bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cup is essential foroskarmRNA translational repression during earlyDrosophilaoogenesis
Authors: Bayer Livia V. , Milano Samantha , Formel Stephen K. , Kaur Harpreet , Ravichandran Rishi , Cambeiro Juan A. , Slinko Lizaveta , Catrina Irina E. , Bratu Diana P. 
Published: January 2023

ABSTRACTThe proper timing of mRNA translation is crucial across many biological systems for processes such as intercellular communication, body pattern formation, and morphogenesis. The mainD. melanogasterposterior determinant,oskar, is maternally transcribed, but only translated when properly localized at the oocyte’s posterior cortex. Bruno 1 and Cup are two effector proteins known to participate in multiple aspects ofoskarmRNA regulation. Current model describes a mechanism in which Bruno 1 is necessary for Cup’s recruitment tooskarmRNA, and Bruno 1 is indispensable for its translational repression. Here, we reveal that the Bruno 1-Cup interaction, as well as their interdependent influence on each other’s mRNA and protein expression, lead to preciseoskarmRNA regulation during early oogenesis. We show that these factors stably associate with theoskarmRNAin vivo, but surprisingly, Bruno 1’s stable association withoskarmRNA depends on Cup, while Bruno 1 is not necessary for Cup association tooskarmRNA. During early oogenesis, Cup, not Bruno 1, is the essential factor foroskarmRNA repression. Cup is a crucial P-body member that maintains proper P-body morphology during oogenesis, as well as it is necessary foroskarmRNA’s association with P-bodies, thus driving the translational repression and stability ofoskarmRNA. Our experimental results collectively suggest a regulatory mechanism where a feedback loop between Bruno 1 and Cup coordinatesoskarmRNA regulation in the egg chamber allowing for proper development to occur.
Sperm-contributed centrioles segregate stochastically into blastomeres of 4-cell stageC. elegansembryos
Authors: Gönczy Pierre , Balestra Fernando R. 
Published: January 2023

AbstractWhereas both sperm and egg similarly contribute nuclear genetic material to the zygote of metazoan organisms, the inheritance of other cellular constituents is unequal between the two gametes. Thus, the centriole organelle is contributed solely by the sperm to the zygote in most systems. Whereas centrioles can have a stereotyped distribution during some asymmetric divisions, whether sperm-contributed centrioles are distributed in a stereotyped manner in the resulting embryo is not known. Here, we addressed this question inCaenorhabditis elegansusing marked mating experiments, whereby the presence of sperm-contributed centrioles is monitored in the resulting embryos using the stable centriolar component SAS-4::GFP, as well as GFP::SAS-7. Our analysis demonstrates that the distribution of sperm-contributed centrioles is stochastic in 4-cell stage embryos. Moreover, using sperm fromzyg-1mutant males that harbor a single centriole, we show that the older sperm-contributed centriole is also distributed stochastically in the resulting embryo. Overall, we conclude that in contrast to the situation during some asymmetric cell divisions, centrioles contributed by the male germ line are distributed stochastically in embryos ofC. elegans.
In situ modeling of acquired resistance to RTK/RAS pathway targeted therapies
Authors: Sealover Nancy E. , Theard Patricia T. , Linke Amanda J. , Hughes Jacob M. , Daley Brianna R. , Kortum Robert L. 
Published: January 2023

AbstractIntrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Preclinical studies that identify synergistic combinations enhance therapeutic efficacy to target intrinsic resistance, however, methods to study acquired resistance in cell culture are lacking. Here, we describe anin situresistance assay (ISRA), performed in a 96-well culture format, that models acquired resistance to RTK/RAS pathway targeted therapies. Using osimertinib resistance inEGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show acquired resistance can be reliably modeled across cell lines with objectively defined osimertinib doses. We further show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using two distinct SHP2 inhibitors. Similar to patient populations, isolated osimertinib-resistant populations showed resistance via enhanced activation of multiple parallel RTKs so that individual RTK inhibitors did not re-sensitize cells to osimertinib. In contrast, inhibition of proximal RTK signaling using the SHP2 inhibitor RMC-4550 both re-sensitized resistant populations to osimertinib. Similar, objectively defined drug doses were used to model resistance to additional RTK/RAS pathway targeted therapies including the KRASG12Cinhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.HighlightsAcquired resistance to RTK/RAS pathway members can be modeled in situSHP2 inhibitors reduce the development of acquired osimertinib resistanceIsolated osimertinib-resistant populations show hyperactivation of multiple RTKsSHP2 inhibitors re-sensitize resistant populations to osimertinib treatment
Bridging model and experiment in systems neuroscience with Cleo: the Closed-Loop, Electrophysiology, and Optophysiology simulation testbed
Authors: Johnsen Kyle A. , Cruzado Nathanael A. , Menard Zachary C. , Willats Adam A. , Charles Adam S. , Markowitz Jeffrey E. , Rozell Christopher J. 
Published: January 2023

AbstractSystems neuroscience has experienced an explosion of new tools for reading and writing neural activity, enabling exciting new experiments such as all-optical or closed-loop control that effect powerful causal interventions. At the same time, improved computational models are capable of reproducing behavior and neural activity with increasing fidelity. Unfortunately, these advances have drastically increased the complexity of integrating different lines of research, resulting in the missed opportunities and untapped potential of suboptimal experiments. Experiment simulation can help bridge this gap, allowing model and experiment to better inform each other by providing a low-cost testbed for experiment design, model validation, and methods engineering. Specifically, this can be achieved by incorporating the simulation of the experimental interface into our models, but no existing tool integrates optogenetics, two-photon calcium imaging, electrode recording, and flexible closed-loop processing with neural population simulations. To address this need, we have developed Cleo: the Closed-Loop, Electrophysiology, and Optophysiology experiment simulation testbed. Cleo is a Python package enabling injection of recording and stimulation devices as well as closed-loop control with realistic latency into a Brian spiking neural network model. It is the only publicly available tool currently supporting two-photon and multi-opsin/wavelength optogenetics. To facilitate adoption and extension by the community, Cleo is open-source, modular, tested, and documented, and can export results to various data formats. Here we describe the design and features of Cleo, validate output of individual components and integrated experiments, and demonstrate its utility for advancing optogenetic techniques in prospective experiments using previously published systems neuroscience models.
Large polyacrylamide hydrogels for large-batch cell culture and mechanobiological studies
Authors: Shi Xuechen , Janmey Paul 
Published: January 2023

AbstractThe rigidity of a cell’s substrate or extracellular matrix plays a vital role in regulating cell and tissue functions. Polyacrylamide (PAAm) hydrogels are one of the most widely used cell culture substrates that provide a physiologically relevant range of stiffness. However, it is still arduous and time-consuming to prepare PAAm substrates in large batches for high-yield or multi-scale cell cultures. Here we present a simple method to prepare PAAm hydrogels with less time cost and easily accessible materials. The hydrogel is mechanically uniform and supports cell culture in a large batch. We further show that the stiffness of the hydrogel covers a large range of Young’s modulus and is sensed by cells, regulating various cell features including changes in cell morphology, proliferation, and contractility. This method improves reproducibility of mechanobiology studies and can be easily applied for mechanobiology research requiring large numbers of cells or experimental groups.
Role of Strong Localized vs. Weak Distributed Interactions in Disordered Protein Phase Separation
Authors: Rekhi Shiv , Devarajan Dinesh Sundaravadivelu , Howard Michael P. , Kim Young C. , Nikoubashman Arash , Mittal Jeetain 
Published: January 2023

AbstractInteraction strength and localization are critical parameters controlling the single-chain and condensed-state properties of intrinsically disordered proteins (IDPs). Here, we decipher these relationships using coarse-grained heteropolymers comprised of hydrophobic (H) and polar (P) monomers as model IDPs. We systematically vary the fraction of P monomersXPand employ two distinct particle-based models that include either strong localized attractions between only H–H pairs (HP model) or weak distributed attractions between both H–H and H–P pairs (HP+ model). To compare different sequences and models, we first carefully tune the attraction strength for all sequences to match the single-chain radius of gyration. Interestingly, we find that this procedure produces similar conformational ensembles, nonbonded potential energies, and chain-level dynamics for single chains of almost all sequences in both models, with some deviations for the HP model at largeXP. However, we observe a surprisingly rich phase behavior for the sequences in both models that deviates from the expectation that similarity at the single-chain level will translate to similar phase-separation propensity. Coexistence between dilute and dense phases is only observed up to a model-dependentXPdespite the presence of favorable interchain interactions, which we quantify using the second virial coefficient. Instead, the limited number of attractive sites (H monomers) leads to the self-assembly of finite-sized clusters of different sizes depending onXP. Our findings strongly suggest that models with distributed interactions favor the formation of liquid-like condensates over a much larger range of sequence compositions compared to models with localized interactions.
Biological and structural analysis of new potent Integrase-LEDGF allosteric HIV-1 inhibitors
Authors: Le Rouzic Erwann , Bonnard Damien , Le Strat Frédéric , Batisse Claire , Batisse Julien , Amadori Céline , Chasset Sophie , Emiliani Stéphane , Ledoussal Benoit , Ruff Marc , Moreau François , Benarous Richard 
Published: January 2023

AbstractLEDGF/p75 (LEDGF) main cellular cofactor of HIV-1 integrase (IN), acts as tethering factor to target integration of HIV in actively transcribed genes. Recently a class of IN inhibitors based on inhibition of LEDGF-IN interaction has been developed. We describe here a new series of IN-LEDGF allosteric inhibitors (INLAIs), with potent anti-HIV-1 activity in the one-digit nanomolar range. These compounds inhibited IN-LEDGF interaction while enhancing IN-IN aberrant multimerization by allosteric mechanism. Compounds of this series were fully active on HIV-1 mutants resistant to IN strand transfer inhibitors (INSTIs) and other class of anti-HIV drugs, confirming that they belong to a new class of antiretrovirals. These compounds displayed most potent antiretroviral activity at post-integration due to aberrant IN polymerization responsible of infectivity defect of viral particles produced. INLAI-resistant mutants were selected by dose escalation method and the most detrimental mutation found was T174I. The impact of these resistance mutations was analyzed by fold shift EC50with regard to wild type virus and the replication capacity of mutated viruses were determined. Crystal structure of BDM-2, the lead compound of this series in complex with IN catalytic core domain (CCD) was elucidated. No antagonism was observed between BDM-2 and a panel of 16 antiretroviral drugs from different classes. In conclusion, the overall virologic profile of BDM-2 warrants the recently completed single ascending dose phase I trial (ClinicalTrials.govId:NCT03634085) and supports further clinical investigation for potential use in combination with other antiretroviral drugs.Author summaryIntegrase-LEDGF allosteric inhibitors are a new class of antiretrovirals recently developed that target the interaction of HIV-1 Integrase with its cellular cofactor LEDGF/p75 required for HIV-1 integration in actively transcribed genes. The great interest of developing such new class of antiretroviral is to add to the anti-HIV drug arsenal compounds that are fully active on resistant viruses to all other classes of drugs currently used in clinic. However, none of these inhibitors are currently in clinical use or in late clinical trials. Here we describe a series of highly potent Integrase allosteric inhibitors that can be considered as precursors of a new class of antiretroviral drugs, with fully conserved activity on viruses resistant to currently used anti-HIV drugs, and a lead compound that has no antagonism with a large panel of present anti-HIV drugs and that was successfully validated in a phase I clinical trial.
The biology of aging in a social world: insights from free-ranging rhesus macaques
Authors: Newman Laura E. , Testard Camille , DeCasien Alex R. , Chiou Kenneth L. , Watowich Marina M. , Janiak Mareike C. , Pavez-Fox Melissa A. , Sanchez Rosado Mitchell R. , Cooper Eve B. , Costa Christina E. , Petersen Rachel M. , Montague Michael J. , Platt Michael L. , Brent Lauren J.N. , Snyder-Mackler Noah , Higham James P. 
Published: January 2023

AbstractSocial adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individual’s life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago Island, which is home to the world’s longest continuously monitored free-ranging population of rhesus macaques. We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.
Hub architecture of the human structural connectome: Links to aging and processing speed
Authors: Li Xin , Salami Alireza , Persson Jonas 
Published: January 2023

AbstractThe human structural brain network, or connectome, has a rich-club organization with a small number of brain regions showing high network connectivity, called hubs. Hubs are centrally located in the network, energy costly, and critical for human cognition. Aging has been associated with changes in brain structure, function, and cognitive decline, such as processing speed. At a molecular level, the aging process is a progressive accumulation of oxidative damage, which leads to subsequent energy depletion in the neuron and causes cell death. However, it is still unclear how age affects hub connections in the human connectome. The current study aims to address this research gap by utilizing a novel measure of structural connectivity strength, fiber bundle capacity (FBC), which is derived from Constrained Spherical Deconvolution (CSD) modeling of white-matter fiber bundles. FBC represents the capacity of a fiber bundle to transfer information and is a less biased measure for quantifying connection strength within biological pathways. We found that hubs exhibit longer-distance connections and higher metabolic rates compared to peripheral brain regions, suggesting that hubs are biologically costly. Although the landscape of structural hubs was relatively age-invariant, there were wide-spread age effects on FBC in the connectome. Critically, these age effects were larger in connections within hub compared to peripheral brain connections. These findings were supported by both a cross-sectional sample with wide age-range (N=137) and a longitudinal sample across 5 years (N=83). Moreover, our results demonstrated that associations between FBC and processing speed were more concentrated in hub connections than chance level, and FBC in hub connections mediated the age-effects on processing speed. Overall, our findings indicate that structural connections of hubs, which demonstrate greater energy demands, are particular vulnerable to aging. The vulnerability may contribute to age-related impairments in processing speed among older adults.
Investigating the impact of introduced crabs on the distribution and morphology of littorinid snails: Implications for the survival of the snailLittorina saxatilis
Authors: Wells Christopher D. , Van Volkom Kaitlin S. , Edquist Sara , Marovelli Sinead , Marovelli John 
Published: January 2023

AbstractIntroduced species can have profound impacts on communities by displacing and consuming native species. The intertidal communities in the Gulf of Maine have been radically altered through a suite of invasions including the herbivorous snailLittorina littoreaand the omnivorous crabCarcinus maenasleading to morphological and spatial distribution changes in two native gastropod grazers (Littorina saxatilisandLittorina obtusata). Subsequently, another intertidal omnivorous crabHemigrapsus sanguineushas become abundant in the intertidal, occurring in areas which were once refuges from crab predation. In order to quantify the potential impact ofH. sanguineuson native snails, we conducted bothinandex situexperiments, testing the susceptibility of different sized snails to predation by introduced crabs. Additionally, we measured the distribution, abundance, and morphology of intertidal snails and crabs. Smaller snails of all species were the most susceptible to predation, although susceptibility differed among snail species.Littorina saxatiliswas the most vulnerable to predation, with 73 and 64% of the population susceptible to largeH. sanguineusand smallC. maenas, respectively, while more than 89% of theL. littoreapopulation was resistant to predation.Littorina saxatilishas been relegated to the high intertidal where there is high abiotic stress and poor-quality food, but until the invasion ofH. sanguineus, there was little predation risk. Now, it seems thatL. saxatilisis at the most risk of all three snail species, and may be at threat of local extirpation at locations with high populations ofH. sanguineus.
MIIP downregulation promotes colorectal cancer progression via inducing adjacent adipocytes browning
Authors: Wang Qinhao , Su Yuanyuan , Sun Ruiqi , Xiong Xin , Guo Kai , Wei Mengying , Ru Yi , Yang Guodong , Zhang Zhengxiang , Qiao Qing , Li Xia 
Published: January 2023

AbstractThe enrichment of peri-cancerous adipocytes is one of the distinctive features of colorectal cancer (CRC), which accelerates the disease progression and worsens the prognosis. The communication between tumor cells and adjacent adipocytes plays an important role in this process. However, the detailed mechanisms remain largely unknown. Here we demonstrated MIIP is downregulated in high-grade CRC, and revealed its role and mechanism in tumor cell-adipocyte communication. By detecting MIIP expression in CRC tissues and adjacent normal tissues, we found MIIP was significantly decreased in CRC, and was closely related to adjacent adipocytes browning. In detail, MIIP reduction altered the N-linked glycosylation modification of AZGP1 and thus alleviated the inhibition of secretion. AZGP1, a critical lipid mobilization factor, led to the intensification of adipocytes browning and the release of free fatty acids (FFAs), which in turn fueled for CRC progression. Our data demonstrate that MIIP plays a key regulatory role in the communication between CRC and neighboring adipocytes by mediating AZGP1 secretion, and MIIP reduction leads to adipose browning-induced cancer rapid progression and poor prognosis.
Audiovisual integration is preserved in older adults across the cortical hierarchy
Authors: Jones Samuel A. , Noppeney Uta 
Published: January 2023

AbstractEffective interactions with the environment rely on integration of multisensory signals: our brains must efficiently combine signals that share a common source, and segregate those that do not. Healthy ageing can change or impair this process. This functional magnetic resonance imaging study assessed the neural mechanisms underlying age differences in the integration of auditory and visual spatial cues. Participants were presented with synchronous audiovisual signals at various degrees of spatial disparity and indicated their perceived sound location. Behaviourally, older adults were able to maintain localisation accuracy, albeit with longer response times. At the neural level, they integrated auditory and visual cues into spatial representations along dorsal auditory and visual processing pathways similarly to their younger counterparts, but showed greater activations in a widespread system of frontal, temporal and parietal areas. According to multivariate Bayesian decoding, these areas encoded critical stimulus information beyond that which was encoded in the brain areas commonly activated by both groups. Surprisingly, however, the boost in information provided by these areas with age-related activation increases was comparable across the two age groups.This dissociation—between comparable response accuracy and information encoded in brain activity patterns across the two age groups, but age-related increases in response times and regional activations—suggests that older participants accumulate noisier sensory evidence for longer, to maintain reliable neural encoding of stimulus-relevant information and thus preserve localisation accuracy.
Germline TFAM levels regulate mitochondrial DNA copy number and mutant heteroplasmy inC. elegans
Authors: Schwartz Aaron Z.A. , Nance Jeremy 
Published: January 2023

AbstractThe mitochondrial genome (mtDNA) is packaged into discrete protein-DNA complexes called nucleoids. mtDNA packaging factor TFAM (mitochondrial transcription factor-A) promotes nucleoid compaction and is required for mtDNA replication. Here, we investigate how changing TFAM levels affects mtDNA in theCaenorhabditis elegansgerm line. We show that increasing germline TFAM activity boosts mtDNA number and significantly increases the relative proportion of a selfish mtDNA mutant,uaDf5. We conclude that TFAM levels must be tightly controlled to ensure appropriate mtDNA composition in the germ line.