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Comparative analysis of (meta)genomes necessitates aggregation, integration, and synthesis of well-annotated data using standards. The Genomic Standards Consortium (GSC) collaborates with the research community to develop and maintain the Minimum Information about any (x) Sequence (MIxS) reporting standard for genomic data. To facilitate the use of the GSC's MIxS reporting standard, we provide a description of the structure and terminology, how to navigate ontologies for required terms in MIxS, and demonstrate practical usage through a soil metagenome example.

Despite recent advances in our understanding of pathogenic access to the central nervous system (CNS), the mechanisms by which intracellular pathogens disseminate within the dense cellular network of neural tissue remain poorly understood. To address this issue, longitudinal analysis of Toxoplasma gondii dissemination in the brain was conducted using 2-photon imaging through a cranial window in living mice that transgenically express enhanced green fluorescent protein (eGFP)-claudin-5. Extracellular T. gondii parasites were observed migrating slowly (1.37 ± 1.28 μm/min) and with low displacement within the brain. In contrast, a population of highly motile infected cells transported vacuoles of T. gondii significantly faster (6.30 ± 3.09 μm/min) and with a higher displacement than free parasites. Detailed analysis of microglial dynamics using CX3CR1-GFP mice revealed that T. gondii-infected microglia remained stationary, and infection did not increase the extension/retraction of microglial processes. The role of infiltrating immune cells in shuttling T. gondii was examined by labeling of peripheral hematopoietic cells with anti-CD45 antibody. Infected CD45+ cells were found crawling along the CNS vessel walls and trafficked T. gondii within the brain parenchyma at significantly higher speeds (3.35 ± 1.70 μm/min) than extracellular tachyzoites. Collectively, these findings highlight a dual role for immune cells in neuroprotection and in facilitating parasite dissemination within the brain. IMPORTANCE T. gondii is a foodborne parasite that infects the brain and can cause fatal encephalitis in immunocompromised individuals. However, there is a limited understanding of how the parasites disseminate through the brain and evade immune clearance. We utilized intravital imaging to visualize extracellular T. gondii tachyzoites and infected cells migrating within the infected mouse brain during acute infection. The infection of motile immune cells infiltrating the brain from the periphery significantly increased the dissemination of T. gondii in the brain compared to that of free parasites migrating using their own motility: the speed and displacement of these infected cells would enable them to cover nearly 1 cm of distance per day! Among the infiltrating cells, T. gondii predominantly infected monocytes and CD8+ T cells, indicating that the parasite can hijack immune cells that are critical for controlling the infection in order to enhance their dissemination within the brain.

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically promotes a distinct CD8αα+CD4+ intraepithelial lymphocyte (IEL) population that acquires their functional differentiation at the intestinal epithelium. Loss of IL-27 in IECs leads to a selective defect in CD8αα+CD4+ IELs over time. Consequently, mice with IEC-specific IL-27 ablation exhibited elevated pathogen burden during parasitic infection, and this could be rescued by transfer of exogenous CD8αα+CD4+ IELs. Collectively, our data reveal that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity by inducing a specific IEL subset and further suggest that IL-27 produced by different cell types plays distinct roles in maintaining intestinal homeostasis.

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

Military service presents unique challenges and opportunities for health care and public health. In the USA, there are over 2 million military servicemembers, 20 million veterans, and millions more military and veteran family members. Military servicemembers and eligible family members, many veterans, and retirees receive health care through the two largest learning health care systems in the USA, managed and delivered through the Departments of Defense (DoD), Veterans Affairs (VA), and contracted health care organizations. Through a network of collaborative relationships, DoD, VA, and partnering health care and research organizations (university, corporate, community, and government) accelerate research translation into best practices and policy across the USA and beyond. This article outlines military and veteran health research translation as summarized from a collaborative workshop led by experts across health care research, practice, and administration in DoD, VA, the National Institutes of Health, and affiliated universities. Key themes and recommendations for research translation are outlined in areas of: (a) stakeholder engagement and collaboration; (b) implementation science methods; and (c) funding along the translation continuum. Overall, the ability to rapidly translate research into clinical practice and policy for positive health outcomes requires collaborative relationships among many stakeholders. This includes servicemembers, veterans, and their families along with researchers, health care clinicians, and administrators, as well as policymakers and the broader population.

Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that Toxoplasma infection induces a dysbiosis dominated by Enterobacteriaceae and an increased potential for nitrate respiration. In vivo experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of Enterobacteriaceae in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Enterobacteriaceae Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with T. gondii, in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology.IMPORTANCEToxoplasma gondii is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with Toxoplasma-as well as numerous other pathogens-is the overgrowth of Escherichia coli or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.

Introduction: Early identification of sepsis significantly improves outcomes, suggesting a role for prehospital screening. An end-tidal carbon dioxide (ETCO2) value ≤ 25 mmHg predicts mortality and severe sepsis when used as part of a prehospital screening tool. Recently, the Quick Sequential Organ Failure Assessment (qSOFA) score was also derived as a tool for predicting poor outcomes in potentially septic patients.  Methods: We conducted a retrospective cohort study among patients transported by emergency medical services to compare the use of ETCO2 ≤ 25 mmHg with qSOFA score of ≥ 2 as a predictor of mortality or diagnosis of severe sepsis in prehospital patients with suspected sepsis.  Results: By comparison of receiver operator characteristic curves, ETCO2 had a higher discriminatory power to predict mortality, sepsis, and severe sepsis than qSOFA.  Conclusion: Both non-invasive measures were easily obtainable by prehospital personnel, with ETCO2 performing slightly better as an outcome predictor.

IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.

The widespread adoption of battery electric vehicles (BEVs) is hindered by their limited ranges and long charging times. Optimizing eco-driving strategies and BEV-specific routing through a thorough understanding of the BEV discharge behavior is vital to overcome these barriers in the short term. Therefore, this study investigates the impact of road types on the BEV discharge behavior while accounting for explanatory variables (i.e., ambient temperature, the initial state of charge, and driver). Thirty participants drove a 2017 Volkswagen eGolf along two predefined routes in Rhode Island. The results illustrate that BEVs are the most efficient on-road types with medium speed and low variation (i.e., “major collectors,” “minor arterials,” and “other principal arterials”). Meanwhile, findings confirmed a significantly higher average energy consumption rate on roads with higher average speeds (“interstates” and “other freeways/expressways”). Moreover, “local roads,” associated with a low average travel speed and a high variation in speed, showed a negative effect on BEV efficiency. The study further supported previous findings that BEVs are less efficient in colder temperatures. Thus, adapting eco-driving strategies, including the alteration of route choice to avoid “local roads” and “interstates,” can offer BEV drivers the potential for energy savings and range extensions. We propose a consideration of these findings to mitigate the effects of BEV range limitations and ease BEV adoption and ownership., Author(s): Tim Jonas [1]; Taris Wilde [1]; Christopher D. Hunter [2]; Gretchen A. Macht (corresponding author) [1] 1. Introduction Today, scarcity of nonrenewable energy resources and increasing ecological awareness have [...]

Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Lévy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets.

This case describes an atypical presentation of molar pregnancy in an emergency department patient with abdominal pain and vaginal bleeding. The patient demonstrated clinical features of hydatidiform mole, including acute discharge of a large, grape-like vesicular mass, despite multiple negative urine pregnancy tests. These false-negative qualitative human chorionic gonadotropin assays were likely caused by the “high-dose hook effect” and may have delayed proper care of the patient, who displayed pulmonary choriocarcinoma at the time of diagnosis. [West J Emerg Med. 2011;12(2):213-215.]

To better understand the initiation of CD8(+) T cell responses during infection, the primary response to the intracellular parasite Toxoplasma gondii was characterized using 2-photon microscopy combined with an experimental system that allowed visualization of dendritic cells (DCs) and parasite specific CD8(+) T cells. Infection with T. gondii induced localization of both these populations to the sub-capsular/interfollicular region of the draining lymph node and DCs were required for the expansion of the T cells. Consistent with current models, in the presence of cognate antigen, the average velocity of CD8(+) T cells decreased. Unexpectedly, infection also resulted in modulation of the behavior of non-parasite specific T cells. This TCR-independent process correlated with the re-modeling of the lymph node micro-architecture and changes in expression of CCL21 and CCL3. Infection also resulted in sustained interactions between the DCs and CD8(+) T cells that were visualized only in the presence of cognate antigen and were limited to an early phase in the response. Infected DCs were rare within the lymph node during this time frame; however, DCs presenting the cognate antigen were detected. Together, these data provide novel insights into the earliest interaction between DCs and CD8(+) T cells and suggest that cross presentation by bystander DCs rather than infected DCs is an important route of antigen presentation during toxoplasmosis.