Exposure to metal mixtures and telomere length in Bangladeshi children.

Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (µg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.

Perceived Stress From Childhood to Adulthood and Cardiometabolic End Points in Young Adulthood: An 18-Year Prospective Study.

BACKGROUND: We investigated how childhood-to-adulthood perceived stress patterns predict adult cardiometabolic risk. METHODS AND RESULTS: This study included 276 participants from the Southern California Children's Health Study (2003-2014), and a follow-up assessment (2018-2021). Perceived stress (Perceived Stress Scale) was initially reported by participants' parents for themselves during early childhood (mean age, 6.3 years), and later self-reported during adolescence (13.3 years) and young adulthood (23.6 years). Participants were grouped into 4 stress patterns: consistently high, decreasing, increasing, and consistently low. Cardiometabolic risk was assessed in young adulthood by carotid artery intima-media thickness, systolic and diastolic blood pressure, obesity, percent body fat, android/gynoid ratio, and glycated hemoglobin. A cardiometabolic risk score was generated by summing the clinically abnormal markers. Multivariable linear and logistic regression models were used to (1) examine the associations between Perceived Stress Scale at 3 time points and adult cardiometabolic risk, and (2) assess the impact of stress pattern on adult cardiometabolic risk. Findings suggested that in adulthood, higher Perceived Stress Scale score was associated with increased overall cardiometabolic risk (ß=0.12 [95% CI, 0.01-0.22]), carotid artery intima-media thickness (ß=0.01 [95% CI, 0.0003-0.02]), systolic blood pressure (ß=1.27 [95% CI, 0.09-2.45]), and diastolic blood pressure (ß=0.94 [95% CI, 0.13-1.75]). Individuals with a consistently high adolescence-to-adulthood stress pattern had greater overall cardiometabolic risk (ß=0.31 [95% CI, 0.02-0.60]), android/gynoid ratio (ß=0.07 [95% CI, 0.02-0.13]), percent body fat (ß=2.59 [95% CI, 0.01-5.17]), and greater odds of obesity (odds ratio, 5.57 [95% CI, 1.62-19.10]) in adulthood, compared with those with a consistently low Perceived Stress Scale score. CONCLUSIONS: Consistently high perceived stress from adolescence to adulthood may contribute to greater cardiometabolic risk in young adulthood.

Discovery of extracellular vesicle-delivered miR-185-5p in the plasma of patients as an indicator for advanced adenoma and colorectal cancer.

BACKGROUND: We aimed to evaluate whether extracellular vesicles (EV)-derived microRNAs (miRNAs) can be used as biomarkers for advanced adenoma (AA) and colorectal cancer (CRC). METHODS: We detected the changes in the plasma EV-delivered miRNA profiles in healthy donor (HD), AA patient, and I-II stage CRC patient groups using miRNA deep sequencing assay. We performed the TaqMan miRNA assay using 173 plasma samples (two independent cohorts) from HDs, AA patients, and CRC patients to identify the candidate miRNA(s). The accuracy of candidate miRNA(s) in diagnosing AA and CRC was determined using the area under the receiver-operating characteristic curve (AUC) values. Logistic regression analysis was performed to evaluate the association of candidate miRNA(s) as an independent factor for the diagnosis of AA and CRC. The role of candidate miRNA(s) in the malignant progression of CRC was explored using functional assays. RESULTS: We screened and identified four prospective EV-delivered miRNAs, including miR-185-5p, which were significantly upregulated or downregulated in AA vs. HD and CRC vs. AA groups. In two independent cohorts, miR-185-5p was the best potential biomarker with the AUCs of 0.737 (Cohort I) and 0.720 (Cohort II) for AA vs. HD diagnosis, 0.887 (Cohort I) and 0.803 (Cohort II) for CRC vs. HD diagnosis, and 0.700 (Cohort I) and 0.631 (Cohort II) for CRC vs. AA diagnosis. Finally, we demonstrated that the upregulated expression of miR-185-5p promoted the malignant progression of CRC. CONCLUSION: EV-delivered miR-185-5p in the plasma of patients is a promising diagnostic biomarker for colorectal AA and CRC. Trial registration The study protocol was approved by the Ethics Committee of Changzheng Hospital, Naval Medical University, China (Ethics No. 2022SL005, Registration No. of China Clinical Trial Registration Center: ChiCTR220061592).

Assessment of the statistical optimization strategies and clinical evaluation of an artificial intelligence-based automated diagnostic system for thyroid nodule screening.

Background: Thyroid cancer is the most common endocrine cancer in the world. Accurately distinguishing between benign and malignant thyroid nodules is particularly important for the early diagnosis and treatment of thyroid cancer. This study aimed to investigate the best possible optimization strategies for an already-trained artificial intelligence (AI)-based automated diagnostic system for thyroid nodule screening and, in addition, to scrutinize the clinically relevant limitations using stratified analysis to better standardize the application in clinical workflows. Methods: We retrospectively reviewed a total of 1,092 ultrasound images associated with 397 thyroid nodules collected from 287 patients between April 2019 and January 2021, applying postoperative pathology as the gold standard. We applied different statistical approaches, including averages, maximums, and percentiles, to estimate per-nodule-based malignancy scores from the malignancy scores per image predicted by AI-SONIC Thyroid v. 5.3.0.2 (Demetics Medical Technology Ltd., Hangzhou, China) system, and we assessed its diagnostic efficacy on nodules of different sizes or tumor types with per-nodule analysis using performance metrics. Results: Of the 397 thyroid nodules, 272 thyroid nodules were overrepresented by malignant nodules according to the results of the surgical pathological examinations. Taking the median of the malignancy scores per image to estimate the nodule-based score with a cutoff value of 0.56 optimized for the means of sensitivity and specificity, the AI-based automated detection system demonstrated slightly lower sensitivity, significantly higher specificity (almost independent of nodule size), and similar accuracy to that of the senior radiologist. Both the AI system and the senior radiologist demonstrated higher sensitivity in diagnosing smaller nodules (≤25 mm) and comparable diagnostic performances for larger nodules. The mean diagnostic time per nodule of the AI system was 0.146 s, which was in sharp contrast to the 2.8 to 4.5 min of the radiologists. Conclusions: Using our optimization strategy to achieve nodule-based diagnosis, the AI-SONIC Thyroid automated diagnostic system demonstrated an overall diagnostic accuracy equivalent to that of senior radiologists. Thus, it is expected that it can be used as a reliable auxiliary diagnostic method by radiologists for the screening and preoperative evaluation of malignant thyroid nodules.

Does crime trigger genetic risk for type 2 diabetes in young adults? A G x E interaction study using national data.

BACKGROUND: Living in neighborhoods perceived as disordered exacerbates genetic risk for type 2 diabetes (T2D) among older adults. It is unknown whether this gene-neighborhood interaction extends to younger adults. The present study aims to investigate whether crime, an objectively measured indicator of neighborhood disorder, triggers genetic risk for T2D among younger adults, and whether this hypothesized triggering occurs through exposure to obesity. METHODS: Data were from the Wave I (2008) National Longitudinal Study of Adolescent to Adult Health. A standardized T2D polygenic score was created using 2014 GWAS meta-analysis results. Weighted mediation analyses using generalized structural equation models were conducted in a final sample of 7606 adults (age range: 25-34) to test the overall association of T2D polygenic scores with T2D, and the mediating path through obesity exposure in low, moderate, and high county crime-rate groups. Age, sex, ancestry, educational degree, household income, five genetic principal components, and county-level concentrated advantage and population density were adjusted. RESULTS: The overall association between T2D polygenic score and T2D was not significant in low-crime areas (p = 0.453), marginally significant in moderate-crime areas (p = 0.064), and statistically significant in high-crime areas (p = 0.007). The mediating path through obesity was not significant in low or moderate crime areas (ps = 0.560 and 0.261, respectively), but was statistically significant in high-crime areas (p = 0.023). The indirect path through obesity accounted for 12% of the overall association in high-crime area. CONCLUSION: A gene-crime interaction in T2D was observed among younger adults, and this association was partially explained by exposure to obesity.

In the eyes of the beholder: Race, place and health.

Racial and ethnic health disparities are fundamentally connected to neighborhood quality. For example, as a result of historical systemic inequities, racial and ethnic minorities are more likely to live in neighborhoods with signs of physical disorder (e.g., graffiti, vandalism), and physically disordered environments have been noted to associate with increased risk for chronic illness. Degree of exposure to neighborhood disorder may alter peoples' perception of their neighborhoods, however, with those most exposed (e.g., historically marginalized racial/ethnic groups) perhaps perceiving less threat from signs of neighborhood disorder. The purpose of the present study was to examine the complex interrelationships between people and place by investigating whether exposure to neighborhood physical disorder relates to residents' (1) perceptions of neighborhood safety and (2) perceptions of their health, and (3) examining whether these links vary by race/ethnicity. Using 2016-2018 Health and Retirement Study (HRS) data, a representative sample of US adults aged 51 years and older (n = 9,080, mean age 68 years), we conducted a series of weighted linear regressions to examine the role of neighborhood disorder in relation to both perceived neighborhood safety and self-rated health. Results indicated that greater neighborhood physical disorder was statistically significantly related to feeling less safe among non-Hispanic Whites and Hispanics, but not non-Hispanic Blacks. Regarding self-rated health, neighborhood physical disorder was statistically significantly related to poorer health among all racial/ethnic groups. These findings suggest that, despite differential interpretation of neighborhood disorder as a threat to safety, this modifiable aspect of peoples' environment is related to poor health regardless of one's race/ethnicity.

Genome-Wide Identification and Expression Analysis of CsCaM/CML Gene Family in Response to Low-Temperature and Salt Stresses in Chrysanthemum seticuspe.

Calmodulin (CaM) and calmodulin-like proteins (CML) act as significant Ca2+ sensors binding Ca2+ with EF-hand motifs and have been reported to be involved in various environmental stresses in plants. In this study, calmodulin CsCaM/CML gene family members were identified based on the genome of Chrysanthemum seticuspe published recently; a phylogenetic tree was constructed; gene structures and chromosomal locations of CsCaM/CML were depicted; cis-acting regulatory elements were predicted; collinearity and duplicate events of CaM/CML were analyzed using MCScanX software; and the expression levels of CsCaM/CML in response to abiotic stress were analyzed, based on the published RNA-seq data. We identified 86 CsCaM/CML (4 CsCaMs and 82 CsCMLs) genes in total. Promoter sequences of CsCaM/CML contained elements related to abiotic stresses (including low-temperature and anaerobic stresses) and plant hormones (including abscisic acid (ABA), MeJA, and salicylic acid). CsCaM/CML genes were distributed on nine chromosomes unevenly. Collinearity analysis indicated that recent segmental duplications significantly enlarged the scale of the CML family in C. seticuspe. Four CsCMLs (CsCML14, CsCML50, CsCML65, and CsCML79) were statistically differentially regulated under low-temperature and salt stress compared with those in the normal condition. These results indicate diverse roles of CsCaM/CML in plant development and in response to environmental stimuli in C. seticuspe.

Eisenmenger Syndrome Among Children with Unrepaired Congenital Heart Defects in Yunnan, China.

Eisenmenger syndrome is a life-threatening complication of congenital heart defects (CHD). Since Eisenmenger syndrome among children of repaired CHD is rare, very few studies have had the necessary data to investigate its distribution in children. The current study used data collected in rural China to investigate the prevalence of Eisenmenger syndrome in children with unrepaired CHD. Data were from the 2006 to 2016 patient medical records of China California Heart Watch, which is a traveling cardiology clinic in Yunnan Province, China. Patients were included if they (1) aged 18 or below, (2) had CHD(s), and (3) the defect was not repaired by the time of the clinic visit. The prevalence of Eisenmenger syndrome was calculated in each age and defect group. Using logistic regression models, we tested whether oxygen saturation, Down syndrome, sex, and age were significantly associated with Eisenmenger syndrome. Of the 1301 study participants, ventricular septum defect (VSD), atrial septal defect (ASD), and patent ductus arteriosus (PDA) were the most common CHD. About one-sixth of the patients had pulmonary hypertension and 1.5% had Eisenmenger syndrome. The percentages of Eisenmenger syndrome were 1.8% in VSD patients, 0 in ASD patients, and 0.9% in PDA patients. Patients in the age group between 15 and 18 years had the highest percentages of Eisenmenger syndrome (11.5%). Age and presence of Down syndrome were significantly associated with the presence of Eisenmenger syndrome. Our finding highlights the importance of early detection and correction of CHD.

Obesogenic environments and cardiovascular disease: a path analysis using US nationally representative data.

INTRODUCTION: People living in obesogenic environments, with limited access to healthful food outlets and exercise facilities, generally have poor health. Previous research suggests that behavioral risk factors and indicators of physiological functioning may mediate this link; however, no studies to date have had the requisite data to investigate multi-level behavioral and physiological risk factors simultaneously. The present study conducted serial and parallel mediation analyses to examine behavioral and physiological pathways explaining the association between environmental obesogenicity and cardiovascular disease (CVD). METHODS: This cross-sectional observational study used data from the 2012-2016 Health and Retirement Study, a representative survey of US older adults (n = 12,482, mean age 65.9). Environmental obesogenicity was operationalized as a combined score consisting of nine environmental measures of food and physical activity. CVD and health-compromising behaviors (diet, alcohol consumption, smoking, and exercise) were self-reported. Physiological dysregulation was assessed with measured blood pressure, heart rate, HbA1c, cholesterol levels, BMI, and C-reactive protein. The Hayes Process Macro was used to examine serial and parallel paths through health-compromising behaviors and physiological dysregulation in the environmental obesogenicity-CVD link. RESULTS: People living in more obesogenic environments had greater odds of self-reported CVD (odds ratio = 1.074, 95% confidence interval (CI): 1.028, 1.122), engaged in more health-compromising behaviors (ß = 0.026, 95% CI: 0.008, 0.044), and had greater physiological dysregulation (ß = 0.035, 95% CI: 0.017, 0.054). Combined, health-compromising behaviors and physiological dysregulation accounted for 7% of the total effects of environmental obesogenicity on CVD. CONCLUSION: Behavioral and physiological pathways partially explain the environmental obesogenicity-CVD association. Obesogenic environments may stymie the success of cardiovascular health-promotion programs by reducing access to resources supporting healthy lifestyles.

Genome-wide identification of expansin gene family in barley and drought-related expansins identification based on RNA-seq.

Expansins are cell wall loosening proteins and involved in various developmental processes and abiotic stress. No systematic research, however, has been conducted on expansin genes family in barley. A total of 46 expansins were identified and could be classified into three subfamilies in Hordeum vulgare: HvEXPA, HvEXPB, and HvEXLA. All expansin proteins contained two conserved domains: DPBB_1 and Pollen_allerg_1. Expansins, in the same subfamily, share similar motifs composition and exon-intron organization; but greater differences were found among different subfamilies. Expansins are distributed unevenly on 7 barley chromosomes; tandem duplicates, including the collinear tandem array, contribute to the forming of the expansin genes family in barley with few whole-genome duplication events. Most HvEXPAs mainly expressed in embryonic and root tissues. HvEXPBs and HvEXLAs showed different expression patterns in 16 tissues during different developmental stages. In response to water deficit, expansins in wild barley were more sensitive than that in cultivated barley; the expressions of HvEXPB5 and HvEXPB6 were significantly induced in wild barley under drought stress. Our study provides a comprehensive and systematic analysis of the barley expansin genes in genome-wide level. This information will lay a solid foundation for further functional exploration of expansin genes in plant development and drought stress tolerance.

What predicts how safe people feel in their neighborhoods and does it depend on functional status?

Feeling unsafe in one's neighborhood is related to poor health. Features of the neighborhood environment have been suggested to inform perceptions of neighborhood safety. Yet, the relative contribution of these features (e.g., uneven sidewalks, crime, perceived neighborhood physical disorder) on perceived neighborhood safety, particularly among people with disabilities who may view themselves as more vulnerable, is not well understood. We examined whether sidewalk quality assessed by third party raters, county-level crime rates, and perceived neighborhood disorder would relate to neighborhood safety concerns, and whether functional limitations would exacerbate these links. Using data from the 2012/2014 waves of the Health and Retirement Study (n = 10,653, mean age = 66 years), a national sample of older US adults, we demonstrate that those with and without functional limitations felt less safe in areas with more crime and perceived as more disordered. When considered simultaneously, however, only perceived disorder statistically significantly predicted safety concerns. Living in neighborhoods with better sidewalk quality was statistically significantly related to feeling less safe, but only among those with functional limitations. Sidewalk quality was not statistically significantly related to safety reports among those without functional limitations. To our knowledge, this study is among the first to examine multiple features of the neighborhood environment simultaneously in relation to perceived neighborhood safety. Our findings highlight the relative importance of perceived physical disorder, and that these perceptions relate to safety concerns. Replication of this research is needed to determine the robustness of these patterns, including rich data on pedestrian use and sidewalk proximity to roadways. Community-level interventions that simultaneously target the multifaceted features of the neighborhood environment that shape people's safety reports may be needed to reduce burden of health.

Dynamic regulation of small RNAs in anthocyanin accumulation during blueberry fruit maturation.

Blueberry is rich in anthocyanins which accumulate during fruit maturation. Previous studies mostly focus on their translational/transcriptional regulation, but usually underestimate their post-transcriptional regulation, e.g. small RNAs. This study aimed to identify sRNAs and their potential pathways associated with anthocyanin biosynthesis. During three typical phases of fruit maturation (green, pink, and blue), we investigated dynamic changes of sRNA by deep sequencing sRNA and examined the interaction of sRNAs with their target genes by degradome and RLM-PCR. During maturation, up-regulation of VcmiRNA156 and VcmiR393 resulted in down-regulation of VcSPLs and VcTIR1/AFBs, respectively. An important gene of anthocyanin biosynthesis, VcDFR, was substantially down-regulated at both the mRNA and protein levels, and potentially responded to regulation of VcSPLs and VcTIR1/AFBs. Additionally, indole acetic acid (IAA) and abscisic acid (ABA) were involved in the regulation of anthocyanin biosynthesis by interacting with VcmiR393-TIR1/AFBs and VcmiRNA319-VcMYBs respectively. This information provides another insight into blueberry anthocyanin biosynthesis.

Revised threshold values for neonatal oxygen saturation at mild and moderate altitudes.

AIM: The aim of this study was to determine reference values for oxygen saturation (SpO2 ) in neonates at mild and moderate altitudes. METHODS: Our study included 41 097 consecutively born, asymptomatic neonates from 35 hospitals, located in Yunnan, China, with altitudes ranging from 267 to 2202 m. Pre-and post-ductal SpO2 of each neonate was measured at 24 hours of age and before hospital discharge. All study participants, according to the altitude of birth, were categorised into three groups: low (0-500 m), mild (500-1500 m) and moderate altitude (1500-2500 m). RESULTS: Every 1000-m increase in altitude was associated with a 1.54 per cent decrease in mean SpO2 . The means of pre-ductal SpO2 at low, mild and moderate groups were 97.9%, 96.4% and 95.5%, respectively. We used the 2.5th percentile of SpO2 distribution as the cut-off for neonatal SpO2 screening and defined new cut-off values of ≤93% for mild altitudes, ≤92% for moderate altitudes and no adjustment for low altitudes. CONCLUSION: We recommend revised cut-off values for neonatal SpO2 at mild and moderate altitudes and provide new values for paediatricians to refer to when screening neonates for severe congenital heart or lung diseases.

Functional analysis of FLOWERING LOCUS T orthologs from spring orchid (Cymbidium goeringii Rchb. f.) that regulates the vegetative to reproductive transition.

The FLOWERING LOCUS T (FT) gene plays crucial roles in regulating the vegetative-to-reproductive phase transition. The FT-like gene of spring orchid (Cymbidium goeringii Rchb. f.), CgFT, was isolated and characterized. CgFT mRNA was detected in leaves, pseudobulb, and flowers. In flowers, CgFT was expressed more in young flower buds than in mature flowers, and was predominantly expressed in young ovary and sheath. Seasonal expression analysis in leaves of a three-year-old spring orchid showed that a large increase in transcription, which started on June 20 for CgFT. We propose that the increased transcription in the middle of June marks the beginning of flower induction in this species. The ectopic expression of CgFT in transgenic tobacco plants showed novel phenotypes by flowering earlier than wild-type plants. Further analysis of the flowering time-related genes indicated that the expression of LEAFY, APETALLA1, FRUITFULL and SEPALLATA1 were significantly upregulated in 35S::CgFT transgenic tobacco plants. These results indicated that CgFT is a putative FT homolog in spring orchid that regulates flower transition, similar to its homolog in Arabidopsis. This study provides the first information on the spring orchid floral gene to elucidate the regulation of the flowering transition in spring orchid.

MiR-18a regulates expression of the pancreatic transcription factor Ptf1a in pancreatic progenitor and acinar cells.

The basic helix-loop-helix (bHLH) transcription factor Ptf1a plays stage-specific roles in the developing pancreas. During early pancreatic development, low levels of Ptf1a preferentially promote the differentiation of pancreatic progenitor cells into endocrine cells, whereas high levels of Ptf1a shift pancreatic progenitors towards an exocrine cell fate. In adults, Ptf1a is essential for the production of exocrine enzymes by pancreatic acinar cells. In this paper, we show that Ptf1a expression is repressed by miR-18a in pancreatic progenitors and acinar cells via its binding to the 3'UTR of Ptf1a mRNA. Furthermore, overexpression of miR-18a exerts little effect on pancreatic progenitors and acinar cells. These results indicate that miR-18a plays a fine-tuning role in regulating pancreatic progenitors and exocrine cells through the repression of Ptf1a expression.