Browsing by Subject "Mammals"
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Item Open Access 29 mammalian genomes reveal novel exaptations of mobile elements for likely regulatory functions in the human genome.(PloS one, 2012-01) Lowe, Craig B; Haussler, DavidRecent research supports the view that changes in gene regulation, as opposed to changes in the genes themselves, play a significant role in morphological evolution. Gene regulation is largely dependent on transcription factor binding sites. Researchers are now able to use the available 29 mammalian genomes to measure selective constraint at the level of binding sites. This detailed map of constraint suggests that mammalian genomes co-opt fragments of mobile elements to act as gene regulatory sequence on a large scale. In the human genome we detect over 280,000 putative regulatory elements, totaling approximately 7 Mb of sequence, that originated as mobile element insertions. These putative regulatory regions are conserved non-exonic elements (CNEEs), which show considerable cross-species constraint and signatures of continued negative selection in humans, yet do not appear in a known mature transcript. These putative regulatory elements were co-opted from SINE, LINE, LTR and DNA transposon insertions. We demonstrate that at least 11%, and an estimated 20%, of gene regulatory sequence in the human genome showing cross-species conservation was co-opted from mobile elements. The location in the genome of CNEEs co-opted from mobile elements closely resembles that of CNEEs in general, except in the centers of the largest gene deserts where recognizable co-option events are relatively rare. We find that regions of certain mobile element insertions are more likely to be held under purifying selection than others. In particular, we show 6 examples where paralogous instances of an often co-opted mobile element region define a sequence motif that closely matches a transcription factor's binding profile.Item Open Access A high-resolution map of human evolutionary constraint using 29 mammals.(Nature, 2011-10-12) Lindblad-Toh, Kerstin; Garber, Manuel; Zuk, Or; Lin, Michael F; Parker, Brian J; Washietl, Stefan; Kheradpour, Pouya; Ernst, Jason; Jordan, Gregory; Mauceli, Evan; Ward, Lucas D; Lowe, Craig B; Holloway, Alisha K; Clamp, Michele; Gnerre, Sante; Alföldi, Jessica; Beal, Kathryn; Chang, Jean; Clawson, Hiram; Cuff, James; Di Palma, Federica; Fitzgerald, Stephen; Flicek, Paul; Guttman, Mitchell; Hubisz, Melissa J; Jaffe, David B; Jungreis, Irwin; Kent, W James; Kostka, Dennis; Lara, Marcia; Martins, Andre L; Massingham, Tim; Moltke, Ida; Raney, Brian J; Rasmussen, Matthew D; Robinson, Jim; Stark, Alexander; Vilella, Albert J; Wen, Jiayu; Xie, Xiaohui; Zody, Michael C; Broad Institute Sequencing Platform and Whole Genome Assembly Team; Baldwin, Jen; Bloom, Toby; Chin, Chee Whye; Heiman, Dave; Nicol, Robert; Nusbaum, Chad; Young, Sarah; Wilkinson, Jane; Worley, Kim C; Kovar, Christie L; Muzny, Donna M; Gibbs, Richard A; Baylor College of Medicine Human Genome Sequencing Center Sequencing Team; Cree, Andrew; Dihn, Huyen H; Fowler, Gerald; Jhangiani, Shalili; Joshi, Vandita; Lee, Sandra; Lewis, Lora R; Nazareth, Lynne V; Okwuonu, Geoffrey; Santibanez, Jireh; Warren, Wesley C; Mardis, Elaine R; Weinstock, George M; Wilson, Richard K; Genome Institute at Washington University; Delehaunty, Kim; Dooling, David; Fronik, Catrina; Fulton, Lucinda; Fulton, Bob; Graves, Tina; Minx, Patrick; Sodergren, Erica; Birney, Ewan; Margulies, Elliott H; Herrero, Javier; Green, Eric D; Haussler, David; Siepel, Adam; Goldman, Nick; Pollard, Katherine S; Pedersen, Jakob S; Lander, Eric S; Kellis, ManolisThe comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.Item Open Access Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.(Cell research, 2023-07) Pan, Christopher C; Maeso-Díaz, Raquel; Lewis, Tylor R; Xiang, Kun; Tan, Lianmei; Liang, Yaosi; Wang, Liuyang; Yang, Fengrui; Yin, Tao; Wang, Calvin; Du, Kuo; Huang, De; Oh, Seh Hoon; Wang, Ergang; Lim, Bryan Jian Wei; Chong, Mengyang; Alexander, Peter B; Yao, Xuebiao; Arshavsky, Vadim Y; Li, Qi-Jing; Diehl, Anna Mae; Wang, Xiao-FanCellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.Item Open Access Behavioural and physiological limits to vision in mammals.(Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2017-04) Field, Greg D; Sampath, Alapakkam PHuman vision is exquisitely sensitive-a dark-adapted observer is capable of reliably detecting the absorption of a few quanta of light. Such sensitivity requires that the sensory receptors of the retina, rod photoreceptors, generate a reliable signal when single photons are absorbed. In addition, the retina must be able to extract this information and relay it to higher visual centres under conditions where very few rods signal single-photon responses while the majority generate only noise. Critical to signal transmission are mechanistic optimizations within rods and their dedicated retinal circuits that enhance the discriminability of single-photon responses by mitigating photoreceptor and synaptic noise. We describe behavioural experiments over the past century that have led to the appreciation of high sensitivity near absolute visual threshold. We further consider mechanisms within rod photoreceptors and dedicated rod circuits that act to extract single-photon responses from cellular noise. We highlight how these studies have shaped our understanding of brain function and point out several unresolved questions in the processing of light near the visual threshold.This article is part of the themed issue 'Vision in dim light'.Item Open Access Body Mass and Tail Girth Predict Hibernation Expression in Captive Dwarf Lemurs.(Physiological and biochemical zoology : PBZ, 2022-03) Blanco, Marina B; Greene, Lydia K; Klopfer, Peter H; Lynch, Danielle; Browning, Jenna; Ehmke, Erin E; Yoder, Anne DAbstractHibernation, a metabolic strategy, allows individuals to reduce energetic demands in times of energetic deficits. Hibernation is pervasive in nature, occurring in all major mammalian lineages and geographical regions; however, its expression is variable across species, populations, and individuals, suggesting that trade-offs are at play. Whereas hibernation reduces energy expenditure, energetically expensive arousals may impose physiological burdens. The torpor optimization hypothesis posits that hibernation should be expressed according to energy availability. The greater the energy surplus, the lower the hibernation output. The thrifty female hypothesis, a variation of the torpor optimization hypothesis, states that females should conserve more energy because of their more substantial reproductive costs. Contrarily, if hibernation's benefits offset its costs, hibernation may be maximized rather than optimized (e.g., hibernators with greater fat reserves could afford to hibernate longer). We assessed torpor expression in captive dwarf lemurs, primates that are obligate, seasonal, and tropical hibernators. Across 4.5 mo in winter, we subjected eight individuals at the Duke Lemur Center to conditions conducive to hibernation, recorded estimates of skin temperature hourly (a proxy for torpor), and determined body mass and tail fat reserves bimonthly. Across and between consecutive weigh-ins, heavier dwarf lemurs spent less time in torpor and lost more body mass. At equivalent body mass, females spent more time torpid and better conserved energy than did males. Although preliminary, our results support the torpor optimization and thrifty female hypotheses, suggesting that individuals optimize rather than maximize torpor according to body mass. These patterns are consistent with hibernation phenology in Madagascar, where dwarf lemurs hibernate longer in more seasonal habitats.Item Embargo Camera trap distance sampling in tropical forests: assessing drivers of terrestrial wildlife abundance in Ivindo National Park, Gabon(2024-04-26) White, ElizabethThe loss of wildlife species and populations, termed defaunation, significantly impacts biodiversity and vertebrate community structure. Terrestrial mammals are especially vulnerable to anthropogenic activities such as habitat destruction, overhunting, and exploitation. Extractive industries are increasing in scale in central African forests, thereby increasing human access to forests and leaving a potential for defaunation. Camera traps are reliable, effective, and non-intrusive technologies to monitor and assess wildlife populations. Using camera trap distance sampling, we estimated wildlife density, capture rates, and species richness to evaluate drivers of wildlife abundance and defaunation in Ivindo National Park, Gabon. We present one of the first uses of camera trap distance sampling to estimate the density of multiple species in a tropical forest. From these estimates, we have baseline population data for this region and can identify factors influencing their populations to inform collaborative conservation and wildlife management efforts.Item Open Access Cell type- and species-specific host responses to Toxoplasma gondii and its near relatives.(International journal for parasitology, 2020-05-11) Wong, Zhee S; Borrelli, Sarah L Sokol; Coyne, Carolyn C; Boyle, Jon PToxoplasma gondii is remarkably unique in its ability to successfully infect vertebrate hosts from multiple phyla and can successfully infect most cells within these organisms. The infection outcome in each of these species is determined by the complex interaction between parasite and host genotype. As techniques to quantify global changes in cell function become more readily available and precise, new data are coming to light about how (i) different host cell types respond to parasitic infection and (ii) different parasite species impact the host. Here we focus on recent studies comparing the response to intracellular parasitism by different cell types and insights into understanding host-parasite interactions from comparative studies on T. gondii and its close extant relatives.Item Open Access China's endemic vertebrates sheltering under the protective umbrella of the giant panda.(Conservation biology : the journal of the Society for Conservation Biology, 2016-04) Li, Binbin V; Pimm, Stuart LThe giant panda attracts disproportionate conservation resources. How well does this emphasis protect other endemic species? Detailed data on geographical ranges are not available for plants or invertebrates, so we restrict our analyses to 3 vertebrate taxa: birds, mammals, and amphibians. There are gaps in their protection, and we recommend practical actions to fill them. We identified patterns of species richness, then identified which species are endemic to China, and then which, like the panda, live in forests. After refining each species' range by its known elevational range and remaining forest habitats as determined from remote sensing, we identified the top 5% richest areas as the centers of endemism. Southern mountains, especially the eastern Hengduan Mountains, were centers for all 3 taxa. Over 96% of the panda habitat overlapped the endemic centers. Thus, investing in almost any panda habitat will benefit many other endemics. Existing panda national nature reserves cover all but one of the endemic species that overlap with the panda's distribution. Of particular interest are 14 mammal, 20 bird, and 82 amphibian species that are inadequately protected. Most of these species the International Union for Conservation of Nature currently deems threatened. But 7 mammal, 3 bird, and 20 amphibian species are currently nonthreatened, yet their geographical ranges are <20,000 km(2) after accounting for elevational restriction and remaining habitats. These species concentrate mainly in Sichuan, Yunnan, Nan Mountains, and Hainan. There is a high concentration in the east Daxiang and Xiaoxiang Mountains of Sichuan, where pandas are absent and where there are no national nature reserves. The others concentrate in Yunnan, Nan Mountains, and Hainan. Here, 10 prefectures might establish new protected areas or upgrade local nature reserves to national status.Item Open Access Deep-tissue SWIR imaging using rationally designed small red-shifted near-infrared fluorescent protein.(Nature methods, 2023-01) Oliinyk, Olena S; Ma, Chenshuo; Pletnev, Sergei; Baloban, Mikhail; Taboada, Carlos; Sheng, Huaxin; Yao, Junjie; Verkhusha, Vladislav VApplying rational design, we developed 17 kDa cyanobacteriochrome-based near-infrared (NIR-I) fluorescent protein, miRFP718nano. miRFP718nano efficiently binds endogenous biliverdin chromophore and brightly fluoresces in mammalian cells and tissues. miRFP718nano has maximal emission at 718 nm and an emission tail in the short-wave infrared (SWIR) region, allowing deep-penetrating off-peak fluorescence imaging in vivo. The miRFP718nano structure reveals the molecular basis of its red shift. We demonstrate superiority of miRFP718nano-enabled SWIR imaging over NIR-I imaging of microbes in the mouse digestive tract, mammalian cells injected into the mouse mammary gland and NF-kB activity in a mouse model of liver inflammation.Item Open Access Dynamic evolution of the alpha (α) and beta (β) keratins has accompanied integument diversification and the adaptation of birds into novel lifestyles.(BMC Evol Biol, 2014-12-12) Greenwold, Matthew J; Bao, Weier; Jarvis, Erich D; Hu, Haofu; Li, Cai; Gilbert, M Thomas P; Zhang, Guojie; Sawyer, Roger HBACKGROUND: Vertebrate skin appendages are constructed of keratins produced by multigene families. Alpha (α) keratins are found in all vertebrates, while beta (β) keratins are found exclusively in reptiles and birds. We have studied the molecular evolution of these gene families in the genomes of 48 phylogenetically diverse birds and their expression in the scales and feathers of the chicken. RESULTS: We found that the total number of α-keratins is lower in birds than mammals and non-avian reptiles, yet two α-keratin genes (KRT42 and KRT75) have expanded in birds. The β-keratins, however, demonstrate a dynamic evolution associated with avian lifestyle. The avian specific feather β-keratins comprise a large majority of the total number of β-keratins, but independently derived lineages of aquatic and predatory birds have smaller proportions of feather β-keratin genes and larger proportions of keratinocyte β-keratin genes. Additionally, birds of prey have a larger proportion of claw β-keratins. Analysis of α- and β-keratin expression during development of chicken scales and feathers demonstrates that while α-keratins are expressed in these tissues, the number and magnitude of expressed β-keratin genes far exceeds that of α-keratins. CONCLUSIONS: These results support the view that the number of α- and β-keratin genes expressed, the proportion of the β-keratin subfamily genes expressed and the diversification of the β-keratin genes have been important for the evolution of the feather and the adaptation of birds into multiple ecological niches.Item Open Access Effects of land use, habitat characteristics, and small mammal community composition on Leptospira prevalence in northeast Madagascar.(PLoS neglected tropical diseases, 2020-12-31) Herrera, James P; Wickenkamp, Natalie R; Turpin, Magali; Baudino, Fiona; Tortosa, Pablo; Goodman, Steven M; Soarimalala, Voahangy; Ranaivoson, Tamby Nasaina; Nunn, Charles LHuman activities can increase or decrease risks of acquiring a zoonotic disease, notably by affecting the composition and abundance of hosts. This study investigated the links between land use and infectious disease risk in northeast Madagascar, where human subsistence activities and population growth are encroaching on native habitats and the associated biota. We collected new data on pathogenic Leptospira, which are bacteria maintained in small mammal reservoirs. Transmission can occur through close contact, but most frequently through indirect contact with water contaminated by the urine of infected hosts. The probability of infection and prevalence was compared across a gradient of natural moist evergreen forest, nearby forest fragments, flooded rice and other types of agricultural fields, and in homes in a rural village. Using these data, we tested specific hypotheses for how land use alters ecological communities and influences disease transmission. The relative abundance and proportion of exotic species was highest in the anthropogenic habitats, while the relative abundance of native species was highest in the forested habitats. Prevalence of Leptospira was significantly higher in introduced compared to endemic species. Lastly, the probability of infection with Leptospira was highest in introduced small mammal species, and lower in forest fragments compared to other habitat types. Our results highlight how human land use affects the small mammal community composition and in turn disease dynamics. Introduced species likely transmit Leptospira to native species where they co-occur, and may displace the Leptospira species naturally occurring in Madagascar. The frequent spatial overlap of people and introduced species likely also has consequences for public health.Item Open Access Encephalic Arterial Canals and Their Functional Significance(2020) Harrington, Arianna RoseA fundamental question in evolutionary anthropology asks how the human brain evolved. Characterized as relatively large and energetically taxing, numerous hypotheses have been proposed to explain how the human brain has evolved to its current size through tradeoffs to improve fitness by increasing behavioral complexity while minimizing caloric costs. The comparative method has been a key approach to testing these hypotheses, but a major hinderance has been the lack of directly measured brain metabolic rates for many comparable species. This dissertation takes an anatomical approach to predict brain metabolic rates from osteological specimens, utilizing the following proposed relationships: 1) that the brain is supplied by arteries (encephalic arteries) which travel through bony canals, 2) the size of the canal reflects the size of the artery within, 3) the size of the artery is proportional to blood flow rate, and 4) encephalic blood flow rate is proportional to brain metabolic rate.
Radii of encephalic arterial canals of a growth series of humans (n= 305 individuals) and of adult mammals (n=329 species) were measured from cadaveric computed tomography scans and osteological specimens, and blood flow rates were predicted using anatomical and physiological equations previously published in the literature. The major goals of this dissertation were to better evaluate the use of encephalic arterial canals in the prediction of brain metabolism and to characterize how mammals vary in their brain size, encephalic blood flow rates, brain metabolism, and whole body metabolism to test hypotheses which have been proposed to explain human and primate brain evolution.
The first research chapter finds that the blood flow rates predicted from the sizes of the encephalic arterial canals tracks the changes in brain metabolism during human growth. The second research chapter finds that patterns of variation in predicted blood flow rate, brain size, and body size across primates and other mammals suggest that predicted blood flow rates are reflecting the metabolic substrate supply needs of the brain. Furthermore, evidence is presented that the relative metabolic rate of the brains of primates is lower than many mammals of comparable brain size. The third research chapter utilizes phylogenetically informed Bayesian methods to predict brain metabolic rates from predicted blood flow rates, and finds that humans devote a high (although not always the highest) proportion of their basal metabolic rate (BMR) and total energy expenditure (TEE) to brain metabolism, even compared to other primates. In turn, primates tend to have elevated predicted brain metabolic rates relative to their BMR and TEE compared to most other mammal groups.
Combined, the evidence presented within this dissertation suggests that 1) osteologically derived predictions of blood flow rates present a viable alternative to understanding patterns of variation in brain metabolic rates during human ontogeny and among mammalian samples, and 2) compared to many other mammals, humans and other primates have evolved physiological mechanisms to reduce the mass-specific metabolic rate of their relatively large, energy-hungry brains.
Item Open Access Endangered species hold clues to human evolution.(The Journal of heredity, 2010-07) Lowe, Craig B; Bejerano, Gill; Salama, Sofie R; Haussler, DavidWe report that 18 conserved, and by extension functional, elements in the human genome are the result of retroposon insertions that are evolving under purifying selection in mammals. We show evidence that 1 of the 18 elements regulates the expression of ASXL3 during development by encoding an alternatively spliced exon that causes nonsense-mediated decay of the transcript. The retroposon that gave rise to these functional elements was quickly inactivated in the mammalian ancestor, and all traces of it have been lost due to neutral decay. However, the tuatara has maintained a near-ancestral version of this retroposon in its extant genome, which allows us to connect the 18 human elements to the evolutionary events that created them. We propose that conservation efforts over more than 100 years may not have only prevented the tuatara from going extinct but could have preserved our ability to understand the evolutionary history of functional elements in the human genome. Through simulations, we argue that species with historically low population sizes are more likely to harbor ancient mobile elements for long periods of time and in near-ancestral states, making these species indispensable in understanding the evolutionary origin of functional elements in the human genome.Item Open Access Environmental fate and effects of Bacillus thuringiensis (Bt) proteins from transgenic crops: a review.(Journal of agricultural and food chemistry, 2005-06) Clark, BW; Phillips, TA; Coats, JRThis paper reviews the scientific literature addressing the environmental fate and nontarget effects of the Cry protein toxins from Bacillus thuringiensis (Bt), specifically resulting from their expression in transgenic crops. Published literature on analytical methodologies for the detection and quantification of the Cry proteins in environmental matrices is also reviewed, with discussion of the adequacy of the techniques for determining the persistence and mobility of the Bt proteins. In general, assessment of the nontarget effects of Bt protein toxins indicates that there is a low level of hazard to most groups of nontarget organisms, although some investigations are of limited ecological relevance. Some published reports on the persistence of the proteins in soil show short half-lives, whereas others show low-level residues lasting for many months. Improvements in analytical methods will allow a more complete understanding of the fate and significance of Bt proteins in the environment.Item Open Access Evidence for a single loss of mineralized teeth in the common avian ancestor.(Science, 2014-12-12) Meredith, Robert W; Zhang, Guojie; Gilbert, M Thomas P; Jarvis, Erich D; Springer, Mark SEdentulism, the absence of teeth, has evolved convergently among vertebrates, including birds, turtles, and several lineages of mammals. Instead of teeth, modern birds (Neornithes) use a horny beak (rhamphotheca) and a muscular gizzard to acquire and process food. We performed comparative genomic analyses representing lineages of nearly all extant bird orders and recovered shared, inactivating mutations within genes expressed in both the enamel and dentin of teeth of other vertebrate species, indicating that the common ancestor of modern birds lacked mineralized teeth. We estimate that tooth loss, or at least the loss of enamel caps that provide the outer layer of mineralized teeth, occurred about 116 million years ago.Item Open Access Evolution of networks and sequences in eukaryotic cell cycle control.(Philos Trans R Soc Lond B Biol Sci, 2011-12-27) Cross, Frederick R; Buchler, Nicolas E; Skotheim, Jan MThe molecular networks regulating the G1-S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.Item Open Access Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication.(Science signaling, 2022-10) Yaron, Tomer M; Heaton, Brook E; Levy, Tyler M; Johnson, Jared L; Jordan, Tristan X; Cohen, Benjamin M; Kerelsky, Alexander; Lin, Ting-Yu; Liberatore, Katarina M; Bulaon, Danielle K; Van Nest, Samantha J; Koundouros, Nikos; Kastenhuber, Edward R; Mercadante, Marisa N; Shobana-Ganesh, Kripa; He, Long; Schwartz, Robert E; Chen, Shuibing; Weinstein, Harel; Elemento, Olivier; Piskounova, Elena; Nilsson-Payant, Benjamin E; Lee, Gina; Trimarco, Joseph D; Burke, Kaitlyn N; Hamele, Cait E; Chaparian, Ryan R; Harding, Alfred T; Tata, Aleksandra; Zhu, Xinyu; Tata, Purushothama Rao; Smith, Clare M; Possemato, Anthony P; Tkachev, Sasha L; Hornbeck, Peter V; Beausoleil, Sean A; Anand, Shankara K; Aguet, François; Getz, Gad; Davidson, Andrew D; Heesom, Kate; Kavanagh-Williamson, Maia; Matthews, David A; tenOever, Benjamin R; Cantley, Lewis C; Blenis, John; Heaton, Nicholas SMultiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.Item Open Access How to protect half of Earth to ensure it protects sufficient biodiversity.(Science advances, 2018-08-29) Pimm, Stuart L; Jenkins, Clinton N; Li, Binbin VIt is theoretically possible to protect large fractions of species in relatively small regions. For plants, 85% of species occur entirely within just over a third of the Earth's land surface, carefully optimized to maximize the species captured. Well-known vertebrate taxa show similar patterns. Protecting half of Earth might not be necessary, but would it be sufficient given the current trends of protection? The predilection of national governments is to protect areas that are "wild," that is, typically remote, cold, or arid. Unfortunately, those areas often hold relatively few species. Wild places likely afford the easier opportunities for the future expansion of protected areas, with the expansion into human-dominated landscapes the greater challenge. We identify regions that are not currently protected, but that are wild, and consider which of them hold substantial numbers of especially small-ranged vertebrate species. We assess how successful the strategy of protecting the wilder half of Earth might be in conserving biodiversity. It is far from sufficient. (Protecting large wild places for reasons other than biodiversity protection, such as carbon sequestration and other ecosystem services, might still have importance.) Unexpectedly, we also show that, despite the bias in establishing large protected areas in wild places to date, numerous small protected areas are in biodiverse places. They at least partially protect significant fractions of especially small-ranged species. So, while a preoccupation with protecting large areas for the sake of getting half of Earth might achieve little for biodiversity, there is more progress in protecting high-biodiversity areas than currently appreciated. Continuing to prioritize the right parts of Earth, not just the total area protected, is what matters for biodiversity.Item Open Access Intercellular Signaling Pathways in the Initiation of Mammalian Forebrain Development(2007-05-03T18:54:17Z) Yang, Yu-PingThe Spemann organizer in amphibians gives rise to the anterior mesendoderm (AME) and is capable of inducing neural tissues. This inductive activity is thought to occur largely via the antagonism of Bone Morphogenetic Protein (BMP) signaling in the organizer. In the mouse, BMP antagonists Chordin and Noggin function redundantly in the AME and are required during forebrain maintenance. However, the timing of forebrain initiation and the function of BMP antagonism in forebrain initiation remained unclear prior to this study. In addition, the Transforming Growth Factor β (TGFβ) ligand Nodal patterns the forebrain via its function in the anterior primitive streak (APS), the precursor tissue of the AME. Whether BMP and Nodal signaling pathways interact has not been previously investigated. The goal of this dissertation was to investigate the cellular and molecular mechanisms involved in early mammalian forebrain establishment by embryonic and genetic manipulations. This study determined that forebrain initiation occurs during early gastrulation and requires signals from the AVE and AME. The AVE was identified as a source of active BMP antagonism in vivo, and the BMP antagonism supplied by exogenous tissues was capable to promote forebrain initiation and maintenance in the murine ectoderm. It is likely that BMP antagonism enhances forebrain gene expression via inhibiting posteriorization. This study further identified a possible crosstalk between BMP and Nodal signaling. Loss of Chordin or Noggin in combination with heterozygosity for Nodal or Smad3 results in holoprosencephaly. Molecular analyses suggest that the BMP-Nodal interaction occurs in the APS and/or the AME. Failure of this interaction results in an imbalance of BMP and Nodal signal levels that devastate APS and AME patterning during early forebrain establishment, ultimately leading to holoprosencephaly in mid-gestation. This interaction is likely to occur extracellularly, possibly by formation of a BMP-Nodal heteromeric complex. Furthermore, the spatiotemporal expression of phospho-Smad1/5/8, an effector of BMP signaling pathway, was characterized during early mouse embryogenesis. Distribution of phospho-Smad1/5/8 serves as a faithful readout of BMP signaling activity and helps to better understand how BMPs are involved in patterning early embryos. The implication of phospho-Smad1/5/8 expression in both wildtype and mutant embryos is also discussed.Item Open Access Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta.(Scientific reports, 2022-06) Sugimoto, Jun; Schust, Danny J; Yamazaki, Tomomi; Kudo, YoshikiSuppressyn (SUPYN) is the first host-cell encoded mammalian protein shown to inhibit cell-cell fusion. Its expression is restricted to the placenta, where it negatively regulates syncytia formation in villi. Since its chromosomal localization overlaps with the Down syndrome critical region and the TS21 placenta is characterized by delayed maturation of cytotrophoblast cells and reduced syncytialization, we hypothesized a potential link between changes in SUPYN expression and morphologic abnormalities in the TS21 placenta. Here we demonstrate that an increase in chromosomal copy number in the TS21 placenta is associated with: (1) reduced fusion of cytotrophoblast cells into syncytiotrophoblast in vivo, (2) increased SUPYN transcription, translation and secretion in vivo, (3) increased SUPYN/syncytin-1 receptor degradation in vivo, (4) increased SUPYN transcription and secretion ex vivo, (5) decreased cytotrophoblast cell fusion ex vivo, and (6) reciprocal response of changes in SUPYN and CGB in TS21 placental cells ex vivo. These data suggest direct links between immature placentation in Down syndrome and increased SUPYN. Finally, we report a significant increase in secreted SUPYN concentration in maternal serum in women with pregnancies affected by Down syndrome, suggesting that SUPYN may be useful as an alternate or additional diagnostic marker for this disease.