Heritability of anthropometric phenotypes in caste populations of Visakhapatnam,India

In this study, we used anthropometric data from six Andhra caste populations to examine heritability patterns of 23 anthropometric phenotypes (linear, craniofacial, and soft tissue measures) with special reference to caste differences. We obtained anthropometric data from 342 nuclear families from Brahmin, Reddy, Telaga, Nagara, Ag. Kshatriya, and Mala castes of Visakhapatnam, India. These caste groups represent the existing hierarchical stratification of Indian populations. We used a variance components approach to determine the heritability (h2) of these 23 anthropometric phenotypes (height, weight, BMI, etc.). The sample consisted of 1918 individuals ranging in age from 6 to 72 years (mean = 21.5, S.D. = 13.8). The heritabilities (h2 +/- S.E.) for all anthropometric traits for the entire sample were significant (p < 0.0001) and varied from 0.25 +/- 0.05 (BMI) to 0.61 +/- 0.05 (bizygomatic breadth) after accounting for sex, age, and caste effects. Since data on socioeconomic and nutritional covariates were available for a subset of families, we repeated the genetic analyses using this subset, which has yielded higher heritabilities ranging from 0.21 +/- 0.16 (head breadth) to 0.72 +/- 0.18 (nasal breadth). In general, craniofacial measurements exhibited higher h2 compared to linear measures. Breadth measurements and circumferences yielded more or less similar heritabilities. Age and sex effects were significant (p < 0.0001 ) for most of the traits, while the effects of caste, socioeconomic status, and nutritional status were inconsistent across the traits. In conclusion, anthropometric phenotypes examined in this study are under appreciable additive genetic influences.     

Distribution of glyoxalase I (GLO) variants in Western Europe and the Indian subcontinent

Summary English, Italian (including Sardinian), and Spanish populations from Europe and Muslim, Hindu, Sikh, Punjabi, and other populations from the Indian subcontinent currently living either in Birmingham or in India were screened for electrophoretically detectable genetic variants of red cell glyoxalase I (GLO), and their frequencies were reported. All the western European populations investigated, including those reported, exhibited an incidence of close to 44% for the GLO ¹ gene. The frequency distribution of the GLO ¹ gene in various populations from the Indian subcontinent, in contrast, was found to range between 0.15 and 0.33. These observations suggest that the European populations in general are genetically more homogeneous than are the populations of the Indian subcontinent.     

Effect of Lipophilicity and Drug Ionization on Permeation Across Porcine Sublingual Mucosa

Sublingual route is one of the oldest alternative routes studied for the administration of drugs. However, the effect of physical-chemical properties on drug permeation via this route has not been systemically investigated. The objective of this study was to determine the effect of two key physicochemical properties, lipophilicity and ionization, on the transport of drugs across porcine sublingual mucosa. A series of β-blockers were used to study the effect of lipophilicity on drug permeation across the sublingual mucosa, while nimesulide (pKa 6.5) was used as a model drug to study the effect of degree of ionization on sublingual mucosa permeation of ionized and unionized species. Permeation of β-blockers increased linearly with an increase in the lipophilicity for the range of compounds studied. The permeability of nimesulide across sublingual mucosa decreased with an increase of pH. The flux of ionized and unionized forms of nimesulide was determined to delineate the contribution of ionized and unionized species to the total flux. At low pH, the apparent flux was primarily contributed by unionized species; however, when the pH is increased beyond its pKa, the primary contributor to the apparent flux, nimesulide, is ionized species. The contribution of each species to the apparent flux was shown to be determined by the thermodynamic activity of ionized or unionized species. This study identified the roles of lipophilicity and thermodynamic activity in drug permeation across the sublingual mucosa. The findings can help guide the design of sublingual drug delivery systems with optimal pH and solubility.     

Role of FAM134 paralogues in endoplasmic reticulum remodeling,ER‐phagy,and Collagen quality control

Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER‐phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER‐phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3‐interacting region (LIR)‐dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER‐phagy flux upon starvation or ER‐stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER‐resident proteins. Utilizing pro‐Collagen I, as a shared ER‐phagy substrate, we observe that FAM134A acts in a LIR‐independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER‐phagy pathways.     

REH2C Helicase and GRBC Subcomplexes May Base Pair through mRNA and Small Guide RNA in Kinetoplastid Editosomes

Mitochondrial mRNAs in Trypanosoma brucei undergo extensive insertion and deletion of uridylates that are catalyzed by the RNA editing core complex (RECC) and directed by hundreds of small guide RNAs (gRNAs) that base pair with mRNA. RECC is largely RNA-free, and accessory mitochondrial RNA-binding complex 1 (MRB1) variants serve as scaffolds for the assembly of mRNA-gRNA hybrids and RECC. However, the molecular steps that create higher-order holoenzymes (“editosomes”) are unknown. Previously, we identified an RNA editing helicase 2-associated subcomplex (REH2C) and showed that REH2 binds RNA. Here we showed that REH2C is an mRNA-associated ribonucleoprotein (mRNP) subcomplex with editing substrates, intermediates, and products. We isolated this mRNP from mitochondria lacking gRNA-bound RNP (gRNP) subcomplexes and identified REH2-associated cofactors 1 and 2 (^H2F1 and ^H2F2). ^H2F1 is an octa-zinc finger protein required for mRNP-gRNP docking, pre-mRNA and RECC loading, and RNP formation with a short synthetic RNA duplex. REH2 and other eukaryotic DEAH/RHA-type helicases share a conserved regulatory C-terminal domain cluster that includes an oligonucleotide-binding fold. Recombinant REH2 and ^H2F1 constructs associate in a purified complex in vitro. We propose a model of stepwise editosome assembly that entails controlled docking of mRNP and gRNP modules via specific base pairing between their respective mRNA and gRNA cargo and regulatory REH2 and ^H2F1 subunits of the novel mRNP that may control specificity checkpoints in the editing pathway.     

Holins in Bacteria,Eukaryotes, and Archaea: Multifunctional Xenologues with Potential Biotechnological and Biomedical Applications

Holins form pores in the cytoplasmic membranes of bacteria for the primary purpose of releasing endolysins that hydrolyze the cell wall and induce cell death. Holins are encoded within bacteriophage genomes, where they promote cell lysis for virion release, and within bacterial genomes, where they serve a diversity of potential or established functions. These include (i) release of gene transfer agents, (ii) facilitation of programs of differentiation such as those that allow sporulation and spore germination, (iii) contribution to biofilm formation, (iv) promotion of responses to stress conditions, and (v) release of toxins and other proteins. There are currently 58 recognized families of holins and putative holins with members exhibiting between 1 and 4 transmembrane α-helical spanners, but many more families have yet to be discovered. Programmed cell death in animals involves holin-like proteins such as Bax and Bak that may have evolved from bacterial holins. Holin homologues have also been identified in archaea, suggesting that these proteins are ubiquitous throughout the three domains of life. Phage-mediated cell lysis of dual-membrane Gram-negative bacteria also depends on outer membrane-disrupting “spanins” that function independently of, but in conjunction with, holins and endolysins. In this minireview, we provide an overview of their modes of action and the first comprehensive summary of the many currently recognized and postulated functions and uses of these cell lysis systems. It is anticipated that future studies will result in the elucidation of many more such functions and the development of additional applications.     

Candidate Gene Identification for Systemic Lupus Erythematosus Using Network Centrality Measures and Gene Ontology

Systemic lupus erythematosus (SLE) commonly accredited as “the great imitator” is a highly complex disease involving multiple gene susceptibility with non-specific symptoms. Many experimental and computational approaches have been used to investigate the disease related candidate genes. But the limited knowledge of gene function and disease correlation and also lack of complete functional details about the majority of genes in susceptible locus, encumbrances the identification of SLE related candidate genes. In this paper, we have studied the human immunome network (undirected) using various graph theoretical centrality measures integrated with the gene ontology terms to predict the new candidate genes. As a result, we have identified 8 candidate genes, which may act as potential targets for SLE disease. We have also carried out the same analysis by replacing the human immunome network with human immunome signaling network (directed) and as an outcome we have obtained 5 candidate genes as potential targets for SLE disease. From the comparison study, we have found these two approaches are complementary in nature.