Explore the vast range of titles available.

Ralstonia solanacearum is one of the most devastating bacterial plant pathogens due to its large host range, worldwide geographic distribution and persistence in fields. This soilborne pathogen is the causal agent of bacterial wilt and it can infect major agricultural crops thereby reducing significantly their yield. To favor infection, the bacterium delivers, through the type three secretion system, effectors that manipulate plant immunity. In this review, the relative efficiency of control strategies and existing resistances to R. solanacearum will be presented. Then, the genetic and molecular insights gained from the study of bacterial wilt in model plants will be described. Finally, I will explore how the knowledge gathered from unraveling avirulence and virulence mechanisms of R. solanacearum effectors could help to develop more durable resistances in crop plants toward this destructive pathogen.

Phenolic glycolipids are produced by a very limited number of slow-growing mycobacterial species, most of which are pathogen for humans. In Mycobacterium tuberculosis, the etiologic agent of tuberculosis, these molecules play a role in the pathogenicity by modulating the host immune response during infection. The major variant of phenolic glycolipids produced by M. tuberculosis, named PGL-tb, consists of a large lipid core terminated by a glycosylated aromatic nucleus. The carbohydrate part is composed of three sugar residues, two rhamnosyl units and a terminal fucosyl residue, which is per-O-methylated, and seems to be important for pathogenicity. While most of the genes responsible for the synthesis of the lipid core domain and the saccharide appendage of PGL-tb have been characterized, the enzymes involved in the O-methylation of the fucosyl residue of PGL-tb remain unknown. In this study we report the identification and characterization of the methyltransferases required for the O-methylation of the terminal fucosyl residue of PGL-tb. These enzymes are encoded by genes Rv2954c, Rv2955c and Rv2956. Mutants of M. tuberculosis harboring deletion within these genes were constructed. Purification and analysis of the phenolglycolipids produced by these strains, using a combination of mass spectrometry and NMR spectroscopy, revealed that Rv2954c, Rv2955c and Rv2956 encode the methyltransferases that respectively catalysed the O-methylation of the hydroxyl groups located at positions 3, 4 and 2 of the terminal fucosyl residue of PGL-tb. Our data also suggest that methylation at these positions is a sequential process, starting with position 2, followed by positions 4 and 3.

Accurate serological tools are essential for monitoring the transmission of arboviruses with pandemic potential, yet cross-reactivity between closely related viruses hampers diagnostics and surveillance. Here, we develop a high-throughput multiplex serological assay to quantify antibody responses to 28 antigens from nine arboviruses (dengue, Zika, yellow fever, West Nile, Usutu, Japanese encephalitis, chikungunya (CHIKV), Mayaro (MAYV), and O’nyong-nyong virus) and apply it to over 4000 samples from epidemiologically distinct sites on four continents. We implement a flexible analytical method based on Bayesian finite mixture models and Receiver Operating Characteristic analysis to evaluate assay performance and define seropositivity thresholds. As a case study, we resolve cross-reactive and virus-specific responses for CHIKV and the emerging MAYV by combining competitive immunoassays with mathematical modelling of multiplex serological and epidemiological data. This approach yields cross-reactivity-adjusted estimates of local transmission dynamics, in agreement with existing epidemiological evidence, and reveals that CHIKV is more prone to induce cross-reactive antibody responses than MAYV. Our results demonstrate the power of combining multiplex serology with experimental validation and modelling to disentangle exposure histories in the face of serological cross-reactivity. This integrative approach holds promise for improving arbovirus surveillance, particularly in settings with overlapping transmission of multiple viruses and limited diagnostic capacity. Arboviruses often co-circulate, but cross-reactivity hampers serological diagnostics. Here, the authors paired multiplex serology with competitive immunoassays and Bayesian modelling to quantify antibody cross-reactivity and extract virus-specific signals from exposure data, enabling reconstruction of transmission dynamics.

AbstractObjectiveTo investigate whether oral ivermectin or topical 5% permethrin can clinically cure scabies in index cases and in members of their households.DesignMulticentre, assessor blinded, cluster randomised clinical trial.Setting28 French hospitals, 19 January 2016 to 16 December 2021.ParticipantsIndex cases; adults and children weighing >15 kg with scabies, confirmed by dermoscopy.InterventionsIndex cases were randomly assigned to the ivermectin group or permethrin group (1:1 ratio). Each member of the cluster, defined as the household of each index case, received the same treatment as the index case, except for children weighing <15 kg who were prescribed topical 5% permethrin. All participants received oral ivermectin 200 µg/kg or 5% permethrin cream on day 0 and day 10. Permethrin cream was applied to the whole body, from head to toe.Main outcome measuresThe primary outcome was clinical cure of the cluster on day 28 (ie, disappearance of clinical signs and symptoms of scabies for all cluster members). Secondary outcomes were index case and individual level analyses and safety. Dermatologists were used as assessors and were masked to the treatment.Results507 participants in 142 households (clusters) were treated with ivermectin and 568 participants in 147 households received permethrin. Cluster level cure rates were 71.8% versus 88.5% (–16.7 percentage point difference, 95% confidence interval (CI) –26.3 to –7.1) for ivermectin versus permethrin. Secondary outcome percentage point differences also showed the inferiority of ivermectin compared with 5% permethrin for index cases (76.6% v 91.5%; percentage point difference –14.9, 95% CI –23.6 to –6.2) and participants (85.3% v 94.2%; –9.2 percentage point difference, –14.9 to –3.5). Intraclass correlation coefficients were higher for permethrin than ivermectin for all clusters (0.68, 95% CI 0.61 to 0.75 v 0.46, 0.37 to 0.56) and for cluster size >1 (0.67, 0.60 to 0.74 v 0.47, 0.37 to 0.56). Cutaneous adverse events were found in 11.9% and 15.6% of participants treated with ivermectin and permethrin, respectively.ConclusionsThe results of this cluster randomised trial of classic scabies, confirmed by dermoscopy, did not show the non-inferiority of oral ivermectin compared with 5% permethrin cream, given on days 0 and 10, in achieving clinical cure of scabies on day 28 in index cases and their household members. Conversely, the trial showed the statistical superiority of 5% permethrin cream.Trial registrationNCT02407782.

Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse.

Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.

BackgroundLevodopa equivalent dopaminergic dose (LEDD) reduction after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease varies widely. Identifying predictors may guide patient selection and programming. Our objectives were to identify predictors of LEDD reduction and to test whether motor improvement mediates this association.MethodsData from 144 patients treated by STN-DBS were analysed. Predictors of LEDD reduction were selected using the Boruta algorithm, a machine-learning method comparing variable importance to randomised features and then tested in a structural equation model for direct and motor-mediated effects.ResultsMean LEDD reduction was 41.7% (±38.2%) and motor improvement was 48.6% (±26.7%) at 1 year. Among the four predictors identified by Boruta, lower baseline LEDD (β=0.39, p=0.001), greater axial impairment (β=−0.25, p=0.003) and higher total volume of tissue activated (β=−0.17, p=0.031) were directly associated with lower LEDD reduction, independent of motor improvement. Sensorimotor STN overlap was not directly linked to LEDD reduction but was positively associated with motor improvement (β=0.34, p=0.001), which showed a trend-level effect on LEDD reduction (β=0.16, p=0.065). The total effect of sensorimotor STN overlap on LEDD reduction was not significant.DiscussionDopaminergic dose reduction after STN-DBS is constrained by preoperative axial symptoms and stimulation spread, independently of motor improvement, while sensorimotor STN overlap improves motor symptoms but not dose reduction. Integrating motor phenotype with anatomical guidance may enhance medication management post DBS.

Ten different French emmental (E1-E10) cheeses (foil packed portions) were evaluated in seven sensory panel sessions. In each session, 34 cheeses were evaluated by sensory profiling. One was chosen as control cheese (T) and presented again in each session. The selected cheeses were the most relevant ones in this market segment. They were bought from food stores, standardising where possible their age (time until best before date).