bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic composition and evolution of the prevalentMycobacteriumtuberculosis lineages 2 and 4 in the Chinese and Zhejiang Province populations
Authors: Wu Beibei , Zhu Wenlong , Wang Yue , Wang Qi , Zhou Lin , Liu Zhengwei , Bi Lijun , Barun Mathema , Kreiswirth Barry N. , Chen Liang , Chen Songhua , Wang Xiaomeng , Wang Weibing 
Published: November 2020

AbstractThe causative agent of tuberculosis (TB) comprises seven human-adapted lineages. Human movements and host genetics are crucial to TB dissemination. We analyzed whole-genome sequencing data for a countrywide collection of 1154 isolates and a provincial collection of 1296 isolates, constructed the best-scoring maximum likelihood phylogenetic tree, conducted Bayesian evolutionary analysis to compute the most recent common ancestors of lineages 2 and 4, and assessed the antigenic diversity in human T cell epitopes by calculating pairwise dN/dS ratios. Of the 1296 Zhejiang isolates, 964 (74.38%) belonged to lineage 2 and 332 (25.62%) belonged to lineage 4. L2.2 is the most ancient sub-lineage in Zhejiang, first appearing approximately 6897 years ago (95% HDI: 6513-7298). L4.4 is the most modern sub-lineage, first appearing approximately 2217 years ago (95% HDI: 1864-2581). The dN/dS ratios revealed that the epitope and non-epitope regions of lineage 2 strains were significantly (P<0.001) more conserved than those of lineage 4. An increase in the frequency of lineage 4 may reflect its successful transmission over the last 20 years. The recent common ancestors and transmission routes of the sub-lineages are related to the entry of humans into China and Zhejiang Province.
Epilepsy-associated Mutations in the Calcium-sensing Receptor Disrupt the Regulation of NALCN Sodium-leak Channel by Extracellular Calcium in Neurons
Authors: Cang Chunlei , Lu Boxun , Ren Dejian 
Published: November 2020

AbstractMost mammalian neurons have a resting membrane potential (RMP) of ~ −50 mV to −70 mV, significantly above the equilibrium potential of K+(EK) of ~ −90 mV. The resting Na+-leak conductance is a major mechanism by which neurons maintain their RMPs above EK. In the hippocampal neurons, the TTX-insensitive, voltage-independent Na+leak is mediated by the NALCN cation channel. Extracellular Ca2+(Ca2+e) also controls the sizes of NALCN current (INALCN) in a G-protein-dependent fashion. The molecular identities of the basal Na+conductances and their regulation in other regions in the central nervous system and in the peripheral nervous system are less established. Here we show that neurons cultured from mouse cortices, ventral tegmental area, spinal cord and dorsal root ganglia all have a NALCN-dependent basal Na+-leak conductance that is absent in NALCN knockout mice. Like in hippocampal neurons, a decrease in [Ca2+]eincreases INALCN. Using shRNA knockdown, we show that the regulation of INALCNby Ca2+ein neurons requires the Ca2+-sensing G-protein-coupled receptor CaSR. Surprisingly, the functional coupling from [Ca2+]eto NALCN requires CaSR’s distal C-terminal domain that is dispensable for the receptor’s ability to couple [Ca2+]eto its canonical signaling targets such as PLC and MAPK. In addition, several epilepsy-associated human CaSR mutations, though sparing the receptor’s ability to sense Ca2+eto maintain systemic [Ca2+], disrupt the ability of CaSR to regulate NALCN. These findings uncover a unique mechanism by which CaSR regulates neuronal excitability via NALCN in the central and peripheral nervous system.
Interactions between axon-like projections extended byDrosophilaFollicle Stem Cells dictate cell fate decisions
Authors: Lee Eric H. , Zinshteyn Daniel , Wang Melissa , Reinach Jessica , Chau Cindy , Costa Kelly , Vargas Alberto , Johnson Aminah , Alexander Jennifer I. , O’Reilly Alana M. 
Published: November 2020

AbstractStem cells cycle between periods of quiescence and proliferation to promote healthy tissue aging. Once proliferation is initiated, mechanisms that control the balance between self-renewal and differentiation must be engaged to ensure maintenance of stem cell pools until the next quiescent cycle occurs. Here, we demonstrate that dynamic axon-like projections extended by Follicle Stem Cells (FSCs) in theDrosophilaovary control the self-renewal-differentiation balance. Known axon growth regulatorsstill lifeandsickieare necessary and sufficient for FSC projection growth, mediating organization of germline cyst architecture during follicle formation, controlling targeting of projections to FSCs or germ cells, and regulating expression of the cell fate determinants Eyes Absent (Eya) and Castor (Cas). Our results support a model in which FSC projections function similarly to axons, providing structural organization to a dynamic organ while mediating communication between distinct cell types to effect the key cell fate decision to self-renew or differentiate.
InMycobacterium abscessus, the stringent factor Rel regulates metabolism, but is not the only (p)ppGpp synthase
Authors: Hunt-Serracín Augusto César , Kazi Misha I. , Boll Joseph M. , Boutte Cara C. 
Published: November 2020

AbstractThe stringent response is a broadly conserved stress response system that exhibits functional variability across bacterial clades. Here, we characterize the role of the stringent factor Rel in the non-tuberculous mycobacterial pathogen,Mycobacterium abscessus(Mab). We found that deletion ofreldoes not ablate (p)ppGpp synthesis, and thatreldoes not provide a survival advantage in several stress conditions, or in antibiotic treatment. Transcriptional data show that RelMabis involved in regulating expression of anabolism and growth genes in stationary phase. However, it does not activate transcription of stress response or antibiotic resistance genes, and actually represses transcription of many antibiotic resistance genes. This work shows that there is an unannotated (p)ppGpp synthetase inMab.ImportanceIn this study, we examined the functional roles of the stringent factor Rel inMycobacterium abscessus(Mab). In most species, stringent factors synthesize the alarmone (p)ppGpp, which globally alters transcription to promote growth arrest and survival under stress and in antibiotic treatment. Our work shows that inMab, an emerging pathogen which is resistant to many antibiotics, the stringent factor Rel is not solely responsible for synthesizing (p)ppGpp. We find that RelMabdownregulates many metabolic genes under stress, but does not upregulate stress response genes and does not promote antibiotic tolerance. This study implies that there is another critical but unannotated (p)ppGpp synthetase inMab, and suggests that RelMabinhibitors are unlikely to sensitizeMabinfections to antibiotic treatment.
K+efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake
Authors: Tyurikova Olga , Shih Pei‐Yu , Dembitskaya Yulia , Savtchenko Leonid P. , McHugh Thomas J. , Rusakov Dmitri A. , Semyanov Alexey 
Published: November 2020

AbstractGlutamatergic transmission prompts K+efflux through postsynaptic NMDA receptors. K+depolarizes local presynaptic terminals, boosting glutamate release, but whether it also affecting glutamate uptake remains unknown. Here, we find that the pharmacological blockade, or conditional knockout, of NMDA receptors suppresses the progressive use‐ dependent increase in the amplitude and decay time of the astrocytic glutamate transporter current (IGluT), whereas blocking the astrocytic inward‐rectifying K+channels prevents the decay time increase only. Glutamate spot‐uncaging reveals that local astrocyte depolarization, rather than extracellular K+rises on their own, reduces the amplitude and prolong the decay of IGluT. Biophysical simulations confirm that local transient elevations of extracellular K+can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two‐pathway test relate postsynaptic K+efflux to enhanced extrasynaptic glutamate signaling. Thus, postsynaptic K+efflux facilitates presynaptic release while reducing local glutamate uptake.
Cognitive insights from evolutionarily new brain structures in prefrontal cortex
Authors: Voorhies Willa I. , Miller Jacob A. , Yao Jewelia K. , Bunge Silvia A. , Weiner Kevin S. 
Published: November 2020

ABSTRACTWhile the disproportionate expansion of lateral prefrontal cortex (LPFC) in humans compared to non-human primates is accepted, the relationship between evolutionarily new LPFC brain structures and uniquely human cognitive skills is largely unknown. Here, we tested the relationship between variability in evolutionarily new LPFC tertiary sulci and reasoning skills in a pediatric cohort. A novel data-driven approach in independentdiscoveryandreplicationsamples revealed that the depth of specific LPFC tertiary sulci predicts individual differences in reasoning skills beyond age. These findings support a classic, yet untested, theory linking the protracted development of tertiary sulci to late-developing cognitive processes. We suggest that deeper LPFC tertiary sulci reflect reduced short-range connections in white matter, which in turn, improve the efficiency of local neural signals underlying cognitive skills such as reasoning that are central to human cognitive development. To expedite discoveries in future neuroanatomical-behavioural studies, we share sulcal definitions with the field.
Downstream Effects: Impact of Antibiotic Pollution on an Aquatic Host-Parasite Interaction
Authors: Melchiorre Hannah G. , Gutierrez Stephanie O. , Minchella Dennis J. , Vannatta J. Trevor 
Published: November 2020

AbstractThe global increase in antibiotic use has led to contamination of freshwater environments occupied by parasites and their hosts. Despite the identified impacts of antibiotics on humans and wildlife, the effect of antibiotics on host-parasite life cycles is relatively unexplored. We utilize the trematode parasiteSchistosoma mansoni, and its snail intermediate hostBiomphalaria glabratato investigate the influence of an ecologically relevant antibiotic concentration on the life history characteristics of both parasite and host. Our results demonstrate that antibiotics not only accelerate parasite development time, but also increase host reproduction and delay parasite-induced host castration. We propose that antibiotic exposure alters host microbiome composition, leading to increased host susceptibility and higher parasite production. Using a mathematical model, we suggest that life history alterations associated with antibiotics are likely to increase parasite transmission and disease burden. Our study suggests that antibiotic pollution could impact freshwater ecosystems by influencing host-parasite dynamics and potentially increase the burden of schistosomiasis in endemic regions.
A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia
Authors: Szabo Attila , Akkouh Ibrahim A. , Vandenberghe Matthieu , Osete Jordi Requena , Hughes Timothy , Heine Vivi , Smeland Olav B. , Glover Joel C. , Andreassen Ole A. , Djurovic Srdjan 
Published: November 2020

ABSTRACTWhile neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In this study we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA-sequencing. The model generated astrocyte-specific patterns of gene expression during differentiation, and demonstrated that these patterns correspond well to astroglia-specific expression signatures ofin vivocortical fetal development. Applying this model, we were able to identify SCZ-specific expression dynamics in human astrocytes, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targetingVWA5AandADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results provide strong support for the validity of our astrocyte model, and implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.
The super repertoire of type IV effectors in the pangenome ofEhrlichiaspp. provides insights into host-specificity and pathogenesis
Authors: Noroy Christophe , Meyer Damien F. 
Published: November 2020

AbstractThe identification of bacterial effectors is essential to understand how obligatory intracellular bacteria such asEhrlichiaspp. manipulate the host cell for survival and replication. Infection of mammals – including humans – by the intracellular pathogenic bacteriaEhrlichiaspp. depends largely on the injection of virulence proteins that hijack host cell processes. Several hypothetical virulence proteins have been identified inEhrlichiaspp., but one so far has been experimentally shown to translocate into host cells via the type IV secretion system. However, the current challenge is to identify most of the type IV effectors (T4Es) to fully understand their role inEhrlichiaspp. virulence and host adaptation. Here, we predict the T4E repertoires of four sequencedEhrlichiaspp. and four otherAnaplasmataceaeas comparative models (pathogenicAnaplasmaspp. andWolbachiaendosymbiont) using previously developed S4TE 2.0 software. This analysis identified 579 predicted T4Es (228 pT4Es forEhrlichiaspp. only). The effector repertoiresof Ehrlichiaspp. overlapped, thereby defining a conserved core effectome of 92 effectors shared by all strains. In addition, 69 species-specific T4Es were predicted with non-canonical GC% mostly in gene sparse regions of the genomes and we observed a bias in pT4Es according to host-specificity. We also identified new protein domain combinations, suggesting novel effector functions. This work presenting the predicted effector collectionof Ehrlichiaspp. can serve as a guide for future functional characterisation of effectors and design of alternative control strategies against these bacteria.
Transarterial embolization modulates the immune response within target and non-target hepatocellular carcinomas
Authors: Tischfield David , Gurevich Alexey , Johnson Omar , Gayatman Isabela , Nadolski Gregory J. , Kaplan David E. , Furth Emma , Hunt Stephen J. , Gade Terence P. F. 
Published: November 2020

AbstractRecent successes in the field of immuno-oncology have generated considerable interest in the investigation of approaches that combine standard of care treatments with immunotherapies. Transarterial embolization (TAE) represents an attractive candidate for this approach given the potential for immune system stimulation, however little is known about the influence of TAE on the tumor immunoenvironment. The purpose of this study was to perform a cellular analysis of tumor infiltrating lymphocytes (TILs) and PD-L1 expression following TAE in a translational rat model of hepatocellular carcinoma (HCC) and to identify factors that influence this response. We show that TAE causes dynamic changes in immune cell populations, with variable increases in CD3, CD4, and CD8 cells within embolized tumors over time. We also show that TAE alters the immunobiology of distant, non-target tumors as demonstrated by an increased number of CD4, CD8, and Foxp3+ cells within the intratumoral compartment of non-target tumors. We demonstrate that, in response to TAE, tumor cells up-regulate expression of PD-L1. Finally, we demonstrate marked differences in terms of the foreign body reactions induced by two commonly used embolic particles, and show changes in lymphocyte and macrophage recruitment that depend on the type of embolic particles and their propensity to extravasate beyond the vasculature and into the tumor parenchyma. These findings hold important implications for the on-going development of novel therapeutic strategies combining locoregional therapy with immunomodulators, as well as for the development of techniques and materials that can further leverage the unique modulation of the tumor immune microenvironment.
Functional characterization of RebL1 highlights the evolutionary conservation of oncogenic activities of the RBBP4/7 orthologue inTetrahymena thermophila
Authors: Nabeel-Shah Syed , Garg Jyoti , Saettone Alejandro , Ashraf Kanwal , Lee Hyunmin , Wahab Suzanne , Ahmed Nujhat , Fine Jacob , Derynck Joanna , Ponce Marcelo , Pu Shuye , Marcon Edyta , Zhang Zhaolei , Greenblatt Jack F , Pearlman Ronald E , Lambert Jean-Philippe , Fillingham Jeffrey 
Published: November 2020

AbstractRetinoblastoma-binding proteins 4 and 7 (RBBP4 and RBBP7) are two highly homologous human histone chaperones. They function in epigenetic regulation as subunits of multiple chromatin-related complexes and have been implicated in numerous cancers. Due to their overlapping functions, our understanding of RBBP4 and 7, particularly outside of Opisthokonts, has remained limited. Here, we report that in the ciliate protozoanTetrahymena thermophilaa single orthologue of human RBBP4 and 7 proteins, RebL1, physically interacts with histone H4 and functions in multiple epigenetic regulatory pathways. Functional proteomics identified conserved functional links associated withTetrahymenaRebL1 protein as well as human RBBP4 and 7. We found that putative subunits of multiple chromatin-related complexes including CAF1, Hat1, Rpd3, and MuvB, co-purified with RebL1 duringTetrahymenagrowth and conjugation. Iterative proteomics analyses revealed that the cell cycle regulatory MuvB-complex inTetrahymenais composed of at least five subunits including evolutionarily conserved Lin54, Lin9 and RebL1 proteins. Genome-wide analyses indicated that RebL1 and Lin54 (Anqa1) bind within genic and intergenic regions. Moreover, Anqa1 targets primarily promoter regions suggesting a role forTetrahymenaMuvB in transcription regulation. RebL1 depletion decreased cellular viability and altered the expression of selected targets. Consistent with observations in glioblastoma tumors, RebL1 depletion suppressed DNA repair protein Rad51 inTetrahymena, thus underscoring the evolutionarily conserved functions of RBBP4/7 proteins. Our results suggest the essentiality of RebL1 functions in multiple epigenetic regulatory complexes in which it impacts transcription regulation and cellular viability.
Surfaceome CRISPR Screen Identifies OLFML3 as a Rhinovirus-inducible IFN Antagonist
Authors: Mei Hong , Zha Zhao , Wang Wei , Xie Yusang , Huang Yuege , Li Wengping , Wei Dong , Zhang Xinxin , Xie Jia , Qu Jieming , Liu Jia 
Published: November 2020

AbstractBackgroundRhinoviruses (RVs) cause more than half of common cold and, in some cases, more severe diseases. Functional genomics analyses of RVs using siRNA or genome-wide CRISPR screen uncovered a limited set of host factors, few of which has proven clinical relevance.ResultsHerein, we systematically compared genome-wide CRISPR screen and surface protein-focused CRISPR screen, referred to as surfaceome CRISPR screen, for their efficiencies in identifying RV host factors. It was found that surfaceome screen outperformed genome-wide screen in the success rate of hit identification. Importantly, using surfaceome screen we have identified olfactomedin like 3 (OLFML3) as a novel host factor of RV serotypes A and B including a clinical isolate. We found that OLFML3 was a RV-inducible suppressor of the innate immune response and that OLFML3 antagonized type I interferon (IFN) signaling in a SOCS3-dependent manner.ConclusionOur study has suggested that RV-induced OLFML3expression is an important mechanism for RV to hijack the immune system and underscored surfaceome CRISPR screen in identifying viral host factors.
Continuous attractors for dynamic memories
Authors: Spalla Davide , Cornacchia Isabel M. , Treves Alessandro 
Published: November 2020

AbstractEpisodic memory has a dynamic nature: when we recall past episodes, we retrieve not only their content, but also their temporal structure. The phenomenon of replay, in the hippocampus of mammals, offers a remarkable example of this temporal dynamics. However, most quantitative models of memory treat memories as static configurations, neglecting the temporal unfolding of the retrieval process. Here we introduce a continuous attractor network model with a memory-dependent asymmetric component in the synaptic connectivity, that spontaneously breaks the equilibrium of the memory configurations and produces dynamic retrieval. The detailed analysis of the model with analytical calculations and numerical simulations shows that it can robustly retrieve multiple dynamical memories, and that this feature is largely independent on the details of its implementation. By calculating the storage capacity we show that the dynamic component does not impair memory capacity, and can even enhance it in certain regimes.
Optimizing Consensus Generation Algorithms for Highly Variable Amino Acid Sequence Clusters
Authors: Mohabati Reyhaneh , Rezaei Reza , Mohajel Nasir , Ranjbar Mohammad Mehdi , Azadmanesh Kayhan , Roohvand Farzin 
Published: November 2020

AbstractProducing a functional consensus sequence is a preliminary bioinformatics task, which is a necessity for many research purposes. However, the existence of hypervariable regions in the input multiple sequence alignment files causes complications in generating a useful consensus sequence. The current methods for consensus generation, Threshold, and majority algorithms, have several problems, which exclude them as applicable algorithms for such highly variable sequence clusters. Hence, we designed a novel alternative algorithm for the same purpose. The algorithm was explained both using a mathematical formula and a practical implementation in Python programming language. A sequence set from HCV genotype 1b E2 protein has been utilized as a practical example for evaluating the algorithm’s performance. A few in silico tests have been performed on the output sequence and the results have been compared to results from other algorithms. Epitope-mapping analysis indicates the functionality of this algorithm, by preserving the hotspot residues in the consensus sequence, and the antigenicity index shows significant antigenicity of the consensus sequence. Moreover, phylogenetic analysis shows no significant change in the placement of the new consensus sequence on the phylogenetic tree compared to other algorithms. This approach will have several implications in designing a new vaccine for highly variable viruses such as HIV-1, Influenza, and Hepatitis C Viruses (HCV).