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Functional study of two flexible regions of the hepatitis E virus ORF1 replicase
No full textHepatitis E virus (HEV), like other positive-sense RNA viruses, encodes a multidomain protein essential for replication, termed ORF1. However, the number, organization, and functions of its domains remain debated. Using AlphaFold2-based structural modeling, we investigated two structurally disordered regions with potential regulatory functions: (i) a 16-residue linker between the Helicase (Hel) and RNA-dependent RNA polymerase (RdRp) domains, proposed as a cleavage site and/or a flexible hinge, and (ii) the RdRp C-terminal tail, suggested to modulate polymerase activity through conformational plasticity. We performed mutagenesis of the Hel/RdRp linker and analyzed the impact of mutations on ORF1 maturation, subcellular localization, and replication efficiency. Using an extensive antibody panel combined with precise protein sizing, we found that ORF1 is predominantly expressed as a full-length protein with an apparent molecular weight of ∼235 kDa by SDS-PAGE, together with several low-abundance truncated products, including the previously described HEV-derived SMAD activator (HDSA) fragment. These results suggest that ORF1 likely undergoes post-translational modifications and partial maturation by cellular proteases and/or spontaneous truncations in exposed regions. Importantly, Hel/RdRp linker mutations did not alter the ORF1 expression profile or subcellular localization, arguing against cleavage within this region. However, substitutions of conserved residues in the linker strongly impaired HEV replication, highlighting the functional importance of this disordered segment for viral genome replication. Similarly, deletions or substitutions within the last 20 C-terminal RdRp residues abolished or severely impaired HEV replication. This demonstrates that the conformational flexibility of the RdRp C-terminal segment is likely critical for ORF1 function, e.g. for polymerase activity. In conclusion, although ORF1 likely undergoes tightly regulated processing, cleavage is unlikely to occur within the Hel/RdRp linker. Nevertheless, this segment and the conformational dynamics of the RdRp C-terminus emerge as key regulatory elements required for efficient HEV replication, pointing to novel mechanistic layers of control in the HEV replication process
Bone Effects of Anti-Cancer Treatments in 2024
No full textInternational audienceConsiderable progress has been made in the management of cancer patients in the last decade with the arrival of anti-cancer immunotherapies (immune checkpoint inhibitors) and targeted therapies. As a result, a broad spectrum of cancers, not just hormone-sensitive ones, have seen several patients achieve profound and prolonged remissions, or even cures. The management of medium- and long-term side-effects of treatment and quality of life of patients are essential considerations. This is especially true for bone, as bone fragility can lead to increased fractures and loss of autonomy, ultimately reducing the possibility of resuming physical activity. Physical activity is essential for lasting oncological remission and prevention of fatigue. While the issue of hormone therapies and their association with breast cancer has been recognized for some time, the situation is relatively new with regards to targeted therapies and immunotherapies. This is particularly challenging given the wide range of available targeted therapies and their application to numerous cancer types. This article provides a comprehensive review of the bone effects of the main anti-cancer therapies currently in use. The review goes beyond glucocorticoids and hormone therapies and discusses for each drug category what is known regarding cellular effects, BMD effects, and fracture incidence
Indoor Microbiome in Asthma: A Differential Abundance Framework Accounting for Zero-Inflation, Compositionality, Spatial Clustering, and Covariate Adjustment
No full textInternational audienceWe investigated the relationship between indoor microbiome composition and asthma using differential abundance and network-based methods tailored for microbiome data. Zero-inflated beta regression and Poisson-lognormal graphical models were applied to household dust samples, adjusting for key environmental and demographic covariates. Several bacterial and fungal taxa were identified as asthma-associated, including both known and novel organisms. Our findings highlight microbial interaction patterns and lay the groundwork for robust analytical frameworks in epidemiological microbiome studies
Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling
No full textInternational audienceInfluenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies cis-aconitate (cisaco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. Cis-aco impairs viral polymerase activity, suppressing viral mRNA expression and protein synthesis to inhibit replication across a range of influenza subtypes. This antiviral efficacy is confirmed in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, cis-aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, cis-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu® is no longer effective. These findings position cis-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe
Expressive prosody in behavioral variant frontotemporal degeneration and late-onset psychiatric disorders.
No full textInternational audienceObjective: Neuropsychological assessment of social cognition has traditionally focused on mentalizing and emotions recognition. Recently developed digital measures allow clinicians to capture direct markers of abnormal social interactions, but they have not yet been used to distinguish neurological from psychiatric populations. This study examined prosodic alterations and explored structural neural correlates in behavioral variant frontotemporal degeneration (bvFTD) versus late-onset or atypical psychiatric disorders (LOAPD) and healthy controls (HCs). Method: We analyzed audio recordings from 31 patients with bvFTD, 15 patients with LOAPD, and 39 HCs across two speech samples: an anamnestic interview and a narrative task. Fundamental frequency (f0) metrics were extracted to assess between-group differences and to identify voxel-based morphometry correlates of prosodic alteration. Results: Compared with HCs, patients with bvFTD showed a reduced f0 range in both the anamnestic interview (p = .025, η2 = .09, 95% CI [–23.83, –1.04]) and the narrative task (p = .002, η2 = .14, 95% CI [–36.21, –4.74]). In the anamnestic interview, both bvFTD (p = .010, 95% CI [–36.59, –6.23]) and LOAPD (p = .012, 95% CI [–46.30, –8.81]) groups exhibited lower f0 variability than HCs; no differences were observed during the narrative task. In bvFTD, reduced prosodic measures correlated with atrophy in the left superior frontal gyrus and the right middle and inferior temporal gyri (p < .05, family-wise error corrected). Conclusions: Patients with bvFTD demonstrate a narrowed pitch span and reduced intonational variability, linked to disruptions in frontotemporal networks integrating emotional and semantic cues into speech. These findings highlight the relevance of prosodic alterations as a target for further research in bvFTD and assessment
Protocol to monitor activation of a two-component system in Dickeya dadantii during chicory leaf infection using Phos-tag gel
No full textInternational audienceProtocol to monitor activation of a two-component system in Dickeya dadantii during chicory leaf infection using Phos-tag gel Quantifying the phosphorylation levels of proteins involved in bacterial signaling pathways is essential for understanding their role in stress adaptation and infection processes. Here, we present a protocol for the semi-quantitative assessment of the phosphorylation level of the transcriptional regulator CpxR during the infection process using Phos-tag gel. We describe steps for Dickeya dadantii infection of chicory leaves, followed by bacterial extraction, rapid acidic cell lysis, and subsequent protein analysis using Phos-tag SDS-PAGE and western blot
Immune profiling in subclinical secondary dengue-infected cases reveals adaptive immune signatures correlated to protection from severe dengue
No full textInternational audienceDevelopment of strategies to prevent severe dengue has been challenging, partly by our incomplete understanding of a protective immune response after dengue virus (DENV) infection. To define adaptive immune signatures associated with protection from hospitalized dengue, we performed in-depth single-cell immunoprofiling and quantified DENV-specific T cells in subclinical or hospitalized dengue-infected children. Individuals with subclinical infection exhibit clonally expanded CD4+ TEMRA cells, increased frequency of DENV-specific CD4+ T cells, and demonstrate a gene expression signature of increased Treg functionality. Across all T cell subsets, subclinical cases upregulated a type I IFN response gene signature. In contrast, expanding CD8+ EM cells from hospitalized patients express more inhibitory markers and fewer cytotoxic proteins. In addition, hospitalized dengue is characterized by high frequencies and clonally expanded immunoglobulin G (Ig)G1-expressing plasmablasts. These findings identify candidate correlates of protection and support a rationale for T cell-directed interventions for dengue disease
Evaluation of the cobas plasma separation card to identify HIV-infected patients in virological failure in real-life conditions in Vietnam
No full textInternational audienceBackground The standard of care for HIV-infected patients on antiretroviral therapy (ART) relies on regular monitoring of HIV viral load. Access to viral load monitoring has improved in recent years, but remains scarce in some settings. Alternatives to plasma, such as dried specimens, can help bring routine viral load testing to remote settings. This study aimed to evaluate performances of the cobas® plasma separation card (PSC) to detect virological failure at the threshold of 1,000 copies/mL in real-life conditions in Vietnam. Setting Patients were enrolled in two hospitals in Hanoi (Vietnam). Methods This cross-sectional evaluation enrolled 250 HIV-infected adults using convenience sampling. All provided plasma and PSC samples. The sensitivity and specificity of PSC, as compared to plasma, to identify patients in virological failure were estimated. Convenience sampling was used to reach the target numbers of 150 and 100 patients with plasma viral load ≥ and <1,000 copies/mL, respectively. Results Overall, 250 patients were enrolled. Of the 127 (50.8%) patients with plasma viral load ≥1,000 copies/mL, the PSC viral load was also ≥1,000 copies/mL in 126 (sensitivity (95% confidence interval (CI)): 99.2% (95.7–99.9)). Of the 123 (49.2%) patients with plasma viral load <1,000 copies/mL, the PSC viral load was also <1,000 copies/mL in 108 (specificity (95% CI): 87.8% (80.7–93.0)). Overall, the concordance rate was 93.6%. Conclusions This field evaluation of the cobas® PSC showed its high effectiveness in identifying patients in virological failure. The specificity was 87.8%, lower than in previous reports. However, in cases of discrepancy, the PSC viral load level was never far from the 1,000 copies/mL threshold, which may be due to measurement error inherent to the technique
Vector competence of Aedes albopictus for Tonate virus highlights transmission risks in temperate and tropical regions
No full textInternational audienceRecent evidence of vertical transmission of Tonate virus (TONV) during early pregnancy and its association with fetal neurological anomalies highlights its potential public health threat. TONV is an understudied alphavirus endemic to French Guiana. The growing presence of Aedes (Ae.) albopictus in Europe raises concerns about its ability to transmit emerging arboviruses, including TONV. We assessed the vector competence of Ae. albopictus populations from mainland France and La Réunion Island via oral infections using different TONV doses. Both populations supported efficient viral replication, with infectious viral particles appearing in saliva by day 5 post-infection. Infection rate (IR), stepwise dissemination rate (sDR), and transmission efficiency (TE) increased with rising viral concentrations. At a viral concentration of 106 PFU/mL IR reached 80%, and TE at day 5 post-infection was 27% for the mainland strain and 37% for the La Réunion strain. Notably, TE declined over time in the mainland strain, while increasing progressively in the La Réunion population. Comparative infections with Chikungunya virus revealed that TONV was transmitted at similar or greater rates, confirming Ae. albopictus as a competent vector. Sequencing of mosquito organs revealed intra-host TONV genetic variability. A recurrent polymorphism at position 11,357 in the 3'UTR was detected in body tissues but not in heads of La Réunion mosquitoes, suggesting tissue-specific selection or bottlenecks. Our results demonstrate that Ae. albopictus from both tropical and temperate areas can efficiently transmit TONV and emphasize the importance of genomic surveillance to anticipate risk of its emergence in areas where this vector is established