Son preference and sex differentials in receipt of key dimensions of children's healthcare: Evidence from Pakistan.

Almost all research on son preference and the consequent sex differentials in child health has focused on India. Pakistan-a country with the second strongest stated desire for sons, no evidence of sex-selective abortion, and relatively high fertility-offers a different context in which to understand unequal health outcomes for boys and girls. I use three rounds of the Pakistan Demographic and Health Survey to examine sex differentials in child healthcare receipt across different family contexts. I find evidence of generalized discrimination: all girls, regardless of sibling composition or birth order, are less likely to receive full immunization or medical treatment. I do not find evidence that girls with older sisters face greater discrimination than other girls. For boys, I find some evidence of selective preferential treatment: among larger families, first sons are more likely to receive healthcare than other sons or daughters.

Assessment of Knowledge About the Risk Factors of Chronic Liver Disease in Patients Admitted in Civil Hospital Karachi.

Background Chronic liver disease (CLD) encompasses a series of single or multifactorial insults to the liver, most common of which are hepatitis, alcohol abuse, and non-alcoholic liver disease. CLD represents a major public health problem worldwide as well as in Pakistan. Unfortunately, studies evaluating the awareness of its risk factors among people are quite scarce. The purpose of this study was to assess the knowledge about risk factors of CLD in patients admitted to Dr. Ruth K M Pfau, Civil Hospital Karachi (CHK). Methods This quantitative cross-sectional study was conducted at CHK, among 368 patients admitted to CHK, during the period from February 2018 to September 2018. Frequencies and percentages were evaluated for categorical variables using Statistical Package for Social Sciences (SPSS), version 22 (IBM Corp., Armonk, NY). Chi-square test was applied to determine if there was any significant association between the variables. A p-value of <0.05 was considered significant. Results A scoring scale was developed to assess the level of knowledge. We found that only 32% of our study population had good knowledge about the risk factors of CLD while majority of them (68%) had poor knowledge. Regarding individual risk factors, >60% patients were aware that obesity, high fat intake, prolonged use of drugs, use of alcohol and hepatitis B and C are risk factors of CLD, while most of them did not know diabetes to be a risk factor as well. 51.4% patients thought that hepatitis B and C could not be transmitted via sexual contact and from mother to her baby. There was a positive association between education level and awareness about the risk factors of CLD (p = 0.006). Conclusion Future interventions to increase public awareness about CLD should promptly be taken. The lack of knowledge about this disease is the main cause of its rapid increment and the reason why it is so prevalent in our part of the world especially Pakistan. More studies and nationwide awareness programs are needed to control its spread.

Women's Assessments of Gender Equality.

Women's assessments of gender equality do not consistently match global indices of gender inequality. In surveys covering 150 countries, women in societies rated gender-unequal according to global metrics such as education, health, labor-force participation, and political representation did not consistently assess their lives as less in their control or less satisfying than men did. Women in these societies were as likely as women in index-equal societies to say they had equal rights with men. Their attitudes toward gender issues did not reflect the same latent construct as in index-equal societies, although attitudes may have begun to converge in recent years. These findings reflect a longstanding tension between universal criteria of gender equality and an emphasis on subjective understandings of women's priorities.

Publisher Correction: ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

This corrects the article DOI: 10.1038/ncomms7186.

THE SECOND DEMOGRAPHIC TRANSITION THEORY: A Review and Appraisal.

References to the second demographic transition (SDT) concept/theoretical framework have increased dramatically in the last two decades. The SDT predicts unilinear change toward very low fertility and a diversity of union and family types. The primary driver of these changes is a powerful, inevitable and irreversible shift in attitudes and norms in the direction of greater individual freedom and self-actualization. First, we describe the origin of this framework and its evolution over time. Second, we review the empirical fit of the framework to major changes in demographic and family behavior in the U.S., the West, and beyond. As has been the case for other unilinear, developmental theories of demographic/family change, the SDT failed to predict many contemporary patterns of change/difference. Finally, we review previous critiques and identify fundamental weaknesses of this perspective, and provide brief comparisons to selected alternative approaches.

Defining the identity of mouse embryonic dermal fibroblasts.

Embryonic dermal fibroblasts in the skin have the exceptional ability to initiate hair follicle morphogenesis and contribute to scarless wound healing. Activation of the Wnt signaling pathway is critical for dermal fibroblast fate selection and hair follicle induction. In humans, mutations in Wnt pathway components and target genes lead to congenital focal dermal hypoplasias with diminished hair. The gene expression signature of embryonic dermal fibroblasts during differentiation and its dependence on Wnt signaling is unknown. Here we applied Shannon entropy analysis to identify the gene expression signature of mouse embryonic dermal fibroblasts. We used available human DNase-seq and histone modification ChiP-seq data on various cell-types to demonstrate that genes in the fibroblast cell identity signature can be epigenetically repressed in other cell-types. We found a subset of the signature genes whose expression is dependent on Wnt/ß-catenin activity in vivo. With our approach, we have defined and validated a statistically derived gene expression signature that may mediate dermal fibroblast identity and function in development and disease. genesis 54:415-430, 2016. © 2016 Wiley Periodicals, Inc.

In the Pursuit of Sons: Additional Births or Sex-Selective Abortion in Pakistan?

Even though Pakistan is a highly patriarchal society, it has not featured prominently in studies focusing on sex-selective abortion and sex ratios at birth. But with fertility declining and existing strong son preference-Pakistan has one of the highest desired sex ratios in the world-how will Pakistani families respond? In the pursuit of sons, will they have additional children or resort to sex-selective abortions? Or is there evidence that the pursuit of sons is weakening? Using data from three rounds of the demographic and health survey, we show clear evidence of son preference in fertility intentions, patterns of contraceptive use and parity progression ratios. More specifically, we find pervasive evidence that Pakistanis continue childbearing to have a son, to have more than one son and to have at least one daughter. We do not find consistent and convincing evidence that sex ratios at birth (which indicate sex-selective abortion) are increasing.

ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

Chromatin interactions connect distal regulatory elements to target gene promoters guiding stimulus- and lineage-specific transcription. Few factors securing chromatin interactions have so far been identified. Here, by integrating chromatin interaction maps with the large collection of transcription factor-binding profiles provided by the ENCODE project, we demonstrate that the zinc-finger protein ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Silencing ZNF143 or modulating its DNA-binding affinity using single-nucleotide polymorphisms (SNPs) as a surrogate of site-directed mutagenesis reveals the sequence dependency of chromatin interactions at gene promoters. We also find that chromatin interactions alone do not regulate gene expression. Together, our results identify ZNF143 as a novel chromatin-looping factor that contributes to the architectural foundation of the genome by providing sequence specificity at promoters connected with distal regulatory elements.

The developmental potential of iPSCs is greatly influenced by reprogramming factor selection.

Induced pluripotent stem cells (iPSCs) are commonly generated by transduction of Oct4, Sox2, Klf4, and Myc (OSKM) into cells. Although iPSCs are pluripotent, they frequently exhibit high variation in terms of quality, as measured in mice by chimera contribution and tetraploid complementation. Reliably high-quality iPSCs will be needed for future therapeutic applications. Here, we show that one major determinant of iPSC quality is the combination of reprogramming factors used. Based on tetraploid complementation, we found that ectopic expression of Sall4, Nanog, Esrrb, and Lin28 (SNEL) in mouse embryonic fibroblasts (MEFs) generated high-quality iPSCs more efficiently than other combinations of factors including OSKM. Although differentially methylated regions, transcript number of master regulators, establishment of specific superenhancers, and global aneuploidy were comparable between high- and low-quality lines, aberrant gene expression, trisomy of chromosome 8, and abnormal H2A.X deposition were distinguishing features that could potentially also be applicable to human.

Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits.

DNA variants (SNPs) that predispose to common traits often localize within noncoding regulatory elements such as enhancers. Moreover, loci identified by genome-wide association studies (GWAS) often contain multiple SNPs in linkage disequilibrium (LD), any of which may be causal. Thus, determining the effect of these multiple variant SNPs on target transcript levels has been a major challenge. Here, we provide evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the GWAS association arises from multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type. This finding suggests a "multiple enhancer variant" hypothesis for common traits, where several variants in LD impact multiple enhancers and cooperatively affect gene expression. Using a novel method to delineate enhancer-gene interactions, we show that multiple enhancer variants within a given locus typically target the same gene. Using available data from HapMap and B lymphoblasts as a model system, we provide evidence at numerous loci that multiple enhancer variants cooperatively contribute to altered expression of their gene targets. The effects on target transcript levels tend to be modest and can be either gain- or loss-of-function. Additionally, the genes associated with multiple enhancer variants encode proteins that are often functionally related and enriched in common pathways. Overall, the multiple enhancer variant hypothesis offers a new paradigm by which noncoding variants can confer susceptibility to common traits.

H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites.

BACKGROUND: In addition to mutations, epigenetic silencing of genes has been recognized as a fundamental mechanism that promotes human carcinogenesis. To date, characterization of epigenetic gene silencing has largely focused on genes in which silencing is mediated by hypermethylation of promoter-associated CpG islands, associated with loss of the H3K4me3 chromatin mark. Far less is known about promoters lacking CpG-islands or genes that are repressed by alternative mechanisms. METHODS: We performed integrative ChIP-chip, DNase-seq, and global gene expression analyses in colon cancer cells and normal colon mucosa to characterize chromatin features of both CpG-rich and CpG-poor promoters of genes that undergo silencing in colon cancer. RESULTS: Epigenetically repressed genes in colon cancer separate into two classes based on retention or loss of H3K4me3 at transcription start sites. Quantitatively, of transcriptionally repressed genes that lose H3K4me3 in colon cancer (K4-dependent genes), a large fraction actually lacks CpG islands. Nonetheless, similar to CpG-island containing genes, cytosines located near the start sites of K4-dependent genes become DNA hypermethylated, and repressed K4-dependent genes can be reactivated with 5-azacytidine. Moreover, we also show that when the H3K4me3 mark is retained, silencing of CpG island-associated genes can proceed through an alternative mechanism in which repressive chromatin marks are recruited. CONCLUSIONS: H3K4me3 equally protects from DNA methylation at both CpG-island and non-CpG island start sites in colon cancer. Moreover, the results suggest that CpG-rich genes repressed by loss of H3K4me3 and DNA methylation represent special instances of a more general epigenetic mechanism of gene silencing, one in which gene silencing is mediated by loss of H3K4me3 and methylation of non-CpG island promoter-associated cytosines.

Epigenomic enhancer profiling defines a signature of colon cancer.

Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, even though distal regulatory elements play a central role in controlling transcription patterns. We used the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome-wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly predictive of the in vivo colon cancer transcriptome. Furthermore, VELs are enriched in haplotype blocks containing colon cancer genetic risk variants, implicating these genomic regions in colon cancer pathogenesis. We propose that reproducible changes in the epigenome at enhancer elements drive a specific transcriptional program to promote colon carcinogenesis.

CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.

CHD7 is one of nine members of the chromodomain helicase DNA-binding domain family of ATP-dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP-seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7(+/+), Chd7(+/-), and Chd7(-/-) ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES-specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation.

beta-Catenin has sequential roles in the survival and specification of ventral dermis.

The dermis promotes the development and maintains the functional components of skin, such as hair follicles, sweat glands, nerves and blood vessels. The dermis is also crucial for wound healing and homeostasis of the skin. The dermis originates from the somites, the lateral plate mesoderm and the cranial neural crest. Despite the importance of the dermis in the structural and functional integrity of the skin, genetic analysis of dermal development in different parts of the embryo is incomplete. The signaling requirements for ventral dermal cell development have not been established in either the chick or the mammalian embryo. We have shown previously that Wnt signaling specifies the dorsal dermis from the somites. In this study, we demonstrate that Wnt/beta-catenin signaling is necessary for the survival of early ventral dermal progenitors. In addition, we show that, at later stages, Wnt/beta-catenin signaling is sufficient for ventral dermal cell specification. Consistent with the different origins of dorsal and ventral dermal cells, our results demonstrate both conserved and divergent roles of beta-catenin/Wnt signaling in dermal development.