bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting metabolic fluxes reverts metastatic transitions in ovarian cancer
Authors: Arora Garhima , Langthasa Jimpi , Banerjee Mallar , Bhat Ramray , Chatterjee Samrat 
Published: May 2023

AbstractSpheroids formation during epithelial ovarian cancer progression correlates with peritoneal organ colonization, disease recurrence, and poor prognosis. Although cancer progression has been demonstrated to be associated with and driven by metabolic changes within transformed cells, possible associations between metabolic dynamics and metastatic morphological transitions remain unexplored. To address this problem, we performed quantitative proteomics to identify protein signatures associated with three distinct morphologies (2D monolayers and two geometrically individual three-dimensional spheroidal states) of the high-grade serous ovarian cancer line OVCAR-3. Integrating the protein states onto genome-scale metabolic models allowed us to construct context-specific metabolic models for each morphological stage of the OVCAR-3 cell line and systematically evaluate their metabolic functionalities. We obtained disease-driving metabolic reaction modules using these models and elucidated gene knockout strategies to reduce metabolic alterations associated with disease progression. We explored the DrugBank database to mine pharmacological agents and evaluated the effect of drugs in impairing cancer progression. Finally, we experimentally validated our predictions by confirming the ability of one of our predicted drugs: the neuraminidase inhibitor oseltamivir, to disrupt the metastatic spheroidal morphologies without any cytotoxic effect on untransformed stromal mesothelial monolayers.
Rapid memory encoding in a recurrent network model with behavioral time scale synaptic plasticity
Authors: Li Pan Ye , Roxin Alex 
Published: May 2023

AbstractEpisodic memories are formed after a single exposure to novel stimuli. The plasticity mechanisms underlying such fast learning still remain largely unknown. Recently, it was shown that cells in area CA1 of the hippocampus of mice could form or shift their place fields after a single traversal of a virtual linear track. In-vivo intracellular recordings in CA1 cells revealed that previously silent inputs from CA3 could be switched on when they occurred within a few seconds of a dendritic plateau potential (PP) in the post-synaptic cell, a phenomenon dubbed Behavioral Time-scale Plasticity (BTSP). A recently developed computational framework for BTSP in which the dynamics of synaptic traces related to the pre-synaptic activity and post-synaptic PP are explicitly modelled, can account for experimental findings. Here we show that this model of plasticity can be further simplified to simple map which describes changes to the synaptic weights after a single trial. The map can be solved analytically and provides a quantitative fit to experimental data from CA1. We use a temporally symmetric version of this map to study the storage of a large number of spatial memories in a recurrent network, such as CA3. Specifically, the simplicity of the map allows us to calculate the correlation of the synaptic weight matrix with any given past environment analytically. We show that the calculated memory trace can be used to predict the emergence and stability of bump attractors in a high dimensional neural network model endowed with BTSP.Author summaryA recently discovered form of in-vivo plasticity, called Behavioral Time-scale Plasticity (BTSP), leads to the generation of a place cell in CA1 from a previously silent cell after a single intracellular plateau potential (PP). We show that this one-shot learning process is well-described by a 1D map, which updates the synaptic weight matrix after the PP. We use the map to study the storage of spatial memories in a recurrent network, such as CA3. The map allows us to calculate the correlation of the weight matrix with all past explored environments analytically. When only a small fraction of cells are place cells in any given environment, we show that the full dynamics of a recurrent network endowed with BTSP is equivalent to its projection onto a series of weakly interacting manifolds, one for each environment. Interestingly, this weak interaction, which takes the form of quenched variability, actually enhances the memory capacity by stabilizing remote memories which otherwise would be unretrievable.
Evidence for conservation of primordial ∼12-hour ultradian gene programs in humans under free-living conditions
Authors: Zhu Bokai , Liu Silvia , David Natalie L. , Dion William , Doshi Nandini K , Siegel Lauren B. , Amorim Tânia , Andrews Rosemary E. , Kumar GV Naveen , Li Hanwen , Irfan Saad , Pesaresi Tristan , Sharma Ankit X. , Sun Michelle , Fazeli Pouneh K. , Steinhauser Matthew L. 
Published: May 2023

AbstractWhile circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit ∼12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of ∼12h ultradian rhythms in humans is lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust ∼12h transcriptional rhythms from three healthy participants. Pathway analysis implicated ∼12h rhythms in RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed ∼12h rhythms of intron retention events of genes involved in MHC class I antigen presentation, synchronized to expression of mRNA splicing genes in all three participants. Gene regulatory network inference revealed XBP1, and GABP and KLF transcription factor family members as potential transcriptional regulators of human ∼12h rhythms. These results suggest that human ∼12h biological rhythms have a primordial evolutionary origin with important implications for human health and disease.
Family-wide analysis of integrin structures predicted by AlphaFold2
Authors: Zhang Heng , Zhu Daniel S. , Zhu Jieqing 
Published: May 2023

AbstractRecent advances in protein structure prediction using AlphaFold2, known for its high efficiency and accuracy, have opened new avenues for comprehensive analysis of all structures within a single protein family. In this study, we evaluated the capabilities of AphaFold2 in analyzing integrin structures. Integrins are heterodimeric cell surface receptors composed of a combination of 18 α and 8 β subunits, resulting in a family of 24 different members. Both α and β subunits consist of a large extracellular domain, a short transmembrane domain, and typically, a short cytoplasmic tail. Integrins play a pivotal role in a wide range of cellular functions by recognizing diverse ligands. Despite significant advances in integrin structural studies in recent decades, high-resolution structures have only been determined for a limited subsets of integrin members, thus limiting our understanding of the entire integrin family. Here, we first analyzed the single-chain structures of 18 α and 8 β integrins in the AlphaFold2 protein structure database. We then employed the newly developed AlphaFold2-multimer program to predict the α/β heterodimer structures of all 24 human integrins. The predicted structures show a high level of accuracy for the subdomains of both α and β subunits, offering high-resolution structure insights for all integrin heterodimers. Our comprehensive structural analysis of the entire integrin family unveils a potentially diverse range of conformations among the 24 members, providing a valuable structure database for studies related to integrin structure and function. We further discussed the potential applications and limitations of the AlphaFold2-derived integrin structures.
D2/D3 dopamine supports the precision of mental state inferences and self-relevance of joint social outcomes
Authors: Barnby J.M. , Bell V. , Deeley Q , Mehta M. , Moutoussis M. 
Published: May 2023

AbstractStriatal dopamine is important in paranoid attributions, although its computational role in social inference remains elusive. We employed a simple game theoretic paradigm and computational model of intentional attributions to investigate the effects of dopamine D2/D3 antagonism on ongoing mental state inference following social outcomes. Haloperidol, compared to placebo, enhanced the impact of partner behaviour on beliefs about the harmful intent of partners, and increased learning from recent encounters. These alterations caused significant changes to model covariation and negative correlations between self-interest and harmful intent attributions. Our findings suggest haloperidol improves belief flexibility about others and simultaneously reduces the self-relevance of social observations. Our results may reflect the role of D2/D3 dopamine in supporting self-relevant mentalisation. Our data and model bridge theory between general and social accounts of value representation. We demonstrate initial evidence for the sensitivity of our model and short social paradigm to drug intervention and clinical dimensions, allowing distinctions between mechanisms that operate across traits and states.Data AvailabilityAll data and code are available online:https://github.com/josephmbarnby/Barnby_etal_2023_D2D3ModellingGraphical Abstract
Genome dynamics across the evolutionary transition to endosymbiosis
Authors: Siozios Stefanos , Jimenez Pol Nadal , Azagi Tal , Sprong Hein , Frost Crystal L , Parratt Steven R , Taylor Graeme , Brettell Laura , Liew Kwee Chin , Croft Larry , King Kayla C , Brockhurst Michael A , Hypša Václav , Novakova Eva , Darby Alistair C , Hurst Gregory DD 
Published: May 2023

SummaryEndosymbiosis – where a microbe lives and replicates within a host – is an important contributor to organismal function that has accelerated evolutionary innovations and catalysed the evolution of complex life. The evolutionary processes associated with transitions to endosymbiosis, however, are poorly understood. Here, we use comparative genomics of the genusArsenophonusto reveal the complex processes that occur on evolution of an endosymbiotic lifestyle. We compared the genomes of 38 strains spanning diverse lifestyles from environmentally acquired infections to obligate inter-dependent endosymbionts. We observed recent endosymbionts had larger genome sizes than closely related environmentally acquired strains, consistent with evolutionary innovation and rapid gain of new function. Increased genome size was a consequence of prophage and plasmid acquisition including a cargo of type III effectors, and concomitant loss of CRISPR-Cas genome defence systems enabling mobile genetic element expansion. Persistent endosymbiosis was also associated with loss of type VI secretion, likely reflecting reduced microbe-microbe competition. Thereafter, the transition to stable endosymbiosis and vertical inheritance was associated with the expected relaxation of purifying selection, pseudogenisation of genes and reduction of metabolism, leading to genome reduction. However, reduced %GC that is typically considered a progressive linear process was observed only in obligate interdependent endosymbionts. We argue that a combination of the need for rapid horizontal gene transfer-mediated evolutionary innovation together with reduced phage predation in endosymbiotic niches drives loss of genome defence systems and rapid genome expansion upon adoption of endosymbiosis. These remodelling processes precede the reductive evolution traditionally associated with adaptation to endosymbiosis.
Moving Past Neonicotinoids and Honeybees: A Systematic Review of Existing Research on Other Insecticides and Bees
Authors: Dirilgen T. , Herbertsson L. , O’Reilly A. , Mahon N. , Stanley D.A. 
Published: May 2023

AbstractSynthetic pesticides are used widely in agriculture to protect crops from pests, weeds and disease. However, their use also comes with a range of environmental concerns. One of which is effects of insecticides on non-target organisms such as bees, who provide pollination services for crops and wild plants. This systematic literature review quantifies the existing research on bees and insecticides broadly, and then focuses more specifically on non-neonicotinoid insecticides and non-honeybees. We find that articles on honeybees (Apis sp.)and insecticides account for 80% of all research, with all other bees combined making up 20%. Neonicotinoids were studied in 34% of articles across all bees and were the most widely studied insecticide class for non-honeybees overall, with almost three times as many studies than the second most studied class. Of non-neonicotinoid insecticide classes and non-honeybees; the most studied were pyrethroids and organophosphates followed by carbamates, and the most widely represented bee taxa were bumblebees (Bombus), followed by leaf-cutter bees (Megachile) and mason bees (Osmia). Research has taken place across several countries, with the highest numbers of articles from Brazil and the US, and with notable gaps from countries in Asia, Africa and Oceania. Mortality was the most studied effect type, while sub-lethal effects such as on behaviour were less studied. Few studies tested how insecticides were influenced by other multiple pressures, such as climate change and co-occurring pesticides (cocktail effects). As anthropogenic pressures do not occur in isolation, we suggest that future research also addresses these knowledge gaps. Given the changing global patterns in insecticide use, and the increasing inclusion of both non-honeybees and sub-lethal effects in pesticide risk assessment, there is a need for expanding research beyond current state to ensure a strong scientific evidence base for the development of risk assessment and associated policy.
Chromatin context-dependent effects of epigenetic drugs on CRISPR-Cas9 editing
Authors: Schep Ruben , Trauernicht Max , Morris Ben , Vergara Xabier , Beijersbergen Roderick L. , Steensel Bas van 
Published: May 2023

ABSTRACTThe efficiency and outcome of CRISPR/Cas9 editing depends on the chromatin state at the cut site. It has been shown that changing the chromatin state can influence both the efficiency and repair outcome, and epigenetic drugs have been used to improve Cas9 editing. However, because the target proteins of these drugs are not homogeneously distributed across the genome, the efficacy of these drugs may be expected to vary from locus to locus. Here, we systematically analyzed this chromatin context-dependency for 160 epigenetic drugs. We used a human cell line with 19 stably integrated reporters to induce a double-stranded break (DSB) in different chromatin environments. We then measure Cas9 editing efficiency and repair pathway usage by sequencing the mutational signatures. We identified 67 drugs that modulate Cas9 editing efficiency and/or repair outcome dependent on the local chromatin environment. For example, we find a subset of histone deacetylase inhibitors that improve Cas9 editing efficiency throughout all types of heterochromatin (e.g., PCI-24781), while others were only effective in H3K27me3-marked regions (e.g., Vorinostat). In summary, this study reveals that most epigenetic drugs alter CRISPR editing in a chromatin-dependent manner, and provides a detailed guide to improve Cas9 editing more selectively at the desired location.HIGHLIGHTSA screen identifies dozens of drugs that alter Cas9 editing in a chromatin context-dependent mannerMany HDAC inhibitors boost Cas9 editing efficiency throughout all types of heterochromatinThe DNMT inhibitor Decitabine completely blocks resection-dependent repair across the genome
Hindbrain boundaries as niches of neural progenitor/stem cells regulated by the extracellular matrix proteoglycan chondroitin sulphate
Authors: Hutchings Carmel , Nuriel Yarden , Lazar Daniel , Kohl Ayelet , Muir Elizabeth , Nevo Yuval , Benyamini Hadar , Sela-Donenfeld Dalit 
Published: May 2023

ABSTRACTThe interplay between neural progenitor/stem cells (NPSC) and their extracellular matrix (ECM), is a crucial regulatory mechanism that determines their behavior. Nonetheless, how the ECM dictates internal processes remains elusive. The hindbrain is valuable to examine this relationship, as cells in the hindbrain boundaries (HB), which arise between any two neighboring rhombomeres, express the NPSC-marker Sox2 while being surrounded with the ECM molecule chondroitin sulphate proteoglycan (CSPG), in chick and mouse embryos. CSPG expression was used to isolate HB/Sox2+ cells for RNA-sequencing, revealing their distinguished molecular properties as typical NPSCs, which express known and newly-identified genes relating to stem cells, cancer, matrisome and cell-cycle. In contrast, the CSPG-/non-HB cells, displayed clear neural-differentiation transcriptome. To address whether CSPG is significant for hindbrain development, its expression was manipulated in vivo and in vitro. CSPG-manipulations shifted the stem versus differentiation state of HB cells, evident by their behavior and altered gene expression. These results provide novel understanding on the uniqueness of hindbrain boundaries as repetitive pools of NPSCs in-between the rapidly-growing rhombomeres, which rely on their microenvironment to maintain undifferentiated during development.SUMMARY:Transcriptomic analysis of hindbrain boundaries revels them to harbor cells with neural progenitor\stem cell properties that rely on local extracellular matrix to maintain their undifferentiated state.
Automatic annotation of the bHLH gene family in plants
Authors: Thoben Corinna , Pucker Boas 
Published: May 2023

AbstractBackgroundThe bHLH transcription factor family is named after the basic helix-loop-helix (bHLH) domain that is a characteristic element of their members. Understanding the function and characteristics of this family is important for the examination of a wide range of functions. As the availability of genome sequences and transcriptome assemblies has increased significantly, the need for automated solutions that provide reliable functional annotations is emphasised.ResultsA phylogenetic approach was adapted for the automatic identification and functional annotation of the bHLH transcription factor family. The bHLH_annotator for the automated functional annotation of bHLHs was implemented in Python3. Sequences of bHLHs described in literature were collected to represent the full diversity of bHLH sequences.Previously described orthologs form the basis for the functional annotation assignment to candidates which are also screened for bHLH-specific motifs. The pipeline was successfully deployed on the twoArabidopsis thalianaaccessions Col-0 and Nd-1, the monocot speciesDioscorea dumetorum, and a transcriptome assembly ofCroton tiglium.Depending on the applied search parameters for the initial candidates in the pipeline, species-specific candidates or members of the bHLH family which experienced domain loss can be identified.ConclusionsThe bHLH_annotator allows a detailed and systematic investigation of the bHLH family in land plant species and classifies candidates based on bHLH-specific characteristics, which distinguishes the pipeline from other established functional annotation tools. This provides the basis for the functional annotation of the bHLH family in land plants and the systematic examination of a wide range of functions regulated by this transcription factor family.
Isoform Specific Regulation of Adenylyl Cyclase 5 by Gβγ
Authors: Yen Yu-Chen , Li Yong , Chen Chun-Liang , Klose Thomas , Watts Val J , Dessauer Carmen W , Tesmer John J. G. 
Published: May 2023

AbstractThe nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein Gαs, but their response to Gβγ regulation is isoform-specific. For example, AC5 is conditionally activated by Gβγ. Here, we report cryo-EM structures of ligand-free AC5 in complex with Gβγ and of a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. The interface with Gβγ involves AC5 residues that are subject to gain-of-function mutations in humans with familial dyskinesia, indicating that the observed interaction is important for motor function. A molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core, is proposed. Because our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.
Defining a critical role of an essential membrane protein in mycolic acid transport in mycobacteria
Authors: Liang Jeremy , Chen Yushu , Chng Shu-Sin 
Published: May 2023

AbstractA major feature of the mycobacterial outer membrane (OM) is the presence of long, branched chain mycolic acids (MAs), which render the OM hydrophobic and impervious against various noxious substances, including antibiotics. While the biosynthesis of MA is well studied, the mechanisms governing its transport from the inner membrane to the OM remain largely elusive. In this study, we characterized the function of MSMEG_0317 inMycobacterium smegmatis, a membrane protein encoded within a conserved genetic locus that has been implicated in MA metabolism and/or transport. Using a conditional knockout mutant, we demonstrate thatmsmeg_0317is essential for mycobacterial growth. Depletingmsmeg_0317from cells blocks the formation of MA species found at the OM, establishing a critical function in MA transport across the cell envelope. We further reveal that MSMEG_0317 exists as stable dimersin vitrothat require the presence of its N- and C-terminal transmembrane helices, both of which are important for functionality in cells. Our work defines the essential role of MSMEG_0317 in MA metabolism and/or transport, and offers new insights into cell envelope biogenesis in mycobacteria.
Disease resistance gene count increases with rainfall inSilphium integrifolium
Authors: Keepers Kyle , Peterson Kelsey , Raduski Andrew , Turner Kathryn M. , Van Tassel David , Smith Kevin , Harkess Alex , Bever James D. , Brandvain Yaniv 
Published: May 2023

ABSTRACTIntracellular plant defense against pathogens is mediated by a class of disease resistance genes known as NB-LRRs or NLRs (R genes). Many of the diseases these genes protect against are more prevalent in regions of higher rainfall, which provide better growth conditions for the pathogens. As such, we expect a higher selective pressure for the maintenance and proliferation of R genes in plants adapted to wetter conditions. In this study, we enriched libraries for R genes using RenSeq from baits primarily developed from the common sunflower (Helianthus annuus) reference genome. We sequenced the R gene libraries ofSilphium integrifoliumMichx, a perennial relative of sunflower, from 12 prairie remnants across a rainfall gradient in the Central Plains of the United States, with both Illumina short-read (n=99) and PacBio long-read (n=10) approaches. We found a positive relationship between the mean effective annual precipitation of a plant’s source prairie remnant and the number of R genes in its genome, consistent with intensity of plant pathogen coevolution increasing with precipitation. We show that RenSeq can be applied to the study of ecological hypotheses in non-model relatives of model organisms.