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Inhibition of influenza virus replication by artificial proteins (αReps) targeting its RNA-polymerase
No full textAbstract Seasonal epidemics and pandemics caused by influenza A viruses still represent a main public health burden in the world. Influenza viruses replicate and transcribe their genome in the nucleus of the infected cells, two functions that are supported by the viral RNA-dependent RNA-polymerase (FluPol) through extensive structural rearrangements and differential interactions with host cell factors. To get insights into its functioning, we screened a phage-display library of biosynthetic proteins (named αReps and build on a rigid alpha-helicoidal HEAT-like scaffold) against the structurally invariant FluPol core and several flexibly-linked domains of the FluPol PB2 subunit. Several αReps specific of the cap binding domain [CBD], the 627-domain and the NLS domain of the PB2 FluPol subunit displayed FluPol inhibitory and virus neutralization activities when transiently expressed in the cytosol. Furthermore, intracellular ectopic inducible expression of the αReps C3 and F3 (specific of the CBD and the 627-domain, respectively) in influenza virus permissive cells blocked transcription and multiplication of viruses representative of the H1N1, H3N2 and H7N1 subtypes, even when induced at late times post-infection. A synergic inhibitory effect on FluPol activity and virus multiplication was evidenced when the two αReps were covalently linked. These results suggest that i) interfering with FluPol structural rearrangements that are concomitant to its various activities may represent a promising strategy to block virus multiplication and to design new types of antivirals such as dual binders targeting distant sites on FluPol and ii) the 627-domain could be efficiently targeted to design influenza antivirals. Author Summary The influenza virus RNA-polymerase (FluPol) ensures genome transcription and replication in the nucleus of the infected cells. To select ligands able to interfere with FluPol functions, we screened a library of phages encoding biosynthetic proteins (named αReps) for binding to FluPol subunits and domains. When expressed intracellularly, several of them display efficient FluPol blocking and virus neutralizing activities. αReps C3 and F3 assembled through covalent linkages blocked FluPol activity more efficiently than their precursors. These αReps impaired multiplication of H1N1, H3N2 and H7N1 viruses, showing that their binding sites may constitute effective targets for new antiviral development
Mucin anchoring of SARS-CoV-2 neutralizing nanobinders increases intranasal antiviral efficacy
No full textAbstract Respiratory viruses represent a major threat for human health, and despite effectiveness to limit the severity of the disease, they fail to block transmission. Recent advances have shown that the nasal cavity is the primal infection site of respiratory viruses, and thus represents a very attractive target for prophylactic treatment with antivirals in order to limit virus dissemination. However, mucociliary clearance limits the efficiency of a local treatment in the nasal cavity. We have previously developed a potent anti-Spike nanobinder blocking SARS-CoV-2 entry. Here, it was used as a proof of concept to show the strength of anchoring this synthetic antiviral to the mucin layer with a mucin-binding domain, increasing its residence time in the nasal cavity up to 6 hours post-instillation. This was very effective as a prophylactic treatment to limit infection of sentinel hamsters. Our strategy could be extended to antivirals against other major respiratory viruses such as RSV or influenza viruses, but also in other diseases by targeting specific epithelia increasing residence time and local concentration of the drug
Deep Learning for the Early Diagnosis of Candidemia
No full textInternational audienceIntroduction: Candidemia carries a heavy burden in terms of mortality, especially when presenting as septic shock, and its early diagnosis remains crucial.Methods: We assessed the performance of a deep learning model for the early differential diagnosis between candidemia and bacteremia. The model was trained on a large dataset of automatically extracted laboratory features.Results: A total of 12,483 episodes of candidemia (1275; 10%) or bacteremia (11,208; 90%) were included. For recognizing candidemia, a deep learning model showed sensitivity 0.80, specificity 0.59, positive predictive value (PPV) 0.18, weighted PPV (wPPV) 0.88, and negative predictive value (NPV) 0.96 on the training set (area under the curve [AUC] 0.69), and sensitivity 0.70, specificity 0.58, PPV 0.16, wPPV 0.87, and NPV 0.95 on the test set (AUC 0.64). Then, the learned discriminatory ability was tested in the subgroup of patients with available serum β-D-glucan (BDG) and procalcitonin (PCT) values to explore additive or synergistic effects with these more specific markers. Both feature selection and transfer learning did not improve the diagnostic performance of a model based on BDG and PCT only.Conclusions: A deep learning model trained on nonspecific laboratory features showed some discriminatory ability to differentiate candidemia from bacteremia, highlighting the ability of deep learning to exploit complex patterns within nonspecific laboratory data. However, the learned patterns did not improve the diagnostic performance of more specific markers. Further exploration of candidemia prediction using laboratory features through machine learning techniques remains a promising area of research, serving as a valuable complement to the development of large-scale models that also incorporate clinical features
Pro-inflammatory processes and metabolic syndrome: combined risk of resistance to treatment in patients with schizophrenia from the FACE-SZ cohort
No full textInternational audienceSchizophrenia (SZ) is characterized by a variable clinical expression and course peppered/hampered by severe complications. In particular, resistance to treatment (overall-TRS, treatment resistant SZ including UTRS, ultra-TRS) and metabolic syndrome (MetS) are highly prevalent, and both demonstrated to be underpinned, at least partly, by pro-inflammatory processes. Given that such processes also underlie SZ per se , we hypothesized that potential inter-twinning between SZ-and MetS-related inflammatory processes may exert a combined effect on the risk of having overall-TRS/UTRS. A total of 419 outpatients with SZ underwent clinical assessments and blood sample collection. Using the values of circulating levels of eleven cytokines, we built a ratio between pro-and anti-inflammatory components respectively corresponding to the immunoinflammatory response system (IRS) and the compensatory immunoregulatory reflex system (CIRS) which overall reflect the underlying in-flammatory status. Such ratios allowed to categorize the patients according to Inflammation and MetS on four categories as follow: symbolscript symbolscript symbolscript and Inflam-mation(-)MetS(-). Multivariate logistic regression analysis showed that the combination of inflammation and MetS modulate the risk of having the overall-TRS symbolscript symbolscript 95 %CI [1.04-5.00], p symbolscript 0.039 and symbolscript symbolscript 95 % CI [1.76-11.97], p symbolscript 0.002 overall in comparison to Inflammation(-)MetS(-)]. Moreover, we observed that individuals with UTRS are those associated with both inflammation and/or MetS. Our results demonstrated the potential combined effect of MetS and inflammation towards resistance to treatment. Given that overall-TRS/UTRS are unpredictable while both inflammation and MetS can be early detected and managed, our findings shed new light on the possibility to better prevent treatment resistance in SZ
Genome-wide association study of copy number variations in Parkinson's disease.
No full textInternational audienceObjective: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. Methods: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. Results: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. Interpretation: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk
Left ventricular diastolic dysfunction is prevalent but not associated with mortality in patients with septic shock
No full textInternational audiencePurpose: Prognostic impact of left ventricular diastolic dysfunction (LVDD) in septic shock patients has not been determined using current diagnostic guidelines. We assessed the relation between LVDD during the first 3 days following intensive care unit (ICU) admission for septic shock and Day-28 mortality.Methods: This prospective, multicenter, observational study enrolled 402 patients (age: 63 ± 13 year; 59% male; SAPS II: 59 ± 20; SOFA: 9.4 ± 3.6; mechanical ventilation: 74%) with septic shock (Sepsis-3 definition). Patients were echocardiographically assessed within 12 h after admission (Day 1), on Day 2, Day 3, at ICU and at hospital discharge (or Day 28 whichever occurred first), using 2016 American-European guidelines.Results: LVDD was present at least once between Day 1 and 3 in 304 patients (76%), and in 56% and 44% of patients at ICU discharge and on Day 28 (or hospital discharge), respectively (43% of patients with follow-up). Seventy-eight of 172 patients (45%) exhibited similar LV diastolic properties throughout the study period while 58 patients (34%) improved their LVDD at follow-up (lower grade: n = 9, regression: n = 49). Day-28 mortality was not statistically different between patients with and without LVDD (80/304 [26%] vs. 25/88 [28%]; OR: 0.900 [0.530-1.527]; p = 0.696). Similar results were obtained when adjusting the multivariate model on SAPSII or SOFA score on admission, together with fluid balance during the first three days of ICU stay (OR: 0.838 [0.471-1.491]: p = 0.547 and OR: 0.887 [0.513-1.534]: p = 0.668, respectively).Conclusion: LVDD was highly prevalent in patients with septic shock but not associated with mortality. It appeared improving in one-third of survivors
Why governments want to learn about citizens’ preferences. Explaining the representational logic behind government polling
No full textInternational audienceAssessing empirically to what extent citizens’ preferences are considered during the elaboration of public policy remains a challenge for political science research, even though it concerns one of the central pillars of modern democracies. Governments in most democracies make extensive use of public opinion research, especially in times of multiple crises. However, we do not know much about the way they mobilize this resource. While recent research examines the factors that determine the intensity of government polling at different moments of the electoral cycle and the different logics of representation behind this activity (Durovic and Schnatterer 2023), empirical evidence on the more qualitative aspect of government polling is still lacking. What types of policy issues are covered by government polls? Why are some topics overrepresented at the expense of others? Our paper sheds light on issue selection in government-commissioned opinion polls. Understanding governments as actors in the production of public opinion, not just as passive consumers, we study government polls as dependent variable. Public opinion is often considered as a possible actor in the process of the emergence of new issues. In all these models, public opinion is regarded as an exogenous entity that is known to the researcher (or at least can be measured) and, as far as we know, there is no single study on the political agenda of survey opinion. If we consider, however, that public opinion, at least in its surveyed form, is itself a social construction, it becomes necessary to focus as a first step on the political agenda of opinion polls and their agenda-setting dynamics. To do this, we develop an innovative research design and systematically analyze the factors that determine why an issue makes it onto the government's agenda. We present evidence from Germany, mobilizing an original database of all survey questions directly commissioned by the German federal government during the 18th and 19th legislative periods (2013-2021). Using a conditional logit approach, we analyze how different types of issues (regulatory, distributive and redistributive), the interest group density in the policy domain and institutional constraints in the German federal system affect the likelihood that policy issues are covered by government polls. We also control for government priorities, different types of salience (national, personal and media salience) and issue ownership by government. Our findings show that the commissioning of public opinion polls by governments takes place in a competitive environment, and that governments are torn between citizen priorities, interest group lobbying, and institutional constraints
Long-term health in individuals born preterm or with low birth weight: A cohort study
No full textInternational audienceBackgroundTo measure the association of prematurity and non-preterm low birth weight (LBW) with several long-term health outcomes. MethodsWe selected adult participants from the Constances cohort. Associations between preterm birth (= 37 weeks) and outcomes were measured using modified Poisson regression with adjustment for participant age and parental history. We used the same modeling methods to measure the association between LBW (i.e., ResultsAmong 30,295 participants, preterm birth (5.2%) was associated with (RR[CI95]): obesity (1.25[1.08-1.46]), hypertriglyceridemia (1.23[1.07-1.42]), high LDL-cholesterol (1.16[1.05-1.28]), high blood pressure (HBP) (1.22[1.08-1.36]), metabolic syndrome (1.35[1.06-1.71]), non-alcoholic fatty liver disease (1.26[1.08-1.47]), allergic and atopic symptoms (1.06[1.01-1.12]), and lack of tertiary education (1.11[1.02-1.20]). Women had a significantly higher risk of hypertriglyceridemia and metabolic syndrome. In non-preterm participants, LBW was associated with prediabetes/diabetes (1.30[1.12-1.52]), HBP (1.22[(1.12-1.33]) and lack of tertiary education (1.13[1.07-1.20]), whereas the risk of obesity (0.83[0.73-0.95]) and abdominal obesity (0.84[0.76-0.93]) was reduced. ConclusionPreterm birth and non-preterm LBW are both risk factors for several adult outcomes. However, regarding excess fat storage, their long-term effect seems to be in the opposite direction. Impact statementPreterm birth is associated with a higher long-term risk of obesity, whereas low birth weight is not.This study improves the understanding of the common idea that low birth weight is associated with a long-term risk of obesity, whereas it might depend on the cause of low birth weight.These findings provide new insights into the difficult distinction between the long-term adverse health effects of preterm birth and low birth weight
From research misconduct to disciplinary sanction: an empirical examination of French higher education case law
No full textInternational audienceReporting and investigating research misconduct can lead to disciplinary proceedings being initiated, and ultimately to disciplinary sanctions being imposed on convicted scientists. The conversion of research misconduct findings into disciplinary sanctions is poorly understood. This article analyses all the disciplinary decisions handed down on appeal by the Conseil national de l'enseignement supérieur et de la recherche (CNESER) between 1991 and 2023, concerning breaches of research integrity by academics and doctoral students (n=333). Three findings are highlighted. Firstly, the article describes how the CNESER sanctioned research misconduct even before the notion of research integrity became part of French law, by monitoring scientists' compliance with “deontological rules”. Secondly, we show that assessing disciplinary fault involves evaluating a much broader set of circumstances than the mere existence of research misconduct, which can explain why the latter do not result in disciplinary sanctions or lighter sanctions. Thirdly, the research highlights situations where research misconduct is intertwined with other allegations, blurring the relative importance of these motives in the awarding of disciplinary sanctions. The article concludes with a call for greater accessibility to the disciplinary decisions handed down by universities in the first instance, as a key next step in gaining a better understanding of the disciplinary response to research misconduct