Tofacitinib as a Rescue Therapy for Ulcerative Colitis in Pregnancy.

Tofacitinib, a potentially teratogenic nonselective Janus Kinase inhibitor was used as salvage therapy for ulcerative colitis during pregnancy with corticosteroids, maintenance ustekinumab, and rectal 5-ASA therapy. Corticosteroid-free remission ensued, resulting in term delivery without congenital malformations and avoidance of colectomy.

Integrative systems biology of wheat susceptibility to Fusarium graminearum uncovers a conserved gene regulatory network and identifies master regulators targeted by fungal core effectors.

BACKGROUND: Plant diseases are driven by an intricate set of defense mechanisms counterbalanced by the expression of host susceptibility factors promoted through the action of pathogen effectors. In spite of their central role in the establishment of the pathology, the primary components of plant susceptibility are still poorly understood and challenging to trace especially in plant-fungal interactions such as in Fusarium head blight (FHB) of bread wheat. Designing a system-level transcriptomics approach, we leveraged the analysis of wheat responses from a susceptible cultivar facing Fusarium graminearum strains of different aggressiveness and examined their constancy in four other wheat cultivars also developing FHB. RESULTS: In this study, we describe unexpected differential expression of a conserved set of transcription factors and an original subset of master regulators were evidenced using a regulation network approach. The dual-integration with the expression data of pathogen effector genes combined with database mining, demonstrated robust connections with the plant molecular regulators and identified relevant candidate genes involved in plant susceptibility, mostly able to suppress plant defense mechanisms. Furthermore, taking advantage of wheat cultivars of contrasting susceptibility levels, a refined list of 142 conserved susceptibility gene candidates was proposed to be necessary host's determinants for the establishment of a compatible interaction. CONCLUSIONS: Our findings emphasized major FHB determinants potentially controlling a set of conserved responses associated with susceptibility in bread wheat. They provide new clues for improving FHB control in wheat and also could conceivably leverage further original researches dealing with a broader spectrum of plant pathogens.

Distinct chikungunya virus polymerase palm subdomains contribute to virus replication and virion assembly.

Alphaviruses encode an error-prone RNA-dependent RNA polymerase (RdRp), nsP4, required for genome synthesis, yet how the RdRp functions in the complete alphavirus life cycle is not well-defined. Previous work using chikungunya virus (CHIKV) has established the importance of the nsP4 residue cysteine 483 in maintaining viral genetic fidelity. Given the location of residue C483 in the nsP4 palm domain, we hypothesized that other residues within this domain and surrounding subdomains would also contribute to polymerase function. To test this hypothesis, we designed a panel of nsP4 variants via homology modeling based on the Coxsackievirus B3 3 polymerase. We rescued each variant in both mammalian and mosquito cells and discovered that the palm domain and ring finger subdomain contribute to polymerase host-specific replication and genetic stability. Surprisingly, in mosquito cells, these variants in the ring finger and palm domain were replication competent and produced viral structural proteins, but they were unable to produce infectious progeny, indicating a yet uncharacterized role for the polymerase in viral assembly. Finally, we have identified additional residues in the nsP4 palm domain that influence the genetic diversity of the viral progeny, potentially via an alteration in NTP binding and/or discrimination by the polymerase. Taken together, these studies highlight that distinct nsP4 subdomains regulate multiple processes of the alphavirus life cycle, placing nsP4 in a central role during the switch from RNA synthesis to packaging and assembly.

Localized osmotic stress activates systemic responses to N limitation in Medicago truncatula-Sinorhizobium symbiotic plants.

In mature symbiotic root nodules, differentiated rhizobia fix atmospheric dinitrogen and provide ammonium to fulfill the plant nitrogen (N) demand. The plant enables this process by providing photosynthates to the nodules. The symbiosis is adjusted to the whole plant N demand thanks to systemic N signaling controlling nodule development. Symbiotic plants under N deficit stimulate nodule expansion and activate nodule senescence under N satiety. Besides, nodules are highly sensitive to drought. Here, we used split-root systems to characterize the systemic responses of symbiotic plants to a localized osmotic stress. We showed that polyéthylène glycol (PEG) application rapidly inhibited the symbiotic dinitrogen fixation activity of nodules locally exposed to the treatment, resulting to the N limitation of the plant supplied exclusively by symbiotic dinitrogen fixation. The localized PEG treatment triggered systemic signaling stimulating nodule development in the distant untreated roots. This response was associated with an enhancement of the sucrose allocation. Our analyses showed that transcriptomic reprogramming associated with PEG and N deficit systemic signaling(s) shared many targets transcripts. Altogether, our study suggests that systemic N signaling is a component of the adaptation of the symbiotic plant to the local variations of its edaphic environment.

Plasticity QTLs specifically contribute to the genotype × water availability interaction in maize.

KEY MESSAGE: Multi-trial genome wide association study of plasticity indices allow to detect QTLs specifically involved in the genotype x water availability interaction. Concerns regarding high maize yield losses due to increasing occurrences of drought events are growing, and breeders are still looking for molecular markers for drought tolerance. However, the genetic determinism of traits in response to drought is highly complex and identification of causal regions is a tremendous task. Here, we exploit the phenotypic data obtained from four trials carried out on a phenotyping platform, where a diversity panel of 254 maize hybrids was grown under well-watered and water deficit conditions, to investigate the genetic bases of the drought response in maize. To dissociate drought effect from other environmental factors, we performed multi-trial genome-wide association study on well-watered and water deficit phenotypic means, and on phenotypic plasticity indices computed from measurements made for six ecophysiological traits. We identify 102 QTLs and 40 plasticity QTLs. Most of them were new compared to those obtained from a previous study on the same dataset. Our results show that plasticity QTLs cover genetic regions not identified by QTLs. Furthermore, for all ecophysiological traits, except one, plasticity QTLs are specifically involved in the genotype by water availability interaction, for which they explain between 60 and 100% of the variance. Altogether, QTLs and plasticity QTLs captured more than 75% of the genotype by water availability interaction variance, and allowed to find new genetic regions. Overall, our results demonstrate the importance of considering phenotypic plasticity to decipher the genetic architecture of trait response to stress.

Measurement of the Induced Magnetic Polarisation of Rotated-Domain Graphene Grown on Co Film with Polarised Neutron Reflectivity.

In this paper, we determine the magnetic moment induced in graphene when grown on a cobalt film using polarised neutron reflectivity (PNR). A magnetic signal in the graphene was detected by X-ray magnetic circular dichroism (XMCD) spectra at the C K-edge. From the XMCD sum rules an estimated magnetic moment of 0.3 µB/C atom, while a more accurate estimation of 0.49 µB/C atom was obtained by carrying out a PNR measurement at 300 K. The results indicate that the higher magnetic moment in Co is counterbalanced by the larger lattice mismatch between the Co-C (1.6%) and the slightly longer bond length, inducing a magnetic moment in graphene that is similar to that reported in Ni/graphene heterostructures.

A Sensitive Micro Conductometric Ethanol Sensor Based on an Alcohol Dehydrogenase-Gold Nanoparticle Chitosan Composite.

In this paper, a microconductometric sensor has been designed, based on a chitosan composite including alcohol dehydrogenase-and its cofactor-and gold nanoparticles, and was calibrated by differential measurements in the headspace of aqueous solutions of ethanol. The role of gold nanoparticles (GNPs) was crucial in improving the analytical performance of the ethanol sensor in terms of response time, sensitivity, selectivity, and reproducibility. The response time was reduced to 10 s, compared to 21 s without GNPs. The sensitivity was 416 µS/cm (v/v%)-1 which is 11.3 times higher than without GNPs. The selectivity factor versus methanol was 8.3, three times higher than without GNPs. The relative standard deviation (RSD) obtained with the same sensor was 2%, whereas it was found to be 12% without GNPs. When the air from the operator's mouth was analyzed just after rinsing with an antiseptic mouthwash, the ethanol content was very high (3.5 v/v%). The background level was reached only after rinsing with water.

A hierarchical modeling approach to predict the distribution and density of Sierra Nevada Red Fox (Vulpes vulpes necator).

Carnivores play critical roles in ecosystems, yet many species are declining worldwide. The Sierra Nevada Red Fox (Vulpes vulpes necator; SNRF) is a rare and endangered subspecies of red fox limited to upper montane forests, subalpine, and alpine environments of California and Oregon, United States. Having experienced significant distribution contractions and population declines in the last century, the subspecies is listed as at-risk by relevant federal and state agencies. Updated information on its contemporary distribution and density is needed to guide and evaluate conservation and management actions. We combined 12 years (2009-2020) of detection and nondetection data collected throughout California and Oregon to model the potential distribution and density of SNRFs throughout their historical and contemporary ranges. We used an integrated species distribution and density modeling approach, which predicted SNRF density in sampled locations based on observed relationships between environmental covariates and detection frequencies, and then projected those predictions to unsampled locations based on the estimated correlations with environmental covariates. This approach provided predictions that serve as density estimates in sampled regions and projections in unsampled areas. Our model predicted a density of 1.06 (95% credible interval = 0.8-1.36) foxes per 100 km2 distributed throughout 22,926 km2 in three distinct regions of California and Oregon-Sierra Nevada, Lassen Peak, and Oregon Cascades. SNRFs were most likely to be found in areas with low minimum temperatures and high snow water equivalent. Our results provide a contemporary baseline to inform the development and evaluation of conservation and management actions, and guide future survey efforts.

Elevating Mentorship Competency for Sustained Impact via the University of Zambia Mentor Training Program.

The University of Zambia (UNZA) Mentor Training Program is conducted annually to strengthen the mentorship capacity of postgraduate programs for the health professions. This intensive five-session course trains faculty members in the mentorship of students. Established by senior UNZA leaders and US-based collaborators, this program was designed to address gaps in mentorship identified at the institutional level. Faculty facilitators developed the course curriculum and used a train-the-trainer model to ensure program sustainability. Participants were faculty members who mentor PhD and Master of Medicine students. To assess the program's impact, mentors and their mentees completed questionnaires on the mentor's mentoring competencies at the end of the course and 1 year later. Competency scores were compared longitudinally to quantify potential changes in mentoring behaviors. Mentors and mentees alike noted mentor growth in all competency domains from postcourse to 1 year later, providing evidence of a trend toward improvement in mentorship and that the program may have sustainable and positive effects on mentoring behaviors over time. Salient areas of growth corresponded to emphasized topics and discussions, including addressing diversity, aligning expectations, assessing capacities, motivating mentees, and fostering independence. These findings suggest that mentors internalized this content and transferred it to behavior change. The behavior changes may reveal a larger change in the institutional environment around the mentoring of students. The UNZA Mentor Training Program appears to have sustained impact after a year and should bode well for future benefits to students, faculty, and the institution.

The battle for silver binding: How the interplay between the SilE, SilF, and SilB proteins contributes to the silver efflux pump mechanism.

The resistance of gram-negative bacteria to silver ions is mediated by a silver efflux pump, which mainly relies on a tripartite efflux complex SilCBA, a metallochaperone SilF and an intrinsically disordered protein SilE. However, the precise mechanism by which silver ions are extruded from the cell and the different roles of SilB, SilF, and SilE remain poorly understood. To address these questions, we employed nuclear magnetic resonance and mass spectrometry to investigate the interplay between these proteins. We first solved the solution structures of SilF in its free and Ag+-bound forms, and we demonstrated that SilB exhibits two silver binding sites in its N and C termini. Conversely to the homologous Cus system, we determined that SilF and SilB interact without the presence of silver ions and that the rate of silver dissociation is eight times faster when SilF is bound to SilB, indicating the formation of a SilF-Ag-SilB intermediate complex. Finally, we have shown that SilE does not bind to either SilF or SilB, regardless of the presence or absence of silver ions, further corroborating that it merely acts as a regulator that prevents the cell from being overloaded with silver. Collectively, we have provided further insights into protein interactions within the sil system that contribute to bacterial resistance to silver ions.

Increased retention of functional mitochondria in mature sickle red blood cells is associated with increased sickling tendency, hemolysis and oxidative stress.

Abnormal retention of mitochondria in mature red blood cells (RBC) has been recently reported in sickle cell anemia (SCA) but their functionality and their role in the pathophysiology of SCA remain unknown. The presence of mitochondria within RBC was determined by flow cytometry in 61 SCA patients and ten healthy donors. Patients were classified according to the percentage of mature RBC with mitochondria contained in the whole RBC population: low (0-4%), moderate (>4% and <8%), or high level (>8%). RBC rheological, hematological, senescence and oxidative stress markers were compared between the three groups. RBC senescence and oxidative stress markers were also compared between mature RBC containing mitochondria and those without. The functionality of residual mitochondria in sickle RBC was measured by high-resolution respirometry assay and showed detectable mitochondrial oxygen consumption in sickle mature RBC but not in healthy RBC. Increased levels of mitochondrial reactive oxygen species were observed in mature sickle RBC when incubated with Antimycin A versus without. In addition, mature RBC retaining mitochondria exhibited greater levels of reactive oxygen species compared to RBC without mitochondria, as well as greater Ca2+, lower CD47 and greater phosphatidylserine exposure. Hematocrit and RBC deformability were lower, and the propensity of RBC to sickle under deoxygenation was higher, in the SCA group with a high percentage of mitochondria retention in mature RBC. This study showed the presence of functional mitochondria in mature sickle RBC, which could favor RBC sickling and accelerate RBC senescence, leading to increased cellular fragility and hemolysis.

Accueil et suivi des personnes en demande de transition en soins de premiers recours : retour sur plus de dix ans d'expérience.

Ten years ago, trans-gender people were looking for respectful and safe accompaniment. It was in this context of difficulty in finding answers that the Maison Dispersée de Santé de Lille began to set up a support service. The approach was immediately anchored in the gender transition pathway within primary care medicine, i.e. in access to local care. Caregivers and users, we build together our practice of health and care by meeting, debating, listening and sharing individual and collective expertise. Thus, we have gradually built a rigorous and non-rigid framework of a global, bio-psycho-social accompaniment that takes into account experiential learning. This framework must take into account the health of each individual in order to propose, follow and adapt a hormone replacement treatment. It allows for the accompaniment of physical changes, possible pre-existing psychological suffering or that which appears during the transition, as well as the upheaval of one's place in society. People with gender variations need medical support because they are part of a social reality that leads to this demand. The prevalence of transidentity has long been underestimated and this need has also been underestimated. Our experience of more than ten years of accompanying transitions of women and men in this context shows the feasibility of transitions in primary care within the French system of care and medico social support.

Exploring the added value of pretherapeutic MR descriptors in predicting breast cancer pathologic complete response to neoadjuvant chemotherapy.

OBJECTIVES: To evaluate the association between pretreatment MRI descriptors and breast cancer (BC) pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Patients with BC treated by NAC with a breast MRI between 2016 and 2020 were included in this retrospective observational single-center study. MR studies were described using the standardized BI-RADS and breast edema score on T2-weighted MRI. Univariable and multivariable logistic regression analyses were performed to assess variables association with pCR according to residual cancer burden. Random forest classifiers were trained to predict pCR on a random split including 70% of the database and were validated on the remaining cases. RESULTS: Among 129 BC, 59 (46%) achieved pCR after NAC (luminal (n = 7/37, 19%), triple negative (n = 30/55, 55%), HER2 + (n = 22/37, 59%)). Clinical and biological items associated with pCR were BC subtype (p < 0.001), T stage 0/I/II (p = 0.008), higher Ki67 (p = 0.005), and higher tumor-infiltrating lymphocytes levels (p = 0.016). Univariate analysis showed that the following MRI features, oval or round shape (p = 0.047), unifocality (p = 0.026), non-spiculated margins (p = 0.018), no associated non-mass enhancement (p = 0.024), and a lower MRI size (p = 0.031), were significantly associated with pCR. Unifocality and non-spiculated margins remained independently associated with pCR at multivariable analysis. Adding significant MRI features to clinicobiological variables in random forest classifiers significantly increased sensitivity (0.67 versus 0.62), specificity (0.69 versus 0.67), and precision (0.71 versus 0.67) for pCR prediction. CONCLUSION: Non-spiculated margins and unifocality are independently associated with pCR and can increase models performance to predict BC response to NAC. CLINICAL RELEVANCE STATEMENT: A multimodal approach integrating pretreatment MRI features with clinicobiological predictors, including tumor-infiltrating lymphocytes, could be employed to develop machine learning models for identifying patients at risk of non-response. This may enable consideration of alternative therapeutic strategies to optimize treatment outcomes. KEY POINTS: • Unifocality and non-spiculated margins are independently associated with pCR at multivariable logistic regression analysis. • Breast edema score is associated with MR tumor size and TIL expression, not only in TN BC as previously reported, but also in luminal BC. • Adding significant MRI features to clinicobiological variables in machine learning classifiers significantly increased sensitivity, specificity, and precision for pCR prediction.

Evaluation of Knowledge, Attitudes, and Practice in an Online Faculty Development Course for Anesthesia Educators in East Africa.

INTRODUCTION: Faculty in low-resourced communities often have limited training on teaching and learning. An innovative, online, 13-week course using a flipped classroom model was developed for junior faculty anesthesiologists at teaching hospitals in East Africa and piloted in Ethiopia and Tanzania. METHODS: Quantitative and qualitative data were collected and analyzed to evaluate potential change in participants' knowledge, skills, and attitudes as well as the feasibility of e-learning in the region. RESULTS: Analysis of data revealed that top areas of change in participants' knowledge were in the flipped classroom approach (increased by 79%), effective mentoring practices (67%), and elements of effective course goals and objectives (58%). Leading areas of change in skills were in developing goals and objectives (72%), using case-based learning (67%), and engaging learners through PowerPoint (64%). Change in attitudes was largest in the areas of effective mentoring and strong leadership (27%), using course and lecture learning objectives (26%), and student-centered learning theory (26%). Qualitative data revealed that participants were satisfied with the course; found the structure, presentations, and delivery methods to be effective; and appreciated the flexibility of being online but experienced challenges, particularly in connectivity. DISCUSSION: This evaluation demonstrated the efficacy of using e-learning in East Africa and highlights the innovation of online faculty development in a region where it has not been done before. By using participants as future instructors, this course is scalable in the region and worldwide, and it can help address limited access to training by providing a critical mass of trainers competent in teaching, mentoring, and leading.

A conductometric enzymatic methanol sensor based on polystyrene - PAMAM dendritic polymer electrospun nanofibers.

Methanol (MeOH) is a solvent and cleaning agent used in industry, but it is poisonous when ingested. The recommended release threshold for MeOH vapor is 200 ppm. We present a novel sensitive micro-conductometric MeOH biosensor created by grafting alcohol oxidase (AOX) onto electrospun polystyrene-poly(amidoamine) dendritic polymer blend nanofibers (PS-PAMAM-ESNFs) on interdigitated electrodes (IDEs). The analytical performance of the MeOH microsensor was evaluated using gaseous MeOH, ethanol, and acetone samples collected from the headspace above aqueous solution with known concentration. The sensor's response time (tRes) fluctuates from 13 s to 35 s from lower to higher concentrations. The conductometric sensor has a sensitivity of 150.53 µS.cm-1 (v/v) for MeOH and a detection limit of 100 ppm in the gas phase. The MeOH sensor is 7.3 times less sensitive to ethanol and 136.8 times less sensitive to acetone. The sensor was verified for detecting MeOH in commercial rubbing alcohol samples.

Determining the Proximity Effect-Induced Magnetic Moment in Graphene by Polarized Neutron Reflectivity and X-ray Magnetic Circular Dichroism.

We report the magnitude of the induced magnetic moment in CVD-grown epitaxial and rotated-domain graphene in proximity with a ferromagnetic Ni film, using polarized neutron reflectivity (PNR) and X-ray magnetic circular dichroism (XMCD). The XMCD spectra at the C K-edge confirm the presence of a magnetic signal in the graphene layer, and the sum rules give a magnetic moment of up to ∼0.47 µB/C atom induced in the graphene layer. For a more precise estimation, we conducted PNR measurements. The PNR results indicate an induced magnetic moment of ∼0.41 µB/C atom at 10 K for epitaxial and rotated-domain graphene. Additional PNR measurements on graphene grown on a nonmagnetic Ni9Mo1 substrate, where no magnetic moment in graphene is measured, suggest that the origin of the induced magnetic moment is due to the opening of the graphene's Dirac cone as a result of the strong C pz-Ni 3d hybridization.

Transforming medical education in Liberia through an international community of inquiry.

A critical component of building capacity in Liberia's physician workforce involves strengthening the country's only medical school, A.M. Dogliotti School of Medicine. Beginning in 2015, senior health sector stakeholders in Liberia invited faculty and staff from U.S. academic institutions and non-governmental organizations to partner with them on improving undergraduate medical education in Liberia. Over the subsequent six years, the members of this partnership came together through an iterative, mutual-learning process and created what William Torbert et al describe as a "community of inquiry," in which practitioners and researchers pair action and inquiry toward evidence-informed practice and organizational transformation. Incorporating faculty, practitioners, and students from Liberia and the U.S., the community of inquiry consistently focused on following the vision, goals, and priorities of leadership in Liberia, irrespective of funding source or institutional affiliation. The work of the community of inquiry has incorporated multiple mixed methods assessments, stakeholder discussions, strategic planning, and collaborative self-reflection, resulting in transformation of medical education in Liberia. We suggest that the community of inquiry approach reported here can serve as a model for others seeking to form sustainable global health partnerships focused on organizational transformation.

Effects of a Maximal Exercise Followed by a Submaximal Exercise Performed in Normobaric Hypoxia (2500 m), on Blood Rheology, Red Blood Cell Senescence, and Coagulation in Well-Trained Cyclists.

Acute normoxic exercise impacts the rheological properties of red blood cells (RBC) and their senescence state; however, there is a lack of data on the effects of exercise performed in hypoxia on RBC properties. This crossover study compared the effects of acute hypoxia vs. normoxia on blood rheology, RBC senescence, and coagulation during exercise. Nine trained male cyclists completed both a session in normoxia (FiO2 = 21%) and hypoxia (FiO2 = 15.3% ≈ 2500 m). The two sessions were randomly performed, separated by one week, and consisted of an incremental and maximal exercise followed by a 20 min exercise at the first ventilatory threshold (VT1) on a home-trainer. Blood samples were taken before and after exercise to analyze hematological parameters, blood rheology (hematocrit, blood viscosity, RBC deformability and aggregation), RBC senescence markers (phosphatidylserine (PS) and CD47 exposure, intraerythrocyte reactive oxygen species (ROS), and calcium content), and blood clot viscoelastic properties. Hemoglobin oxygen saturation (SpO2) and blood lactate were also measured. In both conditions, exercise induced an increase in blood viscosity, hematocrit, intraerythrocyte calcium and ROS content, and blood lactate concentration. We also observed an increase in blood clot amplitude, and a significant drop in SpO2 during exercise in the two conditions. RBC aggregation and CD47 exposure were not modified. Exercise in hypoxia induced a slight decrease in RBC deformability which could be related to the slight increase in mean corpuscular hemoglobin concentration (MCHC). However, the values of RBC deformability and MCHC after the exercise performed in hypoxia remained in the normal range of values. In conclusion, acute hypoxia does not amplify the RBC and coagulation changes induced by an exercise bout.

Accelerating Organizational Change to Build Mentorship Culture in Zambian Universities.

Strong cultures of mentorship and research remain underdeveloped at many African universities, threatening future knowledge generation essential for health and development on the continent. To address these challenges, a mentorship program was developed in 2018 at the University of Zambia with an aim to enhance the institutional culture of mentorship and to build institutional capacity through an innovative 'train the trainer' faculty development model. In this study, we documented perceptions of lived experiences related to mentorship culture by following trainers and trainees and their mentees over two years. We analyzed these perceptions to assess changes in institutional attributes regarding mentorship. We identified positive change in institutional culture towards mentorship, and this change appeared sustainable over time. However, a slight decrease in indicators for year two emphasizes the need for a continued culture of learning rather than assuming that one-off training will be sufficient to change culture.