bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Genetic Suppressors for a Berardinelli-Seip Congenital Generalized Lipodystrophy Type 2 (BSCL2) Pathogenic Variant inC. elegans
Authors: Bai Xiaofei , Smith Harold E. , Golden Andy 
Published: September 2023

AbstractMaintaining the metabolic homeostasis of fatty acids is crucial for human health. Excess fatty acids are stored in lipid droplets (LDs), the primary energy reservoir that helps regulate fat and lipid homeostasis in nearly all cell types. Seipin (BSCL2), a conserved endoplasmic reticulum protein, plays a critical role in LD biogenesis and regulating LD morphology. Pathogenic variants of seipin are associated with multiple human genetic diseases, including Berardinelli-Seip Congenital Generalized Lipodystrophy Type 2 (BSCL2). However, the cellular and molecular mechanisms by which dysfunctional seipin leads to these diseases remain unclear. To model BSCL2 disease, we generated an orthologousBSCL2pathogenic variantseip-1(A185P)using CRISPR/Cas9 genome editing inCaenorhabditis elegans. This variant led to severe developmental and cellular defects, including embryonic lethality, impaired eggshell formation, and abnormally enlarged LDs. We set out to identify genetic determinants that could suppress these defective phenotypes in theseip-1(A185P)mutant background. To this end, we conducted an unbiased chemical mutagenesis screen to identify genetic suppressors that restore embryonic viability in theseip-1(A185P)mutant background. A total of five suppressor lines were isolated and recovered from the screen. The defective phenotypes ofseip-1(A185P), including embryonic lethality and impaired eggshell formation, were significantly suppressed in each suppressor line. Two of the five suppressor lines also alleviated the enlarged LDs in the oocytes. We then mapped a suppressor candidate gene,R05D3.2(renamed aslmbr-1), which is an ortholog of humanLMBR1(limb development membrane protein 1). The CRISPR/Cas9 editedlmbr-1suppressor alleles,lmbr-1(Ser647Phe)andlmbr-1(Pro314Leu), both significantly suppressed embryonic lethality and defective eggshell formation in theseip-1(A185P)background. The newly identified suppressor lines offer valuable insights into potential genetic interactors and pathways that may regulate seipin in the lipodystrophy model.
Synthetic control of actin polymerization and symmetry breaking in active protocells
Authors: Razavi Shiva , Wong Felix , Abubaker-Sharif Bedri , Matsubayashi Hideaki T. , Nakamura Hideki , Sandoval Eduardo , Robinson Douglas N. , Chen Baoyu , Liu Jian , Iglesias Pablo A. , Inoue Takanari 
Published: September 2023

AbstractNon-linear biomolecular interactions on the membranes drive membrane remodeling that underlies fundamental biological processes including chemotaxis, cytokinesis, and endocytosis. The multitude of biomolecules, the redundancy in their interactions, and the importance of spatiotemporal context in membrane organization hampers understanding the physical principles governing membrane mechanics. A minimal, in vitro system that models the functional interactions between molecular signaling and membrane remodeling, while remaining faithful to cellular physiology and geometry is powerful yet remains unachieved. Here, inspired by the biophysical processes underpinning chemotaxis, we reconstituted externally-controlled actin polymerization inside giant unilamellar vesicles, guiding self-organization on the membrane. We show that applying undirected external chemical inputs to this system results in directed actin polymerization and membrane deformation that are uncorrelated with upstream biochemical cues, indicating symmetry breaking. A biophysical model of the dynamics and mechanics of both actin polymerization and membrane shape suggests that inhomogeneous distributions of actin generate membrane shape deformations in a non-linear fashion, a prediction consistent with experimental measurements and subsequent local perturbations. The active protocellular system demonstrates the interplay between actin dynamics and membrane shape in a symmetry breaking context that is relevant to chemotaxis and a suite of other biological processes.
Orthogonality of sensory and contextual categorical dynamics embedded in a continuum of responses from the second somatosensory cortex
Authors: Bayones Lucas , Zainos Antonio , Alvarez Manuel , Romo Ranulfo , Franci Alessio , Rossi-Pool Román 
Published: September 2023

AbstractHow does the brain simultaneously process signals that bring complementary information, like raw sensory signals and their transformed counterparts, without any disruptive interference? Contemporary research underscores the brain’ ss adeptness in using decorrelated responses to reduce such interference. Both neurophysiological findings and artificial neural networks (ANNs) support the notion of orthogonal representation for signal differentiation and parallel processing. Yet, where, and how raw sensory signals are transformed into more abstract representations remains unclear. Using a temporal pattern discrimination task (TPDT) in trained monkeys, we revealed that the second somatosensory cortex (S2) efficiently segregates faithful and transformed neural responses into orthogonal subspaces. Importantly, S2 population encoding for transformed signals, but not for faithful ones, disappeared during a non-demanding version of the task, which suggests that signal transformation and their decoding from downstream areas are only active on-demand. A mechanistic computation model points to gain modulation as a possible biological mechanism for the observed context-dependent computation. Furthermore, individual neural activities that underlie the orthogonal population representations exhibited a continuum of responses, with no well-determined clusters. These findings advocate that the brain, while employing a continuum of heterogeneous neural responses, splits population signals into orthogonal subspaces in a context-dependent fashion to enhance robustness, performance, and improve coding efficiency.SIGNIFICANCE STATEMENTAn important function of the brain is turning sensation into perception. Yet, how this function is implemented remains unknown. Current research, insights from artificial neural networks, highlights using of orthogonal representations as an effective means to transform sensory signals into perceptual signals while separating and simultaneously processing the two information streams. Neuronal recordings in S2 while trained monkeys performed the TPDT, revealed that this function is implemented at the population level. While S2 encodes sensory information independently of context, the encoding of categorical information, like task parameters, is only performed when the task demands it. Such distinct and flexible organization, enriched by a spectrum of neural activities, reflects the brain’s efficiency, resilience, and overall purpose for solving cognitive tasks.
Local adaptation of a marine diatom is governed by genome-wide changes in diverse metabolic processes
Authors: Pinseel Eveline , Ruck Elizabeth C. , Nakov Teofil , Jonsson Per R. , Kourtchenko Olga , Kremp Anke , Pinder Matthew I.M. , Roberts Wade R. , Sjöqvist Conny , Töpel Mats , Godhe Anna , Hahn Matthew W. , Alverson Andrew J. 
Published: September 2023

ABSTRACTMarine phytoplankton play essential roles in global primary production and biogeochemical cycles. Yet, the evolutionary genetic underpinnings of phytoplankton adaptation to complex marine and coastal environments, where many environmental variables fluctuate and interact, remain unclear. We combined population genomics data with experimental transcriptomics to investigate the genomic basis underlying a natural evolutionary experiment that has played out over the past 8,000 years in one of the world’s largest brackish water bodies: the colonization of the Baltic Sea by the marine diatomSkeletonema marinoi. To this end, we used a novel approach for protist population genomics, combining target capture of the entire nuclear genome with pooled sequencing, and showed that the method performs well on both cultures and single cells. Genotype-environment association analyses identified >3,000 genes with signals of selection in response to major environmental gradients in the Baltic Sea, which apart from salinity, include marked differences in temperature and nutrient availability. Locally adapted genes were related to diverse metabolic processes, including signal transduction, cell cycle, DNA methylation, and maintenance of homeostasis. The locally adapted genes showed significant overlap with salinity-responsive genes identified in a laboratory common garden experiment, suggesting the Baltic salinity gradient is a major factor driving local adaptation ofS. marinoi. Altogether, our data show that local adaptation of phytoplankton to complex coastal environments, which are characterized by a multitude of environmental gradients, is driven by intricate changes in diverse metabolic pathways and functions.
Ketone supplementation dampens subjective and objective responses to alcohol in rats and humans
Authors: Li Xinyi , Shi Zhenhao , Todaro Dustin , Pond Timothy , Byanyima Juliana , Vesslee Sianneh , Reddy Rishika , Reddy Nanga Ravi Prakash , Kass Gabriel , Ramchandani Vijay , Kranzler Henry R. , Vendruscolo Janaina C.M. , Vendruscolo Leandro F. , Wiers Corinde E. 
Published: September 2023

AbstractPrevious preclinical and human studies have shown that high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-β-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 min prior to an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration (BrAC) and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 min after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 min later by an oral alcohol dose (0.8 g/kg). BAL were monitored for 240 min after alcohol exposure. In humans, the intake of KS prior to alcohol significantly blunted BrAC and BAL, reduced ratings of alcohol liking and wanting, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. In conclusion, KS altered physiological and subjective responses to alcohol in both humans and rats and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating and rewarding effects of alcohol and thus be a novel intervention for treating alcohol use disorder.
The representational geometry of emotional states in basolateral amygdala
Authors: O’Neill Pia-Kelsey , Posani Lorenzo , Meszaros Jozsef , Warren Phebe , Schoonover Carl E. , Fink Andrew J.P. , Fusi Stefano , Salzman C. Daniel 
Published: September 2023

AbstractSensory stimuli associated with aversive outcomes cause multiple behavioral responses related to an animal’s evolving emotional state, but neural mechanisms underlying these processes remain unclear. Here aversive stimuli were presented to mice, eliciting two responses reflecting fear and flight to safety: tremble and ingress into a virtual burrow. Inactivation of basolateral amygdala (BLA) eliminated differential responses to aversive and neutral stimuli without eliminating responses themselves, suggesting BLA signals valence, not motor commands. However, two-photon imaging revealed that neurons typically exhibited mixed selectivity for stimulus identity, valence, tremble and/or ingress. Despite heterogeneous selectivity, BLA representational geometry was lower-dimensional when encoding valence, tremble and safety, enabling generalization of emotions across conditions. Further, tremble and valence coding directions were orthogonal, allowing linear readouts to specialize. Thus BLA representational geometry confers two computational properties that identify specialized neural circuits encoding variables describing emotional states: generalization across conditions, and readouts lacking interference from other readouts.
Caveolin-1 Autonomously Regulates Hippocampal Neurogenesis Via Mitochondrial Dynamics
Authors: Stephen Terilyn K. L. , Cofresi Luis Aponte , Quiroz Elvis , Owusu-Ansah Kofi , Ibrahim Yomna , Qualls Ellis , Marshall Jeffery , Li Wenping , Shetti Aashutosh , Bonds Jacqueline A , Minshall Richard D. , Cologna Stephanie M. , Lazarov Orly 
Published: September 2023

SummaryThe mechanisms underlying adult hippocampal neurogenesis (AHN) are not fully understood. AHN plays instrumental roles in learning and memory. Understanding the signals that regulate AHN has implications for brain function and therapy. Here we show that Caveolin-1 (Cav-1), a protein that is highly enriched in endothelial cells and the principal component of caveolae, autonomously regulates AHN. Conditional deletion of Cav-1 in adult neural progenitor cells (nestin +) led to increased neurogenesis and enhanced performance of mice in contextual discrimination. Proteomic analysis revealed that Cav-1 plays a role in mitochondrial pathways in neural progenitor cells. Importantly, Cav-1 was localized to the mitochondria in neural progenitor cells and modulated mitochondrial fission-fusion, a critical process in neurogenesis. These results suggest that Cav-1 is a novel regulator of AHN and underscore the impact of AHN on cognition.
ER mediates spatial regulation of lysosome-endosome interactionsviamotion switch at junction sites
Authors: Li Wenjing , Qiu Mengxuan , Zhang Yudong , Guo Yuanhao , Yang Yutong , Hu Junjie , Yang Ge 
Published: September 2023

AbstractMembrane-bound intracellular organelles engage in extensive direct interactions through membrane contact or fusion to work together for vital physiological functions. However, how their interactions are regulated is unclear. Lysosomes, for example, interact with ER and endosomes through membrane contact or fusion/fission to receive macromolecular cargos for recycling and degradation. The interactions are thought to be spatially regulated because participating lysosomes and endosomes must be positioned in close proximity. But the mechanism of spatial regulation is unknown. In this study, we examined how individual lysosomes and endosomes move along the endoplasmic reticulum (ER) network and found primarily two modes of movement. In the fast mode they explore different regions. In the slow mode they often pause and become confined near ER junctions to come near each other for interactions. The pause and confinement of lysosomes and endosomes occur in ER regions with elevated network density and connectivity and are mediated by condensation of the actin cytoskeleton, in which the VAP-STARD3-YWHAH pathway plays a key role. Together, these results reveal that ER mediates spatial regulation of lysosome-endosome interactions. Other organelles such as lipid droplets and peroxisomes are also found to pause near ER junctions. Overall, our findings suggest a general ER-mediated mechanism for spatial regulation of organelle interactions.
Perisaccadic and Attentional Remapping of Receptive Fields in Lateral Intraparietal Area and Frontal Eye Fields
Authors: Wang Xiao , Zhang Cong , Yang Lin , Jin Min , Goldberg Michael E. , Zhang Mingsha , Qian Ning 
Published: September 2023

SummaryThe nature and function of perisaccadic receptive-field (RF) remapping have been controversial. We used a delayed saccade task to reduce previous confounds and examined the remapping time course in areas LIP and FEF. In the delay period, the RF shift direction turned from the initial fixation to the saccade target. In the perisaccadic period, RFs first shifted toward the target (convergent remapping) but around the time of saccade onset/offset, the shifts became predominantly toward the post-saccadic RF locations (forward remapping). Thus, unlike forward remapping that depends on the corollary discharge (CD) of the saccade command, convergent remapping appeared to follow attention from the initial fixation to the target. We modelled the data with attention-modulated and CD-gated connections, and showed that both sets of connections emerged automatically in neural networks trained to update stimulus retinal locations across saccades. Our work thus unifies previous findings into a mechanism for transsaccadic visual stability.
A potential acoustic role for CFTR ion channel in conductive hearing loss
Authors: Liyanage Pramodha , Mun Kyu-Shik , Carraro Gianni , Ogden Herbert Luke , Huang Yunjie , Lee Jesun , Ramananda Yashaswini , Stripp Barry R , Arora Kavisha , Salomonis Nathan , Hunter Lisa L. , Naren Anjaparavanda P. 
Published: September 2023

AbstractLoss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF). The middle ear and eustachian tube could be adversely affected in CF. In this study, we provide evidence of the role of CFTR function in conductive hearing. We developed an in-situ model to determine CFTR dependent fluid secretion in the middle ear using native mouse auditory capsule. A unique middle ear-on-a-chip was developed to address the functional and molecular basis of conductive hearing impairment. Using single-cell transcriptomics, middle ear cell composition and the associated transcriptomic signature were compared between CF and WT groups. A specialized subset of epithelial cells expressed CFTR with an overlapping signature with secretory epithelial cells. Genes related to ciliogenesis, hearing and ossification were significantly altered in CF mice middle ear. Our data suggest that CF middle ear may be at higher risk for conductive hearing loss.
Cross-reactive macaque antibodies targeting marburgvirus glycoprotein induced by multivalent immunization
Authors: Janus Benjamin M. , Wang Ruixue , Cleveland Thomas E. , Metcalf Matthew C. , Lemmer Aaron C. , Class Kenneth , Fuerst Thomas R. , Ofek Gilad 
Published: September 2023

AbstractWe utilized B cells from a Rhesus macaque immunized with a multivalent prime-boost regimen of filovirus antigens to isolate a novel panel of marburgvirus glycoprotein (GP)-specific monoclonal antibodies (mAbs). A heterologous marburgvirus GP probe was used to sort for B cells with cross-marburgvirus reactive breadth. 33 mAbs belonging to 28 unique lineages were expressed and experimentally characterized. Antibody specificities were assessed by binding competition and overlapping pepscan analyses, and were found to map to a previously characterized protective region on GP2 and a cross-filovirus reactive region on GP1, among others. A third of the lineages targeted the predicted receptor binding region (RBR), including two lineages with potent Marburg pseudovirus neutralization that were structurally analyzed and confirmed to recognize this region. Our study describes the discovery and characterization of a diverse panel of antibodies against marburgvirus GP induced by multivalent immunization and provides candidate immunotherapeutics for further study and development.Author SummaryMarburgviruses were the first filoviruses characterized to emerge in humans in 1967, and have led to multiple outbreaks since then with average case fatality rates of ∼50%. Although a vaccine and monoclonal antibody countermeasures have been approved for clinical use against the related Ebola viruses, these are ineffective against marburgviruses or other filoviruses. As such, gaps exist in the clinical toolkit against filoviruses, in particular marburgviruses. Here, we isolated and characterized a novel panel of monoclonal antibodies directed against the marburgvirus surface glycoprotein from an immunized Rhesus macaque. We utilized an antibody isolation method that ensured broad antibody recognition across multiple marburgvirus isolates. Functional and structural analyses revealed that roughly half of the antibodies in the panel mapped to regions on the glycoprotein shown previously to protect from infection, including the receptor binding domain and a protective region on the membrane-anchoring subunit, while a quarter of the antibodies did not fall into any known binding competition group indicating potential novel specificities. Our study advances the understanding of marburgvirus glycoprotein antigenicity and furthers efforts to develop candidate antibody countermeasures against these lethal viruses.
Signature-Informed Selection Detection: A Novel Method for Multi-Locus Wright-Fisher Models with Recombination
Authors: Xu Yuehao , Khoo Sherman , Futschik Andreas , Dutta Ritabrata 
Published: September 2023

AbstractIn this manuscript, we present an innovative Bayesian framework tailored for the inference of the selection coefficients in multi-locus Wright-Fisher models. Utilizing a signature kernel score, our approach offers an innovative solution for approximating likelihoods by extracting informative signatures from the trajectories of haplotype frequencies. Moreover, within the framework of a generalized Bayesian posterior, we derive the scoring rule posterior, which we then pair with a Population Monte Carlo (PMC) algorithm to obtain posterior samples for selection coefficients. This powerful combination enables us to infer selection dynamics efficiently even in complex high-dimensional and temporal data settings. We show that our method works well through extensive tests on both simulated and real-world data. Notably, our approach effectively detects selection not just in univariate, but also in multivariate Wright-Fisher models, including 2-locus and 3-locus models with recombination. Our proposed novel technique contributes to a better understanding of complex evolutionary dynamics.
Whole mount multiplexed visualization of DNA, mRNA, and protein in plant-parasitic nematodes
Authors: Sperling Alexis L. , Eves-van den Akker Sebastian 
Published: September 2023

AbstractBackgroundPlant-parasitic nematodes compromise the agriculture of a wide variety of the most common crops worldwide. Obtaining information on the fundamental biology of these organisms and how they infect the plant has been restricted by the ability to visualize intact nematodes using small molecule stains, antibodies, orin situhybridization. Consequently, there is limited information available about the internal composition of the nematodes or the biology of the effector molecules they use to reprogram their host plant.ResultsWe present the Sperling prep -a whole mount method for nematode preparation that enables staining with small molecules, antibodies, orin situhybridization chain reaction. This method does not require specialized apparatus and utilizes typical laboratory equipment and materials. By dissociating the strong cuticle and interior muscle layers, we enabled entry of the small molecule stains into the tissue. After permeabilization, small molecule stains can be used to visualize the nuclei with the DNA stain DAPI and the internal structures of the digestive tract and longitudinal musculature with the filamentous actin stain phalloidin. The permeabilization even allows entry of larger antibodies, albeit with lower efficiency. Finally, this method works exceptionally well within situHCR. Using this method, we have visualized effector transcripts specific to the dorsal gland and the subventral grand of the sugar beet cyst nematode,Heterodera schachtii, multiplexed in the same nematode.ConclusionWe were able to visualize the internal structures of the nematode as well as key effector transcripts that are used during plant infection and parasitism. Therefore, this method provides an important toolkit for studying the biology of plant-parasitic nematodes.