Over 1/3 of Americans have prediabetes, while 9.4% have type 2 diabetes. The aim of our study was to estimate the prevalence of prediabetes in Mexican Americans, with known 28.2% prevalence of type 2 ...diabetes, by age and sex and to identify critical socio-demographic and clinical factors associated with prediabetes.
Data were collected between 2004 and 2017 from the Cameron County Hispanic Cohort in Texas. Weighted crude and sex- and age- stratified prevalences were calculated. Survey weighted logistic regression analyses were conducted to identify risk factors for prediabetes.
The prevalence of prediabetes (32%) was slightly higher than the alarmingly high rate of type 2 diabetes (28.2%). Hispanic men had the highest overall (37.8%) and highest age stratified prevalence of prediabetes. Males had higher odds of prediabetes than females 1.56 (1.19, 2.06), controlling for the effect of family history of diabetes, age, BMI, and high-density lipoprotein. Family history of diabetes was a strong independent risk factor for prediabetes in all men, and in men and women in the age group 40–64 years. Elevated triglycerides (p = 0.003) was an independent risk factor for men and women in the age group 18–39 years.
Despite the very high prevalence of type 2 diabetes, prediabetes prevalence among Mexican Americans is only marginally less than national prediabetes rates. This suggests that progression to type 2 diabetes is more rapid and occurs earlier than nationally. Earlier screening and interventions for prediabetes, especially for men, are necessary to slow the transition to diabetes.
Bayesian Network analysis of piglet scours McCormick, Benjamin J J; Van Breda, Lechelle K; Ward, Michael P
Scientific reports,
07/2017, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Diarrhoeal disease (scours) in piglets, often associated with enterotoxigenic Escherichia coli (ETEC), is a substantial financial burden to the pig industry worldwide. Previous research has not ...explicitly examined the relationships between farm, pen and microbiological factors. Here we present a state of the art analysis to reveal empirical indirect - as well as direct - associations between management factors as putative risks for scours in pre- and post-weaned piglets. A Bayesian Network is constructed to identify the optimal structural model describing the relationships between risk factors. An additive model is then built to estimate more epidemiologically familiar odds ratios. Farm-level variance dominates the model, making many pen-level associations null. However, there is evidence that pre-weaning scours are less likely on farms with <400 sows (0.14, 0.03-0.50). Our results strongly suggest that smaller production units (piglets/pen) could reduce the incidence of scours in piglets. There is also some evidence that ownership of other livestock is a potential risk factor for pre-weaning scours, although this was observed only at one farm. Future research should be directed at better understanding the role of herd size and investigating the relationship between managing other livestock and the occurrence of scours in pig herds.
•This study focused on hepatic igfbp responses to EDCs in Atlantic salmon.•In fry and smolts, hepatic ghr, igf1 and -2 were diminished by EDC exposure.•In fry, EDCs diminished igfbp1b1, -2a, -2b1, ...-4, -5b2 and -6b1.•In smolts, EDCs diminished igfbp1b1, -4 and -6b1.•igfbp5a was stimulated by EDCs in both fry and smolts.
Feminizing endocrine disrupting compounds (EDCs) affect the growth and development of teleost fishes. The major regulator of growth performance, the growth hormone (Gh)/insulin-like growth-factor (Igf) system, is sensitive to estrogenic compounds and mediates certain physiological and potentially behavioral consequences of EDC exposure. Igf binding proteins (Igfbps) are key modulators of Igf activity, but their alteration by EDCs has not been examined. We investigated two life-stages (fry and smolts) of Atlantic salmon (Salmo salar), and characterized how the Gh/Igf/Igfbp system responded to waterborne 17α-ethinylestradiol (EE2), 17β-estradiol (E2) and 4-nonylphenol (NP). Fry exposed to EE2 and NP for 21 days had increased hepatic vitellogenin (vtg) mRNA levels while hepatic estrogen receptor α (erα), gh receptor (ghr), igf1 and igf2 mRNA levels were decreased. NP-exposed fry had reduced body mass and total length compared to controls. EE2 and NP reduced hepatic igfbp1b1, -2a, -2b1, -4, -5b2 and -6b1, and stimulated igfbp5a. In smolts, hepatic vtg mRNA levels were induced following 4-day exposures to all three EDCs, while erα only responded to EE2 and E2. EDC exposures did not affect body mass or fork length; however, EE2 diminished plasma Gh and Igf1 levels in parallel with reductions in hepatic ghr and igf1. In smolts, EE2 and E2 diminished hepatic igfbp1b1, -4 and -6b1, and stimulated igfbp5a. There were no signs of compromised ionoregulation in smolts, as indicated by unchanged branchial ion pump/transporter mRNA levels. We conclude that hepatic igfbps respond (directly and/or indirectly) to environmental estrogens during two key life-stages of Atlantic salmon, and thus may modulate the growth and development of exposed individuals.
Abstract
Older adults in nursing homes (NHs) have increased frailty, medication, and antimicrobial exposures, all factors that are known to affect the composition of gut microbiota. Our objective was ...to define which factors have the greatest association with the NH resident gut microbiota, explore patterns of dysbiosis and compositional changes in gut microbiota over time in this environment. We collected serial stool samples from NH residents. Residents were assessed using the Mini Nutritional Assessment tool and Clinical Frailty Scale. Bacterial composition of resident stool samples was determined by metagenomic sequencing. We used mixed-effect random forest modeling to identify clinical covariates that associate with microbiota. We enrolled and followed 166 residents from 5 NHs collecting 512 stool samples and following 15 residents for > 1 year. Medications, particularly psychoactive and antihypertensive medications, had the greatest effect on the microbiota. Age and frailty also contributed, and were associated with increased and decreased diversity, respectively. The microbiota of residents who had lived in the NH for > 1 year were enriched in inflammatory and pathogenic species and reduced in anti-inflammatory and symbiotic species. We observed intraindividual stability of the microbiome among older adults who had lived in the NH already for >1 year followed with sample collections 1 year apart. Older adult NH gut microbiome is heavily influenced by medications, age, and frailty. This microbiome is influenced by the length of NH residency with dysbiosis becoming evident at 12 months, however, after this point there is demonstrated relative stability over time.
Aging is associated with an elevated risk of heat-related mortality and morbidity, attributed, in part, to declines in thermoregulation. However, comparisons between young and older adults have been ...limited to brief exposures (1-4 h), which may not adequately reflect the duration or severity of the heat stress experienced during heat waves. We therefore evaluated physiological responses in 20 young (19-31 yr; 10 females) and 39 older (61-78 yr; 11 females) adults during 9 h of rest at 40°C and 9% relative humidity. Whole body heat exchange and storage were measured with direct calorimetry during the first 3 h and final 3 h. Core temperature (rectal) was monitored continuously. The older adults stored 88 kJ 95% confidence interval (CI): 29, 147 more heat over the first 3 h of exposure (
= 0.006). Although no between-group differences were observed after 3 h young: 37.6°C (SD 0.2°C) vs. older: 37.7°C (0.3°C);
= 0.216, core temperature was elevated by 0.3°C 0.1, 0.4 (adjusted for baseline) in the older group at
37.6°C (0.2°C) vs. 37.9°C (0.2°C);
< 0.001 and by 0.2°C 0.0, 0.3 at
37.7°C (0.3°C) vs. 37.8°C (0.3°C), although the latter comparison was not significant after multiplicity correction (
= 0.061). Our findings indicate that older adults sustain greater increases in heat storage and core temperature during daylong exposure to hot dry conditions compared with their younger counterparts. This study represents an important step in the use of ecologically relevant, prolonged exposures for translational research aimed at quantifying the physiological and health impacts of hot weather and heat waves on heat-vulnerable populations.
We found greater increases in body heat storage and core temperature in older adults than in their younger counterparts during 9 h of resting exposure to hot dry conditions. Furthermore, the age-related increase in core temperature was exacerbated in older adults with common heat-vulnerability-linked health conditions (type 2 diabetes and hypertension). Impairments in thermoregulatory function likely contribute to the increased risk of heat-related illness and injury seen in older adults during hot weather and heat waves.
O6-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O6-alkylating agents and can render cells ...highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using 3H-methylated-DNA-based MGMT inactivation assays and calculated the IC50 values. Using the results of 370 compounds, we performed quantitative structure–activity relationship (QSAR) modeling to identify the correlation between the chemical structure and MGMT-inactivating ability. Modeling was based on subdividing the sorted pIC50 values or on chemical structures or was random. A total of nine molecular descriptors were presented in the model equation, in which the mechanistic interpretation indicated that the status of nitrogen atoms, aliphatic primary amino groups, the presence of O-S at topological distance 3, the presence of Al-O-Ar/Ar-O-Ar/R..O..R/R-O-C=X, the ionization potential and hydrogen bond donors are the main factors responsible for inactivation ability. The final model was of high internal robustness, goodness of fit and prediction ability (R2pr = 0.7474, Q2Fn = 0.7375–0.7437, CCCpr = 0.8530). After the best splitting model was decided, we established the full model based on the entire set of compounds using the same descriptor combination. We also used a similarity-based read-across technique to further improve the external predictive ability of the model (R2pr = 0.7528, Q2Fn = 0.7387–0.7449, CCCpr = 0.8560). The prediction quality of 66 true external compounds was checked using the “Prediction Reliability Indicator” tool. In summary, we defined key structural features associated with MGMT inactivation, thus allowing for the design of MGMT inactivators that might improve clinical outcomes in cancer treatment.
Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while ...protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131's ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.
A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could ...provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/β signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.
Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the ...protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from "helper" to "executioner", triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.
Synopsis
Ecological transitions across salinity boundaries have led to some of the most important diversification events in the animal kingdom, especially among fishes. Adaptations accompanying such ...transitions include changes in morphology, diet, whole-organism performance, and osmoregulatory function, which may be particularly prominent since divergent salinity regimes make opposing demands on systems that maintain ion and water balance. Research in the last decade has focused on the genetic targets underlying such adaptations, most notably by comparing populations of species that are distributed across salinity boundaries. Here, we synthesize research on the targets of natural selection using whole-genome approaches, with a particular emphasis on the osmoregulatory system. Given the complex, integrated and polygenic nature of this system, we expected that signatures of natural selection would span numerous genes across functional levels of osmoregulation, especially salinity sensing, hormonal control, and cellular ion exchange mechanisms. We find support for this prediction: genes coding for V-type, Ca2+, and Na+/K+-ATPases, which are key cellular ion exchange enzymes, are especially common targets of selection in species from six orders of fishes. This indicates that while polygenic selection contributes to adaptation across salinity boundaries, changes in ATPase enzymes may be of particular importance in supporting such transitions.
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