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In 2018/2019, two large Guillain–Barré Syndrome (GBS) outbreaks took place in Peru. Here, we report a comprehensive analysis of biological samples from GBS patients from the 2019 outbreak. We applied metagenomic, microbiologic, and serological analyses to different biological samples collected from GBS patients. Further phenotypic and genomic characterization was conducted on Campylobacter jejuni isolates from GBS samples. Microbiologic and metagenomic analyses revealed several patients with multiple co-infections, yet no common infectious agents were found other than C. jejuni. Four C. jejuni isolates were isolated from rectal swabs. Twenty-one patients had detectable IgG serum antibodies related to C. jejuni, of whom seven had IgM antibodies. Genomic analyses showed that these four strains were clonal (ST2993) and contained the class A lipooligosaccharide biosynthesis locus. These results further support the idea that that C. jejuni is the etiological agent that triggered the GBS outbreak in Peru in 2019 and that the strains are not restricted to Peru, hence could be regarded as a broad public health concern. Furthermore, though we cannot delineate the role played by co-infections in GBS development, results obtained herein highlight metagenomic analysis as a potential new tool for depicting a yet unknown area of research in GBS.

Castration-resistant prostate cancer (CRPC) is the main driving force of mortality in prostate cancer patients. Among the parameters contributing to the progression of CRPC and treatment failure, elevation of the steroidogenic enzyme AKR1C3 and androgen receptor variant 7 (AR-V7) are frequently reported. The AKR1C3/AR-V7 complex has been recognized as a major driver for drug resistance in advanced prostate cancer. Herein we report that the level of AKR1C3 is reciprocally regulated by the full-length androgen receptor (AR-FL) through binding to the distal enhancer region of the AKR1C3 gene. A novel function of PTUPB in AKR1C3 inhibition was discovered and PTUPB showed more effectiveness than indomethacin and celecoxib in suppressing AKR1C3 activity and CRPC cell growth. PTUPB synergizes with enzalutamide treatment in tumor suppression and gene signature regulation. Combination treatments with PTUPB and enzalutamide provide benefits by blocking AR/AR-V7 signaling, which inhibits the growth of castration relapsed VCaP xenograft tumors and patient-derived xenograft organoids. Targeting of the ARK1C3/AR/AR-V7 axis with PTUPB and enzalutamide may overcome drug resistance to AR signaling inhibitors in advanced prostate cancer.

Melioidosis is a potentially severe disease caused by the gram-negative soil-dwelling bacterium called Burkholderia pseudomallei. The true breadth of the distribution of this tropical pathogen is starting to emerge with environmental and clinical isolates frequently characterized in new countries and regions. Even so, isolates, clinical cases, and genetic data from the continent of Africa remain scant. We previously confirmed the presence of B. pseudomallei in the environment of Ghana, unmasking a new area of endemicity for this pathogen. Here, we describe the genetic characteristics of isolates obtained from that environmental survey. Twenty-one isolates were subjected to whole genome sequencing and found to represent three discrete sequence types (ST), one of which was novel, and designated ST2058. Phylogenetic analysis places this novel isolate within a B. pseudomallei clade that includes genomes derived from the Americas, although it is closely related to a sub-clade that includes isolates from Africa. Importantly, phenotypic characterization demonstrates common features including API 20NE profiles and B. pseudomallei CPS to support existing diagnostics, and susceptibility to standard of care antibiotics often used in the clinical management of melioidosis. These findings add to our knowledge about the presence and distribution of B. pseudomallei in Africa and represent the first published genomes out of Ghana.

Background: In South Carolina (SC), 42% of youth are overweight or obese. Two sets of modifiable behaviors contributing to obesity are physical activity (PA) and dietary habits. School-based interventions have successfully improved these behaviors. The purpose of this study was to identify SC public school personnel perspectives on the most common barriers and facilitators to regular PA and healthy eating behaviors in schools. Methods: A needs assessment survey was conducted with school personnel statewide. There were 17 questions on the survey that addressed: (1) demographic information about participants' educational backgrounds, (2) barriers to regular PA and healthy eating behaviors in schools, and (3) facilitators to regular PA and healthy eating behaviors in schools. Univariate and bivariate descriptive statistical analyses were performed using IBM SPSS Statistics 27. Results: Participants (N = 1311) indicated insufficient time for regular PA (n = 514, 39.2%) and limited access to healthy foods for healthy eating (n = 271, 20.7%) as main barriers. The primary facilitators were support from administrators for regular PA (n = 264, 20.1%) and support from cafeteria staff for healthy eating (n = 234, 17.8%). Further analyses explored how factors compared based on roles in schools, academic levels, and school district classifications. Conclusions: Results suggest that overarching barriers and facilitators to school-based interventions addressing childhood obesity exist, so common strategies to mitigate challenges and maximize supports can be used in schools. Future studies are needed to examine how decreasing barriers and enhancing facilitators affect the implementation and outcomes of these school-based interventions.

Infection with either Rickettsia prowazekii or Orientia tsutsugamushi is common, yet diagnostic capabilities are limited due to the short window for positive identification. Until now, although targeted enrichment had been applied to increase sensitivity of sequencing-based detection for various microorganisms, it had not been applied to sequencing of R. prowazekii in clinical samples. Additionally, hybridization-based targeted enrichment strategies had only scarcely been applied to qPCR of any pathogens in clinical samples. Therefore, we tested a targeted enrichment technique as a proof of concept and found that it dramatically reduced the limits of detection of these organisms by both qPCR and high throughput sequencing. The enrichment methodology was first tested in contrived clinical samples with known spiked-in concentrations of R. prowazekii and O. tsutsugamushi DNA. This method was also evaluated using clinical samples, resulting in the simultaneous identification and characterization of O. tsutsugamushi directly from clinical specimens taken from sepsis patients. We demonstrated that the targeted enrichment technique is helpful by lowering the limit of detection, not only when applied to sequencing, but also when applied to qPCR, suggesting the technique could be applied more broadly to include other assays and/or microbes for which there are limited diagnostic or detection modalities.

IntroductionWe sought to determine pre-infection correlates of protection against SARS-CoV-2 post-vaccine inzfections (PVI) acquired during the first Omicron wave in the United States.MethodsSerum and saliva samples from 176 vaccinated adults were collected from October to December of 2021, immediately before the Omicron wave, and assessed for SARS-CoV-2 Spike-specific IgG and IgA binding antibodies (bAb). Sera were also assessed for bAb using commercial assays, and for neutralization activity against several SARS-CoV-2 variants. PVI duration and severity, as well as risk and precautionary behaviors, were assessed by questionnaires.ResultsSerum anti-Spike IgG levels assessed by research assay, neutralization titers against Omicron subvariants, and low home risk scores correlated with protection against PVIs after multivariable regression analysis. Commercial assays did not perform as well as research assay, likely due to their lower dynamic range.DiscussionIn the 32 participants that developed PVI, anti-Spike IgG bAbs correlated with lower disease severity and shorter duration of illness.

Abstract Background Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of allergic lung disease. However, the molecular mechanisms through which MWCNTs exacerbate allergen-induced lung disease remain to be elucidated. We hypothesized that protease-activated receptor 2 (PAR2), a G-protein coupled receptor previously implicated in the pathogenesis of various diseases including pulmonary fibrosis and asthma, may play an important role in the exacerbation of house dust mite (HDM) allergen-induced lung disease by MWCNTs. Methods Wildtype (WT) male C57BL6 mice and Par2 KO mice were exposed to vehicle, MWCNTs, HDM extract, or both via oropharyngeal aspiration 6 times over a period of 3 weeks and were sacrificed 3-days after the final exposure (day 22). Bronchoalveolar lavage fluid (BALF) was harvested to measure changes in inflammatory cells, total protein, and lactate dehydrogenase (LDH). Lung protein and RNA were assayed for pro-inflammatory or profibrotic mediators, and formalin-fixed lung sections were evaluated for histopathology. Results In both WT and Par2 KO mice, co-exposure to MWCNTs synergistically increased lung inflammation assessed by histopathology, and increased BALF cellularity, primarily eosinophils, as well as BALF total protein and LDH in the presence of relatively low doses of HDM extract that alone produced little, if any, lung inflammation. In addition, both WT and par2 KO mice displayed a similar increase in lung Cc1-11 mRNA, which encodes the eosinophil chemokine CCL-11, after co-exposure to MWCNTs and HDM extract. However, Par2 KO mice displayed significantly less airway fibrosis as determined by quantitative morphometry compared to WT mice after co-exposure to MWCNTs and HDM extract. Accordingly, at both protein and mRNA levels, the pro-fibrotic mediator arginase 1 (ARG-1), was downregulated in Par2 KO mice exposed to MWCNTs and HDM. In contrast, phosphorylation of the pro-inflammatory transcription factor NF-κB and the pro-inflammatory cytokine CXCL-1 was increased in Par2 KO mice exposed to MWCNTs and HDM. Conclusions Our study indicates that PAR2 mediates airway fibrosis but not eosinophilic lung inflammation induced by co-exposure to MWCNTs and HDM allergens.

Prostate cancer is one of the most common malignant tumors in men. Initially, it is androgen-dependent, but it eventually develops into castration-resistant prostate cancer (CRPC), which is incurable with current androgen receptor signaling target therapy and chemotherapy. Immunotherapy, specifically with immune checkpoint inhibitors, has brought hope for the treatment of this type of prostate cancer. Approaches such as vaccines, adoptive chimeric antigen receptor-T (CAR-T) cells, and immune checkpoint inhibitors have been employed to activate innate and adaptive immune responses to treat prostate cancer, but with limited success. Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. Prostate cancer has a complex tumor microenvironment (TME) in which various immunosuppressive molecules and mechanisms coexist and interact. Additionally, prostate cancer is considered a "cold" tumor with low levels of tumor mutational burden, low amounts of antigen-presenting and cytotoxic T-cell activation, and high levels of immunosuppressive molecules including cytokines/chemokines. Thus, understanding the mechanisms of immunosuppressive signaling activation and immune evasion will help develop more effective treatments for prostate cancer. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer.

Background: School-based interventions and strategies targeting physical activity (PA) and eating patterns have successfully addressed unhealthy behaviors contributing to excess weight in school-age children. The purpose of this study was to investigate South Carolina (SC) public school administrators' perceptions of and experiences with weight-related issues in schools and associated barriers and facilitators to awareness, selection, and implementation of school-based healthy PA and eating interventions and strategies. Methods: This qualitative descriptive study, guided by the Social Ecological Model and the Steps in Quality Intervention Development Model, involved semistructured interviews with SC public school administrators from all academic levels (N = 28). Data were analyzed using thematic analysis. Results: Four themes were identified from interviews (N = 28): weight-related terminology or stigma, experiences with school-based healthy PA and eating interventions and strategies, barriers to school-based healthy PA and eating interventions and strategies, and facilitators to school-based healthy PA and eating interventions and strategies. Conclusions: Schools are well-positioned to provide interventions and strategies to improve PA and dietary habits leading to childhood obesity. School administrators, while knowledgeable and experienced with weight-related issues and school-based interventions and strategies, encounter barriers and facilitators that impact offerings and delivery. Understanding these challenges and supports is important in the development, adaptation, and implementation of school-based interventions and strategies focused on healthy PA and eating behaviors.

Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.

TNK1 is a non-receptor tyrosine kinase with poorly understood biological function and regulation. Here, we identify TNK1 dependencies in primary human cancers. We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity. Conversely, the release of TNK1 from 14-3-3 allows TNK1 to cluster in ubiquitin-rich puncta and become active. Active TNK1 induces growth factor-independent proliferation of lymphoid cells in cell culture and mouse models. One unusual feature of TNK1 is a ubiquitin-association domain (UBA) on its C-terminus. Here, we characterize the TNK1 UBA, which has high affinity for poly-ubiquitin. Point mutations that disrupt ubiquitin binding inhibit TNK1 activity. These data suggest a mechanism in which TNK1 toggles between 14-3-3-bound (inactive) and ubiquitin-bound (active) states. Finally, we identify a TNK1 inhibitor, TP-5801, which shows nanomolar potency against TNK1-transformed cells and suppresses tumor growth in vivo.

Background: The purpose of this study was to determine whether cold therapy after the first exercise test influences the physical working capacity at the fatigue threshold (PWCFT) during the second exercise test. We hypothesized that cold therapy would delay the onset of PWCFT for the second exercise test relative to the control visit (i.e., no cold therapy). Methods: Eight healthy college-aged men volunteered for the present study. For each of the two visits, subjects performed incremental, single-leg, knee-extensor ergometer, followed by either resting for 30 min (control visit) or having a cold pack applied for 15 min and then resting for 15 min (experimental visit). Then, the same exercise test was performed. The order of visits (control vs. experimental) was randomized for each subject. The exercise indices and PWCFT were determined for each of the two visits and statistically analyzed using two-way repeated measures analysis of variance. Results: The results indicate no significant (p > 0.05) mean differences for maximal power output, heart rate at end-exercise, and PWCFT between the control and cold therapy visits. Moreover, there were no significant (p > 0.05) mean differences between the first and second exercise workbout within each visit. Conclusions: The findings of this study suggest that cold therapy did not influence neuromuscular fatigue.

Migration patterns are fundamentally linked to the spatio-temporal distributions of prey. How migrating animals can respond to changes in their prey's distribution and abundance remains largely unclear. During the last decade, humpback whales (Megaptera novaeangliae) used specific winter foraging sites in fjords of northern Norway, outside of their main summer foraging season, to feed on herring that started overwintering in the area. We used photographic matching to show that whales sighted during summer in the Barents Sea foraged in northern Norway from late October to February, staying up to three months and showing high inter-annual return rates (up to 82%). The number of identified whales in northern Norway totalled 866 individuals by 2019. Genetic sexing and hormone profiling in both areas demonstrate a female bias in northern Norway and suggest higher proportions of pregnancy in northern Norway. This may indicate that the fjord-based winter feeding is important for pregnant females before migration. Our results suggest that humpback whales can respond to foraging opportunities along their migration pathways, in some cases by continuing their feeding season well into winter. This provides an important reminder to implement dynamic ecosystem management that can account for changes in the spatio-temporal distribution of migrating marine mammals.

Abstract Interdisciplinary teams are on the rise as scientists attempt to address complex environmental issues. While the benefits of team science approaches are clear, researchers often struggle with its implementation, particularly for new team members. The challenges of large projects often weigh on the most vulnerable members of a team: trainees, including undergraduate students, graduate students, and post‐doctoral researchers. Trainees on big projects have to navigate their role on the team, with learning project policies, procedures, and goals, all while also training in key scientific tasks such as co‐authoring papers. To address these challenges, we created and participated in a project‐specific, graduate‐level team science course. The purposes of this course were to: (1) introduce students to the goals of the project, (2) build trainees' understanding of how big projects operate, and (3) allow trainees to explore how their research interests dovetailed with the overall project. Additionally, trainees received training regarding: (1) diversity, equity & inclusion, (2) giving and receiving feedback, and (3) effective communication. Onboarding through the team science course cultivated psychological safety and a collaborative student community across disciplines and institutions. Thus, we recommend a team science course for onboarding students to big projects to help students establish the skills necessary for collaborative research. Project‐based team science classes can benefit student advancement, enhance the productivity of the project, and accelerate the discovery of solutions to ecological issues by building community, establishing a shared project vocabulary, and building a workforce with collaborative skills to better answer ecological research questions.

We present ADIOS 2, the latest version of the Adaptable Input Output (I/O) System. ADIOS 2 addresses scientific data management needs ranging from scalable I/O in supercomputers, to data analysis in personal computer and cloud systems. Version 2 introduces a unified application programming interface (API) that enables seamless data movement through files, wide-area-networks, and direct memory access, as well as high-level APIs for data analysis. The internal architecture provides a set of reusable and extendable components for managing data presentation and transport mechanisms for new applications. ADIOS 2 bindings are available in C++11, C, Fortran, Python, and Matlab and are currently used across different scientific communities. ADIOS 2 provides a communal framework to tackle data management challenges as we approach the exascale era of supercomputing.

Vacancies are generated in semiconductor devices while operating in the space radiation environment, impacting semiconductor carrier concentrations and dynamics. Positron annihilation lifetime spectroscopy (PALS) is used to probe these defect concentrations in bulk grown GaN, GaP, InAs, InP, Si, MgO, and ZnO both as-grown and as a function of 2–4 MeV proton irradiation. All samples were irradiated to yield a common initial damage production and characterized identically. In as-grown samples, PALS reveals vacancy concentrations above the saturation limit in the oxides, disabling further analysis. As a function of dose, of the materials in which defect accumulation could be probed, it is observed that GaN is the most resistant to the accumulation of defects (attributed to the Ga vacancies) and Si is the least. GaP (attributed to the Ga vacancy) and InAs exhibit slightly higher rates of vacancy accumulation than GaN. InP exhibits high defect accumulation rates approaching that of Si. This information is key to understanding the operation of a diverse set of semiconductors in the space radiation environment. [ABSTRACT FROM AUTHOR]