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In the field of rheumatic diseases, prospective individual-level data on (prevalent) cohorts of patients over a long period of time are collected. One of the many uses of such data is to investigate mortality. Excess mortality, time trends (temporal variation) in mortality rates, life expectancy and life years lost of patients, and risk factors for mortality may all be of interest. In this article, we show how careful application of Poisson and Cox relative risk regression models can be used to tackle these questions, illustrating the methods with cohort data from patients with systemic lupus erythematosus and psoriatic arthritis. For external comparisons of a cohort with a standard (or reference) population, Poisson regression can be used to generalize the usual standardized mortality ratio (SMR) analyses. For assessing the pattern of (excess) mortality over time, unadjusted and adjusted “rolling average” SMRs are developed and shown to provide further insight concerning an observed decline in SMR over time for psoriatic arthritis patients. An extension of the traditional life expectancy and years of life lost calculations is also derived. For comparisons within a cohort, we demonstrate how Cox regression models can incorporate time measured on a variety of scales to allow the identification of a calendar time decline in mortality risk for lupus patients which is demonstrably independent of possible declines with disease duration and/or time in clinic and of other disease related explanatory variables. [ABSTRACT FROM AUTHOR]

Many neurodegenerative diseases are characterized by ubiquitin-positive protein aggregates or inclusion bodies. Ubiquitin-conjugated proteins are degraded by the 20/26S proteasome, and reduced proteasome peptidase activities in brain homogenates have been reported in pathologic lesions of Parkinson's and Alzheimer's diseases. However, it is unknown whether crude extracts of human brain contain other proteases having peptidase activities. We found a novel pro-tease of molecular weight of approximately 105 kDa in normal human brain, which exhibited trypsin-like (T-L) and chymotrypsin-like (ChT-L) activities (corresponding to 52% and 21% of the total activities in crude extracts) but not peptidyl glutamyl peptide hydrolase activity. Both T-L and ChT-L activities of this protease were partially inhibited by proteasome inhibitors (MG132, lactacystin) and, in contrast to those of the proteasome, also by sodium dodecyl sulfate. A simple method to obtain a brain fraction specific to the 20/26S proteasome was developed. Our human brain data suggest that T-L and ChT-L activity levels of the proteasome reported previously may include those of the 105 kDa protease, an enzyme of as yet unknown biological significance, and that it is necessary to separate the proteasome from this protease to evaluate the actual status of the ubiquitin-proteasome system in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

This study examines the resting and exercise hemodynamic performance of the pulmonary autografts in the aortic position as well as of the homografts used for right ventricular outflow reconstruction in patients undergoing the Ross operation. Previous studies have reported excellent resting hemodynamics in patients who underwent aortic valve replacement with a pulmonary autograft. However, there are very few studies of their hemodynamic performance during exercise. Twenty adult subjects who underwent the Ross operation and 12 normal control subjects were submitted to maximum romp bicycle exercise. The valve effective orifice areas and transvalvular gradients of both aortic (autograft) and pulmonary (homograft) valves were measured at rest and at peak of maximum exercise using Doppler echocardiography. Valve areas were indexed for body surface area. The hemodynamics of the aortic valve were very similar in Ross subjects and in control subjects at rest and during exercise. However, the indexed valve area of the pulmonary valve at rest was significantly (p < 0.001) lower in the Ross subjects (1.10 +/- 0.46 cm2/ m2) than in the control subjects (1.95 +/- 0.41 cm2/m2), resulting in higher (p = 0.004) mean gradients at rest (Ross: 9 +/- 7 mm Hg vs control: 2 +/- 1 mm Hg) and at peak exercise (Ross: 21 +/- 14 mm Hg vs control: 7 +/- 2 mm Hg). The pulmonary autograft provided excellent hemodynamics in the aortic position either at rest or during maximum exercise, whereas moderately high gradients were found during exercise across the homograft implanted in the pulmonary valve position. Future improvement of the Ross procedure should be oriented toward the search of new methods to prevent the deterioration of the homografts. [ABSTRACT FROM AUTHOR]

PARP inhibitors (PARPi) have been shown to improve progression-free survival, particularly in homologous recombination deficient (HRD) ovarian cancers. Identifying patients eligible to PARPi is currently based on next-generation sequencing (NGS), but the persistence of genomic scars in tumors after restoration of HR or epigenetic changes can be a limitation. Functional assays could thus be used to improve this profiling and faithfully identify HRD tumors. The RECAP test assesses the formation of RAD51 foci in proliferating cells after irradiation and can be used on tumors as well as on patient-derived tumor organoids (PDTO). However, RAD51 foci scoring is often performed manually without standardization. The purpose of this translational study was to develop an automated tool for scoring RAD51-mediated HR based on whole slide imaging of ovarian PDTO. To that end, we quantified Cyclin A2 and RAD51 immunofluorescence on 9 PDTO models derived from 8 ovarian cancer patients and next compared RECAP test results to genome instability score (GIScar) and to the patient clinical response. We therefore developed a standardized and automatized quantitative histo-imaging tool allowing a comparative RAD51 foci evaluation and thus to define the HR status in PDTO. Our RECAP-based classification was correlated to the GIScar score, offering a new opportunity for standardization of HR assessment in PDTO. This new automated tool to score HR status, that remains to be validated on a large cohort of patients, may thus be used as a complement to NGS-based tests in order to improve the identification of the number of patients eligible to PARPi., (Copyright © 2025. Published by Elsevier Inc.)

Fossils and other preserved specimens are integral for informing timing and evolutionary history in every biological system. By isolating a plant pathogen genome from herbarium-preserved diseased grapevine material from 1906 (Herb&#95;1906), we were able to answer questions about an enigmatic system. The emergence of Pierce's disease (PD) of grapevine has shaped viticultural production in North America; yet, there are uncertainties about the geographic origin of the pathogen (Xylella fastidiosa subsp. fastidiosa, Xff) and the timing and route of its introduction. We produced a high-quality, de novo genome assembly of this historical plant pathogen and confirmed degradation patterns unique to ancient DNA. Due to the inclusion of the Herb&#95;1906 sample, we were able to generate a significant temporal signal in the genomic data. This allowed us to build a time-calibrated phylogeny, where we estimate the introduction of Xff into the US between 1734 and 1741 CE, an earlier time frame than previously inferred. In a large collection of >300 Xff genomes, the Herb&#95;1906 sample was genetically most similar to a small population from Northern California but not basal to the entire Xff California clade. Based on phylogenetic placement and a phylogeographic reconstruction, our data support a single introduction of Xff into the Southeastern US from Central America, with multiple subsequent introductions into California., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bacterial canker of tomato caused by the Gram-positive corynebacterial species Clavibacter michiganensis is one of the most destructive seed-borne diseases in both open air and greenhouse tomatoes. The pathogen is a regulated agent in all tomato-producing countries as translocation of infected tomato materials transports the bacterium into new areas. Clavibacter michiganensis is generally known to have yellow-pigmented colonies on culture media, which is a key differentiative phenotypic feature in standard diagnostic guidelines. During 2020 and 2021, pink-pigmented corynebacterial strains were isolated from tomato seeds (cv. Sun 6189F1) and plants showing severe canker symptoms in Southern Iran. The six pink-pigmented strains were pathogenic on tomato and pepper seedlings under greenhouse conditions, and gave positive results with C. michiganensis -specific primers pairs described in the literature. Phylogenomics and DNA similarity calculations showed that the pink-pigmented strains were highly similar to the authentic yellow-pigmented members of the pathogen. Thus, they were identified as a new phenotypic variant of tomato bacterial canker pathogen. Whole genome screenings accomplished with PCR-based assays showed that the pink strains contain all pathogenicity determinant genes described in C. michiganensis . Further, orthologous gene clusters in the pink-pigmented strains were more similar to the pathogenic members of C. michiganensis than to those of non-pathogenic tomato-associated Clavibacter species. Results obtained in this study demonstrate the emergence of a new pink-pigmented variant of C. michiganensis and highlight the importance of colony pigmentation/morphology in culture-based detection of the bacterium. The need for updating diagnostic guidelines on the colony variants of the pathogen is further discussed.

The Western Mediterranean coast is under the influence of anthropogenic pressures, including land use, increasing amounts of dangerous waste and habitat destruction. In 2021, the French RINBIO network (http://www.ifremer.fr/envlit/) originally dedicated to assess chemical contamination in the region, focused on biological effects produced by contaminants and the interaction with natural variability in mussels using an active caging strategy. Cell and tissue level biomarkers were applied for 17 sampling sites divided in three sub-regions categorized by different environmental conditions. Results provide critical information for ecosystem health assessment using mussels as sentinel species in the Western Mediterranean Sea. The influence of natural and confounding factors (trophic condition, reproductive cycle, caging strategy), on biological responses to mild chemical contamination, was discussed and discriminated for health status assessment. Results provide valuable data available as reference values for the assessment of biomarkers and histopathological alterations for large-scale active biomonitoring campaigns in the Western Mediterranean Sea., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Xanthomonas citri pv. fuscans ( Xcf ) and Xanthomonas phaseoli pv. phaseoli ( Xpp ) are responsible for the Common Bacterial Blight (CBB), a major common bean ( Phaseolus vulgaris ) disease. The pathogenicity of Xcf and Xpp is known to be dependent upon a functional Type III Secretion System (T3SS) allowing the injection of numerous bacterial Type III Effectors (T3Es) into plant cells. T3Es have been described as able to disrupt plant defence and manipulate plant metabolism. In this work we described the transcriptomic response of one susceptible (Flavert) and one resistant (Vezer) cultivars of P. vulgaris to the inoculation of the virulent strain Xcf CFBP4885 or its avirulent T3SS-defective hrcV mutant (CFBP13802). Leaves of both bean cultivars were infiltrated with water or bacterial suspensions. Inoculated leaves were sampled at 24 or 48 h post inoculation (hpi). The experiment was independently repeated three times for total RNA extraction and sequencing analysis. Library construction and total RNA sequencing were performed with BGISEQ-500 at Beijing Genomics Institute (BGI, Hong-Kong), generating an average of 24M of paired-end reads of 100bp per sample. FastQC was used to check reads quality. Mapping analyses were made using a quasi-mapping alignment from Salmon (version 1.2.1) against the Phaseolus vulgaris reference genome (version 2.1), revealing the expression profiles of 36,978 transcripts in leaf tissues. Fastq raw data and count files from 36 samples are available in the Gene Expression Omnibus (GEO) repository of the National Center for Biotechnology Information (NCBI) under the accession number GSE271236. This dataset is a valuable resource to investigate the role of T3Es in subverting the cellular functions of bean., (© 2024 Published by Elsevier Inc.)

Although seed represents an important means of plant pathogen dispersion, the seed-pathogen dialogue remains largely unexplored. A multiomic approach was performed at different seed developmental stages of common bean (Phaseolus vulgaris L.) during asymptomatic colonization by Xanthomonas citri pv. fuscans (Xcf), At the early seed developmental stages, we observed high transcriptional changes both in seeds with bacterial recognition and defense signal transduction genes, and in bacteria with up-regulation of the bacterial type 3 secretion system. This high transcriptional activity of defense genes in Xcf-colonized seeds during maturation refutes the widely diffused assumption considering seeds as passive carriers of microbes. At later seed maturation stages, few transcriptome changes indicated a less intense molecular dialogue between the host and the pathogen, but marked by changes in DNA methylation of plant defense genes, in response to Xcf colonization. We showed examples of pathogen-specific DNA methylations in colonized seeds acting as plant defense silencing to repress plant immune response during the germination process. Finally, we propose a novel plant-pathogen interaction model, specific to the seed tissues, highlighting the existence of distinct phases during seed-pathogen interaction with seeds being actively interacting with colonizing pathogens, then both belligerents switching to more passive mode at later stages., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Aging is characterized by several major changes, including altered body composition, which is associated with numerous negative clinical consequences such as sarcopenia, osteoporosis, and frailty. The study is to evaluate body composition parameters depending on age and sex in a population ranging from the young adult to the very old, and to identify break points in the association between body composition and age. In this cross-sectional study, we included the enrolment population of the French INSPIRE-T prospective cohort, accounting for 915 subjects (62% female). Age ranged from 20 to 93 years, median age (years) was 63 (IQR 27). Body composition (lean mass, fat mass, and bone mineral content) was assessed with dual-X-ray absorptiometry (DXA). Different break points in the relationship between age and body composition variables in males and females were identified using a segmented regression analysis adjusted on physical activity, nutritional status, educational level, and comorbidities. Lean mass decreased from the age of 55 years for males (CI 95% 44-66) and 31 years for females (CI 95% 23-39). For fat mass, we observed a trend towards an increase with age for males. For females, we observed an increase with age up to age 75 (CI 95% 62-86), followed by a decreasing trend. In this study, we described the relationship between body composition and age as a function of sex, establishing a foundation for further studies on predictive biomarkers of age-related body composition alteration., (© 2024. The Author(s).)

Background: Ovarian cancer is the first cause of death from gynecological malignancies mainly due to development of chemoresistance. Despite the emergence of PARP inhibitors, which have revolutionized the therapeutic management of some of these ovarian cancers, the 5-year overall survival rate remains around 45%. Therefore, it is crucial to develop new therapeutic strategies, to identify predictive biomarkers and to predict the response to treatments. In this context, functional assays based on patient-derived tumor models could constitute helpful and relevant tools for identifying efficient therapies or to guide clinical decision making., Method: The OVAREX study is a single-center non-interventional study which aims at investigating the feasibility of establishing in vivo and ex vivo models and testing ex vivo models to predict clinical response of ovarian cancer patients. Patient-Derived Xenografts (PDX) will be established from tumor fragments engrafted subcutaneously into immunocompromised mice. Explants will be generated by slicing tumor tissues and Ascites-Derived Spheroids (ADS) will be isolated following filtration of ascites. Patient-derived tumor organoids (PDTO) will be established after dissociation of tumor tissues or ADS, cell embedding into extracellular matrix and culture in specific medium. Molecular and histological characterizations will be performed to compare tumor of origin and paired models. Response of ex vivo tumor-derived models to conventional chemotherapy and PARP inhibitors will be assessed and compared to results of companion diagnostic test and/or to the patient's response to evaluate their predictive value., Discussion: This clinical study aims at generating PDX and ex vivo models (PDTO, ADS, and explants) from tumors or ascites of ovarian cancer patients who will undergo surgical procedure or paracentesis. We aim at demonstrating the predictive value of ex vivo models for their potential use in routine clinical practice as part of precision medicine, as well as establishing a collection of relevant ovarian cancer models that will be useful for the evaluation of future innovative therapies., Trial Registration: The clinical trial has been validated by local research ethic committee on January 25th 2019 and registered at ClinicalTrials.gov with the identifier NCT03831230 on January 28th 2019, last amendment v4 accepted on July 18, 2023., (© 2024. The Author(s).)

The classical lineage of Mycobacterium ulcerans is the most prevalent clonal group associated with Buruli ulcer in humans. Its reservoir is strongly associated with the environment. We analyzed together 1,045 isolates collected from 13 countries on two continents to define the evolutionary history and population dynamics of this lineage. We confirm that this lineage spread over 7,000 years from Australia to Africa with the emergence of outbreaks in distinct waves in the 18th and 19th centuries. In sharp contrast with its global spread over the last century, transmission chains are now mostly local, with little or no dissemination between endemic areas. This study provides new insights into the phylogeography and population dynamics of M. ulcerans, highlighting the importance of comparative genomic analyses to improve our understanding of pathogen transmission., Importance: Mycobacterium ulcerans is an environmental mycobacterial pathogen that can cause Buruli ulcer, a severe cutaneous infection, mostly spread in Africa and Australia. We conducted a large genomic study of M. ulcerans , combining genomic and evolutionary approaches to decipher its evolutionary history and pattern of spread at different geographic scales. At the scale of villages in an endemic area of Benin, the circulating genotypes have been introduced in recent decades and are not randomly distributed along the river. On a global scale, M. ulcerans has been spreading for much longer, resulting in distinct and compartmentalized endemic foci across Africa and Australia., Competing Interests: The authors declare no conflict of interest.

Synthetic Communities (SynComs) are being developed and tested to manipulate plant microbiota and improve plant health. To date, only few studies proposed the use of SynCom on seed despite its potential for plant microbiota engineering. We developed and presented a simple and effective seedling microbiota engineering method using SynCom inoculation on seeds. The method was successful using a wide diversity of SynCom compositions and bacterial strains that are representative of the common bean seed microbiota. First, this method enables the modulation of seed microbiota composition and community size. Then, SynComs strongly outcompeted native seed and potting soil microbiota and contributed on average to 80% of the seedling microbiota. We showed that strain abundance on seed was a main driver of an effective seedling microbiota colonization. Also, selection was partly involved in seed and seedling colonization capacities since strains affiliated to Enterobacteriaceae and Erwiniaceae were good colonizers while Bacillaceae and Microbacteriaceae were poor colonizers. Additionally, the engineered seed microbiota modified the recruitment and assembly of seedling and rhizosphere microbiota through priority effects. This study shows that SynCom inoculation on seeds represents a promising approach to study plant microbiota assembly and its consequence on plant fitness., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)