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• Are there similarities in executive attention pathophysiology following TBI and in normal age-related decline?. • We derived a biomarker of executive attention pathophysiology that was common to both aging-related and post-TBI-related impairments, and in moderate-severe TBI. • Our findings identify biomarkers to track recovery, impact of interventions and guide development of targeted therapeutics following brain injuries. Executive attention impairments are a persistent and debilitating consequence of traumatic brain injury (TBI). To make headway towards treating and predicting outcomes following heterogeneous TBI, cognitive impairment specific pathophysiology first needs to be characterized. In a prospective observational study, we measured EEG during the attention network test aimed at detecting alerting, orienting, executive attention and processing speed. The sample (N = 110) of subjects aged 18–86 included those with and without traumatic brain injury: n = 27, complicated mild TBI; n = 5, moderate TBI; n = 10, severe TBI; n = 63, non-brain-injured controls. Subjects with TBI had impairments in processing speed and executive attention. Electrophysiological markers of executive attention processing in the midline frontal regions reveal that, as a group, those with TBI and elderly non-brain-injured controls have reduced responses. We also note that those with TBI and elderly controls have responses that are similar for both low and high-demand trials. In subjects with moderate-severe TBI, reductions in frontal cortical activation and performance profiles are both similar to that of controls who are ∼4 to 7 years older. Our specific observations of frontal response reductions in subjects with TBI and in older adults is consistent with the suggested role of the anterior forebrain mesocircuit as underlying cognitive impairments. Our results provide novel correlative data linking specific pathophysiological mechanisms underlying domain-specific cognitive deficits following TBI and with normal aging. Collectively, our findings provide biomarkers that may serve to track therapeutic interventions and guide development of targeted therapeutics following brain injuries. [ABSTRACT FROM AUTHOR]

Although a large collection of cancer cell lines are useful surrogates for patient samples, the physiological relevance of observed molecular phenotypes in cell lines remains controversial. Because transcriptome data are a representative set of molecular phenotypes in cancers, we systematically analyzed the discrepancy of global gene expression profiles between patient samples and cell lines in breast cancers. While the majority of genes exhibited general consistency between patient samples and cell lines, the expression of genes in the categories of extracellular matrix, collagen trimers, receptor activity, catalytic activity and transporter activity were significantly up-regulated only in tissue samples. Genes in the extracellular matrix, particularly collagen trimers, showed a wide variation of expression in tissue, but minimal expression and variation in cell lines. Further analysis of tissue samples exclusively revealed that collagen genes exhibited a cancer stage-dependent expressional variation based on their supramolecular structure. Prognostic collagen biomarkers associated with survival rate were also readily predicted from tissue-oriented transcriptome analysis. This study presents the limitations of cell lines and the exclusive features of tissue samples in terms of functional categories of the cancer transcriptome. [ABSTRACT FROM AUTHOR]

To perform their biological functions, individual genes exhibit varying ranges of expression levels. Thus, considering the intrinsic variability of gene expression can improve geneset-based functional analyses which are typically used to interpret transcriptome data. Through the extensive quantitative analysis of the expressional variability of individual genes using large collections of transcriptome and proteome data, we found the existence of the intrinsic variability of gene expression at the transcriptional level. Interestingly, genes under post-translational regulation were not sensitively regulated at the transcriptional level. Because genes have intrinsically different levels of regulation at the transcription and translation stages, the functional geneset-based interpretation of transcriptome data should only include genes that are significantly varied at the transcriptional level. Thus, by removing genes with low transcriptional variation from the DNA microarray data, we showed that geneset enrichment analysis could provide improved resolution in prioritizing target functional pathways in several different experimental datasets. [ABSTRACT FROM AUTHOR]

Abstract: Let be an elliptic curve with j-invariant 0 defined over a number field K. In this paper, we give a simple condition on K which determines whether all cubic twists of have the same root number or not. This is a cubic twist analogue to the work [D-D] of Dokchitser and Dokchitser on quadratic twists of elliptic curves. [Copyright &y& Elsevier]

Abstract: Activation of quiescent hepatic stellate cells (HSCs) into myofibroblast-like cells is a key event of liver fibrosis, and adipogenic transcription factors, PPAR-γ and C/EBP-α, reverse HSC activation. As albumin was reported to maintain the quiescent phenotype of stellate cells, we examined whether it plays a role in PPAR-γ and C/EBP-α-mediated effects. Pancreatic stellate cells (PSCs) were isolated from rat pancreas and used in their culture-activated phenotype. Forced expression of PPAR-γ or C/EBP-α in PSCs increased albumin mRNA and protein levels by >2.5-fold, which is accompanied with increased C/EBP-β binding to albumin promoter. PPAR-γ and C/EBP-α also induced a phenotypic switch from activated to quiescent cells and, interestingly, suppression of albumin using short-hairpin RNA (shRNA) blocked their effects. Therefore, our findings suggest that albumin may be a downstream effector of PPAR-γ and C/EBP-α in PSCs and that it can be an attractive molecular target for anti-fibrotic therapies. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate if the HEROES Initiative, a school-based childhood obesity prevention program based on the U. S. Centers for Disease Control and Prevention (CDC)'s coordinated school health approach was able to effectively increase physical activity among elementary and middle school students who were exposed to the program for 18months and to determine student and school-level predictors of success. Method: Students who participated in physiological data collection were invited to participate in a survey at baseline, 6months, and 18months (N=1091, 8 schools). The dropout rate at 18months was 39.1% when graduates were counted. Data was analyzed using generalized estimating equations. Results: A significant increase (p =.0067) was observed in vigorous-intensity physical activity (VPA) but a non-significant increase (p =.1753) was observed in moderate-intensity physical activity (MPA). Each school's implementation fidelity score was also only associated with VPA increases. Students' screen time and vegetable/fruit intake were independently associated with both VPA and MPA increases. Body mass index of students was not predictive of VPA or MPA changes. Conclusion: An 18-month school-based intervention that employs the CDC's coordinated school health approach appears to be effective in increasing physical activity among elementary and middle school children. [Copyright &y& Elsevier]

Abstract: Several cellular stress signaling pathways initiate apoptosis in eukaryotic cells, but the interactions and coordination between the pathways have not been elucidated. In this study, apoptosis was triggered in MCF7 human breast carcinoma cells using doxorubicin, a topoisomerase inhibitor, and an endoplasmic reticulum (ER) stress inducer, thapsigargin, the latter causing the unfolded protein response (UPR). Interestingly, compared to treatment with doxorubicin or thapsigargin alone, cell death was reduced by treatment with both stress inducers. In contrast to another topoisomerase inhibitor, etoposide, doxorubicin markedly decreased apoptosis induced by thapsigargin; this doxorubicin effect was accompanied by reduced expression of the UPR-specific proapoptotic protein, C/EBP-homologous protein, and its upstream transcription factor, ATF4. We further found that doxorubicin downregulates the expression of ATF4 mRNA, indicating that doxorubicin interferes with the UPR at the level of ATF4 transcription. Taken together, the data suggest that ER stress-initiated cell death might be regulated by doxorubicin. [Copyright &y& Elsevier]

Effective treatments for smoking cessation exist but are underused. Proactive chronic care approaches may enhance the reach of cessation treatment and reduce the prevalence of smoking in healthcare systems. This pragmatic study evaluated a population-based Comprehensive Tobacco Intervention Program (CTIP) implemented in all (6) adult primary care clinics in a Madison, Wisconsin, USA healthcare cooperative, assessing treatment reach, reach equity, and effectiveness in promoting smoking cessation. CTIP launched in 3 waves of 2 clinics each in a multiple baseline design. Electronic health record (EHR) tools facilitated clinician-delivered pharmacotherapy and counseling; guiding tobacco care managers in phone outreach to all patients who smoke; and prompting multimethod bulk outreach to all patients on a smoking registry using an opt-out approach. EHR data were analyzed to assess CTIP reach and effectiveness among 6894 adult patients between January 2018 and February 2020. Cessation treatment reach increased significantly after CTIP launch in 5 of 6 clinics and was significantly higher when clinics were active vs. inactive in CTIP [Odds Ratio (OR) range = 2.0-3.0]. Rates of converting from current to former smoking status were also higher in active vs. inactive clinics (OR range = 2.2-10.5). Telephone treatment reach was particularly high in historically underserved groups, including African-American, Hispanic, and Medicaid-eligible patients. Implementation of a comprehensive, opt-out, chronic-care program aimed at all patients who smoke was associated with increases in the rates of pharmacotherapy and counseling delivery and quitting smoking. Proactive outreach may help reduce disparities in treatment access. [ABSTRACT FROM AUTHOR]

Highlights: [•] Bacillus subtilis-derived γPGA stimulates NKDCs in vitro and in vivo. [•] γPGA stimulation up-regulates MHC class II & co-stimulatory molecules on NKDCs. [•] γPGA stimulates NKDCs to produce pro-inflammatory cytokines such as IFNγ and TNFα. [•] γPGA-activated NKDCs show enhanced cytotoxicity against tumor cells. [•] Thus, NKDCs are one of the key players in anti-tumor immunity induced by γPGA. [Copyright &y& Elsevier]

Highlights: [•] Lentivirus-delivered short hairpin RNA induces methylation of HBV cccDNA. [•] shRNA-directed methylation is mainly limited to the homologous target site. [•] shRNA-directed methylation suppresses transcriptional activity of HBV cccDNA. [ABSTRACT FROM AUTHOR]

Abstract: Excessive alcohol intake accelerates disease progression in chronic hepatitis B virus (HBV) infection, but the mechanisms by which ethanol worsens the prognosis of chronic hepatitis B (CHB) are not fully understood. The aim of this study was to investigate whether HBV replication is augmented by alcohol or alcohol-induced cytochrome p450 2E1 (CYP2E1), and if so, whether oxidative stress is involved in the process. Ethanol treatment promoted HBV replication in HepAD38 cells that permit the conditional viral replication. Luciferase reporter assays confirmed that HBV core, preS1 and preS2/S promoter activities were augmented by ethanol. Ethanol did not induce oxidative stress in HepAD38 cells with minimal expression of CYP2E1. However, over-expression of CYP2E1 induced oxidative stress and amplified transcriptional activation of HBV by ethanol. Antioxidant glutathione treatment attenuated CYP2E1-mediated augmentation of HBV replication in ethanol-treated cells. In conclusion, ethanol enhances transcriptional activity of HBV promoters in human hepatoma cells in an oxidative stress-independent manner; and CYP2E1-mediated oxidative stress potentiates the ethanol-induced transactivation of HBV. [Copyright &y& Elsevier]

Abstract: Similar to fasting, the ketogenic diet (KD) has anti-inflammatory effects and protects against excitotoxicity-mediated neuronal cell death. Recent studies have shown that peroxisome proliferator-activated receptor (PPAR)γ has anti-inflammatory effects in seizure animal models. However, the exact mechanisms underlying the anti-inflammatory effects of the KD have not been determined for seizures. Here we investigated the effect of the KD and acetoacetate (AA) on neuroinflammation in a seizure animal model and glutamate-treated HT22 cells, respectively. Mice were fed the KD for 4weeks and sacrificed 2 or 6h after KA injection. The KD reduced hippocampal tumor necrosis factor alpha (TNF-α) levels and nuclear factor (NF)-κB translocation into the nucleus 2h after KA treatment. KD-induced PPARγ activation was decreased by KA in neurons as assessed by western blotting and immunofluorescence. Finally, the KD inhibited cyclooxygenase (COX)-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1) expression in the hippocampus 6h after KA treatment. AA treatment also protected against glutamate-induced cell death in HT22 cells by reducing TNF-α and PPARγ-mediated COX-2 expression. Thus, the KD may inhibit neuroinflammation by suppressing a COX-2-dependent pathway via activation of PPARγ by the KD or AA. [Copyright &y& Elsevier]