bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promoting osteointegration effect of Cu-alloyed titanium in ovariectomized rats
Authors: Zhang Xiyue , Liu Hui , Li Ling , Huang Cuishan , Meng Xiangbo , Liu Junzuo , Bai Xueling , Ren Ling , Wang Xinluan , Yang Ke , Qin Ling 
Published: February 2022

AbstractOsteoporosis is a common skeletal disease making patients be prone to the osteoporotic fracture. However, the clinical implants made of titanium and its alloys with a poor osseointegration need a long time for healing and easily to loosening. Thus, a new class of Cu-alloyed titanium (TiCu) alloys with excellent mechanical properties and bio-functionalization has been developed. In this study, the osteoporosis modeled rats were used to study the osteointegration effect and underlying mechanism of TiCu. The results showed that after implantation for 4 weeks, TiCu alloy could promote the reconstruction of vascular network around the implant by up-regulating vascular endothelial growth factor expression. After 8 weeks, it could further promote the proliferation and differentiation of osteoblasts, mineralization and deposition of collagens, and then significantly increasing bone mineral density around the implant. In conclusion, TiCu alloy would enhance the fixation stability, accelerate the osteointegration, and thus reduce the risk of aseptic loosening during the long-term implantation in the osteoporosis environment. This study was the first to report the role and mechanism of a Cu-alloyed metal in promoting osteointegration in osteoporosis environment, which provides a new attractive support for the improvement of future clinical applications of Cu-alloyed antibacterial titanium alloys.
Personalized tourniquet pressure may be a better choice than uniform tourniquet pressure during total knee arthroplasty
Authors: Sun Changjiao , Yang Xin , Zhang Xiaofei , Ma Qi , Yu Peng , Cai Xu , Zhou Yonggang 
Published: February 2022

Abstract

Background:
Pneumatic tourniquets are widely used in total knee arthroplasty (TKA). Some surgeons prefer a uniform tourniquet inflation pressure (UTIP) for all patients; others use personalized tourniquet inflation pressures (PTIP) based on systolic blood pressure and limb occlusion pressure. However, no consensus exists regarding the optimal mode of inflation pressure during TKA. This review aimed to appraise if personalized tourniquet inflation pressures are better than uniform tourniquet inflation.

Methods:
The databases (Web of Science, Embase, PubMed, Cochrane Controlled Trials Register, Cochrane Library, Highwire, CBM, CNKI, VIP, Wanfang) were searched on March 2021 to systematically identify and screen the literature for randomized controlled trials involving PTIP and UTIP during total knee arthroplasty.

Results:
Thirteen randomized controlled trials, involving 1204 TKAs (1201 patients) were included in the systematic review. The meta-analysis identified a trend toward less visual analogue scale (VAS) score at rest with PTIP group at 1 day (P = .002), 2 to 3 days (P = .01), and less VAS score at activity 1 day (P < .0001), 2 to 3 days after the operation (P < .00001), and discharge (P < .0001). No significant difference was found between the groups in terms of VAS score at rest when discharge (P = 1.0). We also found no significant difference in terms of intraoperative blood loss (P = .48), total blood loss (P = .15), lower limb vein thrombosis (P = .42), and thigh bullae (P = .17). However, in the PTIP group, we found a significant higher hospital for special surgery (HSS) score (P = .007), broader knee Range of motion (P = .02), less rate of thigh ecchymosis (P = .00001), and shorter thigh circumference at 1 day (P = .006), 2 to 3 days (P = .0005), and discharge (P = .02).

Conclusion:
PTIP provides a similar bloodless surgical field compared with the conventional UTIP. Furthermore, PTIP provides less pain intensity, thigh circumference, rate of thigh ecchymosis, higher hospital for special surgery, and better initial recovery of knee flexion in total knee arthroplasty. Therefore, we recommend using a PTIP method during TKA. More adequately powered and better-designed randomized controlled trials studies with long-term follow-up are required to produce evidence-based guidelines regarding the PTIP method.
Expression of Unfolded Protein Response Genes in Post-transplantation Liver Biopsies
Authors: Liu Xiaoying , Taylor Sarah A. , Celaj Stela , Levitsky Josh , Green Richard M. 
Published: February 2022

AbstractCholestatic liver diseases are a major source of morbidity and mortality that can progress to end-stage liver disease. There are few effective medical therapies for primary biliary cholangitis, primary sclerosing cholangitis and other cholestatic liver diseases, in part, due to our incomplete understanding of the pathogenesis of cholestatic liver injury. The hepatic unfolded protein response (UPR) is an adaptive cellular response to endoplasmic reticulum stress that is important in the pathogenesis of many liver diseases and recent animal studies have demonstrated the importance of the UPR in the pathogenesis of cholestatic liver injury. However, the role of the UPR in human cholestatic liver diseases is largely unknown. In this study, we utilized liver biopsies from patients after liver transplantation as a disease model to determine the transcriptional profile and hepatic UPR gene expression that is associated with liver injury and cholestasis. RNA-seq analysis revealed that patients with hyperbilirubinemia had enhanced expression of hepatic UPR pathways. Alternatively, liver biopsy samples from patients with acute rejection had enhanced gene expression ofLAG3andCDK1. Pearson correlation analysis of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin levels demonstrated significant correlations with the hepatic expression of several UPR genes, as well as genes involved in hepatic bile acid metabolism and inflammation. In contrast, serum alkaline phosphatase levels were correlated with the level of hepatic bile acid metabolism gene expression but not liver UPR gene expression.ConclusionOverall, these data indicate that hepatic UPR pathways are increased in cholestatic human liver biopsy samples and supports an important role of the UPR in the mechanism of human cholestatic liver injury.
Antisense modulation of IL7R splicing to control sIL7R expression in human CD4+T cells
Authors: Galarza-Muñoz Gaddiel , Kennedy-Boone Debbie , Schott Geraldine , Bradrick Shelton S. , Garcia-Blanco Mariano A. 
Published: February 2022

ABSTRACTThe interleukin 7 receptor (IL7R) is strongly associated with increased risk to develop multiple sclerosis (MS), an autoimmune disease of the central nervous system, and this association is likely driven by upregulation of the soluble isoform of IL7R (sIL7R). Expression of sIL7R is determined by exclusion of the alternative exon 6 from IL7R transcripts, and our previous work revealed that the MS risk allele of the SNP rs6897932 within this exon enhances the expression of sIL7R by promoting exclusion of exon 6. sIL7R potentiates the activity of IL7, leading to enhanced expansion of T cells and increased disability in the Experimental Autoimmune Encephalomyelitis (EAE) murine model of MS. This role in modulating T cell-driven immunity positions sIL7R as an attractive therapeutic target whose expression could be reduced for treatment of MS or increased for treatment of cancers. In this study we identified novel antisense oligonucleotides (ASOs) that effectively control the inclusion (anti-sIL7R ASOs) or exclusion (pro-sIL7R ASOs) of this exon in a dose-dependent fashion. These ASOs provided excellent control of exon 6 splicing and sIL7R secretion in human primary CD4+T cells. Supporting their potential for therapeutic targeting, we showed that lead anti-sIL7R ASOs correct the enhanced exon 6 exclusion imposed by the MS risk allele of rs6897932, whereas lead pro-sIL7R ASOs phenocopy it. The data presented here form the foundation for future pre-clinical studies that will test the therapeutic potential of these ASOs in MS and immuno-oncology.
Uncovering circuit mechanisms of current sinks and sources with biophysical simulations of primary visual cortex
Authors: Rimehaug Atle E. , Stasik Alexander J. , Hagen Espen , Billeh Yazan N. , Siegle Joshua H. , Dai Kael , Olsen Shawn R. , Koch Christof , Einevoll Gaute T. , Arkhipov Anton 
Published: February 2022

AbstractLocal field potential (LFP) recordings reflect the dynamics of the current source density (CSD) in brain tissue. The synaptic, cellular and circuit contributions to current sinks and sources are ill-understood. We investigated these in mouse primary visual cortex using public Neuropixels recordings and a detailed circuit model based on simulating the Hodgkin-Huxley dynamics of numerous cortical neurons belonging to 17 cell types. The model simultaneously captured spiking and CSD responses and demonstrated a two-way dissociation: Firing rates are altered with minor effects on the CSD pattern by adjusting synaptic weights, and CSD is altered with minor effects on firing rates by adjusting synaptic placement on the dendrites. We describe how thalamocortical inputs and recurrent connections sculpt specific sinks and sources early in the visual response, whereas cortical feedback crucially alters them in later stages. Our findings show that CSD analysis provides powerful constraints for modeling beyond those from considering spikes.
Dynamic Generalised Additive Models (DGAM) for forecasting discrete ecological time series
Authors: Clark Nicholas J , Wells Konstans 
Published: February 2022

ABSTRACTGeneralised Additive Models (GAMs) are increasingly popular for describing smooth nonlinear relationships between predictors and response variables. GAMs are particularly relevant in ecology for representing hierarchical functions for discrete responses that encompass complex features including zero-inflation, bounding and uneven sampling. However, GAMs are less useful for producing forecasts as their smooth functions provide unstable predictions outside the range of training data.We introduce Dynamic Generalised Additive Models (DGAMs), where the GAM linear predictor is jointly estimated with unobserved dynamic components to model time series that evolve as a function of nonlinear predictor associations and latent temporal processes. These models are particularly useful for multivariate series, as they can estimate hierarchical smooths while learning complex temporal associations via dimension-reduced latent factor processes. We implement our models in themvgamR package, which uses themgcvandrjagspackages to construct smoothing splines and estimate unobserved parameters in a probabilistic framework.Using simulations, we illustrate how our models outperform competing formulations in realistic ecological forecasting tasks while identifying important smooth predictor functions. We use a real-world case study to highlight some ofmvgam’skey features, which include functions for: calculating correlations among series’ latent trends, performing model selection using rolling window forecasts, online data augmentation via a recursive particle filter, and visualising probabilistic uncertainties for smooths and predictions.Dynamic GAMs (DGAM) offer a solution to the challenge of forecasting discrete time series while estimating ecologically relevant nonlinear predictor associations. Our Bayesian latent factor approach will be particularly useful for exploring competing dynamic ecological models that encompass hierarchical smoothing structures while providing forecasts with robust uncertainties, tasks that are becoming increasingly important in applied ecology.
Genomic surveillance of SARS-CoV-2 reveals emergence of Omicron BA.2 in Islamabad, Pakistan
Authors: Umair Massab , Ikram Aamer , Rehman Zaira , Haider Syed Adnan , Ammar Muhammad , Badar Nazish , Ali Qasim , Rana Muhammad Suleman , Salman Muhammad 
Published: February 2022

AbstractThe Omicron variant of SARS-CoV-2 has rapidly replace previous variants of SARS CoV2 around the globe and is now a major variant of concern. The genomic surveillance of Omicron variant also reveals spread of its subvariant BA.2 which has differing transmissibility in comparison to its other subvariant BA.1. BA.1 and BA.2 harbors different mutational profile. One of the important change in both the subvariants is the presence of 69-70 deletion in BA.1 and absence of this deletion in BA.2. This deletion can be used as tool for the detection of omicron sub variants using real time PCR. In the current study we have used the TaqPath COVID-19 PCR kit for the detection of 69-70 deletion followed by genotyping using SNPsig® SARS-CoV-2 (EscapePLEX) kit (PrimerDesign, UK) that target K417N, E484K, and P681R mutations. The samples with the amplification of spike gene and K417N were termed as probable BA.2 cases. A subset of samples (n=13) were further subjected to whole genome sequencing. The results showed all the 13 samples were of BA.2. Hence, this assay can be used as a cost effective method for the detection of omicron BA.2 variant using real time PCR in resource limiting settings. Moreover, the detection of BA.2 with highly transmissible mutations in Islamabad, Pakistan may potentially increase the number of positive cases. In that scenario, there has to be stringent genomic surveillance to understand the circulating lineages in the country.
Modeling predicts mechanisms altered by mutations of the SARS-CoV-2 delta and omicron variants
Authors: Pearson Jason , Wessler Timothy , Chen Alex , Boucher Richard C. , Freeman Ronit , Lai Samuel K. , Pickles Raymond , Forest M. Gregory 
Published: February 2022

AbstractWe apply our mechanistic, within-host,pre-immunity, respiratory tract infection model for unvaccinated, previously uninfected, and immune-compromised individuals. Starting from published cell infection and viral replication data for the SARS-CoV-2 alpha variant, we explore variability in outcomes of viral load and cell infection due to three plausible mechanisms altered by SARS-CoV-2 mutations of delta and omicron. We seek a mechanistic explanation of clinical test results: delta nasal infections express ∼3 orders-of-magnitude higher viral load than alpha, while omicron infections express an additional 1 to 2 orders-of-magnitude rise over delta. Model simulations revealshortening of the eclipse phase(the time between cellular uptake of the virus and onset of infectious viral replication and shedding)alone can generate 3-5 orders-of-magnitude higher viral load within 2 days post initial infection. Higher viral replication rates by an infected cell can generate at most one order-of-magnitude rise in viral load, whereas higher cell infectability has minimal impact and lowers the viral load.
Fuzzy Supertertiary Interactions within PSD-95 Enable Ligand Binding
Authors: Hamilton George L. , Saikia Nabanita , Basak Sujit , Welcome Franceine S. , Wu Fang , Kubiak Jakub , Zhang Changcheng , Hao Yan , Seidel Claus A.M. , Ding Feng , Sanabria Hugo , Bowen Mark E. 
Published: February 2022

ABSTRACTThe scaffold protein PSD-95 links postsynaptic receptors to sites of presynaptic neurotransmitter release. Flexible linkers between folded domains in PSD-95 enable a dynamic supertertiary structure. Interdomain interactions within the PSG supramodule, formed by PDZ3, SH3 and GuK domains, regulate PSD-95 activity. Here we combined Discrete Molecular Dynamics and single molecule FRET to characterize the PSG supramodule, with time resolution spanning picoseconds to seconds. We used a FRET network to measure distances in full-length PSD-95 and model the conformational ensemble. We found that PDZ3 samples two conformational basins, which we confirmed with disulfide mapping. To understand effects on activity, we measured binding of the synaptic adhesion protein neuroligin. We found that PSD-95 bound neuroligin well at physiological pH while truncated PDZ3 bound poorly. Our hybrid structural models reveal how the supertertiary context of PDZ3 enables recognition of this critical synaptic ligand.
Omicron BA.1 and BA.2 are antigenically distinct SARS-CoV-2 variants
Authors: Mykytyn Anna Z. , Rissmann Melanie , Kok Adinda , Rosu Miruna E. , Schipper Debby , Breugem Tim I. , van den Doel Petra B. , Chandler Felicity , Bestebroer Theo , de Wit Maurice , van Royen Martin E. , Molenkamp Richard , Oude Munnink Bas B. , de Vries Rory D. , GeurtsvanKessel Corine , Smith Derek J. , Koopmans Marion P. G. , Rockx Barry , Lamers Mart M. , Fouchier Ron , Haagmans Bart L. 
Published: February 2022

AbstractThe emergence and rapid spread of SARS-CoV-2 variants may impact vaccine efficacy significantly1. The Omicron variant termed BA.2, which differs genetically substantially from BA.1, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed2,3. Here, we used antigenic cartography to quantify and visualize antigenic differences between SARS-CoV-2 variants using hamster sera obtained after primary infection. Whereas early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape (vaccine-induced) antibody responses as a result of different antigenic characteristics. Close monitoring of the antigenic changes of SARS-CoV-2 using antigenic cartography can be helpful in the selection of future vaccine strains.
Epstein-Barr virus promotes T cell dysregulation in a humanized mouse model of multiple sclerosis
Authors: Allanach Jessica R. , Fettig Naomi M. , Hardman Blair K. , Fan Vina , Rosen Ariel R. , Goldberg Erin J. , Morse Zachary J. , Shanina Iryna , Vorobeychik Galina , Osborne Lisa C. , Horwitz Marc S. 
Published: February 2022

ABSTRACTInfection with the human-tropic Epstein-Barr virus (EBV) is a strong risk factor for multiple sclerosis (MS), though the underlying mechanisms remain unclear. To investigate the immunomodulatory effects of latent EBV infection, we induced experimental autoimmune encephalomyelitis (EAE) in immunocompromised mice humanized with peripheral blood mononuclear cells (PBMCs) from individuals with or without a history of EBV infection and/or a diagnosis of relapsing MS. HuPBMC EAE mice generated from EBV seronegative healthy donors were less susceptible to developing severe clinical disease than EBV seropositive healthy donor and RRMS cohorts. Donor EBV seropositivity and RRMS led to a significant incremental increase in the number of brain and spinal cord infiltrating effector T cells, in the absence of viral reactivation, due to enhanced proliferation of donor T cells and reduced regulatory T cell expansion. The data indicate that a history of EBV infection, further compounded by a diagnosis of RRMS, promotes T cell-mediated disease in a novel humanized mouse model of MS.SUMMARYIn a novel humanized mouse model of multiple sclerosis (MS), donor history of Epstein-Barr virus (EBV) infection exacerbates disease severity by skewing the balance of effector and regulatory T cells in the brain and spinal cord. These results reveal an immunomodulatory mechanism by which latent EBV infection could predispose to the development of autoimmune disease.
Targetome analysis of malaria sporozoite transcription factor AP2-Sp reveals its role as a master regulator
Authors: Yudaa Masao , Kaneko Izumi , Murata Yuho , Iwanaga Shiroh , Nishi Tsubasa 
Published: February 2022

AbstractMalaria transmission to humans begins with sporozoite infection of the liver. The elucidation of gene regulation during the sporozoite stage will promote the investigation of mechanisms of liver infection by this parasite and contribute to the development of strategies for preventing malaria transmission. AP2-Sp is a transcription factor (TF) essential for the formation of sporozoites or sporogony, which takes place in oocysts in the midgut of infected mosquitoes. To understand the role of this TF in the transcriptional regulatory system of this stage, we performed ChIP-seq analyses using whole mosquito midguts containing late oocysts as starting material and explored its genome-wide target genes. We identified 697 target genes, comprising those involved in distinct processes parasites experience during this stage, from sporogony to development into the liver-stage, and representing the majority of genes highly expressed in the sporozoite stage. These results suggest that AP2-Sp determines basal patterns of gene expression by targeting a broad range of genes directly. The ChIP-seq analyses also showed that AP2-Sp maintains its own expression by a transcriptional auto-activation mechanism (positive feedback loop) and induces all TFs reported to be transcribed at this stage, including AP2-Sp2, AP2-Sp3, and SLARP. The results showed that AP2-Sp exists at the top of the transcriptional cascade of this stage and triggers the formation of this stage as a master regulator.
The impact of COVID passport mandates on the number of cases of and hospitalizations with COVID-19 in the UK: a difference-in-differences analysis
Authors: López-Güell Kim , Prats-Uribe Albert , Català Martí , Prats Clara , Hein Jotun , Prieto-Alhambra Daniel 
Published: February 2022

SummaryBackgroundMandatory COVID-19 certification was introduced at different times in the four countries of the UK. We aimed to study the effect of this intervention on the incidence of cases and hospital admissions.MethodsThe main outcome was the weekly averaged incidence of COVID-19 confirmed cases and hospital admissions. We performed Negative Binomial Segmented Regression (NBSR) and Autoregressive Integrated Moving Average (ARIMA) analyses for the four countries (England, Northern Ireland, Scotland and Wales), and fitted Difference-in-Differences (DiD) models to compare the latter three to England, where COVID-19 certification was imposed the latest.FindingsNBSR methods suggested COVID-19 certification led to a decrease in the incidence of cases in Northern Ireland, but not in hospitalizations. In Wales, they also caused a decrease in the incidence of cases but not in hospital admissions. In Scotland, we observed a decrease in both cases and admissions. ARIMA models confirmed these results. The DiD model showed that the intervention decreased the incidence of COVID compared to England in all countries except Wales, in October. Then, the incidence rate of cases already had a decreasing tendency, as well as in England, hence a particular impact of Covid Passport was less obvious. In Wales, the model coefficients were 2.2 (95% CI -6.24,10.70) for cases and -0.144 (95% CI -0.248, -0.039) for admissions in October and -7.75 (95% CI -13.1, -2.46) for cases and -0.169 (95% CI-0.308, -0.031) for admissions in November. In Northern Ireland, -10.1 (95% CI -18.4, -1.79) for cases and -0.269 (95% CI -0.385, -0.153) for admissions. In Scotland they were 7.91 (95% CI 4.46,11.4) for cases and -0.097 (95% CI - 0.219,0.024) for admissions.InterpretationThe introduction of mandatory certificates decreased cases in all countries except in England. Differences on concomitant measures, on vaccination uptake or Omicron variant prevalence could explain this discrepancy.