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The incidence of obesity has markedly increased globally over the last several decades and is believed to be associated with the easier availability of energy-dense foods, including high-fat foods. The reinforcing hedonic properties of high-fat foods, including olfactory cues, activate reward centers in the brain, motivating eating behavior. Thus, there is a growing interest in the understanding of the genetic changes that occur in the brain that are associated with obesity and eating behavior. This growing interest has paralleled advances in genomic methods that enable transcriptomic-wide analyses. Here, we examined the transcriptomic-level differences in the olfactory bulb and striatum, regions of the brain associated with olfaction and hedonic food-seeking, respectively, in high-fat-diet (HFD)-fed obese mice. To isolate the dietary effects from obesity, we also examined transcriptomic changes in normal-chow-fed and limited-HFD-fed groups, with the latter being pair-fed with an HFD isocaloric to the consumption of the normal-chow-fed mice. Using RNA sequencing, we identified 274 differentially expressed genes (DEGs) in the striatum and 11 in the olfactory bulb of ad libitum HFD-fed mice compared to the chow-fed group, and thirty-eight DEGs in the striatum between the ad libitum HFD and limited-HFD-fed groups. The DEGs in both tissues were associated with inflammation and immune-related pathways, including oxidative stress and immune function, and with mitochondrial dysfunction and reward pathways in the striatum. These results shed light on potential obesity-associated genes in these regions of the brain.

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.

A recently developed nonpartisan authoritarian aggression scale (NAAS) has a robust nomological network that includes attitudes toward women and LGBTQ+ individuals. The current research was meant to further validate the scale by demonstrating its ability to predict unique variance in attitudes relating to sex crimes (i.e., rape myth acceptance) and anti-transgender hate crimes when controlling for potentially relevant cognitive (i.e., need for cognition, intolerance of uncertainty) and cultural (i.e., Christian nationalism) variables. A sample of 100 U.S. participants was recruited from Prolific and completed an online survey via Qualtrics. A series of correlation analyses showed that the NAAS was significantly related to all of the other predictor variables as well as both the sex and hate crime outcomes at the bivariate level, adding to the nomological network of the NAAS. Multiple regression analyses showed that the combination of predictors explained significant variance in both outcomes and that the NAAS was the only predictor to explain unique variance in both sex crime and anti-transgender hate crime attitudes. The results imply that authoritarian aggression poses a danger for women, transgender individuals, and victims of sex crimes and hate crimes more broadly. Future research should examine ways of attenuating authoritarian aggression in individuals and communities to protect those who are vulnerable due to their sex, sexual orientation, or gender identity.

Viral cancers show oncogene addiction to viral oncoproteins, which are required for survival and proliferation of the dedifferentiated cancer cell. Human Merkel cell carcinomas (MCCs) that harbor a clonally integrated Merkel cell polyomavirus (MCV) genome have low mutation burden and require viral T antigen expression for tumor growth. Here, we showed that MCV⁺ MCC cells cocultured with keratinocytes undergo neuron-like differentiation with neurite outgrowth, secretory vesicle accumulation, and the generation of sodium-dependent action potentials, hallmarks of a neuronal cell lineage. Cocultured keratinocytes are essential for induction of the neuronal phenotype. Keratinocyte-conditioned medium was insufficient to induce this phenotype. Single-cell RNA sequencing revealed that T antigen knockdown inhibited cell cycle gene expression and reduced expression of key Merkel cell lineage/MCC marker genes, including HES6, SOX2, ATOH1, and KRT20. Of these, T antigen knockdown directly inhibited Sox2 and Atoh1 expression. MCV large T up-regulated Sox2 through its retinoblastoma protein-inhibition domain, which in turn activated Atoh1 expression. The knockdown of Sox2 in MCV⁺ MCCs mimicked T antigen knockdown by inducing MCC cell growth arrest and neuron-like differentiation. These results show Sox2-dependent conversion of an undifferentiated, aggressive cancer cell to a differentiated neuron-like phenotype and suggest that the ontology of MCC arises from a neuronal cell precursor.

AbstractObjectiveTo investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.DesignIndividual participant data meta-analysis.Data sourcesEligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.Review methodsData from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.ResultsOf 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed.ConclusionsThese data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.

Objective To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval −0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95% confidence interval −0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=−0.21, 95% confidence interval −0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with −0.11 (95% confidence interval −0.20 to −0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined. We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene ( -13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between ( ) dairy intake and BMI, ( ) rs4988235 and dairy intake, and ( ) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies. Higher dairy intake was associated with higher BMI (β = 0.03 kg/m per serving/day; 95% CI, 0.00-0.06; = 0.04), whereas the genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14-0.25) serving/day higher dairy intake ( = 3.15 × 10 ) and 0.12 (95% CI, 0.06-0.17) kg/m higher BMI ( = 2.11 × 10 ). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m per serving/day; 95% CI, 0.27-0.92; = 3.0 × 10 ). The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

Traumatic brain injury (TBI) is responsible for the majority of trauma-related deaths and is a leading cause of disability. It is characterized by an inflammatory process involved in the progression of secondary brain injury. TBI is measured by the Glasgow Coma Scale (GCS) with scores ranging from 15-3, demonstrating mild to severe brain injury. Apart from this clinical assessment of TBI, compendiums of literature have been published on TBI-related serum markers.Herein we create a comprehensive appraisal of the most prominent serum biomarkers used in the assessment and care of TBI.The PubMed, Scopus, Cochrane, and Web of Science databases were queried with the terms \"biomarker\" and \"traumatic brain injury\" as search terms with only full-text, English articles within the past 10 years selected. Non-human studies were excluded, and only adult patients fell within the purview of this analysis. A total of 528 articles were analyzed in the initial search with 289 selected for screening. A further 152 were excluded for primary screening. Of the remaining 137, 54 were included in the final analysis. Serum biomarkers were listed into the following broad categories for ease of discussion: immune markers and markers of inflammation, hormones as biomarkers, coagulation and vasculature, genetic polymorphisms, antioxidants and oxidative stress, apoptosis and degradation pathways, and protein markers. Glial fibrillary acidic protein(GFAP), S100, and neurons specific enolase (NSE) were the most prominent and frequently cited markers. Amongst these three, no single serum biomarker demonstrated neither superior sensitivity nor specificity compared to the other two, therefore noninvasive panels should incorporate these three serum biomarkers to retain sensitivity and maximize specificity for TBI.Traumatic brain injury (TBI) is responsible for the majority of trauma-related deaths and is a leading cause of disability. It is characterized by an inflammatory process involved in the progression of secondary brain injury. TBI is measured by the Glasgow Coma Scale (GCS) with scores ranging from 15-3, demonstrating mild to severe brain injury. Apart from this clinical assessment of TBI, compendiums of literature have been published on TBI-related serum markers.Herein we create a comprehensive appraisal of the most prominent serum biomarkers used in the assessment and care of TBI.The PubMed, Scopus, Cochrane, and Web of Science databases were queried with the terms \"biomarker\" and \"traumatic brain injury\" as search terms with only full-text, English articles within the past 10 years selected. Non-human studies were excluded, and only adult patients fell within the purview of this analysis. A total of 528 articles were analyzed in the initial search with 289 selected for screening. A further 152 were excluded for primary screening. Of the remaining 137, 54 were included in the final analysis. Serum biomarkers were listed into the following broad categories for ease of discussion: immune markers and markers of inflammation, hormones as biomarkers, coagulation and vasculature, genetic polymorphisms, antioxidants and oxidative stress, apoptosis and degradation pathways, and protein markers. Glial fibrillary acidic protein(GFAP), S100, and neurons specific enolase (NSE) were the most prominent and frequently cited markers. Amongst these three, no single serum biomarker demonstrated neither superior sensitivity nor specificity compared to the other two, therefore noninvasive panels should incorporate these three serum biomarkers to retain sensitivity and maximize specificity for TBI.

Synthetic glucocorticoid (sGC) administration in pregnancy has greatly reduced the risk of respiratory distress, intraventricular hemorrhage and necrotizing enterocolitis in premature infants. Significant evidence has accumulated in human and animal models that prenatal exposure to sGCs can lead to adverse side effects such as reduced birthweight, increased risk for hypertension, cardiovascular, metabolic, and neurological problems later in life. Phosphorylation of the glucocorticoid receptor (GR) has been shown to play a significant role in a cells response to sGC administration, altering target gene activation versus repression, the magnitude and duration of the response. The GR receptor is phosphorylated on three sites (S203, S211, S226) in the N-terminal. An increased in the ratio of phosphorylation on S211 to S226 is associated with enhanced transcriptional activation. Furthermore, changes in S221/S226 ratio are associated with distinct neurological disorders in humans. We have previously shown that in-utero exposure to a single dose of dexamethasone (Dex) reduces proliferation in cerebral cortical and hypothalamic neural stem cells (NSCs), alters neuronal differentiation, neuronal morphology and adult behavior. To investigate the role of receptor phosphorylation on NSCs biology and brain development, mice with a serine (S211) to alanine (S211A) knockin were generated. NSCs were isolated from the mouse E14.5 cerebral cortex and the transcriptional and biological response of cells were examined in response to sGC or vehicle stimulation. Affymetrix complete genome arrays were used to identify changes in global gene expression in response to 4 hours of 10-7 M Dex exposure. Basally, 2651 genes were >1.5 fold (p < 0.05) differentially regulated in S211A versus wildtype, with 929 distinct upregulated and 1722 downregulated. Sex specific differences were observed basally, with 382 upregulated and 824 down regulated in females compared to 1191 upregulated and 1353 downregulated in males. Ingenuity pathway analysis (IPA) revealed that the only significant pathways that were altered basally in S211A versus wildtype were valine and isoleucine degradation, fatty acid beta oxidation and glutathione redox reaction I, all with negative Z scores (Z scores -2.1 to -3.16, P < 1.3E-01 to 1.3E-06). In response to a 4-hour Dex stimulation, 473 and 657 genes were upregulated and 782 and 996 genes were downregulated in females versus male respectively in S211A compared to wildtype. IPA analysis revealed that only one significant pathway with a Z score >2 that was altered in S211A versus wildtype in response to dex was of activation LPS/IL1 mediated inhibition of RXR function (Z = 2.82, p <3.08E-03). Some of the most significant genes changed basally in S211A versus wildtype include genes involved in the cell cycle. To determine if these transcriptional changes led to a distinct biological response, proliferation and differentiation studies were performed. Basally, S211A cells exhibit enhanced proliferation compared to wildtype cells in vitro. These findings were validated by in-vivo findings demonstrated by increased expression of TBR2, an immediate progenitor cell marker in the cerebral cortex at E17.5. These studies identify distinct pathways and developmental neurological processes that are sensitive to phosphorylation of GR on S211 basally and in response to sGC exposure.