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The purpose of this design case was to document rigorously the process and decisions made during the development of a five-day, pre-semester virtual orientation for International Graduation Teaching Assistants (IGTAs) and their domestic counterparts, teaching in an English as a Second Language Composition (ESLC) Program of a large land-grant university. The design was grounded in a front-end analysis as well as a theoretical framework comprising Crenshaw's (1989) Intersectionality and Wenger's (1998) Virtual Community of Practice (VCoP) theory. These theories were leveraged to focus the design on IGTAs' educator identity development and their linguistic and cultural marginalization. VCoP theory provided a practical architecture for the virtual learning environment with its three modes of belonging (i.e., "engagement," "imagination," and "alignment") as well as several enabling structures (i.e., "support," "sponsorship," and "recognition"). The design intended to purposefully engage IGTAs in social practices and dialogue that would support their sense of belonging and educator identity. While significance can be extracted from the pre-planned, explicit alignment of certain design elements with the modes of belonging, precedent can also be derived from elements that emerged during the design process.

Abstract Objective Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. Results Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence. Methods TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated β-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment. Results OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro. Conclusion The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.

Digital Mental Health and Peer support has the potential to bridge gaps in support through its scalability and accessibility. Despite the increasing use of these platforms, there remains a lack of understanding of how they operate in real life, from initial engagement to longer-term impact. We aimed to explore the key inputs, processes, user interactions, assumptions, barriers, facilitators, outcomes, and impacts associated with the use of DMH and peer support platforms by developing a Theory of Change with stakeholders. Stakeholders (n = 77) contributed to the formulation of the Theory of Change through a series of online workshops, focus groups, interviews, and open-ended survey feedback. Workshops were structured to capture information related to aspects of the Theory of Change and to allow stakeholders to provide feedback to improve the diagram. A thematic framework approach was used to analyze transcripts to enable comparisons of factors reported by members, commissioners, and platform staff. Stakeholders identified a variety of factors contributing to initial inputs, processes, outcomes, and impact. Engagement emerged as the most significant barrier to the use of platforms. Motivations for use included filling in gaps in available support, connecting with others and upskilling. Different member types determined how users would interact with the platform which could influence the social response of others. Outcomes were largely positive including provision of a safe online space, improvement in wellbeing, and feeling connected to others. Stakeholders noted impact was harder to identify due to the preventative nature of these platforms but suggested this related to the knowledge of available support, reduction in waiting for support and in referrals, and increasing engagement and uptake of the platforms. Stakeholders identified assumptions regarding internet access as a significant barrier. The Theory of Change illustrated three distinct pathways in digital mental health and peer support. Further research is needed to improve engagement and factors influencing engagement, the member experience and how impact is measured.

The gut microbiome can affect various aspects of both behavior and physiology, including exercise ability, but effects on voluntary exercise have rarely been studied. We studied females from a selection experiment in which 4 replicate High Runner (HR) lines of mice are bred for voluntary exercise and compared with 4 non-selected control (C) lines. HR and C mice differ in several traits that likely interact with the gut microbiome, including higher daily running distance, body temperatures when running, spontaneous physical activity when housed without wheels, and food consumption. After two weeks of wheel access to reach a stable plateau in daily running, mice were administered broad-spectrum antibiotics for 10 days. Antibiotic treatment caused a significant reduction in daily wheel-running distance in the HR mice (-21%) but not in the C mice. Antibiotics did not affect body mass or food consumption in either HR or C mice, and we did not observe sickness behavior. Wheel running by HR mice did not recover during the 12 days following cessation of antibiotics. The decreased wheel-running in HR but not C mice, with no apparent negative side effects of antibiotics, suggests that the HR microbiome is an important component of their high-running phenotype.

The COVID-19 pandemic obliged Argentina to adopt distance learning to continue university classes during 2020. In this article, a study is presented on the perceptions and perspectives of the faculty in the School of Education Sciences of the Universidad Nacional de Entre Ríos regarding this emergency educational virtualization. The methodology regards a case study. For the collection of information, a virtual survey was used that led to a qualitative and quantitative analysis of the responses. A statistical analysis of language patterns was implemented through the program Linguistic Inquiry and Word Count in order to examine affective, cognitive, and social processes linked to the use of technologies during the pandemic. The results indicate that, whereas the faculty had available technologies, abilities to use them, and an appropriate institutional environment, in that moment emerging difficulties manifested related to the conditions of livability and the possibilities of spatial-temporal organization for carrying out telework. It is concluded that extracognitive factors, such as domestic conditions and perceptions of virtuality in teaching, are two unavoidable aspects for moving towards modalities with a higher degree of mediatization during the post-pandemic period.

AimsTo characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI).MethodsAdult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin.Key findingsCompared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces.SignificanceOur findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.

Microgravity has been shown to be an excellent tool for protein crystal formation. A retrospective analysis of all publicly available crystallization data, including many that have not yet been published, clearly demonstrates the value of the microgravity environment for producing superior protein crystals. The parameters in the database (the Butler Microgravity Protein Crystal Database, BμCDB) that were evaluated pertain to both crystal morphology and diffraction quality. Success metrics were determined as improvements in size, definition, uniformity, mosaicity, diffraction quality, resolution limits, and B factor. The proteins in the databases were evaluated by molecular weight, protein type, the number of subunits, space group, and Mattew’s Coefficient. Compared to ground experiments, crystals grown in a microgravity environment continue to show improvement across all metrics evaluated. General trends as well as numerical differences are included in the assessment of the BμCDB. The microgravity environment improves crystal formation across a spectrum of metrics and the datasets utilized for this investigation are excellent tools for this evaluation.

Abstract Parturition and the early neonatal period are critical life history stages in ungulates with considerable implications for population growth and persistence. Understanding the changes in behaviour induced by ungulate parturition is important for supporting effective population management, but reliably identifying birth sites and dates presents a challenge for managers. Rocky Mountain bighorn sheep (Ovis canadensis canadensis) are one such highly valued and ecologically important species in montane and subalpine ecosystems of Western North America. In the face of changing patterns of anthropogenic land use, wildlife managers increasingly require site-specific knowledge of the movement and habitat selection characteristics of periparturient sheep to better inform land use planning initiatives and ensure adequate protections for lambing habitat. We used movement data from GPS collared parturient (n = 13) and non-parturient (n = 8) bighorn sheep in Banff National Park, Canada to (1) identify lambing events based on changes in key movement metrics, and (2) investigate how resource selection and responses to human use change during the periparturient period. We fit a hidden Markov model (HMM) to a multivariate characterization of sheep movement (step length, daily home range area, residence time) to predict realistic lambing dates for the animals in our study system. Leave-one-out cross validation of our model resulted in a 93% success rate for parturient females. Our model, which we parameterized using data from known parturient females, also predicted lambing events in 25% of known non-parturient ewes in a test dataset. Using a latent selection difference function and resource selection functions, we tested for postpartum changes in habitat use, as well as seasonal differences in habitat selection. Immediately following lambing, ewes preferentially selected high-elevation sites on solar aspects that were more rugged, closer to escape terrain, and further from roads. Within-home range habitat selection was similar between individuals in different reproductive states, but parturient ewes had stronger selection for low snow depth, sites closer to barren ground, and sites further from trails. We propose that movement-based approaches such as HMMs are a valuable tool for identifying critical parturition habitat in species with complex movement patterns and may have particular utility in study areas without access to extensive field observations or vaginal implant transmitters. Furthermore, our results suggest that managers should minimize human disturbance in lambing areas to avoid interfering with maternal behaviour and ensure access to a broad range of suitable habitat in the periparturient period.

Abstract Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity.

The use of nonsteroidal anti-inflammatory drug (NSAID) medications is a risk factor for peptic ulcer disease (PUD). PUD in the postpartum period is rare, despite the common use of NSAIDs. A G1P0 presented 6 days postcesarean section with fatigue, lightheadedness, melenic stools, and a hemoglobin of 5.4 g/dL after using NSAIDs and acetaminophen for postoperative pain control. An esophagogastroduodenoscopy (EGD) was performed for a suspected upper gastrointestinal bleed and found one gastric and one duodenal ulcer. Though typically used for a short course in the postpartum period, NSAIDs remain a predisposing risk factor for PUD postpartum, and patients and providers must be aware of this risk.

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Emotional problems in early childhood increase the risk of mental health problems into adolescence and adulthood, but the cross-cultural etiological risk factors are unclear. We examined predictors of emotional problems in preschoolers, using a national cohort of children in Chile and in Scotland. Participants included 1648 children and their families enrolled in the Chilean Encuesta Longitudinal de la Primera Infancia (ELPI) cohort and 3786 children and their families enrolled in the Growing Up in Scotland (GUS) cohort. Data were collected between 2005 and 2012. Information on emotional problems along with social and health determinants were collected via maternal reports. Emotional problems in the clinical range were identified in 10.4% of children from the ELPI cohort and in 3.6% of children from the GUS cohort. The difference between cohorts was statistically significant. Logistic regression revealed that maternal unemployment predicted emotional problems across cohorts. Lower maternal education and living in rural areas predicted higher risk of emotional problems for the ELPI cohort only, whereas having a younger mother, daily parent-child shared activities such as a lower frequency of sharing letters/shapes, and a higher exposure to television predicted higher risk for emotional problems for the GUS cohort. Maternal unemployment as a risk factor across cohorts indicates the importance of shared cross-cultural factors. However, sample specific differences highlight the importance and need for greater attention towards cultural specificities in policy and intervention development for child mental health., Author(s): Chamarrita Farkas [sup.1] , Lisa-Christine Girard [sup.2] , Angus MacBeth [sup.2] Author Affiliations: (1) grid.7870.8, 0000 0001 2157 0406, Psychology School, Faculty of Social Sciences, Pontificia Universidad Católica de [...]

The bacterium Vibrio cholerae is the etiologic agent of the severe human diarrheal disease cholera. The gut microbiome, or the native community of microorganisms found in the human gastrointestinal tract, is increasingly being recognized as a factor in driving susceptibility to infection, in vivo fitness, and host interactions of this pathogen. Here, we review a subset of the emerging studies in how gut microbiome structure and microbial function are able to drive V. cholerae virulence gene regulation, metabolism, and modulate host immune responses to cholera infection and vaccination. Improved mechanistic understanding of commensal-pathogen interactions offers new perspectives in the design of prophylactic and therapeutic approaches for cholera control.

Inflammatory bowel disease (IBD) pathogenesis involves significant contributions from genetic and environmental factors. Loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene increase IBD risk and are associated with altered microbiome population dynamics in IBD. Expansion of intestinal pathobionts, such as adherent-invasive E. coli (AIEC), is strongly implicated in IBD pathogenesis as AIEC increases pro-inflammatory cytokine production and alters tight junction protein regulation - suggesting a potential mechanism of pathogen-induced barrier dysfunction and inflammation. We aimed to determine if PTPN2 deficiency alters intestinal microbiome composition to promote expansion of specific bacteria with pathogenic properties. In mice constitutively lacking Ptpn2, we identified increased abundance of a novel mouse AIEC (mAIEC) that showed similar adherence and invasion of intestinal epithelial cells, but greater survival in macrophages, to the IBD-associated AIEC, LF82. Furthermore, mAIEC caused disease when administered to mice lacking segmented-filamentous bacteria (SFB), and in germ-free mice but only when reconstituted with a microbiome, thus supporting its classification as a pathobiont, not a pathogen. Moreover, mAIEC infection increased the severity of, and prevented recovery from, induced colitis. Although mAIEC genome sequence analysis showed >90% similarity to LF82, mAIEC contained putative virulence genes with >50% difference in gene/protein identities from LF82 indicating potentially distinct genetic features of mAIEC. We show for the first time that an IBD susceptibility gene, PTPN2, modulates the gut microbiome to protect against a novel pathobiont. This study generates new insights into gene-environment-microbiome interactions in IBD and identifies a new model to study AIEC-host interactions.

Eating disorders (ED) are serious disorders characterized by an alteration of eating habits and excessive concern about weight and body shapes (Fairburn, 2002), accompanied by significant impairment inequality of life, high mortality rates and serious organic consequences (Jenkins et al., 2011; Treasure et al., 2015; 2020). Although evidence-based psychological therapies for nonunderweight ED presentations such as cognitive behavioral therapy for eating disorders (CBT-ED) are widely available, there is substantial scope for improvements, particularly in terms of efficacy and adherence. One option is to develop interventions to address elements of pathology not fully addressed by existing empirical supported treatments, such as incorporating techniques aimed at addressing interpersonal problems and personality disorder features into existing treatment delivery. We adapted Metacognitive Interpersonal Therapy, a psychological intervention supported by evidence for treating personality disorders and integrated it with existing CBT techniques for eating disorders (MIT-ED). MIT-ED targets aspects of ED that are not included in the transdiagnostic CBT-E model such as poor metacognition, or maladaptive interpersonal schemas. This is a pre-registered (Protocol number: 0000781) pilot randomized clinical trial aimed at assessing acceptability and feasibility of MIT-ED and establishing preliminary evidence of effectiveness for future larger studies. Twenty patients (10 in each arm) will be randomized to 20 sessions of individual psychotherapy, either MIT-ED or CBTE. Repeated follow-ups will be collected up to 24 months. Participants are recruited at a private outpatient clinic for ED treatment. Acceptability will be assessed via session attendance, completion rates and preliminary outcomes. The primary outcome is ED pathology assessed with the Eating Disorder Examination Questionnaire-6. Other ED outcomes assessed will be eating disorder attitudes, clinical impairment and binge eating pathology. Secondary treatment outcomes are anxiety, depression, and global symptomatology. We will also assess emotional awareness, emotion regulation and therapeutic alliance. Based on previous studies of MIT for personality disorders we hypothesize that MIT-ED will be acceptable to patients, evidenced by high treatment adherence and retention. We hypothesize that MIT-ED will be associated with reductions in eating disorder pathology, at least equivalent to CBT-E. Results will be used to inform the study design, sampling, likely effect sizes and choice of outcome measures for future larger trials of MIT-ED in ED samples.