bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24
Authors: Cao Xiongwen , Khitun Alexandra , Luo Yang , Na Zhenkun , Phoodokmai Thitima , Sappakhaw Khomkrit , Olatunji Elizabeth , Uttamapinant Chayasith , Slavoff Sarah A. 
Published: March 2020

AbstractThousands of previously unannotated small and alternative open reading frames (alt-ORFs) have recently been revealed in the human genome, and hundreds are now known to be required for cell proliferation. Many alt-ORFs are co-encoded with proteins of known function in multicistronic human genes, but the functions of only a handful are currently known in molecular detail. Using a proteomic strategy for discovery of unannotated short open reading frames in human cells, we report the detection of alt-RPL36, a 148-amino acid protein co-encoded with and overlapping human RPL36 (ribosomal protein L36). Alt-RPL36 partially localizes to the endoplasmic reticulum, where it interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 in HEK 293T cells increases PI(4,5)P2levels in the plasma membrane, upregulates the PI3K-AKT-mTOR signaling pathway, and increases cell size. Four serine residues of alt-RPL36 are phosphorylated, and mutation of these four serines to alanine abolishes interaction with TMEM24 and, consequently, abolishes alt-RPL36 effects on PI3K signaling and cell size. These results implicate alt-RPL36 as a novel regulator of PI(4,5)P2synthesis upstream of the PI3K-AKT-mTOR signaling pathway. More broadly, these results show that the alt-RPL36 transcript can express two sequence-independent polypeptides from overlapping ORFs that regulate the same process – protein synthesis – via different molecular mechanisms (PI3K signaling and ribosome composition), expanding our knowledge of the mechanisms by which multicistronic human genes function.
Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CC-GWAS
Authors: Peyrot Wouter J. , Price Alkes L. 
Published: March 2020

AbstractPsychiatric disorders are highly genetically correlated, and many studies have focused on their shared genetic components. However, little research has been conducted on the genetic differences between psychiatric disorders, because case-case comparisons of allele frequencies among cases currently require individual-level data from cases of both disorders. We developed a new method (CC-GWAS) to test for differences in allele frequency among cases of two different disorders using summary statistics from the respective case-control GWAS; CC-GWAS relies on analytical assessments of the genetic distance between cases and controls of each disorder. Simulations and analytical computations confirm that CC-GWAS is well-powered and attains effective control of type I error. In particular, CC-GWAS identifies and discards false positive associations that can arise due to differential tagging of a shared causal SNP (with the same allele frequency in cases of both disorders), e.g. due to subtle differences in ancestry between the input case-control studies. We applied CC-GWAS to publicly available summary statistics for schizophrenia, bipolar disorder and major depressive disorder, and identified 116 independent genome-wide significant loci distinguishing these three disorders, including 21 CC-GWAS-specific loci that were not genome-wide significant in the input case-control summary statistics. Two of the CC-GWAS-specific loci implicate the genesKLF6andKLF16from the Kruppel-like family of transcription factors; these genes have been linked to neurite outgrowth and axon regeneration. We performed a broader set of case-case comparisons by additionally analyzing ADHD, anorexia nervosa, autism, obsessive-compulsive disorder and Tourette’s Syndrome, yielding a total of 196 independent loci distinguishing eight psychiatric disorders, including 72 CC-GWAS-specific loci. We confirmed that loci identified by CC-GWAS replicated convincingly in applications to data sets for which independent replication data were available. In conclusion, CC-GWAS robustly identifies loci with different allele frequencies among cases of different disorders using results from the respective case-control GWAS, providing new insights into the genetic differences between eight psychiatric disorders.
SCA4 locus-associated gene Ronin (Thap11) increases Ataxin-1 protein levels and induces cerebellar degeneration in a mouse model of ataxia
Authors: Zwaka Thomas P. , Richman Ronald , Dejosez Marion 
Published: March 2020

ABSTRACTSpinocerebellar ataxias (SCAs) are a group of genetically heterogeneous inherited neurodegenerative disorders characterized by progressive ataxia and cerebellar degeneration. Here, we tested if Ronin (Thap11), a polyglutamine-containing protein encoded in a region on human chromosome 16q22.1 that has been genetically linked to SCA4, can be connected with SCA disease in a mouse model. We report that transgenic expression ofRoninin mouse cerebellar Purkinje cells leads not only histopathologically to detrimental loss of Purkinje cells but also phenotypically to the development of severe ataxia as early as 10-12 weeks after birth. Mechanistically, we find that Ronin is part of a protein complex in the cerebellum that is distinct from the one previously found in embryonic stem cells. Importantly, ectopically expressedRoninraises the protein level of Ataxin-1 (Atxn1), the causative gene of the most common type of SCA, SCA1. Hence, our data provide evidence for a link between Ronin and SCAs, and also suggest that Ronin may be involved in the development of other neurodegenerative diseases.
Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein
Authors: Majewski Jaroslaw , Jones Emmalee M. , Vander Zanden Crystal M. , Biernat Jacek , Mandelkow Eckhard , Chi Eva Y. 
Published: March 2020

AbstractThe aggregation of the intrinsically disordered tau protein into highly ordered β-sheet fibrils is implicated in many neurodegenerative disorders. Fibrillation mechanism remains unresolved, particularly early events that trigger tau misfolding and assembly. We investigated the role membrane plays in modulating aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation mutant hTau40/3Epi. Despite being charged and soluble, tau proteins were also highly surface active and favorably interacted with anionic, but not zwitterionic, lipid monolayer at the air/water interface. Membrane binding induced macroscopic tau phase separation and β-sheet-rich tau oligomer formation. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau’s inherent surface activity and favorable electrostatic interactions drive tau-membrane association, inducing tau phase separation that is accompanied by misfolding and self-assembly of disordered tau into β-sheet-rich oligomers, which subsequently seed fibrillation and deposition into diseased tissues.
Path integration error and adaptable search behaviors in a mantis shrimp
Authors: Patel Rickesh N. , Cronin Thomas W. 
Published: March 2020

AbstractMantis shrimp of the speciesNeogonodactylus oerstediioccupy small burrows in shallow waters throughout the Caribbean. These animals use path integration, a vector-based navigation strategy, to return to their homes while foraging. Here we report that path integration inN. oerstediiis prone to error accumulated during outward foraging paths and we describe the search behavior thatN. oerstediiemploys after it fails to locate its home following the route provided by its path integrator. This search behavior forms continuously expanding, non-oriented loops that are centered near the point of search initiation. The radius of this search is apparently scaled to the animal’s accumulated error during path integration, improving the effectiveness of the search. The search behaviors exhibited byN. oerstediibear a striking resemblance to search behaviors in other animals, offering potential avenues for the comparative examination of search behaviors and how they are optimized in disparate taxa.Summary StatementMantis shrimp use path integration, an error-prone navigational strategy, when travelling home. When path integration fails, mantis shrimp employ a stereotyped yet flexible search pattern to locate their homes.
The polymorphism ofHydramicrosatellite sequences provides strain-specific signatures
Authors: Schenkelaars Quentin , Perez-Cortez Diego , Perruchoud Chrystelle , Galliot Brigitte 
Published: March 2020

ABSTRACTHydraare freshwater polyps widely studied for their amazing regenerative capacity, adult stem cell populations, low senescence and value as ecotoxicological marker. Many wild-type strains ofH. vulgarishave been collected worldwide and maintained effectively under laboratory conditions by asexual reproduction, while stable transgenic lines have been continuously produced since 2006. Efforts are now needed to ensure the genetic characterization of all these strains, which despite similar morphologies, show significant variability in their response to gene expression silencing procedures, pharmacological treatments or environmental conditions. Here, we established a rapid and reliable procedure at the single polyp level to produce via PCR amplification of three distinct microsatellite sequences molecular signatures that clearly distinguish betweenHydrastrains and species. The TG-rich region of an uncharacterized gene (ms-c25145) helps to distinguish between EurasianH. vulgarisstrains (Hm-105,Basel1,Basel2andreg-16), between Eurasian and North AmericanH. vulgarisstrains (H. carnea, AEP), and between theH. vulgarisandH. oligactisspecies. The AT-rich microsatellite sequences located in theAIPgene (Aryl Hydrocarbon Receptor Interaction Protein, ms-AIP) also differ between Eurasian and North AmericanH. vulgarisstrains. Finally, the AT-rich microsatellite located in theMyb-Like cyclin D-binding transcription factor1gene (ms-DMTF1) gene helps to distinguish certain transgenicAEPlines. This study shows that the analysis of microsatellite sequences provides a barcoding tool that is sensitive and robust for the identification ofHydrastrains. It is also capable of identifying cryptic species by tracing microevolutionary events within the genusHydra.
Overexposure to apoptosis via disrupted glial specification perturbsDrosophilamacrophage function and reveals roles of the CNS during injury
Authors: Armitage Emma Louise , Roddie Hannah Grace , Evans Iwan Robert 
Published: March 2020

AbstractApoptotic cell clearance by phagocytes is a fundamental process during development, homeostasis and the resolution of inflammation. However, the demands placed on phagocytic cells such as macrophages by this process, and the limitations these interactions impose on subsequent cellular behaviours are not yet clear. Here we seek to understand how apoptotic cells affect macrophage function in the context of a genetically-tractableDrosophilamodel in which macrophages encounter excessive amounts of apoptotic cells. We show that loss of the glial transcription factorrepo, and corresponding removal of the contribution these cells make to apoptotic cell clearance, causes macrophages in the developing embryo to be challenged with large numbers of apoptotic cells. As a consequence, macrophages become highly vacuolated with cleared apoptotic cells and their developmental dispersal and migration is perturbed. We also show that the requirement to deal with excess apoptosis caused by a loss ofrepofunction leads to impaired inflammatory responses to injury. However, in contrast to migratory phenotypes, defects in wound responses cannot be rescued by preventing apoptosis from occurring within arepomutant background. In investigating the underlying cause of these impaired inflammatory responses, we demonstrate that wound-induced calcium waves propagate into surrounding tissues, including neurons and glia of the ventral nerve cord, which exhibit striking calcium waves on wounding, revealing a previously unanticipated contribution of these cells during responses to injury. Taken together these results demonstrate important insights into macrophage biology and howrepomutants can be used to study macrophage-apoptotic cell interactions in the fly embryo.Furthermore, this work shows how these multipurpose cells can be ‘overtasked’ to the detriment of their other functions, alongside providing new insights into which cells govern macrophage responses to injury in vivo.
A comparative analysis ofCaenorhabditisandDrosophilatranscriptional changes in response to pathogen infection
Authors: Unckless Robert L. , Lansdon Patrick A. , Ackley Brian D. 
Published: March 2020

AbstractDrosophila melanogasterandCaenorhabditis elegansare well-used invertebrate models for studying the innate immune system. The organisms are susceptible to bacterial pathogens that includePseudomonasspecies,(entomophilia – Drosophila) or (aeruginosa – Caenorhabditis), E. faecalisandP. rettgeri, which are or are related to human pathogens. Further, the consequences of exposure to these pathogens, in terms of organismal survival, are roughly equivalent when compared. That is, worms and flies are more susceptible to infection byPseudomonasthanE. faecalis, whereas organismal survival onE. faecalisandP. rettgeriare roughly the same in both. To better understand how these organisms are coordinating their responses to these bacterial pathogens we examined transcriptomes in infected animals. We grouped our analysis based on protein orthology. Of the 3611 pairs analyzed, we found genes whose responses were conserved across the different species at a higher than expected rate for two of the three pathogens. Interestingly within the animals, genes with 1:1 orthologs between species behaved differently. Such genes were more likely to be expressed inD. melanogaster, and less likely to be expressed inC. elegans. From this analysis we found that the gene nucleobindin (nucb-1/NUCB1inC. elegansandD. melanogaster, respectively) was upregulated in both species in response to Gram negative bacteria. We used RNAi to knock downnucb-1and found the treated animals were more susceptible to infection by the Gram negative pathogenP. rettgerithan controls. These results provide insight into some of the conserved mechanisms of pathogen defense, but also suggest that these divergent organisms have evolved specific means to orchestrate the defense against pathogens.Article SummaryWe analyzed transcriptomic data fromC. elegansandD. melanogasterto compare the expression of orthologous pairs of genes in response to bacterial pathogens. Our results indicated that only a handful of genes that are orthologous between species are differentially expressed in response to pathogens, but that the pattern of expression was different when comparing one-to-one orthologs versus those that are restricted to one of the two organisms. These results suggest that, although broad patterns of susceptibility to bacterial pathogens are conserved, the regulatory framework by which the organisms fight pathogens is less well conserved. Further our results suggest a more complete analysis of the evolutionary changes in organismal responses to pathogens is required.
Novel Functional metabolites that affect biofilm formation are regulated by bioavailable iron with siderophore-dependent pathway
Authors: Guo Rui , Luo Xilin , Liu Jingjing , Lu Haitao 
Published: March 2020

AbstractBiofilms are broadly formed by diverse microorganisms under stressful environments and are basically surrounded by an EPS matrix, enabling bacterial cells to confer more resistance to biocides, antibiotics and other invasions than their planktonic counterparts. However, biofilm formation causes problems in various fields, including clinical infections, environmental pollution, agricultural production and industrial contamination. Unfortunately, the mechanism of biofilm formation has not been completely elucidated, and currently, we lack an efficient strategy to tackle these tough problems and destroy biofilms. In the present study, we sought to decipher the mechanism of biofilm formation through the regulation of functional metabolites regulated by iron. By exposing bacterial cells to various concentrations of iron, we found that iron can regulate biofilm formation, and phenotypic changes were obviously dependent on iron concentration. A functional metabolome assay was further implemented to investigate the regulatory mechanism of iron on biofilm formation; we verified that siderophores (linear enterobactin, yersiniabactin, di-glucosylated-salmochelin and HPTT-COOH) mostly account for the transportation of iron into bacterial cells. Then, bioavailable iron was recruited by bacterial cells to direct the biosynthesis and expression of five functional metabolites (L-tryptophan, 5’-MTA, spermidine, CMP and L-leucine), which were identified as new effectors that directly regulate biofilm formation. Taken together, this study is the first to identify five new metabolic effectors to efficiently regulate biofilm formation, the biosynthesis and expression of these functional metabolites can be targeted to tackle the challenging problems associated with biofilm formation in different fields.
Autoencoder networks extract latent variables and encode these variables in their connectomes
Authors: Farrell Matthew , Recanatesi Stefano , Reid R. Clay , Mihalas Stefan , Shea-Brown Eric 
Published: March 2020

AbstractSpectacular advances in imaging and data processing techniques are revealing a wealth of information about brain connectomes. This raises an exciting scientific opportunity: to infer the underlying circuit function from the structure of its connectivity. A potential roadblock, however, is that – even with well constrained neural dynamics – there are in principle many different connectomes that could support a given computation. Here, we define a tractable setting in which the problem of inferring circuit function from circuit connectivity can be analyzed in detail: the function of input compression and reconstruction, in an autoencoder network with a single hidden layer. Here, in general there is substantial ambiguity in the weights that can produce the same circuit function, because largely arbitrary changes to “input” weights can be undone by applying the inverse modifications to the “output” weights. However, we use mathematical arguments and simulations to show that adding simple, biologically motivated regularization of connectivity resolves this ambiguity in an interesting way: weights are constrained such that the latent variable structure underlying the inputs can be extracted from the weights by using nonlinear dimensionality reduction methods.
Chromosomal Resistance to Metronidazole inClostridioides difficilecan be Mediated By Epistasis Between Iron Homeostasis and Oxidoreductases
Authors: Deshpande Aditi , Wu Xiaoqian , Huo Wenwen , Palmer Kelli L. , Hurdle Julian G. 
Published: March 2020

AbstractChromosomal resistance to metronidazole has emerged in clinicalClostridioides difficile, but the genetic mechanisms remain unclear. This is further hindered by the inability to generate spontaneous metronidazole-resistant mutants in the lab to aid genetic studies. We therefore constructed a mismatch repair mutator, in non-toxigenic ATCC 700057, to unbiasedly survey the mutational landscape forde novoresistance mechanisms. In separate experimental evolutions, the mutator adopted a deterministic path to resistance, with truncation of ferrous iron transporter FeoB1 as a first-step mechanism of low level resistance. Allelic deletion offeoB1in ATCC 700057 reduced intracellular iron content, appearing to shift cells toward flavodoxin-mediated oxidoreductase reactions, which are less favorable for metronidazole’s cellular action. Higher level resistance evolved from sequential acquisition of mutations to catalytic domains of pyruvate-ferredoxin oxidoreductase (PFOR encoded bynifJ); a synonymous codon change toxdhA1(xanthine dehydrogenase subunit A), likely affecting its translation; and lastly, frameshift and point mutations that inactivated the iron-sulfur cluster regulator (IscR). Gene silencing ofnifJ, xdhA1oriscRwith catalytically dead Cas9 revealed that resistance involving these genes only occurred whenfeoB1was inactivated i.e. resistance was only seen in anfeoB1-deletion mutant and not the isogenic wild-type parent. These findings show that metronidazole resistance inC. difficileis complex, involving multi-genetic mechanisms that could intersect with iron-dependent metabolic pathways.
Suitability of Deep Weakly Supervised Learning to detect Acute Ischemic Stroke and Hemorrhagic Infarction Lesions Using Diffusion-weighted Imaging
Authors: Cao Chen , Liu Zhiyang , Liu Guohua , Jin Song , Xia Shuang 
Published: March 2020

AbstractObjectivesThe automatic detection of acute ischemic stroke (AIS) and hemorrhagic infarction (HI) based on deep learning could avoid missed diagnosis. The fully supervised learning requires the amount of time and the expertise to manually outline lesions, which limits its applicability. The weakly supervised learning has the potential to reduce the labeling workload. The purpose of this study was to evaluate a weakly supervised method in detection of AIS and HI location using DWI.MethodsWe proposed to adopt weakly supervised learning to spatially-locate AIS lesions by residual neural network (ResNet) and visual geometry group (VGG) network. On an AIS dataset, the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity and precision were calculated. Next, ResNet, which presented superior performance on the AIS dataset, was further applied to an HI dataset.ResultsIn the AIS dataset, the AUCs of ResNet and VGG on identifying image slices with AIS were 0.97 and 0.94, respectively. On spatially-locating the AIS lesions, ResNet provided higher sensitivity and a lower missed diagnosis rate than VGG, especially for pontine AIS lesions. In the HI dataset, the sensitivity of ResNet was 87.73% for AIS detection, and 86.20% for HI detection, respectively.ConclusionsWeakly supervised learning can effectively detect the location of AIS and HI lesions in DWI, which is of paramount importance in avoiding misdiagnosis in clinical scenario.Key pointsThe deep weakly supervised learning can reduce the labeling workload; ResNet can obtain more exact results, especially for pontine AIS lesions; Weakly supervised learning can effectively detect AIS and HI lesions in DWI