Core transcriptional regulatory circuitry in human hepatocytes

We mapped the transcriptional regulatory circuitry for six master regulators in human hepatocytes using chromatin immunoprecipitation and high-resolution promoter microarrays. The results show that these regulators form a highly interconnected core circuitry, and reveal the local regulatory network motifs created by regulator–gene interactions. Autoregulation was a prominent theme among these regulators. We found that hepatocyte master regulators tend to bind promoter regions combinatorially and that the number of transcription factors bound to a promoter corresponds with observed gene expression. Our studies reveal portions of the core circuitry of human hepatocytes

Core transcriptional regulatory circuitry in human hepatocytes

We mapped the transcriptional regulatory circuitry for six master regulators in human hepatocytes using chromatin immunoprecipitation and high-resolution promoter microarrays. The results show that these regulators form a highly interconnected core circuitry, and reveal the local regulatory network motifs created by regulator–gene interactions. Autoregulation was a prominent theme among these regulators. We found that hepatocyte master regulators tend to bind promoter regions combinatorially and that the number of transcription factors bound to a promoter corresponds with observed gene expression. Our studies reveal portions of the core circuitry of human hepatocytes

Stress adaptation in a pathogenic fungus

Funding We are grateful to our funding bodies for their support. This work was supported by the European Commission [FINSysB, PITN-GA-2008-214004; STRIFE, ERC-2009-AdG-249793], by the UK Biotechnology and Biological Research Council [grant numbers BBS/B/06679; BB/C510391/1; BB/D009308/1; BB/F000111/1; BB/F010826/1; BB/F00513X/1], and by the Wellcome Trust [grant numbers 080088, 097377]. M.D.L. was also supported by a Carnegie/Caledonian Scholarship and a Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust [grant number 096072]. Deposited in PMC for immediate release.Peer reviewedPublisher PD

Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia.

Decreased autophagy contributes to malignancies, however it is unclear how autophagy impacts on tumour growth. Acute myeloid leukemia (AML) is an ideal model to address this as (i) patient samples are easily accessible, (ii) the hematopoietic stem and progenitor population (HSPC) where transformation occurs is well characterized, and (iii) loss of the key autophagy gene Atg7 in hematopoietic stem and progenitor cells (HSPCs) leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of Atg5 results in an identical HSPC phenotype as loss of Atg7, confirming a general role for autophagy in HSPC regulation. Compared to more committed/mature hematopoietic cells, healthy human and mouse HSCs displayed enhanced basal autophagic flux, limiting mitochondrial damage and reactive oxygen species in this long-lived population. Taken together, with our previous findings these data are compatible with autophagy limiting leukemic transformation. In line with this, autophagy gene losses are found within chromosomal regions that are commonly deleted in human AML. Moreover, human AML blasts showed reduced expression of autophagy genes, and displayed decreased autophagic flux with accumulation of unhealthy mitochondria indicating that deficient autophagy may be beneficial to human AML. Crucially, heterozygous loss of autophagy in an MLL-ENL model of AML led to increased proliferation in vitro, a glycolytic shift, and more aggressive leukemias in vivo. With autophagy gene losses also identified in multiple other malignancies, these findings point to low autophagy providing a general advantage for tumour growth

Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study

Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. Results Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores (P = .05) and those initiating hormonal therapy having lower LM scores at 12 months (P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant (P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (−0.40; 95% CI, −0.79 to −0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures (P < .001); frailty was associated with baseline APE and self-reported decline (P < .001). Conclusion Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning

What Role Do Traditional Beliefs Play in Treatment Seeking and Delay for Buruli Ulcer Disease?–Insights from a Mixed Methods Study in Cameroon

Victims of Buruli ulcer disease (BUD) frequently report to specialized units at a late stage of the disease. This delay has been associated with local beliefs and a preference for traditional healing linked to a reportedly mystical origin of the disease. We assessed the role beliefs play in determining BUD sufferers' choice between traditional and biomedical treatments.Anthropological fieldwork was conducted in community and clinical settings in the region of Ayos and Akonolinga in Central Cameroon. The research design consisted of a mixed methods study, triangulating a qualitative strand based on ethnographic research and quantitative data obtained through a survey presented to all patients at the Ayos and Akonolinga hospitals (N = 79) at the time of study and in four endemic communities (N = 73) belonging to the hospitals' catchment area.The analysis of BUD sufferers' health-seeking behaviour showed extremely complex therapeutic itineraries, including various attempts and failures both in the biomedical and traditional fields. Contrary to expectations, nearly half of all hospital patients attributed their illness to mystical causes, while traditional healers admitted patients they perceived to be infected by natural causes. Moreover, both patients in hospitals and in communities often combined elements of both types of treatments. Ultimately, perceptions regarding the effectiveness of the treatment, the option for local treatment as a cost prevention strategy and the characteristics of the doctor-patient relationship were more determinant for treatment choice than beliefs.The ascription of delay and treatment choice to beliefs constitutes an over-simplification of BUD health-seeking behaviour and places the responsibility directly on the shoulders of BUD sufferers while potentially neglecting other structural elements. While more efficacious treatment in the biomedical sector is likely to reduce perceived mystical involvement in the disease, additional decentralization could constitute a key element to reduce delay and increase adherence to biomedical treatment

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK–/– mice. Transplantation of MerTK–/– bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK–/– leukocytes exhibited lower tumor cell–induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK–/– mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK–/– mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Health Disparities Between Appalachian and Non-Appalachian Counties in Virginia USA

The examination of health disparities among people within Appalachian counties compared to people living in other counties is needed to find ways to strategically target improvements in community health in the United States of America (USA). Methods: A telephone survey of a random sample of adults living in households within communities of all counties of the state of Virginia (VA) in the USA was conducted. Findings: Health status was poorer among those in communities within Appalachian counties in VA and health insurance did not make a difference. Health perception was significantly worse in residents within communities in Appalachian counties compared to non-Appalachian community residents (30.5 vs. 17.4% rated their health status as poor/fair), and was worse even among those with no chronic diseases. Within communities in Appalachian counties, black residents report significantly better health perception than do white residents. Conclusion: Residents living in communities in Appalachian counties in VA are not receiving adequate health care, even among those with health insurance. More research with a larger ethnic minority sample is needed to investigate the racial/ethnic disparities in self-reported health and health care utilization within communities