bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Associative Memory Hamiltonian Model for DNA and Nucleosomes
Authors: Lu Weiqi , Onuchic José N. , Pierro Michele Di 
Published: October 2022

AbstractA model for DNA and nucleosomes is introduced with the goal of studying chromosomes from a single base level all the way to higher-order chromatin structures. This model, dubbed the Widely Editable Chromatin Model (WEChroM), is able to reproduce the complex mechanics of the double helix including its bending persistence length and twisting persistence length, and their respective temperature dependence. The WEChroM Hamiltonian is composed of chain connectivity, steric interactions, and associative memory terms representing all remaining interactions leading to the structure, dynamics, and mechanical characteristics of the B-DNA. Several applications of this model are discussed to demonstrate its applicability. WEChroM is used to investigate the behavior of circular DNA in the presence of positive and negative supercoiling. We show that it recapitulates the formation of plectonemes and of structural defects that relax mechanical stress. The model spontaneously manifests an asymmetric behavior with respect to positive or negative supercoiling, similarly to what was previously observed in experiments. Additionally, we show that the associative memory Hamiltonian is also capable of reproducing the free energy of partial DNA unwrapping from nucleosomes. WEChroM can readily emulate the continuously variable mechanical properties of the 10nm fiber and, by virtue of its simplicity, allows the simulation of molecular systems large enough to study the structural ensembles of genes. WEChroM is implemented in the OpenMM simulation toolkits and is freely available for public use.Author SummaryThe structural ensembles of genes have been so far out of the reach of theoretical and computational investigations because genes are molecular complexes too big to be tackled with even the most efficient computational chemistry approaches and yet too strongly affected by heterogeneous molecular factors to be effectively modeled as a simple polymer. In this work, we develop a computationally efficient, easy-to-use, and widely editable chromatin model to study the principles of DNA folding at the gene scale. Using the framework of Associative Memory Hamiltonians, this model reproduces the structural and mechanical properties of double-stranded DNA and accounts for the effects of nucleosome-forming histone octamers and other proteins bound to DNA. Our results open the path to studying the structural and mechanical ensembles of genetic systems as large as tens of kilobases of chromatin, i.e., the size of mammalian genes.
PIC50: An open source tool for interconversion of PIC50values and IC50for efficient data representation and analysis
Authors: Thakur Aman , Kumar Ajay , Sharma Vivek , Mehta Vineet 
Published: October 2022

AbstractHalf-maximal inhibitory concentration (IC50) is used to determine the potency of a drug against a variety of enzymes/ biological targets associated with the pathogenesis of multiple disorders. The IC50values can be depicted in multiple ways, which makes it difficult to analyze the results presented in different concentrations. Representing data in the form of PIC50values depicting the IC50values as the negative logarithm of IC50in molar concentration is considered to be a better approach as it not only makes data easily understandable but also eliminates the possibility of errors in data representation and reproducibility. Considering the importance of data representation for a better understanding of data and comparing efficacy and potency of the drugs, besides, the significance of PIC50value in the field of CADD, we found that at present there is no single open-source software available to convert the IC50values to PIC50values and vice versa from millimolar to picomolar range. Therefore, in the present study, we develop a tool that could help researchers to interconvert IC50values and PIC50values in a reliable way to eliminate the possibility of errors. We validated our tool through three case studies where the data generated by our tool was found to be 100% accurate. Moreover, we present a case where data was published in literature with errors in calculated PIC50values and demonstrated the importance and reliability of our tool.
Green leaf volatiles co-opt proteins involved in molecular pattern signaling in plant cells
Authors: Tanarsuwongkul Sasimonthakan , Fisher Kirsten , Mullis B. Todd , Roberts Jamie , Negi Harshita , Wang Qiang , Stratmann Johannes W. 
Published: October 2022

AbstractThe green leaf volatiles (GLVs)Z-3-hexen-1-ol andZ-3-hexenyl acetate are airborne infochemicals released from damaged plant tissues that prime defenses against herbivores and pathogens in receiver plants. They are conceptually similar to well-known damage-associated molecular patterns (DAMPs), but little is known about their mechanism of action. Using tomato cell cultures, we found that rapid responses to the two GLVs and the polypeptide DAMP systemin showed a significant overlap but also GLV-specific patterns. Within five minutes, GLVs induced changes in MAPK activity and proton-fluxes as well as rapid and massive changes in the phosphorylation status of proteins. Many of these proteins are involved in reprogramming the proteome from cellular homeostasis to stress and include pattern recognition receptors, a receptor-like cytoplasmic kinase, MAPK cascade components, calcium signaling proteins, and transcriptional regulators, all of which are also components of DAMP signaling pathways. This phosphoproteome may represent an early priming state that enables plants to respond forcefully to a subsequent stress signal.
WGT: Tools and algorithms for recognizing, visualizing and generating Wheeler graphs
Authors: Chao Kuan-Hao , Chen Pei-Wei , Seshia Sanjit A. , Langmead Ben 
Published: October 2022

AbstractSummaryA Wheeler graph represents a collection of strings in a way that is particularly easy to index and query. Such a graph is a practical choice for representing a graph-shaped pangenome, and it is the foundation for current graph-based pangenome indexes. However, there are no practical tools to visualize or to check graphs that may have the Wheeler properties. Here we presentWheelie, an algorithm that combines arenaming heuristicwith a permutation solver (Wheelie-PR) or a Satisfiability Modulo Theory (SMT) solver (Wheelie-SMT) to check whether a given graph has the Wheeler properties, a problem that is NP complete in general.Wheeliecan check a variety of random and real-world graphs in far less time than any algorithm proposed to date. It can check a graph with 1,000s of nodes in seconds. We implement these algorithms together with complementary visualization tools in the WGT toolkit, available as open source software athttps://github.com/Kuanhao-Chao/Wheeler_Graph_Toolkit.
Variability of visual field maps in human early extrastriate cortex challenges the canonical model of organization of V2 and V3
Authors: Ribeiro Fernanda L. , York Ashley , Zavitz Elizabeth , Bollmann Steffen , Rosa Marcello G. P. , Puckett Alexander M. 
Published: October 2022

AbstractVisual field maps in human early extrastriate areas (V2 and V3) are traditionally thought to form mirror-image representations which surround the primary visual cortex (V1). According to this scheme, V2 and V3 form nearly symmetrical halves with respect to the calcarine sulcus, with the dorsal halves representing lower contralateral quadrants, and the ventral halves representing upper contralateral quadrants. This arrangement is considered to be consistent across individuals, and thus predictable with reasonable accuracy using templates. However, data that deviate from this expected pattern have been observed, but mainly treated as artifactual. Here we systematically investigate individual variability in the visual field maps of human early visual cortex using the 7T Human Connectome Project (HCP) retinotopy dataset. Our results demonstrate substantial and principled inter-individual variability. Visual field representation in the dorsal portions of V2 and V3 was more variable than in their ventral counterparts, including substantial departures from the expected mirror-symmetrical patterns. In addition, left hemisphere retinotopic maps were more variable than those in the right hemisphere. Surprisingly, only one-third of individuals had maps that conformed to the expected pattern in the left hemisphere. Visual field sign analysis further revealed that in many individuals the area conventionally identified as dorsal V3 shows a discontinuity in the mirror-image representation of the retina, associated with a Y-shaped lower vertical representation. Our findings challenge the current view that inter-individual variability in early extrastriate cortex is negligible, and that the dorsal portions of V2 and V3 are roughly mirror images of their ventral counterparts.
TPLATE complex dependent endocytosis is required for shoot apical meristem maintenance by attenuating CLAVATA1 signaling
Authors: Wang Jie , Jiang Qihang , Pleskot Roman , Grones Peter , Denay Grégoire , Galván-Ampudia Carlos , Bahafid Elmehdi , Xu Xiangyu , Vandorpe Michael , Mylle Evelien , De Smet Ive , Vernoux Teva , Simon Rüdiger , Nowack Moritz K. , Van Damme Daniel 
Published: October 2022

AbstractEndocytosis regulates the turnover of cell surface localized receptors, which are crucial for plants to sense and rapidly respond to both endogenous and environmental stimuli. The evolutionarily ancient TPLATE complex (TPC) plays an essential role in clathrin-mediated endocytosis (CME) in Arabidopsis plants. Knockout or strong knockdown of single TPC subunits causes male sterility and seedling lethality phenotypes, complicating analysis of the roles of TPC during plant development. Partially functional alleles of TPC subunits however only cause very mild developmental deviations. Here, we took advantage of the recently reported partially functional TPLATE allele, WDXM2, to investigate a role for TPC-dependent endocytosis in receptor-mediated signalling. We discovered that reduced TPC-dependent endocytosis confers a hypersensitivity to very low doses of CLAVATA3 (CLV3) peptide signalling. This hypersensitivity correlated with the abundance of the CLV3 receptor protein kinase CLAVATA1 (CLV1) at the plasma membrane. Genetic analysis and live-cell imaging revealed that TPC-dependent regulation of CLV3-dependent internalization of CLV1 from the plasma membrane is required for CLV3 function in the shoot. Our findings provide evidence that clathrin-mediated endocytosis of CLV1 is a mechanism to dampen CLV3-mediated signaling during plant development.
A fast-killing tyrosine amide ((S)-SW228703) with blood and liver-stage antimalarial activity associated with the Cyclic Amine Resistance Locus (PfCARL)
Authors: Imlay Leah S. , Lawong Aloysus K. , Gahalawat Suraksha , Kumar Ashwani , Xing Chao , Mittal Nimisha , Wittlin Sergio , Churchyard Alisje , Niederstrasser Hanspeter , Crespo-Fernandez Benigno , Posner Bruce , Gamo Francisco Javier , Baum Jake , Winzeler Elizabeth A. , Laleu Benoît , Ready Joseph M. , Phillips Margaret A. 
Published: October 2022

AbstractCurrent malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations inPlasmodium falciparumcyclic amine resistance locus (PfCARL) andP. falciparumacetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of (S)-SW703 is shared with some reportedPfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for activity of (S)-SW703, suggesting differences in mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.
CRF neurons of the BNST promote resilience by blunting the internal experience of aversion
Authors: Haynes Sherod E , Mayberg Helen S , Young Larry J. , Han Ming-Hu 
Published: October 2022

AbstractThe Bed Nucleus of the Stria Terminalis (BNST) has been studied extensively for its coordination of opposing adaptive behaviors. Previously, we uncovered a critical role for Corticotropin-Releasing Factor (CRF)-expressing neurons of the oval nucleus of the BNST (BNSTovCRF) in maintaining resilience to social defeat through stress-dependent self-sustaining neuronal activity.1However, as mice develop resilience, it is not well-understood how affect and motivation are altered to achieve adaptive behavior in the face of ongoing threat. Here, we explore how this neuronal population exerts a powerful influence over internal state in various stress contexts to promote adaptive social responding. Using cell-type-selective optogenetics, a suite of behavioral paradigms, and transgenic Crf-ChR2 mice, we show that BNSTovCRFneurons induce resiliency by altering the encoding of psychosocial stress, enhancing the appetitiveness of social interaction, and enhancing tolerability to physical stress. Adaptive responses to stress typically emanate as a response to negative internal states by external stimuli; here, we show that in resilient mice, stressful environments are less aversive than susceptible mice, suggesting a different motivational capacity to endure stress in this group. Thus, we describe a novel role for BNSTovCRFneurons in resisting the emotional effects of cumulative stress by reducing the internal experience of aversion
Selecting 16S rRNA primers for microbiome analysis in a host-microbe system: the case of the jellyfishRhopilema nomadica
Authors: Barak Noga , Fadeev Eduard , Brekhman Vera , Aharonovich Dikla , Lotan Tamar , Sher Daniel 
Published: October 2022

AbstractAmplicon sequencing of the 16S rRNA gene is extensively used to characterize bacterial communities, including those living in association with eukaryotic hosts. Deciding which region of the 16S rRNA gene to analyze and selecting the appropriate PCR primers remained a major decision when initiating any new microbiome study. Here, we compared three commonly used primers targeting different hypervariable regions of the 16S rRNA gene, V1V2, V3V4, and V4V5, using the jellyfishRhopilema nomadicaas a model. Although all primers exhibit a similar pattern in bacterial community composition, the performance of the V3V4 primer set was superior to V1V2 and V4V5. The V1V2 primers misclassified bacteria from the Bacilli class and exhibited low classification resolution for Rickettsiales, which represent the second most abundant 16S rRNA gene sequence in all the primers. The V4V5 primer set detected almost the same community composition as the V3V4, but the ability of these primers to also amplify eukaryotic 18S rRNA gene may hinder bacterial community observations. However, after overcoming the challenges possessed by each one of those primers, we found that all three of them show very similar bacterial community dynamics and composition. Nevertheless, based on our results, we propose that the V3V4 primer set is the most suitable for studying jellyfish-associated bacterial communities. Our results suggest that, at least for jellyfish samples, it may be feasible to directly compare microbial community estimates from different studies, each using different primers but otherwise similar experimental protocols. More generally, we recommend specifically testing different primers as a prelude to large-scale 16S rRNA gene amplicon analyses, especially of previously unstudied host-microbe associations.
The open field assay is influenced by room temperature and by drugs that affect core body temperature
Authors: Jiménez Jessica A. , McCoy Eric S. , Lee David F. , Zylka Mark J. 
Published: October 2022

AbstractThe open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the center of a chamber that is maintained at ambient room temperature. However, the ambient temperature in most laboratories varies daily and seasonally and can differ substantially between buildings. Here, we sought to evaluate how varying ambient temperature and core body temperature (CBT) affected open field locomotor activity and center time of wild-type (WT) andTrpm8knock-out (Trpm8-/-) mice. TRPM8 is an ion channel that detects cool temperatures and is activated by cooling agents, including icilin and menthol. We found that the cooling agent icilin increased CBT and profoundly reduced distance traveled and center time of WT mice relative to vehicle controls. Likewise, cooling the ambient temperature to 4°C reduced distance traveled and center time of WT mice relative toTrpm8-/-mice. Conversely, the TRPM8 antagonist (M8-B) reduced CBT and increased distance traveled and center time of WT mice when tested at 4°C. Predictably, the TRPM8 antagonist (M8-B) had no effect on CBT or open field behavior ofTrpm8-/-mice. The anxiolytic diazepam reduced CBT in both WT andTrpm8-/-mice. When tested at 4°C, diazepam increased distance traveled and center time in WT mice but did not alter open field behavior ofTrpm8-/-mice. Our study shows that environmental temperature and drugs that affect CBT can influence locomotor behavior and center time in the open field assay, highlighting temperature (ambient and core) as sources of environmental and physiologic variability in this commonly used behavioral assay.
Functionally annotating cysteine disulfides and metal binding sites in the plant kingdom using AlphaFold2 predicted structures
Authors: Willems Patrick , Huang Jingjing , Messens Joris , Van Breusegem Frank 
Published: October 2022

ABSTRACTDeep learning algorithms such as AlphaFold2 predict three-dimensional protein structure with high confidence. The recent release of more than 200 million structural models provides an unprecedented resource for functional protein annotation. Here, we used AlphaFold2 predicted structures of fifteen plant proteomes to functionally and evolutionary analyze cysteine residues in the plant kingdom. In addition to identification of metal ligands coordinated by cysteine residues, we systematically analyzed cysteine disulfides present in these structural predictions. Our analysis demonstrates most of these predicted disulfides are trustworthy due their high agreement (~96%) with those present in X-ray and NMR protein structures, their characteristic disulfide stereochemistry, the biased subcellular distribution of their proteins and a higher degree of oxidation of their respective cysteines as measured by proteomics. Adopting an evolutionary perspective, zinc binding sites are increasingly present at the expense of iron-sulfur clusters in plants. Interestingly, disulfide formation is increased in secreted proteins of land plants, likely promoting sequence evolution to adapt to changing environments encountered by plants. In summary, Alphafold2 predicted structural models are a rich source of information for studying the role of cysteines residues in proteins of interest and for protein redox biology in general.
Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Authors: Jahn Helene , Bartoš Ladislav , Dearden Grace I. , Dittman Jeremy S. , Holthuis Joost C. M. , Vácha Robert , Menon Anant K. 
Published: October 2022

ABSTRACTMitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identified the voltage-dependent ion channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a new class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act by an unprecedented mechanism to import lipids into mitochondria.
Foxp1 acts upstream of Vegfa, suppresses cortical angiogenesis, and promotes hypoxia in radial glia
Authors: Pearson Caroline A. , Buth Jessie E. , Harrison Michael R.M. , Ross M. Elizabeth , Novitch Bennett G. 
Published: October 2022

ABSTRACTRadial glia progenitors within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions at later times, yet the mechanisms controlling this transition remain unclear. Previous work has shown that the autism-linked transcription factor Foxp1 is endogenously expressed by early but not late radial glia, and both loss and gain of Foxp1 can alter their neural progenitor activities and fate choices. Here, we show that premature loss of Foxp1 leads to an increase in transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with an elevation in Vegfa expression in radial glia and precocious vascular network development. Thus, the endogenous decline in Foxp1 expression appears to orchestrate changes in the tissue environment adjacent to radial glia that influence their metabolic state which in turn can alter their self-renewal and neurogenic capacities.
A programmed response precedes cell lysis and death in a mat-forming cyanobacterium
Authors: Zorz Jackie , Paquette Alexandre J. , Gillis Timber , Kouris Angela , Khot Varada , Demirkaya Cigdem , De La Hoz Siegler Hector , Strous Marc , Vadlamani Agasteswar 
Published: October 2022

AbstractCyanobacteria form dense multicellular communities that experience transient conditions in terms of access to light and oxygen. These systems are productive but also undergo substantial biomass turnover, supplementing heightened heterotrophic respiration and oxygen drawdown. Here we use metagenomics and metaproteomics to survey the cellular response of a mat-forming cyanobacterium undergoing mass cell lysis after exposure to dark and anoxic conditions. A lack of evidence for visral, bacterial, or eukaryotic antagonism contradicts commonly held beliefs on the causative agent for cyanobacterial death during dense growth. Instead, proteogenomics data indicated that lysis resulted from a genetically programmed response triggered by a failure to maintain osmotic pressure in the wake of severe energy limitation. Cyanobacterial DNA was rapidly degraded, yet cyanobacterial proteins remained abundant. A subset of proteins, including enzymes involved in amino acid metabolism, peptidases, toxin-antitoxin systems, and a potentially self-targeting CRISPR-Cas system, were upregulated upon lysis, indicating involvement in the programmed cell death response. We propose this natural form of programmed cell death could provide new pathways for controlling harmful algal blooms and for sustainable bioproduct production.