A fiber-enriched diet alleviates Staphylococcus aureus-induced mastitis by activating the HDAC3-mediated antimicrobial program in macrophages via butyrate production in mice.

Mounting evidence suggests that the gut microbiota plays an important role in the pathogenesis of mastitis, an important disease affecting the health of lactating women and the development of the dairy industry. However, the effect of the regulation of the gut microbiota by dietary components on mastitis development remains unknown. In this study, we found that a fiber-enriched diet alleviated Staphylococcus aureus (S. au)-induced mastitis in mice, which was dependent on the gut microbiota as depletion of the gut microbiota by antibiotics abolished this protective effect. Likewise, fecal microbiota transplantation (FMT) from high-inulin (HI)-treated mice (HIF) to recipient mice improved S. au-induced mastitis in mice. Consumption of an HI diet and HIF increased fecal short-chain fatty acid (SCFA) levels compared with the control group. Moreover, treatment with SCFAs, especially butyrate, alleviated S. au-induced mastitis in mice. Mechanistically, consumption of an HI diet enhanced the host antimicrobial program in macrophages through inhibiting histone deacetylase 3 by the production of butyrate. Collectively, our results suggest that modulation of the gut microbiota and its metabolism by dietary components is a potential strategy for mastitis intervention and serve as a basis for other infectious diseases.

Hexadecanamide alleviates Staphylococcus aureus-induced mastitis in mice by inhibiting inflammatory responses and restoring blood-milk barrier integrity.

Subacute ruminal acidosis (SARA) has been demonstrated to promote the development of mastitis, one of the most serious diseases in dairy farming worldwide, but the underlying mechanism is unclear. Using untargeted metabolomics, we found hexadecanamide (HEX) was significantly reduced in rumen fluid and milk from cows with SARA-associated mastitis. Herein, we aimed to assess the protective role of HEX in Staphylococcus aureus (S. aureus)- and SARA-induced mastitis and the underlying mechanism. We showed that HEX ameliorated S. aureus-induced mastitis in mice, which was related to the suppression of mammary inflammatory responses and repair of the blood-milk barrier. In vitro, HEX depressed S. aureus-induced activation of the NF-κB pathway and improved barrier integrity in mouse mammary epithelial cells (MMECs). In detail, HEX activated PPARα, which upregulated SIRT1 and subsequently inhibited NF-κB activation and inflammatory responses. In addition, ruminal microbiota transplantation from SARA cows (S-RMT) caused mastitis and aggravated S. aureus-induced mastitis, while these changes were reversed by HEX. Our findings indicate that HEX effectively attenuates S. aureus- and SARA-induced mastitis by limiting inflammation and repairing barrier integrity, ultimately highlighting the important role of host or microbiota metabolism in the pathogenesis of mastitis and providing a potential strategy for mastitis prevention.

Associations between Individual- and Structural-Level Racism and Gestational Age at Birth in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be.

The purpose of this study was to investigate the associations between multilevel racism and gestational age at birth among nulliparous women. We conducted a secondary analysis of data of the nuMoM2b Study (2010-2013) to examine the associations between individual- and structural-level experiences of racism and discrimination and gestational age at birth among nulliparous women (n = 9148) at eight sites across the U.S. Measures included the individual Experiences of Discrimination (EOD) scale and the Index of Concentration at the Extremes (ICE) to measure structural racism. After adjustment, we observed a significant individual and structural racism interaction on gestational length (p = 0.012). In subgroup analyses, we found that among those with high EOD scores, women who were from households concentrated in the more privileged group had significantly longer gestations (ß = 1.27, 95% CI: 0.48, 2.06). Women who reported higher EOD scores and more economic privilege had longer gestations, demonstrating the moderating effect of ICE as a measure of structural racism. In conclusion, ICE may represent a modifiable factor in the prevention of adverse birth outcomes in nulliparas.

Epigenome-Wide Association Study of Depressive Symptoms in Black Women in the InterGEN Study.

(1) The prevalence of depression is two times higher in women than men. Black women have an increased risk of depression due to stressors such as low socioeconomic status and perceived discrimination. Depression is likely influenced by both genetic and environmental factors. Psychosocial stressors can influence DNA methylation (DNAm), leading to changes in gene expression and ultimately, depression. The objective of this study was to examine associations between DNAm and depressive symptoms in Black women. (2) This study was a secondary analysis of data from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) Study. Perceived discrimination was assessed using Krieger's Experiences of Discrimination and Waelde's Race-Related Events Scale, and participants were screened for depressive symptoms with the Beck Depression Inventory. Raw data from saliva samples were analyzed using the Illumina Infinium Epic (850 K) BeadChip and then preprocessed in RStudio. (3) Differential methylation analysis identified DNAm sites and regions associated with depressive symptoms. Six DNAm sites had a q-value less than 0.05. Additionally, of the 25 regions identified, 12 were associated with neurological diseases or disorders. (4) These findings suggest that there is a neurological component to depression, which should be considered during treatment.

Phytosphingosine alleviates Staphylococcus aureus-induced mastitis by inhibiting inflammatory responses and improving the blood-milk barrier in mice.

Mastitis is one of the common diseases in dairy cows which threatens the health of cows and impacts on economic benefits seriously. Recent studies have been showed that Subacute Ruminal Acidosis (SARA) increased the susceptibility of cow mastitis. SARA leads the disturbance of the rumen microbiota, and the rumen bacterial disordered community is an important endogenous factor of cow mastitis. That is to say, cows which suffer from SARA have a disordered rumen microbiota, a prolonged decline in ruminal PH and a high level of lipopolysaccharide (LPS) in the rumen, blood. Therefore, ruminal metabolism is closely related to the rumen microbiota. However, the specific mechanism of SARA and mastitis still not clear. We found an intestinal metabolite according to the metabonomics, which is correlated to inflammation. Phytophingosine (PS), a product from rumen fluid and milk of the cows which suffer from SARA and mastitis. It has the effect of killing bacteria and anti-inflammatory. Emerging evidences indicate that PS can alleviate inflammatory diseases. However, how PS affects mastitis is largely unknown. In this study, we explored the concrete role of PS on Staphylococcus aureus (S. aureus) -induced mastitis in mice. We found that PS obviously decreased the level of the proinflammatory cytokines. Meanwhile, PS also significantly relieved the mammary gland inflammation caused by S. aureus and restored the function of the blood-milk barrier. Here, we showed that PS increased the expression of the classic Tight-junctions (TJs) proteins including ZO-1, Occludin and Claudin-3. Moreover, PS improves S. aureus-induced mastitis by inhibiting the activation of the NF-κB and NLRP3 signaling pathways. These data indicated that PS relieved S. aureus-induced mastitis effectively. This also provides a reference for exploring the correlation between the intestinal metabolism and inflammation.

Retinoic acid ameliorates low-grade endotoxemia-induced mastitis by limiting inflammatory responses in mice.

Mastitis is a serious disease for humans and animals, which causes huge economic losses in the dairy industry and is hard to prevent due to the complex and unclear pathogenesis. Subacute ruminal acidosis (SARA) has contributed to the development of mastitis by inducing ruminal dysbiosis and subsequent low-grade endotoxemia (LGE), however, how ruminal metabolic changes regulate this progress is still unclear. Our previous study revealed that cows with SARA had increased ruminal retinoic acid (RA) levels, a metabolic intermediate of vitamin A that plays an essential role in mucosal immune responses. Hence, the aim of this study was to investigate the protective effect of RA on LGE-induced mastitis and the underlying mechanisms in mice. The results showed that RA alleviated LGE-induced mastitis, as evidenced by RA significantly reduced the increase in mammary proinflammatory cytokines and improved blood-milk barrier injury caused by LGE. In addition, RA increased the expression of tight junction proteins, including ZO-1, occludin and claudin-3. Furthermore, we found that RA limited the mammary inflammatory responses by inhibiting the activation of NF-κB and NLRP3 signaling pathways. These findings suggest that RA effectively alleviates LGE-induced mastitis and implies a potential strategy for the treatment and prevention of mastitis and other diseases.

Analysis of the brain transcriptome for substance-associated genes: An update on large-scale genome-wide association studies.

Substance use disorder (SUD) arises from the initiation to subsequent regular, irregular and harmful use of substances such as alcohol, tobacco/nicotine and cannabis. While thousands of genetic variants have been identified from recent large-scale genome-wide association studies (GWAS), understanding their functions in substance involvement and investigating the mechanisms by which they act in the addiction circuits remains challenging. In this study, we re-analysed the brain regional transcriptome data from the most comprehensive postmortem transcriptomic study, with a focus on up- or down-regulation of substance-associated protein-coding genes in the addiction circuit-related brain regions (AddictRegions), including six cortical and 11 subcortical regions. We found that substance-associated genes were overrepresented in AddictRegions. Interestingly, we observed a greater degree of genetic overlap between initiation and use and between use and SUD than between initiation and SUD. Moreover, substance initiation, use and SUD-associated genes tend to shift their enriched AddictRegions from the cortical for initiation and, to a lesser extent, substance use to subcortical regions for SUD (e.g., thalamus, substantia nigra and ventral tegmental area). We also uncovered a pattern of coordinated cortical up-regulation and subcortical down-regulation for the genes associated with tobacco initiation and alcohol use. Moreover, the Gene Ontology terms of glutamate receptor activity and neurotransmitter binding were most significantly overrepresented in AddictRegion-upregulated, substance-associated genes, with the strongest enrichment for those involved in common substance use behaviours. Overall, our analysis provides a resource of AddictRegion-related transcriptomes for studying substance-associated genes and generates intriguing insights into the genetic control of substance initiation, use and SUD.

Group-Based Medical Mistrust in Adolescents With Poorly Controlled Asthma Living in Rural Areas.

Black youth and rural adolescents are two groups who experience asthma disparities. Racism and discrimination in health care likely lead to group-based (systems-level) medical mistrust for some adolescents. Group-based medical mistrust, one pathway by which racism drives health inequities, is associated with poorer outcomes for patients with chronic conditions. Despite its potential importance in adolescent asthma, previous research has not considered group-based medical mistrust in this population. To fill this gap, we characterize group-based medical mistrust among rural adolescents with poorly controlled asthma, examining demographic differences. We analyzed baseline data from a school-based clinical trial in which 164 adolescents (mean age = 16.3; 76.2% Black) completed the Group-Based Medical Mistrust Scale (GBMMS). Using linear regression, we tested associations with race, gender, and age, controlling for recent medical visits and insurance status. The total GBMMS mean score was 2.3 (SD = 1.22); subscale scores ranged from 2.3 to 2.4. Black adolescents reported significantly higher total GBMMS scores (ß = .45, p = .003) and significantly higher scores on two GBMMS subscales: suspicion of health care providers (ß = .56, p = .007) and lack of support from health care providers (ß = .36, p = .007). Gender and age were not associated with GBMMS scores. Health care providers need to consider medical mistrust and its role in their clinical care. Together with their institutions, health care providers and researchers should work toward changing systems that perpetuate racism to build trust as a means of reducing asthma disparities among adolescents.

Associations Between Smoking Status and Physical and Mental Health-Related Quality of Life Among Individuals With Mobility Impairments.

BACKGROUND: In the general population, quitting smoking is associated with improved health-related quality of life (QoL), but this association has not been examined in smokers with chronic mobility impairments (MIs). PURPOSE: We examined associations between smoking status and health-related QoL over 6 months, and whether relationships are moderated by depression and MI severity. METHODS: This is a secondary analysis of a smoking cessation induction trial among smokers with MIs (n = 241, 56% female, 36% Black) assessed at baseline, and 4 and 6 months after. Participants were grouped into "Smokers" (smoking at 4 and 6 months), "Abstainers" (quit at 4 and 6 months), "Relapsers" (relapsed at 6 months), and "Late-quitters" (quit at 6 months). Physical and mental health-related QoL was assessed with the Short-Form Health Survey. Depression was defined as scores ≥10 on the Patient Health Questionnaire, and MI severity by the use of skilled care for personal needs. Data were analyzed with linear mixed models. RESULTS: Aggregating across time, among nondepressed participants, compared with "Smokers," the "Abstainer," and "Late-quitter" groups improved their physical health scores. "Late-quitters" also improved compared with "Relapsers." Among the total sample, compared with "Smokers," "Abstainers" showed improvements in mental health scores overtime, whereas "Relapsers" improved their score at 4 months, and "Late-quitters" improved at 6 months. CONCLUSIONS: Quitting smoking is associated with improvements in physical health-related QoL regardless of the severity of MI but only among those without depression at baseline. For mental health-related QoL, associations with quitting smoking were independent of baseline depression and severity of MI.

The Association of Mental Health, Asthma Control and Acute Care Visits Among Rural Adolescents with Poorly Controlled Asthma.

Anxiety and depressive symptoms are associated with asthma-related acute care utilization. Few studies include rural adolescents. Asthma control may be the mechanism by which mental health affects acute care. This study explored associations between generalized anxiety, asthma-related anxiety, depressive symptoms, and acute care visits, and tested if asthma control mediates these associations among 197 rural adolescents with asthma. Data analysis included descriptive statistics and regression. Controlling for age, sex and race/ethnicity, asthma-related anxiety was associated with higher odds of acute care visits (OR = 2.09, 95% CI [1.42, 3.07]). Asthma control mediated this relationship: one unit increase in anxiety, on average, increased the odds of having any acute care visit by 5%. Generalized anxiety and depressive symptoms were not associated with acute care visits. Helping adolescents reduce their concerns regarding asthma while improving their self-management skill may potentially to reduce acute care among rural adolescents.

A quantitative bias analysis to assess the impact of unmeasured confounding on associations between diabetes and periodontitis.

AIM: To investigate unmeasured confounding in bidirectional associations between periodontitis and diabetes using quantitative bias analysis. METHODS: Subsamples from the Veterans Affairs Dental Longitudinal Study were selected. Adjusted for known confounders, we used Cox proportional hazards models to estimate associations between pre-existing clinical periodontitis and incident Type II Diabetes (n = 672), and between pre-existing diabetes and incident severe periodontitis (n = 521), respectively. Hypothetical confounders were simulated into the dataset using Bernoulli trials based on pre-specified distributions of confounders within categories of each exposure and outcome. We calculated corrected hazard ratios (HR) over 10,000 bootstrapped samples. RESULTS: In models using periodontitis as the exposure and incident diabetes as the outcome, adjusted HR = 1.21 (95% CI: 0.64-2.30). Further adjustment for simulated confounders positively associated with periodontitis and diabetes greatly attenuated the association or explained it away entirely (HR = 1). In models using diabetes as the exposure and incident periodontitis as the outcome, adjusted HR = 1.35 (95% CI: 0.79-2.32). After further adjustment for simulated confounders, the lower bound of the simulation interval never reached the null value (HR ≥ 1.03). CONCLUSIONS: Presence of unmeasured confounding does not explain observed associations between pre-existing diabetes and incident periodontitis. However, presence of weak unmeasured confounding eliminated observed associations between pre-existing periodontitis and incident diabetes. These results clarify the bidirectional periodontitis-diabetes association.

Longitudinal assessment of salivary vitamin D binding protein during orthodontic tooth movement.

BACKGROUND: Vitamin D is critical for bone physiology. In this study, we quantified Vitamin D Binding Protein (VitDBP) levels in saliva as a measure of Vitamin D during orthodontic tooth movement. METHODS: In this longitudinal study, saliva samples were collected from 73 orthodontic patients for 4 timepoints for the first six months of orthodontic treatment, along with dental casts at the beginning and the end of the study period. The saliva was measured for VitDBP as a biological marker for bone apposition and clinical tooth movement. We used the absolute change in Little's Irregularity Index as a quantitative measure for alignment. In addition, we measured the levels of alkaline phosphatase (ALP) in saliva as a marker of bone turnover. RESULTS: Both low (< 2.75 ng/ml) and high (> 6.48 ng/ml) VitDBP levels were associated with reduced tooth movement. Significant (p < 0.05) seasonal changes in VitDBP using a two-season year model were found with lower levels observed in the summer (Apr-Sept) than in the winter (Oct-Mar). CONCLUSIONS: Clinically significant orthodontic tooth movement is associated with an optimal range of VitDBP in saliva. Normal levels of VitDBP correlated with more orthodontic tooth movement, suggesting a "normal" range of salivary content of VitDBP. Given the strong trend that is independent of the confounding factors (ex. age, race or gender), the predictive value or salivary VitDBP for tooth movement should be studied in larger cohorts in future studies.

The association between the supplemental nutrition assistance programme participation and dental caries among U.S. adults.

INTRODUCTION: The Supplemental Nutrition Assistance Programme (SNAP) is a federal programme aimed to alleviate hunger and improve food insecurity. The impact of SNAP participation on overall health has been studied. However, little is known about the effects of SNAP participation on oral health. We aimed to investigate the association between participating in SNAP and dental caries and to explore the role of food insecurity as a moderator in this relationship. METHODS: We obtained data from the National Health and Nutrition Examination Survey (NHANES) cycles 2011-2012 and 2013-2014.The primary outcome was untreated dental caries (none vs. one or more). Self-reported SNAP participation status in the past 12 months was the predictor, and food security was the moderator. Food security was measured as overall food security status (full food secure/ food insecure) and household-level food security (full, marginal, low and very low). Bivariate and multiple logistic regression analyses were conducted to evaluate the relationship between SNAP and dental caries, and whether food insecurity moderates this relationship. Statistical analysis was carried out in September 2020. RESULTS: Our results suggested that after adjusting for potential confounders, SNAP participants were more likely to have untreated dental caries than non-SNAP participants (odds ratio: 1.6; 95% CI: 1.2-2.0). Food security status did not alter the relationship between SNAP participation and untreated dental caries. CONCLUSIONS: Food security status did not alter the relationship between SNAP participation and untreated dental caries. SNAP participation was associated with untreated dental caries among U.S. adults, and this was not affected by their food security status.

The impact of periodontitis exposure misclassification bias from partial-mouth measurements on association with diabetes and cardiovascular disease.

AIM: To quantify exposure misclassification bias arising from use of partial-mouth protocols in studies of periodontitis-systemic disease associations. MATERIALS AND METHODS: Using data from 10,134 adults participating in the National Health and Nutrition Examination Survey, we classified periodontal status based on full-mouth clinical examinations and three commonly used partial-mouth protocols. Associations between periodontitis and self-reported diabetes and cardiovascular disease were evaluated under each protocol using adjusted logistic regression. Percent relative bias was calculated to evaluate magnitude and direction of bias. RESULTS: Misclassification primarily resulted in underestimation of associations, the extent of which depended on both the outcome under study and exposure severity. Bias due to misclassification of severe periodontitis was negligible for cardiovascular disease (0%-4.1%) compared to diabetes (177.7%-234.1%). In contrast, bias in moderate periodontitis associations was comparable across each outcome-diabetes (28.4%-39.5%) and cardiovascular disease (8.9%-46.7%). Results did not meaningfully change based on the partial-mouth protocol implemented. Stratified analyses showed increased bias among those with ≤15 teeth. Use of mean attachment loss as a continuous exposure resulted in minimal-to-no bias. CONCLUSIONS: Exposure misclassification bias due to use of partial-mouth protocols can yield inaccurate conclusions about periodontitis-systemic disease associations, the extent of which may depend on periodontitis classification and the association under study.

Opioid Prescribing Patterns Among Oral and Maxillofacial Surgeons: A Regional Survey-Based Study.

PURPOSE: We sought to obtain baseline statistics regarding the amount of opioid tablets prescribed by oral and maxillofacial surgeons (OMSs) in the New England area after office-based procedures and to identify factors that might be predictors of their prescription patterns. MATERIALS AND METHODS: An anonymous online survey was e-mailed to practicing OMSs in the New England area. The survey explored the quantity of opioid medications prescribed for various procedures, how opioid precautions were given, practitioners' attitude toward opioid dependency, and whether certain surgeon- or patient-related factors influenced prescription behavior. Statistical analyses were used to categorize the OMSs according to their prescription patterns and to identify the most common factors affecting their decision to prescribe opioids. RESULTS: Of 315 OMSs, 151 (43%) responded to the survey. Our analyses were of complete data obtained from 118 respondents. For procedures, such as extraction of 7 or more teeth, the placement of 4 or more implants, office-based sinus surgery, cortical block grafts, and removal of third molar teeth, respondents indicated they typically prescribed 8 to 12 opioid tablets. For all other procedures, they typically never or rarely prescribed opioid tablets. The respondents were grouped into low-, medium-, and high-quantity opioid prescribers. Regardless of their grouping status, the respondents showed general agreement regarding their roles in reducing opioid prescription-related issues. No group differences were found in terms of the demographic variables. Relative to the factors predicting increased prescribing habits, the results suggested that OMSs working either exclusively or primarily in academic settings tended to prescribe fewer opioid tablets than those working primarily in the private setting (ß = -2.73; P < .001). Additionally, 109 respondents (92.4%) reported that OMSs could play a role in decreasing opioid dependency. CONCLUSIONS: Most practicing OMSs in the New England area prescribed opioids after office-based surgery and are cognizant of the risks of opioid medications.

Estimating Residual Life Distributions of Complex Operational Systems Using a Remaining Maintenance Free Operating Period (RMFOP)-Based Methodology.

Recent developments in the area of condition monitoring research have been targeted towards predicting machinery health condition for the purpose of preventative maintenance. Typically, published research uses data collected from rotating components (bearings, cutting tools, etc.) working in an idealized lab environment as the case study for prognosis algorithm validations. However, the operational implementation in industry is still very sporadic, mainly owing to the lack of proper data allowing sufficiently mature development of comprehensive methodologies. The prognosis methodology presented herein bridges the gap between academic research and industrial implementations by employing a novel time period for prognosis and implementing random coefficients regression models. The definition of the remaining maintenance-free operating period (RMFOP) is proposed first, which helps to transform the usefulness of the degradation data that is readily available from data short of failure. Degradation patterns are subsequently extracted from the original degradation data, before fitting into either of two regression models (linear or exponential). The system residual life distributions are then computed and updated by estimating the parameter statistics within the model. This RMFOP-based methodology is validated using real-world degradation data collected from multiple operational railway switch systems across Great Britain. The results indicate that both the linear model and the exponential model can produce residual life distributions with a sufficient prediction accuracy for this specific application. The exponential model gives better predictions, the accuracy of which also improves as more of system life percentage has elapsed. By using the RMFOP methodology, switch system health condition affected by an incipient overdriving fault is recognized and predicted.

Brain age prediction: Cortical and subcortical shape covariation in the developing human brain.

Cortical development is characterized by distinct spatial and temporal patterns of maturational changes across various cortical shape measures. There is a growing interest in summarizing complex developmental patterns into a single index, which can be used to characterize an individual's brain age. We conducted this study with two primary aims. First, we sought to quantify covariation patterns for a variety of cortical shape measures, including cortical thickness, gray matter volume, surface area, mean curvature, and travel depth, as well as white matter volume, and subcortical gray matter volume. We examined these measures in a sample of 869 participants aged 5-18 from the Healthy Brain Network (HBN) neurodevelopmental cohort using the Joint and Individual Variation Explained (Lock et al., 2013) method. We validated our results in an independent dataset from the Nathan Kline Institute - Rockland Sample (NKI-RS; N = 210) and found remarkable consistency for some covariation patterns. Second, we assessed whether covariation patterns in the brain can be used to accurately predict a person's chronological age. Using ridge regression, we showed that covariation patterns can predict chronological age with high accuracy, reflected by our ability to cross-validate our model in an independent sample with a correlation coefficient of 0.84 between chronologic and predicted age. These covariation patterns also predicted sex with high accuracy (AUC = 0.85), and explained a substantial portion of variation in full scale intelligence quotient (R2 = 0.10). In summary, we found significant covariation across different cortical shape measures and subcortical gray matter volumes. In addition, each shape measure exhibited distinct covariations that could not be accounted for by other shape measures. These covariation patterns accurately predicted chronological age, sex and general cognitive ability. In a subset of NKI-RS, test-retest (<1 month apart, N = 120) and longitudinal scans (1.22 ±â€¯0.29 years apart, N = 77) were available, allowing us to demonstrate high reliability for the prediction models obtained and the ability to detect subtle differences in the longitudinal scan interval among participants (median and median absolute deviation of absolute differences between predicted age difference and real age difference = 0.53 ±â€¯0.47 years, r = 0.24, p-value = 0.04).

Brain Imaging-Guided Analysis Reveals DNA Methylation Profiles Correlated with Insular Surface Area and Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is a wide-spread, heritable brain disease, but few studies have linked genetic variants or epigenetic factors to brain structures related to AUD in humans, due to many factors including the high-dimensional nature of imaging and genomic data. METHODS: To provide potential insights into the links among epigenetic regulation, brain structure, and AUD, we have performed an integrative analysis of brain structural imaging and blood DNA methylome data from 52 AUD and 58 healthy control (HC) subjects collected in the Nathan Kline Institute-Rockland Sample. RESULTS: We first found that AUD subjects had significantly larger insular surface area than HC in both left and right hemispheres. We then found that 7,827 DNA methylation probes on the HumanMethylation450K BeadChip had significant correlations with the right insular surface area (false discovery rate [FDR] < 0.05). Furthermore, we showed that 44 of the insular surface area-correlated methylation probes were also strongly correlated with AUD status (FDR < 0.05). These AUD-correlated probes are annotated to 36 protein-coding genes, with 16 genes (44%) having been reported by others to be related to AUD or alcohol response, including TAS2R16 and PER2. The remaining 20 genes, in particular ARHGAP22, might represent novel genes involved in AUD or responsive to alcohol. CONCLUSIONS: We have identified 36 insular surface area- and AUD-correlated protein-coding genes that are either known to be AUD- or alcohol-related or not yet reported by prior studies. Therefore, our study suggests that the brain imaging-guided epigenetic analysis has a potential of identifying possible epigenetic mechanisms involved in AUD.

C-terminal domain (CTD) phosphatase links Rho GTPase signaling to Pol II CTD phosphorylation in Arabidopsis and yeast.

Rho GTPases, including the Rho, Cdc42, Rac, and ROP subfamilies, act as pivotal signaling switches in various growth and developmental processes. Compared with the well-defined role of cytoskeletal organization in Rho signaling, much less is known regarding transcriptional regulation. In a mutant screen for phenotypic enhancers of transgenic Arabidopsis plants expressing a constitutively active form of ROP2 (designated CA1-1), we identified RNA polymerase II (Pol II) C-terminal domain (CTD) phosphatase-like 1 (CPL1) as a transcriptional regulator of ROP2 signaling. We show that ROP2 activation inhibits CPL1 activity by promoting its degradation, leading to an increase in CTD Ser5 and Ser2 phosphorylation. We also observed similar modulation of CTD phosphorylation by yeast Cdc42 GTPase and enhanced degradation of the yeast CTD phosphatase Fcp1 by activated ROP2 signaling. Taken together, our results suggest that modulation of the Pol II CTD code by Rho GTPase signaling represents an evolutionarily conserved mechanism in both unicellular and multicellular eukaryotes.