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Unlocking TRPM7 Interactions: A Database-Driven Quest
No full textInternational audienceTransient receptor potential cation channel subfamily M member 7 (TRPM7) is a dual function protein comprising a non-selective cation channel and an atypical kinase domain. TRPM7 has been involved in many diseases including malignancies. Indeed, TRPM7 is proposed as a promising target for therapeutical drug design. Numerous studies have shown that TRPM7 interacts with proteins involved in regulating intracellular signaling. Therefore, a better understanding of the TRPM7 interactome would provide insight into pathophysiological mechanisms at the cellular and molecular levels. It could also open up new therapeutic avenues for molecules targeting either the proteins of interest directly or protein-protein interactions.In the first part of this work, we present the interaction partners described in the literature for TRPM7 and their potential impacts on cell biology. In the second part of the manuscript, we use public databases and protein interaction modeling tools to characterize the TRPM7 interactome. In particular, the analysis of the TRPM7 interactome using experimental data (BioGRID) and modeling tools (ProteinPrompt) has allowed us to isolate 19 genes of interest mainly related to small GTPase pathways involved in digestive neoplasia such as colorectal and pancreatic cancers.In summary, we provide an extended overview of potential TRPM7 interactors which need to be validated in cellular models. This will provide crucial insights into the molecular mechanisms at the tumor cell membrane, helping us to propose new therapeutic targets for precision medicine
Green cities and the risk for vector-borne disease transmission for humans and animals: a scoping review
No full textInternational audienceBackground: Greening cities is a nature-based strategy to sustainable urban development that integrates natural elements like plants or water bodies, to mitigate climate change impacts and enhance human well-being. However, urban green infrastructures (UGIs) can influence the distribution of disease vectors, potentially affecting vector-borne diseases (VBDs). UGIs may provide new suitable environments for urban vectors, while also creating opportunities to mitigate VBD risks through predation, competition, and dilution effects. This article examined the relationships between UGIs, vectors, and associated pathogens, impacting both human and animal health, highlighting knowledge gaps and identifying research priorities to support VBD risk mitigation measures and to guide smart urban planning and design. Methods: A systematic literature search was conducted following PRISMA guidelines in three databases (Pubmed, Scopus, Web of Science). Selected articles involved (i) any aspect of a urban vector system, (ii) in UGIs, and (iii) statistically analyzing the effects of UGIs on VBD risk. Methods employed to characterize UGIs and VBDs were described and the identified impacts were summarized by vector group. Results: Among the 99 articles reviewed, most addressed mosquito-pathogen systems (67) and tick-pathogen systems (29), with studies often confined to a single city or several cities within the same country and focused on one vector group. Urban vegetation generally appeared to heighten the risk of tick-borne diseases. In contrast, the influence of UGIs on the risk of mosquito-borne diseases varied depending on the vector system and on the environmental and climatic context. The diversity of indicators used to assess UGIs and VBD risks may affect the observed impact on VBD risk. Conclusion: Given the increasing popularity of urban greening, it is crucial to investigate its potential implications for public health, and thereby urban planning decisions. However, the lack of standardized protocols complicates the accurate assessment of the effects of UGIs on the risk for VBD emergence and transmission and consequently, on potential mitigation measures
Characterisation of the Novel <i>HLA-DQB1*05:356</i> Allele by Sequencing-Based Typing
No full textInternational audienceHLA-DQB1*05:356 differs from HLA-DQB1*05:03:01:01 by one nucleotide substitution in codon 14 in exon 2
Debulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: a retrospective cohort study
No full textInternational audienceNo abstract
Long-term patient-derived ovarian cancer organoids closely recapitulate tumor of origin and clinical response
No full textInternational audienceBackground: Ovarian cancers are the second cause of death from gynecological cancers worldwide, due to a late diagnosis combined with the development of resistance to chemotherapy. However, half of these cancers present alterations in Homologous Recombination (HR), making them sensitive to inhibitors of the PARP protein (PARPi), involved in DNA repair. Nevertheless, identifying patients who respond to chemotherapy and selecting those eligible for PARPi remains a challenge for clinicians. In this context, the use of Patient-Derived Tumor Organoids (PDTO) for predictive functional testing represents an interesting prospect for clinical decision making.Methods Here we established a panel of 37 long-term PDTO models of various histological subtypes from 31 ovarian cancer patients. Histological and molecular profiles of PDTO were compared to tumor sample of origin using immunohistochemical analyses and global approaches (copy number variation and transcriptomic profiling). PDTO models were exposed to standard drugs for ovarian cancer patients, including PARPi, and response was assessed using viability assay. To further define the HR status of PDTO, we performed a functional assay evaluating the ability of PDTO to initiate HR (RECAP test) using automated histo-imaging quantitative analysis of RAD51 foci, as well as an NGS analysis based on the sequencing of an HR-related genes panel to obtain a Genome Instability Score (GIS).Results: We demonstrated that PDTO mimicked histological and expression of tumor markers of paired tumors. Moreover, non-negative matrix factorization approach revealed that PDTO recapitulated the transcriptomic profile of the cancer component from their sample of origin. Screening of chemotherapeutic drugs showed that PDTO exhibit heterogeneous responses, and that response of PDTO from high-grade serous ovarian carcinoma to carboplatin recapitulated patient response to first-line treatment. Additionally, the detection of HRD phenotype of PDTO using functional assay was associated with the results of the HRD test Genomic Instability Scar (GIScar). Conclusion Although larger-scale investigations are needed to confirm the predictive potential of PDTO, these results provide further evidence of the potential interest of ovarian PDTO for functional precision medicine
Dermal trypanosomes in seropositive suspects of gambiense human African trypanosomiasis in Côte d’Ivoire
No full textInternational audienceIn the population at risk of gambiense human African trypanosomiasis (gHAT), the prevalence of extravascular parasite carriage remains unclear. Here, we conducted an observational clinical study in the hypo-endemic gHAT foci of Sinfra and Bonon in Côte d’Ivoire from 2019 to 2022. A total of 74 individuals were enrolled, including 45 suspects previously found positive at least once in a serological test for gHAT and followed by the national elimination programme of Côte d’Ivoire, as well as 29 seronegative controls. No significant differences between groups were observed for any epidemiological parameters and any clinical parameters at enrolment. Whereas trypanosome DNA was detected in the blood of 0/29 controls and 2/45 suspects, the presence of extravascular dermal trypanosomes was confirmed by immuno-histochemistry (fixed trypanosome cells) and/or PCR (trypanosome DNA) in about 1/3 of the suspects (14/45, 31%). However, no gambiense -specific test was found positive in the present study. Hence, the skin could represent an anatomical reservoir for African trypanosomes sustaining a low level of transmission in hypo-endemic foci
Genomic characterization of novel bat kobuviruses in Madagascar: Implications for viral evolution and zoonotic risk
No full textInternational audienceKobuviruses (family Picornaviridae , genus Kobuvirus ) are enteric viruses that infect a wide range of both human and animal hosts. Much of the evolutionary history of kobuviruses remains elusive, largely due to limited screening in wildlife. Bats have been implicated as major sources of virulent zoonoses, including coronaviruses, henipaviruses, lyssaviruses, and filoviruses, though much of the bat virome still remains uncharacterized. While most bat virus research has historically focused on immediately recognizable zoonotic clades (e.g., SARS-related coronaviruses), a handful of prior reports catalog kobuvirus carriage in bats and posit the role of bats as progenitors of downstream kobuvirus evolution. As part of a multi-year study, we carried out metagenomic Next Generation Sequencing (mNGS) on fecal samples obtained from endemic, wild-caught Madagascar fruit bats to characterize potentially zoonotic viruses circulating within these populations. The wild bats of Madagascar represent diverse Asian and African phylogeographic histories, presenting a unique opportunity for viruses from disparate origins to mix, posing a significant public health threat. Here, we report detection of kobuvirus RNA in Malagasy fruit bats ( Eidolon dupreanum ) and undertake phylogenetic characterization of Malagasy kobuvirus sequences, which nest within the Aichivirus A clade – a kobuvirus clade known to infect a wide range of hosts including humans, rodents, canids, felids, birds, and bats. Given the propensity of kobuviruses for recombination and cross-species transmission, further characterization of this clade is critical for accurate evaluation of future zoonotic threats
Clinical, Phenotypic and Genotypic Characteristics of Von Willebrand Disease in Afro‐Caribbeans: Results From a Study in Martinique Island, French West Indies
No full textInternational audienceABSTRACT Background Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); very few have focused on the Afro‐Caribbean population. Objectives To determine the genotypic and phenotypic characterization of VWD in a large cohort of Afro‐Caribbean patients living in Martinique. Materials and Methods A total of 31 families comprising 63 Afro‐Caribbean patients with VWD were enrolled. A standardized questionnaire and blood samples were collected for biological and molecular genetic analyses of von Willebrand factor (VWF). The impact of new missense variants has been predicted by in silico studies. Results The median age of patients was 53 years (range 9–99). The most frequent symptoms were menorrhagia (49%), easy bruising (44%) and prolonged bleeding after tooth extraction (42%). Fifteen patients (24%) had quantitative deficiencies of VWF, of whom 13 (21%) were assigned as VWD‐type 1, 1 (1%) as VWD‐type 1C and 1 (2%) as VWD‐type 3. Forty‐five patients were diagnosed with VWD‐type 2 (qualitative defects of VWF) (71%). VWD‐type 2A was the most frequent, with 36 patients. Seven patients had VWD‐type 2M and two patients had VWD‐type 2B. Three patients (5%) had an indeterminate effect of the VWF defect due to ISTH BAT at 0. Forty‐eight different VWF variants, including 4 novel variants, were identified in 63 patients. The variants consisted of 34 (71%) missense, 7 (15%) synonymous, 3 (6%) frameshifts, 2 (4%) small deletions and 2 (4%) gene conversions. Conclusions This study emphasizes the unique distribution of genotypes in our cohort of Afro‐Caribbean VWD patients living in Martinique. Essentials Genotype‐phenotype correlation was assessed in VWD Afro‐Caribbean patients with one or more VWF variants. Menorrhagia, easy bruising and prolonged bleeding after tooth extraction are common in VWD patients. Efforts to increase the awareness and diagnosis of VWD have contributed to a better identification of patients with bleeding disorders
Molecular Docking Observations on Enantiomeric Retention Trends and Selection of Chiral Stationary Phase
No full textInternational audienceThis study explores molecular docking as a predictive tool for enantiomeric separations in supercritical fluid chromatography, focusing on the binding mechanisms of chiral stationary phases. The enantiomeric separation of five chiral molecules and thalidomide was systematically evaluated using six polysaccharide‐based chiral stationary phases in supercritical fluid chromatography. The influence of chiral selector type (amylose vs. cellulose), chlorination, and mobile phase composition on enantioseparation was assessed. Maximum resolution values for compounds 1–5 ranged from 1.40 to 8.90, while thalidomide achieved a resolution of up to 11.45. Retention factors (k) varied between 2.85 and 12.38, depending on CSP interactions. To gain molecular‐level insights into enantioselective recognition, docking simulations using AutoDock Vina were performed, predicting binding affinities between −7.85 and −6.40. These predictions were systematically compared with experimental results to assess docking's reliability in capturing key retention descriptors. The study further characterized the absolute configurations of semipreparatively isolated enantiomers through X‐ray crystallography and optical rotation measurements, confirming stereochemistry and validating enantiomeric purity. By bridging computational modeling with experimental workflows, this study demonstrates the potential of molecular docking to support chromatographic method development, reducing reliance on trial‐and‐error optimization
Perceptions of tuberculosis and home-based infection screening among families and providers in Madagascar: a qualitative study
No full textInternational audienceBackground Madagascar is a country with a high tuberculosis (TB) burden, and the incidence of the disease has remained unchanged since 2013. TB detection largely relies on passive strategies, with little attention given to TB infections (TBIs), which are silent reservoirs that fuel future active TB cases.Method This qualitative study investigated how Malagasy communities perceive TB and an innovative approach for TBI screening and care. This approach was developed through the APRECIT operational research project in partnership with the National Tuberculosis Control Program (NTP). Semi-structured in-depth interviews were conducted between March and May 2023 with a sample of stakeholders and health workers (26 HWs) at the national, regional and community levels and focus groups with household contacts (46 HHCs) of TB patients.Results. The fight against TB remains challenging in Madagascar. Community knowledge of TB is limited, and the disease is perceived as shameful. Individuals with TB and their families face stigmatization within their own family and the community. At the provider level, HWs reported challenges in promptly detecting and treating TB people with TB due to structural constraints within the health system and barriers at the household (HH) level. The introduction of home-based screening for TBI was perceived as a way to interrupt disease progression and help reduce stigma. For HWs, this strategy helps to limit TB transmission. However, HWs expressed concerns about giving treatment to asymptomatic people and the replicability of the strategy at the national level. ConclusionImproving communication about TB and implementing a home-based screening strategy for HHCs to identify individuals at high risk of TB progression have the potential to improve TB control in Madagascar.</div