Optimizing data integration improves gene regulatory network inference in Arabidopsis thaliana.

MOTIVATIONS: Gene regulatory networks (GRNs) are traditionally inferred from gene expression profiles monitoring a specific condition or treatment. In the last decade, integrative strategies have successfully emerged to guide GRN inference from gene expression with complementary prior data. However, datasets used as prior information and validation gold standards are often related and limited to a subset of genes. This lack of complete and independent evaluation calls for new criteria to robustly estimate the optimal intensity of prior data integration in the inference process. RESULTS: We address this issue for two regression-based GRN inference models, a weighted random forest (weigthedRF) and a generalized linear model estimated under a weighted LASSO penalty with stability selection (weightedLASSO). These approaches are applied to data from the root response to nitrate induction in Arabidopsis thaliana. For each gene, we measure how the integration of transcription factor binding motifs influences model prediction. We propose a new approach, DIOgene, that uses model prediction error and a simulated null hypothesis in order to optimize data integration strength in a hypothesis-driven, gene-specific manner. This integration scheme reveals a strong diversity of optimal integration intensities between genes, and offers good performance in minimizing prediction error as well as retrieving experimental interactions. Experimental results show that DIOgene compares favorably against state-of-the-art approaches and allows to recover master regulators of nitrate induction. AVAILABILITY AND IMPLEMENTATION: The R code and notebooks demonstrating the use of the proposed approaches are available in the repository https://github.com/OceaneCsn/integrative_GRN_N_induction.

Endoscopic Gastrointestinal Placement of Capsule Endoscopy to Investigate the Small Bowel: a Multicentric European Retrospective Series of 630 Procedures in Adult Patients.

BACKGROUND AND AIMS: Small bowel (SB) capsule endoscopy (CE) is a first line procedure for exploring the SB. Endoscopic GastroIntestinal PlacemenT (EGIPT) of SB CE is sometimes necessary. While the experience of EGIPT is large in pediatric populations, we aimed to describe the safety, efficacy and outcomes of EGIPT of SB CE in adult patients. METHODS: The international CApsule endoscopy REsearch (iCARE) group set up a retrospective multicenter study. Patients over 18 year-old who underwent EGIPT of SB CE before May 2022 were included. Data were collected from medical records and capsule recordings. The primary endpoint was the technical success rate of the EGIPT procedures. RESULTS: 630 patients were included (mean age 62.5 years old, 55.9% female) from 39,565 patients (1.6%) issued from 29 centers. EGIPT technical success was achieved in 610 procedures (96.8%). Anesthesia (moderate/deep sedation or general anesthesia) and centers with intermediate or high procedure loads were independent factors of technical success. Severe adverse events occurred in three (0.5%) patients. When technically successful, EGIPT was associated with a high SB CE completion rate (84.4%) and with a substantial diagnostic yield (61.1%). Completion rate was significantly higher when the capsule was delivered in the SB compared to when delivered in the stomach. CONCLUSION: EGIPT of SB CE is highly feasible, safe and comes with high completion rate and diagnostic yield. When indicated, it should rather be performed under anesthesia and the capsule should be delivered in the duodenum rather than in the stomach, for better SB examination outcomes.

Impact of Peripheral Hydrogen Bond on Electronic Properties of the Primary Acceptor Chlorophyll in the Reaction Center of Photosystem I.

Photosystem I (PS I) is a photosynthetic pigment-protein complex that absorbs light and uses the absorbed energy to initiate electron transfer. Electron transfer has been shown to occur concurrently along two (A- and B-) branches of reaction center (RC) cofactors. The electron transfer chain originates from a special pair of chlorophyll a molecules (P700), followed by two chlorophylls and one phylloquinone in each branch (denoted as A-1, A0, A1, respectively), converging in a single iron-sulfur complex Fx. While there is a consensus that the ultimate electron donor-acceptor pair is P700+A0-, the involvement of A-1 in electron transfer, as well as the mechanism of the very first step in the charge separation sequence, has been under debate. To resolve this question, multiple groups have targeted electron transfer cofactors by site-directed mutations. In this work, the peripheral hydrogen bonds to keto groups of A0 chlorophylls have been disrupted by mutagenesis. Four mutants were generated: PsaA-Y692F; PsaB-Y667F; PsaB-Y667A; and a double mutant PsaA-Y692F/PsaB-Y667F. Contrary to expectations, but in agreement with density functional theory modeling, the removal of the hydrogen bond by Tyr → Phe substitution was found to have a negligible effect on redox potentials and optical absorption spectra of respective chlorophylls. In contrast, Tyr → Ala substitution was shown to have a fatal effect on the PS I function. It is thus inferred that PsaA-Y692 and PsaB-Y667 residues have primarily structural significance, and their ability to coordinate respective chlorophylls in electron transfer via hydrogen bond plays a minor role.

Identification of Key Parameters Inducing Microbial Modulation during Backslopped Kombucha Fermentation.

The aim of this study was to assess the impact of production parameters on the reproducibility of kombucha fermentation over several production cycles based on backslopping. Six conditions with varying oxygen accessibility (specific interface surface) and initial acidity (through the inoculation rate) of the cultures were carried out and compared to an original kombucha consortium and a synthetic consortium assembled from yeasts and bacteria isolated from the original culture. Output parameters monitored were microbial populations, biofilm weight, key physico-chemical parameters and metabolites. Results highlighted the existence of phases in microbial dynamics as backslopping cycles progressed. The transitions between phases occurred faster for the synthetic consortium compared to the original kombucha. This led to microbial dynamics and fermentative kinetics that were reproducible over several cycles but that could also deviate and shift abruptly to different behaviors. These changes were mainly induced by an increase in the Saccharomyces cerevisiae population, associated with an intensification of sucrose hydrolysis, sugar consumption and an increase in ethanol content, without any significant acceleration in the rate of acidification. The study suggests that the reproducibility of kombucha fermentations relies on high biodiversity to slow down the modulations of microbial dynamics induced by the sustained rhythm of backslopping cycles.

Clinical, Technical, and MRI Features Associated with Patients' Outcome at 3 Months and 2 Years following Prostate Artery Embolization: Is There an Added Value of Radiomics?

Our aim was to investigate which features were associated with clinical successes at short- and mid-terms following prostate artery embolization (PAE) for symptomatic benign prostate hypertrophy (BPH). All adults treated by PAE for BPH at our referral center between January 2017 and March 2021, with pre-treatment MRI, technical success, and follow-up at 3 months and 2 years were included in this single-center retrospective study. Radiologists reviewed the prostatic protrusion index (PPI), adenomatous dominant BPH (adBPH), and Wasserman classification on pre-treatment MRI. Radiomics analysis was achieved on the transitional zone on pre-treatment T2-weighted imaging (WI) and ADC, and comprised reproducibility assessment, unsupervised classifications, and supervised radiomics scores obtained with cross-validated Elasticnet regressions. Eighty-eight patients were included (median age: 65 years), with 81.8% clinical successes at 3 months and 60.2% at 2 years. No feature was associated with success at 3 months, except the radiomics score trained on T2-WI and ADC (AUROC = 0.694). Regarding success at 2 years, no radiomics approaches provided significant performances; however, Wasserman type-1 and change in international prostate symptom score (IPSS) at 3 months ≤ -35% were associated with success in multivariable analysis (OR = 5.82, p = 0.0296, and OR = 9.04, p = 0.0002). Thus, while radiomics provided limited interest, Wasserman classification and early IPSS changes appeared predictive of mid-term outcomes.

Natural genetic variation underlying the negative effect of elevated CO2 on ionome composition in Arabidopsis thaliana.

The elevation of atmospheric CO2 leads to a decline in plant mineral content, which might pose a significant threat to food security in coming decades. Although few genes have been identified for the negative effect of elevated CO2 on plant mineral composition, several studies suggest the existence of genetic factors. Here, we performed a large-scale study to explore genetic diversity of plant ionome responses to elevated CO2, using six hundred Arabidopsis thaliana accessions, representing geographical distributions ranging from worldwide to regional and local environments. We show that growth under elevated CO2 leads to a global decrease of ionome content, whatever the geographic distribution of the population. We observed a high range of genetic diversity, ranging from the most negative effect to resilience or even to a benefit in response to elevated CO2. Using genome-wide association mapping, we identified a large set of genes associated with this response, and we demonstrated that the function of one of these genes is involved in the negative effect of elevated CO2 on plant mineral composition. This resource will contribute to understand the mechanisms underlying the effect of elevated CO2 on plant mineral nutrition, and could help towards the development of crops adapted to a high-CO2 world.

Sarco/endoplasmic reticulum calcium ATPase 3 (SERCA3) expression in gastrointestinal stromal tumours.

Accurate characterisation of gastrointestinal stromal tumours (GIST) is important for prognosis and the choice of targeted therapies. Histologically the diagnosis relies on positive immunostaining of tumours for KIT (CD117) and DOG1. Here we report that GISTs also abundantly express the type 3 Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA3). SERCA enzymes transport calcium ions from the cytosol into the endoplasmic reticulum and play an important role in regulating the intensity and the periodicity of calcium-induced cell activation. GISTs from various localisations, histological and molecular subtypes or risk categories were intensely immunopositive for SERCA3 with the exception of PDGFRA-mutated cases where expression was high or moderate. Strong SERCA3 expression was observed also in normal and hyperplastic interstitial cells of Cajal. Decreased SERCA3 expression in GIST was exceptionally observed in a zonal pattern, where CD117 staining was similarly decreased, reflecting clonal heterogeneity. In contrast to GIST, SERCA3 immunostaining of spindle cell tumours and other gastrointestinal tumours resembling GIST was negative or weak. In conclusion, SERCA3 immunohistochemistry may be useful for the diagnosis of GIST with high confidence, when used as a third marker in parallel with KIT and DOG1. Moreover, SERCA3 immunopositivity may be particularly helpful in cases with negative or weak KIT or DOG1 staining, a situation that may be encountered de novo, or during the spontaneous or therapy-induced clonal evolution of GIST.

Lichen planus pemphigoides with predominant mucous membrane involvement: a series of 12 patients and a literature review.

Background: Lichen planus pemphigoides (LPP), an association between lichen planus and bullous pemphigoid lesions, is a rare subepithelial autoimmune bullous disease. Mucous membrane involvement has been reported previously; however, it has never been specifically studied. Methods: We report on 12 cases of LPP with predominant or exclusive mucous membrane involvement. The diagnosis of LPP was based on the presence of lichenoid infiltrates in histology and immune deposits in the basement membrane zone in direct immunofluorescence and/or immunoelectron microscopy. Our systematic review of the literature, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, highlights the clinical and immunological characteristics of LPP, with or without mucous membrane involvement. Results: Corticosteroids are the most frequently used treatment, with better outcomes in LPP with skin involvement alone than in that with mucous membrane involvement. Our results suggest that immunomodulators represent an alternative first-line treatment for patients with predominant mucous membrane involvement.

BedBiopsy: Diagnostic performance of bedside ultrasound-guided bone biopsies for the management of diabetic foot infection.

OBJECTIVE: We aimed to assess the feasibility and diagnostic performance of ultrasound-guided bone biopsies at the bedside of diabetic patients admitted for suspected foot osteitis not requiring surgery. RESEARCH DESIGN AND METHODS: In this retrospective monocentric study, we compared the performance of ultrasound-guided (n = 29 consecutive patients, Dec.2020-Oct.2022) versus surgical (n = 24 consecutive patients, Jan.2018-Nov.2020) bone biopsies at confirming or ruling out diabetic foot osteitis (primary outcome). RESULTS: Patient characteristics were similar in the two intervention groups, including arteritis prevalence (62.3 %), SINBAD score, and wound location (phalanges 36 %, metatarsus 43 %, and calcaneus 21 %). However, the ultrasound-guided group was older (67 ± 11 versus 60 ± 13 years respectively, P = 0.047) and had more type 2 diabetes (97 % versus 75 %, P = 0.038). Diagnostic performance (i.e., capacity to confirm or rule out suspected osteitis) was similar for ultrasound-guided (28/29 cases: 25 confirmations, 3 invalidations) and surgical (24 confirmations/24) biopsies, P = 0.358. No biopsy-related side effect or complication was observed for either intervention, even for patients on antiaggregation and/or anticoagulation therapy. The mean (± standard deviation) time necessary to perform the biopsy was shorter in the ultrasound-guided group (2.6 ± 3.0 versus 7.2 ± 5.8 days, respectively, P < 0.001) and wound evolution at three months was more favorable (83.3 versus 41.2 %, P = 0.005) (94.4 % versus 66.7 %, respectively, patients with new surgical procedure within six months excluded; P = 0.055). Even though not statistically significant, healing rates in terms of wound and osteitis at six months were also better in the ultrasound-guided group (wound: 40.9 % versus 36.8 %; P = 0.790, and osteitis: 81.8 vs 55.6 % P = 0.071). CONCLUSION: In diabetic patients with suspected foot osteitis not requiring surgery, bedside ultrasound-guided bone biopsies may constitute a promising alternative to surgical biopsies. This intervention provided excellent tolerance and microbiological documentation, short lead-times, and more favorable wound prognosis.