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• Changes in gut microbiota composition are implicated in disease. • Gut microbiota composition impacts immune system function. • Extrinsic and intrinsic factors govern relative abundance of gut microbiota commensals. • Manipulation of gut microbiota could impact anti-tumor immunity. Numerous independent studies link gut microbiota composition and disease and imply a causal role of select commensal microbes in disease etiology. In the gut, commensal microbiota or pathobionts secrete metabolites that underlie pathological conditions, often impacting proximal tissues and gaining access to the bloodstream. Here we focus on extrinsic and intrinsic factors affecting composition of gut microbiota and their impact on the immune system, as key drivers of anti-tumor immunity. In discussing exciting advances relevant to microbiome-tumor interaction, we note existing knowledge gaps that need to be filled to advance basic and clinical research initiatives. [ABSTRACT FROM AUTHOR]

Summary Mannose is an important monosaccharide for protein glycosylation in mammals but is an inefficient cellular energy source. Using a C57BL6/J mouse model of diet-induced obesity, we show that mannose supplementation of high-fat-diet-fed mice prevents weight gain, lowers adiposity, reduces liver steatosis, increases endurance and maximal O 2 consumption, and improves glucose tolerance. Mannose-supplemented mice have higher fecal energy content, suggesting reduced caloric absorption by the host. Mannose increases the Bacteroidetes to Firmicutes ratio in the gut microbiota, a signature associated with the lean phenotype. These beneficial effects of mannose are observed when supplementation is started early in life. Functional transcriptomic analysis of cecal microbiota revealed profound and coherent changes in microbial energy metabolism induced by mannose that are predicted to lead to reduced energy harvest from complex carbohydrates by gut microbiota. Our results suggest that the gut microbiota contributes to mannose-induced resistance to deleterious effects of a high-fat diet. Video Abstract Graphical Abstract Highlights • Providing mannose in early life prevents high-fat-diet-induced obesity in mice • Mannose does not benefit when initiated post-obesity onset (8 weeks post-weaning) • Mannose-induced lean and fit phenotype correlates with gut microbiota changes • Less energy harvest by microbiota partly explains mannose-mediated lean phenotype Sharma et al. show that mannose supplementation prevents adverse outcomes of high-fat diet when initiated early in life, not when provided later. Beneficial effects correlate with changes in gut microbial composition and could be partly attributed to lower energy harvest by the gut microbiota and host energy absorption. [ABSTRACT FROM AUTHOR]

On-road emissions vary widely on time scales as short as minutes and length scales as short as tens of meters. Detailed data on emissions at these scales are a prerequisite to accurately quantifying ambient pollution concentrations and identifying hotspots of human exposure within urban areas. We construct a highly resolved inventory of hourly fluxes of CO, NO 2 , NO x , PM 2.5 and CO 2 from road vehicles on 280,000 road segments in eastern Massachusetts for the year 2012. Our inventory integrates a large database of hourly vehicle speeds derived from mobile phone and vehicle GPS data with multiple regional datasets of vehicle flows, fleet characteristics, and local meteorology. We quantify the ‘excess’ emissions from traffic congestion, finding modest congestion enhancement (3–6%) at regional scales, but hundreds of local hotspots with highly elevated annual emissions (up to 75% for individual roadways in key corridors). Congestion-driven reductions in vehicle fuel economy necessitated ‘excess’ consumption of 113 million gallons of motor fuel, worth ∼ $415M, but this accounted for only 3.5% of the total fuel consumed in Massachusetts, as over 80% of vehicle travel occurs in uncongested conditions. Across our study domain, emissions are highly spatially concentrated, with 70% of pollution originating from only 10% of the roads. The 2011 EPA National Emissions Inventory (NEI) understates our aggregate emissions of NO x , PM 2.5 , and CO 2 by 46%, 38%, and 18%, respectively. However, CO emissions agree within 5% for the two inventories, suggesting that the large biases in NO x and PM 2.5 emissions arise from differences in estimates of diesel vehicle activity. By providing fine-scale information on local emission hotspots and regional emissions patterns, our inventory framework supports targeted traffic interventions, transparent benchmarking, and improvements in overall urban air quality. [ABSTRACT FROM AUTHOR]

Summary Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5 + stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here, we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease. Kaplan-Meier survival analysis of colorectal cancer (CRC) patients revealed that low PRKCI levels correlated with significantly worse patient survival rates. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis. [ABSTRACT FROM AUTHOR]

The Btla inhibitory receptor limits innate and adaptive immune responses, both preventing the development of autoimmune disease and restraining anti-viral and anti-tumor responses. It remains unclear how the functions of Btla in diverse lymphocytes contribute to immunoregulation. Here, we show that Btla inhibits activation of genes regulating metabolism and cytokine signaling, including Il6 and Hif1a , indicating a regulatory role in humoral immunity. Within mucosal Peyer's patches, we find T-cell-expressed Btla-regulated Tfh cells, while Btla in T or B cells regulates GC B cell numbers. Treg-expressed Btla is required for cell-intrinsic Treg homeostasis that subsequently controls GC B cells. Loss of Btla in lymphocytes results in increased IgA bound to intestinal bacteria, correlating with altered microbial homeostasis and elevations in commensal and pathogenic bacteria. Together our studies provide important insights into how Btla functions as a checkpoint in diverse conventional and regulatory lymphocyte subsets to influence systemic immune responses. [Display omitted] • BTLA controls inflammatory and metabolic signatures in both T and B cells • BTLA and HVEM regulate germinal center homeostasis in mucosal Peyer's patches • BTLA is required for homeostasis of regulatory T cells in the mucosa • The BTLA-HVEM network controls gut microbiome homeostasis Stienne et al. investigate how BTLA and HVEM receptors control inflammatory and metabolic signaling in lymphocytes. A major function of these receptors in intestinal lymphoid tissue is to regulate mucosal antibody production. Ultimately, this system controls the composition of the intestinal microbiome, including pathogenic bacteria. [ABSTRACT FROM AUTHOR]

On-road emissions are a major contributor to rising concentrations of atmospheric greenhouse gases. In this study, we applied a downscaling methodology based on commonly available spatial parameters to model on-road CO2 emissions at the 1 × 1 km scale for the Boston, MA region and tested our approach with surface-level CO2 observations. Using two previously constructed emissions inventories with differing spatial patterns and underlying data sources, we developed regression models based on impervious surface area and volume-weighted road density that could be scaled to any resolution. We found that the models accurately reflected the inventories at their original scales (R 2 = 0.63 for both models) and exhibited a strong relationship with observed CO2 mixing ratios when downscaled across the region. Moreover, the improved spatial agreement of the models over the original inventories confirmed that either product represents a viable basis for downscaling in other metropolitan regions, even with limited data. [Copyright &y& Elsevier]

Outbreaks of listeriosis caused by the ingestion of Listeria-contaminated ready-to-eat foods have been reported worldwide. Many ready-to-eat foods, such as deli meat products, contain high amounts of salt, which can disrupt the maintenance of osmotic balance within bacterial cells. To understand how Listeria monocytogenes adapts to salt stress, we examined the growth and global gene expression profiles of L. monocytogenes strain F2365 under salt stress using oligonucleotide probe-based DNA array and quantitative real-time PCR (qRT-PCR) analyses. The growth of L. monocytogenes in brain heart infusion (BHI) medium with various concentrations of NaCI (2.5, 5, and 10%) was significantly inhibited (P < 0.01) when compared with growth in BHI with no NaCI supplementation. Microarray data indicated that growth in BHI medium with 1.2% NaCI upregulated 4 genes and down-regulated 24 genes in L. monocytogenes, which was confirmed by qRT-PCR. The transcript levels of genes involved in the uptake of glycine betaine/L-proline were increased, whereas genes associated with a putative phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS), metabolic enzymes, and virulence factor were down-regulated. Specifically, the expression levels of PTS transport genes were shown to be dependent on NaCI concentration. To further examine whether the down- regulation of PTS genes is related to decreased cell growth, the transcript levels of genes encoding components of enzyme II, involved in the uptake of various sugars used as the primary carbon source in bacteria, were also measured using qRT-PCR. Our results suggest that the decreased transcript levels of PTS genes may be caused by salt stress or reduced cell growth through salt stress. Here, we report global transcriptional profiles of L. monocytogenes in response to salt stress, contributing to an improved understanding of osmotolerance in this bacterium. [ABSTRACT FROM AUTHOR]

Abstract: We examine the potential economic implications of using vehicle batteries to store grid electricity generated at off-peak hours for off-vehicle use during peak hours. Ancillary services such as frequency regulation are not considered here because only a small number of vehicles will saturate that market. Hourly electricity prices in three U.S. cities were used to arrive at daily profit values, while the economic losses associated with battery degradation were calculated based on data collected from A123 Systems LiFePO4/Graphite cells tested under combined driving and off-vehicle electricity utilization. For a 16kWh (57.6MJ) vehicle battery pack, the maximum annual profit with perfect market information and no battery degradation cost ranged from ∼US$140 to $250 in the three cities. If the measured battery degradation is applied, however, the maximum annual profit (if battery pack replacement costs fall to $5000 for a 16kWh battery) decreases to ∼$10–120. It appears unlikely that these profits alone will provide sufficient incentive to the vehicle owner to use the battery pack for electricity storage and later off-vehicle use. We also estimate grid net social welfare benefits from avoiding the construction and use of peaking generators that may accrue to the owner, finding that these are similar in magnitude to the energy arbitrage profit. [Copyright &y& Elsevier]

Abstract: The effects of combined driving and vehicle-to-grid (V2G) usage on the lifetime performance of relevant commercial Li-ion cells were studied. We derived a nominal realistic driving schedule based on aggregating driving survey data and the Urban Dynamometer Driving Schedule, and used a vehicle physics model to create a daily battery duty cycle. Different degrees of continuous discharge were imposed on the cells to mimic afternoon V2G use to displace grid electricity. The loss of battery capacity was quantified as a function of driving days as well as a function of integrated capacity and energy processed by the cells. The cells tested showed promising capacity fade performance: more than 95% of the original cell capacity remains after thousands of driving days worth of use. Statistical analyses indicate that rapid vehicle motive cycling degraded the cells more than slower, V2G galvanostatic cycling. These data are intended to inform an economic model. [Copyright &y& Elsevier]

Background: Widespread lockdowns imposed during the coronavirus disease 2019 crisis may impact birth outcomes.Objective: This study aimed to evaluate the association between the COVID-19 lockdown and the risk of adverse birth outcomes in Botswana.Study Design: In response to the coronavirus disease 2019 crisis, Botswana enforced a lockdown that restricted movement within the country. We used data from an ongoing nationwide birth outcomes surveillance study to evaluate adverse outcomes (stillbirth, preterm birth, small-for-gestational-age fetuses, and neonatal death) and severe adverse outcomes (stillbirth, very preterm birth, very-small-for-gestational-age fetuses, and neonatal death) recorded prelockdown (January 1, 2020-April 2, 2020), during lockdown (April 3, 2020-May 7, 2020), and postlockdown (May 8, 2020-July 20, 2020). Using difference-in-differences analyses, we compared the net change in each outcome from the prelockdown to lockdown periods in 2020 relative to the same 2 periods in 2017-2019 with the net change in each outcome from the prelockdown to postlockdown periods in 2020 relative to the same 2 periods in 2017-2019.Results: In this study, 68,448 women delivered a singleton infant in 2017-2020 between January 1 and July 20 and were included in our analysis (mean [interquartile range] age of mothers, 26 [22-32] years). Across the included calendar years and periods, the risk of any adverse outcome ranged from 27.92% to 31.70%, and the risk of any severe adverse outcome ranged from 8.40% to 11.38%. The lockdown period was associated with a 0.81 percentage point reduction (95% confidence interval, -2.95% to 1.30%) in the risk of any adverse outcome (3% relative reduction) and a 0.02 percentage point reduction (95% confidence interval, -0.79% to 0.75%) in the risk of any severe adverse outcome (0% relative reduction). The postlockdown period was associated with a 1.72 percentage point reduction (95% confidence, -3.42% to 0.02%) in the risk of any adverse outcome (5% relative reduction) and a 1.62 percentage point reduction (95% confidence interval, -2.69% to -0.55%) in the risk of any severe adverse outcome (14% relative reduction). Reductions in adverse outcomes were largest among women with human immunodeficiency virus and among women delivering at urban delivery sites, driven primarily by reductions in preterm birth and small-for-gestational-age fetuses.Conclusion: Adverse birth outcomes decreased from the prelockdown to postlockdown periods in 2020, relative to the change during the same periods in 2017-2019. Our findings may provide insights into associations between mobility and birth outcomes in Botswana and other low- and middle-income countries. [ABSTRACT FROM AUTHOR]

Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process. • Mucin and inulin, prebiotics, inhibit melanoma growth in syngeneic mouse models • Changes in gut microbiota taxa by these prebiotics induce anti-tumor immunity • Inulin attenuates melanoma resistance to MEKi in a mouse melanoma model • Inulin and mucin elicit distinct microbiota changes and an additive effect in select models Li et al. show that the gut microbiota effect on anti-tumor immunity is affected by inulin or mucin, prebiotics that inhibit melanoma and colon cancer growth in syngeneic models and attenuate melanoma resistance to MEKi. These studies highlight a potential therapeutic role for prebiotics in shaping the microbiota composition to promote anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Under what search conditions does attention affect perceptual processes, resulting in capacity limitations, rather than affecting noisy decision-making processes? Does parallel or serial processing cause the capacity limitations? To address these issues, we varied stimulus complexity, set size, and whether distractors were mirror images of the target. Both target detection and localization produced similar patterns of results. Capacity limitations only occurred for complex stimuli used in within-object conjunction searches. Parallel processing, rather than serial processing, probably caused these capacity limitations. Moreover, although mirror-image symmetry adversely affected early visual processing, it did not place additional demands on attention. [Copyright &y& Elsevier]

Purpose: To prospectively compare survival between human immunodeficiency virus (HIV)-infected versus HIV-uninfected cervical cancer patients who initiated curative chemoradiation therapy (CRT) in a limited-resource setting.Methods and Materials: Women with locally advanced cervical cancer with or without HIV infection initiating radical CRT in Botswana were enrolled in a prospective, observational, cohort study from July 2013 through January 2015.Results: Of 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122 of 143) had stage II/III cervical cancer, and 67% (96 of 143) were HIV-infected. All HIV-infected patients were receiving antiretroviral therapy (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The 2-year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54%-74%) and 66% for HIV-uninfected women (95% CI 49%-79%) (P = .70). Factors associated with better 2-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, P = .003), total radiation dose ≥75 Gy (HR 0.52, 95% CI 0.27-0.97, P = .04), and age <40 years versus 40-59 years (HR 2.17, 95% CI 1.05-4.47, P = .03).Conclusions: Human immunodeficiency virus status had no effect on 2-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status. [ABSTRACT FROM AUTHOR]

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4. [ABSTRACT FROM AUTHOR]