Long-term exposure to ambient air pollution and measures of central hemodynamics and arterial stiffness among multiethnic Chicago residents.

OBJECTIVES: To examine whether long-term air pollution exposure is associated with central hemodynamic and brachial artery stiffness parameters. METHODS: We assessed central hemodynamic parameters including central blood pressure, cardiac parameters, systemic vascular compliance and resistance, and brachial artery stiffness measures [including brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR)] using waveform analysis of the arterial pressure signals obtained from a standard cuff sphygmomanometer (DynaPulse2000A, San Diego, CA). The long-term exposures to particles with an aerodynamic diameter < 2.5 µm (PM2.5) and nitrogen dioxide (NO2) for the 3-year periods prior to enrollment were estimated at residential addresses using fine-scale intra-urban spatiotemporal models. Linear mixed models adjusted for potential confounders were used to examine associations between air pollution exposures and health outcomes. RESULTS: The cross-sectional study included 2,387 Chicago residents (76% African Americans) enrolled in the ChicagO Multiethnic Prevention And Surveillance Study (COMPASS) during 2013-2018 with validated address information, PM2.5 or NO2, key covariates, and hemodynamics measurements. We observed long-term concentrations of PM2.5 and NO2 to be positively associated with central systolic, pulse pressure and BAR, and negatively associated with BAD, and BAC after adjusting for relevant covariates. A 1-µg/m3 increment in preceding 3-year exposures to PM2.5 was associated with 1.8 mmHg higher central systolic (95% CI: 0.98, 4.16), 1.0 mmHg higher central pulse pressure (95% CI: 0.42, 2.87), a 0.56%mmHg lower BAD (95% CI: -0.81, -0.30), and a 0.009 mL/mmHg lower BAC (95% CI: -0.01, -0.01). CONCLUSION: This population-based study provides evidence that long-term exposures to PM2.5 and NO2 is related to central BP and arterial stiffness parameters, especially among African Americans.

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy.

Background and Objective: In sporadic colorectal carcinomas (CRC), microsatellite instability (MSI) pathways play important roles. Previously, we showed differences in DNA methylation patterns in microsatellite stable (MSS) colorectal carcinomas and MSI-CRC. In the current study, we explore the similarities and differences in gene expression profiles in MSS and MSI at the gene level and at the pathway level to better understand CRC pathogenesis and/or the potential for therapeutic opportunities. Material and Methods: Seventy-one CRC patients (MSI = 18, MSS = 53) were studied. Paired tumor and adjacent normal tissues were used for genome-wide gene expression assays. Result: At the gene level, we compared the list of differentially expressed genes (fold change (FC) ≥ 3 and FDR < 0.05) in tumor tissues compared to corresponding normal tissue in CRC patients with MSI tumors (190 genes) and MSS tumors (129 genes). Of these, 107 genes overlapped. The list of genes that were differentially expressed in MSI tumors only showed enrichment predominantly in two broad categories of pathways-(a) Inflammation-related pathways including the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, chemokine signaling, nuclear factor kappa B (NFκB) signaling, and cytokine-cytokine interactions, and (b) metabolism-related pathways, including retinol metabolism, steroid hormone biosynthesis, drug metabolism, pentose and glucoronate interconversions, and ascorbate and aldarate metabolism. The genes in inflammation-related pathways were up-regulated whereas genes in metabolism-related pathways were down-regulated in MSI tumor tissue. Pathway-level analysis also revealed similar results confirming the gene enrichment findings. For example, the 150 genes involved in the IL-17 signaling pathway were on average up-regulated by 1.19 fold (CI 1.16-1.21) in MSI compared to 1.14 fold (CI 1.13-1.16) in MSS patients (interaction p = 0.0009). Conclusions: We document an association between MSI status and differential gene expression that broadens our understanding of CRC pathogenesis. Furthermore, targeting one or more of these dysregulated pathways could provide the basis for improved therapies for MSI and MSS CRC.

The association of cigarette smoking with DNA methylation and gene expression in human tissue samples.

Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types.

Neurochemical Predictors of Generalized Learning Induced by Brain Stimulation and Training.

Methods of cognitive enhancement for humans are most impactful when they generalize across tasks. However, the extent to which such "transfer" is possible via interventions is widely debated. In addition, the contribution of excitatory and inhibitory processes to such transfer is unknown. Here, in a large-scale neuroimaging individual differences study with humans (both sexes), we paired multitasking training and noninvasive brain stimulation (transcranial direct current stimulation, tDCS) over multiple days and assessed performance across a range of paradigms. In addition, we varied tDCS dosage (1.0 and 2.0 mA), electrode montage (left or right prefrontal regions), and training task (multitasking vs a control task) and assessed GABA and glutamate concentrations via ultrahigh field 7T magnetic resonance spectroscopy. Generalized benefits were observed in spatial attention, indexed by visual search performance, when multitasking training was combined with 1.0 mA stimulation targeting either the left or right prefrontal cortex (PFC). This transfer effect persisted for ∼30 d post intervention. Critically, the transferred benefits associated with right prefrontal tDCS were predicted by pretraining concentrations of glutamate in the PFC. Thus, the effects of this combined stimulation and training protocol appear to be linked predominantly to excitatory brain processes.

Simultaneous Measurement of GABA, Glutathione, and Glutamate-Glutamine in the Thalamus using Edited MR Spectroscopy: Feasibility and Applications in Traumatic Brain Injury.

BACKGROUND: MR spectroscopy (MRS) is a noninvasive tool for evaluating biochemical alterations, such as glutamate (Glu)/gamma-aminobutyric acid (GABA) imbalance and depletion of antioxidative glutathione (GSH) after traumatic brain injury (TBI). Thalamus, a critical and vulnerable region post-TBI, is challenging for MRS acquisitions, necessitating optimization to simultaneously measure GABA/Glu and GSH. PURPOSE: To assess the feasibility and optimize acquisition and processing approaches for simultaneously measuring GABA, Glx (Glu + glutamine (Gln)), and GSH in the thalamus, employing Hadamard encoding and reconstruction of MEscher-GArwood (MEGA)-edited spectroscopy (HERMES). STUDY TYPE: Prospective. SUBJECTS: 28 control subjects (age: 35.9 ± 15.1 years), and 17 mild TBI (mTBI) patients (age: 32.4 ± 11.3 years). FIELD STRENGTH/SEQUENCE: 3T/T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE), HERMES. ASSESSMENT: We evaluated the impact of acquisition with spatial saturation bands and post-processing with spectral alignment on HERMES performance in the thalamus among controls. Within-subject variability was examined in five controls through repeated scans within a week. The HERMES spectra in the posterior cingulate cortex (PCC) of controls were used as a reference for assessing HERMES performance in a reliable target. Furthermore, we compared metabolite levels and fitting quality in the thalamus between mTBI patients and controls. STATISTICAL TESTS: Unpaired t-tests and within-subject coefficient-of-variation (CV). A P-value <0.05 was deemed significant. RESULTS: HERMES spectra, acquired with saturation bands and processed with spectral alignment, yielded reliable metabolite measurements in the thalamus. The mean within-subject CV for GABA, Glx, and GSH levels were 18%, 10%, and 16% in the thalamus (7%, 9%, and 16% in the PCC). GABA (3.20 ± 0.60 vs 2.51 ± 0.55, P < 0.01) and Glx (8.69 ± 1.23 vs 7.72 ± 1.19, P = 0.03) levels in the thalamus were significantly higher in mTBI patients than in controls, with GSH (1.27 ± 0.35 vs 1.22 ± 0.28, P = 0.65) levels showing no significant difference. DATA CONCLUSION: Simultaneous measuring GABA/Glx and GSH using HERMES is feasible in the thalamus, providing valuable insight into TBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Draft whole-genome sequences of three Borrelia burgdorferi isolates from Western Canada.

Whole-genome sequences are presented for three Borrelia burgdorferi, a causative agent of Lyme disease in North America, isolated from Ixodes pacificus ticks collected in British Columbia, Canada. Shotgun DNA libraries were prepared with Illumina DNA Prep and sequenced using the MiniSeq platform. Genome assemblies enabled multilocus sequence typing and ospC typing.

Glutamate measurements using edited MRS.

PURPOSE: To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES). METHODS: Density-matrix simulations of HERMES (TE 80 ms) and 1D J-resolved (TE 31-229 ms) of glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), and glutathione (GSH) were performed. HERMES comprised four sub-experiments with editing pulses applied as follows: (A) 1.9/4.56 ppm simultaneously (ONGABA /ONGSH ); (B) 1.9 ppm only (ONGABA /OFFGSH ); (C) 4.56 ppm only (OFFGABA /ONGSH ); and (D) 7.5 ppm (OFFGABA /OFFGSH ). Phantom HERMES and 1D J-resolved experiments of Glu were performed. Finally, in vivo HERMES (20-ms editing pulses) and 1D J-resolved (TE 31-229 ms) experiments were performed on 137 participants using 3 T MRI scanners. LCModel was used for quantification. RESULTS: HERMES simulation and phantom experiments show a Glu-edited signal at 2.34 ppm in the Hadamard sum combination A+B+C+D with no overlapping Gln signal. The J-resolved simulations and phantom experiments show substantial TE modulation of the Glu and Gln signals across the TEs, whose average yields a well-resolved Glu signal closely matching the Glu-edited signal from the HERMES sum spectrum. In vivo quantification of Glu show that the two methods are highly correlated (p < 0.001) with a bias of ∼10%, along with similar between-subject coefficients of variation (HERMES/TE-averaged: ∼7.3%/∼6.9%). Other Hadamard combinations produce the expected GABA-edited (A+B-C-D) or GSH-edited (A-B+C-D) signal. CONCLUSION: HERMES simulation and phantom experiments show the separation of Glu from Gln. In vivo HERMES experiments yield Glu (without Gln), GABA, and GSH in a single MRS scan.

The Role of Health Insurance Type and Clinic Visit on Hypertension Status Among Multiethnic Chicago Residents.

PURPOSE: To investigate the joint relationship of health insurance and clinic visit with hypertension among underserved populations. DESIGN: Population-based cohort study. SUBJECTS: Data from 1092 participants from the Chicago Multiethnic Prevention and Surveillance Study (COMPASS) between 2013 and 2020 were analyzed. MEASURES: Five health insurance types were included: uninsured, Medicaid, Medicare, private, and other. Clinic visit over past 12 months were retrieved from medical records and categorized into 4 groups: no clinic visit, 1-3 visits, 4-7 visits, >7 visits. ANALYSIS: Inverse-probability weighted logistic regression was used to estimate odds ratios (OR) and 95% confidence interval (CI) for hypertension status according to health insurance and clinic visit. Models were adjusted for individual socio-demographic variables and medical history. RESULTS: The study population was predominantly Black (>85%) of low socioeconomic status. Health insurance was not associated with more clinic visit. Measured hypertension was more frequently found in private insurance (OR = 6.48, 95% CI: 1.92-21.85) compared to the uninsured group, while 1-3 clinic visits were associated with less prevalence (OR = .59, 95% CI: .35-1.00) compared to no clinic visit. These associations remained unchanged when health insurance and clinic visit were adjusted for each other. CONCLUSION: In this study population, private insurance was associated with higher measured hypertension prevalence compared to no insurance. The associations of health insurance and clinic visit were independent of each other.

Air quality and cancer risk in the All of Us Research Program.

INTRODUCTION: The NIH All of Us Research Program has enrolled over 544,000 participants across the US with unprecedented racial/ethnic diversity, offering opportunities to investigate myriad exposures and diseases. This paper aims to investigate the association between PM2.5 exposure and cancer risks. MATERIALS AND METHODS: This work was performed on data from 409,876 All of Us Research Program participants using the All of Us Researcher Workbench. Cancer case ascertainment was performed using data from electronic health records and the self-reported Personal Medical History questionnaire. PM2.5 exposure was retrieved from NASA's Earth Observing System Data and Information Center and assigned using participants' 3-digit zip code prefixes. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Generalized additive models (GAMs) were used to investigate non-linear relationships. RESULTS: A total of 33,387 participants and 46,176 prevalent cancer cases were ascertained from participant EHR data, while 20,297 cases were ascertained from self-reported survey data from 18,133 participants; 9,502 cancer cases were captured in both the EHR and survey data. Average PM2.5 level from 2007 to 2016 was 8.90 µg/m3 (min 2.56, max 15.05). In analysis of cancer cases from EHR, an increased odds for breast cancer (OR 1.17, 95% CI 1.09-1.25), endometrial cancer (OR 1.33, 95% CI 1.09-1.62) and ovarian cancer (OR 1.20, 95% CI 1.01-1.42) in the 4th quartile of exposure compared to the 1st. In GAM, higher PM2.5 concentration was associated with increased odds for blood cancer, bone cancer, brain cancer, breast cancer, colon and rectum cancer, endocrine system cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. CONCLUSIONS: We found evidence of an association of PM2.5 with breast, ovarian, and endometrial cancers. There is little to no prior evidence in the literature on the impact of PM2.5 on risk of these cancers, warranting further investigation.

Phylogenetic status and diet of red fox (Vulpes vulpes griffithii) inhabiting Ayubia National Park, Pakistan

Abstract The red fox (Vulpes vulpes) is a medium-sized carnivore that occurs in different regions of Pakistan, however, still lacks scientific data on its ecology and distribution. The current study investigated the phylogenetic status and diet of the red fox (V.v. griffithii) occurring in Ayubia National Park, Pakistan. Through camera trapping and molecular analysis, we confirmed the occurrence of red fox in the study area. Based on mitochondrial cytochrome B (304 bp) and limited sampling, nearly all red foxes of Ayubia National Park and surrounding Himalayan ranges fall within Holarctic maternal lineage, whereas red foxes found in plains of Pakistan are part of the basal Palearctic maternal lineage. Using 32 scats, we found that red fox diet comprises of 80% animal-based prey species (both wild and domestic) and 19% plant matter. The wild animal prey species included Cape hare (Lepus capensis) and flying squirrel (Pteromyini sp.), which constituted 17% and 15% of diet, respectively. Red foxes infrequently consumed House mouse (Mus musculus), Himalayan Palm civet (Paguma larvata) and sheep (Ovis aries), each comprising around 6% to 9% of red fox diet. The fox species also scavenged on domestic donkey opportunistically. Based on our sampling, our study suggests that the red fox (V.v. griffithii) that occurs in Ayubia National Park and across the lesser Himalayan ranges belongs to Holarctic maternal lineage. The study also highlights consumption of plant seeds by red foxes, indicating it may play an important ecological role in seed dispersal in Ayubia National Park.

Resumo A raposa-vermelha (Vulpes vulpes) é um carnívoro de médio porte que ocorre em diferentes regiões do Paquistão, porém ainda carece de dados científicos sobre sua ecologia e distribuição. O presente estudo investigou o status filogenético e a dieta da raposa-vermelha (V.v. griffithii) que ocorre no Parque Nacional de Ayubia, Paquistão. Por meio de armadilhas fotográficas e análises moleculares, confirmamos a ocorrência de raposa-vermelha na área de estudo. Com base no citocromo B mitocondrial (304 bp) e amostragem limitada, quase todas as raposas-vermelhas do Parque Nacional de Ayubia e áreas circundantes do Himalaia se enquadram na linhagem materna holártica, enquanto as raposas-vermelhas encontradas nas planícies do Paquistão fazem parte da linhagem materna basal paleártica. Usando 32 fezes, descobrimos que a dieta da raposa-vermelha compreende 80% de espécies de presas de origem animal (selvagens e domésticas) e 19% de matéria vegetal. As espécies de presas de animais selvagens incluíram a lebre-do-cabo (Lepus capensis) e o esquilo-voador (Pteromyini sp.), que constituíram 17% e 15% da dieta, respectivamente. As raposas-vermelhas consumiam raramente ratos domésticos (Mus musculus), algas do Himalaia (Paguma larvata) e ovelhas (Ovis aries), cada um compreendendo cerca de 6% a 9% da dieta da raposa-vermelha. A espécie de raposa também se alimentava de burros domésticos de forma oportunista. Com base em nossa amostragem, nosso estudo sugere que a raposa-vermelha (V.v. griffithii) que ocorre no Parque Nacional de Ayubia e nas cordilheiras menores do Himalaia pertence à linhagem materna holártica. O estudo também destaca o consumo de sementes de plantas por raposas-vermelhas, indicando que pode desempenhar um papel ecológico importante na dispersão de sementes no Parque Nacional de Ayubia.

Duration-sensitive association between air pollution exposure and changes in cardiometabolic biomarkers: Evidence from a predominantly African American cohort.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure has been related to cardiometabolic diseases, but the underlying biological pathways remain unclear at the population level. OBJECTIVE: To investigate the effect of PM2.5 exposure on changes in multiple cardiometabolic biomarkers across different exposure durations. METHOD: Data from a prospective cohort study were analyzed. Ten cardiometabolic biomarkers were measured, including ghrelin, resistin, leptin, C-peptide, creatine kinase myocardial band (CK-MB), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin, and interleukin-6 (IL-6). PM2.5 levels across exposure durations from 1 to 36 months were assessed. Mixed effect model was used to estimate changes in biomarker levels against 1 µg/m3 increase in PM2.5 level across different exposure durations. RESULTS: Totally, 641 participants were included. The average PM2.5 exposure level was 9 µg/m3. PM2.5 exposure was inversely associated with ghrelin, and positively associated with all other biomarkers. The magnitudes of these associations were duration-sensitive and exhibited a U-shaped or inverted-U-shaped trend. For example, the association of resistin were ß = 0.05 (95% CI: 0.00, 0.09) for 1-month duration, strengthened to ß = 0.27 (95% CI: 0.14, 0.41) for 13-month duration, and weakened to ß = 0.12 (95% CI: -0.03, 0.26) for 24-month duration. Similar patterns were observed for other biomarkers except for CK-MB, of which the association direction switched from negative to positive as the duration increased. Resistin, leptin, MCP-1, TNF-alpha, and troponin had a sensitive exposure duration of nearly 12 months. Ghrelin and C-peptide were more sensitive to longer-term exposure (>18 months), while NT-proBNP and IL-6 were more sensitive to shorter-term exposure (<6 months). CONCLUSION: PM2.5 exposure was associated with elevated levels in cardiometabolic biomarkers related to insulin resistance, inflammation, and heart injury. The magnitudes of these associations depended on the exposure duration. The most sensitive exposure durations of different biomarkers varied.

Neuronal and Glial Metabolite Abnormalities in Participants With Persistent Neuropsychiatric Symptoms After COVID-19: A Brain Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: The aim of this study was to determine whether neurometabolite abnormalities indicating neuroinflammation and neuronal injury are detectable in individuals post-coronavirus disease 2019 (COVID-19) with persistent neuropsychiatric symptoms. METHODS: All participants were studied with proton magnetic resonance spectroscopy at 3 T to assess neurometabolite concentrations (point-resolved spectroscopy, relaxation time/echo time = 3000/30 ms) in frontal white matter (FWM) and anterior cingulate cortex-gray matter (ACC-GM). Participants also completed the National Institutes of Health Toolbox cognition and motor batteries and selected modules from the Patient-Reported Outcomes Measurement Information System. RESULTS: Fifty-four participants were evaluated: 29 post-COVID-19 (mean ± SD age, 42.4 ± 12.3 years; approximately 8 months from COVID-19 diagnosis; 19 women) and 25 controls (age, 44.1 ± 12.3 years; 14 women). When compared with controls, the post-COVID-19 group had lower total N-acetyl compounds (tNAA; ACC-GM: -5.0%, P = .015; FWM: -4.4%, P = .13), FWM glutamate + glutamine (-9.5%, P = .001), and ACC-GM myo-inositol (-6.2%, P = .024). Additionally, only hospitalized patients post-COVID-19 showed age-related increases in myo-inositol, choline compounds, and total creatine (interaction P = .029 to <.001). Across all participants, lower FWM tNAA and higher ACC-GM myo-inositol predicted poorer performance on several cognitive measures (P = .001-.009), while lower ACC-GM tNAA predicted lower endurance on the 2-minute walk (P = .005). CONCLUSIONS: In participants post-COVID-19 with persistent neuropsychiatric symptoms, the lower-than-normal tNAA and glutamate + glutamine indicate neuronal injury, while the lower-than-normal myo-inositol reflects glial dysfunction, possibly related to mitochondrial dysfunction and oxidative stress in Post-COVID participants with persistent neuropsychiatric symptoms.

CD45RA and CD45RO Are Regulated in a Cell-Type Specific Manner in Inflammation and Sepsis.

CD45 is a transmembrane glycoprotein that is located on the surface of all leukocytes and modulates both innate and adaptive immune system functions. In a recent study, inflammation modulated the CD45 expression in leukocytes, but the effect on the expression of CD45 subtypes is unknown. In the present study, we therefore investigated the effect of inflammatory conditions in humans (surgery, sepsis) and ex vivo incubation with lipopolysaccharides (LPS) on the expression of the subtypes CD45RA and CD45RO in granulocytes, lymphocytes, and monocytes. Whole blood samples were obtained from healthy volunteers, postoperative patients, and patients with sepsis at day 1 of diagnosis, respectively. Samples were incubated with fluorescent antibodies directed against CD45, CD45RA and CD45RO in the absence and presence of lipopolysaccharide and subjected to flow cytometry. In comparison to volunteers, CD45RA surface expression in postoperative and septic patients was reduced by 89% exclusively on granulocytes, but not on lymphocytes or monocytes. In contrast, CD45RO was exclusively reduced on lymphocytes, by 82%, but not on other cell types. Receiver operating characteristic curve analyses demonstrated that CD45RA (on granulocytes) and CD45RO (on lymphocytes) allow a good differentiation of volunteers and patients with sepsis (AUC = 0.9; p = 0.0001). The addition of LPS to the whole blood samples obtained from volunteers, postoperative patients, and septic patients markedly increased the CD45RO expression in granulocytes, lymphocytes, and monocytes. In contrast, LPS reduced CD45RA exclusively on monocytes. In conclusion, the surface expression of CD45RA and CD45RO is regulated in inflammation in a cell-type- and stimulus-specific manner. Considering that CD45 subtypes are critically involved in immune system signaling, the pathophysiologic and diagnostic implications warrant further investigation.

Long-term exposure to ambient air pollution and measures of central hemodynamics and arterial stiffness among multiethnic Chicago residents.

Objectives: To examine whether air pollution exposure is associated with central hemodynamic and brachial artery stiffness parameters. Methods: We assessed central hemodynamic parameters, brachial artery stiffness measures [including brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR)] using waveform analysis of the arterial pressure signals obtained from a standard cuff sphygmomanometer (DynaPulse2000A, San Diego, CA). The long-term exposures to particles with an aerodynamic diameter < 2.5µm (PM2.5) and nitrogen dioxide (NO2) for the 3-year periods prior to enrollment were estimated at residential addresses using fine-scale intra-urban spatiotemporal models. Linear mixed models adjusted for potential confounders were used to examine associations between air pollution exposures and health outcomes. Results: The cross-sectional study included 2,387 Chicago residents (76% African Americans) enrolled in the ChicagO Multiethnic Prevention And Surveillance Study (COMPASS) during 2013-2018 with validated address information, PM2.5 or NO2, key covariates, and hemodynamics measurements. We observed long-term concentrations of PM2.5 and NO2 to be positively associated with central systolic, pulse pressure and BAR, and negatively associated with BAD, and BAC after adjusting for relevant covariates. A 1-µg/m3 increment in preceding 3-year exposures to PM2.5 was associated with 1.8 mmHg higher central systolic (95% CI: 0.98, 4.16), 1.0 mmHg higher central pulse pressure (95% CI: 0.42, 2.87), a 0.56%mmHg lower BAD (95% CI: -0.81, -0.30), and a 0.009 mL/mmHg lower BAC (95% CI: -0.01, -0.01). Conclusion: This population-based study provides evidence that long-term exposures to PM2.5 and NO2 is related to central BP and arterial stiffness parameters, especially among African Americans.

Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19.

Objectives: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC. Methods: 29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels. Results: PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region. Conclusions: The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.

The Site and Type of CLCN5 Genetic Variation Impact the Resulting Dent Disease-1 Phenotype.

Introduction: Dent disease is an X-linked recessive disorder associated with low molecular weight proteinuria (LMWP), nephrocalcinosis, kidney stones, and kidney failure in the third to fifth decade of life. It consists of Dent disease 1 (DD1) (60% of patients) because of pathogenic variants in the CLCN5 gene and Dent disease 2 (DD2) with changes in OCRL. Methods: Retrospective review of 162 patients from 121 different families with genetically confirmed DD1 (82 different pathogenic variants validated using American College of Medical Genetics [ACMG] guidelines). Clinical and genetic factors were compared using observational statistics. Results: A total of 110 patients had 51 different truncating (nonsense, frameshifting, large deletions, and canonical splicing) variants, whereas 52 patients had 31 different nontruncating (missense, in-frame, noncanonical splicing, and stop-loss) changes. Sixteen newly described pathogenic variants were found in our cohort. Among patients with truncating variants, lifetime stone events positively correlated with chronic kidney disease (CKD) evolution. Patients with truncating changes also experienced stone events earlier in life and manifested a higher albumin excretion rate than the nontruncating group. Nevertheless, neither age of nephrocalcinosis nor CKD progression varied between the truncating versus nontruncating patients. A large majority of nontruncating changes (26/31; 84%) were clustered in the middle exons that encode the voltage ClC domain whereas truncating changes were spread across the protein. Variants associated with kidney failure were restricted to truncating (11/13 cases), plus a single missense variant previously shown to markedly reduce ClC-5 functional activity that was found in the other 2 individuals. Conclusion: DD1 manifestations, including the risk of kidney stones and progression to kidney failure, may relate to the degree of residual ClC-5 function.

Pathways Related to Colon Inflammation Are Associated with Colorectal Carcinoma: A Transcriptome- and Methylome-Wide Study.

The association of chronic inflammation with colorectal carcinoma (CRC) development is well known in ulcerative colitis (UC). However, the role of inflammatory changes in sporadic CRC pathogenesis is less widely appreciated. In this study, in the first step using RNA-seq, we identified gene-pathway-level changes in UC-associated CRC (UC CRC, n = 10) and used the changes as a proxy for inflammation in human colon to ask if there were associations of inflammatory pathway dysregulations in sporadic CRC pathogenesis (n = 8). We found down-regulations of several inflammation-related metabolic pathways (nitrogen metabolism, sulfur metabolism) and other pathways (bile secretion, fatty acid degradation) in sporadic CRC. Non-inflammation-related changes included up-regulation of the proteasome pathway. In the next step, from a larger number of paired samples from sporadic CRC patients (n = 71) from a geographically and ethnically different population and using a different platform (microarray), we asked if the inflammation-CRC association could be replicated. The associations were significant even after stratification by sex, tumor stage, grade, MSI status, and KRAS mutation status. Our findings have important implications to widen our understanding of inflammatory pathogenesis of sporadic CRC. Furthermore, targeting of several of these dysregulated pathways could provide the basis for improved therapies for CRC.

The impact of neighborhood disadvantage on colorectal cancer screening among African Americans in Chicago.

Historically, colorectal cancer (CRC) screening rates have been lower among African Americans. Previous studies that have examined the relationship between community characteristics and adherence to CRC screening have generally focused on a single community parameter, making it challenging to evaluate the overall impact of the social and built environment. In this study, we will estimate the overall effect of social and built environment and identify the most important community factors relevant to CRC screening. Data are from the Multiethnic Prevention and Surveillance Study (COMPASS), a longitudinal study among adults in Chicago, collected between May 2013 to March 2020. A total 2,836 African Americans completed the survey. Participants' addresses were geocoded and linked to seven community characteristics (i.e., community safety, community crime, household poverty, community unemployment, housing cost burden, housing vacancies, low food access). A structured questionnaire measured adherence to CRC screening. Weighted quantile sum (WQS) regression was used to evaluate the impact of community disadvantages on CRC screening. When analyzing all community characteristics as a mixture, overall community disadvantage was associated with less adherence to CRC screening even after controlling for individual-level factors. In the adjusted WQS model, unemployment was the most important community characteristic (37.6%), followed by community insecurity (26.1%) and severe housing cost burden (16.3%). Results from this study indicate that successful efforts to improve adherence to CRC screening rates should prioritize individuals living in communities with high rates of insecurity and low socioeconomic status.

Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms.

BACKGROUND: Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis. METHODS: Glx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms. RESULTS: While no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers. CONCLUSIONS: We provide evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.

Enhancing the performance of Ni nanoparticle modified carbon felt towards glycerol electrooxidation: impact of organic additive.

Organic additives are widely used in the deposition baths of metals and alloys thanks to their special function which affects the growth and the building of the crystal. This study investigates the effect of glycerol on Ni deposition onto carbon felt (CF) and its effect on the catalytic activity towards glycerol electrooxidation. The impact of glycerol on the morphology, distribution, and particle size of the electrodeposited Ni is disclosed using a scanning electron microscope (SEM). X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and cyclic voltammetry (CV) techniques were used to probe the possible changes of the electrodeposited Ni oxide phases. Electrochemical measurements show that the as-synthesized Ni0.05@CF electrocatalyst prepared in the presence of 50 mM glycerol has a marked activity towards glycerol electrooxidation, as confirmed by the impressive increase of the oxidation current by about 1.6 times concurrently with a favorable negative shift of its onset potential. Moreover, the charge transfer resistance (R ct) is much reduced from 140 to 87 ohm. The addition of glycerol to the deposition bath is believed to retard the growth of the formed Ni deposits while enhancing the nucleation rate and thus increases the particle density and, consequently, the distribution of deposited Ni over the entire CF is improved along with increasing the surface concentration and surface-active sites. This assumption is supported by density functional theory (DFT) calculations.