bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic review of genotype-stratified treatment for monogenic insulin resistance
Authors: Semple Robert K. , Pate Kashyap A. , Auh Sungyoung ,   ADA/EASD PMDI, Brown Rebecca J. 
Published: April 2023

AbstractObjectiveTo assess the effects of pharmacologic and/or surgical interventions in monogenic insulin resistance (IR), stratified by genetic aetiology.DesignSystematic review.Data sourcesPubMed, MEDLINE and Embase, from 1 January 1987 to 23 June 2021.Review methodsStudies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual subject data were extracted and duplicate data removed. Outcomes were analyzed for each affected gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.Results10 non-randomised experimental studies, 8 case series, and 21 single case reports met inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin was associated with lower triglycerides and hemoglobin A1c in aggregated lipodystrophy (n=111), in partial lipodystrophy (n=71) and generalised lipodystrophy (n=41)), and inLMNA,PPARG,AGPAT2orBSCL2subgroups (n=72,13,21 and 21 respectively). Body Mass Index (BMI) was lower after treatment in partial and generalised lipodystrophy overall, and inLMNA or BSCL2, but notPPARGorAGPAT2subgroups. Thiazolidinedione use was associated with improved hemoglobin A1c and triglycerides in aggregated lipodystrophy (n=13), improved hemoglobin A1c only in thePPARGsubgroup (n=5), and improved triglycerides only in theLMNAsubgroup (n=7). InINSR-related IR, use of rhIGF-1, alone or with IGFBP3, was associated with improved hemoglobin A1c (n=15). The small size or absence of all other genotype-treatment combinations precluded firm conclusions.ConclusionsThe evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to have beneficial metabolic effects in lipodystrophy, and rhIGF-1 appears to lower hemoglobin A1c in INSR-related IR. For other interventions there is insufficient evidence to assess efficacy and risks either in aggregated lipodystrophy or in genetic subgroups. There is a pressing need to improve the evidence base for management of monogenic IR.
Evaluation of coronavirus decay in French coastal water and application to SARS-CoV-2 risk evaluation using Porcine Epidemic Diarrhea Virus as surrogate
Authors: Contrant Maud , Bigault Lionel , Andraud Mathieu , Desdouits Marion , Rocq Sophie , Le Guyader Françoise S. , Blanchard Yannick 
Published: April 2023

AbstractSARS-CoV-2 in infected patient mainly display pulmonary and oronasal tropism however, the presence of the virus has also been demonstrated in stools of patients and consequently in wastewater treatment plant effluents, questioning the potential risk of environmental contamination (such as seawater contamination) through inadequately treated wastewater spill-over into surface or coastal waters. The environmental detection of RNA alone does not substantiate risk of infection, and evidence of an effective transmission is not clear where empirical observations are lacking.Therefore, here, we decided to experimentally evaluate the persistence and infectious capacity of the Porcine epidemic diarrhea virus (PEDv), considered as a coronavirus representative model and SARS-CoV-2 surrogate, in the coastal environment of France. Coastal seawater was collected, sterile-filtered, and inoculated with PEDv before incubation for 0–4 weeks at four temperatures representative of those measured along the French coasts throughout the year (4, 8, 15, and 24°C). The decay rate of PEDv was determined using mathematical modeling and was used to determine the half-life of the virus along the French coast in accordance with temperatures from 2000 to 2021.We experimentally observed an inverse correlation between seawater temperature and the persistence of infectious viruses in seawater and confirm that the risk of transmission of infectious viruses from contaminated stool in wastewater to seawater during recreational practices is very limited. The present work represents a good model to assess the risk of transmission of not only SARS-CoV-2 but may also be used to model the risk of other coronaviruses, specifically enteric coronaviruses.ImportanceThis present work is a follow up addressing the question of the persistence of coronavirus in marine environment owing to the fact that SARS-CoV-2 is regularly detected in wastewater treating plan and the coastal environment is particularly at risk since it is subjected to increasing anthropogenic pressure and is the final receiver of surface waters and treated or sometimes insufficiently depurated waste waters. Our findings are of interest to researchers and authorities seeking to monitor SARS-CoV-2 and also enteric coronaviruses in the environment, either in tourist areas or in regions of the world, where centralized systems for wastewater treatment are not implemented, and more broadly, to the scientific community involved in “One Health” approaches.
CRB3 and ARP2/3 regulate cell biomechanical properties to set epithelial monolayers for collective movement
Authors: Massey-Harroche Dominique , Conte Vito , Gouirand Niels , Sebbagh Michäel , Bivic André Le , Bazellières Elsa 
Published: April 2023

SummarySeveral cellular processes during morphogenesis, tissue healing or cancer progression involve epithelial to mesenchymal plasticity that leads to collective motion (plasticity?). Even though a rich variety of EMP programs exist, a major hallmark unifying them is the initial breaking of symmetry that modifies the epithelial phenotype and axis of polarity. During this process, the actin cytoskeleton and cellular junctions are extensively remodelled correlating with the build-up of mechanical forces. As the collective migration proceeds, mechanical forces generated by the actin cytoskeleton align with the direction of migration ensuring an organized and efficient collective cell behaviour, but how forces are regulated during the breaking of symmetry at the onset of EMP remains an unaddressed question. It is known that the polarity complex CRB3/PALS1/PATJ, and in particular, CRB3 regulates the organization of the actin cytoskeleton associated to the apical domain thus pointing at a potential role of CRB3 in controlling mechanical forces. Whether and how CRB3 influences epithelial biomechanics during the epithelial-mesenchymal plasticity remains, however, largely unexplored. Here, we systematically combine mechanical and molecular analyses to show that CRB3 regulates the biomechanical properties of collective epithelial cells during the initial breaking of symmetry of the EMP. CRB3 interacts with ARP2/3 and controls the remodelling of actin throughout the monolayer via the modulation of the Rho-/Rac-GTPase balance. Taken together, our results identified CRB3, a polarity protein, as a regulator of epithelial monolayer mechanics during EMP.
Electrophysiological correlates of attention in the locus coeruleus - anterior cingulate cortex circuit during the rodent continuous performance test
Authors: Hallock Henry L. , Adiraju Suhaas , Miranda-Barrientos Jorge , McInerney Jessica M. , Oh Seyun , DeBrosse Adrienne C. , Li Ye , Carr Gregory V. , Martinowich Keri 
Published: April 2023

ABSTRACTSustained attention, the ability to focus on an activity or stimulus over time, is significantly impaired in many psychiatric disorders, and there remains a major unmet need in treating impaired attention. Continuous performance tests (CPTs) were developed to measure sustained attention in humans, non-human primates, rats, and mice, and similar neural circuits are engaged across species during CPT performance, supporting their use in translational studies to identify novel therapeutics. Here, we identified electrophysiological correlates of attentional performance in a touchscreen-based rodent CPT (rCPT) in the locus coeruleus (LC) and anterior cingulate cortex (ACC), two inter-connected regions that are implicated in attentional processes. We used viral labeling and molecular techniques to demonstrate that neural activity is recruited in LC-ACC projections during the rCPT, and that this recruitment increases with cognitive demand. We implanted male mice with depth electrodes within the LC and ACC for local field potential (LFP) recordings during rCPT training, and identified an increase in ACC delta and theta power, and an increase in LC delta power during correct responses in the rCPT. We also found that the LC leads the ACC in theta frequencies during correct responses while the ACC leads the LC in gamma frequencies during incorrect responses. These findings may represent translational biomarkers that can be used to screen novel therapeutics for drug discovery in attention.
Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration
Authors: Dey Debabrata , Marciano Shir , Poryvai Anna , Groborz Ondřej , Wohlrábová Lucie , Slanina Tomás , Schreiber Gideon 
Published: April 2023

ABSTRACTFor drugs to be active they have to reach their targets. Within cells this requires crossing the cell membrane, and then free diffusion, distribution, and availability. Here, we explored the in-cell diffusion rates and distribution of a series of small molecular fluorescent drugs, in comparison to proteins, by microscopy and fluorescence recovery after photobleaching (FRAP). While all proteins diffused freely, we found a strong correlation between pKaand the intracellular diffusion and distribution of small molecule drugs. Weakly basic, small-molecule drugs displayed lower fractional recovery after photobleaching and 10-to-20-fold slower diffusion rates in cells than in aqueous solutions. As, more than half of pharmaceutical drugs are weakly basic, they, are protonated in the cell cytoplasm. Protonation, facilitates the formation of membrane impermeable ionic form of the weak base small molecules. This results in ion trapping, further reducing diffusion rates of weakly basic small molecule drugs under macromolecular crowding conditions where other nonspecific interactions become more relevant and dominant. Our imaging studies showed that acidic organelles, particularly the lysosome, captured these molecules. Surprisingly, blocking lysosomal import only slightly increased diffusion rates and fractional recovery. Conversely, blocking protonation byN-acetylated analogues, greatly enhanced their diffusion and fractional recovery after FRAP. Based on these results,N-acetylation of small molecule drugs may improve the intracellular availability and distribution of weakly basic, small molecule drugs within cells.
Impact of water models on structure and dynamics of enzyme tunnels
Authors: Sethi Aaftaab , Agrawal Nikhil , Brezovsky Jan 
Published: April 2023

ABSTRACTProtein hydration plays a vital role in many biological functions and molecular simulations are frequently used to study the effect of protein hydration at the atomic level. However, the accuracy of these simulations has often been highly sensitive to the water model used, a phenomenon best known in the case of intrinsically disordered proteins. In the present study, we investigated the extent to which the choice of water model alters the behavior of complex networks of transport tunnels. Tunnels are essential because they allow substrates and products to access and exit the active sites of enzymes that are otherwise deeply embedded within the protein structure. The ability of these tunnels to regulate access directly affects enzyme efficiency and selectivity, making their study crucial for understanding enzyme function and inhibition at a mechanistic level. By performing all-atom molecular dynamics simulations of the wild-type haloalkane dehalogenase LinBWT and its two variants, LinB32 and LinB86, with synthetically engineered tunnel networks in TIP3P and OPC water models, we investigated the effects of these models on the overall tunnel topology. We also analyzed the properties of the main tunnels, such as their conformation, bottleneck dimensions, sampling efficiency, and duration of the tunnel opening. Our data demonstrate that all three proteins exhibited similar conformational behavior in both water models and differed in the geometrical characteristics of their auxiliary tunnels, in line with experimental observations. Interestingly, the results indicate that the stability of the open tunnels is sensitive to the water model and the system under question. Our findings suggest that the 3-point TIP3P model can provide comparable inference on the overall topology of the networks of primary tunnels and their geometry, and thus may be a desirable choice when computational resources are limited or when compatibility issues impede usage of OPC with certain protein force fields. However, when a more thorough investigation is performed, such as the calculation of ligand unbinding rates via such tunnel networks, where precision and intricate details are paramount, the more costly 4-point OPC model would be more suited.Graphical Abstract
Multiparametric domain insertional profiling of Adeno-Associated Virus VP1
Authors: Hoffmann Mareike D. , Zdechlik Alina C. , He Yungui , Nedrud David , Aslanidi George , Gordon Wendy , Schmidt Daniel 
Published: April 2023

ABSTRACTEvolved properties of Adeno-Associated Virus (AAV), such as broad tropism and immunogenicity in humans, are barriers to AAV-based gene therapy. Previous efforts to re-engineer these properties have focused on variable regions near AAV’s 3-fold protrusions and capsid protein termini. To comprehensively survey AAV capsids for engineerable hotspots, we determined multiple AAV fitness phenotypes upon insertion of large, structured protein domains into the entire AAV-DJ capsid protein VP1. This is the largest and most comprehensive AAV domain insertion dataset to date. Our data revealed a surprising robustness of AAV capsids to accommodate large domain insertions. There was strong positional, domain-type, and fitness phenotype dependence of insertion permissibility, which clustered into correlated structural units that we could link to distinct roles in AAV assembly, stability, and infectivity. We also identified new engineerable hotspots of AAV that facilitate the covalent attachment of binding scaffolds, which may represent an alternative approach to re-direct AAV tropism.
Molecular details of the CPSF73-CPSF100 C-terminal heterodimer and interaction with Symplekin
Authors: Thore Stéphane , Raoelijaona Finaritra , Talenton Vincent , Fribourg Sébastien , Mackereth Cameron D. 
Published: April 2023

ABSTRACTEukaryotic pre-mRNA is processed by a large multiprotein complex to accurately cleave the 3’ end, and to catalyze the addition of the poly(A) tail. Within this cleavage and polyadenylation specificity factor (CPSF) machinery, the CPSF73 endonuclease subunit directly contacts both CPSF100 and the scaffold protein Symplekin to form a subcomplex known as the core cleavage complex (CCC) or mammalian cleavage factor (mCF). Here we have taken advantage of a stable CPSF73-CPSF100 minimal heterodimer from E. cuniculi to determine the solution structure formed by the first and second C-terminal domain (CTD1 and CTD2) of both proteins. We find a large number of contacts between both proteins in the complex, and notably in the region between CTD1 and CTD2. A similarity is also observed between CTD2 and the TATA-box binding protein (TBP) domains. Separately, we have determined the structure of the terminal CTD3 domain of CPSF73, which also belongs to the TBP domain family and is connected by a flexible linker to the rest of CPSF73. Biochemical assays demonstrate a key role for the CTD3 of CPSF73 in binding Symplekin, and structural models of the trimeric complex from other species allow for comparative analysis and support an overall conserved architecture.
Self-referencing rates in biological disciplines
Authors: Cascarina Sean M. 
Published: April 2023

AbstractThe use of citation counts (among other bibliometrics) as a facet of academic research evaluation can influence citation behavior in scientific publications. One possible unintended consequence of this bibliometric is excessive self-referencing, where an author favors referencing their own publications over related publications from different research groups. Peer reviewers are often prompted by journals to examine whether references listed in the manuscript under review are unbiased, but there is no consensus on what is considered “excessive” self-referencing. Here, self-referencing rates are estimated across multiple journals in the fields of biology, genetics, computational biology, medicine, pathology, and cell biology. Median self-referencing rates are between 8-13% across a range of journals within these subdisciplines. However, self-referencing rates vary as a function of total number of references, number of authors, author status/rank, author position, and total number publications for each author. These results may serve as useful statistical guidelines for authors, editors, reviewers, and journals when considering referencing practices for individual publications.
Decision Considerations and Strategies for Lip Surgery in Patients with Cleft lip/Palate: A Qualitative Study
Authors: Trotman Carroll Ann , Faraway Julian , Bennett M. Elizabeth , Garson G. David , Phillips Ceib , Bruun Richard , Daniel Renie , David Lisa Renee , Ganske Ingrid , Leeper Lauren K , Rogers-Vizena Carolyn R. , Runyan Christopher , Scott Andrew R. , Wood Jeyhan 
Published: April 2023

ObjectiveTo qualitatively assess surgeons decision making for lip surgery in patients with cleft lip/palate (CL/P).DesignProspective, non-randomized, clinical trial.SettingClinical data institutional laboratory setting.Patients, ParticipantsThe study included both patient and surgeon participants recruited from four craniofacial centers. The patient participants were babies with a CL/P requiring primary lip repair surgery (n=16) and adolescents with repaired CL/P who may require secondary lip revision surgery (n=32). The surgeon participants (n=8) were experienced in cleft care. Facial imaging data that included 2D images, 3D images, videos, and objective 3D visual modelling of facial movements were collected from each patient, and compiled as a collage termed the Standardized Assessment for Facial Surgery (SAFS) for systematic viewing by the surgeons.InterventionsThe SAFS served as the intervention. Each surgeon viewed the SAFS for six distinct patients (two babies and four adolescents) and provided a list of surgical problems and goals. Then an in-depth-interview (IDI) was conducted with each surgeon to explore their decision-making processes. IDIs were conducted either in person or virtually, recorded, and then transcribed for qualitative statistical analyses using the Grounded Theory Method.ResultsRich narratives/themes emerged that included timing of the surgery; risks/limitations and benefits of surgery; patient/family goals; planning for muscle repair and scarring; multiplicity of surgeries and their impact; and availability of resources. For diagnoses/treatments, surgeons agreed, and level of surgical experience was not a factor.ConclusionsThe themes provided important information to populate a checklist of considerations to serve as a guide for clinicians.
Designing a brief and simple intervention to help young people with type 1 diabetes to live well: protocol for developing a novel intervention with participation from young people
Authors: Howland Samantha , Huber Jörg , Aicken Catherine 
Published: April 2023

ABSTRACTYoung people living with type 1 diabetes (T1D) navigate daily complex diabetes related tasks as they take on increasing (and eventually full) responsibility for managing their condition, in addition to developing their lives as independent adults. Alongside the need for careful day-to-day diabetes management, the psychosocial burden and mental health impact and stigma are well recognised. Despite advances in psychological care, many young people with diabetes still experience a greater mental health burden than those without diabetes. This study aims to develop a brief and simple intervention for young people with T1D that will support their wellbeing day to day, as required, and grow their ability to live confidently with their condition that requires lifelong meticulous management. This study will consist of qualitative research and collaboration with young people with T1D and their siblings, friends, and peers to co-create a testable intervention. In Part 1, research interviews will be conducted with young people (16-24 years old) with T1D and, where possible, their siblings/peers to understand the day-to-day challenges of type 1 and what a novel intervention should address. Thematic analysis of interviews will inform the generation of a prototype intervention to take into part two, focus group discussions. Focus groups with (i) young people with T1D and, separately (ii) carers (comprising parents, carers, teachers, specialist nurses). Collaborative principles will be used to review, redesign and evolve the intervention to meet user needs. A blend of narrative and thematic analysis will inform the findings and report.Insights from Parts 1 and 2 will shape a user-defined and formatively analysed brief and simple intervention and future study design ready for pilot testing. The aim of this part of the research is to maximise acceptability and usability of a testable intervention by the target population. To aim of the future intervention will be to demonstrate effectiveness in helping young adults to live well with T1D.METADATAThis research is funded by a studentship to the first author, provided by University of Brighton as part of its partnership activities with the National Institute for Health Research (NIHR) Applied Research Collaboration Kent, Surrey, Sussex. The funders did not and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.Ethical approval for this study was provided by Cornwall and Plymouth Research Ethics Committee on behalf of the Health Research Authority and Health and Care Research Wales on 22 Aug 2022 (22/SW/0097). The University of Brighton is the Sponsor (protocol number 2022-9871).
Sialoglycan binding triggers spike opening in a human coronavirus
Authors: Pronker Matti F. , Creutznacher Robert , Drulyte Ieva , Hulswit Ruben J.G. , Li Zeshi , van Kuppeveld Frank J.M. , Snijder Joost , Lang Yifei , Bosch Berend-Jan , Boons Geert-Jan , Frank Martin , Groot Raoul J. de , Hurdiss Daniel L. 
Published: April 2023

AbstractCoronavirus (CoV) spikes mediate receptor binding and membrane fusion, making them prime targets for neutralising antibodies. In the cases of SARS-CoV, SARS-CoV-2, and MERS-CoV, spikes transition freely between open and closed conformations to balance host cell attachment and immune evasion. The open conformation exposes domain S1B, allowing it to bind to proteinaceous cell surface receptors. It also facilitates protein refolding during spike-mediated membrane fusion. However, with a single exception, the pre-fusion spikes of all other CoVs studied so far have been observed exclusively in the closed state. This raises the possibility of regulation, where spikes more commonly transition to open states in response to specific cues, rather than spontaneously. In our study, using cryo-EM and molecular dynamics simulations, we show that the spike protein of the common cold human coronavirus HKU1 undergoes local and long-range conformational changes upon binding a sialoglycan-based primary receptor to domain S1A. This binding triggers the transition of S1Bdomains to the open state via allosteric inter-domain cross-talk. Our findings paint a more elaborate picture of CoV attachment, with possibilities of dual receptor usage and priming of entry as a means of immune escape.