bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct neural states encode task identity in frontal eye field and interact with its core spatial properties
Authors: Mouille A. , Gaillard C. , Astrand E. , Wardak C. , Hamed S. Ben , Amengual J.L. 
Published: September 2023

AbstractThe prefrontal cortex (PFC) plays a key role in selecting, maintaining and representing sensory information, and in its integration with our current internal goals and expectations, implementing such cognitive processes as executive functions, attention, decision making and working memory. Performing computation over all of these functional cognitive processes and dynamically shifting from one to the other based on task demands requires a complex functional organization and a high degree of coding flexibility. The PFC cells show a non-linear mixed selectivity characterized by specific tuning for multiple task- and behaviour related parameters. This non-linear mixed selectivity thought to allow for a high-dimensional representation of information. Here, we asked if the PFC is mainly involved in specific task-parameters representation, or if it additionally holds a higher order representation for task-identity. We thus trained two macaques to perform three different tasks: a memory guided saccade task and two detection tasks involving different attention mechanisms. Multi-unit activity was recorded in the frontal eye field, bilaterally, while monkeys performed these three tasks in a same session. Using demixed Principal Component Analysis, we found a two-dimensional neural state that characterized each of these tasks. The lower dimensional representation of the activity recorded during the performance of the two attentional tasks were more similar to each other than to the memory-guided saccade task. Furthermore, we report that task and spatial information are non-linearly mixed, a signature of a high-dimensional neural representation. Overall, this indicates that PFC encodes task identity information and flexibly adjusts its sensory processes as a function of the specific ongoing task.Significance StatementOne long lasting question in cognitive neuroscience is whether PFC mainly represents the different parameters that are needed to perform any given task, or if it additionally holds a higher order representation for task-identity. We recorded from the macaque frontal eye fields while monkeys performed a memory guided saccade task and two detection tasks involving different attention mechanisms. We found a task-identity neural state in which the two attentional tasks were represented similarly to each other but differently from the memory-guided saccade task. We also report that task and spatial information are non-linearly mixed, a signature of a high-dimensional neuronal representation. Overall, this indicates that PFC encodes task identity information and flexibly adjusts its sensory processes as a function of the specific ongoing task.
Thermodynamic Forces from Protein and Water Govern Condensate Formation of an Intrinsically Disordered Protein Domain
Authors: Mukherjee Saumyak , Schäfer Lars V. 
Published: September 2023

AbstractLiquid-liquid phase separation (LLPS) can drive a multitude of cellular processes by compartmentalizing biological cells via the formation of dense liquid biomolecular condensates, which can function as membraneless organelles. Despite its importance, the molecular-level understanding of the underlying thermodynamics of this process remains incomplete. In this study, we use atomistic molecular dynamics simulations of the low complexity domain (LCD) of human fused in sarcoma (FUS) protein to investigate the contributions of water and protein molecules to the free energy changes that govern LLPS. Both protein and water components are found to have comparably sizeable thermodynamic contributions to the formation of FUS condensates. Moreover, we quantify the counteracting effects of water molecules that are released into the bulk upon condensate formation and the waters retained within the protein droplets. Among the various factors considered, solvation entropy and protein interaction enthalpy are identified as the most important contributions, while solvation enthalpy and protein entropy changes are smaller. These insights provide detailed molecular insights on the intricate thermodynamic interplay between protein- and solvation-related forces underlying the formation of biomolecular condensates.
Analytical strength-duration curve for the spiking response of the LIF neuron to an alpha-function-shaped excitatory current pulse
Authors: Paraskevov Alexander 
Published: September 2023

AbstractWhether or not the neuron emits a spike in response to stimulation by an excitatory current pulse is determined by a strength-duration curve (SDC) for the pulse parameters. The SDC is a dependence of the minimal pulse amplitude required to elicit the spiking response on either the pulse duration or its decay time. Excitatory neurons affect the others through pulses of excitatory postsynaptic current. A simple yet plausible approximation for the time course of such a pulse is the alpha function, with linear rise at the start and exponential decay at the end. However, an exact analytical SDC for this case is hitherto not known, even for the leaky integrate- and-fire (LIF) neuron, the simplest spiking neuron model used in practice. We have obtained general SDC equations for the LIF neuron. Using the Lambert W function — a widely-implemented special function, we have found the exact analytical SDC for the spiking response of the LIF neuron stimulated by an excitatory current pulse in the form of the alpha function. To compare results in a unified way, we have also derived the analytical SDCs for (i) rectangular pulse, (ii) ascending ramp pulse, and (iii) instantly rising and exponentially decaying pulse. In the limit of no leakage, we show that the SDC is reduced to the classical hyperbola for all considered cases.
Virion-associated US28 rapidly modulates Akt activity to suppress HCMV lytic replication in monocytes
Authors: Mahmud Jamil , Geiler Brittany W. , Biswas Juthi , Miller Michael J. , Myers Julia E. , Matthews Stephen M. , Wass Amanda B. , O’Connor Christine M. , Chan Gary C. 
Published: September 2023

AbstractEstablishing a non-productive quiescent/silent infection within monocytes is essential for spread of human cytomegalovirus (HCMV). Yet, how HCMV establishes a quiescent infection in monocytes remains unclear. US28 is a viral G protein-coupled receptor (GPCR) essential for silent infections within cells of the myeloid lineage. We found virion-associated US28 was rapidly delivered to monocytes, whilede novosynthesized US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic replication cycle. Mechanistically, viral entry of US28Δ phosphorylated Akt at both serine 473 (S473) and threonine 308 (T308), which contrasted with the site-specific phosphorylation of Akt at S473 following WT infection. Preventing Akt bi-phosphorylation prevented lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of WT infection. Our data demonstrate that virion-delivered US28 fine-tunes Akt activity to permit HCMV infection to enter a quiescent state following primary infection of monocytes.
Rosetta Energy Analysis of AlphaFold2 models: Point Mutations and Conformational Ensembles
Authors: Stein Richard A. , Mchaourab Hassane S. 
Published: September 2023

ABSTRACTThere has been an explosive growth in the applications of AlphaFold2, and other structure prediction platforms, to accurately predict protein structures from a multiple sequence alignment (MSA) for downstream structural analysis. However, two outstanding questions persist in the field regarding the robustness of AlphaFold2 predictions of the consequences of point mutations and the completeness of its prediction of protein conformational ensembles. We combined our previously developed method SPEACH_AF with model relaxation and energetic analysis with Rosetta to address these questions. SPEACH_AF introduces residue substitutions across the MSA and not just within the input sequence. With respect to conformational ensembles, we combined SPEACH_AF and a new MSA subsampling method, AF_cluster, and for a benchmarked set of proteins, we found that the energetics of the conformational ensembles generated by AlphaFold2 correspond to those of experimental structures and explored by standard molecular dynamic methods. With respect to point mutations, we compared the structural and energetic consequences of having the mutation(s) in the input sequence versus in the whole MSA (SPEACH_AF). Both methods yielded models different from the wild-type sequence, with more robust changes when the mutation(s) were in the whole MSA. While our findings demonstrate the robustness of AlphaFold2 in analyzing point mutations and exploring conformational ensembles, they highlight the need for multi parameter structural and energetic analyses of these models to generate experimentally testable hypotheses.
Pervasive mislocalization of pathogenic coding variants underlying human disorders
Authors: Lacoste Jessica , Haghighi Marzieh , Haider Shahan , Lin Zhen-Yuan , Segal Dmitri , Reno Chloe , Qian Wesley Wei , Xiong Xueting , Shafqat-Abbasi Hamdah , Ryder Pearl. V. , Senft Rebecca , Cimini Beth A. , Roth Frederick P. , Calderwood Michael , Hill David , Vidal Marc , Yi S. Stephen , Sahni Nidhi , Peng Jian , Gingras Anne-Claude , Singh Shantanu , Carpenter Anne E. , Taipale Mikko 
Published: September 2023

SUMMARYWidespread sequencing has yielded thousands of missense variants predicted or confirmed as disease-causing. This creates a new bottleneck: determining the functional impact of each variant – largely a painstaking, customized process undertaken one or a few genes or variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,547 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of unknown significance. Our publicly available resource will likely accelerate the understanding of coding variation in human diseases.
Backmapping with Mapping and Isomeric Information
Authors: Kim Siyoung 
Published: September 2023

ABSTRACTI present a powerful and flexible backmapping tool named Multiscale Simulation Tool (mstool) that converts a coarse-grained (CG) system into all-atom (AA) resolution and only requires AA to CG mapping and isomeric information (cis/trans/dihedral/chiral). The backmapping procedure includes two simple steps: a) AA atoms are randomly placed near the corresponding CG beads according to the provided mapping scheme. b) Energy minimization is performed with two modifications in the AA force field (FF). First, nonbonded interactions are replaced with cosine functions to ensure numerical stability. Second, additional torsions are imposed to maintain molecules’ isomeric properties. To test the simplicity and robustness of the tool, I backmapped multiple membrane and protein CG structures into AA resolution, including a four-bead CG lipid model (resolution increased by a factor of 34) without using intermediate resolution. The tool is freely available atgithub.com/ksy141/mstool.TABLE OF CONTENTS (TOC)
Host cell glycosylation selects for infection with CCR5- versus CXCR4-tropic HIV-1
Authors: Itell Hannah L. , Humes Daryl , Baumgarten Nell E. , Overbaugh Julie 
Published: September 2023

ABSTRACTHIV-1 infection involves a selection bottleneck that leads to transmission of one or a few HIV variants, which nearly always use CCR5 as the coreceptor (R5 viruses) for viral entry as opposed to CXCR4 (X4 viruses). The host properties that drive this selection are not well understood and may hold keys to factors that govern HIV susceptibility. In this report, we identified SLC35A2, a transporter of UDP-galactose, as a candidate X4-specific restriction factor in CRISPR-knockout screens in primary target CD4+T cells. SLC35A2 inactivation in CD4+T cells, which resulted in truncation of glycans due to the absence of galactose, not only increased X4 infection levels, but also consistently decreased infection levels of R5 HIV strains. Single cycle infections demonstrated that the effect is host cell dependent. SLC35A2 is expressed in CD4+T cells at different tissue sites, with high levels in the genital tract – the site of most HIV infections. These data support a role for a host cell protein that regulates glycan structure on HIV infection, with enhanced R5 infection but reduced X4 infection associated with SLC35A2-mediated glycosylation. Host cell glycosylation may therefore contribute to R5 selection and host susceptibility during HIV transmission.
Simple Adjustment of Intra-nucleotide Base-phosphate Interaction in OL3 AMBER Force Field Improves RNA Simulations
Authors: Mlýnský Vojtěch , Kührová Petra , Stadlbauer Petr , Krepl Miroslav , Otyepka Michal , Banáš Pavel , Šponer Jiří 
Published: September 2023

ABSTRACTMolecular dynamics (MD) simulations represent an established tool to study RNA molecules. Outcome of MD studies depends, however, on the quality of the used force field (ff). Here we suggest a correction for the widely used AMBER OL3ffby adding a simple adjustment of nonbonded parameters. The reparameterization of Lennard-Jones potential for the –H8…O5’– and –H6…O5’– atom pairs addresses an intra-nucleotide steric clash occurring in the type 0 base-phosphate interaction (0BPh). The non-bonded fix (NBfix) modification of 0BPh interactions (the NBfix0BPhmodification) was tuned via reweighting approach and, subsequently, tested using extensive set of standard and enhanced sampling simulations of both unstructured and folded RNA motifs. The modification corrects minor but visible intra-nucleotide clash for theantinucleobase conformation. We observed that structural ensembles of small RNA benchmark motifs simulated with the NBfix0BPhmodification provide better agreement with experiments. No side-effects of the modification were observed in standard simulations of larger structured RNA motifs. We suggest that the combination of OL3 RNAffand NBfix0BPhmodification is a viable option to improve RNA MD simulations.
Conserved nucleocytoplasmic density homeostasis drives cellular organization across eukaryotes
Authors: Biswas Abin , Muñoz Omar , Kim Kyoohyun , Hoege Carsten , Lorton Benjamin M. , Shechter David , Guck Jochen , Zaburdaev Vasily , Reber Simone 
Published: September 2023

AbstractThe packing and confinement of macromolecules in the cytoplasm and nucleoplasm has profound implications for cellular biochemistry. How intracellular density distributions vary and affect cellular physiology remains largely unknown. Here, we show that the nucleus is less dense than the cytoplasm and that living systems establish and maintain a constant density ratio between these compartments. Using label-free biophotonics and theory, we show that nuclear density is set by a pressure balance across the nuclear envelopein vitro,in vivoand during early development. Nuclear transport establishes a specific nuclear proteome that exerts a colloid osmotic pressure, which, assisted by entropic chromatin pressure, draws water into the nucleus. UsingC. elegans, we show that while nuclear-to-cytoplasmic (N/C)volumeratios change during early development, the N/Cdensityratio is robustly maintained. We propose that the maintenance of a constant N/Cdensityratio is the biophysical driver of one of the oldest tenets of cell biology: the N/Cvolumeratio. In summary, this study reveals a previously unidentified homeostatic coupling of macromolecular densities that drives cellular organization with implications for pathophysiologies such as senescence and cancer.
Robust nuclease-dead S. aureus dCas9-mediated alpha-synuclein knockdown in substantia nigra in a humanized mouse model of Parkinson’s disease
Authors: Torres C. Alejandra Morato , Zafar Faria , Sastre Danuta , Hermesky De’Angelo , Chen Max Y. , Vazquez Jocelyn Palafox , Qi Lei Stanley , Kirik Deniz , Schüle Birgitt 
Published: September 2023

AbstractParkinson’s disease (PD) is becoming increasingly prevalent due to an aging society, which places a substantial disease burden on patients and their families and an annual cost estimated at 52 billion dollars. However, no approved disease modulatory therapies that halt disease progression are available. Alpha-synuclein is a critical therapeutic target found in aggregated form in Lewy bodies which is the diagnostic hallmark of PD. Familial autosomal dominant forms of PD can present with causative exonic point mutations, copy number multiplications, and non-coding risk variants in the alpha-synuclein gene. The disease onset, severity, and progression depend on the gene expression levels of the alpha-synuclein. Here, we demonstrate thatStreptococcus aureusdCas9 (sadCas9)-mediated CRISPR interference (CRISPRi) reduces alpha-synuclein mRNA and protein levels in a humanized mouse model. The mechanism of action is based on the principle that a complementary single guide RNA (sgRNA) recruits the sadCas9 protein to the promoter region of alpha-synuclein and modulates target gene transcription, leading to reduced gene expression. We show robust downregulation of alpha-synuclein in neurons after unilateral stereotactic injection into the substantia nigra of adult mice 1 and 6 months after surgery. This work shows proof of concept that viral-mediated sadCas9 CRISPR interference can be a promising therapeutic strategy to reduce alpha-synucleinin vivo.Graphical abstracteTOC synopsisThis study focuses on the development of an AAV9 nuclease-dead S. aureus CRISPR/Cas9 expression system designed to target the humanSNCApromoter. The objective is to achieve downregulation of α-synuclein (a-syn) expression. After performing surgery and introducing the expression system, the levels of a-syn were measured at 1 month and 6 months post-surgery. The results indicate a significant downregulation of a-syn at both time points. Furthermore, it was observed that the initial immune response to the system attenuated over time, reaching control levels at the 6-month mark. These findings suggest the potential of this expression system for long-term downregulation of a-syn and provide insights into the immune response dynamics associated with its use.
Characterization of Turkish Pine Honey and Differentiation from Floral Honeys by NMR Spectroscopy and Chemometric Analysis
Authors: Kahraman Kerem , Göcenler Oktay , Dağ Çağdaş 
Published: September 2023

AbstractHoney is a viscous, supersaturated sugar solution produced by bees through the enzymatic transformation of nectar from flowers, containing a complex mixture of carbohydrates, organic acids, enzymes, and other minor constituents. Although honey has been used for thousands of years for its nutritional and medicinal properties, it has been the subject of increasing attention in recent years due to increasing adulterated honey production. Consequently, assessment of honey quality and authenticity has become essential to ensure consumer confidence of regional honey and to perverse the practice of authentic honey production. In this study, we employed nuclear magnetic resonance (NMR) spectroscopy and chemometric analysis to characterize Turkish Pine honey and compare it to flower honey originating from the Oceania, Aegean, and West Coast of North America regions. Utilizing1H NMR spectroscopy, the chemical profile of Turkish Pine honey was characterized, and unique peaks were found. Additionally, PLS-DA statistical analysis was employed to further investigate the distinction of Turkish Pine honey among other floral and regional honeys. Upon completion of our statistical analysis, we were able to effectively distinguish Turkish Pine honey from other regional honey types, allowing us to formulate a universal test for authenticity of Turkish Pine Honey.
Germ cells do not progress through spermatogenesis in the infertile zebrafish testis
Authors: Sposato Andrea L. , Llewellyn Darren R. , Weber Jenna M. , Hollins Hailey L. , Schrock Madison N. , Farrell Jeffrey A. , Gagnon James A. 
Published: September 2023

AbstractVertebrate spermatogonial stem cells maintain sperm production over the lifetime of an animal but fertility declines with age. While morphological studies have greatly informed our understanding of typical spermatogenesis, the molecular and cellular mechanisms underlying spermatogenesis are not yet understood, particularly with respect to the onset of fertility. We used single-cell RNA sequencing to generate a developmental atlas of the zebrafish testis. Using 5 timepoints across the adult life of a zebrafish, we described cellular profiles in the testis during and after fertility. While all germ cell stages of spermatogenesis are detected in testes from fertile adult zebrafish, testes from older infertile males only contained spermatogonia and a reduced population of spermatocytes. These remaining germ cells are transcriptionally distinct from fertile spermatogonia. Immune cells including macrophages and lymphocytes drastically increase in abundance in infertile testes. Our developmental atlas reveals the cellular changes as the testis ages and defines a molecular roadmap for the regulation of male fertility.
Temporal dynamics of hippocampal activity predict stable patterns of sensitization or habituation to noxious stimulation across sessions
Authors: Harrison Richard , van Reekum Carien M. , Adams Greig , Gandhi W. , Salomons Tim V. 
Published: September 2023

AbstractAcute pain serves to warn an organism of potential damage. When nociceptive stimulation persists, two possible responses emerge: If no risk of harm is anticipated, habituation may occur. If harm is considered possible, pain sensitization is likely. An individual’s adaptation to prolonged pain may provide insight into their ability to manage resources, and possibly their likelihood of developing chronic pain. Yet, little is known about the stability of these individual differences or their underlying neural mechanisms. Eighty-five participants undertook a repetitive noxious stimulation task and a resting-state scan in an MRI scanner, in a first session. They then completed the same task outside the scanner on three separate days. Pain adaptation was operationalized as the slope of change in pain ratings within session. Intraclass correlations were calculated between slopes across the four sessions, which demonstrated high stability and association with emotional disposition. Individuals who habituated to repeated stimuli showed increasing activity in the anterior hippocampus and amygdala, while individuals who sensitized showed increasing activity in the sensorimotor cortices. These clusters were then used as seeds in resting state analysis, with habituation associated with higher functional connectivity between hippocampus/amygdala and ventromedial prefrontal cortex(vmPFC), and higher connectivity between sensorimotor regions and the hippocampus, amygdala and insula cortex. Our findings suggest that pain adaptation is a stable phenotypic trait, which may have implications for the prediction of chronic pain.This study implicates neural sensory and appraisal systems in these stable responses, offering insight into the mechanisms underlying trait-like responses to prolonged nociceptive input.