Miracle-dz/UniFAR-FTUs huggingface dataset:
APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity

Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we used acyl-biotin exchange, coimmunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins, such as postsynapse density-95 (PSD-95) and glutamate receptors, and detected if depalmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, postsynapse density localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons were all enhanced by TTX pretreatment, and these can be reversed by inhibition of palmitoylation with palmitoyl acyl transferases inhibitors, 2-bromopalmitate and N-(tert-butyl) hydroxylamine hydrochloride. Importantly, we also found that acyl-protein thioesterase 1 (APT1)-mediated depalmitoylation is involved in palmitoylation of PSD-95 and glutamatergic synaptic transmission. Knockdown of APT1, not protein palmitoyl thioesterase 1, with shRNA, or selective inhibition, significantly increased AMPAR-mediated synaptic strength, palmitoylation levels, and synaptic or surface expression of PSD-95 and AMPARs. Results from hippocampal tissues and fear-conditioned rats showed that palmitoylation is required for synaptic strengthening and fear memory formation. These results suggest that palmitoylation and APT1-mediated depalmitoylation have critical effects on the regulation of glutamatergic synaptic plasticity, and it may serve as a potential target for learning and memory-associated disorders. SIGNIFICANCE STATEMENT Fear-related anxiety disorders, including post-traumatic stress disorder, are prevalent psychiatric conditions, and fear memory is associated with hyperexcitability in the hippocampal CA1 region. Palmitoylation is involved in learning and memory, but mechanisms coupling palmitoylation with fear memory acquisition remain poorly understood. This study demonstrated that palmitoylation is essential for postsynapse density-95 clustering and hippocampal glutamatergic synaptic transmission, and APT1-mediated depalmitoylation plays critical roles in the regulation of synaptic plasticity. Our study revealed that molecular mechanism about downregulation of APT1 leads to enhancement of AMPAR-mediated synaptic transmission, and that palmitoylation cycling is implicated in fear conditioning-induced synaptic strengthening and fear memory formation.
JAK inhibitors in crohn’s disease: ready to go?

ABSTRACT Introduction Crohn’s disease (CD) is a chronic, relapsing inflammatory bowel disease that can lead to significant organ damage and impaired quality of life. To date, a considerable proportion of patients does not respond to biologic compounds. It is, therefore, necessary to find alternative options with adequate efficacy and safety profiles in order to increase the chances of obtaining an enduring remission of disease. Janus kinase (JAK) inhibitors are a new class of compounds that might well serve this purpose. The aim of our review is to report the available data from clinical trials testing these new drugs in patients suffering from CD. Areas covered PubMed database and ClinicalTrials.gov website were consulted in order to find the clinical trials evaluating the efficacy and safety profiles of JAK-inhibitors in CD patients, including the following compounds: tofacitinib, filgotinib, upadacitinib, TD-1473, and Pf-06651600/Pf-06700841. Expert opinion JAK-inhibitors are a promising class of oral compounds in moderate-severe CD. Further clinical trials are necessary in order to implement the available knowledge, especially on their long-term safety issues.
Limitations of Phylogenomic Data Can Drive Inferred Speciation Rate Shifts

Abstract Biodiversity analyses of phylogenomic timetrees have produced many high-profile examples of shifts in the rate of speciation across the tree of life. Temporally correlated events in ecology, climate, and biogeography are frequently invoked to explain these rate shifts. In a re-examination of 15 genomic timetrees and 25 major published studies of the pattern of speciation through time, we observed an unexpected correlation between the timing of reported rate shifts and the information content of sequence alignments. Here, we show that the paucity of sequence variation and insufficient species sampling in phylogenomic data sets are the likely drivers of many inferred speciation rate shifts, rather than the proposed biological explanations. Therefore, data limitations can produce predictable but spurious signals of rate shifts even when speciation rates may be similar across taxa and time. Our results suggest that the reliable detection of speciation rate shifts requires the acquisition and assembly of long phylogenomic alignments with near-complete species sampling and accurate estimates of species richness for the clades of study.
Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial.

BACKGROUND Preclinical data suggested anti-inflammatory properties of tedizolid. OBJECTIVES To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. METHODS In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid. RESULTS Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541] pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632] pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69] pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280] pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge. CONCLUSIONS Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid.
Chromosome-Level Genome Assemblies of Two Hypnales (Mosses) Reveal High Intergeneric Synteny

Abstract Mosses compose one of the three lineages of bryophytes. Today, about 13,000 species of mosses are recognized from across the globe, and at least one-third of this diversity composes the Hypnales, a lineage characterized by an early rapid radiation. We sequenced and de novo assembled the genomes of two hypnalean mosses, namely Entodon seductrix and Hypnum curvifolium, based on the 10x genomics and Hi-C data. The genome assemblies of E. seductrix and H. curvifolium comprise 348.4 and 262.0 Mb, respectively, estimated by k-mer analyses to represent 93.3% and 97.2% of their total genome size. Both genomes were assembled at the chromosome level, with scaffold N50 of 30.0 and 20.7 Mb, respectively. The annotated genome of E. seductrix comprises 25,801 protein-coding genes and that of H. curvifolium 29,077, estimated to represent 96.8% and 97.2%, respectively, of the total gene spaces based on BUSCO (Benchmarking Universal Single-Copy Ortholog) assessment. For both genomes, most contigs were anchored to the largest 11 pseudomolecules, corresponding to the 11 chromosomes of the two species, and each with a putative sex-related chromosome characterized by low gene density. The chromosomes of E. seductrix and H. curvifolium are highly syntenic, suggests limited architectural shifts occurred following the rapid radiation of the Hypnales. We compared their genomic features to the model moss Physcomitrium patens. The hypnalean moss genomes lack signatures of recent whole-genome duplication. The presented high-quality moss genomes provide new resources for comparative genomics to potentially unveil the genomic evolution of derived moss lineages.
The Least Biased d to rpb-rpb to d Conversion Formula Combinations for the Meta-Analysis of Studies Using the Two Independent-Groups Design

In a meta-analysis of ds, the utility of converting d to a point-biserial correlation (rpb), correcting rpb for study artifacts, and then converting rpb back to d depends on how accurately the d to rpb-rpb to d (dr-rd) method reproduces the original uncorrected ds. This study compared test ds (dt) converted to dr-rd ds to control ds (dc) to determine the dr-rd formula combinations with the least bias, defined as the difference between dr-rd ds and dc. dt were calculated with available conversion and rpb correction formulas at various base rates and SD ratios, whereas dc were calculated without conversion formulas at base rate . 50 and SD ratio 1.00. Results showed that the lowest bias formula combinations reproduced dc at SD ratio 1.00, bias increased as SD ratio decreased, and formula combinations that produced the lowest bias values were, on average, more accurate than formula combinations that produced the next to lowest bias values. Findings provide the lowest bias dr-rd formula combinations for artifact-corrected meta-analyses of studies using the two independent-groups design.
SARS-CoV-2 infection in Africa: a systematic review and meta-analysis of standardised seroprevalence studies, from January 2020 to December 2021

Introduction Estimating COVID-19 cumulative incidence in Africa remains problematic due to challenges in contact tracing, routine surveillance systems and laboratory testing capacities and strategies. We undertook a meta-analysis of population-based seroprevalence studies to estimate SARS-CoV-2 seroprevalence in Africa to inform evidence-based decision making on public health and social measures (PHSM) and vaccine strategy. Methods We searched for seroprevalence studies conducted in Africa published 1 January 2020–30 December 2021 in Medline, Embase, Web of Science and Europe PMC (preprints), grey literature, media releases and early results from WHO Unity studies. All studies were screened, extracted, assessed for risk of bias and evaluated for alignment with the WHO Unity seroprevalence protocol. We conducted descriptive analyses of seroprevalence and meta-analysed seroprevalence differences by demographic groups, place and time. We estimated the extent of undetected infections by comparing seroprevalence and cumulative incidence of confirmed cases reported to WHO.PROSPERO: CRD42020183634. Results We identified 56 full texts or early results, reporting 153 distinct seroprevalence studies in Africa. Of these, 97 (63%) were low/moderate risk of bias studies. SARS-CoV-2 seroprevalence rose from 3.0% (95% CI 1.0% to 9.2%) in April–June 2020 to 65.1% (95% CI 56.3% to 73.0%) in July–September 2021. The ratios of seroprevalence from infection to cumulative incidence of confirmed cases was large (overall: 100:1, ranging from 18:1 to 954:1) and steady over time. Seroprevalence was highly heterogeneous both within countries—urban versus rural (lower seroprevalence for rural geographic areas), children versus adults (children aged 0–9 years had the lowest seroprevalence)—and between countries and African subregions. Conclusion We report high seroprevalence in Africa suggesting greater population exposure to SARS-CoV-2 and potential protection against COVID-19 severe disease than indicated by surveillance data. As seroprevalence was heterogeneous, targeted PHSM and vaccination strategies need to be tailored to local epidemiological situations.
Determinants of antibody responses to two doses of ChAdOx1 nCoV-19 or BNT162b2 and a subsequent booster dose of BNT162b2 or mRNA-1273: population-based cohort study (COVIDENCE UK)

Background: Antibody responses to SARS-CoV-2 vaccination vary for reasons that remain poorly understood. Methods: We tested for presence of combined IgG, IgA and IgM (IgGAM) anti-spike antibodies before and after administration of two doses of ChAdOx1 nCoV-19 (ChAdOx1, Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) in UK adults participating in a population-based longitudinal study who received their first dose of vaccine from December 15, 2020 to July 10, 2021. Information on sixty-six potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of serological response to vaccination was captured using serial online questionnaires. We used logistic regression to estimate multivariable-adjusted odds ratios (aORs) for associations between independent variables and risk of seronegativity following two vaccine doses. Participants who were seronegative after receiving two vaccine doses were offered an additional antibody test following subsequent administration of a booster dose of BNT162b2 or mRNA-1273 (Moderna) from September 23 to December 12, 2021. Findings: Serology results following two vaccine doses were available for 9,101 participants, of whom 5,770 (63.4%) received ChAdOx1 and 3,331 (36.6%) received BNT162b2. Anti-spike IgGAM was undetectable in 378 (4.2%) participants at a median of 8.6 weeks (IQR 6.4-10.7 weeks) after their second dose of vaccine. Seronegativity following two doses of SARS-CoV-2 vaccination was associated with administration of ChAdOx1 vs BNT162b2 (aOR 7.03, 95% CI 4.39-11.24), shorter interval between first and second vaccine doses (aOR 2.37, 1.06-5.26, for <6 weeks vs >10 weeks; aOR 1.59, 1.18-2.13, for 6-10 weeks vs >10 weeks), poorer self-assessed general health (aOR 3.33, 1.49-7.46, for poor vs excellent), immunodeficiencies (aOR 6.75, 2.63-17.35) and prescription of systemic immunosuppressants (aOR 3.76, 2.44-5.78). By contrast, pre-vaccination SARS-CoV-2 seropositivity (aOR 0.16, 0.04-0.70, for symptomatic seropositives vs seronegatives) and supplemental vitamin D intake (aOR 0.73, 0.53-0.99) were associated with reduced risk of post-vaccination seronegativity. 247/378 (65.3%) of participants who were seronegative after two doses of ChAdOx1 vs BNT162b2 provided a third sample at a median of 7.8 weeks (IQR 5.8-10.4) after receiving a booster dose of BNT162b2 or mRNA-1273: eight (3.2%) of them remained seronegative after three vaccine doses, all of whom either had a primary immunodeficiency or were taking systemic immunosuppressant drugs. Interpretation: We identify multiple determinants of antibody responses to two doses of ChAdOx1 or BNT162b2, many of which are potentially modifiable. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in those who failed to mount antibody responses following two doses of ChAdOx1 or BNT162b2.
Cost-effectiveness of Ezetimibe plus statin lipid-lowering therapy: A systematic review and meta-analysis of cost-utility studies

Introduction: In addition to statin therapy, Ezetimibe, a non-statin lipid-modifying agent, is increasingly used to reduce low-density lipoprotein cholesterol and atherosclerotic cardiovascular disease risk. Literature suggests the clinical effectiveness of Ezetimibe plus statin (EPS) therapy; however, primary evidence on its economic effectiveness is inconsistent. Hence we pooled incremental net benefit to synthesise the cost-effectiveness of EPS therapy. Methods: We identified economic evaluation studies reporting outcomes of EPS therapy compared with other lipid-lowering therapeutic agents or placebo by searching PubMed, Embase, Scopus, and Tufts Cost-Effective Analysis registry. Using random-effects meta-analysis, we pooled Incremental Net Benefit (INB) in the US $ with a 95% confidence interval (CI). We used the modified economic evaluations bias checklist and GRADE quality assessment for quality appraisal. The review was apriori registered with PROSPERO, CRD42021248531. Results: The pooled INB from twenty-one eligible studies showed that EPS therapy was significantly cost-effective compared to other lipid-lowering therapeutic agents or placebo. The pooled INB (95% CI) was $4,274 (621 to 7,927), but there was considerable heterogeneity (I2=84.21). On subgroup analysis EPS therapy is significantly cost-effective in high-income countries [$4,356 (621 to 8,092)], for primary prevention [$4,814 (2,523 to 7,106)], and for payers perspective [$3,255 (571 to 5,939)], and from lifetime horizon [$4,571 (746 to 8,395)]. Conclusion: EPS therapy is cost-effective compared to other lipid-lowering therapeutic agents or placebo in high-income countries and for primary prevention. However, there is a dearth of evidence from lower-middle-income countries and the societal perspective.
In pursuit of the epileptogenic zone in focal epilepsy: A dynamical network biomarker approach

The success of resective surgery for drug-resistant epilepsy patients hinges on the correct identification of the epileptogenic zone (EZ) consisting of the subnetwork of brain regions that underlies seizure genesis in focal epilepsy. The dynamic network biomarker (DNB) method is a dynamical systems-based network analysis approach for identifying subnetworks that are the first to exhibit the transition as a complex system undergoes a bifurcation. The approach was devised and validated in the context of complex disease onset where the dynamics is known to be nonlinear and high-dimensional. We here adapt and implement the DNB approach for the identification of the EZ from the analysis of SEEG data. The method is first successfully tested on simulated data generated with a large-scale brain network model of epilepsy using The Virtual Brain neuroinformatic platform and then applied to clinical SEEG data from focal epilepsy patients. The results are compared with those obtained by expert clinicians that designate the EZ using the Epileptogenicity Index (EI) method. High average precision values are obtained and posit the presented approach as a promising candidate tool for the pursuit of EZ in focal epilepsy.
Avoidable burden of stomach cancer and potential gains in healthy life years from gradual reductions in salt consumption in Vietnam, 2019–2030: a modelling study

Abstract Objective: Excess salt consumption is causally linked with stomach cancer, and salt intake among adults in Vietnam is about twice the recommended levels. The aim of this study was to quantify the future burden of stomach cancer that could be avoided from population-wide salt reduction in Vietnam. Design: A dynamic simulation model was developed to quantify the impacts of achieving the 2018 National Vietnam Health Program (8 g/d by 2025 and 7 g/d by 2030) and the WHO (5 g/d) salt reduction policy targets. Data on salt consumption were obtained from the Vietnam 2015 WHO STEPS survey. Health outcomes were estimated over 6-year (2019–2025), 11-year (2019–2030) and lifetime horizons. We conducted one-way and probabilistic sensitivity analyses. Setting: Vietnam. Participants: All adults aged ≥ 25 years (61 million people, 48·4 % men) alive in 2019. Results: Achieving the 2025 and 2030 national salt targets could result in 3400 and 7200 fewer incident cases of stomach cancer, respectively, and avert 1900 and 4800 stomach cancer deaths, respectively. Achieving the WHO target by 2030 could prevent 8400 incident cases and 5900 deaths from stomach cancer. Over the lifespan, this translated to 344 660 (8 g/d), 411 060 (7 g/d) and 493 633 (5 g/d) health-adjusted life years gained, respectively. Conclusions: A sizeable burden of stomach cancer could be avoided, with gains in healthy life years if national and WHO salt targets were attained. Our findings provide impetus for policy makers in Vietnam and Asia to intensify salt reduction strategies to combat stomach cancer and mitigate pressure on the health systems.
Posouzení signálního programu světelného signalizačního zařízení s využitím simulace

The work focuses on the results and utilization of the experimental research method of modelling and simulation to assess the alternative traffic lights signalling. The theoretical part describes the basic principles of modelling and simulation, the principles of signalling programme designs, basic information about the traffic simulator Aimsun and ways of modelling signal plans in this application. The practical part includes the study of the present traffic control in Karla IV. - Jahnova junction in Pardubice, traffic intensity analysis and alternative signal plans calculation. The traffic research and signalling plans are used in the case study which evaluates the particular ways of controlling the junction on the basis of the chosen traffic-engineering indicators.
Urinary collagen-derived peptides as sensitive markers for bone resorption and bisphosphonate treatment in kidney transplant patients

Kidney transplant recipients (KTR) are at increased risk of fractures. Total urinary hydroxyproline excretion used to be a marker for bone resorption (BR) but faded into the background when more specific markers like Beta-CrossLaps (CTX) became available. Proteomic studies identified numerous hydroxyproline-containing urinary collagen peptides but their origin remains unknown. We followed the hypothesis that some of the urinary collagen peptides are associated with BR and are markers for pathophysiological changes in bone metabolism of KTR. Clinical and laboratory data including serum levels of CTX in 96 KTR from two French centers (Strasbourg, n=38; Paris-Necker, n=58) were correlated with the signal intensity of urinary peptides identified by capillary electrophoresis (CE) coupled to mass spectrometry (MS) and tandem-MS. The effect of oral bisphosphonates on urinary peptides was studied in an independent group of 11 KTR. Eighty-two urinary peptides were identified to be significantly correlated with serum CTX levels in both cohorts. Statistical association with parameters other than BR markers were not significant. Collagen alpha-1(I) chain (COL1A1) was the most frequently identified peptide source. COL1A1 peptides associated with BR were significantly more hydroxylated than those showing no association (55.9% versus 45,2%, p<0.0003 by a chi2-test). From the 82 urinary peptides correlated to CTX, 17 were significantly associated with bisphosphonate treatment. All of these 17 peptides showed a marked reduction in their excretion levels after 410 +- 344 days of bisphosphonate treatment compared to baseline levels. We studied the cleavage sites of these COL1A1 peptides and observed a signature of Cathepsin K and Matrix Metallopeptidase 9. This study provides strong evidence for the occurrence of collagen peptides in the urine of KTR that are associated with BR and that are sensitive to bisphosphonate treatment. Their assessment might become a valuable tool to monitor bone status in KTR.