A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders

Genetic polymorphisms in TNF genes and tuberculosis in North Indians

<p>Abstract</p> <p>Background</p> <p>Pulmonary tuberculosis, the most common clinical form of mycobacterial diseases, is a granulomatous disease of the lungs caused by <it>Mycobaterium tuberculosis</it>. A number of genes have been identified in studies of diverse origins to be important in tuberculosis. Of these, both tumor necrosis factor α (TNF-α) and lymphotoxin α (LT-α) play important immunoregulatory roles.</p> <p>Methods</p> <p>To investigate the association of <it>TNF </it>polymorphisms with tuberculosis in the Asian Indians, we genotyped five potentially functional promoter polymorphisms in the <it>TNFA </it>gene and a <it>LTA_NcoI </it>polymorphism (+252 position) of the <it>LTA </it>gene in a clinically well-defined cohort of North-Indian patients with tuberculosis (N = 185) and their regional controls (N = 155). Serum TNF-α (sTNF-α) levels were measured and correlated with genotypes and haplotypes.</p> <p>Results</p> <p>The comparison of the allele frequencies for the various loci investigated revealed no significant differences between the tuberculosis patients and controls. Also, when the patients were sub-grouped into minimal, moderately advanced and far advanced disease on the basis of chest radiographs, TST and the presence/absence of cavitary lesions, none of the polymorphisms showed a significant association with any of the patient sub-groups. Although a significant difference was observed in the serum TNF-α levels in the patients and the controls, none of the investigated polymorphisms were found to affect the sTNF-α levels. Interestingly, it was observed that patients with minimal severity were associated with lower log sTNF-α levels when compared to the patients with moderately advanced and far advanced severity. However, none of these differences were found to be statistically significant. Furthermore, when haplotypes were analyzed, no significant difference was observed.</p> <p>Conclusions</p> <p>Thus, our findings exclude the <it>TNF </it>genes as major risk factor for tuberculosis in the North Indians.</p

Ellis Van Creveld syndrome

Ellis Van Creveld syndrome is a rare disorder and is a form of short-limbed dwarfism. It is an autosomal recessive disorder characterized by tetrad of disproportionate dwarfism, post-axial polydactyly, ectodermal dysplasia and heart defects. This case report presents a classical case of a seven-year-old boy with Ellis Van Creveld syndrome presented with discrete clinical findings

Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults

The elderly population is growing at increased rates and is expected to double in size by 2050 in the United States and worldwide. The consumption of healthy foods and enriched diets have been associated with improved cognition and brain health. The key nutrients common to many healthy foods and diets are the omega-3 polyunsaturated fatty acids (omega-3 FAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We explored whether omega-3 FA levels are associated with brain volume and cognition. Forty healthy, cognitively normal, Seventh-day Adventist older adults (mean age 76.3 years at MRI scan, 22 females) completed neurocognitive testing, a blood draw, and structural neuroimaging from 2016 to 2018. EPA and an overall omega-3 index were associated with individual measures of delayed recall (RAVLT-DR) and processing speed (Stroop Color) as well as entorhinal cortex thickness. EPA, DHA, and the omega-3 index were significantly correlated with the total white matter volume. The entorhinal cortex, frontal pole, and total white matter were associated with higher scores on delayed memory recall. This exploratory study found that among healthy, cognitively older adults, increased levels of omega-3 FAs are associated with better memory, processing speed, and structural brain measures

DNA Polymerase zeta Is a Major Determinant of Resistance to Platinum-Based Chemotherapeutic Agents

Abstract Oxaliplatin, satraplatin, and picoplatin are cisplatin analogs that interact with DNA forming intrastrand and interstrand DNA crosslinks (ICLs). Replicative bypass of cisplatin DNA adducts requires the cooperative actions of at least three translesion DNA synthesis (TLS) polymerases: eta (Polη), REV1, and zeta (Polζ). Because oxaliplatin, satraplatin, and picoplatin contain bulker chemical groups attached to the platinum core as compared to cisplatin, we hypothesized that these chemical additions may impede replicative bypass by TLS polymerases and reduce tolerance to platinum-containing adducts. We examined multiple responses of cancer cells to oxaliplatin, satraplatin, or picoplatin treatment under conditions where expression of a TLS polymerase was limited. Our studies revealed that although Polη contributes to the tolerance of cisplatin adducts, it plays a lesser role in promoting replication through oxaliplatin, satraplatin, and picoplatin adducts. REV1 and Polζ were necessary for tolerance to all four platinum analogs and prevention of hyper-activation of the DNA damage response following treatment. In addition, REV1 and Polζ were important for the resolution of DNA doublestranded breaks (DSBs) created during replication-associated repair of platinum-containing ICLs. Consistent with ICLs being the predominant cytotoxic lesion, depletion of REV1 or Polζ rendered two different model cell systems extremely sensitive to all four drugs, whereas Polη depletion had little effect. Together, our data suggest that REV1 and Polζ are critical for promoting resistance to all four clinically relevant platinum-based drugs by promoting both translesion DNA synthesis and DNA repair