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Crohn’s disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR ( P = 0.003) samples and positively correlated with levels of anti- Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli , suggesting that these organisms interact in the gut. The mass and thickness of triple-species ( C. tropicalis plus S. marcescens plus E. coli ) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis / E. coli , while E. coli was closely apposed with C. tropicalis . Specific interkingdom microbial interactions may be key determinants in CD. IMPORTANCE Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal ( Candida tropicalis ) and bacterial ( Serratia marcescens and Escherichia coli ) species that are associated with CD dysbiosis. Additionally, we found that the level of anti- Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis . We also identified positive interkingdom correlations between C. tropicalis , E. coli , and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays. Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal ( Candida tropicalis ) and bacterial ( Serratia marcescens and Escherichia coli ) species that are associated with CD dysbiosis. Additionally, we found that the level of anti- Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis . We also identified positive interkingdom correlations between C. tropicalis , E. coli , and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.

Multipotency refers to the ability of a cell to differentiate into multiple, yet limited as opposed to pluripotency, number of cell types within a specific lineage or tissue. Studies using transgenic mouse models of the mammary gland have revealed a cellular hierarchy in which both luminal and basal lineages are replenished by unipotent progenitor cells. Hence, despite the existence of bipotent stem cells, normal mammary gland homeostasis is intimately linked with unipotency. However, recent literature revealed that under specific physiological or experimental conditions, lineage-restricted mammary cells can reacquire multipotency and undergo a lineage switch, challenging the traditional unidirectional model of cell differentiation. This reactivation of multipotency has been observed , for instance, in response to pregnancy, lineage ablation or oncogenic stimuli , indicating a certain level of plasticity that may have consequences in the context of tumorigenesis. Understanding the molecular mechanisms governing this phenomenon could provide valuable insights into mammary gland cellular hierarchy and breast cancer progression. Indeed, reactivation of multipotency is a result of developed cell plasticity, which can drive tumor heterogeneity, promote disease aggressiveness and hamper diagnosis. This review provides an overview of models that have inferred reactivation of multipotency, discusses the underlying molecular and cellular mechanisms and proposes future perspectives for research.

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

Purpose Patients with abdominal rectus diastasis (ARD) may have muscular functional impairments, but clinics lack appropriate objective assessment tools. The aim was to establish the relative and absolute reliability, and convergent validity, of muscular activity using Surface Electromyography (SEMG) during isometric abdominal muscle strength testing in patients with ARD and controls without ARD. Methods Twenty-six patients with ARD were matched for age, sex and BMI with controls without ARD. Participants were tested twice during isometric muscular contractions using SEMG located on six abdominal sites. Mean amplitude, fatigue, and recruitment order were analyzed. Relative reliability was evaluated with Intraclass Correlation Coefficients (ICC), while absolute reliability was estimated by calculating the Standard Error of Measurement and Minimal Detectable Change. Convergent validity was addressed in relation to participant characteristics, functional ability, and symptoms. Results Mean SEMG amplitude for all abdominal wall muscle contractions showed moderate to excellent relative test–retest reliability, with ICC values ranging from 0.46 to 0.97. In contrast, fatigue and recruitment order displayed poor to moderate relative reliability in both groups. Absolute reliability measures were generally high. A moderate to high convergent validity (ARD: rho-value 0.41–0.70; Controls: rho-value 0.41–0.75) was observed for mean amplitude in relation to a functional sit-to-stand test, abdominal circumference, BMI, back pain, and quality-of-life. Conclusions The results of applying SEMG during isometric abdominal muscle support practicing the method in clinics, although additional development is needed with further standardization and more functional testing. Furthermore, the method demonstrates construct validity in patients with ARD and in age- and sex-matched controls.

Background Studies of the molecular mechanisms of nerve regeneration have led to the discovery of several proteins that are induced during successful nerve regeneration. RICH proteins were identified as proteins induced during the regeneration of the optic nerve of teleost fish. These proteins are 2’,3’-cyclic nucleotide, 3’-phosphodiesterases that can bind to cellular membranes through a carboxy-terminal membrane localization domain. They interact with the tubulin cytoskeleton and are able to enhance neuronal structural plasticity by promoting the formation of neurite branches. Results PC12 stable transfectant cells expressing a fusion protein combining a red fluorescent protein with a catalytically inactive mutant version of zebrafish RICH protein were generated. These cells were used as a model to analyze effects of the protein on neuritogenesis. Differentiation experiments showed a 2.9 fold increase in formation of secondary neurites and a 2.4 fold increase in branching points. A 2.2 fold increase in formation of secondary neurites was observed in neurite regeneration assays. Conclusions The use of a fluorescent fusion protein facilitated detection of expression levels. Two computer-assisted morphometric analysis methods indicated that the catalytically inactive RICH protein induced the formation of branching points and secondary neurites both during differentiation and neurite regeneration. A procedure based on analysis of random field images provided comparable results to classic neurite tracing methods. Graphical Abstract

In this study, the capabilities of a WC/a-C:H coating and a black oxide surface treatment to affect the onset of micropitting in SAE 52100 bearing steel are examined. Experiments are conducted in which three pairs of contacts (steel on steel, black oxide on black oxide and steel on WC/a-C:H), and three sliding-to-rolling ratios of −10, 0 and +10 % are tested at high contact stress and in a low Λ regime. Results reveal that the WC/a-C:H coating can dramatically increase the micropitting resistance of the coated part, achieving a much higher number of contact cycles and higher levels of contact stress than the steel-on-steel contact. On the other hand, it is found that black oxide surface treatments provide no improvement in micropitting resistance over untreated steel–steel contacts. Specimens tested at the higher slide-to-roll ratios have lower rates of wear with the black oxide surface treatment than with the untreated steel–steel contacts.

Introduction: Movement related impairments and limitations in walking are common long-term after stroke. This multi-arm randomized controlled trial explored the impact of training with an electromechanically assisted gait training (EAGT) system, i.e., the Hybrid Assistive Limb ® (HAL), when integrated with conventional rehabilitation focused on gait and mobility. Material and Methods: Participants, aged 18–70 years with lower extremity paresis but able to walk with manual support or supervision 1–10 years after stroke, were randomized to (A) HAL-training on a treadmill, combined with conventional rehabilitation interventions (HAL-group), or (B) conventional rehabilitation interventions only (Conventional group), 3 days/week for 6 weeks, or (C) no intervention (Control group). Participants in the Control group were interviewed weekly regarding their scheduled training. Primary outcome was endurance in walking quantified by the 6 Minute Walk Test (6MWT). A rater blinded to treatment allocation performed assessments pre- and post-intervention and at follow-ups at 6 and 12 months. Baseline assessment included the National Institute of Health Stroke Scale (NIHSS) and the Modified Ranking Scale (MRS). Secondary outcomes included the Fugl Meyer Assessment- Lower Extremity, 10 Meter Walk Test, Berg Balance Scale (BBS), Barthel Index (BI) and perceived mobility with the Stroke Impact Scale. Results: A total of 48 participants completed the intervention period. The HAL-group walked twice as far as the Conventional group during the intervention. Post-intervention, both groups exhibited improved 6 MWT results, while the Control group had declined. A significant improvement was only found in the Conventional group and when compared to the Control group (Tukey HSD p = 0.022), and not between the HAL group and Conventional group (Tukey HSD p = 0.258) or the HAL- group and the Control group (Tukey HSD p = 0.447). There was also a significant decline in the Conventional group from post-intervention to 6 months follow up ( p = 0.043). The best fitting model to predict outcome included initial balance (BBS), followed by stroke severity (NIHSS), and dependence in activity and participation (BI and MRS). Conclusion: Intensive conventional gait training induced significant improvements long-term after stroke while integrating treadmill based EAGT had no additional value in this study sample. The results may support cost effective evidence-based interventions for gait training long-term after stroke and further development of EAGT. Trial registration: Published on clinicaltrials.gov (NCT02545088) August 24, 2015.

A sex ratio is one of the most basic demographic estimates produced because it is easy to collect and provides deeper insight into population dynamics for the species under consideration. For inconsistently or intermittently breeding species, the breeding sex ratio (BSR) and adult sex ratio (ASR), both reported as the proportion of males, can be quite different. The entire adult population of some wide‐ranging species may never be present and capable of being sampled in the same time and place. We explore equations to indirectly estimate ASRs and annual abundance estimates from annual surveys of BSRs. We sampled Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) from 2013 through 2019 and implanted acoustic transmitters during those sampling periods. The BSRs calculated during capture from 2015 through 2019 were 0.65, 0.75, 0.69, 0.75, and 0.64 each year. Relying on telemetry detections from the lowest potential spawning region, the expected BSRs in the same years were 0.64, 0.74, 0.67, 0.69, and 0.60, suggesting telemetry is a reliable and passive way to estimate BSR. The BSRs were used to indirectly estimate ASR to be approximately 0.51 (95% confidence limits of 0.43–0.58). Estimates of annual abundance derived through sex ratios matched previously published mark–recapture estimates of the same breeding population, but provide additional detail on abundances of each sex. For populations where BSR is more accessible, ASR and abundance estimates can be estimated with capture data and acoustic telemetry.

The EU Directive 2010/63/EU changed the requirements regarding the use of laboratory animals and raised important issues related to assessing the severity of all procedures undertaken on laboratory animals. However, quantifiable parameters to assess severity are rare, and improved assessment strategies need to be developed. Hence, a Sheep Grimace Scale (SGS) was herein established by observing and interpreting sheep facial expressions as a consequence of pain and distress following unilateral tibia osteotomy. The animals were clinically investigated and scored five days before surgery and at 1, 3, 7, 10, 14 and 17 days afterwards. Additionally, cortisol levels in the saliva of the sheep were determined at the respective time points. For the SGS, video recording was performed, and pictures of the sheep were randomized and scored by blinded observers. Osteotomy in sheep resulted in an increased clinical severity score from days 1 to 17 post-surgery and elevated salivary cortisol levels one day post-surgery. An analysis of facial expressions revealed a significantly increased SGS on the day of surgery until day 3 post-surgery; this elevated level was sustained until day 17. Clinical severity and SGS scores correlated positively with a Pearson´s correlation coefficient of 0.47. Further investigations regarding the applicability of the SGS revealed a high inter-observer reliability with an intraclass correlation coefficient of 0.92 and an accuracy of 68.2%. In conclusion, the SGS represents a valuable approach for severity assessment that may help support and refine a widely used welfare assessment for sheep during experimental procedures, thereby meeting legislation requirements and minimizing the occurrence of unrecognized distress in animal experimentation.

To evaluate the effect of oral nutritional supplementation with and without oligosaccharides on gut bacteriology, in particular the bifidogenic flora, and on immunology and inflammatory parameters in older persons at risk of malnutrition. Prospective, randomized, double-blind, controlled study. Division of Geriatric Medicine, St. Louis University, Missouri, United States. Seventy-four community dwelling elderly and/or nursing home subjects (age superior 70 y; 84 +/- 7 years) either undernourished or at risk of undernutrition. Daily liquid supplements, with (1.3 g/250 ml) and without oligosaccharides (OS) for 12 weeks. Nutritional evaluation, serum immunoglobulins, lymphocyte subsets, various cytokines and the endotoxin soluble receptor CD14 (sCD14) in serum, and cytokines specific mRNA in peripheral blood mononuclear cells at baseline and 12 weeks, and fecal bacteriologicy. Specific mRNA extracted from blood leucocytes showed a different level of pro-inflammatory gene activation: TNF-alpha mRNA and IL-6 mRNA diminished in the OS group after 12 weeks, while no changes were detected in the control group (P=0.05 and P=0.04 respectively). Serum levels of sCD14, a product shed by activated macrophages, decreased only in the OS group without reaching statistical significance (P=0.08). No significant differences were detected in the fecal gut flora or in the nutritional parameters. This study shows that the administration of supplements in older persons at risk of malnutrition may benefit from the addition of prebiotics that can improve the low noise inflammatory process frequently observed in this population.