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Abstract Background Tailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. Methods Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. Results No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. Conclusions We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Abstract Introduction In 2013, rituximab was approved in France for the treatment of ANCA-associated vasculitis (AAV). The aim of the study was to compare the treatment and health events of adult incident patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), included before rituximab approval (over 2010–2012, Group 1) and those included after rituximab approval (over 2014–2017, Group 2). Method Data were extracted from the French National Health Insurance database (SNDS) including outpatient health care consumption and hospital discharge forms. Comparisons between inclusion periods were performed using Wilcoxon and χ² tests. Kaplan-Meier method was used to model the duration of treatment induction, maintenance, and off-drug periods. Fine and Gray tests were used to compare treatment phase durations. Results A total of 694 GPA and 283 MPA patients were included in Group 1, while 668 GPA and 463 MPA patients were included in Group 2. Between the two inclusion periods, the proportions of patients treated with rituximab increased in the induction and maintenance phases whereas treatment with azathioprine declined. These proportions remained stable in the case of methotrexate, cyclophosphamide, and glucocorticoid-treated patients. Frequency of first-time hospitalized infections, diabetes and renal failure during the first year after inclusion increased for both groups. Limitations of the study This is a retrospective study based on claims data including only 76% of people covered by health insurance in France. The period studied includes the learning phase of using rituximab. This study lacks biological data and precise quantitative analysis for the use of steroids, therefore the criteria for establishing diagnosis and therapeutic choice were unknown. Conclusions Introduction of rituximab reduced the use of azathioprine without affecting the use of glucocorticoids or cyclophosphamide.

In Rwanda, cattle and milk hold a cultural and historical significance, providing an opportunity for pro-dairy governmental policies aimed to alleviate food insecurity, malnutrition, and improve livelihoods. The government of Rwanda has identified strategies to grow the dairy sector through strategic investment to achieve these goals. It is estimated two-thirds of lactating cows in Rwanda have clinical or subclinical mastitis, which reduces milk production and increases the risk of milk as a source for zoonotic disease if the milk is consumed undercooked or unpasteurized. This case study outlines the implementation of a One Health framework that integrates education, research, and outreach in Rwanda to improve food safety and food security, for the social, economic, and health benefit of Rwandans and their livestock. Twenty-five Rwandan Extension Specialists participated in the Dairy Dynamic Management education, research, and outreach program. Once trained, the extension specialists supported 30 small holder dairy farmers in performing proper husbandry and animal health practices for mastitis control and reduction of bacterial counts in the udder. Over the 16-week program, 30 small holder dairy farmers and 100 dairy cows were surveyed weekly for animal husbandry, animal health, and mastitis indicators. Outcomes were evaluated by monitoring animal health, foodborne pathogens in milk, and compliance to animal husbandry protocols. Quarter milk samples were collected weekly and evaluated for the presence of bacteria that are common causes of mastitis. We found a statistically significant reduction of mean total bacterial counts and prevalence of bacterial species in quarters over the 16-week training (P ≤ .01). Smallholders were monitored through observing farmers performing hygienic milking protocols. Farmers conducted the protocol correctly greater than 90% of the time by the end of the 16-week program for 5 of 7 steps for proper hygienic milking procedures, indicating farmers were eager to learn and adopt the procedures. However, follow-up and retraining with Extension Specialists is vital to continued success. We demonstrate that an integrative One Health education, research, and outreach program can be successful in improving animal health, food safety, and food security and this framework can be applied to other agricultural sectors and geographic regions.

Ionic Covalent Organic Frameworks are a special subgroup that has risen as promising materials for innovative applications. In parallel, some of the so-called Reticular Innovative Organic compounds (RIOs), which are ionic and non-ionic porous materials have been used with great versatility, for several purposes. In this work, the ionic dye-based RIO-55 was chosen to capture a series of lanthanides (Eu, Gd, Dy, and Tb) from water, observing their affinity with the lattice and the performance of the adsorbent. Thus, the higher adsorbed amount was referred to as Eu3+ (Qmax = 370 mg/g), as well as the best affinity (KL = 5x10−3), following the Langmuir model. The impregnated Eu3+@RIO-55 was used for chemical sensing, capturing dopant molecules (ephedrine and dopamine) from water, showing great performance, even after some reuse cycles. In addition, some initial fluorescence tests were performed using RIO-55 and Eu3+@RIO-55 to observe the spectrum before and after lanthanide impregnation.

Abstract Equiluminant stimuli help assess the integrity of colour perception and the relationship of colour to other visual features. As a result of individual variation, it is necessary to calibrate experimental visual stimuli to suit each individual’s unique equiluminant ratio. Most traditional methods rely on training observers to report their subjective equiluminance point. Such paradigms cannot easily be implemented on pre-verbal or non-verbal observers. Here, we present a novel Pupil Frequency-Tagging Method (PFTM) for detecting a participant’s unique equiluminance point without verbal instruction and with minimal training. PFTM analyses reflexive pupil oscillations induced by slow (

The widespread misuse of antibiotics to combat bacterial infections in dairy farming is a global concern contributing to antimicrobial resistance (AMR). To gain insights within small-scale dairy farming, a study was conducted in Nyabihu district of Rwanda from September 2021 to April 2023 to assess practices and factors associated with antibiotic use, investigate antibiotic residues in cow milk and undertake a comprehensive training program to improve quality milk production. A mixed-methods approach, combining cross-sectional and longitudinal intervention studies, involved 42 regular dairy farmers from both open and zero-grazing systems delivering milk to the Union pour la Promotion des Cooperatives des Eleveurs en Nyabihu (UPROCENYA) milk collection center (MCC). Standardized questionnaires and farm interviews were conducted to assess antibiotic use practices while bulk tank milk samples from the same farmers were collected and tested for antibiotic residues using rapid tests over 16 months (8 months before and 8 months after training).Out of 451 bulk tank milk samples tested, 27 samples (6%) contained antibiotic residues, primarily tetracyclines (55.3%) and beta-lactams (44.7%). Before farmers training, 5182.75 l of milk were rejected monthly due to antibiotic residues. Following training, milk rejections decreased to 3192.75 l per month, reflecting 38.35% monthly decrease. However, no statistically significant difference was found by independent t-test (t = 1.441; p = 0.173) between milk rejected before and after training. 97.6% of interviewed farmers reported using antibiotics within six months preceding data collection, with 71.4% primarily used for disease treatment, notably targeting tick-borne diseases (34.0%). Alarming practices included administering antibiotics without referring samples for laboratory examination (100%), disregarding withdrawal periods (88.1%) and administering antibiotics without a veterinary doctor's prescription (85.7%). Factors contributing to these practices included limited farmer’s knowledge on antibiotics, easy access to antibiotics in local agro-veterinary shops, and insufficient veterinary services. Antibiotic-laden milk was used to feed calves (38.6%), consumed at home (26.5%), and sold (12.0%).The observed misuse of antibiotics and disregard for antibiotic withdrawal periods pose significant threats to both milk quality and human health. The authors recommend that dairy farmers prioritize animal health monitoring and implementing biosecurity measures to prevent diseases and thus reduce antibiotic usage. Collaborative efforts among stakeholders are highly recommended to enhance capacity building for dairy farmers and support research initiatives. Furthermore, it is strongly suggested to strengthen regulations on the prudent use of antibiotics within the Rwandan food production system to curb antimicrobial resistance across both animal and human populations.

BackgroundCongenital syphilis (CS) has reemerged as a global maternal and child health crisis. Kern County, California and East Baton Rouge Parish, Louisiana are among the highest CS morbidity regions in the United States. We previously reported on social-ecological and structural barriers to prenatal care and maternal syphilis testing and treatment in these two regions. The aim of this study was to examine perinatal patient's health preferences and perceptions of patient-provider relationships in the prenatal care clinic setting.MethodsBetween May 2018 and January 2019 we conducted 20 in-depth qualitative interviews with prenatal providers and 8 focus group discussions with pregnant and postpartum individuals in Kern County and East Baton Rouge Parish. We applied an adapted health services framework to analyze participants' understanding of health disparities and vulnerable populations; perinatal patient's health and prenatal care preferences; and participants' perspectives of clinical encounters in the context of prenatal care and maternal syphilis testing and treatment.ResultsSite-specific determinants of syphilis infection emerged but participants from both locations felt CS prevention efforts should be prioritized among youth, racial/ethnic minority populations, people experiencing socioeconomic limitations and people with other commonly occurring health conditions. Although perinatal patients expressed clear health preferences, they reported inconsistent receipt of respectful, patient-centered care. Inconsistencies were connected with limited ethnic and cultural competence among providers, and implicit, negative attitudes toward patients using substances, experiencing homelessness, or engaging in sex work. Providers clearly aimed to offer high quality prenatal care. However, some clinic and health systems level factors were thought to reduce positive and communicative patient-provider relationships, contributing to gaps in use of prenatal care and syphilis testing and treatment.ConclusionsOur findings suggest that interventions tailored to address setting-specific determinants (including clinic and health system factors) of disparities in CS risk could improve pregnant people's access to prenatal care and ensure they and their sex partners receive timely syphilis screening and treatment. We recommend all prenatal care providers receive training on how to identify and mitigate implicit biases and provide competent and compassionate patient-centered care.

Optical coherence tomography is a noninvasive imaging technique that provides three-dimensional visualization of subsurface tissue structures. OCT has been proposed and explored in the literature as a tool to assess oral cancer status, select biopsy sites, or identify surgical margins. Our endoscopic OCT device can generate widefield (centimeters long) imaging of lesions at any location in the oral cavity—but it is challenging for raters to quantitatively assess and score large volumes of data. Leveraging a previously developed epithelial segmentation network, this work develops quantifiable biomarkers that provide direct measurements of tissue properties in three dimensions. We hypothesize that features related to morphology, tissue attenuation, and contrast between tissue layers will be able to provide a quantitative assessment of disease status (dysplasia through carcinoma). This work retrospectively assesses seven biomarkers on a lesion-contralateral matched OCT dataset of the lateral and ventral tongue (40 patients, 70 sites). Epithelial depth and loss of epithelial–stromal boundary visualization provide the strongest discrimination between disease states. The stroma optical attenuation coefficient provides a distinction between benign lesions from dysplasia and carcinoma. The stratification biomarkers visualize subsurface changes, which provides potential for future utility in biopsy site selection or treatment margin delineation.

Purpose:. This study examined the leadership development themes that global orthopaedic surgeons in differently resourced countries perceive as essential components and evaluated barriers to attending leadership development programs. Methods:. This multinational, 45-question survey engaged orthopaedic surgeons (one expert per country). The questionnaire collected participants' demographics, perception of effective leadership traits, and valuation of various leadership themes based on importance and interest. Results:. The survey was completed by 110 orthopaedic surgeons worldwide. Respondents most commonly reported holding a leadership position (87%) in hospital settings (62%), clinical settings (47%), and national orthopaedic societies (46%). The greatest proportion of participants reported having never attended a leadership course (42%). Participants regarded “high performing team-building,” “professional ethics,” and “organizational structure and ability to lead” as the most important leadership themes. No significant (P ≤ 0.05) differences were identified among perceived importance or interest in leadership themes between income levels; however, statistically significant differences were identified in the questionnaire; respondents in low- and middle-income countries (LICs/LMICs) demonstrated a stronger interest in attending a leadership course than those in high-income countries (HICs) (98% vs. 79%, P = 0.013), and fewer surgeons in LICs/LMICs had taken personality assessment tests than those in HICs (22% vs. 49%, P = 0.019). The most common barriers to attending leadership courses were lack of opportunities and invitations (57%), difficulty missing work (22%), and cost of course attendance (22%). Conclusions:. These findings can better inform the development of effective curricula and provide a framework for a successful model for the future. Level of Evidence:. V.

Despite the availability of various treatment approaches for patients with posttraumatic stress disorder (PTSD), some patients do not respond to these therapies, and novel treatment approaches are needed. This study investigated the efficacy of mifepristone, a glucocorticoid receptor antagonist, in treatment-resistant PTSD patients. Three patients with PTSD who were resistant to standard psychological and pharmacological treatments were prescribed mifepristone (600–1,200 mg/day) for 1 week. A baseline-controlled single-case design was used, involving a 2-week baseline phase (no intervention), a 1-week intervention phase (mifepristone), and a 2-week postintervention phase. The primary outcome measure, self-reported PTSD symptom severity (PCL-5), was assessed daily, with participants providing their own control condition. Two of the three patients experienced a significant reduction in PTSD symptom severity after the intervention phase and no longer met the diagnostic criteria for PTSD. These positive results were maintained during long-term follow-up. These findings support the potential effectiveness of mifepristone in the treatment of patients with treatment-resistant PTSD. However, our findings must be interpreted with caution, and further studies with larger sample sizes and more rigorous designs are necessary to confirm the promising results.

BackgroundOne of the ways genomes respond to stress is by producing extrachromosomal circular DNAs (eccDNAs). EccDNAs can contain genes and dramatically increase their copy number. They can also reinsert into the genome, generating structural variation. They have been shown to provide a source of phenotypic and genotypic plasticity in several species. However, whole circularome studies have so far been limited to a few model organisms. Fungal plant pathogens are a serious threat to global food security in part because of their rapid adaptation to disease prevention strategies. Understanding the mechanisms fungal pathogens use to escape disease control is paramount to curbing their threat.ResultsWe present a whole circularome sequencing study of the rice blast pathogen, Magnaporthe oryzae. We find that M. oryzae has a highly diverse circularome that contains many genes and shows evidence of large LTR retrotransposon activity. We find that genes enriched on eccDNAs in M. oryzae occur in genomic regions prone to presence-absence variation and that disease-associated genes are frequently on eccDNAs. Finally, we find that a subset of genes is never present on eccDNAs in our data, which indicates that the presence of these genes on eccDNAs is selected against.ConclusionsOur study paves the way to understanding how eccDNAs contribute to adaptation in M. oryzae. Our analysis also reveals how M. oryzae eccDNAs differ from those of other species and highlights the need for further comparative characterization of eccDNAs across species to gain a better understanding of these molecules.

Abstract Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and β-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2.

Many familiar traits in the natural world-from lions' manes to the longevity of bristlecone pine trees-arose in the distant past, and have long since fixed in their respective species. A key challenge in evolutionary genetics is to figure out how and why species-defining traits have come to be. We used the thermotolerance growth advantage of the yeast Saccharomyces cerevisiae over its sister species Saccharomyces paradoxus as a model for addressing these questions. Analyzing loci at which the S. cerevisiae allele promotes thermotolerance, we detected robust evidence for positive selection, including amino acid divergence between the species and conservation within S. cerevisiae populations. Because such signatures were particularly strong at the chromosome segregation gene ESP1, we used this locus as a case study for focused mechanistic follow-up. Experiments revealed that, in culture at high temperature, the S. paradoxus ESP1 allele conferred a qualitative defect in biomass accumulation and cell division relative to the S. cerevisiae allele. Only genetic divergence in the ESP1 coding region mattered phenotypically, with no functional impact detectable from the promoter. Our data support a model in which an ancient ancestor of S. cerevisiae, under selection to boost viability at high temperature, acquired amino acid variants at ESP1 and many other loci, which have been constrained since then. Complex adaptations of this type hold promise as a paradigm for interspecies genetics, especially in deeply diverged traits that may have taken millions of years to evolve.

Abstract Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Background: As of 2019, the United States (US) was not on track to achieve targets for elimination, due to increasing incidence and treatment barriers. In 2020, the COVID-19 pandemic disrupted HCV services globally and in the US. As healthcare services normalize, there is an urgent need to reassess progress and evaluate scenarios that restore a pathway toward HCV elimination. Methods: We updated a validated Markov model to estimate HCV-related morbidity and mortality in the US. Five scenarios were developed to bookend possible HCV outcomes in the wake of the pandemic. These included 1) return to pre-COVID-19 treatment forecasts; 2) achieve elimination targets through treatment and harm reduction; 3) long-term treatment disruptions; 4/5) achieve elimination targets through increased treatment without increased harm reduction, starting in either 2022 or 2025. Findings: From 2014–2019, more than 1.2 million patients were treated for HCV in the US. Elimination targets in 2030 could be achieved in the US by treating an additional 3.2–3.3 million patients from 2020 to 2030, or by preventing new infections through expanded harm reduction programs and treating up to 2.7 million patients. Intervention scenarios could prevent over 30,000 HCC cases and over 29,000 liver-related deaths. Interpretation: The US has made strides toward HCV elimination, but gains could be lost in the wake of the pandemic. However, it is still possible to avert nearly 30,000 deaths through increased harm reduction and increased treatment rates. This requires a coordinated effort from the entire HCV community.

The Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) will observe several Deep Drilling Fields (DDFs) to a greater depth and with a more rapid cadence than the main survey. In this paper, we describe the 'DeepDrill' survey, which used the Spitzer Space Telescope Infrared Array Camera (IRAC) to observe three of the four currently defined DDFs in two bands, centred on 3.6 and 4.5 μm. These observations expand the area that was covered by an earlier set of observations in these three fields by the Spitzer Extragalactic Representative Volume Survey (SERVS). The combined DeepDrill and SERVS data cover the footprints of the LSST DDFs in the Extended Chandra Deep Field-South (ECDFS) field, the ELAIS-S1 field (ES1), and the XMM-Large-Scale Structure Survey field (XMM-LSS). The observations reach an approximate 5σ point-source depth of 2 μJy (corresponding to an AB magnitude of 23.1; sufficient to detect a 1011 M⊙ galaxy out to z ≈ 5) in each of the two bands over a total area of ≈ 29 deg2. The dual-band catalogues contain a total of 2.35 million sources. In this paper, we describe the observations and data products from the survey, and an overview of the properties of galaxies in the survey. We compare the source counts to predictions from the Shark semi-analytic model of galaxy formation. We also identify a population of sources with extremely red ([3.6]-[4.5] >1.2) colours which we show mostly consists of highly obscured active galactic nuclei.

Our paper introduces a simulation-based framework designed to interpret differential phase contrast (DPC) magnetic imaging within the transmission electron microscope (TEM). We investigate patterned magnetic membranes, particularly focusing on nano-patterned Co70Fe30 thin-film membranes fabricated via focused ion beam (FIB) milling. Our direct magnetic imaging reveals regular magnetic domain patterns in these carefully prepared systems. Notably, the observed magnetic structure aligns precisely with micromagnetic simulations based on the dimensions of the underlying nanostructures. This agreement emphasizes the usefulness of micromagnetic simulations, not only for the interpretation of DPC data, but also for the prediction of possible microstructures in magnetic sensor systems with nano-patterns.

Three galaxy clusters selected from the XXL X-ray survey at high redshift and low mass (z ~ 1 and M500 ~ 1 – 2 × 1014 M⊙) were observed with NIKA2 to image their Sunyaev-Zel'dovich effect (SZ) signal. They all present an SZ morphology, together with the comparison with X-ray and optical data, that indicates dynamical activity related to merging events. Despite their disturbed intracluster medium, their high redshifts, and their low masses, the three clusters follow remarkably well the pressure profile and the SZ flux-mass relation expected from standard evolution. This suggests that the physics that drives cluster formation is already in place at z ~ 1 down to M500 ~ 1014 M⊙.

Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases, including myopathies and muscular atrophy. However, the mechanistic understanding of specific components of the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive remain poorly understood. To characterize the KLHL40-regulated ubiquitin-modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of klhl40a mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy, biosynthetic metabolic processes, and vesicle trafficking. Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes, and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients.

There is increasing interest in the plant microbiome as it relates to both plant health and agricultural sustainability. One key unanswered question is whether we can select for a plant microbiome that is robust after colonization of target hosts. We used a successive passaging experiment to address this question by selecting upon the tomato phyllosphere microbiome. Beginning with a diverse microbial community generated from field-grown tomato plants, we inoculated replicate plants across 5 plant genotypes for 4 45-d passages, sequencing the microbial community at each passage. We observed consistent shifts in both the bacterial (16S amplicon sequencing) and fungal (internal transcribed spacer region amplicon sequencing) communities across replicate lines over time, as well as a general loss of diversity over the course of the experiment, suggesting that much of the naturally observed microbial community in the phyllosphere is likely transient or poorly adapted within the experimental setting. We found that both host genotype and environment shape microbial composition, but the relative importance of genotype declines through time. Furthermore, using a community coalescence experiment, we found that the bacterial community from the end of the experiment was robust to invasion by the starting bacterial community. These results highlight that selecting for a stable microbiome that is well adapted to a particular host environment is indeed possible, emphasizing the great potential of this approach in agriculture and beyond. In light of the consistent response of the microbiome to selection in the absence of reciprocal host evolution (coevolution) described here, future studies should address how such adaptation influences host health.