Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch.

Fetal hemoglobin (HbF, α2γ2) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2ß2) disorders, sickle cell disease, and ß-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to ß- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in γ-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.

Between Life and Death: How do Muslim Terminal Patients in Pakistan cope with Hepatitis C utilizing their Beliefs and Social Support?

Life-threatening events including terminal illness intensify the search for meaning and incite individuals to get closer to religion. Terminal patients can often find religious practices as helpful as medical therapy for bettering both physical and mental health. The present research aims to explain the interaction between religion, spirituality, and social support in coping with terminal illness among Muslim hepatitis C patients in Pakistan. A semi-structured open-ended interview guide was utilized to collect the data. Participants expressed that the deployment of religious and spiritual beliefs along with socio-emotional support during illness fostered medical therapy. Participants also revealed that belief in God provided them the strength to be steadfast during the terminal stage of the disease. Religious beliefs enabled terminal participants to accept death as an eventual reality and a normal part of their lives. Furthermore, participants put forward their longing for those kinds of religious practices that terminal diseases usually restrained them from receiving. The emotional support stemming from social relationships also improved resilience to cope with the terminal stage of illness. The study concludes that the interplay of religion, spirituality, and social support normalizes the fear of death, lessens pain, and improves resilience among Muslim hepatitis C patients in Pakistan.

Ba2-xBixCoRuO6 (0.0 ≤ x ≤ 0.6) Hexagonal Double-Perovskite-Type Oxides as Promising p-Type Thermoelectric Materials.

A new series of Ba2-xBixCoRuO6 (0.0 ≤ x ≤ 0.6) hexagonal double perovskite oxides have been synthesized by a solid-state reaction method by substituting Ba with Bi. The polycrystalline materials are structurally characterized by the laboratory X-ray diffraction, synchrotron X-ray, and neutron powder diffraction. The lattice parameters are found to increase with increasing Bi doping despite the smaller ionic radius of Bi3+ compared to Ba2+. The expansion is attributed to the reduction of Co/Ru-site cations. Scanning electron microscopy further shows that the grain size increases with the Bi content. All Ba2-xBixCoRuO6 (0.0 ≤ x ≤ 0.6) samples exhibit p-type behavior, and the electrical resistivity (ρ) is consistent with a small polaron hopping model. The Seebeck coefficient (S) and thermal conductivity (κ) are improved significantly with Bi doping. High values of the power factor (PF ∼ 6.64 × 10-4 W/m·K2) and figure of merit (zT ∼ 0.23) are obtained at 618 K for the x = 0.6 sample. These results show that Bi doping is an effective approach for enhancing the thermoelectric properties of hexagonal Ba2-xBixCoRuO6 perovskite oxides.

Investigation of the Crystal Structure and Ionic Pathways of the Hexagonal Perovskite Derivative Ba3-xVMoO8.5-x.

The hexagonal perovskite derivatives Ba3NbMoO8.5, Ba3NbWO8.5, and Ba3VWO8.5 have recently been reported to exhibit significant oxide ion conductivity. Here, we report the synthesis and crystal structure of the hexagonal perovskite derivative Ba3-xVMoO8.5-x. Rietveld refinement from neutron and X-ray diffraction data show that the cation vacancies are ordered on the M2 site, leading to a structure consisting of palmierite-like layers of M1Ox polyhedra separated by vacant octahedral layers. In contrast to other members of the Ba3M'M″O8.5 family, Ba3-xVMoO8.5-x is not stoichiometric and both barium and oxygen vacancies are present. Although synthesized in air at elevated temperatures, Ba3-xVMoO8.5-x is unstable at lower temperatures, as illustrated by the formation of BaCO3 and BaMoO4 by heat treatment in air at 400 °C. This precludes measurement of the electrical properties. However, bond-valence site energy (BVSE) calculations strongly suggest that oxide ion conductivity is present in Ba3-xVMoO8.5-x.

BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis.

Enhancers, critical determinants of cellular identity, are commonly recognized by correlative chromatin marks and gain-of-function potential, although only loss-of-function studies can demonstrate their requirement in the native genomic context. Previously, we identified an erythroid enhancer of human BCL11A, subject to common genetic variation associated with the fetal haemoglobin level, the mouse orthologue of which is necessary for erythroid BCL11A expression. Here we develop pooled clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse enhancers. This approach reveals critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear to be primate-specific. Through editing of primary human progenitors and mouse transgenesis, we validate the BCL11A erythroid enhancer as a target for fetal haemoglobin reinduction. The detailed enhancer map will inform therapeutic genome editing, and the screening approach described here is generally applicable to functional interrogation of non-coding genomic elements.

Coping Through Religiosity, Spirituality and Social Support Among Muslim Chronic Hepatitis Patients.

Academics acknowledge religiosity, spirituality and social support as socio-behavioral factors that influence patients' ability to deal with chronic illness. This study has attempted to describe empirical reality of how these factors influence patients. The sample of this study was 500 chronically ill hepatitis patients and was selected through the multistage sampling techniques. Through structured interview schedule, data were collected during the period of September 2016 to March 2017 from five most populated cities of Punjab (Pakistan). Data were analyzed through descriptive (frequency and percentage) and inferential statistics (Cronbach's alpha, Pearson correlation, and structural equation modeling). The study suggests some recommendations and suggestions to policy makers regarding the significance of religiosity, spirituality and social support as coping strategies during chronic illness. The findings illustrate that social support has more association with coping than religiosity and spirituality of the patients.

Strict in vivo specificity of the Bcl11a erythroid enhancer.

BCL11A, a repressor of human fetal (γ-)globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such, this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10-kb intronic sequences were removed. Bcl11a enhancer-deleted mice, Bcl11a(Δenh), phenocopy the BCL11A-null state with respect to alterations of globin expression, yet are viable and exhibit no observable blood, brain, or other abnormalities. These preclinical findings provide strong in vivo support for genetic modification of the enhancer for therapy of hemoglobin disorders.

Absence of colossal magnetoresistance in the oxypnictide PrMnAsO0.95F0.05.

We have recently reported a new mechanism of colossal magnetoresistance (CMR) in electron doped manganese oxypnictides NdMnAsO1-xFx. Magnetoresistances of up to -95% at 3 K have been observed. Here we show that upon replacing Nd for Pr, the CMR is surprisingly no longer present. Instead a sizable negative magnetoresistance is observed for PrMnAsO0.95F0.05 below 35 K (MR7T (12 K) = -13.4% for PrMnAsO0.95F0.05). A detailed neutron and synchrotron X-ray diffraction study of PrMnAsO0.95F0.05 has been performed, which shows that a structural transition, Ts, occurs at 35 K from tetragonal P4/nmm to orthorhombic Pmmn symmetry. The structural transition is driven by the Pr 4f electrons degrees of freedom. The sizable -MR observed below the transition most likely arises due to a reduction in magnetic and/or multipolar scattering upon application of a magnetic field.

Renewable energy consumption - financial globalization-tourism nexus with nonlinearity and cross-sectional dependence during Asia's carbon-free transition.

Adopting renewable energy consumption is one of the most important aspects of international efforts to combat climate change, improve energy security, and encourage the shift to a more robust and sustainable energy system. Therefore, the empirics and policymakers worldwide are searching for factors that can promote renewable energy consumption. This analysis intends to investigate the role of financial globalization and tourism on renewable energy consumption in Asia and sub-regions such as Central Asia, East Asia, South Asia, Southeast Asia, and West Asia. The analysis utilized the linear and nonlinear CS-ARDL methods. Long-run outcomes of the linear and nonlinear models confirm that a rise in financial globalization and tourism promotes renewable energy consumption in Asia and all sub-regions. However, the nonlinear model highlights that a fall in financial globalization hurts renewable energy consumption in Central and South Asian regions, and tourism only hurts renewable energy consumption in Asia. In addition, ICT, GDP, and GHG emissions help promote renewable energy consumption. These results suggest that Asian policymakers must increase collaboration in the financial sectors and promote sustainable tourism in the regions to promote renewable energy consumption.