Impact of selection, mutation rate and genetic drift on human genetic variation

Evolutionary Dynamics of Evolutionary Ecology Evolutionary dynamics in evolutionary ecology is a complex and fascinating field that explores the interactions between organisms and their environment, and how these interactions drive the process of evolution. This area of study is crucial for understanding how species adapt to changing environmental conditions, how new species arise, and how ecosystems function and evolve over time. In this response, we will delve into the various aspects of evolutionary dynamics in evolutionary ecology, including the mechanisms of evolution, the role of genetic variation, and the impact of ecological interactions on evolutionary processes.One of the key concepts in evolutionary dynamics is natural selection, which was first proposed by Charles Darwin in the 19th century. Natural selection acts on heritable traits within a population, favoring those that increase an organism's chances of survival and reproduction in a given environment. This process leads to the accumulation of advantageous traits over generations, ultimately driving the adaptation of species to their ecological niche. Natural selection can occur through various mechanisms, such as directional selection, stabilizing selection, and disruptive selection, each of which can shape the genetic diversity and phenotypic traits within a population.Another important aspect of evolutionary dynamics is genetic variation, which provides the raw material for evolution to act upon. Genetic variation arises through processes such as mutation, genetic recombination, and gene flow, and it is essential for the long-term survival of species in changing environments. High levels of genetic variation can enhance a population's ability to adapt to new conditions, while low levels of variation may limit its evolutionary potential. Understanding the patterns and sources of genetic variation is therefore crucial for predicting the evolutionary responses of species to environmental changes and disturbances.In addition to natural selection and genetic variation, ecological interactions play a significant role in shaping evolutionary dynamics. Species do not evolve in isolation, but rather in the context of their interactions with other organisms and their environment. For example, coevolutionary processes, such as predator-prey interactions and mutualisticrelationships, can drive the evolution of traits in multiple species, leading to complex patterns of adaptation and counter-adaptation. Furthermore, the structure and dynamics of ecological communities can influence the evolutionary trajectories of species within them, as well as the overall diversity and functioning of ecosystems.Moreover, the field of evolutionary ecology also encompasses the study of life history evolution, which examines how the timing and allocation of resources to different life history traits, such as growth, reproduction, and survival, are shaped by ecological factors and evolutionary trade-offs. For instance, organisms may face trade-offs between investing in current reproduction versus future survival, or between allocating resources to growth versus defense. Understanding these trade-offs and their ecological basis is crucial for predicting the responses of species to environmental changes and for conserving biodiversity in the face of global challenges such as climate change and habitat loss.In conclusion, evolutionary dynamics in evolutionary ecology is a multifaceted and dynamic field that integrates principles from ecology, genetics, and evolutionary biology to understand the processes driving the diversity and adaptation of life on Earth. By studying the mechanisms of evolution, the role of genetic variation, the impact of ecological interactions, and the patterns of life history evolution, researchers can gain insights into the complex and interconnected processes that shape the natural world. This knowledge is not only intellectually enriching but also essential for addressing pressing environmental issues and for guiding the conservation and management of biodiversity in a rapidly changing world.。

基因突变变异比例在英文中的用法基因突变和变异比例在英文中通常可以用以下方式表达：1. Gene Mutation: This term is commonly used to refer to any change in the DNA sequence that can affect the structure or function of an organism. It is a broad term that encompasses various types of genetic alterations.2. Mutation Rate: This refers to the frequency at whicha particular gene or set of genes undergoes changes in its DNA sequence. It is often expressed as the number of mutations per generation or per unit of time.3. Variant Frequency: This term is used to describe the proportion of individuals in a population who carry a specific genetic variant. It is often expressed as a percentage or a fraction.4. Allele Frequency: This refers to the relative frequency of a particular allele (one of two or morealternative forms of a gene) in a population. It is a measure of how common a specific genetic variant is within a population.5. Genetic Variation: This term encompasses all the differences in DNA sequence between individuals within a population. It can be used to describe the overall level of genetic diversity within a population.These terms are commonly used in scientific literature, research papers, and discussions related to genetics, genomics, and evolutionary biology to describe the occurrence and prevalence of genetic mutations and variations within populations.。

Tuning Genetic Algorithms for Problems Including Neutral Networks -The Simplest Case:The Balance Beam Function-Yoshiaki Katada1,Kazuhiro Ohkura2and Kanji Ueda31Graduate School of Science and Technology,Kobe University,Kobe,JAPAN 2Faculty of Engineering,Kobe University,Kobe,JAPANPhone/Fax:+81-78-803-6135Email:{katada,ohkura}@rci.scitec.kobe-u.ac.jp3RACE(Research into Artifacts,Center for Engineering),The University of Tokyo,Meguro,JAPANPhone:+81-3-5453-5887Fax:+81-3-3467-0648Email:ueda@race.u-tokyo.ac.jpAbstractNeutral networks,which occur infitness land-scapes containing neighboring points of equalfit-ness,have attracted much research interest in re-cent years.In this work,we applied a standard GA and an extended GA with a variable mutation rate strategy to an abstract model of neutral networks in order to investigate the effects of selection pressure and mutation rate on the speed of population move-ment.Our results demonstrate that speed has an optimal mutation rate and an error threshold since plotting speed against mutation rate results in a con-cave curve.Increasing selection pressure increased the speed of a population’s movement on a neutral network.The variable mutation rate strategy of the extended GA improved the efficiency of the search. For both GAs,we found that high selection pressure was preferable,both for increasing the speed of pop-ulation movement and for avoiding the effects of an error threshold on a neutral network.1IntroductionSelective neutrality has been found in many real-world applications of artificial evolution,such as the evolution of neural network controllers in robotics [1],and on-chip electronic circuit evolution[2].This characteristic,caused by highly redundant mappings from genotype to phenotype,is also found in natu-ral systems,and has been of particular interest to evolutionary theorists and molecular biologists[3]. Landscapes which include neutrality have been con-ceptualized as containing neutral networks.Harvey[4]first introduced the concept of neutral networks into the GA community.His definition is as follows:“A neutral network of afitness landscape is defined as a set of connected points of equivalent fitness,each representing a separate genotype:here connected means that there exists a path of single (neutral)mutations which can traverse the network between any two points on it without affectingfit-ness.”It has been shown that there is a clear transition in evolutionary dynamics for populations on neutral networks over the mutation rate range.At a very low mutation rate,the population is maintained in a cluster on the neutral network,analogously to quasi-species[5].As the mutation rate increases,the pop-ulation gradually loses the current network.That is, some individuals fall to lower neutral networks.At a certain critical mutation rate,the whole popula-tion will have fallen to lower neutral networks.This mutation rate is called the phenotypic error thresh-old1[7][8].Generally,the error threshold sets the upper limit for a mutation rate that will enable effi-cient search.This implies that if we adopt a constant mutation rate strategy,we should set a low mutation rate so as to avoid any error threshold effects dur-ing the process of evolution.From a practical point of view,however,it would be efficient to shorten the equilibrium period2which dominates the whole com-putation(Fig.1).One approach would be to employ variable mutation rate strategies,which change the effective mutation rate adaptively during the process of evolution.Another would be to investigate the ef-fects of the constant(base)mutation rate,selection pressure and population size on search efficiency.In this paper,we employ a standard GA,which employs a constant mutation rate,and an extended GA,which can change its mutation rate strategy,in order to investigate the effect of the selection pres-sure and mutation rate on the speed of population movement.Section2describes an abstract model of very simple neutral networks,called the Balance Beam Function,which is used as a test problem in this work.Section3gives the results of our computer simulations.Section4discusses the effect of selec-tion pressure and the variable mutation rate strategyF i t n e s sGenerationFigure 1:Typical evolutionary dynamics on a fitness landscape featuring neutral networks,which can be classified into transient periods and equilibrium pe-riods [8]:Instead of being stuck in a local optimum,populations may be exploring in the genotype space.on the evolutionary dynamics on the simple neutral networks.Conclusions are given in the last section.2Abstract Model of Simple Neutral NetworksThe Balance Beam Function,proposed by Yasuda et al.[9],was employed as the test function in our computer simulations.It is relatively easy to in-vestigate evolutionary dynamics with this function,because it has a landscape composed of only two neutral networks,each of a different fitness—one of which has the shape of a “balance beam”.The Bal-ance Beam Function (BBF )is formulated as follows:F =1.0,if (A ≤ li =1s i ≤B )and F =0.0,other-wise,where F ,l and s i ∈{0,1}are the fitness value,the length of the genotype and the value of the i -th locus,respectively.A and B (0<A <B ≤l )are constant integers.The neutrality is tunable by changing A and B .The abstract width,w ,of a neutral pathway is calculated as B −A .We focus on the moving speed of the individuals which keep remaining on the higher neutral network (F =1.0).As the initial setting,all individuals in the popu-lation are placed on a particular point on the higher neutral network,for instance,s i =1,i =1,...,d and s i =0,i =d +1,...,l ,where d is a constant integer between A and B .This would be a situa-tion similar to a population just after a transition period.In the process of evolution,each individual moves along the pathway by flipping the values of loci.Distance is defined as the number of 0s be-tween the 1st locus and the d -th locus if the indi-vidual is on the higher neutral network.Distance is not defined for an individual on the lower neutral network.Therefore,the moving speed of a popula-tion can be measured as the number of generations (for generational GAs),or the number of evaluations (for steady state GAs)for one of individuals to reach the furthest distance,d .For the BBF ,the optimal mutation rate,q o ,is identified as the mutation rate which results in the fastest speed over the mutationrate range.The phenotypic error threshold,q err ,is identified as the mutation rate where the transition mentioned in Section 1occurs.3Computer Simulations3.1Simulation ConditionsComputer simulations were conducted by setting the population size to 50and the length of the geno-type to 200.The extended GA used in this paper is called the operon-GA [10].The operon-GA uses standard bit mutation and five additional genetic operators:connection ,division ,duplication ,deletion and inversion .The probabilities for genetic opera-tions were set at 0.3for connection and division ,0.1for duplication and 0.05for deletion and inversion ,as recommended by Ohkura and Ueda [10].The length of the value list in a locus was 6.The ge-netic operation for the standard GA was standard bit mutation.For both GAs,the per-bit muta-tion rate,q ,was set between 0.00001and 0.1with step sizes of ∆q =0.0001(if q <0.001),0.001(if 0.001≤q ≤0.01)and 0.01(if 0.01<q ≤0.1).Crossover was not used for either GA.Tournament selection was adopted.Elitism 3was optionally ap-plied.The tournament size was set at s =2,4and 6.A generational GA was used.Each run lasted 10,000generations 4.We conducted 10inde-pendent runs for each problem with the parameters (A,B )=(19,20),(19,24),(19,29)and (19,39);that is,with neutral pathways of width w =1,5,10and 20.d was set at 19.All results were averaged over 10runs.3.2Simulation ResultsFig.2and 3show the average number of gener-ations to reach the furthest distance,d ,with s ={2,4,6}and w ={1,5,10,20},for non-elitism and elitism ,for the standard GA (SGA)and the operon-GA (OGA)respectively.The curves are U-shaped as a function of the mutation rate,q ,and have an optimal mutation rate and an error threshold.With non-elitism ,the speed falls sharply when q exceeds q o .Moreover,the optimal mutation rate is just below the error threshold (Fig.2(a),2(b)and Fig.3(a),3(b)).With elitism ,both the optimal mu-tation rate and the error threshold increase,and so does the distance between them (Fig.2(c),2(d)and Fig.3(c),3(d)).Increasing the tournament size increases the op-timal mutation rate and the error threshold.It also results in improved speeds over the mutation rate range q o <q <q err (Fig.2(a),2(c)and Fig.3(a),3(c)).Due to space restrictions we only show resultsfor w=1.However,increasing tournament size had the same effect for all widths.The OGA produced higher speeds than the SGA when q was below q o both with non-elitism and elitism(Fig.4).Fig.5shows the average effective mutation rate in an OGA population for non-elitism and elitism,with s=6,w=1and a per-bit mu-tation rate q=0.001.(The evolutionary dynamics shown are representative of all OGA runs in this study.)The effective mutation rate is calculated as the number offlipped bits per genotype after the ge-netic operators have been applied.It is distributed around the optimal mutation rate q o=0.006(for non-elitism)and q o=0.01(for elitism).4DiscussionOur results suggest that optimal mutation rates and error thresholds are strongly correlated with se-lection pressure.With non-elitism,the optimal mu-tation rate will be just below the error threshold. If the mutation rate is set by estimating the opti-mal mutation rate,a misjudgement could result in the error threshold being exceeded,and thus lead to poor performance.With higher selection pressure, the optimal mutation rate and error threshold both increase.Elitism improves the moving speed when q is larger than q o.Note that extreme elitism(e.g. 50%of offspring are identical to their parents)will reduce the moving speed,since the population will tend to repeatedly sample the same genotypes[11]. This may be related to the effects of samplingfluc-tuation.Nimwegen et al.[8]have suggested that there is an appreciable chance that all individuals on higher neutral networks will be lost through sam-plingfluctuations5.From these results,we can say that high selection pressure decreases the probability with which the individuals are lost through sampling fluctuation,with the result that the optimal muta-tion rate and error threshold are shifted to higher mutation rates.This would explain why,when q ex-ceeds q o,the moving speed improves if(relatively) high selection pressure is applied.We have also shown that,for the BBF,the vari-able mutation rate strategy of the OGA improves the efficiency of the search when q is less than q o,as a result of adaptively varying the effective mutation rate.5ConclusionsWe have investigated the effect of the selection pressure and the mutation rate on the speed of pop-ulation movement on landscapes with different levels of neutrality,using a standard GA and the operon-GA.Our results can be summarized as follows:(1) For a given population size,the speed of a popu-lation plotted as a function of the mutation rate2000400060008000100001.0e-041.0e-031.0e-02 1.0e-01G e n e r a t i o nMutation rates=2s=4s=6(a)w =1,non-elitism2000400060008000100001.0e-041.0e-031.0e-021.0e-01G e n e r a t i o nMutation ratew=1w=5w=10w=20(b)s =6,non-elitism2000400060008000100001.0e-041.0e-03 1.0e-02 1.0e-01G e n e r a t i o nMutation rates=2s=4s=6(c)w =1,elitism2000400060008000100001.0e-041.0e-03 1.0e-02 1.0e-01G e n e r a t i o nMutation ratew=1w=5w=10w=20(d)s =6,elitismFigure 2:Average generations to reach the furthest distance in ten runs by the SGA 02000400060008000100001.0e-041.0e-031.0e-02 1.0e-01G e n e r a t i o nMutation rates=2s=4s=6(a)w =1,non-elitism2000400060008000100001.0e-041.0e-03 1.0e-021.0e-01G e n e r a t i o nMutation ratew=1w=5w=10w=20(b)s =6,non-elitism2000400060008000100001.0e-041.0e-031.0e-021.0e-01G e n e r a t i o nMutation rates=2s=4s=6(c)w =1,elitism2000400060008000100001.0e-041.0e-031.0e-021.0e-01G e n e r a t i o nMutation ratew=1w=5w=10w=20(d)s =6,elitismFigure 3:Average generations to reach the furthest distance in ten runs by the OGA 02000400060008000100001.0e-041.0e-031.0e-02 1.0e-01G e n e r a t i o nMutation ratesga oga(a)non-elitism2000400060008000100001.0e-041.0e-03 1.0e-02 1.0e-01G e n e r a t i o nMutation ratesga oga(b)elitismFigure 4:Comparison between the SGA and the OGA (w =1,s =6)0.0050.010.0150.020.0250.03500100015002000M u t a t i o n r a t eGeneration(a)non-elitism0.0050.010.0150.020.0250.03500100015002000M u t a t i o n r a t eGeneration(b)elitismFigure 5:Effective mutation rate by the OGA (w =1,s =6,q =0.001)。

高三英语培优外刊阅读班级：____________学号：____________姓名：____________外刊精选｜人高马大的欧洲人：乳糖不耐也要喝牛奶上个月，新疆牛奶品牌麦趣尔产品抽检不合格，再次引发了关于如何选好牛奶的网络热议。

实际上，很多中国人其实根本不适合喝牛奶，因为中国人乳糖不耐受的比例要远高于欧美人。

而国外的一项新研究发现，原来我们印象中离不开牛奶的欧洲人，很多也是乳糖不耐受的体质。

究竟为什么会有人乳糖不耐受？科学家还有哪些新发现？Early Europeans Could Not T olerate Milk but Drank It Anyway,Study FindsIn many ways, humans are weird mammals. And our relationship with milk is especially weird.In every mammalian species, females produce milk to feed their young. The babies digest the milk with the help of an enzyme called lactase. When the young mammals are weaned, they stop making lactase.But it is common for our species to keep consuming milk into adulthood. What’s more, about one-third of people carry genetic mutations that allow them to produce lactase throughout their lives, making it easier to digest milk.Scientists have long suspected that dairy consumption and the persistence of lactase rose together in human history. When people started herding cattle and other livestock some 10,000 years ago, the theory went, those with a mutation for lactase persistence gained a new source of calories and protein.But a new study suggests that the traditional story does not hold up. Researchers have found that Europeans were consuming milk without lactase for thousands of years, despite the misery from gas and cramping it might have caused.Over the years,scientists have found milk on thousands of pottery fragments across Europe and neighboring regions.For the new study,the scientists used this database to create a map of milk consumption over the past 9,000 years.【词汇过关】请写出下面文单词在文章中的中文意思。

染色质（chromatin）是由DNA、RNA、蛋白质等组成的复合物，是核基因的载体，在真核细胞间期呈伸展状态。

染色体（chromosome ）细胞在有丝分裂或减数分裂过程中，由染色质凝缩而成的棒状结构。

常染色质(euchromatin)：细胞间期核内纤维折叠盘曲程度小，分散度大，染色较浅且具有转录活性的染色质。

异染色质(heterochromatin)：细胞间期核内纤维折叠盘曲紧密，呈凝集状态，染色较深且很少有转录活性的染色质。

由于雌性细胞中的两条X染色体中的一条发生异固缩，失去转录活性，这保证了雌雄两性细胞中都只有一条X染色体保持转录活性，使两性X连锁基因产物的量保持在相同水平上，这种效应称为X染色体的剂量补偿(dosage compensation)。

基因(Gene）：遗传的基本单位，含有编码一种RNA，大多数情况是编码一种多肽的信息单位；负载特定遗传信息的DNA片段，其结构包括由DNA编码序列、非编码调节序列和内含子组成的DNA区域。

微卫星DNA（Microsatellite）、STR（Short Tandem Repeat）、DNA指纹是由2—6bp重复单位构成核心序列，也称短串联重复序列(STR)，是一种广泛分布在人类基因组中的DNA片段，主要由核心序列拷贝数目的变化产生长度多态性，其在人群中存在个体间的高度变化，是DNA指纹的形成基础。

指基因组水平上由单个核苷酸的变异所引起的DNA 序列多态性,在群体中的发生频率不小于1 %，就称为单核苷酸多态性（Single Nucleotide Polymorphism, SNP）。

外显子（exon）内含子（intron）突变(mutation)：遗传物质所发生的可被检测和可遗传的改变；通常对机体有害。

广义：包括染色体和DNA的改变；狭义：指基因组DNA分子的碱基组成或其顺序的改变。

转换（transition）颠换（transversion）错义突变（missense mutation）同义突变（same sense mutation）无义突变（nonsense mutation）动态突变（Dynamic Mutation）人类基因组中的短串联重复序列，尤其是基因编码区或侧翼序列的三核苷酸重复，在一代代传递过程中重复次数发生明显增加，从而导致基因功能改变而产生疾病。

Population Genetics and EvolutionPopulation genetics is the study of genetic variation within and among populations. It is a field of biology that deals with the genetic makeup of populations, and how genes are passed on from one generation to the next. Evolution, on the other hand, is the process by which species change over time. It is a fundamental principle of biology that explains how organisms adapt to changing environments and how new species arise. In this essay, I will discuss the relationship between population genetics and evolution, and how they are intertwined.Population genetics is the foundation of evolutionary biology. It provides the basic principles that explain how genetic variation arises and how it is maintained within populations. The study of population genetics has revealed that genetic variation is the raw material upon which natural selection acts, and that the frequency of alleles in a population can change over time due to various evolutionary forces. These forces include mutation, genetic drift, migration, and natural selection.Mutation is the ultimate source of genetic variation. It is a random process that introduces new alleles into a population. Mutations can be beneficial, harmful, or neutral, and their effects on the fitness of an organism depend on the environment in which it lives. Genetic drift is a random process that can cause the frequency of alleles in a population to change over time due to chance events. Small populations are more susceptible to genetic drift than large populations, and it can lead to the fixation of alleles that are not necessarily beneficial or harmful.Migration, or gene flow, is the movement of individuals or their genes from one population to another. It can introduce new alleles into a population and prevent genetic differentiation between populations. Natural selection is the process by which organisms with traits that are advantageous in a particular environment have a greater chance of survival and reproduction than those with less advantageous traits. Natural selection can lead to the adaptation of populations to their environment and the evolution of new species.Evolutionary biologists use population genetics to study the patterns and mechanisms of evolution. They use mathematical models to predict how the frequency of alleles in a population will change over time, and to test hypotheses about the causes of evolutionary change. They also use molecular techniques to study the genetic makeup of populations and to reconstruct the evolutionary history of species.One of the most important applications of population genetics is in conservation biology. Many species are threatened with extinction due to habitat loss, climate change, and other human activities. Population genetics can help conservation biologists to understand the genetic diversity of populations, to identify genetically distinct populations, and to develop strategies for conserving genetic diversity. For example, the genetic diversity of captive populations can be maintained by breeding individuals from different populations, and the genetic diversity of wild populations can be enhanced by translocating individuals from other populations.In conclusion, population genetics and evolution are two closely related fields of biology. Population genetics provides the foundation for evolutionary biology by explaining how genetic variation arises and is maintained within populations. Evolutionary biologists use population genetics to study the patterns and mechanisms of evolution, and to develop strategies for conserving genetic diversity. The relationship between population genetics and evolution is a complex and dynamic one, and it is an area of active research in biology. As we continue to study the genetic makeup of populations and the processes that drive evolutionary change, we will gain a better understanding of how life on Earth has evolved and how we can protect it for future generations.。

遗传算法交叉概率的设定英文回答：Setting the Crossover Probability in Genetic Algorithms.The crossover probability is a key parameter in genetic algorithms (GAs). It controls the rate at which genetic material is exchanged between parent chromosomes to create offspring. Setting the crossover probability too high ortoo low can have a significant impact on the performance of the GA.The optimal crossover probability depends on a numberof factors, including the size of the population, the selection pressure, and the mutation rate. In general, a higher crossover probability is more likely to result in convergence to a global optimum, while a lower crossover probability is more likely to result in premature convergence to a local optimum.There are a number of different methods for setting the crossover probability. One common approach is to use afixed value, such as 0.5 or 0.7. Another approach is to use an adaptive value, which changes over the course of the GA. For example, the crossover probability could be decreased as the population converges to a solution, in order to reduce the likelihood of破坏 the best solutions.The best approach for setting the crossover probability will vary depending on the specific problem being solved. However, by understanding the role of the crossover probability and the factors that affect it, GAs can be more effectively tuned to achieve optimal performance.中文回答：遗传算法交叉概率的设定。

Unit11、Some factors that may lead to the plaint:·Neuron o verload·Patients* high expectations·Mistrust and misunderstanding between the patient and the doctor2、 Mrs、Osorio’s conditio n:·A 56-year-old woman·Somewhat overweight·Reasonably well-controlled diabetes and hypertension·Cholesterol on the high side without any medications for it·Not enough exercises she should take·Her bones a little thin on her last DEXA scan3、 Good things:·B lood tests done·Glucose a little better·Her blood pressure a little better but not so great Bad things:·Cholesterol not so great·Her weight a little up·Her bones a little thin on her last DEXA scan 44、The situation:·The author was in a moderate state of panic: juggling so many thoughts about Mrs、Osorio’s conditions and t rying to resolve them al l before the clock ran down、·Mrs、 Osor io made a tr ivial request, not so important as pared to her conditions、· Mrs 、Osor io seemed to care on ly about her “ innocent — and p lete ly justified —request”: the form signed by her doctor、·The d octor tried to or at least pretended to pay attention to the patient while pleting documentation、5、Similarities:· In puter multitasking, a microprocessor actual ly performs only one task at a time、 Like microprocessors, we human beings carft actually concentrate on two thoughts at the same exact time、 Multitasking is just an illusion both in puters and human beings、Differences:·The concept of multitasking originated in puter science 、·At best, human beings can juggle only a handful of thoughts in a multitasking manner, but puters can do much better、·The more thoughts human beings juggle, the less human beings are able to attune fully to any given thought, but puters can do much better 、6、·7 medical issues to consider·5 separate thoughts, at least, for each issue·7 x 5 = 35 thoughts· 10 patients that afternoon·35 x 10 = 350 thoughts·5 residents under the authors supervision ·4 patients seen by each resident· 10 thoughts, at least, generated from each patient·5 x 4 x 10 = anther 200 thoughts·350 + 200 = 550 thoughts to be handled in total· If the doctor does a good job juggling 98% of the time, that still leaves about 10 thoughts that might get lost in the process 、7、Possible solutions:·puter-generated reminders·Case managers·Ancillary se rvices·The simplest solution: timeUnit21、The author implies:• Peoples inadequate consciousness about the consequence of neglecting the re- emerging infectious diseases·Unjustifiabi lity of peoples placency about the prevention and control of the infectious diseases·Unfinished war against infectious diseases2、Victory declarations:·Surgeon General Wi l liam Stewart's hyperbolic statement of closing “thebook on infectious disease ”、·A string of impressive victories incurred by antibiotics and vaccines·The thought that the war against infectious diseases was almost overWhat followed ever since:·Appearance of new diseases such as AIDS and Ebola·eback of the old afflictions:» Diphtheria in the former Soviet Union» TB in urban centers like New York City» Rising Group A streptococcal conditions like scarlet fever·The fear of a powerful new flu strain sweeping the world3、Elaborate on the joined battle:·WHO established a new division devoted to worldwide surveillance and control of emerging disease in October 1995、·CDC launched a prevention strategy in 1994 、·Congress raised fund from $6、7 mi l lion in 1995 to $26 mi l lion in 1997、4、The borders are meaningless to pathogenic microbes, which can travel from one country to another remote country in a very short time 、5、TB:·Prisons and homeless shelters as ideal places for TB spread ·Emerging of drug-resistant strain or even multi-drug-resistant strain·A ride on the HIV w^on by attacking the immunopromised Group A strep:·A change in virulence·Mutation in the exterior of the bacteriumFlu:Constant changes in its coat (surface antigens) and resultant changes in its level of virulence6、Examples:·Experiment in England is seeing the waning immunity because of no vaccination、· Due to poor vaccination efforts, the diphtheria situation in the former Soviet Union is serious 、 '• The vaccination rates are dropping i n some American cities, and it wi l l lead to more diphtheria and whooping cough 、7、The four areas of focus:·The need for surveillance·Updated science capable of dealing with discoveries in the field ·Appropriate prevention and control1、Terry's life before·Strong public health infrastructure8、The infectious diseases such as TB, flu, diphtheria and scarlet fever will never really go away, and the war against them will never end 、Unit31、Terry's life before·She loved practicing Tae Kwon Do· She loved the surge of adrenal ine that came with the control led bat of tournaments、·She peted nationally, even won bronze medal in the trials for the Pan American Games、·She attended medical school, practiced as an internal medicine resident, and became an academic general internist、·She got married and got a son and a daughter 、2、The symptoms of MS and autoimmune disease:·Loss of stamina and strength·Problems with balance·Bouts of horrific facial pain·Dips in visual acuity3、Terry did the following before she self-experimented:·She started injections、·She adopted many pharmacotherapies、·She began her own study of literature:» She read articles on websites such as PubMed 、» She searched for articles testing new MS drugs in animal models 、» She turned to artic les concerning neurodegeneration of a l l types —dementia,Parkinson's disease,Huntington's disease,and Lou Gehrig's disease、» She relearned basic sciences such as cellular physiology, biochemistry, and neurophysiology、4、Approaches Terry mainly used:· Self-exper imentation with var ious nutr ients to s low neurodegeneration based on literature reports on animal models·Self-experimentation with neuromuscular electrical stimulation which is not an approved treatment for MS·Online search to identify the sources of micronutrients and having a new diet·Reduction of food allergies and toxic load5、Cases mentioned in the text:· Increased mercury stores in the brains of people with dental fillings ·High levels of the herbicide atrazine in private wells in Iowa·The strong association between pesticide exposure and neurodegeneration·The association of single nucleotide polymorphisms involving metabolism of sulfur and/or B vitamins· Inef ficient clearing of toxins6、With 70% to 90% of the r isk for diabetes, heart disease, cancer, andautoimmunity being due to environmental factors other than the genes, we can take many health problems and the health care crisis under our control, for example, optimizing our nutrition and reducing our toxic load 、Unit41、Two concepts:·plementary medicine refers to the use of conventional therapies together with alternative treatments such as using acupuncture in addition to usual care to help lessen pain、 plementary and alternative medicine is shortened as CAM、·Alternative medicine refers to healing treatments that are not part of conventional therapies —like acupuncture,massage therapy,or herbal medicine、 They are called so because people used to consider practices like these outside the mainstream、2· TCM does not require advanced, p l icated, and in most cases, expensive facilities、·TCM employs needles, cups, coins, to mention but a few 、·Most procedures and operations of TCM are noninvasive 、·The substances used as medicine are raw herbs or abstracts from them, and they are indeed all natural, from nature、·TCM has been practiced as long as the Chinese history, so the efficiency proven and ensured、is·Ongoing research around the wor ld on acupuncture, herbs, massage and Tai Chi have shed light on some of the theories and practices of TCM3、 It may be used as an adjunct treatment, an alternative, or part of a prehensive management program for a number of conditions: post-operative and chemotherapy induced nausea and vomiting,post-operative dental pain, addiction, stroke rehabilitation, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, low back pain, carpal tunnel syndrome, and asthma、4、A well-justified NO:·More intense research to uncover additional areas for the use of acupuncture·Higher adoption of acupuncture as a mon therapeutic modality not only in treatment but also in prevention of disease and promotion of wellness· Exp loration and perfection of innovative methods of acupuncture pointstimulation with technological advancement·Improved understanding of neuroscience and other aspects of human physiology and function by basic research on acupuncture·Greater interest by stakeholders·An increasing number of physician acupuncturists5、·Appropriate uses of herbs depend on proper guidance:» Proper TCM diagnosis of the zheng of the patient»Correct selection of the corresponding therapeutic strategies and principles that guide the choice of herbs and herbal formulas ·Digression from either of the above guidence will lead to misuses of herbs, and will result in plications in patient6、·Randomized controlled trialsAdvantages:» Elimination of the potential bias in the al locat ion of participants to the intervention group or control group» Tendency to produce parable groups» Guaranteed validity of statistical tests of significance Limitations:»Difficulty in generalizing the results obtained from the selected sampling to the population as a whole» A poor choice for research where temporal factors are an issue» Extremely heavy resources, requiring very large samplegroups•Quasi-experimentsAdvantages:» Control group parisons possible» Reduced threats to external validity as natural environments donot suffer the same problems of artificiality as pared to awell-controlled laboratory setting、» Generalizations of the findings to be made about population since quasiexperiments are natural experimentsLimitations:»Potential for non-equivalent groups as quasi-experimental designs do not use random sampling in constructing experimental and control groups、» Potential for low internal validity as a result of not using random sampling methods to construct the experimental and control groups •Cohort studiesAdvantages:» Clear indication of the temporal sequence between exposure and oute» Part icu lar use for eva luat ing the effects of rare or unusua l exposure» Ability to examine multiple outes of a single risk factorLimitations:»Larger,longer,and more expensive»Prone to certain types of bias»Not practical for rare outes•Case-control studiesAdvantages:»The only feasible method in the case of rare diseases and those with long periods between exposure and oute»Time and cost effective with relatively fewer subjects as pared to other observational methodsLimitations:»Unable to provide the same level of evidence as randomized controlled trials as it is observational in nature»Difficult to establish the timeline of exposure to disease oute •“N=1”trialsAdvantages» Easy to manage» InexpensiveLimitations:»Findings difficult to be generalized to the whole population» Weakest evidence due to the number of the subject 7、• Synthesis of evidence is pletely dependent on:» The pleteness of the literature search (unavailable for foreign studies) » The accuracy of evaluation·There are situations in which no answer can be found for the questions of interest in RCTs and database analyses、·There's the requirement of using less stringent information rather than “hard data”8、·Assessment of the intrinsic value of traditional medicine in society ·Research and education·Political, economic, and social factorsUnit51、·Dis-ease refers to the imbalance arising from:» Continuous stress» Pain» Hardships·Disease is a health crisis ascribable to various dis-eases 、·Prompting elimination of dis-eases can alleviate some diseases 、2、·Wel lness is a state involving every aspect of our being: body, mind and spirit、·Manifestations of a healthy person:» Energy and vitality» A certain zip in gait» A warm feeling of peace of heart seen through behavior3、·Constant messages, positive and negative,are sent to our mind about the health of our body、·Physical symptoms are suppressed by people who go through life on automatic pilot、·Being well equals to being disease- or illness-free in the minds of them、·They confused wellness with an absence of symptoms 、4、·People's minds are infected by spin:» Half-truth» Fearful fictions» Blatant deceit: some as a form of self-deceit·Spin is a result of unconscious living、·The kind of falseness is pandemic、5·Our body intelligence is suppressed or dormant from a lack of use 、·There are tremendous amount of stress on a daily basis 、·Our bodies are easi ly ignored for years because of a lack of recreation time、·Limiting, self-defeating and even self-destructive behaviors undermine our wellbeing and keep them from achieving our full potential 、6·We grow more reluctant to take risks、·We lose the abi lity to feel and acknowledge our deepest feelings and the courage to speak our truth、·We continue to deny and repress our feelings to protect ourselves 、·Fear, denial and disconnection from our bodies and feelings bee an unconscious, self-protective habit, a kind of default response to life、7·A multi-faceted process:»Looking for roots of and resolutions for the issues in different dimensions» Building our wellness toolbox slowly» Picturing our whole state of being·Attention to the little stuff:» Examining our lives honestly and setting clear intentions to change » Striving to maintain a balance of our mind, body and spirit » Taking small steps in the way to perceive and resolve conflict8·Try to awaken and evolve in order to live more consciously 、·Get in touch with our genuine feelings and emotions 、·e to terms with the toxic emotionsUnit61 、In the past, most people died at home、 But now, more and more people arecared in hospitals and nursing homes at their end of life, which of course brings a new set of questions to consider 、·Sixty-four years old with a history of congestive heart failure·Deciding to do everything medically possible to extend his life·Avai labi l ity of around-the-c lock medical services and a fu l l range of treatment choices, tests, and other medical care·Relaxed visiting hours, and personal items from home2 、Avai labi l ity of around-the-c lock medica l resources, inc luding doctors,nurses, and facility、·Taking on a job which is big physically, emotionally, and financially ·Hiring a home nurse for additional help·Arranging for services (such as visiting nurses) and special equipment (likea hospital bed or bedside mode)5、·H ealth insurance·Planning by a professional, such as a hospital discharge plaimer or a social worker·Help from local governmental agencies·Doctor's supervision at home6、·Traditionally, it is only about symptom care 、·Recently, it is a prehensive approach to improving the quality of life for people who are living with potentially fatal diseases 、7、·Stopping treatment specifically aimed at curing an illness equals discontinuing all treatment、·Choosing a hospice is a permanent decision 、·A dying patient·Decision whether to withdraw life-support machines and medication and start fort measures·The family's refusal to make any decision or withdraw any treatments 2、·The doctor as exclusive decision-maker·The patient as participant with little say in the final choice3、·Respect for the patient, especially the patient s autonomy·Patient-centered care·The patient as decision-maker based on the information provided by the doctor4、·Patients are forced to make decisions they never want to 、·Patients, at least a large majority of them, prefer their doctors to make final decisions、·Shifting re sponsibi lity of decision-making to patients wi l l bring about more stress to patients and their families, especially when the best option for the patient is uncertain、5、Doctors are very much cautious about mitting some kind of ethicaltransgression、Unit8·Shouldering responsibi lity together with the patient may be better than having the patient make decisions on their own 、·Balancing between paternalism and respect for patients autonomy constitutes a large part of medical practice、Unit81、·Research:An activity to test hypothesis, to permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge·Practice:Interventions solely to enhance the wel l-being of an individual patient or client and that have a reasonable expectation of success·Blu rred distinction:»Cooccurrence of research and practice like in research designed to evaluate a therapy» Notable departures from standard practice being called “experimental” with the terms “experimenta l ” and “research”carelessly defined2、·Autonomy:Individuals treated as autonomous agents 、·Protection:Persons with diminished autonomy entitled to protection·A case in point:Prisoners involved in research3· “Do no harm” as the primary principle·Maximization of possible benefits and minimization of possible harms 、·Balance between benefits and potential risks involved in every step of seeding the benefits4、· “Do no harm” as a fundamental principle of medical ethics·Extension of it to the realm of research by Claude Bernard·Benefits and risks as a set “duet” in both medical practice and rese arch 5、·Unreasonable denial of entitled benefit and unduly imposed burden:Enrolment of patients in new drug trial: Who should be enrol led and who should not?·Equal treatment of equals:Determining factors of equal ity: age, sex, severity of the condition, financial status, social status6、·Definition:The opportunity to choose what shall or shall not happen to them·App lication:» A process rather than signing a written form» Adequate information as the premise» A well-informed decision as the expected result7、·Requirements for consent as entailed by the principle of respect for persons ·Risk/benefit assessment as entailed by the principle of beneficence ·More requirements of fairness as entailed by the principle of justice: » At the individual level: fairness» At the social level: distinction between classes。

LETTEROPENThe impact of receptor-binding domain natural mutations on antibody recognition of SARS-CoV-2Signal Transduction and Targeted Therapy(2021) 6:132 ;https:///10.1038/s41392-021-00536-0Dear Editor,The ongoing COVID-19pandemic has resulted in over25.0 million confirmed cases and over840,000deaths globally.As the third severe respiratory disease outbreak caused by the coronavirus,COVID-19has led to much larger infected popula-tions and coverage of geographic areas than SARS and MERS. Such high prevalence of infection has raised significant concerns about the emergence and spread of escape variants,which may evade human immunity and eventually render candidate vaccines and antibody-based therapeutics ineffective.Indeed, some naturally mutated SARS-CoV or MERS-CoV strains from the sequential outbreaks were reported to resist neutralization by the antibodies isolated during thefirst outbreak1,2.Furthermore, a number of natural mutations have already been identified in the spike protein of SARS-CoV-2.Among them,a variant with the D614G mutation has rapidly become the dominant pandemic form probably due to itsfitness advantage3.Another spike mutation,the N501Y,wasfirst identified in a mouse-adapted strain of SARS-CoV-24,and also occurred recently in natural human infections.Therefore,it is essential to continuously monitor the emergence of SARS-CoV-2spike mutations and their potential roles in viral escape from existing neutralizing antibodies.To analyze the SARS-CoV-2mutations,we retrieved all the 101,131full-length SARS-CoV-2nucleotide sequences uploaded in the GISAID database(https://)up to Septem-ber15,2020.We focused on the receptor-binding domain(RBD) of SARS-CoV-2spike protein,due to the fact that RBD is the most dominant antigenic site for inducing SARS-CoV-2neu-tralizing antibodies and contains the majority of neutralizing epitopes5.Afterfiltering out ambiguous sequences,a total of 94,079full-length SARS-CoV-2RBD sequences were obtained and aligned with the Wuhan-Hu-1strain(GenBank: MN_908947).A total of216mutational events have been observed in169RBD residues across5188sequences,account-ing for87.1%of all amino acids in RBD(169out of194residues). Such mutation rate is comparable to that of SARS-CoV-2S1 (88.7%,597out of673residues)and S2(89.0%,470out of528 residues)subunits(Fig.1a).Although RBD has undergone intensive mutations,the mutant sequences compromise only a small percentage of the94,079available RBD sequences(Fig. 1b,Supplementary Table S1),suggesting that these RBD mutations have not beenfixed in viral populations.To evaluate the impact of RBD natural mutations on the binding efficacy of anti-SARS-CoV-2antibodies,we expressed and purified41 representative RBD variants,which included mutations of the three most frequently-mutated residues(S477,N439,T478),as well as all the variants emerged during thefirst4months of SARS-CoV-2 outbreak.All RBDs expressed well(Supplementary Fig.S1)and retained the capability to bind ACE2(Supplementary Fig.S2–S4). Then,we measured the binding ability of the RBD mutants to a panel of8antibodies,developed by us and other groups that recognize a diverse set of epitopes on SARS-CoV-2RBD6–9.According to the binding epitopes,these antibodies could be divided into two groups: those who recognize epitopes within the ACE2-RBD binding interface and could compete with ACE2for RBD binding(ACE2-competing group),and those could not(ACE2non-competing group).Surpris-ingly,we found that all of the ACE2-competing antibodies exhibited negligible binding to at least one of the mutant RBDs as measured by ELISA(Fig.1c)and bio-layer interferometry(Fig.1d).For instance, 414-1,a potent SARS-CoV-2neutralizing antibody isolated from a COVID-19recovered patient7,exhibited no binding to the RBD mutants L452R and N501Y,and evidently reduced binding to nine other RBD mutants.In contrast,the antibodies S3098and n30636that engage epitopes distinct from the receptor-binding motif showed exceptional breadth,with no escape mutants observed.The antibodies n31306and CR30229were reported to target cryptic epitopes located in the spike trimeric interface,and retained their binding affinities towards most of the RBD variants(Fig.1c).Taken together,these results indicate that a single natural mutation on the SARS-CoV-2RBD was able to completely abolish antibody binding. Besides,it seems that the natural RBD mutants had a higher tendency to escape the binding of ACE2-competing antibodies than non-competing antibodies(Fig.1e and f),although further studies on more extensive panels of antibodies are required to confirm this finding.Next,we evaluated the binding breadth of a combination of two antibodies recognizing distinct epitopes.Notably,the combination of ACE2-competing antibody414-1with non-competing antibody n3130resulted in full coverage of SARS-CoV-2RBD variants(Fig.1c).The mixture exhibited strong binding to most of the RBD variants,and slightly reduced binding only to one double mutant(K448R/H519P).To confirm whether the reduction in RBD binding potency correlates with reduced SARS-CoV-2neutralization,we also measured the neutralizing activity of the antibodies against SARS-CoV-2pseudoviruses bearing RBD mutations.As expected,414-1and n3130did not show effective neutralization against pseudoviruses with their corresponding escape mutations(N501Y and E516Q,respectively),while the mixture of the two antibodies broadly neutralized all the tested viruses(Fig.1g).All the RBD variants pseudoviruses still possessed the infectivity of target cells(Supplementary Fig.S5).In addition, plasma from convalescent COVID-19patients were also measured for their binding and neutralization activities.Similarly,all plasma samples had superior breadth in binding to naturally mutated RBDs and neutralizing multiple viral variants(Supplementary Figs. S6,S7).Considering that a number of neutralizing antibodies are being developed to treat COVID-19,our results suggest that some of these antibodies should be used in combinations to increase the neutralization breadth and reduce the possibility that an escape mutant isfixed in the treated host population.Never-theless,the low frequencies of RBD mutants identified hereReceived:4October2020Revised:1February2021Accepted:4February /sigtransSignal Transduction and Targeted Therapy ©The Author(s)2021revealed that they are more likely from randomized mutation,and may not represent the result of fitness selection.Collectively,these results con firmed the capability of SARS-CoV-2to escape from antibodies,especially the ACE2-competing antibodies,by acquiring resistance mutations in RBD.Such escape mutations can occur within the binding epitopes of antibodies,or regions away from antibody epitopes but may affect immunogenicity of RBD and render antibodies ineffective (Fig.1f).Notably,the ACE2-competing antibodies constitute the majority of anti-RBD antibodies elicitedbyLetter2Signal Transduction and Targeted Therapy (2021) 6:132SARS-CoV-2infection or vaccination.Therefore,our findings highlight the importance of continuously monitoring RBD natural mutations and evaluating their impact on antibody recognition of SARS-CoV-2,which may help guide the devel-opment and implementation of therapeutic antibodies and vaccines against SARS-CoV-2.ACKNOWLEDGEMENTSThis work was supported by grants from the National Key R&D Program of China (2019YFA0904400),National Natural Science Foundation of China (81822027,81630090),National Megaprojects of China for Major Infectious Diseases (2018ZX10301403,2018ZX10101003),and the staff from Core Facility of Microbiology and Parasitology,Shanghai Medical College,Fudan University.AUTHOR CONTRIBUTIONST.Y.and Y.W.conceived,wrote the paper,and supervised the study.C.L.,X.T.,X.J.,J.W.,L.L.,S.J.,F.L.,and Y.L.performed the experiments and analyzed the data.All authors reviewed and approved the final version of the manuscript.ADDITIONAL INFORMATIONSupplementary information The online version contains supplementary material available at https:///10.1038/s41392-021-00536-0.Competing interests:The authors declare no competing interests.Cheng Li 1,Xiaolong Tian 1,Xiaodong Jia 2,Jinkai Wan 3,Lu Lu 1,Shibo Jiang 1,Fei Lan 3,Yinying Lu 2,Yanling Wu 1andTianlei Ying 11MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai,China;2Department of Comprehensive Liver Cancer,The Fifth Medical Center,Chinese PLA General Hospital,Beijing,China and 3Shanghai Key Laboratory of Medical Epigenetics,International Co-laboratory of Medical Epigenetics and Metabolism,Ministry of Science and Technology,Institutes of Biomedical Sciences,Fudan University,Shanghai,ChinaThese authors contributed equally:Cheng Li,Xiaolong Tian,Xiaodong JiaCorrespondence:Yinying Lu (*********************)orYanling Wu (*******************.cn)orTianlei Ying (****************.cn)REFERENCES1.Sui,J.et al.Effects of human anti-spike protein receptor binding domain anti-bodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness.J.Virol.88,13769–13780(2014).2.Kim,Y.S.et al.Sequential emergence and wide spread of neutralization escape middle east respiratory syndrome coronavirus mutants,South Korea,2015.Emerg.Infect.Dis.25,1161–1168(2019).3.Korber,B.et al.Tracking changes in SARS-CoV-2spike:evidence that D614G increases infectivity of the COVID-19virus.Cell 182,812–827(2020).e819.4.Gu,H.et al.Adaptation of SARS-CoV-2in BALB/c mice for testing vaccine ef ficacy.Science 369,1603–1607(2020).5.Yu,F.et al.Receptor-binding domain-speci fic human neutralizing monoclonal antibodies against SARS-CoV and SARS-CoV-2.Signal Transduct.Target Ther.5,212(2020).6.Wu,Y.et al.Identi fication of human single-domain antibodies against SARS-CoV-2.Cell host microbe 27,891–898(2020).e895.7.Wan,J.et al.Human-IgG-neutralizing monoclonal antibodies block the SARS-CoV-2infection.Cell Rep.32,107918(2020).8.Pinto,D.et al.Cross-neutralization of SARS-CoV-2by a human monoclonal SARS-CoV antibody.Nature 583,290–295(2020).9.Tian,X.et al.Potent binding of 2019novel coronavirus spike protein by a SARS coronavirus-speci fic human monoclonal antibody.Emerg.Microbes Infect.9,382–385(2020).Open Access This article is licensed under a Creative Commons Attribution 4.0International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons license,and indicate if changes were made.The images or other third party material in this article are included in the article ’s Creative Commons license,unless indicated otherwise in a credit line to the material.If material is not included in the article ’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this license,visit /licenses/by/4.0/.©The Author(s)2021Fig.1Binding and neutralizing sensitivity of the naturally occurring RBD variants to SARS-CoV-2binding antibodies and convalescent serum.a Surface representations of natural amino acid substitutions in SARS-CoV-2RBD colored by red.b Frequency of the originally reported genome (SARS-CoV-2Wuhan-Hu-1)and RBD mutants in available RBD sequences at the time of writing (2020).High-frequencies amino acid mutation sites were identi fied:S477N/R/I/G/T (4.07%),N439K (0.19%),T4781/K/A/R (0.11%).c Binding capacity of antibodies against SARS-CoV-2RBD,human plasma from five COVID-19convalescent patients,and ACE2to 41SARS-CoV-2RBD mutants,as measured by ELISA.Shades of colors in the boxes indicate retained binding activity of ACE2-competing antibodies (purple),ACE2non-competing antibodies (blue),convalescent plasma (green),antibody cocktail (red),and ACE2(orange).Dark color filled boxes indicate the binding ability >50%;light color filled boxes indicate binding ability ranging 50–20%;and white color filled boxes indicate escape to antibodies (binding ability <20%).d Escape mutations to antibodies were further con firmed by BLI.e Correlation between ACE2competion values and relative escape of antibodies.ACE2competion values were obtained from previous reports.f Position of binding resistance-conferring substitutions.Structure of the RBD (from PDB 6M17)with positions that are occupied by amino acids whose substitution confers partial or complete (binding ability<50%)escape to antibodies are indicated for ACE2-competing antibodies (purple)and ACE2non-competing antibodies (blue).g Neutralization of luciferase-encoding pseudotyped virus with SARS-CoV-2S proteins harboring the indicated naturally occurring mutations.Each pseudotyped viruses preincubated with serial dilutions of antibodies or convalescent plasma were used to infect Huh-7cells,and inhibitory rates (%)of infection were calculated by luciferase activities in cell lysates.Error bars indicate mean±s.d.from three independent Letter3Signal Transduction and Targeted Therapy (2021) 6:132。

The origin of life has been a topic of great interest and debate among scientists, philosophers, and scholars for centuries. As a seventhgrade student, I find this subject particularly fascinating, and Id like to share my thoughts on it.Firstly, the idea of spontaneous generation suggests that life could arise from nonliving matter. This theory was popular in ancient times but has since been disproven by the scientific community. Its interesting to think about how people once believed that life could just spontaneously appear, like mice from dirty rags or maggots from rotting meat.On the other hand, the theory of abiogenesis posits that life originated from simple organic compounds that eventually evolved into more complex forms. This is supported by the famous MillerUrey experiment, which demonstrated that amino acids, the building blocks of proteins, could be synthesized from inorganic precursors under conditions thought to resemble the early Earths atmosphere.Another intriguing hypothesis is panspermia, which proposes that life on Earth may have been seeded by microorganisms or organic molecules from outer space. This idea is supported by the discovery of extremophiles, organisms that can survive in extreme environments, and the presence of organic molecules on comets and meteorites. However, the most widely accepted theory is evolution by natural selection, as proposed by Charles Darwin. According to this theory, life began with a single common ancestor and gradually diversified into the myriad species we see today through a process of mutation, selection, and adaptation.In conclusion, the origin of life remains a mystery, with various theories offering different perspectives. As a seventhgrade student, I am excited to learn more about this subject and contribute to our understanding of how life began on our planet. The study of lifes origins not only helps us appreciate the complexity and diversity of life but also inspires us to explore the possibility of life beyond Earth.。