bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Spiking Neural Network Model of Rodent Head Direction calibrated with Landmark Free Learning
Authors: Stentiford Rachael , Knowles Thomas C. , Pearson Martin J. 
Published: February 2022

AbstractMaintaining a stable estimate of head direction requires both self motion (ideothetic) information and environmental (allothetic) anchoring. In unfamiliar or dark environments ideothetic drive can maintain a rough estimate of heading but is subject to inaccuracy, visual information is required to stabilise the head direction estimate. When learning to associate visual scenes with head angle, animals do not have access to the ‘ground truth’ of their head direction, and must use egocentrically derived imprecise head direction estimates.We use both discriminative and generative methods of visual processing to learn these associations without extracting explicit landmarks from a natural visual scene, finding all are sufficiently capable at providing corrective signal. Further, we present a spiking continuous attractor model of head direction (SNN), which when driven by ideothetic input is subject to drift. We show that head direction predictions made by the chosen model-free visual learning algorithms can correct for drift, even when trained on a small training set of estimated head angles self-generated by the SNN. We validate this model against experimental work by reproducing cue rotation experiments which demonstrate visual control of the head direction signal.
Why SARS-CoV-2 Omicron variant is milder? A single high-frequency mutation of structural envelope protein matters
Authors: Xia Bingqing , wang Yi , pan Xiaoyan , Cheng Xi , Ji Hongying , Zuo Xiaoli , Li Jia , Gao Zhaobing 
Published: February 2022

AbstractSARS-CoV-2 Omicron variant is highly transmissible and extensive morbidity, which has raised concerns for antiviral therapy. In addition, the molecular basis for the attenuated pathogenicity and replication capacity of Omicron remains elusive. Here, we report for the first time that a high-frequency mutation T9I on 2-E of SARS-CoV-2 variant Omicron forms a non-selective ion channel with abolished calcium permeability and reduced acid sensitivity compared to the WT channel. In addition, T9I caused less cell death and a weaker cytokine production. The channel property changes might be responsible for the Omicron variant releases less efficiently and induces a comparatively lower level of cell damage in the infected cells. Our study gives valuable insights into key features of the Omicron variant, further supporting 2-E is a promising drug target against SARS-CoV-2 and providing critical information for the COVID-19 treatment.
Chronic alcohol intake regulates expression of SARS-CoV2 infection-relevant genes in an organ-specific manner
Authors: Friske Marion M. , Giannone Francesco , Senger Mona , Seitz Robin , Hansson Anita C. , Spanagel Rainer 
Published: February 2022

AbstractChronic alcohol consumption and alcohol use disorder (AUD) have a tremendous impact on the patient’s psychological and physiological health. There is some evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but the molecular mechanism is unknown. Here, we generated expression data of SARS-CoV2 infection relevant genes (Ace2, Tmprss2 and Mas) in different organs in rat models of chronic alcohol exposure and alcohol dependence. ACE2 and TMPRSS2 represent the virus entry point whereas Mas is activating the anti-inflammatory response once the cells are infected. Across three different chronic alcohol test conditions, we found a consistent upregulation of Ace2 in the lung, which is the most affected organ in Covid-19 patients. Other organs such as liver, ileum, kidney, heart, and the brain showed also up-regulation of Ace2 and Mas but in a less consistent manner across the different animal models, while Tmprss2 was unaffected in all conditions. We suggest that alcohol-induced up-regulation of Ace2 can lead to an elevated stochastic probability of cellular virus entry and may thus confer a molecular risk factor for a SARS-CoV2 infection.
Distinct silencer states determine epigenetic states of heterochromatin
Authors: Saxton Daniel S. , Rine Jasper 
Published: February 2022

SummaryA remarkable property of heterochromatin is that a given heterochromatic locus can exhibit different transcriptional states in genetically identical cells. Studies demonstrate that epigenetic inheritance of the silenced state requires silencers and therefore cannot be driven by the inheritance of modified histones alone. To address these observations, we surveyed the chromatin architectures of strong and weak silencers in Saccharomyces. We found that strong silencers recruited Sir proteins and silenced the locus in all cells. Strikingly, weakening these silencers reduced Sir protein recruitment and stably silenced the locus in some cells; however, this silenced state could probabilistically convert to an expressed state that lacked Sir protein recruitment. Additionally, changes in the constellation of silencer-bound proteins or the concentration of a structural Sir protein modulated the probability that a locus existed in the silenced or expressed state. These findings argued that distinct states of silencers generate epigenetic states and regulate their dynamics.
Dynamically regulated Focal adhesions coordinate endothelial cell remodelling in developing vasculature
Authors: Chau Tevin CY. , Yordanov Teodor E. , Silva Jason A. da , Paterson Scott , Yap Alpha S. , Hogan Benjamin M. , Lagendijk Anne Karine 
Published: February 2022

ABSTRACTThe assembly of a mature vascular network involves the coordinated control of cell shape changes to regulate morphogenesis of a complex vascular network. Cellular changes include a process of endothelial cell (EC) elongation which is essential for establishing appropriately sized lumens during vessel maturation1-3. However how EC elongation is dynamically regulated in vivo is not fully understood since live monitoring of this event can be challenging in animal models. Here, we utilise the live imaging capacity of the zebrafish to explore how integrin adhesion complexes, known as Focal Adhesions (FAs), control EC dynamics in live flow pressured vasculature. To do this, we generated a zebrafish mutant, deficient for the integrin adaptor protein Talin1. Notably, unlike the severe cardiovascular defects that arise in Talin1 knockout mice4, vasculogenesis still occurs normally talin1 mutants and cardiac output remains sufficient up to two days post fertilisation (dpf). This allowed us to uncouple primary roles for FAs in ECs during subsequent morphogenesis events, including angiogenesis and vessel remodelling, without interference of secondary effects that might occur due to systemic vessel failure or loss of blood flow. We further established a FA marker line, expressing endothelial Vinculin-eGFP, and demonstrated that FAs are lost in our talin1 mutants. This Vinculin transgene represents the first in vivo model to monitor endothelial FA dynamics. Loss of FAs in talin1 mutants, leads to compromised F-actin rearrangements, which perturb EC elongation and cell-cell junction linearisation during vessel remodelling. Chemical induction of actin polymerisation can restore these cellular phenotypes, suggesting a recovery of actin rearrangements that are sufficient to allow cell and junction shape changes. Together, we have identified that FAs are essential for active guidance of EC elongation and junction linearisation in flow pressured vessels. These observations can explain the severely compromised vessel beds, haemorrhage and vascular leakage that has been observed in mouse models that lack integrin signalling4-8.
An ancient endogenous DNA virus in the human genome
Authors: Barreat Jose Gabriel Nino , Katzourakis Aris 
Published: February 2022

AbstractThe genomes of eukaryotes preserve a striking diversity of ancient viruses in the form of endogenous viral elements (EVEs). Study of this genomic fossil record provides insights into the diversity, origin and evolution of viruses across geological timescales. In particular,Maverickshave emerged as one of the oldest groups of viruses infecting vertebrates (≥419 My). They have been found in the genomes of fish, amphibians and non-avian reptiles but had been overlooked in mammals. Thus, their evolutionary history and the causes of their demise in mammals remain puzzling questions. Here, we conduct a detailed evolutionary study of twoMaverick-like integrations found on human chromosomes 7 and 8. We performed a comparative analysis of the integrations and determined their orthology across placental mammals (Eutheria) via the syntenic arrangement of neighbouring genes. The integrations were absent at the orthologous sites in the genomes of marsupials and monotremes. These observations allowed us to reconstruct a time-calibrated phylogeny and infer the age of their most recent common ancestor at 268.61 (199.70–344.54) My. In addition, we estimate the age of the individual integrations at ~105 My which represent the oldest non-retroviral EVEs found in the human genome. Our findings suggest that activeMavericksexisted in the ancestors of modern mammals ~172 My ago (Jurassic Period) and potentially to the end of the Early Cretaceous. We hypothesiseMaverickscould have gone extinct in mammals from the evolution of an antiviral defence system or from reduced opportunities for transmission in terrestrial hosts.ImportanceThe genomes of vertebrates preserve an enormous diversity of endogenous viral elements (remnants of ancient viruses that accumulate in host genomes over evolutionary time). Although retroviruses account for the vast majority of these elements, diverse DNA viruses have also been found and novel lineages are being described. Here we analyse two elements found in the human genome belonging to an ancient group of DNA viruses calledMavericks. We study their evolutionary history, finding that the elements are shared between humans and many different species of placental mammals. These observations suggest the elements inserted at least ~105 Mya in the most recent common ancestor of placentals. We further estimate the age of the viral ancestor around 268 My. Our results provide evidence for some of the oldest viral integrations in the human genome and insights into the ancient interactions of viruses with the ancestors of modern-day mammals.
Minilungs from hESCs to study the interaction ofStreptococcus pneumoniaewith the respiratory tract
Authors: González-Camacho Fernando , Rossi Suélen Andreia , Sempere Julio , de Lucas María Pilar , Rojas-Cabañeros José María , Taborda Carlos Pelleschi , Zaragoza Óscar , Yuste José , Zambrano Alberto 
Published: February 2022

ABSTRACTThe new generation of organoids derived from human pluripotent stem cells holds a promising strategy for modeling host-bacteria interaction studies. Organoids recapitulate the composition, diversity of cell types and, to some extent, the functional features of the native organ. We have generated lung bud organoids derived from human embryonic stem cells to study the interaction ofStreptococcus pneumoniae(pneumococcus) with the alveolar epithelium. Invasive pneumococcal disease is an important health problem that may occur as a result of the spread of pneumococcus from the lower respiratory tract to sterile sites. We show here an efficient experimental approach to model the main events of the pneumococcal infection that occur in the human lung exploring bacterial adherence to the epithelium, internalization, and triggering of an innate response that includes the interaction with the surfactant and the expression of representative cytokines and chemokines. Thus, this model, based on human minilungs, can be used to study pneumococcal virulence factors, the pathogenesis of different serotypes and it will allow therapeutic interventions in a reliable human context.IMPORTANCEStreptococcus pneumoniaeis responsible for high morbidity and mortalities rates worldwide affecting mainly children and adults older than 65 years. Pneumococcus is also the most common etiologic agent of bacterial pneumonia, non-epidemic meningitis, and a frequent cause of bacterial sepsis. Although the advent of pneumococcal vaccines has decreased the burden of the diseases caused by pneumococcus, the emerging of antibiotic-resistant strains and non-vaccine types by serotype replacement, is worrisome. To study the biology of pneumococcus and to establish a reliable human model for pneumococcal pathogenesis, we have generated human minilungs from embryonic stem cells. The results show that these organoids can be used to model some events occurring during the interaction of pneumococcus with the lung such as adherence, internalization, and the initial alveolar innate response. This model also represents a great alternative to study virulence factors involved in pneumonia, drug screening, and other therapeutic interventions.
Ddp1 cooperates with Ppx1 to counter a stress response initiated by non-vacuolar polyphosphate
Authors: McCarthy Liam , Abramchuk Iryna , Wafy Gamal , Denoncourt Alix , Lavallée-Adam Mathieu , Downey Michael 
Published: February 2022

ABSTRACTIn diverse cells from bacterial to mammalian species, inorganic phosphate is stored in long chains called polyphosphates (polyP). These near universal polymers, ranging from 3 to thousands of phosphate moieties in length, are associated with molecular functions including energy homeostasis, protein folding, and cell signaling. In many cell types, polyphosphate is concentrated in subcellular compartments or organelles. In the budding yeast S. cerevisiae, polyP synthesis by the membrane-bound VTC complex is coupled to its translocation into the lumen of the vacuole, a lysosome-related organelle, where it is stored at high concentrations. In contrast, ectopic expression of bacterial polyphosphate kinase, PPK, results in the toxic accumulation of polyP outside of the vacuole. In this study, we used label-free mass spectrometry to investigate the mechanisms underlying this toxicity. We find that PPK expression results in the activation of a stress response mediated in part by the Hog1 and Yak1 kinases, and Msn2/Msn4 transcription factors. This response is countered by the combined action of the Ddp1 and Ppx1 polyphosphatases that function together to counter polyP accumulation and downstream toxicity. In contrast, ectopic expression of previously proposed mammalian polyphosphatases did not impact PPK-mediated toxicity in this model, suggesting either that these enzymes do not function directly as polyphosphatases in vivo or that they require co-factors unique to higher eukaryotes. Our work provides a mechanistic explanation for why polyP accumulation outside of lysosome-related organelles is toxic. Further, it serves as a resource for exploring how polyP may impact conserved biological processes at a molecular level.
Gut commensal bacteria enhance pathogenesis of a tumorigenic murine retrovirus
Authors: Spring Jessica , Lara Sophie , Khan Aly A. , O’Grady Kelly , Wilks Jessica , Gurbuxani Sandeep , Erickson Steven , Fischbach Michael , Jacobson Amy , Chervonsky Alexander , Golovkina Tatyana 
Published: February 2022

SummaryThe influence of the microbiota on viral transmission and replication is well appreciated. However, its impact on retroviral pathogenesis outside of transmission/replication control remained unknown. Using Murine Leukemia Virus (MuLV), we found that some commensal bacteria promoted the development of leukemia induced by this retrovirus. The promotion of leukemia development by commensals was due to suppression of the adaptive immune response through upregulation of several negative regulators of immunity. These negative regulators included Serpinb9b and Rnf128, which are associated with a poor prognosis of some spontaneous human cancers. Upregulation of Serpinb9b was mediated by sensing of bacteria by NOD1/NOD2/RIPK2 pathway. This work describes a novel mechanism by which the microbiota enhances tumorigenesis within gut-distant organs and points at potential new targets for cancer therapy.
Molecular mechanics underlying flat-to-round membrane budding in live secretory cells
Authors: Shin Wonchul , Zucker Ben , Kundu Nidhi , Lee Sung Hoon , Shi Bo , Guo Xiaoli , Chan Chung Yu , Harrison Jonathan T. , Turechek Jaymie Moore , Hinshaw Jenny E. , Kozlov Michael M. , Wu Ling-Gang 
Published: February 2022

AbstractMembrane budding entails forces to transform flat membrane into vesicles essential for cell survival. Accumulated studies have identified coat-proteins (e.g., clathrin) as potential budding factors. However, forces mediating many non-coated membrane buddings remain unclear. By visualizing proteins in mediating endocytic budding in live neuroendocrine cells, performing in vitro protein reconstitution and physical modelling, we discovered how non-coated-membrane budding is mediated: actin filaments and dynamin generate a pulling force transforming flat membrane into Λ-shape; subsequently, dynamin helices surround and constrict Λ-profile’s base, transforming Λ- to Ω-profile, and then constrict Ω-profile’s pore, converting Ω-profiles to vesicles. These mechanisms control budding speed, vesicle size and number, generating diverse endocytic modes differing in these parameters. Their impact is widespread beyond secretory cells, as the unexpectedly powerful functions of dynamin and actin, previously thought to mediate fission and overcome tension, respectively, may contribute to many dynamin/actin-dependent non- coated-membrane buddings, coated-membrane buddings, and other membrane remodelling processes.
Presenilin and APP regulate synaptic kainate receptors
Authors: Barthet Gael , Moreira-de-Sá Ana , Zhang Pei , Castanheira Jorge , Gorlewicz Adam , Mulle Christophe 
Published: February 2022

AbstractKainate receptors (KARs) form a family of ionotropic glutamate receptors which regulate the activity of neuronal networks by both pre- and post-synaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (APP/PS1) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells with a genetic deletion of either presenilin or APP/APLP2 as well as in organotypic cultures treated with γ-secretase inhibitors. Finally, the GluK2 protein interacts with full-length and C-terminal fragments of APP. Overall, our data suggest that APP stabilizes KARs at synapses, possibly through a trans-synaptic mechanism, and this interaction is under the control the γ-secretase proteolytic activity of presenilin.
Coaching to prepare students for their school-to-work transition: conceptualizing core coaching competences
Authors: van der Baan Niels , Gast Inken , Gijselaers Wim , Beausaert Simon 
Published: February 2022

PurposeThe present study proposes coaching as a pedagogical intervention to prepare students for transitioning to the labour market. Taking a competence-based approach, the proposed coaching practice aims to enhance students' employability competences to facilitate a smoother school-to-work transition. However, what transition coaching looks like remains largely unclear. Moreover, in competence-based education, teachers are expected to be highly skilled coaches, facilitating students' transition to the labour market. The present study aims to map the core competencies of a transition coach.Design/methodology/approachA qualitative design was adopted to map the core competences of a transition coach. Data were collected from two focus groups, consisting of coaches in higher education and in the workplace.FindingsResults show that, to create the necessary support conditions, a coach creates a safe coaching environment and supports students in setting goals, guide them in the activities they undertake to attain these goals, and asks reflective questions. Moreover, the coach stimulates students' ownership by putting the student in the centre of the decision-making process. Furthermore, the results emphasize the importance of the coach's professional attitude and knowledge about the transition process and the labour market.Practical implicationsThe article concludes with practical implications for novice transition coaches and teachers in higher education.Originality/valueThe present study adds to the agenda of graduate work readiness by proposing a coaching practice aimed at preparing students for their transition to the labour market.
Violence against emergency healthcare workers: different perpetrators, different approaches
Authors: Spelten Evelien , van Vuuren Julia , O’Meara Peter , Thomas Brodie , Grenier Mathieu , Ferron Richard , Helmer Jennie , Agarwal Gina 
Published: February 2022

Purpose
This study aims to investigate whether emergency health-care workers distinguish between different categories of perpetrators of violence and how they respond to different types of perpetrator profiles.

Design/methodology/approach
Five focus groups with emergency health-care workers were held in Canada. The participants were asked whether they identified different groups of perpetrators of violence and how that impacted their approach. The focus group responses were transcribed verbatim and analysed thematically using a phenomenological approach.

Findings
Participants consistently identified five groups of perpetrators and tailored their approach on their assessment of the type of perpetrator involved. The five categories are: violence or aggressive behaviour from family members or bystander and violence related to; underlying mental health/illness issues; underlying physical health issues; addiction and substance use; and repeat visitors/offenders. Violence with an underlying (mental) health cause was handled professionally and compassionately by the health-care workers, while less patience and understanding was afforded in those instances where violence was associated with (recreational) alcohol or illicit substance use.

Originality/value
Emergency health-care workers can consistently distinguish between types of perpetrators of violence and aggression, which they then use as one factor in the clinical and situational assessments that inform their overall approach to the management incidents. This conclusion supports the need to move the focus away from the worker to the perpetrator and to an organisational rather than individual approach to help minimise violence against emergency health-care workers.