bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different computations over the same inputs produce selective behavior in algorithmic brain networks
Authors: Jaworska Katarzyna , van Rijsbergen Nicola J. , Ince Robin A.A. , Schyns Philippe G. 
Published: February 2021

AbstractA key challenge in systems neuroscience remains to understand where, when and now particularlyhowbrain networks compute over sensory inputs to achieve behavior. We used XOR, OR and AND functions as behavioral tasks, because each requires a different computation over the same inputs to produce correct outputs. In each task, source-localized magnetoencephalographic activity progresses through four systems-level computations identified within individual participants (N = 10/task): (1) linear discrimination of each visual input, first contra-laterally in occipital cortex then (2) jointly in midline occipital cortex and right fusiform gyrus, followed by (3) nonlinear task-dependent input integration in temporal-parietal cortex and finally (4) behavioral response representation in post-central gyrus. Our results show how network algorithms differently compute over the same inputs to produce different behaviors.One sentence summaryFour stages of task-specific computations over the same visual inputs achieve different behaviors in dynamic brain networks
Evolutionary implications of recombination differences across diverging populations ofAnopheles
Authors: Nelson Joel T. , Cornejo Omar E. ,   Ag1000G Consortium
Published: February 2021

AbstractRecombination is one of the main evolutionary mechanisms responsible for changing the genomic architecture of populations; and in essence, it is the main mechanism by which novel combinations of alleles, haplotypes, are formed. A clear picture that has emerged across study systems is that recombination is highly variable, even among closely related species. However, it is only until very recently that we have started to understand how recombination variation between populations of the same species impact genetic diversity and divergence. Here, we used whole-genome sequence data to build fine-scale recombination maps for nine populations within two species ofAnopheles,Anopheles gambiaeandAnopheles coluzzii. The genome-wide recombination averages were on the same order of magnitude for all populations except one. Yet, we identified significant differences in fine-scale recombination rates among all population comparisons. We report that effective population sizes, and presence of a chromosomal inversion has major contribution to recombination rate variation along the genome and across populations. We identified over 400 highly variable recombination hotspots across all populations, where only 9.6% are shared between two or more populations. Additionally, our results are consistent with recombination hotspots contributing to both genetic diversity and absolute divergence (dxy) between populations and species ofAnopheles. However, we also show that recombination has a small impact on population genetic differentiation as estimated with FST. The minimal impact that recombination has on genetic differentiation across populations represents the first empirical evidence against recent theoretical work suggesting that variation in recombination along the genome can mask or impair our ability to detect signatures of selection. Our findings add new understanding to how recombination rates vary within species, and how this major evolutionary mechanism can maintain and contribute to genetic variation and divergence within a prominent malaria vector.
Discovery and Functional Characterization of Pro-growth Enhancers in Human Cancer Cells
Authors: Chen Poshen B. , Fiaux Patrick C. , Li Bin , Zhang Kai , Kubo Naoki , Jiang Shan , Hu Rong , Wu Sihan , Wang Mengchi , Wang Wei , McVicker Graham , Mischel Paul S. , Ren Bing 
Published: February 2021

AbstractPrecision medicine depends critically on developing treatment strategies that can selectively target cancer cells with minimal adverse effects. Identifying unique transcriptional regulators of oncogenic signaling, and targeting cancer-cell-specific enhancers that may be active only in specific tumor cell lineages, could provide the necessary high specificity, but a scarcity of functionally validated enhancers in cancer cells presents a significant hurdle to this strategy. We address this limitation by carrying out large-scale functional screens for pro-growth enhancers using highly multiplexed CRISPR-based perturbation and sequencing in multiple cancer cell lines. We used this strategy to identify 488 pro-growth enhancers in a colorectal cancer cell line and 22 functional enhancers for theMYCandMYBkey oncogenes in an additional nine cancer cell lines. The majority of pro-growth enhancers are accessible and presumably active only in cancer cells but not in normal tissues, and are enriched for elements associated with poor prognosis in colorectal cancer. We further identify master transcriptional regulators and demonstrate that the cancer pro-growth enhancers are modulated by lineage-specific transcription factors acting downstream of growth signaling pathways. Our results uncover context-specific, potentially actionable pro-growth enhancers from cancer cells, yielding insight into altered oncogenic transcription and revealing potential therapeutic targets for cancer treatment.
CRISPR interference identifies vulnerable cellular pathways with bactericidal phenotypes inMycobacterium tuberculosis
Authors: McNeil Matthew B. , Keighley Laura M , Cook Josephine R. , Cheung Chen-Yi , Cook Gregory M. 
Published: February 2021

AbstractMycobacterium tuberculosisremains a leading cause of death for which new drugs are needed. The identification of drug targets has been advanced by high-throughput and targeted genetic deletion strategies. Each though has limitations including the inability to distinguish between levels of vulnerability, lethality and scalability as a molecular tool. Using mycobacterial CRISPR interference in combination with phenotypic screening we have overcome these individual issues to investigate essentiality, vulnerability and lethality for 96 target genes from a diverse array of cellular pathways, many of which are potential antibiotic targets. Essential genes involved in cell wall synthesis and central cellular functions were equally vulnerable and often had bactericidal consequences. Conversely, essential genes involved in metabolism, oxidative phosphorylation or amino acid synthesis were less vulnerable to inhibition and frequently bacteriostatic. In conclusion, this study provides novel insights into mycobacterial genetics and biology that will help to prioritise potential drug targets.
Mosquito community composition shapes virus prevalence patterns along anthropogenic disturbance gradients
Authors: Hermanns Kyra , Marklewitz Marco , Zirkel Florian , Kopp Anne , Kramer-Schadt Stephanie , Junglen Sandra 
Published: February 2021

AbstractPreviously unknown pathogens often emerge from primary ecosystems, but there is little knowledge on the mechanism behind. Most studies analyzing the influence of land-use change on pathogen emergence focus on a single host-pathogen system and often observe contrary effects. We studied virus diversity and prevalence patterns in natural and disturbed ecosystems using a multi-host and multi-taxa approach.We detected 331 viral sequences pertaining to 49 viruses of ten RNA-virus families. Highest host and virus diversity was observed in pristine and intermediately disturbed habitats. The majority of the viruses was detected with low prevalence. However, nine viruses were found frequently of which five viruses increased in prevalence from pristine to disturbed habitats, in congruence with the dilution effect hypothesis. Interestingly, the observed increased prevalence of these five viruses in disturbed habitats was not caused by higher host infection rates but by increased host abundance, an effect tentatively named abundance effect.Impact statementOur data show that ecosystem disturbance can lead to a turnover in host community composition and that more individuals of a single species is a key driver of virus emergence.
LSD’s effects are differentially modulated in arrestin knockout mice
Authors: Rodriguiz Ramona M. , Nadkarni Vineet , Means Christopher R. , Chiu Yi-Ting , Roth Bryan L. , Wetsel William C. 
Published: February 2021

ABSTRACTRecent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, the hallucinogenic side-effects of psychedelics often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2Aserotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin-(βArr) mediated signaling. To separate effects of these signaling modes, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, with non-significant effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and βArr1-KO animals. In contrast, LSD only slightly stimulates head twitches in βArr2-KO mice, without effects on retrograde walking or nose poking. The 5-HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs; PPI is unaffected in βArr2-KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in βArr1-KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in βArr1-KOs, and is without effect in βArr2 mutants. Both MDL and the 5-HT1AR antagonist, WAY 100635 (WAY), block the effects of LSD on body temperatures in WT mice, whereas WAY is effective in βArr1-KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through βArr1 and βArr2, and that LSD’s psychedelic drug-like actions appear to require βArr2.
Human brain mitochondrial-nuclear cross-talk is cell-type specific and is perturbed by neurodegeneration
Authors: Fairbrother-Browne Aine , Ali Aminah T. , Reynolds Regina H. , Garcia-Ruiz Sonia , Zhang David , Chen Zhongbo , Ryten Mina , Hodgkinson Alan 
Published: February 2021

AbstractMitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases as mitochondria are essential to neuronal function. The mitochondrial genome encodes a small number of core respiratory chain proteins, whereas the vast majority of mitochondrial proteins are encoded by the nuclear genome. Here we focus on establishing a profile of nuclear-mitochondrial transcriptional relationships in healthy human central nervous system tissue data, before examining perturbations of these processes in Alzheimer&#8217s disease using transcriptomic data originating from affected human brain tissue. Through cross-central nervous system analysis of mitochondrial-nuclear gene pair relationships, we find that the cell type composition underlies regional variation, and variation is driven at the subcellular level by heterogeneity of nuclear-mitochondrial coordination in post-synaptic regions. We show that nuclear genes causally implicated in sporadic Parkinson&#8217s disease and Alzheimer&#8217s disease show much stronger relationships with the mitochondrial genome than expected by chance, and that nuclear-mitochondrial relationships are significantly perturbed in Alzheimer&#8217s disease cases, particularly amongst genes involved in synaptic and lysosomal pathways. Finally, we present MitoNuclearCOEXPlorer, a web tool designed to allow users to interrogate and visualise key mitochondrial-nuclear relationships in multi-dimensional brain data. We conclude that mitochondrial-nuclear relationships differ significantly across regions of the healthy brain, which appears to be driven by the functional specialisation of different cell types. We also find that mitochondrial-nuclear co-expression in critical pathways is disrupted in Alzheimer&#8217s disease, potentially implicating the regulation of energy balance and removal of dysfunctional mitochondria in the etiology or progression of the disease and making the case for the relevance of bi-genomic co-ordination in the pathogenesis of neurodegenerative diseases.
Uncovering Differences in Hydration Free Energies and Structures for Model Compound Mimics of Charged Sidechains of Amino Acids
Authors: Fossat Martin J. , Zeng Xiangze , Pappu Rohit V. 
Published: February 2021

ABSTRACTFree energies of hydration are of fundamental interest for modeling and understanding conformational and phase equilibria of macromolecular solutes in aqueous phases. Of particular relevance to systems such as intrinsically disordered proteins are the free energies of hydration and hydration structures of model compounds that mimic charged sidechains of Arg, Lys, Asp, and Glu. Here, we deploy a Thermodynamic Cycle based Proton Dissociation (TCPD) approach in conjunction with data from direct measurements to obtain estimates for the free energies of hydration for model compounds that mimic the sidechains of Arg+, Lys+, Asp-, and Glu-. Irrespective of the choice made for the hydration free energy of the proton, the TCPD approach reveals clear trends regarding the free energies of hydration for Arg+, Lys+, Asp-, and Glu-. These trends include asymmetries between the hydration free energies of acidic (Asp-and Glu-) and basic (Arg+and Lys+) residues. Further, the TCPD analysis, which relies on a combination of experimental data, shows that the free energy of hydration of Arg+is less favorable than that of Lys+. We sought a physical explanation for the TCPD derived trends free energies of hydration. To this end, we performed temperature dependent calculations of free energies of hydration and analyzed hydration structures from simulations that use the polarizable AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) forcefield and water model. At 298 K, the AMOEBA model generates estimates of free energies of hydration that are consistent with TCPD values with a free energy of hydration for the proton of ≈ -259 kcal / mol. Analysis of temperature dependent simulations leads to a structural explanation for the observed differences in free energies of hydration of ionizable residues and reveals that the heat capacity of hydration is positive for Arg+and Lys+and negative for Asp-and Glu-.
Cryo-EM Structure of Bacterioferritin Nanocages Provides Insight into the Bio-mineralization of Ferritins
Authors: Jobichen Chacko , Chong Tan Ying , Rattinam Rajesh , Basak Sandip , Srinivasan Mahalashmi , Pandey Kannu Priya , Ngoc Tran Bich , Shi Jian , Angayarkanni Jayaraman , Sivaraman J 
Published: February 2021

AbstractIron is an essential element involved in various metabolic processes. The ferritin family of proteins forms nanocage assembly and are involved in iron oxidation, storage and mineralization. Although several structures of human ferritin and bacterioferritin subunits have been resolved, there is still no complete structure that shows both the trapped Fe-biomineral cluster along with the nanocage. Furthermore, whereas the mechanism of iron trafficking has been explained using various approaches, an atomic-level description of the pathway and the biomineralization that occurs inside the cavity are lacking. Here, we report three cryo-EM structures of different states of theStreptomyces coelicolorbacterioferritin nanocage (i.e., apo, holo) at 3.4 Å to 4.6 Å resolution and the subunit crystal structure at 2.6 Å resolution. The holo forms show different stages of Fe-biomineral accumulation inside the nanocage and suggest the possibility of a different Fe biomineral accumulation process. The cryo-EM map shows connections between the Fe-biomineral cluster and residues such as Thr157 and Lys42 from the protein shell, which are involved in iron transport. Mutation and truncation of the bacterioferritin residues involved in these connections can significantly reduce iron binding as compared with wild type bacterioferritin. Moreover,S. coelicolorbacterioferritin binds to various DNA fragments, similar to Dps (DNA-binding protein from starved cells) proteins. Collectively, our results represent a prototype for the ferritin nanocage, revealing insight into its biomineralization and the potential channel for ferritin-associated iron trafficking.
BGvar - a comprehensive resource for blood group immunogenetics
Authors: Rophina Mercy , Pandhare Kavita , Jadhao Sudhir , Nagaraj Shivashankar H. , Scaria Vinod 
Published: February 2021

AbstractBackgroundBlood groups form the basis of effective and safe blood transfusion. There are about 41 well recognized human blood group systems presently known. Blood groups are molecularly determined by the presence of specific antigens on the red blood cells and are genetically determined and inherited following Mendelian principles. The lack of a comprehensive, relevant, manually compiled and genome-ready dataset of red cell antigens limited the widespread application of genomic technologies to characterise and interpret the blood group complement of an individual from genomic datasets.Materials and MethodsA range of public datasets were used to systematically annotate the variation compendium for its functionality and allele frequencies across global populations. Details on phenotype or relevant clinical importance were collated from reported literature evidence.ResultsWe have compiled the Blood Group Associated Genomic Variant Resource (BGvar), a manually curated online resource comprising all known human blood group related allelic variants including a total of 1672 ISBT approved alleles and 1552 alleles predicted and curated from literature reports. This repository includes 1606 Single Nucleotide Variations (SNVs), 270 Insertions, Deletions (InDels) and Duplications and about 1310 combination mutations corresponding to 41 human blood group systems and 2 transcription factors. This compendium also encompasses gene fusion and rearrangement events occurring in human blood group genes.ConclusionTo the best of our knowledge, BGvar is a comprehensive and a user friendly resource with most relevant collation of blood group alleles in humans. BGvar is accessible online at URL:http://clingen.igib.res.in/bgvar/
Expanded Asgard archaea shed new light on the origin of eukaryotes and support a 2-domain tree of life
Authors: Xie Ruize , Wang Yinzhao , Huang Danyue , Hou Jialin , Li Liuyang , Hu Haining , Zhao Xiaoxiao , Wang Fengping 
Published: February 2021

AbstractThe hypothesis that eukaryotes originated from within the domain Archaea has been strongly supported by recent phylogenomic analyses placing Heimdallarchaeota from the Asgard superphylum as the closest known archaeal sister-group to eukaryotes. At present, only seven phyla are described in the Asgard superphylum, which limits our understanding of the relationship between eukaryotes and archaea, as well as the evolution and ecological functions of Asgard archaea. Here, we describe five novel phylum-level Asgard archaeal lineages, tentatively named Tyr-, Sigyn-, Freyr-, Hoder- and Balderarchaeota. Comprehensive phylogenomic analyses supported a new Asgard lineage Tyrarchaeota was identified as a deeper branching lineage cluster with the eukaryotic nuclear host lineage than Heimdallarchaeota that were previously considered as the closest archaeal relatives of eukaryotes. Metabolic reconstruction of Tyrarchaeota suggests a mixotrophic lifestyle of this archaea, capable of peptides and amino acids utilization while having the potential using the Wood-Ljungdahl pathway for carbon fixation and acetogenesis. This study largely expands the Asgard superphylum, provides additional evidences to support the 2-domain life tree thus sheds new light on the evolution and geochemical functions of the Asgard archaea.
Cellular management of Zinc in group BStreptococcussupports bacterial resistance against metal intoxication and promotes disseminated infection
Authors: Sullivan Matthew J. , Goh Kelvin G. K. , Ulett Glen C. 
Published: February 2021

AbstractZinc (Zn) is an essential trace element for normal bacterial physiology but divergently, can intoxicate bacteria at high concentrations. Here, we define the molecular systems for Zn detoxification inStreptococcus agalactiae, also known as group B Streptococcus, and examine the effects of resistance to Zn stress on virulence. We compared the growth of wild-type bacteria and mutants deleted for the Zn exporter,czcD, and the response regulator,sczA, using Zn-stress conditionsin vitro.Macrophage antibiotic protection assays and a mouse model of disseminated infection were used to assess virulence. Global bacterial transcriptional responses to Zn stress were defined by RNA-sequencing and qRTPCR.czcDandsczAenabledS. agalactiaeto survive Zn stress, with the putative CzcD efflux system activated by SczA. Additional genes activated in response to Zn stress encompassed divalent cation transporters that contribute to regulation of Mn and Fe homeostasis.In vivo, theczcD-sczAZn-management axis supported virulence in the blood, heart, liver and bladder. Additionally, several genes not previously linked to Zn stress in any bacterium, including most notably,arcAfor arginine deamination also mediated resistance to Zn stress; representing a novel molecular mechanism of bacterial resistance to metal intoxication. Taken together, these findings show thatS. agalactiaeresponds to Zn stress bysczAregulation ofczcD, with additional novel mechanisms of resistance supported byarcA, encoding arginine deaminase. Cellular management of Zn stress inS. agalactiaesupports virulence by facilitating bacterial survival in the host during systemic infection.Importance StatementStreptococcus agalactiae, also known as group B streptococcus, is an opportunistic pathogen that causes various diseases in humans and animals. This bacterium has genetic systems that enable Zinc (Zn) detoxification in environments of metal stress, but these systems remain largely undefined. Using a combination of genomic, genetic and cellular assays we show that this pathogen controls Zn export through CzcD to manage Zn stress, and utilizes a system of arginine deamination never previously linked to metal stress responses in bacteria to survive metal intoxication. We show that these systems are crucial for survival ofS. agalactiae in vitroduring Zn stress and also enhance virulence during systemic infection in mice. These discoveries establish new molecular mechanisms of resistance to metal intoxication in bacteria; we suggest these mechanisms are likely to operate in other bacteria as a way to sustain microbial survival in conditions of metal stress, including in host environments.