Paul J Mills’s research while affiliated with University of California, San Diego and other places

Aesculus indica is a remarkable species from Sapindaceae family, traditionally used for the treatment of various ailments due to the presence of a variety of bioactive compounds. The present study was planned to evaluate the chemical characterization, anti‐inflammatory and antioxidant potential of hydroethanolic extract of A. indica using in vitro and in vivo approaches. A. indica fruit was extracted with a hydroethanolic (70% v/v) solution, filtered, concentrated on a rotary evaporator and crude extract was obtained. In vitro anti‐inflammatory potential of A. indica was carried out against peripheral blood mononuclear cells (PBMCs) and a whole blood assay (WBA). Effects of A. indica extracts on proinflammatory cytokines (TNF‐α, IFN‐gamma, IL‐6, IL‐1β) and inflammatory mediators (NF‐κB, NO and PGE2) concentration in the supernatant of PBMCs and WBA were evaluated using commercial ELISA kits. In vivo anti‐inflammatory potential of A. indica hydroethanolic extract was evaluated with carrageenan‐induced paw edema in rats. A total of 36 different compounds (mostly phenolics) were detected in A. indica extract with high performance liquid chromatography (HPLC) and UHPCL‐QTOF‐MS/MS. The extract showed very low cytotoxicity with an IC50 value of 483.68 μg/mL and significantly reduced the levels of proinflammatory cytokines and inflammatory mediators in both PBMCs and WBA models. Furthermore, the extract also effectively inhibited the paw edema by carrageenan in the 2nd hour at 400 mg/kg (73%). Histopathological analysis of rat paw tissue showed significant reduction of cellular infiltration and decrease in swelling of epidermis and dermis by A. indica extracts. The level of enzymatic antioxidants such as superoxide dismutase (SOD) and Catalase (CAT), lipid peroxidation like malondialdehyde (MDA), oxidative stress parameters including total antioxidant status (TAS) and total oxidant status (TOS) and myeloperoxidase (MPO) activity in rat paw tissues were significantly altered after treatment. The combined findings provide evidence that hydroethanolic extract of A. indica is a potential source of bioactive compounds with significant anti‐inflammatory and antioxidant activities.

Background Surf therapy combines physical activity with social support to provide a healing environment. Objective This exploratory pre-to post-intervention study examined the effects of a novel surf therapy program for women who experienced abuse, trauma, and/or mental illness on emotional regulation, resilience, body acceptance, and gratitude. Methods Twenty-seven women (ages 25 to 54; mean 36.32 + SD 7.79) participated in an 8-week Groundswell Surf Therapy Program held in four different coastal cities in California. Standardized self-report questionnaires were administered prior to and following the therapy program, including the Body Acceptance Scale, the Connor-Davidson Resilience Scale (CD-RISC), the Affective Style Questionnaire, and the Gratitude Questionnaire-Six-Item Form (GQ-6) in a pre-post study design. Data were analyzed by repeated measures analysis of variance (ANOVA). Results Body acceptance [ P < 0.001; partial Eta squared = 0.472] and resilience were increased [ P = 0.005; partial Eta squared = 0.319] following the surf therapy intervention. Emotional regulation was examined according to three subscales, with the adjust [ P < 0.001; partial Eta squared = 0.397] and tolerate [ P < 0.001; partial Eta squared = 0.299] subscales increasing following the intervention, and the conceal subscale [ P = 0.459; partial Eta squared = 0.031] remaining unchanged. Gratitude scores were unchanged [ P = 0.425; partial Eta squared = 0.026]. Conclusion A surf therapy program rooted in somatic and trauma-informed models was associated with improved resilience, emotional regulation, and body acceptance in at-risk women.

Background: Obstructive sleep apnea (OSA) is associated with high blood pressure that responds poorly to usual antihypertensive therapy. Methods and results: Forty-one subjects with OSA had 25% higher plasma norepinephrine and 42% higher epinephrine measured every 2 h over 24 h than 20 control subjects. They also excreted more sodium during sleep. This suggested that that a sympatholytic would be a more successful antihypertensive than a diuretic. To test this hypothesis we treated a second group of 23 hypertensive apneics with placebo, 6 weeks of the sympatholytic guanfacine and 6 weeks of hydrochlorothiazide in a crossover study. Guanfacine lowered 24-hour blood pressure by 9.6/6.7 mmHg, more than the 5.4/2.9 mmHg effect of hydrochlorothiazide (P < 0.05). Nighttime systolic blood pressure dipping was poor at 6.6 ± 1.8%. Hydrochlorothiazide did not alter blood pressure dipping but guanfacine improved dipping to 9.1 ± 1.2%, a better result (P = 0.03) than from the diuretic. Central aortic pressure by pulse wave analysis was 120/84 mmHg on hydrochlorothiazide and 109/72 on guanfacine, (P < 0.05). Guanfacine, but not hydrochlorothiazide, improved baroreflex sensitivity, heart rate variability and flow mediated vascular dilation, suggesting that decreasing the elevated sympathetic nerve activity of obstructive sleep apnea returned vascular function toward normal. Conclusions: OSA is the most common condition associated with antihypertensive treatment failure. It increased sympathetic nerve activity day and night. Drugs that block sympathetic nerve function are not among the 4 most commonly recommended classes of antihypertensives but diuretics are. Sympatholytic therapy was superior to diuretic treatment for hypertension associated with sleep apnea. Trial registration: NCT, NCT02699125, Registered 26 February 2016 - Retrospectively registered, https://clinicaltrials.gov/study/NCT02699125 .

Background: The prevalence of liver disorders and metabolic syndrome has increased among youth. Glyphosate, the most widely used herbicide worldwide, could contribute to the development of these conditions. Objective: We aimed to assess whether lifetime exposure to glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), is associated with elevated liver transaminases and metabolic syndrome among young adults. Methods: We conducted a prospective cohort study (n=480 mother-child dyads) and a nested case-control study (n=60 cases with elevated liver transaminases and 91 controls) using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We measured glyphosate and AMPA concentrations in urine samples collected during pregnancy and at child ages 5, 14, and 18 y from cases and controls. We calculated glyphosate residue concentrations: [glyphosate + (1.5×AMPA)]. We estimated the amount of agricultural-use glyphosate applied within a 1-km radius of every residence from pregnancy to age 5 y for the full cohort using California Pesticide Use Reporting data. We assessed liver transaminases and metabolic syndrome at 18 y of age. Results: Urinary AMPA at age 5 y was associated with elevated transaminases [relative risk (RR) per 2-fold increase=1.27, 95% confidence interval (CI): 1.06, 1.53] and metabolic syndrome (RR=2.07, 95% CI: 1.38, 3.11). Urinary AMPA and glyphosate residues at age 14 y were associated with metabolic syndrome [RR=1.80 (95% CI: 1.10, 2.93) and RR=1.88 (95% CI: 1.03, 3.42), respectively]. Overall, a 2-fold increase in urinary AMPA during childhood was associated with a 14% and a 55% increased risk of elevated liver transaminases and metabolic syndrome, respectively. Living near agricultural glyphosate applications during early childhood (birth to 5 y of age) was also associated with metabolic syndrome at age 18 y in the case-control group (RR=1.53, 95% CI: 1.16, 2.02). Discussion: Childhood exposure to glyphosate and AMPA may increase risk of liver and cardiometabolic disorders in early adulthood, which could lead to more serious diseases later in life. https://doi.org/10.1289/EHP11721.

Context: While advances in the Western sciences have increased our understanding of the human biofield, few studies have examined the potential effects of sacred objects on its functioning. Design and study participants: This exploratory study examined the effects of a sacred object called the Sri Yantra / Durga Stone on the human biofield. Twelve women and five men were studied on three separate occasions using the Bio-Well device, which purportedly measures aspects of the biofield: baseline (the day before exposure to the sacred object), pre-exposure (immediately prior to exposure to the sacred object), and post-exposure (immediately following exposure to the sacred object). A set of a priori hypotheses examined outcome effects on a set of variables, including multiple physiological systems. Results: The overall Bio-Well energy state (Bio-Well variables are in units of joules) was significantly changed following exposure to the sacred object (p = 0.001). In addition, the cardiovascular, endocrine, musculoskeletal, digestive, urinogenital, and immune system readings showed significant changes (p's<0.003) while the nervous and respiratory system assessments were unchanged. Chakra (defined as a center of vital prana) energy was changed following exposure to the stone (p = 0.001), while chakra alignment was not (p = 0.145). Conclusions: The findings from this exploratory study suggest that short-term human exposure to this particular sacred object had significant effects on aspects of the human biofield.

Introduction: Cross-sectional association between the neighborhood-built environment and physical activity (PA) has been demonstrated previously, indicating the importance of neighborhood perception characteristics such as walkability, safety, and the connectivity of streets on PA levels. Our study aimed to assess the longitudinal data from participants of the Multi-Ethnic Study of Atherosclerosis (MESA) to evaluate the potential relationship between perceived environment and PA patterns. Methods: We analyzed data from a subset of participants (n = 3097) with available PA data who participated in a prospective cohort conducted from 2000 to 2018. The exposure variables were the perceived aspects of the neighborhood environment and the perception of safety, and the outcome was patterns of PA. Patterns were defined as categories reflecting meeting versus not meeting PA guidelines over time. We created the following categories: adopters (individuals who did not meet guidelines at baseline but met guidelines at Exam 6), relapsers (individuals who met guidelines at baseline but did not meet guidelines at Exam 6), maintainers (individuals who met guidelines both at baseline and Exam 6), and insufficiently active (individuals who did not meet guidelines at either baseline or Exam 6). The maintainers’ group was considered the reference category. We estimated the relative risk to assess the magnitude effect of the association between environmental perceptions and the outcome. Results: Individuals who reported that lack of parks and playgrounds was “not a problem” in their neighborhood had a 2.3-times higher risk of decreasing their physical activity (i.e., the “relapser” category) compared to maintainers. After full adjustment, perceiving poor sidewalks as “somewhat a serious problem” was associated with a 64% lower risk of becoming an adopter than a maintainer. When compared to those who perceive the neighborhood as “very safe”, perception of the neighborhood as “safe” to “not at all safe” (ratings 3, 4, and 5, respectively, on the perceived safety scale) was significantly associated with being classified in the adopter category. Conclusions: As the first longitudinal study of the association of perceived environment and physical activity within the MESA cohort, we conclude that a few aspects are longitudinally associated with being physically active among adults.

With planned deep space and commercial spaceflights, gaps remain to address health risks in astronauts. Multiple studies have shown associations between clonal expansion of hematopoietic cells with hematopoietic malignancies and cardiometabolic disease. This expansion of clones in the absence of overt hematopoietic disorders is termed clonal hematopoiesis (CH) of indeterminate potential (CHIP). Using deep, error-corrected, targeted DNA sequencing we assayed for somatic mutations in CH-driver genes in peripheral blood mononuclear cells isolated from de-identified blood samples collected from 14 astronauts who flew Shuttle missions between 1998–2001. We identified 34 nonsynonymous mutations of relatively low variant allele fraction in 17 CH-driver genes, with the most prevalent mutations in TP53 and DNMT3A. The presence of these small clones in the blood of relatively young astronaut cohort warrants further retrospective and prospective investigation of their clinical relevance and potential application in monitoring astronaut’s health.

During spaceflight, astronauts are exposed to various physiological and psychological stressors, such as microgravity, sleep deprivation, isolation, confinement, and high ionizing radiation have shown adverse health effects. Therefore, there is an unmet need to develop novel diagnostic tools to predict early alterations in astronauts' health. Small nucleolar RNA (snoRNA) is a type of short ncRNAs (60-300 nucleotides) known to guide 2’-O-methylation (Nm) or pseudouridine (ψ) on ribosomal RNA (rRNA), snRNA, or mRNA. Emerging evidence suggests that dysregulated snoRNAs may be key players in regulating fundamental cellular mechanisms and the pathogenesis of cancer, heart, and neurological disease. Therefore, we sought to determine whether the spaceflight-induced snoRNA changes in plasma extracellular vesicles (EV) and astronaut's peripheral blood mononuclear cells (PBMCs) can be utilized as potential biomarkers. Using unbiased small RNA sequencing (sRNAseq), we evaluated the EV snoRNA changes in peripheral blood (PB) plasma of astronauts (n=5/group) who underwent median 12-day long Shuttle missions between 1998-2001. Using stringent cutoff (> log 2-fold change, FDR < 0.05), we detected 20 down-regulated snoRNAs and 10 upregulated PB-EVs at R+3 compared to L-10. qPCR validation revealed that SNORA74A was significantly down-regulated at R+3 compared to L-10. We next determined snoRNA expression levels in astronauts' PBMCs at R+3 and L-10 (n=6/group). qPCR analysis further confirmed a significant increase in SNORA19 and SNORA47 in astronauts' PBMCs at R+3 compared to L-10 Notably, many downregulated snoRNA-guided rRNA modifications, including four Nms and five ψs. Our findings unveiled that spaceflight induced changes in EV and PBMCs snoRNA expression, thus suggesting snoRNAs may serve as novel biomarkers for monitoring astronauts' health.

During spaceflight, astronauts are exposed to various physiological and psychological stressors that have been associated with adverse health effects. Therefore, there is an unmet need to develop novel diagnostic tools to predict early alterations in astronauts’ health. Small nucleolar RNA (snoRNA) is a type of short non-coding RNA (60–300 nucleotides) known to guide 2′-O-methylation (Nm) or pseudouridine (ψ) of ribosomal RNA (rRNA), small nuclear RNA (snRNA), or messenger RNA (mRNA). Emerging evidence suggests that dysregulated snoRNAs may be key players in regulating fundamental cellular mechanisms and in the pathogenesis of cancer, heart, and neurological disease. Therefore, we sought to determine whether the spaceflight-induced snoRNA changes in astronaut’s peripheral blood (PB) plasma extracellular vesicles (PB-EV) and peripheral blood mononuclear cells (PBMCs). Using unbiased small RNA sequencing (sRNAseq), we evaluated changes in PB-EV snoRNA content isolated from astronauts (n = 5/group) who underwent median 12-day long Shuttle missions between 1998 and 2001. Using stringent cutoff (fold change > 2 or log2-fold change >1, FDR < 0.05), we detected 21 down-and 9—up-regulated snoRNAs in PB-EVs 3 days after return (R + 3) compared to 10 days before launch (L-10). qPCR validation revealed that SNORA74A was significantly down-regulated at R + 3 compared to L-10. We next determined snoRNA expression levels in astronauts’ PBMCs at R + 3 and L-10 (n = 6/group). qPCR analysis further confirmed a significant increase in SNORA19 and SNORA47 in astronauts’ PBMCs at R + 3 compared to L-10. Notably, many downregulated snoRNA-guided rRNA modifications, including four Nms and five ψs. Our findings revealed that spaceflight induced changes in PB-EV and PBMCs snoRNA expression, thus suggesting snoRNAs may serve as potential novel biomarkers for monitoring astronauts’ health.