bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel hospital-at-home model for patients with COVID-19 built by a team of local primary care clinics and clinical outcomes: A multi-center retrospective cohort study
Authors: Tsujimoto Yasushi , Kobayashi Masanori , Oku Tomohisa , Ogawa Takahisa , Yamadera Shinichi , Tsukamoto Masako , Matsuda Noriya , Nishihira Morikazu , Terauchi Yu , Tanaka Takahiro , Kawabata Yoshitaka , Miyamoto Yuki , Morikami Yoshiki 
Published: October 2022

AbstractBackgroundHospital-at-home (HaH) care has been proposed as an alternative to inpatient care for patients with COVID-19. Previous reports were hospital-led and involved patients triaged at the hospitals. To reduce the burden on hospitals, we constructed a novel HaH care model organised by a team of local primary care clinics.MethodsWe conducted a multi-center retrospective cohort study of the COVID-19 patients who received our HaH care from Jan 1stto Mar 31st, 2022. Patients who were not able to be triaged for the need for hospitalization by the Health Center solely responsible for the management of COVID-19 patients in Osaka City were included. The primary outcome was receiving medical care beyond the HaH care defined as a composite outcome of any medical consultation, hospitalization, or death within 30 days from the initial treatment.ResultsOf 382 eligible patients, 34 (9%) were triaged for hospitalization immediately after the initial visit. Of the remaining 348 patients followed up, 37 (11%) developed the primary outcome, while none died. Obesity, fever, and gastrointestinal symptoms at baseline were independently associated with an increased risk of needing medical care beyond the HaH care. A further 129 (37%) patients were managed online alone without home visit, and 170 (50%) required only one home visit in addition to online treatment.ConclusionsThe HaH care model with a team of primary care clinics was able to triage patients with COVID-19 who needed immediate hospitalization without involving hospitals, and treated most of the remaining patients at home.
The crucial role of titin in fetal development: recurrent miscarriages and bone, heart, and muscle anomalies characterize the severe end of titinopathies spectrum
Authors: Di Feo Maria Francesca , Lillback Victoria , Jokela Manu , McEntagart Meriel , Homfray Tessa , Giorgio Elisa , Casalis Cavalchini Guido C , Brusco Alfredo , Iascone Maria , Spaccini Luigina , D’Oria Patrizia , Savarese Marco , Udd Bjarne 
Published: October 2022

AbstractBackgroundTitin truncating variants (TTNtv) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. However,TTNis not yet included in many NGS panels for congenital musculoskeletal anomalies and dysmorphisms, and karyotype or chromosomal microarray analyses are often the only tests performed when prenatal anomalies are identified. Thereby, many cases caused byTTNdefects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum.MethodsWe performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.ResultsWe identified recurrent clinical features in antenatal and congenital recessive titinopathies, including fetal akinesia, arthrogryposis, facial dysmorphisms, joint, bone, and heart anomalies resembling complex, syndromic phenotypes.ConclusionWe suggestTTNto be carefully evaluated in any diagnostic process involving patients with the mentioned signs. This step will be essential to improve diagnostic performance, expand our knowledge, and optimize prenatal genetic counseling.Key messageTruncating variants in the titin gene (TTN) have been associated with a large spectrum of skeletal muscle diseases with or without cardiac involvement. The current work demonstrates that truncating biallelic variants in specific exons ofTTNresult in severe developmental anomalies, affecting not only the muscular systems but also bone, heart, and other organs, with a quite high rate of miscarriages and dysmorphisms. Thereby, we suggest TTN variants to be carefully evaluated in any diagnostic process involving patients with the mentioned signs.
Beyond social prescribing - the use of social return on investment (SROI) analysis in integrated health and social care interventions in England and Wales: a protocol for a systematic review
Authors: Hopkins Genevieve , Winrow Eira , Davies Ceryl , Seddon Diane 
Published: October 2022

AbstractIntroductionWith increasing costs of healthcare in England and Wales following the COVID-19 pandemic, finding alternatives to traditional medical interventions is more important than ever. Social prescribing provides a way of addressing health and well-being through using non-medical methods that may help relieve costs to the NHS.Evaluating interventions, such as social prescribing, which have high social (but not easily quantifiable) value, can be problematic. Social return on investment (SROI) is a method of assigning monetary values to both social value as well as traditional assets, so provides a way of evaluating social prescribing initiatives.MethodThis protocol outlines the steps that will be taken in a systematic review of the SROI literature surrounding social prescribing-type integrated health and social care interventions based in the community in England and Wales.Online academic databases such as PubMed Central, ASSIA and Web of Science will be searched, as will grey literature sources such as Google Scholar, the Wales School for Social Prescribing Research (WSSPR) and Social Value UK.Titles and abstracts from the articles returned by the searches will be reviewed by one researcher. Those selected for full text review will be independently reviewed and compared by two researchers. Where the researchers disagree a third reviewer will help resolve any differences.Information collected will include identifying stakeholder groups, assessing the quality of SROI analyses, identifying intended and unintended changes of social prescribing interventions, and comparing social prescribing initiatives in terms of SROI costs and benefits.Quality assessment will be independently conducted on the selected papers by two researchers. The researchers will discuss to obtain consensus. Where there is disagreement, a third researcher will resolve these cases. A pre-existing quality framework will be developed and used to assess the quality of the literature.Protocol registrationProspero registration number:CRD42022318911https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022318911
A Step Towards Generalisability: Training a Machine Learning Scoring Function for Structure-Based Virtual Screening
Authors: Scantlebury Jack , Vost Lucy , Carbery Anna , Hadfield Thomas E. , Turnbull Oliver M. , Brown Nathan , Chenthamarakshan Vijil , Das Payel , Grosjean Harold , von Delft Frank , Deane Charlotte M. 
Published: October 2022

ABSTRACTOver the last few years, many machine learning-based scoring functions for predicting the binding of small molecules to proteins have been developed. Their objective is to approximate the distribution which takes two molecules as input and outputs the energy of their interaction. Only a scoring function that accounts for the interatomic interactions involved in binding can accurately predict binding affinity on unseen molecules. However, many scoring functions make predictions based on dataset biases rather than an understanding of the physics of binding. These scoring functions perform well when tested on similar targets to those in the training set, but fail to generalise to dissimilar targets. To test what a machine learning-based scoring function has learnt, input attribution—a technique for learning which features are important to a model when making a prediction on a particular data point—can be applied. If a model successfully learns something beyond dataset biases, attribution should give insight into the important binding interactions that are taking place. We built a machine learning-based scoring function that aimed to avoid the influence of bias via thorough train and test dataset filtering, and show that it achieves comparable performance on the CASF-2016 benchmark to other leading methods. We then use the CASF-2016 test set to perform attribution, and find that the bonds identified as important by PointVS, unlike those extracted from other scoring functions, have a high correlation with those found by a distance-based interaction profiler. We then show that attribution can be used to extract important binding pharmacophores from a given protein target when supplied with a number of bound structures. We use this information to perform fragment elaboration, and see improvements in docking scores compared to using structural information from a traditional, data-based approach. This not only provides definitive proof that the scoring function has learnt to identify some important binding interactions, but also constitutes the first deep learning-based method for extracting structural information from a target for molecule design.
The neural basis of cost-benefit trade-offs in effort investment: a quantitative activation likelihood estimation meta-analysis
Authors: Silva Castanheira Kevin da , Spreng R. Nathan , Vassena Eliana , Otto A. Ross 
Published: October 2022

AbstractProminent theories of cognitive effort-based decision-making posit that shared brain regions process both potential reward and task demand, supporting the idea that effort allocation are informed by a cost-benefit trade-off, weighing the expected benefits of successful control against the inherent costs of effort exertion. While the dorsal anterior cingulate cortex (dACC) has been proposed as a candidate region supporting this decision, it remains unclear whether dACC activity tracks rewards and costs as independent quantities, or it reflects the effort intensity worth the integrated costs and benefits. While recent accounts of dACC function posit a crucial role the region in negotiating cost-benefit trade-offs, empirical evidence for this account remains scarce across single studies. To address this, we conducted a systematic meta-analysis review of neuroimaging studies, using activation-likelihood estimation method to quantify brain activity across 45 studies (N = 1273 participants) investigating reward-guided effort. We found reliable recruitment of the dACC, putamen, and anterior insula for processing both larger rewards and increasing task demands. However, the dACC clusters sensitive to task demands and rewards were anatomically distinct with no significant overlap: caudal dACC activity tracked increasing task demands, while rostral dACC activity tracked increasing rewards. Critically, we also observed that caudal dACC activity tracked the integration of costs and benefits, compatible with mental effort intensity account. These findings suggest there are distinct signals for demand and effort in the dACC which are also integrated to support the decision to invest effort, supporting recent computational accounts of cost-benefit value integration in effort-based choice.
The Three Waves: Rethinking the Structure of the first Upper Paleolithic in Western Eurasia
Authors: Slimak Ludovic 
Published: October 2022

AbstractThe Neronian is a lithic tradition recognized in the Middle Rhône Valley of Mediterranean France now directly linked toHomo sapiensand securely dated to 54,000 years ago (ka), pushing back the arrival of modern humans in Europe by 10 ka. This incursion of modern humans into Neandertal territory and the relationships evoked between the Neronian and the Levantine Initial Upper Paleolithic (IUP) question the validity of concepts that define the firstH. sapiensmigrations and the very nature of the first Upper Paleolithic in western Eurasia. Direct comparative analyses between lithic technology from Grotte Mandrin and East Mediterranean archeological sequences, especially Ksar Akil, suggest that the three key phases of the earliest Levantine Upper Paleolithic have very precise technical and chronological counterparts in Western Europe, recognized from the Rhône Valley to Franco-Cantabria. These trans-Mediterranean technical connections suggest three distinct waves ofH. sapiensexpansion into Europe between 55-42 ka. These elements support an original thesis on the origin, structure, and evolution of the first moments of the Upper Paleolithic in Europe tracing parallel archaeological changes in the East Mediterranean region and Europe.
The neuropeptidergic connectome ofC. elegans
Authors: Ripoll-Sánchez Lidia , Watteyne Jan , Sun HaoSheng , Fernandez Robert , Taylor Seth R , Weinreb Alexis , Hammarlund Mark , Miller David M , Hobert Oliver , Beets Isabel , Vértes Petra E , Schafer William R 
Published: October 2022

SummaryEfforts are currently ongoing to map synaptic wiring diagrams or connectomes in order to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, “wireless” signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene expression datasets with a biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in theC. elegansnervous system. This connectome is characterized by a high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several of the most important nodes in this connectome are little-studied neurons that are specialized for peptidergic neuromodulation. We anticipate that theC. elegansneuropeptidergic connectome will serve as a prototype to understand basic organizational principles of neuroendocrine signaling networks.
A model of the interactions between the FtsQLB and the FtsWI peptidoglycan synthase complex in bacterial cell division
Authors: Craven Samuel J. , Condon Samson G. F. , Senes Alessandro 
Published: October 2022

AbstractInEscherichia coli, an important step in the divisome assembly pathway is the recruitment of the essential cell wall synthase complex FtsWI to the division site through interactions with the regulatory FtsQLB complex. Here, we investigate a key aspect of this recruitment by characterizing the structural organization of the FtsL-FtsW interaction. Mutations in the cytoplasmic and transmembrane regions of the two proteins result in cell division defects and loss of FtsW localization to division sites. We use thesein vivoresults to help validate the predicted interfaces from an AlphaFold2 model for the entire FtsQLBWI complex. Given the consistency between the predicted FtsQLBWI model and our current understanding of the structure and function of the complex, we further remodeled it, seeking insight into the potential structural transitions that may lead to activation of the FtsWI complex and PG synthesis. The model suggests that FtsLB serves as a support for FtsI, placing its periplasmic domain in an extended and possibly active conformation but it is also compatible with a proposed compact and possibly inactive conformation. Additionally, we reconfigure the model into an Fts[QLBWI]2diprotomeric state, which suggests that FtsLB may act as a central hub during assembly of the PG synthesis machinery. Finally, we propose a possible role for FtsQ in activation of this machinery, potentially by acting as a gatekeeper for the interaction between the FtsL AWI region and FtsI. We propose that this gatekeeping function depends on a hinge next to the FtsLB CCD region, which has implications for the mechanisms behind the FtsLBoff/ontransition that is central to cell division regulation.
Cross-Linking of Catalytically Essential Vicinal Thiols at Active Sites of the Cerebral Sodium Transporter Inactivates its Electrogenic Function
Authors: Ologunagba Titilayo Ibironke , Olorundare Bunmi Olaoluwa , Kade Ige Joseph 
Published: October 2022

ABSTRACTThe inactivation of the electrogenic function of the transmembrane sodium transporter in oxidative stress conditions has been intrinsically linked with the oxidation of its catalytically essential thiols. However, the spatial proximity of these catalytically relevant thiols is yet to be fully elucidated and thus still open. Herein, the influence of a thiol cross-linking [diamide, DA (0.1-2mM)] and a thiol alkylating [iodoacetamide, IA (0.1-5mM)] agent on the activity of the synaptosomal Na+/K+-ATPase were determined. In addition, the ability of dithiothreitol to either prevent or reverse the inhibition imposed by the thiol modifiers on the enzyme activity was also evaluated. The results showed that the thiol cross-linker inactivates the electrogenic function of the synaptosomal Na+/K+-ATPase when exposed to the thiols located at either the nucleotide or cation-binding sites. Conversely, irrespective of the exposed active sites, the thiol alkylating agents have no overt effect on the activity of the pump. Furthermore, dithiothreitol markedly prevented but did not reverse the inactivation of the electrogenic pump caused by cross-linking of its critical thiols. Interestingly, both the thiol cross-linker and alkylating agents markedly oxidize dithiothreitol in a time and concentration-dependent fashion. Consequently, within the limit of the present data, it appears that the catalytically relevant thiols of the transmembrane electrogenic pump located at the cationic and nucleotide binding sites, are in close proximity sufficient enough to allow for their cross-linking.HighlightsThe presence of Na+/K+-ATPase catalytically important thiols at the nucleotide and cationic sites of the enzyme define its vulnerability to oxidative assault.The spatial location of these thiols at vicinal positions at these domains favour the formation of disulphide linkages under oxidative conditionsThe disulphide crosslinking of these thiols culminate in enzyme inactivationThe inactivation can be prevented but not reversed by exogenous thiol compound
Engineering transmembrane signal transduction in synthetic membranes using two-component systems
Authors: Peruzzi Justin A. , Galvez Nina R. , Kamat Neha P. 
Published: October 2022

AbstractCells use signal transduction across their membranes to sense and respond to a wide array of chemical and physical signals. Creating synthetic systems which can harness cellular signaling modalities promises to provide a powerful platform for biosensing and therapeutic applications. As a first step towards this goal, we investigated how bacterial two-component systems can be leveraged to enable transmembrane-signaling with synthetic membranes. Specifically, we demonstrate that a bacterial two-component nitrate-sensing system (NarX-NarL) can be reproduced outside of a cell using synthetic membranes and cell-free protein expression systems. We find that performance and sensitivity of the two-component system can be tuned by altering the biophysical properties of the membrane in which the histidine kinase (NarX) is integrated. Through protein engineering efforts, we modify the sensing domain of NarX to generate sensors capable of detecting an array of ligands. Finally, we demonstrate that these systems can sense ligands in relevant sample environments. By leveraging membrane and protein design, this work helps reveal how transmembrane sensing can be recapitulated outside of the cell, adding to the arsenal of deployable cell-free systems primed for real world biosensing.Significance StatementCells detect and respond to environmental and chemical information by using a combination of membrane proteins and genetic polymers. Recapitulation of this behavior in synthetic systems holds promise for engineering biosensors and therapeutics. Using the nitrate-sensing bacterial two-component system as a model, we demonstrate methods to reproduce and tune transmembrane signaling in synthetic lipid membranes, leading to the synthesis of genetically programmed proteins. Through this study, we gain insight into how membrane augmented cell-free systems can be used as a platform to characterize membrane-receptor interactions and engineer new biosensors.
Structural basis for ion selectivity in potassium-selective channelrhodopsins
Authors: Tajima Seiya , Kim Yoon Seok , Fukuda Masahiro , Byrne Eamon F.X. , Wang Peter Y. , Paggi Joseph M. , Kishi Koichiro E. , Ramakrishnan Charu , Takaramoto Syunki , Nagata Takashi , Konno Masae , Sugiura Masahiro , Katayama Kota , Matsui Toshiki E. , Yamashita Keitaro , Ikeda Hisako , Inoue Masatoshi , Kandori Hideki , Dror Ron O. , Inoue Keiichi , Deisseroth Karl , Kato Hideaki E. 
Published: October 2022

SUMMARYThe KCR channelrhodopsins are recently-discovered light-gated ion channels with high K+selectivity, a property that has attracted broad attention among biologists– due to intense interest in creating novel inhibitory tools for optogenetics leveraging this K+selectivity, and due to the mystery of how this selectivity is achieved in the first place. Indeed, the molecular and structural mechanism for K+selectivity in KCRs has remained especially puzzling since these 7-transmembrane retinal-binding proteins completely lack structural similarity with known K+channels, which generally coordinate K+in a precisely symmetric conduction pathway formed by a tight interface among multiple small monomeric channel subunits (presumably not an accessible mechanism for the large KCR rhodopsin proteins). Here we present the cryo-electron microscopy structures of two KCRs fromHyphochytrium catenoideswith distinct spectral properties for light absorption and channel actuation,HcKCR1, andHcKCR2, at resolutions of 2.6 and 2.5 Å, respectively. Structural comparison revealed first an unusually-shaped retinal binding pocket which induces rotation of the retinal inHcKCR2, explaining the large spectral difference betweenHcKCR1 and 2. Next, our combined structural, electrophysiological, computational, and spectroscopic analyses revealed a new solution to the challenging problem of K+-selective transport. KCRs indeed do not exhibit the canonical tetrameric K+selectivity filter that specifically coordinates dehydrated K+; instead, single KCR monomers form a size exclusion filter using aromatic residues at the extracellular side of the pore which inhibits passage of bulky hydrated ions. This unique feature allows KCRs to function as K+channels under relevant physiological conditions, providing not only a novel mechanism for achieving high K+permeability ratios in biological ion channels, but also a framework for designing the next generation of inhibitory optogenetic tools.In BriefThe first structures of K+-selective channelrhodopsins (HcKCR1 and 2) are determined, revealing a K+selectivity mechanism distinctly different from canonical K+channels.HighlightsThe cryo-EM structures of K+-selective channelrhodopsins,HcKCR1 and 2, in nanodiscConditions under which naturally-occurring microbial rhodopsins have a 6-s-cisretinalIdentification of key residues for high K+permeability ratiosThe unique K+selectivity mechanism of KCRs