PATTERNA: transcriptome-wide search for functional RNA elements via structural data signatures.

Establishing a link between RNA structure and function remains a great challenge in RNA biology. The emergence of high-throughput structure profiling experiments is revolutionizing our ability to decipher structure, yet principled approaches for extracting information on structural elements directly from these data sets are lacking. We present PATTERNA, an unsupervised pattern recognition algorithm that rapidly mines RNA structure motifs from profiling data. We demonstrate that PATTERNA detects motifs with an accuracy comparable to commonly used thermodynamic models and highlight its utility in automating data-directed structure modeling from large data sets. PATTERNA is versatile and compatible with diverse profiling techniques and experimental conditions

MORE SMOKE THAN FIRE NO SPEEDING UP OF PARKINSON‘S DISEASE AFTER COVID-10 LOCKDOWN

peer reviewedBackground and objectives As the influence of stress syndromes on the evolution of Parkinson’s disease (PD) remains largely unexplored, the COVID-19 pandemic offers the opportunity to evaluate the stress impact of the COVID-19 pandemic on PD trajectories. Methods This longitudinal observational case-control study used data from the Luxembourg Parkinson’s Study (1). A pandemic PD group with exposure to the restrictions imposed by the COVID-19 pandemic but without COVID-19 infection (n=79) was compared to a prepandemic PD control group (n= 117) that has never been exposed to any pandemic restrictions. All patients underwent three annual visits. The last analyzed in-person visit of the pandemic group occurred during the early pandemic phase, between September 2020 and March 2021. Motor and cognitive status were established through standardized in-person exams. Patients of the PD pandemic group selfrated their resilience and risk for posttraumatic stress disorder (PTSD) and, at visit 2 and 3, underwent the Olink panel of 92 serological inflammation markers. The primary outcome was motor PD progression as rated by the MDS-UPDRS part III score. The secondary outcomes were other progression scores (MDS-UPDRS I and II), cognitive performance (Montreal Cognitive Assessment), symptoms of depression (Beck Depression Inventory), risk for PTSD (revised Impact of Event Scale) and resilience (Brief Resilience Scale). Measures tested for statistical associations with these outcomes include demographic, lifestyle data and serological inflammation markers. To assess variable associations and correct effects from confounding factors, we used a multiple linear regression approach. Results The deterioration of the motor and cognitive scores from visit 1 to visit 3 was not different in the pandemic group compared to the prepandemic group. 74.7 % of the pandemic PD patients had normal or high resilience scores, whereas 20.3% were at risk of developing PTSD. Resilience was neither correlated with motor scores nor with cognitive scores but was negatively associated with depressive symptomatology and posttraumatic stress. Except for Axin-1, there was no increase in the inflammation markers at visit 3 compared to visit 2. Discussion This case-control study shows that there was no influence by the pandemic-induced stress on the natural progression of PD motor and cognitive trajectories.R-AGR-0592 - FNR - NCER-PD Phase II Coordination (01/06/2015 - 30/11/2023) - KRÜGER Rejko3. Good health and well-bein

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10−13, r2 = 8.9%, β = −0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with—but is statistically distinct from—the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10−37, r2 = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perceptio

Sensitivity of Genome-Wide-Association Signals to Phenotyping Strategy: The PROP-TAS2R38 Taste Association as a Benchmark

Natural genetic variation can have a pronounced influence on human taste perception, which in turn may influence food preference and dietary choice. Genome-wide association studies represent a powerful tool to understand this influence. To help optimize the design of future genome-wide-association studies on human taste perception we have used the well-known TAS2R38-PROP association as a tool to determine the relative power and efficiency of different phenotyping and data-analysis strategies. The results show that the choice of both data collection and data processing schemes can have a very substantial impact on the power to detect genotypic variation that affects chemosensory perception. Based on these results we provide practical guidelines for the design of future GWAS studies on chemosensory phenotypes. Moreover, in addition to the TAS2R38 gene past studies have implicated a number of other genetic loci to affect taste sensitivity to PROP and the related bitter compound PTC. None of these other locations showed genome-wide significant associations in our study. To facilitate further, target-gene driven, studies on PROP taste perception we provide the genome-wide list of p-values for all SNPs genotyped in the current study

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Strategies for the study of the trpX role in Streptomyces coelicolor

Objectifs spécifiques Le gène trpX est une petite orf de la souche Streptomyces coelicolor, qui code pour une protéine hypothétique de 63 acides aminés, TrpX, ayant à ce jour, aucune fonction connue. Ce gène est présent dans l’opéron trpA/B/X/C1, codant pour d’importantes protéines impliquées dans le pathway de la biosynthèse du tryptophane, un acide aminé aromatique. L’objectif spécifique de ce travail est l’étude du gène trpX dans la souche S. coelicolor. En particulier : 1) l’étude de l’expression du gène trpX dans la souche S. coelicolor, dans différentes phase de croissance et milieux de culture, par qRT-PCR. 2) l’analyse de la structure de la protéine TrpX, in silico, avec le programme informatique Robetta server. 3) effectuer des EMSAs sur les régions intergéniques de l’opéron trpA/B/X/C1, avec des extraits protéiques brutes des souche de S. coelicolor wt et de mutants trpX. 4) surexprimer et purifier la protéine TrpX produite dans une souche E. coli. 5) surexprimer le gène trpX dans la souche S. coelicolor Résultats Une analyse par Real-Time RT-PCR a montré que le gène trpX n’est pas exprimer constitutivement mais est dépendant de la phase de croissance. Une approche in silico et des analyses précédentes à ce travail, ont montrés que la protéine TrpX est un possible régulateur du gène trpB, un gène impliqué dans la biosynthèse du tryptophane et une prédiction de la stucture tridimensionnelle de TrpX a montré qu’il s’agit d’une protéine liant l’ADN. L’hypothèse la plus probable du rôle de la protéine TrpX dans S. coelicolor, est qu’elle lie une région intergénique de l’opéron trpA/B/X/C1, régulant l’expression génique du gène trpB. Cette hypothèse n’a pas été confirmée par les analyses effectuées durant ce travail (DNA binding assays), donc d’autres essais sont nécessaires, notamment des DNA or RNA binding assays avec des conditions différentes. La protéine His6-TrpX a été surproduite, avec succès, dans E. coli, et sa purification est, à l’heure actuelle, en cours. Cette protéine purifiée pourra être utilisée dans des DNA or RNA binding assays, afin de confirmer l’hypothèse émise précédemment. La surexpression du gène trpX dans S. coelicolor, permettant d’indiquer des voies, afin de comprendre la fonction de trpX n’as pas été obtenues, mais de nouvelles stratégies ont été étudiées et sont désormais en cours.The emergence of several pathogenic bacteria and the adaptation of part of those resistant to antibiotics currently used, in clinically treatments, needs the research for new antibiotic development and the creation of a “Superhost”, allowing a large scale production of antibiotics. Streptomyces belongs to Actinomycetes , a group of gram-positive bacteria, producing more than 50% of known antibiotics. To increase antibiotic level production in these organisms, the pathway of antibiotic precursors, like tryptophan, must be studied. The trpX gene is a little Streptomyces coelicolor orf, coding for a hypothetical 63-amino acids protein, TrpX , having, to date, unknown function. This gene is present in the trpA/B/X/C1 operon, coding for important enzymes involved in the tryptphan biosynthesis pathway, a aromatic amino acid. Real-Time RT-PCR analysis showed that trpX is not costitutively expressed during the growth in minimal medium, but is growth-phase dependent. In silico approaches and previous experiments have shown that TrpX protein is a putative regulator of the trpB gene, a gene involved in the tryptophan biosynthesis and a tridimentional structure prediction showed that TrpX protein could have a DNA-binding protein structure. The most probable hypothesis of the TrpX protein function in S. coelicolor, is that it binds to intergenic regions of the trpA/B/X/C1 operon, regulating the trpB gene expression. This hypothesis has not been confirmed by DNA binding assays carried out in this work, thus, further DNA or RNA binding assays are necessary. The His6-TrpX protein was successfully overproduced in E. coli, and its purification at present is in progress, it will be used in DNA or RNA binding assays, in order to confirm the previous hypothesis. The trpX gene overexpression in S. coelicolor, indicating ways to understand trpX function, has not been obtained, but new strategies at present are in progess

PATTERNA: transcriptome-wide search for functional RNA elements via structural data signatures

Establishing a link between RNA structure and function remains a great challenge in RNA biology. The emergence of high-throughput structure profiling experiments is revolutionizing our ability to decipher structure, yet principled approaches for extracting information on structural elements directly from these data sets are lacking. We present PATTERNA, an unsupervised pattern recognition algorithm that rapidly mines RNA structure motifs from profiling data. We demonstrate that PATTERNA detects motifs with an accuracy comparable to commonly used thermodynamic models and highlight its utility in automating data-directed structure modeling from large data sets. PATTERNA is versatile and compatible with diverse profiling techniques and experimental conditions