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Globally, millions of diabetic patients require daily life-saving insulin injections. Insulin heat-lability and fibrillation pose significant challenges, especially in parts of the world without ready access to uninterrupted refrigeration. Here, we have synthesized four human insulin analogs by conjugating ε-amine of B29 lysine of insulin with acetic acid, phenylacetic acid, alanine, and phenylalanine residues. Of these, phenylalanine-conjugated insulin, termed FHI, was the most stable under high temperature (65 °C), elevated salt stress (25 mM NaCl), and varying pH levels (ranging from highly acidic pH 1.6 to physiological pH 7.4). It resists fibrillation for a significantly longer duration with sustained biological activity in in vitro, ex vivo, and in vivo and displays prolonged stability over its native counterpart. We further unravel the critical interactions, such as additional aromatic π-π interactions and hydrogen bonding in FHI, that are notably absent in native insulin. These interactions confer enhanced structural stability of FHI and offer a promising solution to the challenges associated with insulin heat sensitivity.

Mammalian Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) and Drosophila Yorkie (Yki) are transcription cofactors of the highly conserved Hippo signaling pathway. It has been long assumed that the YAP/TAZ/Yki signaling drives cell proliferation during organ growth. However, its instructive role in regulating developmentally programmed organ growth, if any, remains elusive. Out-of-context gain of YAP/TAZ/Yki signaling often turns oncogenic. Paradoxically, mechanically strained, and differentiated squamous epithelia display developmentally programmed constitutive nuclear YAP/TAZ/Yki signaling. The unknown, therefore, is how a growth-promoting YAP/TAZ/Yki signaling restricts proliferation in differentiated squamous epithelia. Here, we show that reminiscent of a tumor suppressor, Yki negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the squamous epithelia of Drosophila tubular organs. Thus, downregulation of Yki signaling in the squamous epithelium of the adult male accessory gland (MAG) up-regulates PI3K/Akt/TOR signaling, inducing cell hypertrophy, exit from their cell cycle arrest, and, finally, culminating in squamous cell carcinoma (SCC). Thus, blocking PI3K/Akt/TOR signaling arrests Yki loss-induced MAG-SCC. Further, MAG-SCCs, like other lethal carcinomas, secrete a cachectin, Impl2--the Drosophila homolog of mammalian IGFBP7--inducing cachexia and shortening the lifespan of adult males. Moreover, in the squamous epithelium of other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, downregulation of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy. Our results reveal that Yki signaling plays an instructive, antiproliferative role in the squamous epithelia of tubular organs. [ABSTRACT FROM AUTHOR]

A recessive semi-lethal mutation resulting from the insertion of a P-lacW transposon at the cytological position 23A on the polytene chromosomes of Drosophila melanogaster was found to affect the unfolding and expansion of the wings resulting in a loss of venation and a marked decrease in their size. Lethality was polyphasic with numerous animals dying during early larval development and displaying apparently collapsed tracheal trees. The gene was therefore designated as congested-like tracheae, or colt. The colt mutation resulted from the insertion of a P-lacW transposon within the coding region of a 1.4-kb transcript. Wild-type function was restored by inducing a precise excision of the P-lacW transposon, while a deletion of the colt locus, produced by imprecise excision of the P element, showed a phenotype similar to that of the original P insert. The colt gene consists of a single exon and encodes a protein of 306 amino acids made of three tandem repeats, each characterized by two predicted transmembrane segments and a loop domain. The COLT protein shares extensive homology with proteins in the mitochondrial carrier family and particularly with the DIF-1 protein of Caenorhabditis elegans, which has been shown to be maternally required for embryonic tissue differentiation. Our analysis revealed that zygotic colt function is dispensable for normal embryonic morphogenesis but is required for gas-filling of the tracheal system at hatching time of the embryo and for normal epithelial morphogenesis of the wings.

Genetic mosaics of Drosophila mutant for lethal(2)giant larvae (lgl) were studied to demonstrate that cells lacking the lgl tumor suppressor gene do not promote cell-cell interactions during development. Cells from adult wings mutant for lgl showed abnormal growth and differentiation, indicating defective cell-cell interactions. Further evidence also showed that cells exhibiting neoplastic transformation of imaginal discs also show loss of normal signaling in addition to aberrant cell-cell interactions.

Introduction: Disturbances of intra-ventricular conduction are associated with distinct ECG abnormalities inpatients and QTc interval is found to be prolonged which may be interpreted as higher arrhythmogenic property of such patients. But the repolarisation time of such patients are more or less same which isexpressed by JTc interval. In this study, it is found that JTc interval measurement is more significant than QTc interval in IVCD patients as predictor of cardiac arrhythmogenesis. Methodology: Institution based observational, cross sectional study among 100 patients attending cardiology OPD for a period of approximate 2 years with diagnosis of different IVCDs (RBBB, LBBB, BFB) on surface ECG .QRS, QTc, JTc interval were measured. Result: Mean QRS and QTc value were more for LBBB group as compared to RBBB and BFB group. But corrected JTc value was more or less equal in three groups. Post HOC analysis showed that there was no significant correlation of JTc interval between all the three groups. JTc interval was not found to be statistically significant indicating that repolarisation abnormality is minimum in both RBBB, LBBB and BFB group. Conclusion: JTc interval is not significantly high in LBBB patients indicating long QTcin LBBB is due to depolarization abnormality rather than repolarisation abnormality and not a predictor of arrhythmogenesis. [ABSTRACT FROM AUTHOR]