Lab testing3. What is the main focus of acupuncture in TCM?a) Adjusting the body's Yin and Yang balanceb) Prescribing herbal medicinec) Performing surgeriesd) Applying physical therapies答案：a) Adjusting the body's Yin and Yang balance4. What does the TCM term "Qi" refer to?a) Meridians in the bodyb) The five elements theoryc) The body's vital energyd) Herbal medicine ingredients答案：c) The body's vital energy5. Which of the following is a commonly used herb in TCM for reducing inflammation?a) Ginsengb) Licorice rootc) Ginkgo bilobad) St. John's Wort答案：b) Licorice root二、填空题1. Acupuncture is believed to restore the balance of ________ in the body.答案：Qi2. TCM diagnosis methods include inspection, palpation, ________ and olfaction.答案：auscultation3. The traditional Chinese herb ________ is commonly used for improving digestion.答案：ginger4. In TCM, the concept of "________" refers to the interaction between different body organs.答案：interconnectedness5. ________ exercises, such as Tai Chi and Qigong, are often recommended in TCM for promoting overall well-being.答案：Mind-body三、简答题1. Explain the concept of Yin and Yang in Traditional Chinese Medicine.答案：In TCM, Yin and Yang are two complementary forces that represent the balance and harmony in the body. Yin represents the cooler, more passive aspects, while Yang represents the hotter, more active aspects. The balance between Yin and Yang is crucial for maintaining optimal health. When Yin and Yang are imbalanced, it leads to illness. TCM treatments aim to restore the balance of Yin and Yang to promote overall well-being.2. Discuss the role of herbal medicine in Traditional Chinese Medicine.答案：Herbal medicine plays a significant role in TCM. Different herbs and natural substances are used to promote healing and restore balance in the body. Each herb has specific properties and functions that can be used totreat various conditions. Herbal prescriptions are tailored to an individual's specific needs, taking into account their unique symptoms and constitution. Herbal medicine can be used to address a wide range of health issues, from common colds to chronic diseases.3. Compare and contrast Traditional Chinese Medicine with Western medicine.答案：Traditional Chinese Medicine and Western medicine have different approaches to understanding and treating illnesses. TCM focuseson the holistic view of the body and aims to restore balance and harmony. It emphasizes natural healing methods, such as acupuncture, herbal medicine, and lifestyle adjustments. Western medicine, on the other hand, relies heavily on scientific research and evidence-based practices. It focuses on diagnosis, treatment, and prevention using pharmaceutical drugs, surgery, and advanced medical technologies.While both systems have their strengths and weaknesses, they can also complement each other. Many people choose to integrate both TCM and Western medicine for a comprehensive approach to healthcare.总结：中医英语试题主要包括选择题、填空题和简答题，涉及到中医理论、诊断方法和治疗手段等方面的内容。

Devilbiss JGA-502 喷枪用户手册说明书

Devilbiss jga 502 manual
DevilbissJga 502OwnersManu ■Major Repair Kit KK-4987-2 Minor Repair Kit KK-5034 IMPORTANT: Before using this equip-ment, read all safety precautions and in-structions. Keep for future use. SERVICE BULLETIN SB-2-252-J Replaces SB-2-252-I JGA-510 CONVENTIONAL SPRAY GUN Page 6, if any problems occur.PREVENTIVE MAINTENANCE To clean air cap and fluid tip, brushexterior with a stiff bristle brush. If neces-sary to clean cap holes, use a broom strawor toothpick. Never use a wire or hardinstrument. This may scratch or burr holescausing a distorted spray pattern. To clean fluid passages, remove excessmaterial at source, then flush with a suit-able solvent using a device such as theSolventSaver™ (see Accessories). Wipegun exterior with a solvent dampened cloth.Never completely immerse in solvent asthis is detrimental to the lubricants andpackings. Note When replacing the fluid tip or fluidneedle, replace both at the sametime. Using worn parts can causefluid leakage. Matched sets are avail-able for most pressure feed combi-nations. See Chart 3. Matched setsare particularly recommended withthinner, less viscous materials. Also,replace the needle packing at thistime. Lightly lubricate the threadsof the fluid tip before reassembling.Torque to 20-25 ft. lbs. Do not over-tighten the fluid tip. To prevent damage to the fluid tip(4) or fluid needle (33), be sure toeither 1) pull the trigger and holdwhile tightening or loosening thefluid tip or 2) remove fluid needleadjusting screw (28) to relievespring pressure against needlecollar. DESCRIPTION The JGA-510 can be utilized with the widerange of air caps and needles. It is a generalpurpose, heavy duty, high productionspray gun suitable for use with mosttypes of materials. The fluid tip and needleand internal fluid passages are stainlesssteel. Conversion to HVLP - The JGA-510, plusJGA-503 models, can be converted toHVLP if desired. Contact DeVilbiss for in-formation. Note This gun includes 300 series stain-less steel fluid passages and 300Guns maybe used with chlorinated solventmaterials, but see page 2 foradditional warnings. Important: This gun may be used withmost common coating and finishing ma-terials. It is designed for use with mildlycorrosive and non-abrasive materials. Ifused with other high corrosive or abra-sive materials, it must be expected thatfrequent and thorough cleaning will berequired and the necessity for replace-ment of parts will be increased. OPERATION Note Protective coating and rust inhibitorshave been used to keep the gun ingood condition prior to shipment.Before using the gun, flush it withsolvent so that these materials will beremoved from fluid passages. Strain material thru 60 or 90 mesh screen.Adjust fluid pressure to deliver the desiredpaint volume. Adjust air pressure and flowto provide a uniform dispersion of atomizedpaint throughout the pattern. Keep airpressure as low as possible to minimizebounce - back and overspray. Excessivefluid flow will result in heavy center spraypatterns. Inadequate flows may cause thepattern to split. See “Troubleshooting”, SPRAY GUN LUBRICATION Daily, apply a drop of SSL-10 spray gunlube at trigger bearing stud (21) and thestem of the air valve (13) where it entersthe air valve assembly (17). The shank ofthe fluid needle (33) where it enters thepacking nut (19) should also be oiled. Thefluid needle packing (18) should be lubri-cated periodically. Make sure the baffle (6)and retaining ring (1 or 2 ) threads areclean and free of foreign matter. Beforeassembling retaining ring to baffle, cleanthe threads thoroughly, then add twodrops of SSL-10 spray gun lube tothreads. The fluid needle spring (30) andair valve spring (12) should be coated witha very light grease, making sure that anyexcess grease will not clog the air pas-sages. For best results, lubricate thepoints indicated, daily. A. Trigger Points B. Packing C. Adjusting Valves D. Baffle Threads E. Air Valve Cartridge A C D B E FLUID INLET GASKET (7) REPLACEMENTINSTRUCTIONS 1 . Remove fluid inlet adapter with ap-propriate wrench. 2 . Clean Loctite from gun body inletthreads and seal area. 3 . Place gasket (7) squarely onto the fluidinlet adapter and push it down until itis flat against the boss. 4 . Place a couple of drops of mediumstrength blue No. 242 Loctite onthreads before installing fluid inletadapter.

Defining drug disposition determinants

Drug disposition is influenced by drug metabolizing enzymes (DMEs), drug transport proteins (DTPs), serum binding proteins and transcription factors that regulate DME and DTP expression (BOX 1). Foreknowledge of the specific proteins that influence the disposition of a new chemical entity (NCE) is an important goal of preclinical and early clinical drug develop‑ment. Early availability of this information enables mathematical modelling of the drug interaction potential of an NCE using quantitative kinetic parameters of specific DMEs1. This can therefore lead to better projection of doses for subsequent studies. Although tools exist to assess the roleof most of these proteins for the disposi‑tion of an NCE, drug developers typically learn only about a limited number of them (that is, several cytochrome P450s (CYPs), a few additional DMEs and the DTPP‑glycoprotein), and generally do not know the relative clinical importance of most of the more than 170 drug disposition pathways (TABLES 1,2;BOX 2; Supplementary information S1 (table), S2 (table), S3 (table), S4 (table)). Much of the knowledge aboutdrug disposition determinants comes fromacademic laboratories after a drug is marketed.Such knowledge has been highly beneficial forpatients; for example, when the prevalence ofsevere adverse events in thiopurine S‑methyl‑transferase (TPMT) poor metabolizers dosedwith thiopurines was identified2,3. However,for many drugs, the pathways that determinepharmacokinetic variation remain unknowneven years after regulatory approval. Thislimits the ability of drug developers to identify,manage and understand the consequences ofpharmacokinetic variability for efficacy, safetyand drug–drug interactions. For example,statins were used by many millions of peoplebefore it was discovered that their pharmaco‑kinetic variability, drug interactions, efficacyand safety might be dependent on the DTPsolute carrier organic anion transport protein1B1 (OATP1B1)4–6.Association between a gene variantand drug pharmacokinetics implies amechanistic role of the gene product indrug disposition, and the potential outcomeof making such associations is to learn theextent to which any of a wide range offactors influences the disposition of a drug.Increased knowledge and more accessibletechnology should now make it easier fordrug developers to study which pathwaysare responsible for the disposition of adrug. In this article, after a brief overviewof the preclinical characterization of drugdisposition, we summarize current know‑ledge on pharmacogenetics and drug dispo‑sition. We then propose a new approachin which pharmacogenetic results derivedfrom early clinical studies can both feedback to additional targeted in vitro studiesand feed forward to optimize later‑stage,larger clinical trials for NCEs, contribute tomore informative drug labels, and therebypotentially enable better drug use.Preclinical drug disposition assessmentPreclinical characterization of drug dis‑position generally involves the assessmentof individual proteins for their role in thedisposition of the NCE. A summary ofcurrently available tools for such studies,including purified or recombinantproteins, selective substrates and inhibitors isprovided in Supplementary information S5(table).Although many purified or recombinantDMEs — particularly members of thehuman CYP, flavin monooxygenase (FMO),monoamine oxidase (MAO), UDP glucu‑ronosyltransferase (UGT), sulphotransferase(SULT), N‑acetyltransferase (NAT) andglutathione S‑transferase (GST) families— are commercially available, there aresubstantial gaps in the availability of purifiedor recombinant DMEs from other families.Several DTPs have been functionallyexpressed in recombinant cell‑based assays,but these are generally not commerciallyavailable. When purified or recombinantprotein is not available, selective inhibitors(if known and commercially available) canbe useful to deconstruct the dispositionprocess in perfused organs, tissue slices,isolated cells or subcellular fractions.However, sufficiently selective inhibitors thatdistinguish between closely related proteinshave only been established for a few DMEor DTP families. Even among the CYPs, it isstill not possible to fully distinguish betweeno P i n i o nDefining drug dispositiondeterminants: a pharmacogenetic–pharmacokinetic strategyDavid A. Katz, Bernard Murray, Anahita Bhathena and Leonardo SahelijoAbstract | In preclinical and early clinical drug development, information about thefactors influencing drug disposition is used to predict drug interaction potential,estimate and understand population pharmacokinetic variability, and selectdoses for clinical trials. However, both in vitro drug metabolism studies andpharmacogenetic association studies on human pharmacokinetic parameters havefocused on a limited subset of the proteins involved in drug disposition. Furthermore,there has been a one-way information flow, solely using results of in vitro studiesto select candidate genes for pharmacogenetic studies. Here, we propose a two-way pharmacogenetic–pharmacokinetic strategy that exploits the dramatic recentexpansion in knowledge of functional genetic variation in proteins that influencedrug disposition, and discuss how it could improve drug development.NATUrE rEvIEWS |drug discovery vOLUME 7 | APrIL 2008 |293PersPectIves©2008Nature Publishing Groupthe four CYP3A enzymes, and selective inhibitors for some CYPs (for example, CYP2C18, CYP2G, CYP2r1, CYP2S1) have not been identified. Indeed, little is known at all about these and a number of other DMEs. When a selective inhibitor is not available, it may be possible to take advantage of tissue‑selective expression of particular isoforms within a protein family to learn the extent to which each can influence NCE disposition (for example, the roles of FMO1, FMO2 and FMO3 can be assessed separately in kidney, lung and liver using the same inhibitor). When neither recombinant protein nor selective inhibitor for a DME or DTP is available, observing that an NCE is a competitive inhibitor (in perfused organs, tissue slices, isolated cells or subcellular fractions) towards a known selective sub‑strate (again, if known and commercially available) might indicate that a particular DME or DTP is important for the NCE’sdisposition. If a drug induces DME or DTPexpression by a transcription factor bindingin a heterologous transcription activation assay,it might autoinduce its own disposition aswell as that of other drugs.To provide a comprehensive in vitrosurvey of drug disposition determinants,a laboratory needs the capability to per‑form the diverse assay types mentionedabove, many of which must be developedin‑house. Because of the current lack of acomprehensive toolset and the resourcesrequired — and also because there hasnot been a regulatory imperative foradditional investigation — a typical pre‑clinical in vitro survey has covered onlyseveral DMEs (mainly CYPs) and the DTPP‑glycoprotein. Knowing whether thesefactors can influence the disposition ofan NCE provides valuable but far fromcomprehensive information to predictdrug interaction potential, estimate andunderstand population pharmacokineticvariability, and select doses for subsequentclinical trials. Elucidation of the specific setof disposition pathways that are importantfor a particular NCE’s disposition has notbeen achieved, mainly because the neces‑sary resources have not been available.There is a need for an improved toolsetto identify the most important proteins thatinfluence the disposition of an NCE. Thistoolset should be more comprehensive incoverage of DMEs, DTPs and other factors;less diverse in assay types; feasible duringpreclinical or early clinical development; andaffordable. We propose that a strategy basedon the growing knowledge of the influenceof pharmacogenetic factors on drug disposi‑tion (summarized in the following section)can help provide that toolset.Pharmacogenetics and drug dispositionA genetic component of pharmacokineticvariability was postulated more than 100years ago by Archibald Garrod in studies ofpatients with alkaptonuria7. Half a centurylater, several drugs were shown to haveindistinguishable disposition in mono‑zygotic twins, but often distinct dispositionin dizygotic twins (for example, phenyl‑butazone8). These results established drugdisposition as a heritable trait. Deficienciesof the DMEs NAT and butyrylcholin‑esterase (BCHE) were later identified asrisk factors for adverse effects of isoniazid9and succinylcholine10, respectively, and thegenetic basis for these11–15 and other DMEpoor metabolizer phenotypes (for example,CYP2D616–20, TPMT21–23) were discoveredaround 1990.By the 1990s, there was an understand‑able reticence in the pharmaceutical industryto develop drugs that were substrates ofthese few polymorphic DMEs because of thelikelihood of variable pharmacokinetic anddrug–drug interactions. However, therewere exceptions: atomoxetine, a sensitiveCYP2D6 substrate, was approved for usein 2002 (REF. 24). Also in the 1990s, drugdevelopers began to utilize pharmacogeneticstudies to learn the magnitude of pharmaco‑kinetic variability of NCEs that could beattributed to genetic variation. In general,these studies focused on the few DMEs inwhich there were known polymorphisms,and were undertaken only when they wereconsidered necessary. That is, when in vitroresults indicated that the NCE was asubstrate of the polymorphic DME(hypothesis‑based experiments).P e r s P e c t i v e s294 | APrIL 2008 | vOLUME 7 /reviews/drugdisc©2008Nature Publishing GroupUntil recently, limited knowledge about functional genetic variation in DMEs (and none about polymorphism in other drugdisposition factors) substantially limited the scope of pharmacogenetics–pharmaco‑kinetics research. However, in the past few years, substantial knowledge in this field has been accumulated, and a review of the literature reveals that there are now over 170 gene products known or expected to have a role in drug disposition (BOX 3). These include not only numerous DMEs and DTPs, but also abundant serum binding proteins and regulatory (transcription) factors that control the expression of DMEs and DTPs. More than half of the corresponding genes are known to be poly‑morphic (TABLES 1,2;BOX 2; Supplementary information S1 (table)); most that are not known to contain common functional poly‑morphisms (Supplementary information S2 (table), S3 (table), S4 (table)) have not been adequately studied to state with certainty that they do not.The 16 proteins involved in drug disposition for which consistently replicated associations between variants in the corresponding genes and the human pharmacokinetics of at least one drug havebeen published are shown in TABLE 1. Withthe exception of FMO3, for which only tworeports showing relationship to sulindacpharmacokinetics were found, there werethree or more consistent reports for at leastone drug for each gene. FMO3 was includedin this group because the established associ‑ation of variants in this gene with fish-odoursyndrome25 is additional evidence supportingits relevance for xenobiotic disposition.Nearly all the genes listed in TABLE 1 encodeDMEs, although there is also a gene thatencodes a DTP (OATP1B1). There is robustscientific evidence showing that each genecontains common variants (combinedminor allele frequency of variants sharinga phenotype ≥5%), which have substantialeffects on human pharmacokinetics of oneor more drugs (see TABLE1 for references).However, this does not mean that the rele‑vance of these variants for clinical practicehas been established; in fact, dose adjust‑ments or contraindications based on onlyCYP2D6, CYP2C9, TPMT and UGT1A1 arecurrently included in US drug labels26.TABLE 2 shows the 18 genes for whichcommon variants are likely to have a role indrug disposition, having been shown to beassociated with the human pharmacokineticsof one or more drugs, albeit in single studies.Of these, 15 encode DMEs, 2 encode DTPsand 1 encodes a serum binding protein(α‑1 acid glycoprotein, gene = ORM1).The preponderance of DMEs in TABLE 1 andTABLE 2 reflects that DMEs were the solefocus of pharmacogenetics research relatedto drug disposition until recently. Many ofthe studies cited in TABLE 2 are relativelyrecent, and might therefore be replicatedin the near future. As this occurs, the rangeof genes established as polymorphic deter‑minants of human pharmacokinetics willexpand. In addition to pharmacokinetics,several of these genes have also beenassociated with drug efficacy or safety.Common variants of at least 55 genesencoding drug disposition factors have func‑tional effects on protein activity or expression(Supplementary information S1 (table);BOX 2), but have not yet been associated withhuman pharmacokinetics for any drug. It iscurrently unknown how many of these geneswill be found to have meaningful influenceon human pharmacokinetics. Several ofthem encode DMEs such as CYP3A4 and thetable 1 | Consistently replicated associations between genotype and clinical pharmacokineticsOnline Mendelian Inheritance in Man (OMIM) database web site: /sites/entrez?db=omim.P e r s P e c t i v e sNATUrE rEvIEWS |drug discovery vOLUME 7 | APrIL 2008 |295©2008Nature Publishing GroupP e r s P e c t i v e stable 2 | Associations between genotype and clinical pharmacokinetics*Online Mendelian Inheritance in Man (OMIM) database web site: /sites/entrez?db=omim. NsAID, non-steroidal anti-inflammatory drug; sNP, single nucleotide polymorphism.296 | APrIL 2008 | vOLUME 7 /reviews/drugdisc©2008Nature Publishing GroupUGTs, which are known to metabolize a wide range of drugs27,28, and these may be among those most likely to be found to be relevant for human pharmacokinetic variability. Finally, DMEs, DTPs and regulatory factors for which the relevance of genetic variation to drug disposition has not been established are shown in Supplementary information S2 (table), S3 (table) and S4 (table).Proposal for a new PG–PK strategyThe increase in knowledge about phar‑macogenetics and drug disposition sum‑marized above — coupled with technology advancements that have made genotyping more affordable (with costs of less than US$1 per genotype for multiple available technologies) in the past decade — have made broad application of pharmacogenet‑ics in most drug development programmes more feasible. Several platforms have been developed to screen the known functional variants that might influence drug disposi‑tion in the context of early clinical trials from which high‑quality pharmacokinetic data are also available.The approach we propose includes a broad evaluation of genotype–pharmaco‑kinetic relationships during early drug development, together with in vitro studies, to first generate and then confirm hypoth‑eses about the pathways that are majordisposition determinants of an NCE.Our core strategy for incorporation in NCE development comprises five steps (FIG. 1). The first step is to conduct in vitro experiments before clinical trials to assess whether, and to what extent, selected DMEs and DTPs might influence disposition of the NCE. This activity provides valuable information about the potential role of proteins that are known to influence the disposition of many drugs and to mediate a number of clinically important drug inter‑actions, such as CYP3A and P‑glycoprotein. These experiments have demonstrated utility in drug development planning and decision‑making. Additional in vitro assays may become standard on the basis of new information about drug disposition and interaction factors. For example, recent results from our group29 and others30–33 have demonstrated that the hepatic uptake DTP OATP1B1 (SLCO1B1) is a meaningful determinant of drug disposition for statins and other drugs, and that OATP1B1 inhibi‑tors may have drug interaction potential. recombinant OATP1B1 can be expressed in cell culture, and selective substrates and inhibitors are available (Supplementary information S5 (table)). Learning whetheran NCE is an OATP1B1 substrate or inhibi‑tor could become an ordinary preclinicalactivity.The second step is to conduct a broadsearch for associations of pharmacokineticswith genotypes during the first‑in‑humanstudy (BOX 4). The scope of this search couldinclude all relevant genes for which thereis reasonable expectation that a positiveresult can be obtained (based on studypower) and readily interpreted based oncurrent information about functionalvariants. This includes genes for which thereare well‑established (TABLE 1) or observed(TABLE 2) associations between genetic vari‑ants and human pharmacokinetics, as wellas genes for which in vitro evidence indicatesthat common variants alter the activityor expression of the gene product (BOX 2;Supplementary information S1 (table)).Defining the search scope in this way willinclude over half of known or suspecteddrug disposition determinants. For genes inwhich common variants are known but theirfunction is not (Supplementary informationS2 (table)), associations between genotypeand human pharmacokinetics might notbe readily interpreted without subsequentexperimentation to define the phenotype ofthe associated variant(s). These genes mightbe screened if there is preclinical evidencethat the NCE is a substrate or inhibitor,and perhaps not otherwise. Because first‑in‑human studies are generally not large,the likelihood of finding an associationbetween an uncommon functional variant(Supplementary information S3 (table))and human pharmacokinetics is low. Ifthere is preclinical evidence that the NCEis a substrate or inhibitor, a special study todetermine the clinical relevance of genotypetherein may be a better approach to assessthe effect of uncommon functional variantsthan the general strategy described here.Genes for which there is no publishedinformation regarding common geneticvariation (Supplementary information S3(table)) might be screened using singlenucleotide polymorphisms (SNPs) foundin online databases. Including these SNPswould enable some assessment of essentiallyevery known or expected drug dispositiondeterminant.P e r s P e c t i v e sNATUrE rEvIEWS |drug discovery vOLUME 7 | APrIL 2008 |297©2008Nature Publishing GroupThe third step is to replicate any observed associations during the multiple rising‑dose study (BOX 4). As large numbers of genes may be screened, replication of any observed association from a first‑in‑human study is essential to minimize the risk of making a decision based on false‑positive results. The fourth step is to confirm the gene product’s role using an in vitro assay (if the role was not already known from preclinical work) before or concurrently with Phase II clinical studies (BOX 4). When functional genetic variants affect protein activity (rather than expression), the activities of those variants towards the NCE should also be measured in the in vitro assay, as some variants have substrate‑dependent effects. For example, the *17 allele of CYP2D6 has normal catalytic activity towards codeine but reduced activity towards dextromethorphan and debrisoquin34. If different variants in the same gene were used jointly to classifyindividuals (for example, into poor metabo‑lizer or non‑poor metabolizer) for clinicalpharmacogenetic–pharmacokinetic associa‑tions, the classification should be confirmedby showing that the different variants sharea similar phenotype toward the compound(for example, SLCO1B1 and atrasentan29).The fifth step is to estimate the magni‑tude of genotype effect in a populationpharmacokinetics model during Phase IIclinical studies. At this point, genotype isused as a covariate in the population phar‑macokinetics model, just as sex or weightmight be used. It is often not feasible to usegenotype as a population pharmacokineticsmodel covariate before Phase II, becausethe number of subjects in Phase I clinicalstudies (BOX 4) is generally not large enoughto ensure an accurate estimate of the magni‑tude of genetic effect in a diverse population.Sufficient numbers of individuals havingrare genotypes might not be dosed with anNCE until Phase III clinical studies (BOX 4),or it might be necessary to conduct anenriched clinical study to appropriatelyinform the model.Knowledge about genetic variability rele‑vant to drug disposition can be applied inseveral ways, and these are discussed in thefollowing section.Applications of PG–PK knowledgePotent inhibitors or inducers of a polymor‑phic DME or DTP are likely to have effectsthat are proportional to the magnitude ofeffect of genotype (for example, CYP2C19and ticlopidine35). Thus, associationsbetween human pharmacokinetics of anNCE and genetic variation identifies apotential pathway for drug–drug inter‑actions, and hence the need for specific andadditional drug–drug interaction studies.By contrast, little or no effect of a well‑established genetic variant might show thatcertain drug–drug interaction studies arenot necessary. For example, a CYP2D6 inhib‑itor is unlikely to have a meaningful effecton a CYP2D6 substrate if that substrate’spharmacokinetics are not meaningfullyinfluenced by CYP2D6 genotype. Prioritizingdrug–drug interaction studies on the basis ofclinical pharmacogenetic effects will improveon the current approach of doing so on thebasis of in vitro experiments alone1.CYP2D6 can be used to exemplifyanother application of clinical pharmaco‑genetics: to increase confidence thatpharmacokinetic outliers are not likely tobe an issue in later development. Lack of asignificant effect of any genotype suggeststhat multiple distribution pathways arecontributing to drug disposition equally, andthat genetic pharmacokinetic outliers are atmost very rare (as they would have to carrymultiple rare genotypes). Pharmacogenetic–pharmacokinetic relationships can help todistinguish between ordinary populationvariability and true outliers in a limiteddataset — a relevant factor in decisions ofhow (or whether) to move a programmeforward. For example, in one study we iden‑tified that unusual pharmacokinetics of aCYP2D6 substrate was observed in a personwhose CYP2D6 genotype had a populationfrequency of <0.4% and was thus reasonablyconsidered an outlier36. In other situations,learning that one or more apparent outliersshare genetic constitution with other subjectssuggests a greater level of inter‑individualvariation rather than the existence of twoseparate populations.Box 3 | Survey of genetic variants in drug disposition factorsA search of the scientific literature and online resources was conducted to provide an overview ofthe variation in genes that encode drug metabolizing enzymes (DMEs), the drug transport proteins(DTPs), abundant plasma binding proteins, and factors that regulate DME and DTP expression.For each gene, at least the following sources were searched:• Online Mendelian Inheritance in Man (OMIM) (/entrez/query.fcgi?db=OMIM)• Medline (accessed through Dialog DataStar)was searched using the OMIM gene symbol.If this simple search yielded >100 articles, it was limited by applying the condition AND(pharmacogenetics OR polymorphism-genetic).• The Pharmacogenetics and Pharmacogenomics Knowledge Base ()genes were categorized as follows:• Consistently replicated association of variants with human pharmacokinetics of at least one drug(TABLE 1).• Association of variants with human pharmacokinetics of one or more drugs, but withoutconsistent replication for any drug (TABLE 2).• Functionality of common variants (≥5% combined frequency of variants of similar phenotype)demonstrated by in vitro methods, but no published association with human pharmacokinetics(BOX 2; see Supplementary information S1 (table)).• Common variants have been published, but functionality or association with humanpharmacokinetics have not (see Supplementary information S2 (table)).• Functionality of one or more rare (or unreported frequency) variants demonstrated (seeSupplementary information S3 (table)).• No information on variant functionality or association related to human pharmacokinetics;rare mutations in some of these genes have been linked to Mendelian metabolic disorders (seeSupplementary information S4 (table)).The aim of this overview is to provide a sense of the diversity of pharmacogenetics–pharmacokinetics knowledge. Although extensive, the tables are not necessarily comprehensive.We generally did not include reports of association unrelated to the pharmacokinetics of aspecific drug, even when a phenotype (such as cancer susceptibility) might be related toxenobiotic disposition. Literature citations are either to our choice of review articles orto primary literature supporting what we considered to be the most important sort of informationavailable. For example, if variants in a gene were associated with human pharmacokinetics in aclinical study we do not also cite work showing the molecular phenotype of those variants; if thephenotype of common variants in a gene is understood we do not also cite work concerning thephenotype of rare variants. We apologize in advance to any scientists whose relevantpublications are not cited.P e r s P e c t i v e s298 | APrIL 2008 | vOLUME 7 /reviews/drugdisc©2008Nature Publishing GroupNature Reviews | Drug DiscoveryAssess safety and tolerabilityin healthy volunteersDose verification andproof of conceptLong-term safetyand efficacy The use of genotype–pharmacokinetic associations can also enhance the design of special population or regional bridging studies (BOX 4). If a drug’s pharmacokinetic properties are sensitive to a polymorphism in a gene, success in special population studies may depend on including that gene in the design. How this is most efficiently done may vary between situations, depend‑ing in part on the strength of the effect and frequency of the genotype. For some studies, retrospective determination of whether an unbalanced representation of genotypes contributed to group differences may be sufficient. Sometimes, recruitment of geno‑type‑balanced cohorts or separate matched cohorts of different genotypes, or excluding individuals of a certain genotype, may be desirable to address the key clinical phar‑macology question. These approaches can be particularly relevant in regional bridging studies, as genetic variant frequencies are known to differ substantially betweenpopulations of different geographic origins (for example, CYP2C9 (REF . 37), CYP2C19 (REF . 38), CYP2A6 (REF . 39), UGT1A1 and UGT1A9 (REF . 40), NAT2 (REF . 41), OATP1B1 (REF . 42)).For example, suppose that pharmaco‑genetics–pharmacokinetics research in both first‑in‑human and multiple rising‑dose studies showed that, on average, individu‑als heterozygous for a low activity allele of CYP2A6 (intermediate metabolizers ) had higher levels of an NCE than those homozygous for the wild‑type allele of the gene (extensive metabolizers ). Furthermore,in vitro experiments conducted subsequently showed that the NCE is a CYP2A6 substrate and population pharmacokinetic analysis of Phase II clinical trial results confirm the influence of the CYP2A6 genotype on the pharmacokinetic properties of the NCE. To facilitate global development of the NCE, a pharmacokinetic bridging study between Japanese and Caucasians is a next step 2. Successful conduct of this study could elimi‑nate the need for a separate full development programme in Japan 43. Y et, because of highly different variant frequencies, individuals homozygous for low activity alleles (poor metabolizers) are common among Japanese but not in Caucasians. Hence, random recruitment of Japanese and Caucasians (the standard practice for regional bridging studies) is almost certain to fail to showequivalent pharmacokinetics between the two groups. There are several possible regional bridging trial designs that might provide the evidence to avert a requirement to conduct similar full development programmes in both groups, including recruitment of genotype‑matched cohorts of Japanese and Caucasians. However, there is currently a lack of public experience, and hence uncer‑tainty, as to whether this or other designs will be acceptable to regulatory agencies.Another way to use this information is in dose selection for pivotal studies (BOX 4). Understanding that the dose–exposure relationship differs between identifiable groups may lead to a decision to moveforward with a dose or doses that differ from what might have been selected considering a homogeneous population. For example, it may be desirable to increase the pivotal study dose to enhance efficacy among individuals who can be expected to have lower exposures (FIG. 2). The drug levels of some leading antidepressants (for example, paroxetine, venlafaxine) or antipsychotics (for example, olanzapine, aripiprazole) are moderately influenced by CYP2D6 genotype 44. These drugs are generally safe at a range of doses 45–48; however, there have been reports of poor efficacy related to low drug levels in CYP2D6 ultrarapid metabolizers 49–51. FIGURE 2a illustrates how pharmacogenetics might have been applied during the development of these drugs. Here, the ‘default’ dose represents the lowest dose that showed efficacy in pivotal studies and is generally the recommended starting dose in the drug’s labels. Suppose that the association between CYP2D6 genotype and pharmacokinetics had been established during Phase I and II clinical studies. Then, the developers of these drugs could have predicted that using a somewhat higher dose (the pharmacogenetics‑based dose) in pivotal studies would improve the efficacy profile in ultrarapid metabolizers and not meaningfully diminish the safety profile in other groups (including poor metabolizers). Perhaps they would have selected the phar‑macogenetics‑based doses for their pivotal studies. Because the drug label indicates doses studied in controlled efficacy trials, such a decision would have been reflected in the label and perhaps improved clinical practice using these drugs.Figure 1 | Flow chart of the proposed pharmacogenetic–pharmacokinetic strategy. In vitro experiments are conducted before clinical trials to assess whether, and to what extent, selected drug metabolizing enzymes (DMes) and drug transport proteins (DtPs) might influence the disposition of a new chemical entity (Nce). then, during the first-in-human study, a broad search for associations of pharmacokinetic (PK) properties with genotypes is conducted. Any observed associations are replicated during the multiple rising-dose study. Before or concurrently with Phase IIclinical studies, the gene product’s role is confirmed using an in vitro assay(if the role was not already known from preclinical work). the magnitude of genotype effect in a population pharmacokinetics model is then estimated during Phase II clinical studies.P e r s P e c t i v e sNATUrE rEvIEWS | drug discoveryvOLUME 7 | APrIL 2008 | 299© 2008Nature Publishing Group。

A Survey on Wireless Body Area Networks

A survey on wireless body area networksBenoıˆt Latre ´•Bart Braem •Ingrid Moerman •Chris Blondia •Piet DemeesterPublished online:11November 2010ÓSpringer Science+Business Media,LLC 2010Abstract The increasing use of wireless networks and the constant miniaturization of electrical devices has empow-ered the development of Wireless Body Area Networks (WBANs).In these networks various sensors are attached on clothing or on the body or even implanted under the skin.The wireless nature of the network and the wide variety of sen-sors offer numerous new,practical and innovative applica-tions to improve health care and the Quality of Life.The sensors of a WBAN measure for example the heartbeat,the body temperature or record a prolonged ing a WBAN,the patient experiences a greater physical mobility and is no longer compelled to stay in the hospital.This paper offers a survey of the concept of Wireless Body Area Networks.First,we focus on some applications with special interest in patient monitoring.Then the communi-cation in a WBAN and its positioning between the different technologies is discussed.An overview of the current research on the physical layer,existing MAC and network protocols is given.Further,cross layer and quality of service is discussed.As WBANs are placed on the human body and often transport private data,security is also considered.An overview of current and past projects is given.Finally,the open research issues and challenges are pointed out.Keywords Wireless body area networks ÁRouting ÁMAC1IntroductionThe aging population in many developed countries and the rising costs of health care have triggered the introduction of novel technology-driven enhancements to current health care practices.For example,recent advances in electron-ics have enabled the development of small and intelligent (bio-)medical sensors which can be worn on or implanted in the human body.These sensors need to send their data to an external medical server where it can be analyzed and ing a wired connection for this purpose turns out to be too cumbersome and involves a high cost for deployment and maintenance.However,the use of a wireless interface enables an easier application and is more cost efﬁcient [1].The patient experiences a greater physical mobility and is no longer compelled to stay in a hospital.This process can be considered as the next step in enhancing the personal health care and in coping with the costs of the health care system.Where eHealth is deﬁned as the health care practice sup-ported by electronic processes and communication,the health care is now going a step further by becoming mobile.This is referred to as mHealth [2].In order to fully exploit the beneﬁts of wireless technologies in telemedicine and mHealth,a new type of wireless network emerges:a wire-less on-body network or a Wireless Body Area Network (WBAN).This term was ﬁrst coined by Van Dam et al.[3]and received the interest of several researchers [4–8].A Wireless Body Area Network consists of small,intelligent devices attached on or implanted in the body which are capable of establishing a wireless communica-tion link.These devices provide continuous health moni-toring and real-time feedback to the user or medical personnel.Furthermore,the measurements can be recorded over a longer period of time,improving the quality of the measured data [9].tre´(&)ÁI.Moerman ÁP.Demeester Department of Information Technology,Ghent University/IBBT,Gaston Crommenlaan 8,Box 201,9050Gent,Belgium e-mail:tre@intec.ugent.beB.Braem ÁC.BlondiaDepartment of Mathematics and Computer Science,University of Antwerp/IBBT,Middelheimlaan 1,2020Antwerp,Belgium e-mail:bart.braem@ua.ac.beWireless Netw (2011)17:1–18DOI 10.1007/s11276-010-0252-4Generally speaking,two types of devices can be dis-tinguished:sensors and actuators.The sensors are used to measure certain parameters of the human body,either externally or internally.Examples include measuring the heartbeat,body temperature or recording a prolonged electrocardiogram(ECG).The actuators(or actors)on the other hand take some speciﬁc actions according to the data they receive from the sensors or through interaction with the user,e.g.,an actuator equipped with a built-in reservoir and pump administers the correct dose of insulin to give to diabetics based on the glucose level measurements.Inter-action with the user or other persons is usually handled by a personal device,e.g.a PDA or a smart phone which acts as a sink for data of the wireless devices.In order to realize communication between these devi-ces,techniques from Wireless Sensor Networks(WSNs) and ad hoc networks could be used.However,because of the typical properties of a WBAN,current protocols designed for these networks are not always well suited to support a WBAN.The following illustrates the differences between a Wireless Sensor Network and a Wireless Body Area Network:•The devices used have limited energy resources avail-able as they have a very small form factor(often less than1cm3[10]).Furthermore,for most devices it is impossible to recharge or change the batteries althougha long lifetime of the device is wanted(up to severalyears or even decades for implanted devices).Hence, the energy resources and consequently the computa-tional power and available memory of such devices will be limited;•All devices are equally important and devices are only added when they are needed for an application(i.e.no redundant devices are available);•An extremely low transmit power per node is needed to minimize interference and to cope with health concerns[11];•The propagation of the waves takes place in or on a (very)lossy medium,the human body.As a result,the waves are attenuated considerably before they reach the receiver;•The devices are located on the human body that can be in motion.WBANs should therefore be robust against frequent changes in the network topology;•The data mostly consists of medical information.Hence,high reliability and low delay is required;•Stringent security mechanisms are required in order to ensure the strictly private and conﬁdential character of the medical data;•Andﬁnally the devices are often very heteroge-neous,may have very different demands or may requiredifferent resources of the network in terms of data rates, power consumption and reliability.When referring to a WBAN where each node comprises a biosensor or a medical device with sensing unit,some researchers use the name Body Area Sensor Network (BASN)or in short Body Sensor Network(BSN)instead of WBAN[12].These networks are very similar to each other and share the same challenges and properties.In the following,we will use the term WBAN which is also the one used by the IEEE[13].In this article we present a survey of the state of the art in Wireless Body Area Networks.Our aim is to provide a better understanding of the current research issues in this emergingﬁeld.The remainder of this paper is organized as follows.First,the patient monitoring application is dis-cussed in Sect.2.Next,the characteristics of the commu-nication and the positioning of WBANs amongst other wireless technologies is discussed in Sect.4.Section5 gives an overview of the properties of the physical layer and the issues of communicating near or in the body. Existing protocols for the MAC-layer and network layer are discussed in Sects.6and7,respectively.Section8 deals with cross-layer protocols available for WBANs.The Quality of Service(QoS)and possible security mechanisms are treated in Sects.9and10.An overview of existing projects is given in Sect.11.Finally,the open research issues are discussed in Sects.12and13concludes the paper.2Patient monitoringThe main cause of death in the world is CardioVascular Disease(CVD),representing30%of all global deaths. According to the World Health Organization,worldwide about17.5million people die of heart attacks or strokes each year;in2015,almost20million people will die from CVD.These deaths can often be prevented with proper health care[14].Worldwide,more than246million people suffer from diabetes,a number that is expected to rise to 380million by2025[15].Frequent monitoring enables proper dosing and reduces the risk of fainting and in later life blindness,loss of circulation and other complications [15].These two examples already illustrate the need for continuous monitoring and the usefulness of WBANs. Numerous other examples of diseases would beneﬁt from continuous or prolonged monitoring,such as hypertension, asthma,Alzheimer’s disease,Parkinson’s disease,renal failure,post-operative monitoring,stress-monitoring,pre-vention of sudden infant death syndrome,etc[9,16,17]. These applications can be considered as an indicator for thesize of the market for WBANs.The number of people suffering from diabetics or CVD and the percentage of people in the population age60years and older will grow in the future.Even without any further increase in world population by2025this would mean a very large number of potential customers.WBAN technology could provide the connectivity to support the elderly in managing their daily life and medical conditions[18].A WBAN allows continuous monitoring of the physiological parameters. Whether the patient is in the hospital,at home or on the move,the patient will no longer need to stay in bed,but will be able to move around freely.Furthermore,the data obtained during a large time interval in the patient’s natural environment offers a clearer view to the doctors than data obtained during short stays at the hospital[9].An example of a medical WBAN used for patient moni-toring is shown in Fig.1.Several sensors are placed in clothes,directly on the body or under the skin of a person and measure the temperature,blood pressure,heart rate,ECG, EEG,respiration rate,SpO2-levels,etc.Next to sensing devices,the patient has actuators which act as drug delivery systems.The medicine can be delivered on predetermined moments,triggered by an external source(i.e.a doctor who analyzes the data)or immediately when a sensor notices a problem.One example is the monitoring of the glucose level in the blood of diabetics.If the sensor monitors a sudden drop of glucose,a signal can be sent to the actuator in order to start the injection of insulin.Consequently,the patient will experience fewer nuisances from his disease.Another example of an actuator is a spinal cord stimulator implanted in the body for long-term pain relief[19].A WBAN can also be used to offer assistance to the disabled.For example,a paraplegic can be equipped with sensors determining the position of the legs or with sensors attached to the nerves[20].In addition,actuators posi-tioned on the legs can stimulate the muscles.Interaction between the data from the sensors and the actuators makes it possible to restore the ability to move.Another example is aid for the visually impaired.An artiﬁcial retina,con-sisting of a matrix of micro sensors,can be implanted into the eye beneath the surface of the retina.The artiﬁcial retina translates the electrical impulses into neurological signals.The input can be obtained locally from light sen-sitive sensors or by an external camera mounted on a pair of glasses[21].Another area of application can be found in the domain of public safety where the WBAN can be used byﬁre-ﬁghters,policemen or in a military environment[22].The WBAN monitors for example the level of toxics in the air and warns theﬁreﬁghters or soldiers if a life threatening level is detected.The introduction of a WBAN further enables to tune more effectively the training schedules of professional athletes.Next to purely medical applications,a WBAN can include appliances such as an MP3-player,head-mounted (computer)displays,a microphone,a camera,advanced human-computer interfaces such as a neural interface,etc [20].As such,the WBAN can also be used for gaming purposes and in virtual reality.This small overview already shows the myriad of pos-sibilities where WBANs are useful.The main characteristic of all these applications is that WBANs improve the user’s Quality of Life.3Taxonomy and requirementsThe applications described in the previous section indicate that a WBAN consists of several heterogeneous devices.In this section an overview of the different types of devices used in a WBAN will be given.Further the requirements and challenges are discussed.These include the wide var-iability of data rates,the restricted energy consumption,the need for QoS and reliability,ease-of-use by medical pro-fessionals and security and privacy issues.3.1Types of devices(Wireless)sensor node:A device that responds to and gathers data on physical stimuli,processes the data if necessary and reports this information wirelessly.It consists of several components:sensor hardware,a power unit,a processor,memory and a transmitter or transceiver[23].(Wireless)actuator node:A device that acts according to data received from the sensors or throughinteractionwith the user.The components of an actuator are similar to the sensor’s:actuator hardware(e.g.hardware for medicine administration,including a reservoir to hold the medicine),a power unit,a processor,memory and a receiver or transceiver.(Wireless)personal device(PD):A device that gathers all the information acquired by the sensors and actuators and informs the user(i.e.the patient,a nurse,a GP,etc.) via an external gateway,an actuator or a display/LEDS on the device.The components are a power unit,a (large)processor,memory and a transceiver.This device is also called a Body Control Unit(BCU)[4],body-gateway or a sink.In some implementations,a Personal Digital Assistant(PDA)or smart phone is used.Many different types of sensors and actuators are used in a WBAN.The main use of all these devices is to be found in the area of health applications.In the following,the termnodes refers to both the sensor as actuator nodes.The number of nodes in a WBAN is limited by nature of the network.It is expected that the number of nodes will be in the range of20–50[6,24].3.2Data ratesDue to the strong heterogeneity of the applications,data rates will vary strongly,ranging from simple data at a few kbit/s to video streams of several Mbit/s.Data can also be sent in bursts,which means that it is sent at higher rate during the bursts.The data rates for the different applications are given in in Table1and are calculated by means of the sampling rate,the range and the desired accuracy of the measure-ments[25,26].Overall,it can be seen that the application data rates are not high.However,if one has a WBAN with several of these devices(i.e.a dozen motion sensors,ECG, EMG,glucose monitoring,etc.)the aggregated data rate easily reaches a few Mbps,which is a higher than the raw bit rate of most existing low power radios.The reliability of the data transmission is provided in terms of the necessary bit error rate(BER)which is used as a measure for the number of lost packets.For a medical device,the reliability depends on the data rate.Low data rate devices can cope with a high BER(e.g.10-4),while devices with a higher data rate require a lower BER(e.g. 10-10).The required BER is also dependent on the criti-calness of the data.3.3EnergyEnergy consumption can be divided into three domains: sensing,(wireless)communication and data processing [23].The wireless communication is likely to be the most power consuming.The power available in the nodes is often restricted.The size of the battery used to store the needed energy is in most cases the largest contributor to the sensor device in terms of both dimensions and weight. Batteries are,as a consequence,kept small and energy consumption of the devices needs to be reduced.In some applications,a WBAN’s sensor/actuator node should operate while supporting a battery life time of months or even years without intervention.For example,a pacemaker or a glucose monitor would require a lifetime lasting more than5years.Especially for implanted devices,the lifetime is crucial.The need for replacement or recharging induces a cost and convenience penalty which is undesirable not only for implanted devices,but also for larger ones.The lifetime of a node for a given battery capacity can be enhanced by scavenging energy during the operation of the system.If the scavenged energy is larger than the average consumed energy,such systems could run eternally.How-ever,energy scavenging will only deliver small amounts of energy[5,28].A combination of lower energy consumption and energy scavenging is the optimal solution for achieving autonomous Wireless Body Area Networks.For a WBAN, energy scavenging from on-body sources such as body heat and body vibration seems very well suited.In the former,a thermo-electric generator(TEG)is used to transform the temperature difference between the environment and the human body into electrical energy[27].The latter uses for example the human gait as energy source[29].During communication the devices produce heat which is absorbed by the surrounding tissue and increases the temperature of the body.In order to limit this temperature rise and in addition to save the battery resources,the energy consumption should be restricted to a minimum. The amount of power absorbed by the tissue is expressed Table1Examples of medical WBAN applications[21,25,26,27] Application Data rate Bandwidth(Hz)Accuracy(bits) ECG(12leads)288kbps100–100012ECG(6leads)71kbps100–50012EMG320kbps0–10,00016EEG(12leads)43.2kbps0–15012 Blood saturation16bps0–18 Glucose monitoring1600bps0–5016 Temperature120bps0–18 Motion sensor35kbps0–50012 Cochlear implant100kbps––Artiﬁcial retina50-700kbps––Audio1Mbps––Voice50-100kbps––by the speciﬁc absorption rate(SAR).Since the device may be in close proximity to,or inside,a human body,the localized SAR could be quite large.The localized SAR into the body must be minimized and needs to comply with international and local SAR regulations.The regulation for transmitting near the human body is similar to the one for mobile phones,with strict transmit power requirements [11,30].3.4Quality of service and reliabilityProper QoS handling is an important part in the framework of risk management of medical applications.A crucial issue is the reliability of the transmission in order to guarantee that the monitored data is received correctly by the health care professionals.The reliability can be con-sidered either end-to-end or on a per link base.Examples of reliability include the guaranteed delivery of data(i.e. packet delivery ratio),in-order-delivery,…Moreover, messages should be delivered in reasonable time.The reliability of the network directly affects the quality of patient monitoring and in a worst case scenario it can be fatal when a life threatening event has gone undetected [31].3.5UsabilityIn most cases,a WBAN will be set up in a hospital by medical staff,not by ICT-engineers.Consequently,the network should be capable of conﬁguring and maintaining itself automatically,i.e.self-organization an self-mainte-nance should be supported.Whenever a node is put on the body and turned on,it should be able to join the network and set up routes without any external intervention.The self-organizing aspect also includes the problem of addressing the nodes.An address can be conﬁgured at manufacturing time(e.g.the MAC-address)or at setup time by the network itself.Further,the network should be quickly reconﬁgurable,for adding new services.When a route fails,a back up path should be set up.The devices may be scattered over and in the whole body.The exact location of a device will depend on the application,e.g.a heart sensor obviously must be placed in the neighborhood of the heart,a temperature sensor can be placed almost anywhere.Researchers seem to disagree on the ideal body location for some sensor nodes,i.e.motion sensors,as the interpretation of the measured data is not always the same[32].The network should not be regarded as a static one.The body may be in motion(e.g.walking, running,twisting,etc.)which induces channel fading and shadowing effects.The nodes should have a small form factor consistent with wearable and implanted applications.This will make WBANs invisible and unobtrusive.3.6Security and privacyThe communication of health related information between sensors in a WBAN and over the Internet to servers is strictly private and conﬁdential[33]and should be encrypted to protect the patient’s privacy.The medical staff collecting the data needs to be conﬁdent that the data is not tampered with and indeed originates from that patient.Further,it can not be expected that an average person or the medical staff is capable of setting up and managing authentication and authorization processes. Moreover the network should be accessible when the user is not capable of giving the password(e.g.to guarantee accessibility by paramedics in trauma situations).Security and privacy protection mechanisms use a signiﬁcant part of the available energy and should therefor be energy efﬁcient and lightweight.4Positioning WBANsThe development and research in the domain of WBANs is only at an early stage.As a consequence,the terminology is not always clearly deﬁned.In literature,protocols devel-oped for WBANs can span from communication between the sensors on the body to communication from a body node to a data center connected to the Internet.In order to have clear understanding,we propose the following deﬁ-nitions:intra-body communication and extra-body com-munication.An example is shown on Fig.2.The former controls the information handling on the body between the sensors or actuators and the personal device[34–37],the Fig.2Example of intra-body and extra-body communication in a WBANlatter ensures communication between the personal device and an external network[32,38–40].Doing so,the medical data from the patient at home can be consulted by a phy-sician or stored in a medical database.This segmentation is similar to the one deﬁned in[40]where a multi-tiered telemedicine system is presented.Tier1encompasses the intra-body communication,tier2the extra-body commu-nication between the personal device and the Internet and tier3represents the extra-body communication from the Internet to the medical server.The combination of intra-body and extra-body communication can be seen as an enabler for ubiquitous health care service provisioning.An example can be found in[41]where Utility Grid Com-puting is combined with a WBAN.Doing so,the data extracted from the WBAN is sent to the grid that provides access to appropriate computational services with highbandwidth and to a large collection of distributed time-varying resources.To date,development has been mainly focused on building the system architecture and service platform for extra-body communication.Much of these implementa-tions focus on the repackaging of traditional sensors(e.g. ECG,heart rate)with existing wireless devices.They consider a very limited WBAN consisting of only a few sensors that are directly and wirelessly connected to a personal device.Further they use transceivers with a large form factor and large antennas that are not adapted for use on a body.In Fig.3,a WBAN is compared with other types of wireless networks,such as Wireless Personal(WPAN), Wireless Local(WLAN),Wireless Metropolitan(WMAN) and Wide Area Networks(WAN)[42].A WBAN is operated close to the human body and its communication range will be restricted to a few meters,with typical values around1–2m.While a WBAN is devoted to intercon-nection of one person’s wearable devices,a WPAN is a network in the environment around the person.The com-munication range can reach up to10m for high data rate applications and up to several dozens of meters for low data rate applications.A WLAN has a typical communi-cation range up to hundreds of meters.Each type of net-work has its typical enabling technology,deﬁned by the IEEE.A WPAN uses IEEE802.15.1(Bluetooth)or IEEE 802.15.4(ZigBee),a WLAN uses IEEE802.11(WiFi)and a WMAN IEEE802.16(WiMax).The communication in a WAN can be established via satellite links.In several papers,Wireless Body Area Networks are considered as a special type of a Wireless Sensor Network or a Wireless Sensor and Actuator Network(WSAN)with its own requirements1.However,traditional sensor networks do not tackle the speciﬁc challenges associated with human body monitoring.The human body consists of a complicated internal environment that responds to and interacts with its external surroundings,but is in a way separate and self-contained.The human body environment not only has a smaller scale,but also requires a different type and fre-quency of monitoring,with different challenges than those faced by WSNs.The monitoring of medical data results in an increased demand for reliability.The ease of use of sensors placed on the body leads to a small form factor that includes the battery and antenna part,resulting in a higher need for energy efﬁciency.Sensor nodes can move with regard to each other,for example a sensor node placed on the wrist moves in relation to a sensor node attached to the hip.This requires mobility support.In brief,although challenges faced by WBANs are in many ways similar to WSNs,there are intrinsic differences between the two,requiring special attention.An overview of some of these differences is given in Table2.A schematic overview of the challenges in a WBAN and a comparison with WSNs and WLANs is given in Fig.4.5Physical layerThe characteristics of the physical layer are different for a WBAN compared to a regular sensor network or an ad-hoc network due to the proximity of the human body.Tests with TelosB motes(using the CC2420transceiver)showed lack of communications between nodes located on the chest and nodes located on the back of the patient[46]. This was accentuated when the transmit power was set to a minimum for energy savings reasons.Similar conclusions where drawn with a CC2420transceiver in[47]:when a person was sitting on a sofa,no communication was pos-sible between the chest and the ankle.Better results were obtained when the antenna was placed1cm abovethe Fig.3Positioning of a Wireless Body Area Network in the realm of wireless networks1In the following,we will not make a distinction between a WSAN and a WSN although they have signiﬁcant differences[43].body.As the devices get smaller and more ubiquitous,a direct connection to the personal device will no longer be possible and more complex network topologies will be needed.In this section,we will discuss the characteristics of the propagation of radio waves in a WBAN and other types of communication.5.1RF communicationSeveral researchers have been investigating the path loss along and inside the human body either using narrowband radio signals or Ultra Wide Band(UWB).All of them came to the conclusion that the radio signals experience great losses.Generally in wireless networks,it is known that the transmitted power drops off with d g where d represents the distance between the sender and the receiver and g the coefﬁcient of the path loss(aka propagation coefﬁcient)[48].In free space,g has a value of2.Other kinds of losses include fading of signals due to multi-path propagation.The propagation can be classiﬁed according to where it takes place:inside the body or along the body.5.1.1In the bodyThe propagation of electromagnetic(EM)waves in the human body has been investigated in[49,50].The body acts as a communication channel where losses are mainly due to absorption of power in the tissue,which is dissipated as heat.As the tissue is lossy and mostly consists of water, the EM-waves are attenuated considerably before they reach the receiver.In order to determine the amount of power lost due to heat dissipation,a standard measure of how much power is absorbed in tissue is used:the speciﬁc absorption rate(SAR).It is concluded that the path loss is very high and that,compared to the free space propaga-tion,an additional30–35dB at small distances is noticed.A simpliﬁed temperature increase prediction scheme based on SAR is presented in[50].It is argued that considering energy consumption is not enough and that the tissue is sensitive to temperature increase.The inﬂuence of a patient’s body shape and position on the radiation pattern from an implanted radio transmitter has been studied in [51].It is concluded that the difference between bodyTable2Schematic overview of differences between Wireless Sensor Networks and Wireless Body Area Networks,based on[45] Challenges Wireless sensor network Wireless body area networkScale Monitored environment(m/km)Human body(cm/m)Node number Many redundant nodes for wide area coverage Fewer,limited in spaceResult accuracy Through node redundancy Through node accuracy and robustnessNode tasks Node performs a dedicated task Node performs multiple tasksNode size Small is preferred,but not important Small is essentialNetwork topology Very likely to beﬁxed or static More variable due to body movementData rates Most often homogeneous Most often heterogeneousNode replacement Performed easily,nodes even disposable Replacement of implanted nodes difﬁcultNode lifetime Several years/months Several years/months,smaller battery capacityPower supply Accessible and likely to be replaced moreeasily and frequentlyInaccessible and difﬁcult to replaced in an implantable setting Power demand Likely to be large,energy supply easier Likely to be lower,energy supply more difﬁcultEnergy scavenging source Most likely solar and wind power Most likely motion(vibration)and thermal(body heat) Biocompatibility Not a consideration in most applications A must for implants and some external sensorsSecurity level Lower Higher,to protect patient informationImpact of data loss Likely to be compensated by redundant nodes More signiﬁcant,may require additional measures to ensure QoSand real-time data deliveryWireless technology Bluetooth,ZigBee,GPRS,WLAN,…Low power technologyrequired。

中医跨文化传播智慧树知到答案章节测试2023年浙江中医药大学

第一章测试1.According to episode 1.1.2, what are the three main reasons and benefits oftaking an IC course?（）A:Community investmentB:Financial incentivesC:A bright futureD:Personal commitment答案:ABD2.According to episode 1.1.3, up to the recording this course, TCM has beenspread to _____ countries and regions. （）A:187B:191C:196D:183答案:C3.According to episode 1.1.4, why is it important to develop cultural confidenceon TCM? （）A:TCM belongs to a unique Culture of ChinaB:TCM is always one of China’s highlights (亮点)C:TCM is the gem of Chinese civilizationD:TCM is of long standing (历史悠久)答案:ABCD4.According to episode 1.2.1, which of the following is not mentioned as themain principles of ethical IC? （）A:Nonjudgmentalism & respectB:ReciprocityC:EffectivenessD:Mutuality & Honesty答案:C5.According to episode 1.2.2, what comes out of the combination betweenethical studies and TCM?（）A:Ethics in ICB:IC & TCMC:Ethical considerations in medicineD:Ethics in TCM答案:D第二章测试1.According to episode2.1.3, “气” written in Oracle Bone Script looks verymuch like “三” in Chinese.（）A:对B:错答案:A2.According to episode 2.2.1, how many definitions of the word“communication” are collected in Dance & Larson’s monog raph? （）A:No more than 20B:126C:About 50D:110答案:B3.According to episode 2.2.3, what are the three aspects of tangible andintangible TCM culture that can be transmitted across cultures?（）A:Theories of Chinese medicineB:Chinese Materia Medica (中草药)C:TCM equipmentD:Stories and anecdotes (轶事) of great TCM physicians答案:ABD4.According to episode 2.3.3, the emphasis on preventive treatment of diseaseadvocated by Huangdi Neijing 《黄帝内经》 reflects its ______, based onHofstede’s cultural dimensions.（）A:long-term perspectiveB:harmonious perspectiveC:humanistic perspectiveD:holistic perspective答案:A5.According to episode 2.3.6, what are three aspects of face that are involved inconflict management as proposed by Ting-Toomey?（）A:Self-faceB:Other-faceC:Face of a middlemanD:Mutual-face答案:ABD第三章测试1.According to episode 3.1.1, which two of the following statements are correct?（）A:Intonation plays an indispensable role in Chinese language.B:Chinese is a tone language.C:Tone plays an indispensable role in English language.D:English is an intonation language.答案:BD2.According to episode3.1.3, Yinqu (隐曲) exemplifies which feature of TCMlanguage? （）A:literaryB:conventionalC:exaggeratingD:vague答案:D3.According to episode 3.1.4, Qu Xiang Bi Lei is a typical example of imagethinking. （）A:错B:对答案:B4.According to episode 3.2.2, which of the following best expresses 中药？（）A:Materia MedicaB:Herbs in ChinaC:Chinese Materia MedicaD:Chinese herbs答案:C5.According to episode 3.3.1, what are the three pioneering books in the studyof intercultural nonverbal communication? （）A:The Silent LanguageB:Introduction to KinesicsC:Beyond CultureD:Physics and Character答案:ABD第四章测试1.According to episode 4.1.1, the most obvious barrier to healthcommunication is _____. （）A:Difficulty of recalling medical historyB:Language barrierC:Unwillingness to share medical historyD:Heavy reliance on medical equipment答案:B2.According to episode 4.1.2, which of the following is correct? （）A:TCM as practiced in China, Korea and other parts of the world is typical ofnaturalistic healthcare system.B:Americans’ reliance on science and technology in health managementreflects a nonmechanistic worldview.C:In a biomedical healthcare system, treatment is meant to destroy orremove the causative agent (病因)D:Traditionally, people from Laos, Hmong culture, etc. believe inpersonalistic healthcare system.答案:D3.According to episode4.2.1, from a naturalistic health belief system asrepresented by TCM, being healthy means _______. （）A:No deviation (偏离) from clearly established normsB:balance of yin and yang in your bodyC:no symptomsD:balance between man and nature答案:B4.According to episode 4.2.2, consequences of ignoring the husband duringhealth communication in some cultures are severe; sometimes, the life of the patient will be threatened. （）A:对B:错答案:A5.According to episode 4.2.3, successful health communication in anintercultural setting involves _____. （）A:Recognizing diverse medical systemsB:Learning as many languages as possibleC:Recognizing ethnocentrismD:Sticking to personal expertise答案:ABC第五章测试1.According to episode 5.1.1, since 2013, the Belt and Road Initiative, withpolicy coordination, connectivity of infrastructure, unimpeded trade,financial integration and closer people-to-people ties as its main goals, hasadvanced in solid steps. （）A:错B:对答案:B2.According to episode 5.1.2, TCM is mainly exported to _____ market. （）A:AsianB:AfricanC:EuropeanD:US答案:A3.According to episode 5.2.1, after the introduction of TCM into Japan, itgradually become known as _____. （）A:KampoB:Traditional Japanese MedicineC:Traditional Chinese MedicineD:Conventional Medicine答案:A4.According to episode5.2.3, Felix Briedo passe d the first medical doctor’sthesis on Traditional Chinese Medicine at the University of Montpellier inFrance. （）A:错B:对答案:B5.According to episode 5.2.6, South Africa is one of the first countries thatofficially recognize TCM. （）A:对B:错答案:A第六章测试1.According to episode 6.1.1, which of the following two are possible causes ofcommon stereotypes of TCM in the U. S.? （）A:It is difficult to test TCM and US citizens are used to evidence-basedmedicine.B:US citizens know western medicine much earlier than TCM.C:TCM terminologies (术语) are difficult to understand.D:It takes time for TCM to take effective.答案:AC2.According to episode 6.1.2, ethnocentrism sometimes leads to patriotism. （）A:错B:对答案:B3.According to episode 6.1.3, W-shape Model of Intercultural Adaptationconsists of _____ stages. （）A:threeB:sevenC:fourD:five答案:B4.According to episode 6.2.1, the addition of ______ is a Chinese scholar’scontribution to the conceptualization of intercultural communicationcompetence. （）A:Cognitive dimensionB:Behavioral dimensionC:Affective dimensionD:Moral dimension答案:D5.According to episode6.2.3, we live in a world where profound changes andthe COVID-19 pandemic, both unseen in a century, are intertwined.（）A:对B:错答案:A。

1989 Improved isolation procedure for fucoxanthin=提取

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药学考研英语试题及答案

药学考研英语试题及答案一、选择题（每题2分，共20分）1. Which of the following is not a drug?A. PenicillinB. AspirinC. Vitamin CD. Sugar答案：D2. The term "pharmacology" refers to the study of:A. The origin of diseasesB. The effects of drugs on the bodyC. The production of drugsD. The side effects of drugs答案：B3. The primary function of a drug is to:A. Treat diseasesB. Prevent diseasesC. Enhance physical performanceD. Improve mental state答案：A4. The correct order of drug administration is:A. Oral, intravenous, intramuscularB. Intravenous, oral, intramuscularC. Intramuscular, oral, intravenousD. Intravenous, intramuscular, oral答案：B5. Which of the following is not a method of drug administration?A. OralB. IntravenousC. InhalationD. Topical答案：D6. The half-life of a drug refers to the time it takes for the drug concentration in the body to:A. DoubleB. HalveC. TripleD. Quadruple答案：B7. The therapeutic index of a drug is used to indicate:A. The drug's effectivenessB. The drug's safetyC. The drug's cost-effectivenessD. The drug's side effects答案：B8. The main difference between a prescription drug and an over-the-counter drug is that:A. The former is more expensiveB. The latter requires a prescriptionC. The former requires a prescriptionD. The latter has fewer side effects答案：C9. The side effects of a drug are:A. Always harmfulB. Always beneficialC. Sometimes harmful, sometimes beneficialD. Never harmful答案：C10. The correct storage method for drugs is:A. Exposed to sunlightB. Stored in a cool, dry placeC. Stored in a humid environmentD. Stored in a hot environment答案：B二、填空题（每题2分，共20分）1. The chemical structure of a drug determines its ________. 答案：pharmacological activity2. The ________ of a drug is the concentration at which halfof the drug is eliminated from the body.答案：half-life3. The ________ of a drug is the minimum effective concentration required to produce a therapeutic effect.答案：therapeutic dose4. The ________ of a drug is the maximum concentration that can be tolerated without causing adverse effects.答案：toxic dose5. The ________ of a drug is the process by which the drug is absorbed, distributed, metabolized, and excreted by the body. 答案：pharmacokinetics6. The ________ of a drug is the study of the drug's effects on the body and its mechanism of action.答案：pharmacodynamics7. The ________ of a drug is the study of the drug's interactions with other substances in the body.答案：drug interactions8. The ________ of a drug is the study of the drug's effects on the body's tissues and organs.答案：toxicology9. The ________ of a drug is the study of the drug's effects on the body's immune system.答案：immunopharmacology10. The ________ of a drug is the study of the drug's effects on the body's nervous system.答案：neuropharmacology三、简答题（每题10分，共30分）1. What are the three main categories of drug classifications?答案：The three main categories of drug classifications are therapeutic drugs, diagnostic drugs, and prophylactic drugs.2. Explain the difference between the therapeutic index andthe margin of safety of a drug.答案：The therapeutic index is the ratio of the toxic dose to the therapeutic dose, indicating the safety of a drug. Ahigher therapeutic index means a wider margin between the effective and toxic doses. The margin of safety refers to the difference between the toxic and therapeutic doses,indicating the range within which the drug can be safely used.3. What are the factors that influence drug absorption?答案：Factors that influence drug absorption include the physicochemical properties of the drug, the route of administration, the dosage form, the presence of food in the gastrointestinal tract, and individual physiological differences such as age, gender, and disease state.。

Method and apparatus for the treatment of tinnitus

专利名称：Method and apparatus for the treatment oftinnitus发明人：Michael D. Seidman申请号：US11201454申请日：20050811公开号：US20060036297A1公开日：20060216专利内容由知识产权出版社提供专利附图：摘要：An improved method and apparatus for electrically stimulating the brain to alleviate tinnitus. In one aspect of the invention the areas of the brain to whichstimulation is applied would be determined by a procedure which first involves analysis ofthe patient to determine the nature of the sound perceived by the patient to produce tinnitus. Then these sound frequencies will be provided to the patient while imaging studies are made of the patient's brain. These studies may include magnetoencephalography (MEG) and/or functional magnetic resonance imaging (fMRI). MEG is a non-evasive imaging technique that can be used to image the functional activity of the cortex, while fMRI is based on the increase in blood flow to the local vasculature that accompanies neural activity in the brain. These studies are then analyzed to determine the locus of the tinnitus, and one or more electrodes are placed at the indication region in the patient's brain and a stimulation device for outputting electrical signals to the electrodes is also implanted.申请人：Michael D. Seidman地址：West Bloomfield MI US国籍：US更多信息请下载全文后查看。

CRISPR-Cas结构及该系统介导的主要致病菌耐药机制的研究进展

64中国兽医杂志2020年(第56卷)第10期Chinese Journal of Veterina/MedicineCRIIPR-Cat结构及该系统介导的主要致病菌耐药机制的研究进展潘思宇s党乔1,刘树明1>2>3，孔令聪^3,马红霞1>2>3(1.吉林农业大学动物科学技术学院，吉林长春130118；2.动物生产及产品质量安全省部共建教育部重点实验室，吉林长春130118； 3.吉林省新兽药研发与创制重点实验室，吉林长春130118)中图分类号：S859.7文献标志码：A 兽医临床致病菌在抗微生物药物压力下不断进化、演变，部分菌株已对常用药物呈现多重耐药性,不但为兽医临床的抗感染治疗造成了困难,也对公共卫生安全造成了严重威胁［1］%通常耐药性致病菌的产生由外排泵、产生灭活酶、携带耐药性质粒、可移动耐药原件及靶位置换等介导［2］%但近年研究发现,主要致病菌的免疫系统在抗生素压力下不断进化，也可在一定程度上介导耐药性的产生％其中，聚类规则间隔回文重复序列(Clustered ogumriy interspaced shoO palindromic rv-peats，CRISPR-E vi)系统不仅能稳定病原微生物的遗传性，还参与细菌的生理等功能的调控，为此受到了国内外学者广泛关注％该系统是原核生物基因组中的适应性免疫系统，能够有效抵抗外来基因组分的入侵，维持细菌基因信息的完整性［3］，是特异性核酸的靶向防御机制％CRISPR-E vi系统的免疫功能包括3个不同的机制阶段:适应、表达和干扰⑷％目前，该系统已广泛应用于基因编辑、细菌分型等诸多领域％但Gilt等首次发现了CRISPR-Cas系统可靶向外源DNA，有效阻止接合质粒的转化，在一定程度上减少了病原菌间耐药基因的传播⑸％从此,CRISPR-Cas系统介导的细菌耐药性及毒力研究引起国内外研究人员的高度关注％1细菌CRISPR-Cas系统结构及功能CRISPR-E vi系统是原核生物基因组中新近发现的一种免疫防御系统，广泛存在于细菌和古收稿日期：2020—01—08基金项目：国家重点研发专项计划(2016YFD0501301)&国家自然科学基金青年基金(31702293)&吉林省自然科学基金(2019020 1294JC)作者简介:潘思宇(1996-)，女，硕士，从事细菌耐药机制的研究，E-mail：709708680@通讯作者:马红霞,E-mail：hwyxe0731001@163-com文章编号：0529—6005(2020)10—0064—03菌［6］。

极端酶研究进展及其在食品工业中的应用现状

极端酶研究进展及其在食品工业中的应用现状刘欣;魏雪;王凤忠;辛凤姣【摘要】酶是一种高效的生物催化剂,因其反应条件温和、能耗低、特异性强、绿色环保等优势而广泛应用于食品、纺织、饲料、医药、能源等各个领域中.随着食品工业的迅猛发展,食品制造绿色化的需求急剧增加,食品酶在整个酶制剂市场中所占的份额日益越大.大部分食品加工工艺都涉及高温、高压等较为严苛的条件,因此极端酶在食品工业中显示出了极大优势.综述了嗜热酶、嗜冷酶等极端酶的研究进展,主要从结构生物学的角度阐明了其耐热、耐冷等适应机制,并对其在食品工业中的应用现状进行了详细阐述.【期刊名称】《生物产业技术》【年(卷),期】2017(000)004【总页数】8页(P62-69)【关键词】食品酶;极端酶;食品加工;晶体结构【作者】刘欣;魏雪;王凤忠;辛凤姣【作者单位】中国农业科学院农产品加工研究所,北京 100193;中国农业科学院农产品加工研究所,北京 100193;中国农业科学院农产品加工研究所,北京 100193;中国农业科学院农产品加工研究所,北京 100193【正文语种】中文辛凤姣，博士，博士生导师，研究员，中国农业科学院农产品加工研究所食品酶研究与应用创新团队首席科学家，中国农业科学院青年英才，中国农学会食物与营养专业委员会副秘书长。

长期从事农产品加工领域关键酶的生化性质及晶体结构研究，微生物代谢调控研究，酶制剂等生物制品开发等。

主持创新工程、自然科学基金面上项目等项目5项；发表高水平论文10余篇，申请国家发明专利6项。

E-mail:*******************2017年初，国家发展和改革委员会、工业和信息化部关于促进食品工业健康发展的指导意见（发改产业［2017］19号）中多次强调要“绿色制造”、“提升科技创新能力”、“促进食品工业发生质的转变”。

酶作为“绿色制造”的核心工具，在推动食品工业发展中扮演着至关重要的角色。

酶是一类具有高催化效率、高专一性、高多样性、反应条件温和的生物催化剂，除了具有催化活性的RNA（核酶）之外，几乎均为蛋白质。

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