Chemical genomics reveals histone deacetylases are required for core regulatory transcription

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping

Prevalence of pulmonary TB and spoligotype pattern of Mycobacterium tuberculosis among TB suspects in a rural community in Southwest Ethiopia

<p>Abstract</p> <p>Background</p> <p>In Ethiopia where there is no strong surveillance system and state of the art diagnostic facilities are limited, the real burden of tuberculosis (TB) is not well known. We conducted a community based survey to estimate the prevalence of pulmonary TB and spoligotype pattern of the <it>Mycobacterium tuberculosis </it>isolates in Southwest Ethiopia.</p> <p>Methods</p> <p>A total of 30040 adults in 10882 households were screened for pulmonary TB in Gilgel Gibe field research centre in Southwest Ethiopia. A total of 482 TB suspects were identified and smear microscopy and culture was done for 428 TB suspects. Counseling and testing for HIV/AIDS was done for all TB suspects. Spoligotyping was done to characterize the <it>Mycobacterium tuberculosis </it>isolates.</p> <p>Results</p> <p>Majority of the TB suspects were females (60.7%) and non-literates (83.6%). Using smear microscopy, a total of 5 new and 4 old cases of pulmonary TB cases were identified making the prevalence of TB 30 per 100,000. However, using the culture method, we identified 17 new cases with a prevalence of 76.1 per 100,000. There were 4.3 undiagnosed pulmonary TB cases for every TB case who was diagnosed through the passive case detection mechanism in the health facility. Eleven isolates (64.7%) belonged to the six previously known spoligotypes: T, Haarlem and Central-Asian (CAS). Six new spoligotype patterns of <it>Mycobacterium tuberculosis</it>, not present in the international database (SpolDB4) were identified. None of the rural residents was HIV infected and only 5 (5.5%) of the urban TB suspects were positive for HIV.</p> <p>Conclusion</p> <p>The prevalence of TB in the rural community of Southwest Ethiopia is low. There are large numbers of undiagnosed TB cases in the community. However, the number of sputum smear-positive cases was very low and therefore the risk of transmitting the infection to others may be limited. Active case finding through health extension workers in the community can improve the low case detection rate in Ethiopia. A large scale study on the genotyping of <it>Mycobacterium tuberculosis </it>in Ethiopia is crucial to understand transmission dynamics, identification of drug resistant strains and design preventive strategies.</p

Predictors of adherence to antiretroviral therapy among HIV-infected persons: a prospective study in Southwest Ethiopia

BACKGROUND: The devastating impact of AIDS in the world especially in sub-Saharan Africa has led to an unprecedented global effort to ensure access to antiretroviral (ARV) drugs. Given that medication-taking behavior can immensely affect an individual's response; ART adherence is now widely recognized as an 'Achilles heel' for the successful outcome. The present study was undertaken to investigate the rate and predictors of adherence to antiretroviral therapy among HIV-infected persons in southwest Ethiopia. METHODS: The study was conducted in the antiretroviral therapy unit of Jimma University Specialized Hospital. A prospective study was undertaken on a total of 400 HIV infected person. Data were collected using a pre-tested interviewer-administered structured questionnaire at first month (M0) and third month (M3) follow up visits. RESULTS: A total of 400 and 383 patients at baseline (M0) and at follow up visit (M3) respectively were interviewed. Self-reported dose adherence in the study area was 94.3%. The rate considering the combined indicator (dose, time and food) was 75.7%. Within a three month follow up period, dose adherence decreased by 2% and overall adherence rate decreased by more than 3%. Adherence was common in those patients who have a social support (OR, 1.82, 95%CI, 1.04, 3.21). Patients who were not depressed were two times more likely to be adherent than those who were depressed (OR, 2.13, 95%CI, 1.18, 3.81). However, at the follow up visit, social support (OR, 2.42, 95%CI, 1.29, 4.55) and the use of memory aids (OR, 3.29, 95%CI, 1.44, 7.51) were found to be independent predictors of adherence. The principal reasons reported for skipping doses in this study were simply forgetting, feeling sick or ill, being busy and running out of medication in more than 75% of the cases. CONCLUSION: The self reported adherence rate was high in the study area. The study showed that adherence is a dynamic process which changes overtime and cannot reliably be predicted by a few patient characteristics that are assumed to vary with time. Adherence is a process, not a single event, and adherence support should be integrated into regular clinical follow up

Microbiome to Brain:Unravelling the Multidirectional Axes of Communication

The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome

Dietary diversity and associated factors among pregnant women attending antenatal care at public health facilities in Bale Zone, Southeast Ethiopia

Sintayehu Hailu,1 Bedasa Woldemichael21Department of Public Health, School of Health Sciences, Goba Referral Hospital, Madda Walabu University, Bale-Goba, Ethiopia; 2Department of Nursing, School of Health Sciences, Goba Referral Hospital, Madda Walabu University, Bale-Goba, EthiopiaBackground: Dietary diversity is a proxy indicator of nutrient adequacy. However, little is documented on dietary diversity among pregnant women in Ethiopia in general and specifically in the study area. This study assessed dietary diversity and associated factors among pregnant women attending antenatal care in public health facilities in Bale Zone, Southeast Ethiopia.Methods: An institution-based cross-sectional study was conducted in Bale Zone from January to March 2017. The sample size was determined using a single population proportion formula. Data were collected by pretested structured interviewer-administered questionnaires from a total of 413 pregnant women who were identified through systematic random sampling. The sample was drawn proportionally from selected public health facilities based on the client load. Dietary diversity was computed from information about the nine food groups obtained using a 24-hour dietary recall method. Statistical analysis was done using bivariate and multivariate logistic regression with the P-value&nbsp;&lt;0.05 at 95% confidence&nbsp;interval considered as statistically significant. Results: The mean age of the pregnant women was 26.93 with standard deviation &plusmn;6.12 years. About 55.2% of the pregnant women had inadequate dietary diversity. Getting information from a health professional [AOR =5.26, 95% CI (1.60, 17.36)], being an urban dweller [AOR =8.95, 95% CI (4.42, 18.16)], having a protected water source [AOR =11.16, 95% CI (4.74, 26.27)], having a latrine [AOR =8.21, 95% CI (4.01, 16.80)], having a home garden [AOR =4.26, 95% CI (2.08, 8.70)], having a bank account [AOR =12.25, 95% CI (6.01, 24.97)] and having use of a mobile phone [AOR =3.82, 95% CI (1.92, 7.62)] were significantly associated with dietary diversity. Conclusion: In this community, the prevalence of inadequate dietary diversity is high. Variables which indicate a better living condition such as having a protected source of water, having a latrine, having a home garden, being an urban dweller, having a bank account and having use of a mobile phone were independent predictors of dietary diversity. Therefore, attention should be paid to improve to better living conditions of pregnant women by addressing determinate variables through community awareness.Keywords: dietary diversity, pregnant women, antenatal care, Ethiopi

Epigenetics of memory and plasticity

Although all neurons carry the same genetic information, they vary considerably in morphology and functions and respond differently to environmental conditions. Such variability results mostly from differences in gene expression. Among the processes that regulate gene activity, epigenetic mechanisms play a key role and provide an additional layer of complexity to the genome. They allow the dynamic modulation of gene expression in a locus- and cell-specific manner. These mechanisms primarily involve DNA methylation, posttranslational modifications (PTMs) of histones and noncoding RNAs that together remodel chromatin and facilitate or suppress gene expression. Through these mechanisms, the brain gains high plasticity in response to experience and can integrate and store new information to shape future neuronal and behavioral responses. Dynamic epigenetic footprints underlying the plasticity of brain cells and circuits contribute to the persistent impact of life experiences on an individual's behavior and physiology ranging from the formation of long-term memory to the sequelae of traumatic events or of drug addiction. They also contribute to the way lifestyle, life events, or exposure to environmental toxins can predispose an individual to disease. This chapter describes the most prominent examples of epigenetic marks associated with long-lasting changes in the brain induced by experience. It discusses the role of epigenetic processes in behavioral plasticity triggered by environmental experiences. A particular focus is placed on learning and memory where the importance of epigenetic modifications in brain circuits is best understood. The relevance of epigenetics in memory disorders such as dementia and Alzheimer's disease is also addressed, and promising perspectives for potential epigenetic drug treatment discussed

Epigenetic regulation in neurodevelopment and neurodegenerative diseases

From fertilization throughout development and until death, cellular programs in individual cells are dynamically regulated to fulfill multiple functions ranging from cell lineage specification to adaptation to internal and external stimuli. Such regulation is of major importance in brain cells, because the brain continues to develop long after birth and incorporates information from the environment across life. When compromised, these regulatory mechanisms can have detrimental consequences on neurodevelopment and lead to severe brain pathologies and neurodegenerative diseases in the adult individual. Elucidating these processes is essential to better understand their implication in disease etiology. Because they are strongly influenced by environmental factors, they have been postulated to depend on epigenetic mechanisms. This review describes recent studies that have identified epigenetic dysfunctions in the pathophysiology of several neurodevelopmental and neurodegenerative diseases. It discusses currently known pathways and molecular targets implicated in pathologies including imprinting disorders, Rett syndrome, and Alzheimer's, Parkinson's and Hungtinton's disease, and their relevance to these diseases

Carminomycin I Is an Apoptosis Inducer That Targets the Golgi Complex in Clear Cell Renal Carcinoma Cells

Abstract Clear cell renal cell carcinoma (CCRCC) evolves due to mutations in the Von Hippel–Lindau (VHL) tumor suppressor gene. Although the loss of VHL enables survival and proliferation of CCRCC cells, it is also expected to introduce vulnerabilities that may be exploited for therapeutics discovery. To this end, we developed a high-throughput screen to identify small molecules derived from plants, microorganisms, and marine organisms to which CCRCC cells are sensitive. Screening over 8,000 compounds using this approach, we report here the identification of the microbially derived compound carminomycin I (CA) as an effective inhibitor of VHL-defective (VHL−/−) CCRCC cell proliferation. CA also induced apoptosis in CCRCC cells by a mechanism independent of p53 or hypoxia-inducible factor 2. We found that P-glycoprotein (P-gp) sequestered CA within the Golgi complex. Interestingly, Golgi sequestration was critical for the antiproliferative effects of CA and P-gp inhibitors abrogated this activity. Furthermore, CA induced cleavage of the Golgi protein p115 and the translocation of its C-terminal fragment to the nucleus. Finally, examination of the activity of the VHL-interacting Golgi protein, endoplasmic reticulum-Golgi intermediate compartment, ERGIC-53 showed that VHL could mediate protection from CA in CCRCC cells. Our natural product–based screening approach has revealed the P-gp–mediated localization of anticancer compounds within the Golgi in CCRCC cells as a potential strategy of targeting VHL-deficient CCRCC cells. Cancer Res; 71(1); 134–42. ©2011 AACR.</jats:p