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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]

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]

Conservation of genetic toolkits in disparate phyla may help reveal commonalities in organ designs transcending their extreme anatomical disparities. A male accessory sexual organ in mammals, the prostate, for instance, is anatomically disparate from its analogous, phylogenetically distant counterpart - the male accessory gland (MAG) - in insects like Drosophila. It has not been ascertained if the anatomically disparate Drosophila MAG shares developmental parallels with those of the mammalian prostate. Here we show that the development of Drosophila mesoderm-derived MAG entails recruitment of similar genetic toolkits of tubular organs like that seen in endoderm-derived mammalian prostate. For instance, like mammalian prostate, Drosophila MAG morphogenesis is marked by recruitment of fibroblast growth factor receptor (FGFR) - a signalling pathway often seen recruited for tubulogenesis - starting early during its adepithelial genesis. A specialisation of the individual domains of the developing MAG tube, on the other hand, is marked by the expression of a posterior Hox gene transcription factor, Abd-B, while Hh-Dpp signalling marks its growth. Drosophila MAG, therefore, reveals the developmental design of a unitary bud-derived tube that appears to have been co-opted for the development of male accessory sexual organs across distant phylogeny and embryonic lineages. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Spatiotemporal changes in epithelial cell sizes-or epithelial cell size dynamics (ECD)-during morphogenesis entail interplay between two opposing forces: cell contraction via actomyosin cytoskeleton and cell expansion via cell-cell adhesion. Cell-cell adhesion-based ECD, however, has not yet been clearly demonstrated. For instance, changing levels of homophilic E-cadherin-based cell-cell adhesion induce cell sorting, but not ECD. Here we show that cell-expansive forces of heterophilic cell-cell adhesion regulate ECD: higher cell-cell adhesion results in cell size enlargement. Thus, ECD during morphogenesis in the heminotal epithelia of Drosophila pupae leading to thorax closure corresponds with spatiotemporal gradients of two heterophilic atypical cadherins-Fat (Ft) and Dachsous (Ds)-and the levels of Ft-Ds heterodimers formed concomitantly. Our mathematical modeling and genetic tests validate this mechanism of dynamic heterophilic cell-cell adhesion-based regulation of ECD. Conservation of these atypical cadherins suggests a wider prevalence of heterophilic cell-cell adhesion-based ECD regulation during animal morphogenesis.

During animal development, selector genes determine identities of body segments and those of individual organs. Selector genes are also misexpressed in cancers, although their contributions to tumor progression per se remain poorly understood. Using a model of cooperative tumorigenesis, we show that gain of selector genes results in tumor cooperation, but in only select developmental domains of the wing, haltere and eye-antennal imaginal discs of Drosophila larva. Thus, the field selector, Eyeless (Ey), and the segment selector, Ultrabithorax (Ubx), readily cooperate to bring about neoplastic transformation of cells displaying somatic loss of the tumor suppressor, Lgl, but in only those developmental domains that express the homeo-box protein, Homothorax (Hth), and/or the Zinc-finger protein, Teashirt (Tsh). In non-Hth/Tsh-expressing domains of these imaginal discs, however, gain of Ey in lgl - somatic clones induces neoplastic transformation in the distal wing disc and haltere, but not in the eye imaginal disc. Likewise, gain of Ubx in lgl - somatic clones induces transformation in the eye imaginal disc but not in its endogenous domain, namely, the haltere imaginal disc. Our results reveal that selector genes could behave as tumor drivers or inhibitors depending on the tissue contexts of their gains., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)