bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synaptojanin1 deficiency upregulates basal level autophagosome formation in astrocytes
Authors: Pan Ping-Yue , Zhu Justin , Rizvi Asma , Zhu Xinyu , Tanaka Hikari , Dreyfus Cheryl F. 
Published: January 2021

AbstractMacroautophagy (hereafter, autophagy) dysregulation is implicated in multiple neurological disorders. While the autophagy pathways are heavily investigated in heterologous cells and neurons, how autophagy is regulated in the astrocyte, the most abundant cell type in the mammalian brain, is less understood. Here we report that Synaptojanin1 (Synj1), a neuron enriched lipid phosphatase, is expressed in low levels in astrocytes and represses autophagy at the basal level. Synj1 is encoded by theSynj1gene, whose missense mutations are linked to Parkinsonism with seizure. While the best-known role of Synj1 is to facilitate synaptic vesicle recycling, recent studies suggest that Synj1 also regulates autophagy. Our previous study using theSynj1haploinsufficient (Synj1+/−) mouse demonstrated thatSynj1deficiency was associated with an age-dependent autophagy impairment in multiple brain regions. We now use cultured astrocytes fromSynj1deficient mice to investigate its role in astrocyte autophagy. We demonstrate that Synj1 deficient astrocytes exhibit increased LC3 puncta, which is more pronounced when lysosomal acidification is blocked. The increased autophagosome formation is accompanied by reduced autophagy substrate, p62, but an insensitivity to starvation induced autophagy clearance. Moreover, we show, for the first time, that the Parkinsonism associated R839C mutation impacts astrocyte autophagy. The profound impact of this mutation on Synj1’s phosphatase functions results in elevated basal level autophagosome formation and clearance that mimicsSynj1deletion. We find that energy sensing molecules, including mTOR and AMPK, are altered inSynj1deficient astrocytes, which may contribute to the enhanced basal level autophagy.
The collapse of genetic incompatibilities in hybridizing populations
Authors: Xiong Tianzhu , Mallet James 
Published: January 2021

AbstractDiverging species are often genetically incompatible upon hybridization. Such incompatibilities are considered important in keeping the integrity of species from the disruption of hybrids. However, recent empirical work has shown that not all incompatibilities are gene-flow-proof, and they can collapse due to continuing hybridization. Counterintuitively, many studies found that incompatible alleles are already segregating within species, whereas they should go extinct quickly in a randomly mating population. Due to the complexity of multilocus epistasis, few general principles explain behaviors of incompatibilities under gene flow both within and between species. In the current work, we argue that the redundancy of genetic mechanisms can robustly determine the dynamics of intrinsic incompatibilities under gene flow. While higher genetic redundancy decreases the stability of incompatibilities during hybridization, it also increases the tolerance of incompatibility polymorphism within each species. We treat two general classes of incompatibilities. In the redundant class, similar to the classical Dobzhansky-Muller system, the collapse is continuous and eventually approaches quasi-neutral polymorphism between broadly-sympatric species, often as a result of isolation-by-distance. In the non-redundant class, analogous to the shifting-balance process, incompatibilities collapse abruptly with spatial traveling waves. We obtained simulated and analytical results for several incompatibility models to demonstrate the differences between the two classes. As both redundant and non-redundant genetic mechanisms of incompatibilities are common, the proposed conceptual framework may help understand the abundance of incompatibilities in natural populations.
Explosive diversification following continental colonizations by canids
Authors: Porto Lucas M. V. , Etienne Rampal S. , Maestri Renan 
Published: January 2021

AbstractColonization of a new environment may trigger an explosive radiation process, defined as an accelerated accumulation of species in a short period of time. However, how often colonization events trigger explosive radiations is still an open question. We studied the worldwide dispersal of the subfamily Caninae, to investigate whether the invasion of new continents resulted in explosive radiations. We used a combination of phylogenetic analyses and ancestral area reconstructions to estimate ancestral ranges of 56 extant and extinct species of Caninae, as well as variation in speciation and extinction rates through time and across clades. Our findings indicate that canids experienced an explosive radiation event when lineages were able to cross the Bering Strait and the Isthmus of Panama to reach Eurasia and South America, respectively, around 11 million years ago. This large number of species arising in a short period of time suggests that canids experienced ecological opportunity events within the new areas, implying that the differences in the ecological settings between continents may be responsible for the variation in clade dynamics. We argue that interaction with other carnivores probably also affected the diversification dynamics of canids.
Anti-stress effects of the glucagon-like peptide-1 receptor agonist liraglutide in zebrafish
Authors: Bertelli Pablo R. , Mocelin Ricieri , Marcon Matheus , Sachett Adrieli , Gomez Rosane , Rosa Adriane R. , Herrmann Ana P. , Piato Angelo 
Published: January 2021

ABSTRACTStress-related disorders are extremely harmful and cause significant impacts on the individual and society. Despite the limited evidence regarding glucagon-like peptide-1 receptor (GLP-1R) and mental disorders, a few clinical and preclinical studies suggest that modulating this system could improve symptoms of stress-related disorders. This study aimed to investigate the effects of liraglutide, a GLP-1R agonist, on neurobehavioral phenotypes and brain oxidative status in adult zebrafish. Acute liraglutide promoted anxiolytic-like effects in the light/dark test, while chronic treatment blocked the impact of unpredictable chronic stress on behavioral and physiological parameters. Taken together, our study demonstrates that liraglutide is active on zebrafish brain and may counteract some of the effects induced by stress. More studies are warranted to further elucidate the potential of GLP-1R agonists for the management of brain disorders.
In vivoCGG repeat RNA binding protein capture identifies RAN translation modifiers and suppressors of repeat toxicity
Authors: Malik Indranil , Tseng Yi-Ju , Wright Shannon E. , Zheng Kristina , Ramaiyer Prithika , Green Katelyn M. , Todd Peter K. 
Published: January 2021

AbstractFragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a transcribed CGG repeat expansion in the 5’ UTR ofFMR1. Expanded CGG repeat RNAs both sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic homopolymeric peptides. RBPs that interact with CGG repeats may play a pivotal role in foci formation and/or RAN translation. Here we employed a CGG repeat RNA-tagging system to capture and identify CGG repeat binding RBPsin vivounder different cellular conditions. We found that several SR (serine/arginine-rich domain) proteins interact with CGG repeat RNAs basally and under cellular stress. These same proteins strongly modify toxicity in a Drosophila model of FXTAS, improving eye degeneration and survival. Furthermore, genetic or pharmacological targeting of the serine/arginine protein kinases (SRPKs) suppresses RAN translation in cellular reporters and toxicity in fly models of FXTAS and C9orf72 ALS/FTD. Finally, pharmacological targeting of SRPK1 supressed CGG repeat toxicity and enhanced survival in rodent neurons. Taken together, these findings demonstrate roles for CGG repeat RNA binding proteins in both RAN translation and repeat toxicity and suggest SRPK inhibition may serve as a possible therapeutic strategy in repeat expansion disorders.
The repertoire of testicular extracellular vesicles cargoes and their involvement in inter-compartmental communication required for spermatogenesis
Authors: Choy Kathleen Hoi Kei , Chan Sze Yan , Lam William , Jin Jing , Zheng Tingting , Yu Sidney Siubun , Wang Weiping , Li Linxian , Xie Gangcai , Yim Howard Chi Ho , Chen Hao , Fok Ellis Kin Lam 
Published: January 2021

ABSTRACTExtracellular vesicles (EVs) secreted by the epididymis and prostate are involved in sperm functions and epigenetic inheritance. However, the EVs in the testis remains unexplored. Here, we have established a testis dissociation protocol that allows the isolation of testicular EVs by minimizing the disruption of fragile sperm cells. We showed that testicular EVs were specifically and efficiently uptaken by somatic cells and germ cells in both interstitial space and seminiferous tubules compartments, including the spermatozoa. We profiled the proteome of testicular EVs and probed the cell types that release them. Moreover, we sequenced the small RNAs cargos of testicular EVs and identified sets of small non-coding RNAs that were overlooked in the testis transcriptome. Selected miRNA candidates in testicular EVs were found in sperm RNA payload and demonstrated specific resistance towards ribonuclease A independent of the vesicle membrane. Small molecule inhibition of EVs secretion increased the apoptosis of germ cells via inter-compartmental communication. Together, our study has provided valuable resources on the cargoes of testicular EVs and revealed the inter-compartmental communication that regulates spermatogenesis and may implicate in paternal inheritance.
AncestralClust: Clustering of Divergent Nucleotide Sequences by Ancestral Sequence Reconstruction using Phylogenetic Trees
Authors: Pipes Lenore , Nielsen Rasmus 
Published: January 2021

AbstractMotivationClustering is a fundamental task in the analysis of nucleotide sequences. Despite the exponential increase in the size of sequence databases of homologous genes, few methods exist to cluster divergent sequences. Traditional clustering methods have mostly focused on optimizing high speed clustering of highly similar sequences. We develop a phylogenetic clustering method which infers ancestral sequences for a set of initial clusters and then uses a greedy algorithm to cluster sequences.ResultsWe describe a clustering programAncestralClust, which is developed for clustering divergent sequences. We compare this method with other state-of-the-art clustering methods using datasets of homologous sequences from different species. We show that, in divergent datasets, AncestralClust has higher accuracy and more even cluster sizes than current popular methods.Availability and implementationAncestralClust is an Open Source program available athttps://github.com/lpipes/ancestralclust.Contactlpipes@berkeley.eduSupplementary informationSupplementary figures and table are available online.
Long-lasting reduction of intrinsic excitability in O-LM interneurons is mediated by endocannabinoid-dependent up-regulation of Kv7 channels
Authors: Incontro Salvatore , Sammari Malika , Ankri Norbert , Russier Michael , Fantini Jacques , Debanne Dominique 
Published: January 2021

AbstractKCNQ-Kv7 channels are found at the axon initial segment of pyramidal neurons where they control cell firing and membrane potential. In oriens lacunosum moleculare (O-LM) interneurons, these channels are mainly expressed in the dendrites, suggesting a peculiar function of Kv7 channels in these neurons. The physiology of Kv7 channels is well characterized today but the precise contribution of these channels to neuronal plasticity is still unknown. Here, we show that Kv7 channel activity is up-regulated following induction of presynaptic long-term synaptic depression (LTD) in O-LM interneurons, thus resulting in a synergistic long-term depression of intrinsic neuronal excitability (LTD-IE). Both LTD and LTD-IE involve endocannabinoid (eCB) biosynthesis for their induction. Molecular modeling shows strong interaction of eCBs with Kv7.2/3 channel, suggesting a persistent action of these lipids on Kv7 channel activity. Our data thus unveil a major role for eCB synthesis in triggering both synaptic and intrinsic depression in O-LM interneurons.
Gut microbiome features are associated with sepsis onset and outcomes
Authors: Rao Krishna , Patel Alieysa R. , Seekatz Anna M. , Bassis Christine M. , Sun Yuang , Henig Oryan , Albin Owen R , SantaLucia John , Woods Robert , Bachman Michael A. 
Published: January 2021

AbstractBackgroundEpidemiologic studies have linked antibiotic exposure to subsequent sepsis, suggesting that microbiome disruption may be in the causal pathway and an independent risk factor. This study tests whether variation in the gut microbiota associates with risk of sepsis onset and its outcomes.MethodsUsing a validated surveillance definition, patients with an archived rectal swab from intensive care and hematology units were screened for sepsis. After confirmation by chart review, cases were matched to controls in a 1:2 ratio based on age, gender, and collection date. Relative taxon abundance was measured by sequence analysis of 16S rRNA gene amplicons; total bacterial abundance was measured by qPCR of the 23S rRNA gene. Conditional logistic regression identified clinical and microbiota variables associated with sepsis.ResultsThere were 103 sepsis cases matched to 206 controls. In a final model adjusting for exposure to broad-spectrum antibiotics and indwelling vascular catheters, high relative abundance (RA) ofEnterococcus(Odds Ratio (OR) 1.36 per 10% increase,P=.016) and high total bacterial abundance (OR 1.50 per 10-fold increase in 23S copies/μL,P=.001) were independently associated with sepsis. Decreased RA of butyrate-producing bacteria also independently associated with sepsis (OR 1.20 for 10% decrease in RA,P=.041), and mortality in unadjusted analysis (OR=1.47 for 10% decrease in RA,P=.034).ConclusionsThis study indicates that the microbiota is altered at sepsis onset. The decreased RA of butyrate-producing bacteria in sepsis also associates with mortality, suggesting a therapeutic role for prebiotics and probiotics in the prevention and treatment of sepsis.ImportanceEarly detection of patients at risk for sepsis could enable interventions to prevent or rapidly treat this life-threatening condition. Prior antibiotic treatment is associated with sepsis, suggesting that disruption of the bacterial population in the gut (the intestinal microbiome) could be an important step leading to disease. To investigate this theory, we matched hospitalized patients with and without sepsis and characterized the patients’ microbiomes close to or at onset of sepsis. We found that several microbiome alterations, including having more total bacteria in the gut was associated with onset, regardless of prior antibiotic treatment. This signature of microbiome disruption brings us closer to identifying the biological causes of sepsis and could be used to develop new diagnostic tests to identify patients at risk of sepsis.
Elucidating the CodY regulon inStaphylococcus aureusUSA300 substrains
Authors: Gao Ye , Poudel Saugat , Seif Yara , Shen Zeyang , Palsson Bernhard O. 
Published: January 2021

AbstractCodY is a conserved broad acting transcription factor that regulates the expression of genes related to amino acid metabolism and virulence in methicillin-resistantStaphylococcus aureus(MRSA). CodY target genes have been studied by usingin vitroDNA affinity purification and deep sequencing (IDAP-Seq). Here we performed the firstin vivodetermination of CodY target genes using a novel CodY monoclonal antibody in established ChIP-exo protocols. Our results showed, 1) the same 135 CodY promoter binding sites regulating 165 target genes identified in two closely related virulentS. aureusUSA300 TCH1516 and LAC strains; 2) The differential binding intensity for the same target genes under the same conditions was due to sequence differences in the same CodY binding site in the two strains; 3) Based on transcriptomic data, a CodY regulon comprising 72 target genes that are differentially regulated relative to a CodY deletion strain, representing genes that are mainly involved in amino acid transport and metabolism, inorganic ion transport and metabolism, transcription and translation, and virulence; and 4) CodY systematically regulated central metabolic flux to generate branched-chain amino acids (BCAAs) by mapping the CodY regulon onto a genome-scale metabolic model ofS. aureus. Our study performed the first system-level analysis of CodY in two closely related USA300 TCH1516 and LAC strains giving new insights into the similarities and differences of CodY regulatory roles between the closely related strains.ImportanceWith the increasing availability of whole genome sequences for many strains within the same pathogenic species, a comparative analysis of key regulators is needed to understand how the different strains uniquely coordinate metabolism and expression of virulence. To successfully infect the human host,Staphylococcus aureusUSA300 relies on the transcription factor CodY to reorganize metabolism and express virulence factors. While CodY is a known key transcription factor, its target genes are not characterized on a genome-wide basis. We performed a comparative analysis to describe the transcriptional regulation of CodY between two dominant USA300 strains. This study motivates the characterization of common pathogenic strains and an evaluation of the possibility of developing specialized treatments for major strains circulating in the population.
Cancer risk and sexual conflict as constraints to body size evolution
Authors: Erten E. Yagmur , Kokko Hanna 
Published: January 2021

AbstractSelection often favours large bodies, visible as Cope’s rule over macroevolutionary time — but size increases are not inevitable. One understudied cost of large bodies is the high number of cell divisions and the associated risk of oncogenic mutations. Our elasticity analysis shows that selection against a proportional increase in size becomes ever more intense with increasing body size if cancer is the sole selective agent. Thus cancer potentially halts body size increases even if no other constraint does so. We then provide multicellular realism with potentially sexually dimorphic body sizes and traits that control cell populations from zygote to maturity and beyond (ontogenetic management). This shows sexual conflict to extend to ontogeny; sexual dimorphism in mortalities and other life history measures may evolve even in the absence of any ecological causes underlying size- or sex-dependent mortality. Coadaptation of ontogenetic management and body size is required for substantial increases in size.
Single cell analyses reveal distinct adaptation of typhoidal and non-typhoidalSalmonella entericaserovars to intracellular lifestyle
Authors: Reuter Tatjana , Scharte Felix , Franzkoch Rico , Liss Viktoria , Hensel Michael 
Published: January 2021

AbstractSalmonella entericais a common foodborne, facultative intracellular enteropathogen. Human-restricted typhoidalS. entericaserovars Typhi (STY) or Paratyphi A (SPA) cause severe typhoid or paratyphoid fever, whileS. entericaserovar Typhimurium (STM) has a broad host range and in human hosts usually lead to a self-limiting gastroenteritis. Due to restriction of STY and SPA to primate hosts, experimental systems for studying the pathogenesis of typhoid and paratyphoid fever are limited. Therefore, STM infection of susceptible mice is commonly considered as model system for studying these diseases. The type III secretion system encoded bySalmonellapathogenicity island 2 (SPI2-T3SS) is a key factor for intracellular survival ofSalmonella. Inside host cells, the pathogen resides within theSalmonella-containing vacuole (SCV) and induces tubular structures extending from the SCV, termedSalmonella-induced filaments (SIF). This study applies a set of single cell analyses approaches such as dual fluorescent protein reports, effector translocation, or correlative light and electron microscopy to investigate the fate and activities of intracellular STY and SPA. The SPI2-T3SS of STY and SPA is functional in translocation of effector proteins, SCV and SIF formation. However, only a low proportion of intracellular STY and SPA are actively deploying SPI2-T3SS and STY and SPA exhibited a rapid decline of protein biosynthesis upon experimental induction. A role of SPI2-T3SS for proliferation of STY and SPA in epithelial cells was observed, but not for survival or proliferation in phagocytic host cells. Our results indicate that reduced intracellular activities are factors of the stealth strategy of STY and SPA and facilitate systemic spread and persistence of the typhoidalSalmonella.
Signatures of Mutational Processes in Human DNA Evolution
Authors: Hamidi Hamid , Alinejad-Rokny Hamid , Coorens Tim , Sanghvi Rashesh , Lindsay Sarah J , Rahbari Raheleh , Ebrahimi Diako 
Published: January 2021

AbstractThe human genome contains over 100 million SNPs, most of which are C/T (G/A) variations. The type and sequence context of these SNPs are not random, suggesting that they are caused by distinct mutational processes. Deciphering the mutational signatures is a crucial step to discovering the molecular processes responsible for DNA variations across human populations, and potentially for causing genetic diseases. Our analyses of the 1000 Genomes Project SNPs and germlinede novomutations suggest that at least four mutational processes are responsible for human genetic variations. One process is European-specific and no longer active. The remaining three processes are currently active in all human populations. Two of the active processes co-occur and leave a single joint mutational signature in human nuclear DNA. The third active process is specific to mitochondrial DNA, and inflicts C-to-T mutations at mostly non-CG sites. We found neither evidence of APOBEC-induced cytosine deamination in the human germline, norde novomutation enrichment within certain regions of the human genome.
PepNN: a deep attention model for the identification of peptide binding sites
Authors: Abdin Osama , Nim Satra , Wen Han , Kim Philip M. 
Published: January 2021

AbstractProtein-peptide interactions play a fundamental role in facilitating many cellular processes, but remain underexplored experimentally and difficult to model computationally. Here, we present PepNN-Struct and PepNN-Seq, structure and sequence-based approaches for the prediction of peptide binding sites on a protein given the sequence of a peptide ligand. A main difficulty for the prediction of peptide-protein interactions is the flexibility of peptides and their tendency to undergo conformational changes upon binding. To account for this behaviour, we developed a novel reciprocal attention module that simultaneously updates the encodings of peptide and protein residues and explicitly enforces the symmetry in the updates, allowing for information flow and reflecting the biochemical reality of conformational changes in the peptide. PepNN additionally makes use of modern graph neural network layers that are effective at learning representations of molecular structure. Finally, to compensate for the scarcity of peptide-protein complex structural information, we make use of available protein-protein complex and protein sequence information through a series of transfer learning steps. PepNN-Struct achieves state-of-the-art performance on the task of identifying peptide binding sites, with a ROC AUC of 0.893 and an MCC of 0.483 on an independent test set. Beyond prediction of binding sites on proteins with a known peptide ligand, we also show that the developed models make reasonable peptide-agnostic predictions, allowing for the identification of novel peptide binding proteins.