Mosquito abundance and diversity in central Ohio, USA vary among stormwater wetlands, retention ponds, and detention ponds and their associated environmental parameters.

Mosquitoes (Diptera: Culicidae) are one of the most impactful pests to human society, both as a nuisance and a potential vector of human and animal pathogens. Mosquito larvae develop in still aquatic environments. Eliminating these habitats near high human density or managing them to reduce the suitability for mosquitoes will reduce mosquito populations in these human environments and decrease the overall negative impact of mosquitoes on humans. One common source of standing water in urban and suburban environments is the water that pools in stormwater control measures. Previous studies have shown that some stormwater control measures generate large numbers of mosquitoes while others harbor none, and the reason for this difference remains unclear. Our study focuses on elucidating the factors that cause a stormwater control measure to be more or less suitable for mosquitoes. During the summers of 2021 and 2022, we collected and identified mosquito larvae from thirty stormwater control measures across central Ohio to assess variation in mosquito abundance and diversity among sites. Our goal was to determine if specific types of stormwater control measures (retention ponds, detention ponds, or constructed wetlands) harbored different abundances of mosquitoes or different community structures. We also assessed environmental parameters of these sites to elucidate their effects on mosquito abundance and diversity. Overall, we recorded the highest number of mosquito larvae and species in constructed wetlands. However, these sites were dominated by the innocuous species, Culex territans. Conversely, detention ponds held fewer mosquitoes but a higher proportion of known vector species, including Culex pipiens and Aedes vexans. The total number of mosquitoes across all sites was correlated with higher vegetation, more shade, lower water temperatures, and lower pH, suggesting stormwater control measures with these features may also be hotspots for mosquito proliferation.

The microbiota of Amblyomma americanum reflects known westward expansion.

Amblyomma americanum, a known vector of multiple tick-borne pathogens, has expanded its geographic distribution across the United States in the past decades. Tick microbiomes may play a role shaping their host's life history and vectorial capacity. Bacterial communities associated with A. americanum may reflect, or enable, geographic expansion and studying the microbiota will improve understanding of tick-borne disease ecology. We examined the microbiota structure of 189 adult ticks collected in four regions encompassing their historical and current geographic distribution. Both geographic region of origin and sex were significant predictors of alpha diversity. As in other tick models, within-sample diversity was low and uneven given the presence of dominant endosymbionts. Beta diversity analyses revealed that bacterial profiles of ticks of both sexes collected in the West were significantly different from those of the Historic range. Biomarkers were identified for all regions except the historical range. In addition, Bray-Curtis dissimilarities overall increased with distance between sites. Relative quantification of ecological processes showed that, for females and males, respectively, drift and dispersal limitation were the primary drivers of community assembly. Collectively, our findings highlight how microbiota structural variance discriminates the western-expanded populations of A. americanum ticks from the Historical range. Spatial autocorrelation, and particularly the detection of non-selective ecological processes, are indicative of geographic isolation. We also found that prevalence of Ehrlichia chaffeensis, E. ewingii, and Anaplasma phagocytophilum ranged from 3.40-5.11% and did not significantly differ by region. Rickettsia rickettsii was absent from our samples. Our conclusions demonstrate the value of synergistic analysis of biogeographic and microbial ecology data in investigating range expansion in A. americanum and potentially other tick vectors as well.

Identifying characteristics and clinical conditions associated with hand grip strength in adults: the Project Baseline Health Study.

Low hand grip strength (HGS) is associated with several conditions, but its value outside of the older adult population is unclear. We sought to identify the most salient factors associated with HGS from an extensive list of candidate variables while stratifying by age and sex. We used data from the initial visit from the Project Baseline Health Study (N = 2502) which captured detailed demographic, occupational, social, lifestyle, and clinical data. We applied MI-LASSO using group methods to determine variables most associated with HGS out of 175 candidate variables. We performed analyses separately for sex and age (< 65 vs. ≥ 65 years). Race was associated with HGS to varying degrees across groups. Osteoporosis and osteopenia were negatively associated with HGS in female study participants. Immune cell counts were negatively associated with HGS for male participants ≥ 65 (neutrophils) and female participants (≥ 65, monocytes; < 65, lymphocytes). Most findings were age and/or sex group-specific; few were common across all groups. Several of the variables associated with HGS in each group were novel, while others corroborate previous research. Our results support HGS as a useful indicator of a variety of clinical characteristics; however, its utility varies by age and sex.

LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation.

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson's disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.

Real-world walking behaviors are associated with early-stage heart failure: a Project Baseline Health Study.

BACKGROUND: Data collected via wearables may complement in-clinic assessments to monitor subclinical heart failure (HF). OBJECTIVES: Evaluate the association of sensor-based digital walking measures with HF stage and characterize their correlation with in-clinic measures of physical performance, cardiac function and participant reported outcomes (PROs) in individuals with early HF. METHODS: The analyzable cohort included participants from the Project Baseline Health Study (PBHS) with HF stage 0, A, or B, or adaptive remodeling phenotype (without risk factors but with mild echocardiographic change, termed RF-/ECHO+) (based on available first-visit in-clinic test and echocardiogram results) and with sufficient sensor data. We computed daily values per participant for 18 digital walking measures, comparing HF subgroups vs stage 0 using multinomial logistic regression and characterizing associations with in-clinic measures and PROs with Spearman's correlation coefficients, adjusting all analyses for confounders. RESULTS: In the analyzable cohort (N=1265; 50.6% of the PBHS cohort), one standard deviation decreases in 17/18 walking measures were associated with greater likelihood for stage-B HF (multivariable-adjusted odds ratios [ORs] vs stage 0 ranging from 1.18-2.10), or A (ORs vs stage 0, 1.07-1.45), and lower likelihood for RF-/ECHO+ (ORs vs stage 0, 0.80-0.93). Peak 30-minute pace demonstrated the strongest associations with stage B (OR vs stage 0=2.10; 95% CI:1.74-2.53) and A (OR vs stage 0=1.43; 95% CI:1.23-1.66). Decreases in 13/18 measures were associated with greater likelihood for stage-B HF vs stage A. Strength of correlation with physical performance tests, echocardiographic cardiac-remodeling and dysfunction indices and PROs was greatest in stage B, then A, and lowest for 0. CONCLUSIONS: Digital measures of walking captured by wearable sensors could complement clinic-based testing to identify and monitor pre-symptomatic HF.

An obligate microsporidian parasite modulates defense against opportunistic bacterial infection in the yellow fever mosquito, Aedes aegypti.

The ability of Aedes aegypti mosquitoes to transmit vertebrate pathogens depends on multiple factors, including the mosquitoes' life history traits, immune response, and microbiota (i.e., the microbes associated with the mosquito throughout its life). The microsporidium Edhazardia aedis is an obligate intracellular parasite that specifically infects Ae. aegypti mosquitoes and severely affects mosquito survival and other life history traits critical for pathogen transmission. In this work, we investigated how E. aedis impacts bacterial infection with Serratia marcescens in Ae. aegypti mosquitoes. We measured development, survival, and bacterial load in both larval and adult stages of mosquitoes. In larvae, E. aedis exposure was either horizontal or vertical and S. marcescens was introduced orally. Regardless of the route of transmission, E. aedis exposure resulted in significantly higher S. marcescens loads in larvae. E. aedis exposure also significantly reduced larval survival but subsequent exposure to S. marcescens had no effect. In adult females, E. aedis exposure was only horizontal and S. marcescens was introduced orally or via intrathoracic injection. In both cases, E. aedis infection significantly increased S. marcescens bacterial loads in adult female mosquitoes. In addition, females infected with E. aedis and subsequently injected with S. marcescens suffered 100% mortality which corresponded with a rapid increase in bacterial load. These findings suggest that exposure to E. aedis can influence the establishment and/or replication of other microbes in the mosquito. This has implications for understanding the ecology of mosquito immune defense and potentially disease transmission by mosquito vector species. IMPORTANCE: The microsporidium Edhazardia aedis is a parasite of the yellow fever mosquito, Aedes aegypti. This mosquito transmits multiple viruses to humans in the United States and around the world, including dengue, yellow fever, and Zika viruses. Hundreds of millions of people worldwide will become infected with one of these viruses each year. E. aedis infection significantly reduces the lifespan of Ae. aegypti and is therefore a promising novel biocontrol agent. Here, we show that when the mosquito is infected with this parasite, it is also significantly more susceptible to infection by an opportunistic bacterial pathogen, Serratia marcescens. This novel discovery suggests the mosquito's ability to control infection by other microbes is impacted by the presence of the parasite.

Maternal prenatal lead levels and neonatal brain volumes: Testing moderations by maternal depressive symptoms and family income.

There is considerable evidence that prenatal lead exposure is detrimental to child cognitive and socio-emotional development. Further evidence suggests that the effects of prenatal lead on developmental outcomes may be conditional upon exposure to social stressors, such as maternal depression and low socioeconomic status. However, no studies have examined associations between these co-occurring stressors during pregnancy and neonatal brain volumes. Leveraging a sample of 101 mother-infant dyads followed beginning in mid-pregnancy, we examined the main effects of prenatal urinary lead levels on neonatal lateralized brain volumes (left and right hippocampus, amygdala, cerebellum, frontal lobes) and total gray matter. We additionally tested for moderations between lead and depressive symptoms and between lead and family income relative to the federal poverty level (FPL) on the same neurodevelopmental outcomes. Analyses of main effects indicated that prenatal lead was significantly (ps < 0.05) associated with reduced right and left amygdala volumes (ßs = -0.23- -0.20). The testing and probing of cross-product interaction terms using simple slopes indicated that the negative effect of lead on the left amygdala was conditional upon mothers having low depressive symptoms or high income relative to the FPL. We interpret the results in the context of trajectories of prenatal and postnatal brain development and susceptibility to low levels of prenatal lead in the context of other social stressors.

Perceptions of mindfulness practices as a support for individuals managing caregiving responsibilities and chronic disease: A qualitative study.

OBJECTIVES: Explore the lived experience of individuals managing and/or caregiving for someone with a chronic disease and their perceptions of developing a mindfulness program for stress reduction. METHODS: Sixteen participants with chronic disease and/or caregivers participated. Participants completed eligibility screening, demographic questionnaires, and semi-structured interviews (30-60 min each) online or by phone. Interviews (n = 16) were audio recorded, transcribed, and analyzed using thematic analysis and NVivo® 12. Survey data were analyzed using SPSS® 28. RESULTS: Four themes emerged: (a) Chronic disease management and stress-perspectives on life's stressors; (b) Stress reduction techniques/perceptions of mindfulness-knowledge and implementation of stress reduction practices and familiarity with mindfulness; (c) Mindfulness program acceptability, barriers, and facilitators-interest, barriers, and facilitators to attending; (d) Mindfulness program structure-logistics to increase access and appeal to diverse audiences. DISCUSSION: Mindfulness has the potential for addressing the complexities of stress associated with disease management. Targeting mindfulness programs for populations with chronic disease management and caregiving responsibilities should include: Consideration of group formats with participation limited to this population, structuring programs to overcome barriers (i.e., culturally appropriate location), and equipping members of the community being served as instructors to ensure culturally relevant instruction.

MTGR1 is required to maintain small intestinal stem cell populations.

Undifferentiated intestinal stem cells (ISCs), particularly those marked by Lgr5, are crucial for maintaining homeostasis and resolving injury. Lgr5+ cells in the crypt base constantly divide, pushing daughter cells upward along the crypt axis, where they differentiate into a variety of specialized cell types. This process requires coordinated execution of complex transcriptional programs, which allow for the maintenance of undifferentiated stem cells while permitting differentiation of the wide array of intestinal cells necessary for homeostasis. Thus, disrupting these programs may negatively impact homeostasis and response to injury. Previously, members of the myeloid translocation gene (MTG) family have been identified as transcriptional co-repressors that regulate stem cell maintenance and differentiation programs in multiple organ systems, including the intestine. One MTG family member, myeloid translocation gene related 1 (MTGR1), has been recognized as a crucial regulator of secretory cell differentiation and response to injury. However, whether MTGR1 contributes to the function of ISCs has not yet been examined. Here, using Mtgr1-/- mice, we have assessed the effects of MTGR1 loss on ISC biology and differentiation programs. Interestingly, loss of MTGR1 increased the total number of cells expressing Lgr5, the canonical marker of cycling ISCs, suggesting higher overall stem cell numbers. However, expanded transcriptomic analyses revealed MTGR1 loss may instead promote stem cell differentiation into transit-amplifying cells at the expense of cycling ISC populations. Furthermore, ex vivo intestinal organoids established from Mtgr1 null were found nearly completely unable to survive and expand, likely due to aberrant ISC differentiation, suggesting that Mtgr1 null ISCs were functionally deficient as compared to WT ISCs. Together, these results identify a novel role for MTGR1 in ISC function and suggest that MTGR1 is required to maintain the undifferentiated state.

Identification of a functional peptide of a probiotic bacterium-derived protein for the sustained effect on preventing colitis.

Several probiotic-derived factors have been identified as effectors of probiotics for exerting beneficial effects on the host. However, there is a paucity of studies to elucidate mechanisms of their functions. p40, a secretory protein, is originally isolated from a probiotic bacterium, Lactobacillus rhamnosus GG. Thus, this study aimed to apply structure-functional analysis to define the functional peptide of p40 that modulates the epigenetic program in intestinal epithelial cells for sustained prevention of colitis. In silico analysis revealed that p40 is composed of a signal peptide (1-28 residues) followed by a coiled-coil domain with uncharacterized function on the N-terminus, a linker region, and a ß-sheet domain with high homology to CHAP on the C-terminus. Based on the p40 three-dimensional structure model, two recombinant p40 peptides were generated, p40N120 (28-120 residues) and p40N180 (28-180 residues) that contain first two and first three coiled coils, respectively. Compared to full-length p40 (p40F) and p40N180, p40N120 showed similar or higher effects on up-regulating expression of Setd1b (encoding a methyltransferase), promoting mono- and trimethylation of histone 3 on lysine 4 (H3K4me1/3), and enhancing Tgfb gene expression and protein production that leads to SMAD2 phosphorylation in human colonoids and a mouse colonic epithelial cell line. Furthermore, supplementation with p40F and p40N120 in early life increased H3K4me1, Tgfb expression and differentiation of regulatory T cells (Tregs) in the colon, and mitigated disruption of epithelial barrier and inflammation induced by DSS in adult mice. This study reveals the structural feature of p40 and identifies a functional peptide of p40 that could maintain intestinal homeostasis.

Multi-omic profiling reveals early immunological indicators for identifying COVID-19 Progressors.

We sought to better understand the immune response during the immediate post-diagnosis phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. In lymphocytes, the CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. These early stage observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. BACKGROUND: Much of the literature on immune response post-SARS-CoV-2 infection has been in the acute and post-acute phases of infection. TRANSLATIONAL SIGNIFICANCE: We found differences at early time points of infection in approximately 160 participants. We compared multi-omic signatures in immune cells between individuals progressing to needing more significant medical intervention and non-progressors. We observed widespread evidence of a state of increased inflammation associated with progression, supported by a range of epigenomic, transcriptomic, and proteomic signatures. The signatures we identified support other findings at later time points and serve as the basis for prognostic biomarker development or to inform interventional strategies.

Eosinophils Exert Antitumorigenic Effects in the Development of Esophageal Squamous Cell Carcinoma.

BACKGROUND AND AIMS: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), as their role in ESCC is unknown. METHODS: Eosinophils were enumerated in tissues from 2 ESCC cohorts. Mice were treated with 4-NQO for 8 weeks to induce precancer or 16 weeks to induce carcinoma. The eosinophil number was modified by a monoclonal antibody to interleukin-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11-/-). Esophageal tissue and eosinophil-specific RNA sequencing was performed to understand eosinophil function. Three-dimensional coculturing of eosinophils with precancer or cancer cells was done to ascertain direct effects of eosinophils. RESULTS: Activated eosinophils are present in higher numbers in early-stage vs late-stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in precancer vs cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with precancer. Eosinophil depletion using 3 mouse models (Ccl11-/- mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against precancer and carcinoma. Tissue and eosinophil RNA sequencing revealed eosinophils drive oxidative stress in precancer. In vitro coculturing of eosinophils with precancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with NAC, a reactive oxygen species scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 protumorigenic pathways. CONCLUSION: Eosinophils likely protect against ESCC through reactive oxygen species release during degranulation and suppression of IL-17.

LRRK2 G2019S promotes the development of colon cancer via modulating intestinal inflammation.

LRRK2 G2019S is the most prevalent variant associated with Parkinson's disease (PD), found in 1-3% of sporadic and 4-8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S carriers have an increased risk of cancers including colorectal cancer. However, the underlying mechanisms of the positive correlation between LRRK2-G2019S and colorectal cancer remain unknown. Using a mouse model of colitis-associated cancer (CAC) and LRRK2 G2019S knockin (KI) mice, here we report that LRRK2 G2019S promotes the pathogenesis of colon cancer as evidenced by increased tumor number and tumor size in LRRK2 G2019S KI mice. LRRK2 G2019S promoted intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, we found that LRRK2 G2019S KI mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis. Suppressing the kinase activity of LRRK2 ameliorated the severity of colitis in both LRRK2 G2019S KI and WT mice. At the molecular level, our investigation unveiled that LRRK2 G2019S promotes the production of reactive oxygen species, triggers inflammasome activation, and induces cell necrosis in the gut epithelium in a mouse model of colitis. Collectively, our data provide direct evidence that gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, implicating LRRK2 as a potential target in colon cancer patients with hyper LRRK2 kinase activity.

Dying at home: enablers and barriers.

BACKGROUND: According to the Grattan institute in 2014, 70% of Australians indicated a preference to die at home, however, only 14% of all deaths were at home. AIMS: To identify how patients can be supported to die at home if that is their preference. METHODS: A retrospective medical record audit of eligible Community Palliative Care (CPC) patients who indicated a wish to die at home was undertaken. FINDINGS: Out of a total of 114 patients, 74% indicated a preference to die at home. Of these, 66% achieved a home death, and most lived with a carer. Enablers for home death included family support, regular nursing visits and equipment. People who attended an emergency department in their last month of life, lived alone or were undergoing oncological treatment were more likely to die elsewhere. CONCLUSION: A range of enablers and barriers to home death were found, with many of the enablers being factors that prevented hospital presentations.

Sugar restriction and blood ingestion shape divergent immune defense trajectories in the mosquito Aedes aegypti.

Immune defense is comprised of (1) resistance: the ability to reduce pathogen load, and (2) tolerance: the ability to limit the disease severity induced by a given pathogen load. The study of tolerance in the field of animal immunity is fairly nascent in comparison to resistance. Consequently, studies which examine immune defense comprehensively (i.e. considering both resistance and tolerance in conjunction) are uncommon, despite their exigency in achieving a thorough understanding of immune defense. Furthermore, understanding tolerance in arthropod disease vectors is uniquely relevant, as tolerance is essential to the cyclical transmission of pathogens by arthropods. Here, we tested the effect(s) of dietary sucrose concentration and blood ingestion on resistance and tolerance to Escherichia coli infection in the yellow fever mosquito Aedes aegypti. Resistance and tolerance were measured concurrently and at multiple timepoints. We found that mosquitoes from the restricted sugar treatment displayed enhanced resistance at all timepoints post-infection compared to those from the laboratory standard sugar treatment. Blood also improved resistance, but only early post-infection. While sucrose restriction had no effect on tolerance, we show that consuming blood prior to bacterial infection ameliorates a temporal decline in tolerance that mosquitoes experience when provided with only sugar meals. Taken together, our findings indicate that different dietary components can have unique and sometimes temporally dynamic impacts on resistance and tolerance.

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma.

Background/Aims: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), since their role in ESCC is unknown. Methods: Eosinophils were enumerated in tissues from two ESCC cohorts. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks to induce pre-cancer or 16 weeks to induce carcinoma. Eosinophil number was modified by monoclonal antibody to IL-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 ( Ccl11 -/- ). Esophageal tissue and eosinophil specific RNA-sequencing was performed to understand eosinophil function. 3-D co-culturing of eosinophils with pre-cancer or cancer cells was done to ascertain direct effects of eosinophils. Results: Activated eosinophils are present in higher numbers in early stage versus late stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in pre-cancer versus cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models ( Ccl11 -/- mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against pre-cancer and carcinoma. Tissue and eosinophil RNA-sequencing revealed eosinophils drive oxidative stress in pre-cancer. In vitro co-culturing of eosinophils with pre-cancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with N-acetylcysteine, a reactive oxygen species (ROS) scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways. Conclusion: Eosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.

Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

Multi-omic Profiling Reveals Early Immunological Indicators for Identifying COVID-19 Progressors.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19.

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions.

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.