bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism Driven Early Stage Identification and Avoidance of Antisense Oligonucleotides Causing TRL9 Mediated Inflammatory Responses in Bjab cells
Authors: Pollak Adam J. , Cauntay Patrick , Machemer Todd , Paz Suzanne , Damle Sagar , Henry Scott P. , Burel Sebastien A. 
Published: December 2021

ABSTRACTNucleic acid-based PS-ASOs have the potential to activate cellular innate immune responses, and the level of activation can vary quite dramatically with sequence. Minimizing degree of proinflammatory effect is one of the main selection criteria for compounds intended to move into clinical trials. While a recently developed hPBMC-based assay showed excellent ability to detect innate immune active PS-ASOs, which can then be discarded from the developmental process, this assay is highly resource-intensive and easily affected by subject variability. This compelled us to develop of a more convenient high-throughput assay. Here, we describe a new in vitro assay, utilizing a cultured human Bjab cell line, which was developed and validated to identify PS-ASOs that may cause innate immune activation. The assay was calibrated to replicate results from the hPMBC assay. The Bjab assay was designed to be high throughput and more convenient by using RT-qPCR readout of mRNA of the chemokine Ccl22. The Bjab assay was also shown to be highly reproducible and to provide a large dynamic range in determining the immune potential of PS-ASOs via comparison to known benchmark PS-ASO controls that were previously shown to be either safe or inflammatory in clinical trials. In addition, we demonstrate that Bjab cells can be used to provide mechanistic information on PS-ASO-TLR9 dependent innate immune activation.
Protective effect of peroxisome proliferator-activated receptor-α in regulating the early inflammation response to extended hepatectomy from a comparative transcriptomic analysis
Authors: Shi Cheng-Cheng , Bai Yang , Yan Xin , Cheng Nuo , Guo Wen-Zhi , Zhang Shui-Jun , Shi Ji-Hua 
Published: December 2021

AbstractThe regulation mechanism of small-for-size syndrome remains unclear. Thus, we aimed to analyze the molecular profiles following extended hepatectomy and identify the therapeutic target. Major hepatectomy and extended hepatectomy were performed in the rat model, and the remnant livers were obtained dynamically for the high-throughput transcriptome analysis to identify the differentially expressed genes (DEGs). The general framework for weighted gene co-expression network analysis (WGCNA) was employed to explore the expression patterns of DEGs. As result, WGCNA identified 10 distinct gene co-expression modules according to the correlation between module eigengene and different postoperative time-points. The magenta module (gene count: 289) and the lightcyan module (gene count: 484) were found positively correlated with major hepatectomy instead of extended hepatectomy. In the lightcyan module, peroxisome proliferator-activated receptor-α (PPARα) was selected and found the down-regulation in the remnant liver following extended (marginal) hepatectomy in rats and humans. Besides, administration of PPARα agonist attenuated hepatic inflammation injury while PPARα antagonist increased liver inflammation injury after extended hepatectomy in rats, marked by the significantly changed aminotransferases, tumor necrosis factor-α and interleukin-6 levels in the plasm, and histological Suzuki criteria. Consequently, DEGs and their molecular profiles after extended hepatectomy were identified, and PPARα might be a potential therapy target for small-for-size syndrome.
Age dependent changes in circulating Tfh cells influence the development of functional antibodies to malaria in children
Authors: Chan Jo-Anne , Loughland Jessica R , de la Parte Lauren , Okano Satomi , Ssewanyana Isaac , Nalubega Mayimuna , Nankya Felistas , Musinguzi Kenneth , Rek John , Arinaitwe Emmanuel , Tipping Peta , Bourke Peter , Andrew Dean , Dooley Nicholas , SheelaNair Arya , Wines Bruce D , Hogarth Mark , Beeson James , Greenhouse Bryan , Dorsey Grant , Kamya Moses , Hartel Gunter , Minigo Gabriela , Feeney Margaret , Jagannathan Prasanna , Boyle Michelle J 
Published: December 2021

ABSTRACTT-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies were boosted in children with current infection, and were higher in females. The children with the very highest antibody levels had increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.
biPACT: a method for three-dimensional visualization of mouse spinal cord circuits of long segments with high resolution
Authors: Nakanishi Katsuyuki , Shinozaki Munehisa , Nagoshi Narihito , Nakamura Masaya , Okano Hideyuki 
Published: December 2021

AbstractBackgroundThe spatial complexity of neuronal circuits in the central nervous system is a hurdle in understanding and treating brain and spinal cord injuries. Although several methods have recently been developed to render the spinal cord transparent and label specific neural circuits, three-dimensional visualization of long segments of spinal cord with high resolution remains challenging.New MethodWe present a method that combines tissue staining of neuronal tracts traced with biotinylated dextran amine (BDA) and a modified passive clarity clearing protocol to describe individual fibers in long segments of mouse spinal cord.ResultsCorticospinal tract was traced with BDA with a mouse model of thoracic spinal cord injury. The spinal cord was stained and cleared in two weeks with four solutions: staining solution, hydrogel solution, clearing solution, and observation solution. The samples were observed with a light-sheet microscope, and three-dimensional reconstruction was performed with ImageJ software. High resolution-images comparable with tissue sections were obtained continuously and circumferentially. By tiling, it was possible to obtain high-resolution images of long segments of the spinal cord. The tissue could be easily re-stained in case of fading,Comparison with Existing MethodsThe present method does not require special equipment, can label specific circuits without genetic technology, and re-staining rounds can be easily implemented. It enables to visualize individual neural fiber of specific neural circuit in long spinal cord segments.ConclusionsBy using simple neural staining, and clearing methods, it was possible to acquire a wide range of high-resolution three-dimensional images of the spinal cord.HighlightsNo special devices or genetic tracers are required for a new clearing methodNeuronal fibers are individually depicted in long segments of mouse spinal cord.Re-staining of neuronal fiber is possible.Stereotaxic observation is achieved by 3-D reconstruction with open-source software.
Insights into the role of lipoteichoic acids and MprF function in Bacillus subtilis
Authors: Guyet Aurélie , Alofi Amirah , Daniel Richard A. 
Published: December 2021

AbstractGram-positive bacterial cells are protected from the environment by a cell envelope which comprises of layers of peptidoglycan that maintain the cell shape and teichoic acids polymers whose biological function remains unclear. In Bacillus subtilis, loss of all Class A Penicillin-Binding Proteins (aPBPs) which function in peptidoglycan synthesis is conditionally lethal. Here we show that this lethality is associated with an alteration of the lipoteichoic acids (LTA) and the accumulation of the major autolysin LytE in the cell wall. Our analysis provides further evidence that the length and abundance of LTA acts to regulate the cellular level and activity of autolytic enzymes, specifically LytE. Importantly, we identify a novel function for the aminoacyl-phosphatidylglycerol synthase MprF in the modulation of LTA biosynthesis in B. subtilis and Staphylococcus aureus. This finding has implications for our understanding of antimicrobial resistance (particularly daptomycin) in clinically relevant bacteria and the involvement of MprF in the virulence of pathogens, such as methicillin resistant S. aureus.
Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients
Authors: Lu Lu , Mok Bobo Wing-Yee , Chen Linlei , Chan Jacky Man-Chun , Tsang Owen Tak-Yin , Lam Bosco Hoi-Shiu , Chuang Vivien Wai-Man , Chu Allen Wing-Ho , Chan Wan-Mui , Ip Jonathan Daniel , Chan Brian Pui-Chun , Zhang Ruiqi , Yip Cyril Chik-Yan , Cheng Vincent Chi-Chung , Chan Kwok-Hung , Hung Ivan Fan-Ngai , Yuen Kwok-Yung , Chen Honglin , To Kelvin Kai-Wang 
Published: December 2021

ABSTRACTBackgroundThe SARS-CoV-2 Omicron variant, designated as a Variant of Concern(VOC) by the World Health Organization, carries numerous spike protein mutations which have been found to evade neutralizing antibodies elicited by COVID-19 vaccines. The susceptibility of Omicron variant by vaccine-induced neutralizing antibodies are urgently needed for risk assessment.MethodsOmicron variant strains HKU691 and HKU344-R346K were isolated from patients using TMPRSS2-overexpressing VeroE6 cells. Whole genome sequence was determined using nanopore sequencing. Neutralization susceptibility of ancestral lineage A virus and the Omicron, Delta and Beta variants to sera from 25 BNT162b2 and 25 Coronavac vaccine recipients was determined using a live virus microneutralization assay.ResultsThe Omicron variant strain HKU344-R346K has an additional spike R346K mutation, which is present in 8.5% of strains in GISAID database. Only 20% and 24% of BNT162b2 recipients had detectable neutralizing antibody against the Omicron variant HKU691 and HKU344-R346K, respectively, while none of the Coronavac recipients had detectable neutralizing antibody titer against either Omicron isolates. For BNT162b2 recipients, the geometric mean neutralization antibody titers(GMT) of the Omicron variant isolates(5.43 and 6.42) were 35.7-39.9-fold lower than that of the ancestral virus(229.4), and the GMT of both omicron isolates were significantly lower than those of the beta and delta variants. There was no significant difference in the GMT between HKU691 and HKU344-R346K.ConclusionsOmicron variant escapes neutralizing antibodies elicited by BNT162b2 or CoronaVac. The additional R346K mutation did not affect the neutralization susceptibility. Our data suggest that the Omicron variant may be associated with lower COVID-19 vaccine effectiveness.
Quality-adjusted life expectancy norms for the English population
Authors: Schneider Paul , McNamara Simon , Love-Koh James , Doran Tim , Gutacker Nils 
Published: December 2021

AbstractObjectiveThe National Institute for Health and Care Excellence in England has proposed severity-of-disease modifiers that give greater weight to health benefits accruing to patients who experience a larger shortfall in quality-adjusted life years (QALYs) under current standard of care compared to healthy individuals. This requires an estimate of quality-adjusted life expectancy (QALE) of the general population by age and sex. Previous QALE population norms are based on nearly 30-year old assessments of HRQoL in the general population. This study provides updated QALE estimates for the English population by age and sex.MethodsEQ-5D-5L data for 14,412 participants from the Health Survey for England (waves 2017 and 2018) were pooled and HRQoL population norms were calculated. These norms were combined with official life tables from the Office for National Statistics for 2017-2019 using the Sullivan method to derive QALE estimates by age and sex. Values were discounted using 0%, 1.5% and 3.5% discount rates.ResultsQALE at birth is 68.04 QALYs for men and 68.48 QALYs for women. These values are lower than previously published QALE population norms based on older HRQoL data. Additional data tables and figures are made available through an interactive web application: https://r4scharr.shinyapps.io/shortfall/.ConclusionsThis study provides new QALE population norms for England that serve to establish absolute and relative QALY shortfalls for the purpose of health technology assessments.
Differential impact of Covid-19 on incidence of diabetes mellitus and cardiovascular diseases in acute, post-acute and long Covid-19: population-based cohort study in the United Kingdom
Authors: Rezel-Potts Emma , Douiri Abdel , Sun Xiaohui , Chowienczyk Phillip J , Shah Ajay M , Gulliford Martin C 
Published: December 2021

ABSTRACTObjectiveThis study aimed to estimate the incidence of new diabetes mellitus (DM) and cardiovascular diseases (CVD) up to one year after Covid-19 compared with matched controls.MethodsA cohort study was conducted using electronic records for 1,473 family practices with a population of 14.9 million. Covid-19 patients without DM or CVD were individually matched with controls and followed up to October 2021. A difference-in-difference analysis estimated the net effect of Covid-19 allowing for baseline differences and covariates.ResultsThere were 372,816 Covid-19 patients, with 2,935 CVD and 3,139 DM events, and 372,816 matched controls with 1,193 CVD and 1,861 DM events following the index date. Net incidence of DM increased in acute Covid-19 up to four weeks from index date (adjusted rate ratio, RR 1.71, 1.40 to 2.10) and remained elevated in post-acute (five to 12 weeks from index date; RR 1.17, 1.01 to 1.36) and long-Covid-19 (13 to 52 weeks, 1.20, 1.09 to 1.31). Acute Covid-19 was associated with net increased CVD incidence (RR 6.02, 95% confidence interval 4.84 to 7.47) including pulmonary embolism (RR 14.5, 7.72 to 27.4), atrial arrythmias (6.58, 3.78 to 11.4) and venous thromboses (5.44, 3.22 to 9.17). CVD incidence declined in post-acute Covid-19 (1.68, 1.41 to 2.01) and showed no net increase in long Covid-19 (0.95, 0.85 to 1.06).ConclusionsDM incidence remains elevated up to one year following Covid-19. CVD is increased early after Covid-19 mainly from pulmonary embolism, atrial arrhythmias and venous thromboses.
A meta-analysis of Early Results to predict Vaccine efficacy against Omicron
Authors: Khoury David S. , Steain Megan , Triccas James A. , Sigal Alex , Davenport Miles P. , Cromer Deborah 
Published: December 2021

AbstractIn the studies to date, the estimated fold-drop in neutralisation titre against Omicron ranges from 2- to over 20-fold depending on the study and serum tested. Collating data from the first four of these studies results in a combined estimate of the drop in neutralisation titre against Omicron of 9.7-fold (95% CI 5.5-17.1). We use our previously established model to predict that six months after primary immunisation with an mRNA vaccine, efficacy for Omicron is estimated to have waned to around 40% against symptomatic and 80% against severe disease. A booster dose with an existing mRNA vaccine (even though it targets the ancestral spike) has the potential to raise efficacy for Omicron to 86.2% (95% CI: 72.6-94) against symptomatic infection and 98.2% (95% CI: 90.2-99.7) against severe infection.
Brain injury environment critically influences the connectivity of transplanted neurons
Authors: Grade S. , Thomas J. , Zarb Y. , Thorwirth M. , Conzelmann Karl-Klaus , Hauck Stefanie M. , Götz Magdalena 
Published: December 2021

AbstractCell transplantation is a promising approach for the reconstruction of neuronal circuits after brain damage. Transplanted neurons integrate with remarkable specificity into circuitries of the mouse cerebral cortex affected by neuronal ablation. However, it remains unclear how neurons perform in a local environment undergoing reactive gliosis, inflammation, macrophage infiltration and scar formation, as in traumatic brain injury (TBI). To elucidate this, we transplanted cells from the embryonic mouse cerebral cortex into TBI-injured, inflamed-only, or intact cortex of adult mice. Brain-wide quantitative connectomics unraveled graft inputs from correct regions across the brain in all conditions, with pronounced quantitative differences: scarce in intact and inflamed brain, versus exuberant after trauma. In the latter, excessive synapse pruning follows the initial overshoot of connectivity resulting in only a few connections left. Proteomic profiling identifies candidate molecules involved in the synaptic yield, a pivotal parameter to tailor for functional restoration of neuronal circuits.TeaserNeuronal grafts in a brain area affected by trauma receive excessive yet mostly vulnerable inputs from host circuits.
Structure and dynamics of human disease-complication network
Authors: Jiang Xiong-Fei , Xiong Long , Bai Ling , Lin Jie , Zhang Jing-Feng , Yan Kun , Zhu Jia-Zhen , Zheng Bo , Zheng Jian-Jun 
Published: December 2021

AbstractA complication is an unanticipated disease arisen following, induced by a disease, a treatment or a procedure. We compile the Human Disease-Complication Network from the medical data and investigate the characteristics of the network. It is observed that the modules of the network are dominated by the classes of diseases. The relations between modules are unveiled in detail. Three nontrivial motifs are identified from the network. We further simulate the dynamics of motifs with the Boolean dynamic model. Each motif represents a specific dynamic behavior, which is potentially functional in the disease system, such as generating temporal progressions and governing the responses to fluctuating external stimuli.Author summaryAdvances in molecular biology lead to a new discipline of network medicine, investigating human diseases in a networked structure perspective. Recently, clinical records have been introduced to the research of complex networks of diseases. An important available medical dataset that has been overlooked so far is the complications of diseases, which are vital for human beings. We compile the Human Disease-Complication Network, representing the causality between the upstream diseases and their downstream complications. This work not only helps us to comprehend why certain groups of diseases appear collectively, but also provides a new paradigm to investigate the dynamics of disease progression. For clinical applications, the investigation of complications may yield new approaches to disease prevention, diagnosis and treatment.
An amphipathic and cationic antimicrobial peptide kills colistin resistant Gram-negative pathogens in vivo
Authors: Thomsen Thomas T. , Kolpen Mette , Wigneswaran Vinoth , Kromann Ulrik , Ebbensgaard Anna E. , Hammerum Anette M. , Hasman Henrik , Radmer Stine , Kragh Kasper N. , Hartmann-Petersen Rasmus , Hansen Paul Robert , Folkesson Anders , Frimodt-Møller Niels , Løbner-Olesen Anders 
Published: December 2021

AbstractNew antibiotics are needed against multidrug resistant Gram-negative pathogens that have compromised global health systems. Antimicrobial peptides are generally considered promising lead candidates for the next generation of antibiotics but have not fulfilled this expectation. Here we demonstrate activity of a cationic amphipathic undecapeptide (ChIP; Charge change Independent Peptide) against a wide panel of multidrug resistant Gram-negative pathogens. Importantly, the antimicrobial activity of ChIP is independent of the surface charge changes that confer colistin resistance through modification of Lipid A, while decreased activity of ChIP correlates with GlcN1 tri-acylation of Lipid A. In an in vivo peritonitis mouse model ChIP displays excellent activity against both colistin sensitive and resistant Escherichia coli and Acinetobacter baumannii strains.Author SummaryAntimicrobial peptides hold promise as novel treatment options for diseases caused by multidrug resistant bacteria. Here we present evidence that the ChIP peptide, comprised of 11 D-amino acids, is active against a variety of Gram-negative bacteria that ranks high on the WHO list of critically important pathogens. ChIP initially interacts with the Gram-negative outer membrane, independent of its surface charge, followed by entry into the periplasm and permeabilization of the inner membrane, leading to bacterial cell death. Detailed analyses of the outer membrane indicate that the acylation pattern of lipopolysaccharides plays an important role for ChIP activity. In a mouse infection model, ChIP display excellent activity in reducing bacterial numbers for both Escherichia coli and Acinetobacter baumannii. Importantly, ChIP is highly efficient against bacteria resistant to colistin, an antibiotic normally considered as a last resort treatment of infections caused by multidrug resistant Gram-negative bacteria.
Seasonal resistome diversity and dissemination of WHO priority antibiotic-resistant pathogens in Lebanese estuaries
Authors: Hobeika Wadad , Gaschet Margaux , Ploy Marie-Cécile , Buelow Elena , Sarkis Dolla Karam , Dagot Christophe 
Published: December 2021

AbstractAnthropogenic activities are demonstrated to be the key drivers of antimicrobial resistance (AMR) dissemination in the environment. Lebanese rivers that lead to the Mediterranean Sea were sampled at estuaries’ sites, under high anthropogenic pressure, in spring 2017 and winter 2018 to study seasonal variation of antimicrobial-resistant bacteria (ARBs) and antimicrobial resistance genes (ARGs). Methods: A combined approach using culture techniques and high throughput qPCR identified hotspots for antimicrobial resistance and anthropogenic pressure in particular locations along the Lebanese coast. Results: Multi-resistant Gram-negative (Enterobacterales and Pseudomonas spp) and Gram-positive bacterial pathogens were isolated. A high abundance of certain ARGs (vanB, blaBIC-1, blaGES, tetM, and mcr-1) was detected in 5 Lebanese estuaries. The relative abundance of ARGs was highest in winter and areas with high anthropogenic activities and population growth with an influx of refugees. Conclusion: Qualitative analysis of ARB and the analysis of the Lebanese estuaries’ resistome revealed critical levels of contamination with pathogenic bacteria and provided significant information about the spread of ARGs in anthropogenically impacted estuaries.