bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jointly Modeling Species Niche and Phylogenetic Model in a Bayesian Hierarchical Framework
Authors: McHugh Sean W , Espíndola Anahí , White Emma , Uyeda Josef 
Published: July 2022

ABSTRACTWhen studying how species will respond to climatic change, a common goal is to predict how species distributions change through time. Environmental niche models (ENMs) are commonly used to estimate a species’ environmental niche from observed patterns of occurrence and environmental predictors. However, species distributions are often shaped by non-environmental factors–including biotic interactions and dispersal barriers—truncating niche estimates. Though a truncated niche estimate may accurately predict present-day species distribution within the sampled area, this accuracy decreases when predicting occurrence at different places and under different environmental conditions. Modeling niche in a phylogenetic framework leverages a clade’s shared evolutionary history to pull species estimates closer towards phylogenetic conserved values and farther away from species specific biases. We propose a new Bayesian model of phylogenetic niche estimation implemented in R calledBePhyNE(Bayesian environmental Phylogenetic Niche Estimation). Under our model, species ENM parameters are transformed into biologically interpretable continuous parameters of environmental niche optimum, breadth, and tolerance evolving as a multivariate Brownian motion. Through simulation analyses, we demonstrate model accuracy and precision that improve as phylogeny size increases. We also demonstrate our model on eastern United States Plethodontid salamanders and recover accurate estimates of species niche, even when species occurrence data is lacking and entirely informed by the evolutionary model. Our model demonstrates a novel framework where niche changes can be studied forwards and backwards through time to understand ancestral ranges, patterns of environmental specialization, and estimate niches of data-deficient species.
The DynaSig-ML Python package: automated learning of biomolecular dynamics-function relationships
Authors: Mailhot Olivier , Major François , Najmanovich Rafael 
Published: July 2022

AbstractSummaryThe DynaSig-ML (“Dynamical Signatures - Machine Learning”) Python package allows the efficient, user-friendly exploration of 3D dynamics-function relationships in biomolecules, using datasets of experimental measures from large numbers of sequence variants. The DynaSig-ML package is built around the Elastic Network Contact Model (ENCoM), the first and only sequence-sensitive coarse-grained NMA model, which is used to generate the input Dynamical Signatures. Starting fromin silicomutated structures, the whole pipeline can be run with just a few lines of Python and modest computational resources. The compute-intensive steps can also easily be parallelized in the case of either large biomolecules or vast amounts of sequence variants. As an example application, we use the DynaSig-ML package to predict the evolutionary fitness of the bacterial enzyme VIM-2 lactamase from deep mutational scan data.Availability and implementationDynaSig-ML is open source software available athttps://github.com/gregorpatof/dynasigml_packageContactrafael.najmanovich@umontreal.ca
Epidermal threads reveal the origin of hagfish slime
Authors: Zeng Yu , Plachetzki David , Nieders Kristen , Campbell Hannah , Cartee Marissa , Guillen Kennedy , Fudge Douglas 
Published: July 2022

AbstractFiber-reinforced soft materials possess high flexibility with high strength but are rare in nature. Hagfishes can produce a tough, fibrous slime within a fraction of a second by ejecting two cellular products, mucus and threads, into seawater. With thousands of silk-like threads, the slime is highly effective in defending against large predators. However, the evolutionary origin of hagfish slime remains unresolved, with the presence of another, putatively homologous thread in the epidermis providing circumstantial evidence for an epidermal origin. Here, we investigated the epidermal threads produced in hagfish skin. We found that these threads average ∼2 mm in length and ∼0.5 μm in diameter, or ∼80 times shorter and ∼4 times thinner than the slime threads, characterizing the second longest intracellular fiber. The entire hagfish body is covered by a dense layer of epidermal thread cells, with each square millimeter of skin storing a total of ∼96 cm threads. Experimentally induced damage to a hagfish’s skin caused the release of threads, which together with mucus, formed an adhesive epidermal slime that is more fibrous and less dilute than the defensive slime. Transcriptome analyses further revealed that the epidermal threads are ancestral to the slime threads, with duplication and diversification of thread genes in parallel with the evolution of slime glands. These results support an epidermal origin of hagfish slime and slime glands, as driven by predator selection for stronger and more voluminous slime.
The temporal organization of corticostriatal communications
Authors: Korponay Cole , Stein Elliot A , Ross Thomas J 
Published: July 2022

ABSTRACTThe cortex and striatum are linked by hundreds of thousands of structural connections, and the transmission of temporally aligned communications across many of these connections at once is an electrophysiological prerequisite for striatal activation. Despite the importance of communication timing in corticostriatal circuitry, there is little understanding of its system-level organization and properties. To investigate this, we leveraged emerging methods to “temporally unwrap” fMRI data and measure patterns of cortex-striatum node-pair coactivation at frame-wise (i.e., <1 sec) resolution in low head-motion subjects from the Human Connectome Project. First, we identify communities of cortex-striatum node-pairs with preferentially synchronized coactivation patterns. Surprisingly, we find that the map of striatal areas with temporally aligned cortical coactivation patterns does not simply reflect the map of striatal areas with similar cortical connectivity profiles. As a result of the distinct spatial organization of these gradients, striatal nodes connected to similar areas of cortex may nonetheless interact with these cortical areas at different times, and striatal nodes connected to different areas of cortex may nonetheless interact with these areas at similar times. We provide evidence for a possible mechanism driving this divergence: striatal nodes with similar cortical connectivity profiles may have differently timed interactions with cortex if they have different modulatory input profiles (i.e., from the midbrain and thalamus) that differentially gate their responsivity to cortical input. Overall, this blended organization may serve to both increase the repertoire of striatal responses to frontal input and facilitate coordination across functional domains in the temporal dimension. Findings provide a framework to investigate the role of corticostriatal temporal coordination in behavior and disease.SIGNIFICANCE STATEMENTWe provide the first systems-level account of temporal communication patterns between cortex-striatum node-pairs, mapping communities of node-pairs with synchronized communication patterns using an emerging fMRI temporal-unwrapping technique and providing evidence for the mechanism that dictates the organization of these communities. Findings have broad implications for our understanding of the functional architecture of corticostriatal circuits.
Maast: genotyping thousands of microbial strains efficiently
Authors: Shi Zhou Jason , Nayfach Stephen , Pollard Katherine S. 
Published: July 2022

AbstractGenotyping single nucleotide polymorphisms (SNPs) of intraspecific genomes is a prerequisite to performing population genetic analysis and microbial epidemiology. However, existing algorithms fail to scale for species with thousands of sequenced strains, nor do they account for the biased sampling of strains that has produced considerable redundancy in genome databases. Here we present Maast, a tool that reduces the computational burden of SNP genotyping by leveraging this genomic redundancy. Maast implements a novel algorithm to dynamically identify a minimum set of phylogenetically diverse conspecific genomes that contains the maximum number of SNPs above a user-specified allele frequency. Then it uses these genomes to construct a SNP panel for each species. A species’ SNP panel enables Maast to rapidly genotype thousands of strains using a hybrid of whole-genome alignment and k-mer exact matching. Maast works with both genome assemblies and unassembled sequencing reads. Compared to existing genotyping methods, Maast is more accurate and up to two orders of magnitude faster. We demonstrate Maast’s utility on species with thousands of genomes by reconstructing the genetic structure of Helicobacter pylori across the globe and tracking SARS-CoV-2 diversification during the COVID-19 outbreak. Maast is a fast, reliable SNP genotyping tool that empowers population genetic meta-analysis of microbes at an unrivaled scale.Availabilitysource code of Maast is available at https://github.com/zjshi/Maast.Contactkpollard@gladstone.ucsf.edu
The mRNA decapping machinery targetsLBD3/ASL9to mediate apical hook and lateral root development inArabidopsis
Authors: Zuo Zhangli , Roux Milena Edna , Chevalier Jonathan Renaud , Dagdas Yasin F. , Yamashino Takafumi , Højgaard Søren Diers , Knight Emilie , Østergaard Lars , Rodriguez Eleazar , Petersen Morten 
Published: July 2022

AbstractMulticellular organisms perceive and transduce multiple cues to optimize development. Key transcription factors drive developmental changes, but RNA processing also contributes to tissue development. Here, we report that multiple decapping deficient mutants share developmental defects in apical hook, primary and lateral root growth. More specifically,LATERAL ORGAN BOUNDARIES DOMAIN 3(LBD3)/ASYMMETRIC LEAVES 2-LIKE 9(ASL9) transcripts accumulate in decapping deficient plants and can be found in complexes with decapping components. Accumulation ofASL9inhibits apical hook, primary root growth and lateral root formation. Interestingly, exogenous auxin application restores lateral roots formation in bothASL9over-expressors and mRNA decay-deficient mutants. Likewise, mutations in the cytokinin transcription factors type-B ARABIDOPSIS RESPONSE REGULATORS (B-ARRs)ARR10andARR12restore the developmental defects caused by over-accumulation of cappedASL9transcript uponASL9overexpression. Most importantly, loss-of-function ofasl9partially restores apical hook and lateral root formation in decapping deficient mutants. Thus, the mRNA decay machinery directly targetsASL9transcripts for decay, possibly to interfere with cytokinin/auxin responses, during development.
BysR, a LysR-type Pleiotropic Regulator, Controls Production of Occidiofungin by Activating the LuxR-type transcriptional regulator AmbR1 in Burkholderia sp. JP2-270
Authors: Wu Lijuan , Tang Liqun , He Yuchang , Han Cong , Wang Lei , Zhang Yunzeng , Zhiguo E 
Published: July 2022

ABSTRACTOccidiofungin is a highly effective antifungal glycopeptide produced by certain Burkholderia strains. The ocf gene cluster directing occidiofungin biosynthesis is regulated by cluster-specific regulators encoded by ambR homolog(s) within the same gene cluster, while it remains unknown to what extent occidiofungin biosynthesis is connected with the core regulation network. Here, we report that a LysR-type regulator BysR acts as a pleotropical regulator, and is essential for occidiofungin biosynthesis by directly activating ambR1 transcription in Burkholderia sp. JP2-270. Deletion of bysR and ocfE both abolished the antifungal activity in JP2-270. This defect of the bysR mutant can be recovered by constitutively expressing bysR or ambR1 but not by ambR2. The EMSA assay collectively showed that BysR regulates ambR1 through direct binding to its promoter region. Taken together, occidiofungin produced by JP2-270 is the main substance inhibiting M. oryzae, and BysR controls occidiofungin production by directly activating the expression of ambR1. Besides, transcriptomic analysis revealed altered expression of 350 genes in response to bysR deletion, and the genes engaged in flagellar assembly and bacterial chemotaxis are the most enriched pathways. Also, 400 putative loci targeted by BysR were identified by DAP-seq in JP2-270. These loci not only include genes engaged in key metabolic pathways but also genes involved in secondary metabolic pathways. Collectively, we proposes that BysR may be a novel pleiotropic regulator, and ambR1 is an important target gene of BysR, which is an intra-cluster transcriptional regulatory gene that further activates the transcription of ocf gene cluster.IMPORTANCEThis study shows that BysR, a LysR-type transcriptional regulator (LTTR) from Burkholderia sp. JP2-270, activates the expression of ambR1 gene responsible for regulating the synthesis of occidiofungin. BysR also acts as a pleiotropic regulator that controls primary and secondary metabolism, antibiotic resistance, motility, transport and other cellular processes in Burkholderia sp. JP2-270. This study provides insight into the regulatory mechanism of occidiofungin synthesis and enhances our understanding of the regulatory patterns of the LysR-type regulator.
The emergence of new lineages of the Mpox virus could affect the 2022 outbreak
Authors: Abrahim Mayla , Guterres Alexandro , Costa Neves Patrícia Cristina da , Ano Bom Ana Paula Dinis 
Published: July 2022

AbstractHuman Mpox is a highly contagious viral disease caused by Mpox virus, currently causing outbreaks in various regions of the world and considered a global public health problem. Understanding how the virus adapts or transfers to a new host species is crucial for effective prevention and treatment of viral infections. A comprehensive analysis of 1,318 accessible Mpox genomes was conducted to assess potential phenotypic effects, incorporating the examination of pseudogenes, gene duplication and deletion, as well as sequences obtained from the 2022 outbreak. This study we analyzed the genomic sequences of Mpox viruses from different clades and found that only a small percentage of proteins were conserved across the analyzed clades, with many proteins exhibiting various mutations, indicating the potential correlation between lineage or clade and variations in the pathology of human Mpox disease. The study highlights the importance of analyzing aligned regions in viral genomes to understand the evolution of the virus and the impact of structural changes on protein functions. In brief, further investigations are required to establish a correlation between the effects of these genetic modifications and the novel transmission pathways, average age, clinical manifestations, and symptoms observed in the ongoing outbreak.
Timing along the cardiac cycle modulates neural signals of reward-based learning
Authors: Fouragnan Elsa , Hosking Billy , Cheung Yin , Prakash Brooke , Rushworth Matthew , Sel Alejandra 
Published: July 2022

AbstractNatural fluctuations in cardiac activity influence brain activity associated with sensory stimuli and affect perceptual decisions about low magnitude, near-threshold stimuli. However, little is known about the impact of fluctuations in heart activity on other internal representations. Here we investigate cardiac influences on learning-related internal representations – absolute and signed prediction errors. By combining machine learning techniques with electroencephalography (EEG) and both simple, direct indices of task performance and computational model-derived indices of learning, we demonstrate that just as people are more sensitive to low magnitude, near threshold sensory stimuli in certain cardiac phases, so are they more sensitive to low magnitude absolute prediction errors in the same cycles. Importantly, however, this occurs even when the low magnitude prediction errors are associated with clearly suprathreshold sensory events. In addition, participants exhibiting stronger difference in their prediction errors representations between cardiac cycles exhibited higher learning rates and greater task accuracy.
Astrocytes regulate locomotion by orchestrating neuronal rhythmicity in the spinal network via potassium clearance
Authors: Barbay Tony , Pecchi Emilie , Ducrocq Myriam , Rouach Nathalie , Brocard Frédéric , Bos Rémi 
Published: July 2022

SummaryNeuronal rhythmogenesis in the spinal cord is correlated with variations in extracellular K+ levels ([K+]e). Astrocytes play important role in[K+]e homeostasis and compute neuronal information. Yet it is unclear how neuronal oscillations are regulated by astrocytic K+ homeostasis. Here we identify the astrocytic inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) as a key molecular player for neuronal rhythmicity in the spinal central pattern generator (CPG). By combining two-photon calcium imaging with electrophysiology, immunohistochemistry and genetic tools, we report that astrocytes display Ca2+ transients before and during oscillations of neighbouring neurons. Inhibition of astrocytic Ca2+ transients with BAPTA decreases the barium-sensitive Kir4.1 current responsible of K+ clearance. Finally, we show in mice that Kir4.1 knockdown in astrocytes progressively prevents neuronal oscillations and alters the locomotor pattern resulting in lower motor performances in challenging tasks. These data identify astroglial Kir4.1 channels as key regulators of neuronal rhythmogenesis in the CPG driving locomotion.Significance statementDespite decades of research, the cellular mechanisms responsible of the synchronized rhythmic oscillations driving locomotion remain elusive. To gain insight into the function of the spinal locomotor network, numerous studies have characterized diverse classes of locomotor-related neurons to determine their role in generating rhythmic movements during locomotion. In contrast, studies investigating non-neuronal components of the spinal cord are sparse. Our study represents a significant breakthrough by identifying astrocytic K+ uptake as a key regulator of neuronal rhythmicity synchronization and locomotor pattern at the cellular, microcircuit and system levels. These data provide mechanistic insights into the neuroglial dialogue at play during rhythmogenesis and point to a novel astroglial target for restoring normal neuronal network excitability in brain disorders and neurodegenerative diseases.
Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors
Authors: Irfan Iram , Uddin Amad , Jain Ravi , Gupta Aashima , Gupta Sonal , Napoleon John V. , Hussain Afzal , Alajmi Mohamed F. , Joshi Mukesh C. , Hasan Phool , Abid Mohammad , Singh Shailja 
Published: July 2022

AbstractTo combat the emergence of drug resistance against the existing antimalarials, novel side chain containing 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) were designed and synthesized by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1- yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4- azido-7-chloroquinoline, respectively via a ‘click’ reaction. The selected CQTrICh-analogs: 7l and 7r inhibited chloroquine-sensitive (3D7) and resistant (RKL-9) strains of Plasmodium falciparum, with IC50 values of 2.4 µM & 1.8 µM (7l), and 3.5 µM & 2.7 µM (7r), respectively, and showed insignificant hemolysis and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. Given the importance of Calcium-Dependent Protein Kinase 1 (PfCDPK1) in the parasite biology, notably during late schizogony and subsequent invasion of merozoites into host RBCs, we identified this protein as a possible molecular target of these active hybrids. In silico interaction analysis indicated that 7l and 7r stably interact with the catalytically active ATP-binding pocket of PfCDPK1, by the formation of energetically favorable H-bonds. Furthermore, in vitro Microscale Thermophoresis and kinase assays with recombinant PfCDPK1 demonstrated that the active hybrids interact with and inhibit the kinase activity, thus presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating that they are selective for the parasite kinase. Conceivably, we report the antiplasmodial potential of novel kinase targeting bio-conjugates, a step towards developing pan-kinase inhibitors, which is a prerequisite for cross-stage anti-malarial protection.GRAPHICAL ABSTRACT
The Trouble with Triples: Examining the Impact of Measurement Error in Mediation Analysis
Authors: Gastonguay Madeleine S. , Keele Gregory R. , Churchill Gary A. 
Published: July 2022

AbstractMediation analysis is used in genetic mapping studies to identify candidate gene mediators of quantitative trait loci (QTL). We consider genetic mediation analysis of triplets - sets of three variables consisting of a target trait, the genotype at a QTL for the target trait, and a candidate mediator that is the abundance of a transcript or protein whose coding gene co-locates with the QTL. We show that, in the presence of measurement error, mediation analysis can infer partial mediation even in the absence of a causal relationship between the candidate mediator and the target. We describe a measurement error model and a corresponding latent variable model with estimable parameters that are combinations of the causal effects and measurement errors across all three variables. The relative magnitudes of the latent variable correlations determine whether or not mediation analysis will tend to infer the correct causal relationship in large samples. We examine case studies that illustrate the common failure modes of genetic mediation analysis and demonstrate how to evaluate the effects of measurement error. While genetic mediation analysis is a powerful tool for identifying candidate genes, we recommend caution when interpreting mediation analysis findings.
Deep Phosphoproteomic Elucidation of Metformin-Signaling in Heterogenous Colorectal Cancer Cells
Authors: Salovska Barbora , Gao Erli , Müller-Dott Sophia , Li Wenxue , Dugourd Aurelien , Rosenberger George , Saez-Rodriguez Julio , Liu Yansheng 
Published: July 2022

ABSTRACTThe biguanide drug metformin is a safe and widely prescribed drug for type 2 diabetes. Interestingly, hundreds of clinical trials were set to evaluate the potential role of metformin in the prevention and treatment of cancer including colorectal cancer (CRC). To interrogate cell signaling events and networks in CRC and explore the druggability of the metformin-rewired phosphorylation network, we performed a proteomic and phosphoproteomic analysis on a panel of 12 molecularly heterogeneous CRC cell lines. Using in-depth data-independent analysis mass spectrometry (DIA-MS), we profiled a total of 10,142 proteins and 56,080 phosphosites (P-sites) in CRC cells treated with metformin for 30 minutes and 24 hours. Our results indicate that metformin does not directly trigger or inhibit any immediate phosphorylation events. Instead, it primarily remodels cell signaling in the long-term. Strikingly, the phosphorylation response to metformin was highly heterogeneous in the CRC panel, uncovering four groups of metformin responsivity. We further performed a network analysis to systematically estimate kinase/phosphatase activities and reconstruct signaling cascades in each cell line. We created a “MetScore” which catalogs the most consistently perturbed P-sites among CRC cells for future studies. Finally, we leveraged the metformin P-site signature to identify pharmacodynamic interactions revealing a number of candidate metformin-interacting drugs. Together, we provide a data resource using state-of-the-art phosphoproteomics to understand the metformin-induced cell signaling for potential cancer therapeutics.