胰高血糖素样肽1和肠道菌群（英文）

胃肠道生产20多种肽类激素。其中,胰高血糖素样肽1(GLP-1)在过去的30年里受到最多关注。人们对GLP-1以及另一肠道激素葡萄糖依赖性促胰岛素肽(GIP)功能的研究已导致了两类新的糖尿病治疗药物的开发,分别称为GLP-1R激动剂和DPP-Ⅳ抑制剂。肠道的这些内分泌细胞不是聚集在内分泌腺体中,而是广泛分布在整个胃肠道中,从而与"外部"环境包括食物以及肠道菌群充分接触。本文简要介绍了GLP-1以及营养成分如何调节其分泌,并重点讨论了肠道环境如何影响GLP-1的产生和分泌,包括肠道菌群的贡献。

Duplication and diversification of insulin genes in ray-finned fish

Insulin is a key hormone for the regulation of metabolism in vertebrates.Insulin is produced by pancreatic islet cells in response to elevated glucose levels and leads to the uptake of glucose by tissues such as liver and adipose tissue to store energy.Insulin also has additional functions in regulating development.Previous work has shown that the proglucagon gene,which encodes hormones counter regulating insulin,is duplicated in teleost fish,and that the peptide hormones encoded by these genes have diversified in function.I sought to determine whether similar processes have occurred to insulin genes in these species.Searches of fish genomes revealed an unexpected diversity of insulin genes.A triplication of the insulin gene occurred at the origin of teleost fish,however one of these three genes,insc,has been lost in most teleost fish lineages.The two other insulin genes,insa and insb,have been retained but show differing levels of selective constraint suggesting that they might have diversified in function.Intriguingly,a duplicate copy of the insa gene,which I named insab,is found in many fish.The coding sequenee encoded by insab genes is under weak selective constraint,with its predicted protein sequences losing their potential to be processed into a two-peptide hormone.However,these sequences have retained perfectly conserved cystine residues,suggesting that they maintain insulin's three-dimensional structure and therefore might modulate the processing and secretion of insulin produced by the other genes.

Genomic organization and evolution of ruminant lysozyme c genes

Ruminant stomach lysozyme is a long established model of adaptive gene evolution. Evolution of stomach lysozyme function required changes in the site of expression of the lysozyme c gene and changes in the enzymatic properties of the enzyme. In ruminant mammals, these changes were associated with a change in the size of the lysozyme c gene family. The recent release of near complete genome sequences from several ruminant species allows a more complete examination of the evolution and diversification of the lysozyme c gene family. Here we characterize the size of the lysozyme c gene family in extant ruminants and demonstrate that their pecoran ruminant ancestor had a family of at least 10 lysozyme c genes, which included at least two pseudogenes. Evolutionary analysis of the ruminant lysozyme c gene sequences demonstrate that each of the four exons of the lysozyme c gene has a unique evolutionary history, indicating that they participated independently in concerted evolution. These analyses also show that episodic changes in the evolutionary constraints on the protein sequences occurred, with lysozyme c genes expressed in the abomasum of the stomach of extant ruminant species showing the greatest levels of selective constraints.

The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs-Therapeutic potential exploration in lung injury

Since 2005,GLP-1 receptor(GLP-IR)agonists(GLP-IRAs)have been developed as therapeutic agents for type 2 diabetes(T2D).GLP-IR is not only expressed in pancreatic islets but also other organs,especially the lung.However,controversy on extra pancreatic GLP-IR expression still needs to be further resolved,utilizing different tools including the use of more reliable GLP-IR antibodies in immune-staining and co-immune-staining.Extra-pancreatic expression of GLP-IR has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs,aiming to repurpose them into therapeutic agents for other disorders.Extensive studies have demonstrated promising anti-infammatory features of GLP-IRAs.Whether those features are directly mediated by GLP-IR expressed in immune cells also remains controversial.Following a brief review on GLP-1 as an incretin hormone and the development of GLP-IRAs as therapeutic agents for T2D,we have summarized our current understanding of the antiinflammatory features of GLP-IRAS and commented on the controversy on extra-pancreatic GLP-IR expression.The main part of this review is a literature discussion on GLP-IRA utilization in animal models with chronic airway diseases and acute lung injuries,including studies on the combined use of mesenchymal stem cell(MSC)based therapy.This is followed by a brief summary.

Commentary:Can FXR serve as a potential target for COVID-19 prevention?

A research article has been accepted by Nature very recently entitled:FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.This is a multiple-author study by 80 scientists from 40 different research units in UK,Germany,Greece,USA,Austria,Sweden,and Norway,with Teresa Brevini as the 1st author and one of the senior authors^(1).The pre-print of this study was posted online back to June 7,2021(bioRxiv).

基因重复在基因选配(gene co-option)过程中的重要作用:对motilin/ghrelin荷尔蒙基因家族及其受体基因家族的进化研究

原先存在的基因经过一些改良可能获得新的属性从而承担新的功能.在分子遗传的层次,这个过程通常伴随基因重复以及基因重复后旁系同源基因的功能分化.本研究探索了基因重复后荷尔蒙、受体间特异性相互作用的演化形成.尽管对这个问题已有相关研究报道,但针对更多个案的研究能帮助我们更好地理解此前已经提出的进化模型的普遍性,可能还有助于发现新的进化模式.基于生物信息学的手段,结合比较基因组学、系统发育学的方法,本研究揭示,ghrelin前体基因和motilin前体基因是由一个祖先基因重复而来,基因重复发生在羊膜动物与两栖动物刚刚分歧之后.与此形成鲜明对照,它们各自的特异性受体却呈现了很不一样的进化历史.GPR39最先分化出来,而后一个祖先基因经连续的基因重复分化为鱼类特异的进化支A,GHSR和MLNR,基因重复发生在射线鳍鱼(ray-finned fish)与四足动物分化之前.ghrelin/GHSR信号系统的功能从鱼类到哺乳动物的进化过程中始终保守.motilin-MLNR之间的特异性相互作用是荷尔蒙基因重复后,MLN与GHRL基因分化之后,在羊膜动物世系中配体与受体协同进化而形成的.该结果提示,在分子水平上,基于保守的分子元件,新的神经内分泌响应模式能够通过基因重复后的基因选配过程形成.基因重复既节俭又极具创造力,为生物多样性的演化提供了物质基础.

Motilin and ghrelin gene experienced episodic evolution during primitive placental mammal evolution

Motilin and ghrelin,members of a structure-function-related hormone family,play important roles in gastrointestinal function,regulation of energy homeostasis and growth hormone secretion.We observed episodic evolution in both of their prehormone gene sequences during primitive placental mammal evolution,during which most of the nonsynonymous changes result in radical substitution.Of note,a functional obestatin hormone might have only originated after this episodic evolution event.Early in placental mammal evolution,a series of biology complexities evolved.At the same time the motilin and ghrelin prehormone genes,which play important roles in several of these processes,experienced episodic evolution with dramatic changes in their coding sequences.These observations suggest that some of the lineage-specific physiological adaptations are due to episodic evolution of the motilin and ghrelin genes.

Comparative population genomics reveals genetic basis underlying body size of domestic chickens

Body size is the most important economic trait for animal production and breeding.Several hundreds of loci have been reported to be associated with growth trait and body weight in chickens.The loci are mapped to large genomic regions due to the low density and limited number of genetic markers in previous studies.Herein,we employed comparative population genomics to identify genetic basis underlying the small body size of Yuanbao chicken(a famous ornamental chicken)based on 89 whole genomes.The most significant signal was mapped to the BMP10 gene,whose expression was upregulated in the Yuanbao chicken.Overexpression of BMP10 induced a significant decrease in body length by inhibiting angiogenic vessel development in zebrafish.In addition,three other loci on chromosomes 1,2,and 24 were also identified to be potentially involved in the development of body size.Our results provide a paradigm shift in identification of novel loci controlling body size variation,availing a fast and efficient strategy.These loci,particularly BMP10,add insights into ongoing research of the evolution of body size under artificial selection and have important implications for future chicken breeding.

motilin,ghrelin基因在哺乳动物进化早期经历插曲式的快速进化

motilin,ghrelin是一对结构相似,功能相关的多肽类荷尔蒙.尽管彼此有所区别,二者都在胃肠消化道行使功能,参与调控能量动态平衡和生长激素的释放.研究发现,编码这两种荷尔蒙前体的基因在哺乳动物进化的早期经历了插曲式的快速进化,期间积累了许多改变氨基酸性质(电荷、极性、及空间容量)的非同义替换.值得注意的是,有功能活性的obestatin多肽荷尔蒙很可能是这一插曲式快速进化后才演化出现的.在哺乳动物进化的早期,发生了一系列复杂的变化,与此同时,我们观察到在相关过程中承担重要功能的motilin,ghrelin基因编码区经历了插曲式的快速进化,提示这可能对世系特异的适应性变化有所贡献.

Gene duplication plays a major role in gene co-option: Studies into the evolution of the motilin/ghrelin family and their receptors

Extant genes can be modified, or 'tinkered with', to provide new roles or new characteristics of these genes. At the genetic level, this often involves gene duplication and specialization of the resulting genes into particular functions. We investigate how ligand-receptor partnerships evolve after gene duplication. While significant work has been conducted in this area, the examination of additional models should help us better understand the proposed models and potentially reveal novel evolutionary patterns and dynamics. We use bioinformatics, comparative genomics and phylogenetic analyses to show that preproghrelin and prepromotilin descended from a common ancestor and that a gene duplication generated these two genes shortly after the divergence of amphibians and amniotes. The evolutionary history of the receptor family differs from that of their cognate ligands. GPR39 diverges first, and an ancestral receptor gives rise to receptors classified as fish-specific clade A, GHSR and MLNR by successive gene duplications occurring before the divergence of tetrapods and ray-finned fish. The ghrelin/GHSR system is maintained and functionally conserved from fish to mammals. Motilin-MLNR specificity must have arisen by ligand-receptor coevolution after the MLN hormone gene diverged from the GHRL gene in the amniote lineage. Conserved molecular machinery can give rise to new neuroendocrine response mechanisms by the co-option of duplicated genes. Gene duplication is both parsimonious and creative in producing elements for evolutionary tinkering and plays a major role in gene co-option, thus aiding the evolution of greater biological complexity.

Letter to the editor: Comment on GLP-1-based drugs and COVID-19 treatment

To the Editor:The coronavirus disease 2019(COVID-19)pandemic is now spreading over 187 countries or territories,taking away hundreds to thousands of lives each day.The lack of specific and effective therapeutics is the major challenge in dealing with patients that are suffering from severe symptoms,i.e.,acute respiratory distress syndrome(ARDS).

Diversification of Sisorid catfishes(Teleostei: Siluriformes)in relation to the orogeny of the Himalayan Plateau

Abstract Sisorid catfishes are primarily limited in distribution to rivers of the Himalayan region and Tibetan Plateau. These species have external morphologies that are adapted for extremely fast-flowing riverine systems. Given the diversity of the group and the above qualities of these catfishes, this lineage serves as an ideal group for inferring the geological history of this region based on their phylogenetic relationships reflecting evolu- tionary history. We sequenced the complete mitochondrial genome and four nuclear genes of representative sisorids distributed across river systems in China. Phylogenetic analyses strongly support the monophyly of the Sisoridae and the glyptosternoids. An analysis of the reconstructed ancestral states derived from inferred genealogical relationships suggests that the evolution of this lineage was accompanied by convergent evolution in morphological traits that were presumably in response to environmental pressure involving the rapid flowing river system that were generated during the uplift of the Tibetan Plateau （UTP）. Molecular dating indicates that the Chinese sisorids and the glyptosternoids originated at the later Miocene （~ 10.9-9.8 Mya）, and with further biogeographic analyses indicates that the species of Sisoridae likely originated from a widely distributed ancestor. Moreover, the divergence of the Sisoridae in China can be divided into two phases consis- tent with the UTP. All of these results indicate that the diversification and dispersal events in this lineage occurred as a result of drainage systems formed during and after the UTP in the late Miocene and Quaternary periods.

Integrative analyses of RNA editing,alternative splicing,and expression of young genes in human brain transcriptome by deep RNA sequencing

Next-generation RNA sequencing has been successfully used for identification of transcript assembly,evaluation of gene expression levels,and detection of post-transcriptional modifications.Despite these large-scale studies,additional comprehensive RNA-seq data from different subregions of the human brain are required to fully evaluate the evolutionary patterns experienced by the human brain transcriptome.Here,we provide a total of 6.5 billion RNA-seq reads fromdifferent subregions of the human brain.A significant correlation was observed between the levels of alternative splicing and RNA editing,which might be explained by a competition between the molecularmachineries responsible for the splicing and editing of RNA.Younghuman protein-coding genesdemonstrate biased expression to the neocortical and non-neocortical regions during evolution on the lineage leading to humans.Wealso found that a significantly greater number of young human protein-coding genes are expressed in the putamen,a tissue that was also observed to have the highest level of RNA-editing activity.The putamen,which previously received little attention,plays an important role in cognitive ability,and our data suggest a potential contribution of the putamen to human evolution.

Ambient Temperature is A Strong Selective Factor Influencing Human Development and Immunity

Solar energy,which is essential for the origin and evolution of all life forms on Earth,can be objectively recorded through attributes such as climatic ambient temperature(CAT),ultraviolet radiation(UVR),and sunlight duration(SD).These attributes have specific geographical variations and may cause different adaptation traits.However,the adaptation profile of each attribute and the selective role of solar energy as a whole during human evolution remain elusive.Here,we performed a genome-wide adaptation study with respect to CAT,UVR,and SD using the Human Genome Diversity Project-Centre Etude Polymorphism Humain(HGDP-CEPH)panel data.We singled out CAT as the most important driving force with the highest number of adaptive loci(6 SNPs at the genome-wide 1×10^(-7)level;401 at the suggestive 1×10^(-5)level).Five of the six genomewide significant adaptation SNPs were successfully replicated in an independent Chinese population(N=1395).The corresponding 316 CAT adaptation genes were mostly involved in development and immunity.In addition,265(84%)genes were related to at least one genome-wide association study(GWAS)-mapped human trait,being significantly enriched in anthropometric loci such as those associated with body mass index(χ^(2);P<0.005),immunity,metabolic syndrome,and cancer(χ^(2);P<0.05).For these adaptive SNPs,balancing selection was evident in Euro-Asians,whereas obvious positive and/or purifying selection was observed in Africans.Taken together,our study indicates that CAT is the most important attribute of solar energy that has driven genetic adaptation in development and immunity among global human populations.It also supports the non-neutral hypothesis for the origin of disease-predisposition alleles in common diseases.

Rapid Evolution of the Mammalian HILS1 Gene and the Nuclear Condensation Process during Mammalian Spermiogenesis

Many genes associated with reproduction show rapid evolution across diverse animal groups, a result commonly due to adaptive evolution driven by positive selection （Swanson and Vacquier, 2002）. Different theories have been proposed to explain the elevated rates of evolution （Swanson and Vacquier, 2002）, including sperm competition, where sperm compete to fertilize eggs leading to the proteins in the sper- matozoa adaptively evolving to increase their ability to fertilize eggs; sexual conflict, where the egg experiences a loss of fitness when sperm are too abundant; sexual selection, where eggs bind sperm carrying adaptive alleles （Palumbi, 1999）; and cryptic female choice （reviewed in Swanson and Vacquier, 2002）.

Fibroblast growth factor 21 and dietary interventions: what we know and what we need to know next

Dietary interventions include the change of dietary styles,such as fasting and dietary or nutrient restrictions;or the addition of plant-derived compounds(such as polyphenols known as curcumin,resveratrol,or anthocyanin,or other nutraceuticals)into the diet.During the past a few decades,large number of studies have demonstrated therapeutic activities of these dietary interventions on metabolic and other diseases in human subjects or various animal models.Mechanisms underlying those versatile therapeutic activities,however,remain largely unclear.Interestingly,recent studies have shown that fibroblast growth factor 21(FGF21),a liver-derived hormone or hepatokine,mediates metabolic beneficial effects of certain dietary polyphenols as well as protein restriction.Here I have briefly summarized functions of FGF21,highlighted related dietary interventions,and presented literature discussions on role of FGF21 in mediating function of dietary polyphenol intervention and protein restriction.This is followed by presenting my perspective view,with the involvement of gut microbiota.It is anticipated that further breakthroughs in this field in the near future will facilitate conceptual merge of classical medicine and modern medicine.

Role of cyclic AMP signaling in the production and function of the incretin hormone glucagon-like peptide-1

Pancreatic cells express the proglucagon gene （ gcg ） and thereby produce the peptide hormone glucagon , which stimulates hepa tic glucose production and thereby increases blood glucose levels. The same gcg gene is also expressed in the intesti nal endocrine L cells and certain neural cells in the brain. In the gut, gcg expression leads to the production of glucagon-like peptide-1 （GLP-1）. This incretin hormone stimulates insulin secretion when blood glucose, level is high. In addition, GLP-1 stimulates pancreatic cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells.