bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalization in motor learning: learning bimanual coordination with one hand
Authors: Wang Yiyu , Weinrich Madison M. , Lei Yuming , Wright David L. , Sandhu Milap , Buchanan John J. , Kennedy Deanna M.
Published: May 2024

The ability to coordinate movements between the hands is crucial for many daily tasks. However, the precise mechanisms governing the storage and utilization of bimanual movement and the distinct contributions of each limb in this process are currently not fully understood. Two key questions persist: 1) How is the neural representation of bimanual coordination stored in the brain, and 2) How is the information governing bimanual coordination shared between hemispheres? In this investigation, we used a virtual partner (VP) to systematically address these issues by allowing the same coordination pattern (CP) to be acquired with unimanual and bimanual movements. More specifically, we used four experimental groups: unimanual (left, right) VP, bimanual, and control conditions. For each condition, retention and transfer tests were administered immediately and 6 hours after the initial practice. The control condition employed the same protocol as unimanual conditions without practice. As anticipated, performance after practice and during retention sessions indicated that all groups learned to perform the target CP. Furthermore, generalization from unimanual to bimanual occurred when the same type of visual feedback (VF) was provided. Interestingly, the absence of VF impaired motor generalization from unimanual to bimanual condition unless the participants initially practiced the task bimanually. Taken together, our results demonstrated that both limbs could access the memory representation of the CP. However, this globally shared representation appeared to be encoded in the visual-spatial domain. The conditions without VF underscored the importance of proprioception in forming a motor representation in intrinsic coordinates.

NEW & NOTEWORTHY

Conventional views on acquiring bimanual skills stress the need for simultaneous engagement of both hands. However, our study challenges this notion by demonstrating that the coordination pattern learned in unimanual conditions significantly boosts subsequent bimanual coordination—a novel approach to skill acquisition. Yet, this advantage diminishes without visual feedback, resulting in a breakdown of the intended bimanual coordination, highlighting the limitations of relying solely on unimanual practice.
Copy number variations ofPlasmodium vivax DBP1,EBP/DBP2, andRBP2bin Duffy-positive and Duffy-negative Ethiopians
Authors: Pestana Kareen , Ford Anthony , Rama Rei , Abagero Beka , Kepple Daniel , Tomida Junya , Popovici Jean , Yewhalaw Delenasaw , Lo Eugenia
Published: May 2024

Recent evidence challenges the belief that Duffy-negative individuals are resistant toPlasmodium vivaxdue to lacking Duffy Antigen Receptor for Chemokines (DARC). Erythrocyte Binding Protein (EBP/DBP2) has shown moderate binding to Duffy-negative erythrocytesin vitro. Reticulocyte Binding Protein 2b (RBP2b) interactions with Transferrin Receptor 1 (TfR1) suggest involvement in Duffy-negative infections. Gene copy number variations inPvDBP1,PvEBP/DBP2, andPvRBP2bwere investigated in Duffy-positive and Duffy-negativeP. vivax-infected individuals from Ethiopia. Among Duffy-positive samples, 34% displayedPvDBP1duplications (Cambodian-type). In Duffy-negative infections, 30% showed duplications, mostly Cambodian-type. ForPvEBP/DBP2andPvRBP2b, Duffy-positive samples exhibited higher duplication rates (1-8 copies forPvEBP/DBP2, 1-5 copies forPvRBP2b46% and 43% respectively) compared to Duffy-negatives (20.8% and 26% respectively). The range of copy number variations was lower in Duffy-negative infections. Demographic and clinical factors associated with gene multiplications in both Duffy types were explored, enhancing understanding ofP. vivaxevolution in Duffy-negative Africans.
Dynamic mechanisms for membrane skeleton transitions
Authors: Bonilla-Quintana M. , Ghisleni A. , Gauthier N. , Rangamani P.
Published: May 2024

The plasma membrane and the underlying skeleton form a protective barrier for eukaryotic cells. The molecules forming this complex composite material constantly rearrange under mechanical stress to confer this protective capacity. One of those molecules, spectrin, is ubiquitous in the membrane skeleton and primarily located proximal to the inner leaflet of the plasma membrane and engages in protein-lipid interactions via a set of membrane-anchoring domains. Spectrin is linked by short actin filaments and its conformation varies in different types of cells. In this work, we developed a generalized network model for the membrane skeleton integrated with myosin contractility and membrane mechanics to investigate the response of the spectrin meshwork to mechanical loading. We observed that the force generated by membrane bending is important to maintain a smooth skeletal structure. This suggests that the membrane is not just supported by the skeleton, but has an active contribution to the stability of the cell structure. We found that spectrin and myosin turnover are necessary for the transition between stress and rest states in the skeleton. Our model reveals that the actin-spectrin meshwork dynamics are balanced by the membrane forces with area constraint and volume restriction promoting the stability of the membrane skeleton. Furthermore, we showed that cell attachment to the substrate promotes shape stabilization. Thus, our proposed model gives insight into the shared mechanisms of the membrane skeleton associated with myosin and membrane that can be tested in different types of cells.

Significance Statement

Spectrin was first observed in red blood cells, as a result of which, many theoretical models focused on understanding its function in this cell type. However, recently, experiments have shown that spectrin is an important skeletal component for many different cell types and that it can form different configurations with actin. In this work, we proposed a model to study the shared mechanisms behind the function of the actin-spectrin meshwork in different types of cells. We found that membrane dynamics in addition to spectrin and myosin turnover are necessary to achieve conformational changes when stresses are applied and to guarantee shape stability when the stresses are removed. We observed that membrane bending is important to support skeletal structure. Furthermore, our model gives insight into how cell shape is maintained despite constant spectrin turnover and myosin contraction.
Alleviation of allergic rhinoconjunctivitis symptoms in participants treated with a 0.005% tacrolimus eye drop solution
Authors: Sladek S. , Unger-Manhart N. , Siegl C. , Dellago H. , Zieglmayer P. , Lemell P. , Savli M. , Zieglmayer R. , Geitzenauer W. , Laengauer M. , Prieschl-Grassauer E.
Published: May 2024

Purpose

This randomized, placebo-controlled, crossover, double-blind, single site trial was aimed to evaluate efficacy and safety of Tacrosolv, a novel eye drop solution containing solubilized tacrolimus, in adult participants with grass pollen induced allergic conjunctivitis.

Methods

64 adult participants with proven grass pollen allergy were randomized to either 2.5 µg or 5 µg tacrolimus/eye/day or placebo treatment for 8 days. Allergic symptoms were induced by 4h grass pollen exposure on day 1 and day 8. After a 2-week wash-out period, placebo participants crossed over to high or low dose and vice versa, and repeated treatment and exposure. During exposure, participants recorded ocular, nasal and respiratory allergy symptoms every 15 minutes. The primary endpoint was the mean ‘Total Ocular Symptom Score’ (TOSS) on Day 8. Objective ocular safety parameters were assessed before, during and after exposure. Adverse events (AEs) were recorded throughout the study.

Results

On Day 8, TOSS was reduced towards the end of exposure in participants receiving Tacrosolv high dose compared to placebo (p<0.05 at timepoints 3h45min and 4h). Accordingly, intensity of the single ocular symptoms like redness and watery eyes was reduced versus placebo by end of exposure on Day 8. A 26% reduction of baseline adjusted TOSS from day 1 to day 8 was observed in participants treated with high dose Tacrosolv, whereas placebo treated participants showed no difference in TOSS between day 1 and day 8. Interestingly, a significant reduction of total nasal symptoms, mainly itching and sneezing, was seen both on day 1 and day 8 in participants treated with high dose Tacrosolv (p<0.05). No safety concerns were raised upon ocular assessments by the investigator like redness of the eye, corneal and conjunctival staining. All AEs were resolved within the study period.

Conclusion

Treatment with Tacrosolv at the dose and frequency studied is safe and alleviates symptoms in participants suffering from allergic rhinoconjunctivitis.

Trial registration

NCT04532710; EudraCT No. 2019-002847-62
Rates, risks and routes to reduce vascular dementia (R4VaD), a UK-wide multicentre prospective observational cohort study of cognition after stroke: baseline data and statistical analysis plan (ISRCTN18274006)
Authors: Bath Philip M , Backhouse Ellen , Brown Rosalind , Woodhouse Lisa J , Doubal Fergus , Quinn Terence J , Markus Hugh S , McManus Richard , O’Brien John T , Robinson Thompson , Werring David J , Sprigg Nikola , Parry-Jones Adrian , Touyz Rhian M , Williams Steven , Mah Yee-Haur , Emsley Hedley , Wardlaw Joanna M ,   the R4VaD Investigators
Published: May 2024

Background

Stroke is often followed by vascular cognitive impairment and vascular dementia; these are the most feared complication of stroke. However, there is limited understanding of post-stroke cognitive impairment.

Methods

Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. Patients with haemorrhagic or ischaemic stroke, or transient ischaemic attack, were recruited within six weeks of stroke from hospitals across the UK. Consent was obtained from patients with capacity or from relatives/friends in those without capacity. The primary outcome is cognition and its severity assessed using a 7-level ordinal outcome. Final cognition will be compared in those with mild stroke/TIA (worst NIHSS <=7) versus severe stroke (NIHSS >7). Secondary outcomes will include function, mood and quality of life.

Results

We recruited 2441 patients from 50 hospitals. Of these, 2437 (99.8%) had a qualifying event of stroke or TIA. The mean age was 68.2 years (standard deviation 13.5), females 981 (40.3%), onset to recruitment 6 days [interquartile range 3-13] and diagnosis ICH 193 (7.9%), ischaemic stroke 2101 (86.2%), TIA 143 (5.9%). The distribution of cognition at baseline was: normal 1256 (51.6%), minor neurocognitive disorder-single domain 530 (21.8%), minor neurocognitive disorder-multi domain 320 (13.1%), major neurocognitive disorder-mild 237 (9.7%), major neurocognitive disorder-moderate 90 (3.7%) and major neurocognitive disorder-severe 3 (0.1%). We provide the statistical analysis plan in the appendix.

Conclusion

We provide baseline data and the SAP. Final follow-up will be completed in quarter 2 2024. The data highlight the substantial under-appreciated cognitive burden of stroke, even in the first few days and weeks.
C9orf72repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis
Authors: Spencer Barbara E. , Xie Sharon X. , Elman Lauren , Quinn Colin C. , Amado Defne , Baer Michael , Lee Edward B. , Van Deerlin Vivianna M. , Dratch Laynie , Massimo Lauren , Irwin David J. , McMillan Corey T.
Published: May 2024

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored.

We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69). Only individuals who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or aC9orf72hexanucleotide repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether each was modified by the presence of aC9orf72expansion or initial clinical syndrome.

Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [95% CI 1.97-9.14], p<0.001) and an increased hazard (HR= 4.77 [95% CI 2.33-9.79], p<0.001) for developing secondary symptoms in those with aC9orf72expansion compared to those without. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary symptoms.

These data highlight the need for clinician vigilance to detect the onset of secondary motor and cognitive-behavioral symptoms in patients carrying aC9orf72expansion, regardless of initial clinical syndrome.C9orf72clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.
Development of D-box peptides to inhibit the Anaphase Promoting Complex/Cyclosome
Authors: Eapen Rohan , Okoye Cynthia , Stubbs Christopher , Schimpl Marianne , Tischer Thomas , Fisher Eileen J. , Zacharopoulou Maria , Ferrer Fernando , Barford David , Spring David , Lindon Cath , Phillips Christopher , Itzhaki Laura S.
Published: May 2024

E3 ubiquitin ligases engage their substrates via ‘degrons’ - short linear motifs typically located within intrinsically disordered regions of substrates. As these enzymes are large, multi-subunit complexes that generally lack natural small-molecule ligands and are hard to drug via conventional means, alternative strategies are needed to target them in diseases, and peptide-based inhibitors derived from degrons represent a promising approach. Here we explore peptide inhibitors of Cdc20, a substrate-recognition subunit and activator of the E3 ubiquitin ligase the anaphase promoting complex/cyclosome (APC/C) that is essential in mitosis and consequently of interest as an anti-cancer target. APC/C engages substrates via degrons that include the ‘Destruction box’ (D-box) motif. We used a rational design approach to construct binders containing unnatural amino acids aimed at better filling a hydrophobic pocket on the surface of Cdc20. We confirmed binding by thermal-shift assays and surface plasmon resonance and determined the structures of a number of the Cdc20- peptide complexes. Using a cellular thermal shift assay, we confirmed that the D-box peptides also bind to and stabilise Cdc20 in the cell. We found that the D-box peptides inhibit ubiquitination activity of APC/CCdc20and are more potent than the small molecule inhibitor Apcin. Lastly, these peptides function as portable degrons capable of driving the degradation of a fused fluorescent protein. Interestingly, we find that although inhibitory activity of the peptides correlates with Cdc20-binding affinity, degradation efficacy does not, which may be due to the complex nature of APC/C regulation and effects of degron binding of subunit recruitment and conformational changes. Our study lays the groundwork for the further development of these peptides as molecular therapeutics for blocking APC/C as well as potentially also for harnessing APC/C for targeted protein degradation.
Characteristics of epitopes of limited variability on the head of influenza H1 haemagglutinin
Authors: Lourenco Jose , Zinad Hany , Kempton James , Gupta Sunetra
Published: May 2024

It is commonly assumed that all naturally protective targets of immunity in influenza are highly variable. Our theoretical work suggests, by contrast, that influenza evolution is primarily driven by naturally protective immune responses against epitopes of limited variability (ELV). We have identified and characterised at least one such ELV on the head region of the major influenza antigen, haemagglutinin (HA), of H1 influenza, opening up the possibility of a novel method of producing a universal influenza vaccine. Here we demonstrate that the head region of H1 haemagglutinin can be decomposed into a number of discrete variable regions (VRs): ELVs tend to include a limited number of VRs compared to other epitopes either because of the smaller footprint of the associated antibody or because they are centred on VRs that are relatively isolated from the others. We conclude that the variability of an antibody binding site is determined by the number of variable residues included in its footprint rather than the intrinsic entropy of any particular region.
TheαC helix is a central regulator of PKR activation
Authors: Feinstein Aaron G. , Cole James L. , May Eric R.
Published: May 2024

Protein kinase R (PKR) functions in the eukaryotic innate immune system as a first-line defense against viral infections. PKR binds viral dsRNA, leading to autophosphorylation and activation. In its active state, PKR can phosphorylate its primary substrate, eIF2α, which blocks initiation of translation in the infected cell. It has been established that PKR activation occurs when the kinase domain dimerizes in a back-to-back configuration. However, the mechanism by which dimerization leads to enzymatic activation is not fully understood. Here, we investigate the structural mechanistic basis and energy landscape for PKR activation, with a focus on theαC helix – a kinase activation and signal integration hub – using all-atom equilibrium and enhanced sampling molecular dynamics simulations. By employing window-exchange umbrella sampling, we compute free energy profiles of activation which show that back-to-back dimerization stabilizes a catalytically competent conformation of PKR. Key hydrophobic residues in the homodimer interface contribute to stabilization of theαC helix in an active conformation and the position of its glutamate residue. Using linear mutual information analysis, we analyze allosteric communication connecting the protomers’ N-lobes and theαC helix dimer interface with theαC helix.
Electrophysiological responses to appetitive and consummatory behavior in the rostral nucleus tractus solitarius in awake, unrestrained rats
Authors: Pilato Stephen A. , O’Connell Flynn P. , Victor Jonathan D. , Di Lorenzo Patricia M.
Published: May 2024

As the intermediate nucleus in the brainstem receiving information from the tongue and transmitting information upstream, the rostral portion of the nucleus tractus solitarius (rNTS) is most often described as a “taste relay”. Although recent evidence implicates the NTS in a broad neural circuit involved in regulating ingestion, there is little information about how cells in this structure respond when an animal is eating solid food. Here, single cells in the rNTS were recorded in awake, unrestrained rats as they explored and ate solid foods (Eating paradigm) chosen to correspond to the basic taste qualities: milk chocolate for sweet, salted peanuts for salty, Granny Smith apples for sour and broccoli for bitter. A subset of cells was also recorded as the animal licked exemplars of the five basic taste qualities: sucrose, NaCl, citric acid, quinine and MSG (Lick paradigm). Results showed that most cells were excited by exploration of a food-filled well, sometimes responding prior to contact with the food. In contrast, cells that were excited by food well exploration became significantly less active while the animal was eating the food. Most cells were broadly tuned across foods, and those cells that were recorded in both the Lick and Eating paradigms showed little correspondence in their tuning across paradigms. The preponderance of robust responses to the appetitive versus the consummatory phase of ingestion suggests that multimodal convergence onto cells in the rNTS may be used in decision making about ingestion.

Significance Statement

The rostral part of the NTS has traditionally, but perhaps narrowly, been thought of as a “taste relay”. While it is true that this structure receives and transmits information about tastants in the mouth to higher order structures in the central gustatory pathway, data presented here show that its function is more diverse. Specifically, in addition to the responses to liquid tastants in the mouth, its responses to approach and exploration of solid food define a significant role for the rNTS in the appetitive phase of eating. Moreover, responses to food consumption, albeit weaker than those during appetitive behavior, buttress the idea that the rNTS is part of the larger hindbrain circuit guiding energy regulation.
A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants
Authors: Papageorgiou Grigorios , Ibrahim El-Cherif , Maxson Gabriella , Gorgievski Victor , Lozano Evelyn , Belzeaux Raoul , Carmody Thomas , Tzavara Eleni T. , Trivedi Madhukar H. , Mellios Nikolaos
Published: May 2024

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the inherent complexity and heterogeneity of the disease and the “trial and error” approach in choosing the most effective antidepressant treatment for each patient, allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, to cross the blood-brain-barrier, and to be highly sensitive to changes in neuronal activity or activation of various neuronal receptors. Here we present evidence of a brain-enriched circRNA that is regulated by Serotonin 5-HT2A and Brain-Derived Neurotrophic Factor (BDNF) receptor activity and whose expression in the blood can predict response to SSRI treatment. We present data using circRNA-specific PCR in baseline whole blood samples from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) study, showing that before treatment this circRNA is differentially expressed between future responders and non-responders to sertraline. We further show that the expression of this circRNA is upregulated following sertraline treatment and that its trajectory of change post-treatment is associated with long-term remission. Furthermore, we show that the biomarker potential of this circRNA is specific to SSRIs, and not associated with prediction of response or remission after Placebo or Bupropion treatment. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting that the same circRNA is enriched in the brain and is regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.
Contrasting the development of larval and adult body plans during the evolution of biphasic lifecycles in sea urchins
Authors: McDonald Brennan D. , Massri Abdull J. , Escobar Alejandro Berrio , Byrne Maria , McClay David R. , Wray Gregory A.
Published: May 2024

Biphasic lifecycles are widespread among animals, but little is known about how the developmental transition between larvae and adults is regulated. Sea urchins are a unique system for studying this phenomenon because of the stark differences between their bilateral larval and pentaradial adult body plans. Here, we use single cell RNA-sequencing to analyze the development ofHeliocidaris erythrogramma(He), a sea urchin species with an accelerated, non-feeding mode of larval development. The sequencing time course extends from early embryogenesis to roughly a day before the onset of metamorphosis inHelarvae, which is a period that has not been covered by previous datasets. We find that the non-feeding developmental strategy ofHeis associated with several changes in the specification of larval cell types compared to sea urchins with feeding larvae, such as the loss of a larva-specific skeletal cell population. Furthermore, the development of the larval and adult body plans in sea urchins may utilize largely different sets of regulatory genes. These findings lay the groundwork for extending existing developmental gene regulatory networks to cover additional stages of biphasic lifecycles.

Summary statement

Analysis of a new single cell transcriptomic atlas of sea urchin development reveals the rapid evolution of larval cell type trajectories and provides a candidate list of regulators for adult rudiment development.
Characterizing cell type specific transcriptional differences between the living and postmortem human brain
Authors: Vornholt Eric , Liharska Lora E. , Cheng Esther , Hashemi Alice , Park You Jeong , Ziafat Kimia , Wilkins Lillian , Silk Hannah , Linares Lisa M. , Thompson Ryan C. , Sullivan Brendan , Moya Emily , Nadkarni Girish N. , Sebra Robert , Schadt Eric E. , Kopell Brian H. , Charney Alexander W. , Beckmann Noam D.
Published: May 2024

Single-nucleus RNA sequencing (snRNA-seq) is often used to define gene expression patterns characteristic of brain cell types as well as to identify cell type specific gene expression signatures of neurological and mental illnesses in postmortem human brains. As methods to obtain brain tissue from living individuals emerge, it is essential to characterize gene expression differences associated with tissue originating from either living or postmortem subjects using snRNA-seq, and to assess whether and how such differences may impact snRNA-seq studies of brain tissue. To address this, human prefrontal cortex single nuclei gene expression was generated and compared between 31 samples from living individuals and 21 postmortem samples. The same cell types were consistently identified in living and postmortem nuclei, though for each cell type, a large proportion of genes were differentially expressed between samples from postmortem and living individuals. Notably, estimation of cell type proportions by cell type deconvolution of pseudo-bulk data was found to be more accurate in samples from living individuals. To allow for future integration of living and postmortem brain gene expression, a model was developed that quantifies from gene expression data the probability a human brain tissue sample was obtained postmortem. These probabilities are established as a means to statistically account for the gene expression differences between samples from living and postmortem individuals. Together, the results presented here provide a deep characterization of both differences between snRNA-seq derived from samples from living and postmortem individuals, as well as qualify and account for their effect on common analyses performed on this type of data.
The influence of sensory noise, confidence judgments, and accuracy on pupil responses and associated behavioural adjustments in young and older people
Authors: Oliveira Sara F. , Gomes Catarina F. , Ribeiro Maria J.
Published: May 2024

We investigated the association between pupil responses, decision confidence and decision accuracy, their relationship with behavioural adjustments important for optimal task performance, and if these were altered in older adults.

We tested young and older adults, including men and women, with a dot motion direction discrimination task, while measuring task-related pupil responses. Feedback was provided after each trial. Participants were instructed to report perceived motion direction and simultaneously their decision confidence.

Older adults were overconfident in the presence of high sensory noise and in incorrect trials. Young people’s pupil responses reflected performance lapses. This effect was reduced in older people that showed blunted pupil responses to lapses and to negative feedback. Low confidence, errors, and larger pre-feedback pupil responses were associated with slower reaction time on the subsequent trial. The effects of errors and pupil were stronger in the older group.

In conclusion, older people’s blunted pupil responses following lapses suggest reduced awareness of their own abilities and internal brain state and might impair adjustment of behaviour for optimal performance.
Engineering fluorescent reporters in human pluripotent cells and strategies for live imaging human neurogenesis
Authors: Dady Alwyn , Davidson Lindsay , Loyer Nicolas , Rappich Sophie , Findlay Greg , Sanders Timothy , Januschke Jens , Storey Kate G.
Published: May 2024

Investigation of cell behaviour and cell biological processes underlying human development is facilitated by creation of fluorescent reporters in human pluripotent stem cells, which can be differentiated into cell types of choice. Here we report use of a piggyBac transposon-mediated stable integration strategy to engineer human pluripotent stem cell reporter lines. These express a plasma membrane localised protein tagged with the fluorescent proteins eGFP or mKate2, the photoconvertible nuclear marker H2B-mEos3.2, or the cytoskeletal protein F-tractin tagged with mKate2. Focussing on neural development these lines were used to live image and quantify cell behaviours, including cell cycle progression and cell division orientation in spinal cord rosettes. Further, lipofection-mediated introduction of piggyBac constructs into human neural progenitors labelled single cells and small cell groups within rosettes, allowing individual cell behaviours including neuronal delamination to be monitored. Finally, using the F-tractin-mKate2 hiPSC line, novel actin dynamics were captured during proliferation in cortical neural rosettes. This study presents and validates new tools and techniques with which to interrogate human cell behaviour and cell biology using live imaging approaches.
Cell type and cell signaling innovations underlying mammalian pregnancy
Authors: Stadtmauer Daniel J. , Basanta Martínez Silvia , Maziarz Jamie D. , Cole Alison G. , Dagdas Gülay , Smith Gilbecca Rae , van Breukelen Frank , Pavličev Mihaela , Wagner Günter P.
Published: May 2024

How fetal and maternal cell types have co-evolved to enable mammalian placentation poses a unique evolutionary puzzle. Here, we present a multi-species atlas integrating single-cell transcriptomes from six species bracketing therian mammal diversity. We find that invasive trophoblasts share a gene-expression signature across eutherians, and evidence that endocrine decidual cells evolved stepwise from an immunomodulatory cell type retained inTenrecwith affinity to human decidua of menstruation. We recover evolutionary patterns in ligand-receptor signaling: fetal and maternal cells show a pronounced tendency towards disambiguation, but a predicted arms race dynamic between them is limited. We reconstruct cell communication networks of extinct mammalian ancestors, finding strong integration of fetal trophoblast into maternal networks. Together, our results reveal a dynamic history of cell type and signaling evolution.

Synopsis

The fetal-maternal interface is one of the most intense loci of cell-cell signaling in the human body. Invasion of cells from the fetal placenta into the uterus, and the corresponding transformation of maternal tissues called decidualization, first evolved in the stem lineage of eutherian mammals(1,2). Single-cell studies of the human fetal-maternal interface have provided new insight into the cell type diversity and cell-cell interactions governing this chimeric organ(3–5). However, the fetal-maternal interface is also one of the most rapidly evolving, and hence most diverse, characters among mammals(6), and an evolutionary analysis is missing. Here, we present and compare single-cell data from the fetal-maternal interface of species bracketing key events in mammal phylogeny: a marsupial (opossum,Monodelphis domestica), the afrotherianTenrec ecaudatus,and four Euarchontoglires - guinea pig and mouse (Rodentia) together with recent macaque and human data (primates) (4,5,7). We infer cell type homologies, identify a gene-expression signature of eutherian invasive trophoblast conserved over 99 million years, and discover a predecidual cell in the tenrec which suggests stepwise evolution of the decidual stromal cell. We reconstruct ancestral cell signaling networks, revealing the integration of fetal cell types into the interface. Finally, we test two long-standing theoretical predictions, the disambiguation hypothesis(8) and escalation hypothesis(9), at transcriptome-wide scale, finding divergence between fetal and maternal signaling repertoires but arms race dynamics restricted to a small subset of ligand-receptor pairs. In so doing, we trace the co-evolutionary history of cell types and their signaling across mammalian viviparity.
The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics
Authors: Fornara Basile , Igel Angélique , Béringue Vincent , Martin Davy , Sibille Pierre , Pujo-Menjouet Laurent , Rezaei Human
Published: May 2024

Prion diseases, or Transmissible Spongiform Encephalopathies (TSE), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc) of the cellular prion protein (PrPC). During the pathogenesis, the PrPScseeds disseminate in the central nervous system and convert PrPCleading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrPScstructures. In this work, we implemented the recent developments on PrPScstructural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie Algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain specific phenotypes, tissue tropisms and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.
Representational similarity modulates neural and behavioral signatures of novelty
Authors: Becker Sophia , Modirshanechi Alireza , Gerstner Wulfram
Published: May 2024

Novelty signals in the brain modulate learning and drive exploratory behaviors in humans and animals. While the perceived novelty of a stimulus is known to depend on previous experience, the effect of stimulus representations on novelty computation remains elusive. In particular, existing models of novelty computation fail to account for the effects of stimulus similarities that are abundant in naturalistic environments and tasks. Here, we present a unifying, biologically plausible model that captures how stimulus representations modulate novelty signals in the brain and influence novelty-driven learning and exploration. By applying our model to two publicly available data sets, we quantify and explain (i) how generalization across similar visual stimuli affects novelty responses in the mouse visual cortex, and (ii) how generalization across nearby locations impacts mouse exploration in an unfamiliar environment. Our model unifies and explains distinct neural and behavioral signatures of novelty, and enables theory-driven experiment design to investigate the neural mechanisms of novelty computation.
Incidence and Antibiotic Susceptibility Profile ofPlesiomonas shigelloidesIsolated from Fish, Fish Storage water and Fish seller’s towel
Authors: Agboola Temitope Deborah , Oguntimehin Monica Oluwatoyin , Obadofin Isaac Olaoluwa , Oyeneye Oluwapelumi Ruth
Published: May 2024

This study evaluated the incidence ofPlesiomonas shigelloidesand their antibiogram pattern in fish storage water, fish and fish seller’s towel swab collected from two major markets in Southern part of Ondo State, Nigeria. About 158 presumptivePlesiomonas shigelloideswere recovered from the samples collected from the two markets and only 58 (31.6%) were positive using PCR (polymerase chain reaction) method. Using the disc diffusion method, confirmed isolates were assessed for their antibiogram profiles against 15 antibiotics and multiple antibiotic resistance phenotypes. Resistance of the isolates against the antibiotics followed the order: Erythromycin (85%), Ampicillin (83%), Ceftazidime (81%), Cefuroxime (71%), Tetracycline (67%), Meropenem and Vancomycin (45%), Amoxicillin and Streptomycin (43%), Trimethoprim (41%), Ciprofloxacin and Chloramphenicol (34%), Gentamicin (26%), Cotrimoxazole (22%) and Amikacin (21%). Conversely, all the isolates did not show 100 % susceptibility to any antibiotics, and susceptibility against the antibiotics follows the order: Amikacin (79%), Cotrimoxazole (78%), Gentamicin (74%), Ciprofloxacin and Chloramphenicol (66%), Trimethoprim (59%), Amoxicillin and Streptomycin (57%), Meropenem and Vancomycin (55%), Tetracycline (33%), Cefuroxime (29%), and exhibited less than 20% susceptibility to other antibiotics. The multiple antibiotic-resistance indices of the organism were higher than the accepted threshold of 0.2. This is the first report on assessing the ease at whichP. shigelloidesinClarias gariepinussold in the market can be transmitted. We concluded that this pathogen with multiple antimicrobial resistant phenotypes can be easily transmitted consequently, a public health threat meanwhile, Amikacin, Cotrimoxazole and Gentamicin are important antibiotics that could be used against the pathogen.
A brain-inspired algorithm improves “cocktail party” listening for individuals with hearing loss
Authors: Boyd Alex , Best Virginia , Sen Kamal
Published: May 2024

Selective listening in competing-talker situations (restaurants, parties, etc.) is an extraordinarily difficult task for many people. For individuals with hearing loss, this difficulty can be so extreme that it seriously impedes communication and participation in daily life. Directional filtering is one of the only proven ways to improve speech understanding in competition, and most hearing devices now incorporate some kind of directional technology, although real-world benefits are modest, and many approaches fail in competing-talker situations. We recently developed a biologically inspired algorithm that is capable of very narrow spatial tuning and can isolate one talker from a mixture of talkers. The algorithm is based on a hierarchical network model of the auditory system, in which binaural sound inputs drive populations of neurons tuned to specific spatial locations and frequencies, and the spiking responses of neurons in the output layer are reconstructed into audible waveforms. Here we evaluated the algorithm in a group of adults with sensorineural hearing loss, using a challenging competing-talker task. The biologically inspired algorithm led to robust intelligibility gains under conditions in which a standard beamforming approach failed. The results provide compelling support for the potential benefits of biologically inspired algorithms for assisting individuals with hearing loss in “cocktail party” situations.
Human ESCRT-I and ALIX function as scaffolding helical filamentsin vivo
Authors: Spada Stephanie J. , Rose Kevin M. , Sette Paola , O’Connor Sarah K. , Dussupt Vincent , Siddartha Yerramilli V. , Nagashima Kunio , Sjoelund Virginie Helle , Cruz Phillip , Kabat Juraj , Ganesan Sundar , Smelkinson Margery , Nita-Lazar Aleksandra , Hoyt Forrest , Scarlata Suzanne , Hirsch Vanessa , Best Sonja M. , Grigg Michael E. , Bouamr Fadila
Published: May 2024

The Endosomal Sorting Complex Required for Transport (ESCRT) is an evolutionarily conserved machinery that performs reverse-topology membrane scission in cells universally required from cytokinesis to budding of enveloped viruses. Upstream acting ESCRT-I and ALIX control these events and link recruitment of viral and cellular partners to late-acting ESCRT-III CHMP4 through incompletely understood mechanisms. Using structure-function analyses combined with super-resolution imaging, we show that ESCRT-I and ALIX function as distinct helical filamentsin vivo. Together, they are essential for optimal structural scaffolding of HIV-1 nascent virions, the retention of viral and human genomes through defined functional interfaces, and recruitment of CHMP4 that itself assembles into corkscrew-like filaments intertwined with ESCRT-I or ALIX helices. Disruption of filament assembly or their conformationally clustered RNA binding interfaces in human cells impaired membrane abscission, resulted in major structural instability and leaked nucleic acid from nascent virions and nuclear envelopes. Thus, ESCRT-I and ALIX function as helical filamentsin vivoand serve as both nucleic acid-dependent structural scaffolds as well as ESCRT-III assembly templates.

Significance statement

When cellular membranes are dissolved or breached, ESCRT is rapidly deployed to repair membranes to restore the integrity of intracellular compartments. Membrane sealing is ensured by ESCRT-III filaments assembled on the inner face of membrane; a mechanism termed inverse topology membrane scission. This mechanism, initiated by ESCRT-I and ALIX, is universally necessary for cytokinesis, wound repair, budding of enveloped viruses, and more. We show ESCRT-I and ALIX individually oligomerize into helical filaments that cluster newly discovered nucleic acid-binding interfaces and scaffold-in genomes within nascent virions and nuclear envelopes. These oligomers additionally appear to serve as ideal templates for ESCRT-III polymerization, as helical filaments of CHMP4B were found intertwined ESCRT-I or ALIX filamentsin vivo. Similarly, corkscrew-like filaments of ALIX are also interwoven with ESCRT-I, supporting a model of inverse topology membrane scission that is synergistically reinforced by inward double filament scaffolding.
Developmental disruption ofMef2cin Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function
Authors: Ward Claire , Nasrallah Kaoutsar , Tran Duy , Sabri Ehsan , Vazquez Arenski , Sjulson Lucas , Castillo Pablo E. , Batista-Brito Renata
Published: May 2024

MEF2Cis strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy ofMef2c, or selectively lacking both copies ofMef2cin cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. Using conditional deletions of theMef2cgene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology,in vivorecordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. We found that loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. Our findings indicate that MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to alteredin vivopatterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.
The role of evolving niche choice in herbivore adaptation to host plants
Authors: Nabutanyi Peter , Edison Alitha , Czuppon Peter , Xu Shuqing , Wittmann Meike J.
Published: May 2024

Individuals living in heterogeneous environments often choose microenvironments that provide benefits to their fitness. Theory predicts that such “niche choice” can promote rapid adaptation to novel environments and help maintain genetic diversity. An open question of large applied importance is how niche choice and niche choice evolution affect the evolution of insecticide resistance in phytophagous insects. We, therefore, developed an individual-based model based on phytophagous insects to examine the evolution of insecticide resistance and host plant choice via oviposition preferences. To find biologically realistic parameter ranges, we performed an empirical literature survey on insecticide resistance in major agricultural pests and also conducted a density-dependent survival experiment using potato beetles. We find that, in comparison to a scenario where individuals randomly oviposit eggs on toxic or non-toxic plants, the evolution of niche choice generally leads to slower evolution of resistance and facilitates the coexistence of different phenotypes. Our simulations also reveal that recombination rate and dominance effects can influence the evolution of both niche choice and resistance. Thus, this study provides new insights into the effects of niche choice on resistance evolution and highlights the need for more studies on the genetic basis of resistance and choice.
Recent progress of self-healing polyaniline organic composite coatings: active agents, methods and protection mechanism
Authors: Liu Suyun , Liu Hu , Shao Ningning , Dong Zhijun , Liu Rui , Liu Li , Wang Fuhui
Published: May 2024

Purpose

Polyaniline (PANI) has garnered attention for its potential applications in anticorrosion fields because of its unique properties. Satisfactory outcomes have been achieved when using PANI as a functional filler in organic coatings. More recently, research has extensively explored PANI-based organic coatings with self-healing properties. The purpose of this paper is to provide a summary of the active agents, methods and mechanisms involved in the self-healing of organic coatings.

Design/methodology/approach

This study uses specific doped acids and metal corrosion inhibitors as active and self-healing agents to modify PANI using the methods of oxidation polymerization, template synthesis, nanosheet carrier and nanocontainer loading methods. The anticorrosion performance of the coatings is evaluated using EIS, LEIS and salt spray tests.

Findings

Specific doped acids and metal corrosion inhibitors are used as active agents to modify PANI and confer self-healing properties to the coatings. The coatings’ active protection mechanism encompasses PANI’s own passivation ability, the adsorption of active agents and the creation of insoluble compounds or complexes.

Originality/value

This paper summarizes the active agents used to modify PANI, the procedures used for modification and the self-healing mechanism of the composite coatings. It also proposes future directions for developing PANI organic coatings with self-healing capabilities. The summaries and proposals presented may facilitate large-scale production of the PANI organic coatings, which exhibit outstanding anticorrosion competence and self-healing properties.