Developmental Deformity Due to scalloped Non‐Function in Drosophila Brain Leads to Cognitive Impairment

Neural identity and wiring specificity are fundamental to brain function. Factors affecting proliferation of the progenitor cells leading to an expansion or regression of specific neuronal clusters are expected to challenge the process of formation of precise synaptic connections with their partners and their further integration to result in proper functional neural circuitry. We have investigated the role of scalloped, a Hippo pathway gene in Drosophila brain development and have shown that its function is critical to regulate proliferation of Mushroom Body Neuroblasts and to limit the neuronal cluster size to normal in the fly brain. Here we investigate the consequent effect of the anatomical phenotype of mutant flies on the brain function, as exemplified by their cognitive performance. We demonstrate that the neural expansion in important neural clusters of the olfactory pathway, caused due to Scalloped inactivation, imparts severe disabilities in learning, short‐term memory and long‐term memory. Scalloped knockdown in αβ Kenyon Cell clusters drastically reduces long‐term memory performance. Scalloped deficiency induced neural expansion in antennal lobe and ellipsoid body neurons bring down short‐term memory performance significantly. We also demonstrate that the cognitive impairments observed here are not due to a problem in memory formation or execution in the adult, but are due to the developmental deformities caused in the respective class of neurons. Our results strongly indicate that the additional neurons generated by Scalloped inactivation are not synergistically integrated into, but rather perturb the formation of precise functional circuitry.     

Dissection of DNA Damage Responses Using Multiconditional Genetic Interaction Maps

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Highlights? A resource of genetic modules and networks induced by distinct types of DNA damage ? Networks distinguish DNA damage response pathways with high statistical power ? Rtt109, a histone acetyltransferase, affects the mutagenic bypass of DNA lesions ? The neddylation machinery and Irc21 affect cell-cycle control and genome stability     

p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice

In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase (Cdk) inhibitor 1B (commonly known as p27(kip1) or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27(-/-)) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27(+/+) mice. Moreover, in p27(-/-) ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27(-/-) ovaries was largely depleted, causing premature ovarian failure. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27(-/-) ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9-caspase-3-caspase-7-poly (ADP-ribose) polymeraseapoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans.     

MORC2 Interactome: Its Involvement in Metabolism and Cancer

Microrchidia 2 (MORC2) is an emerging chromatin modifier with a role in chromatin remodeling and epigenetic regulation. MORC2 is found to be upregulated in most cancers, playing a significant role in tumorigenesis and tumor metastasis. Recent studies have demonstrated that MORC2 is a scaffolding protein, which interacts with the proteins involved in DNA repair, chromatin remodeling, lipogenesis, and glucose metabolism. In this review, we discuss the domain architecture and cellular and subcellular localization of MORC2. Further, we highlight MORC2-specific interacting partners involved in metabolic reprogramming and other pathological functions such as cancer progression and metastasis.     

Abnormalities in carbohydrate and lipid metabolisms in high-fructose dietfed insulin-resistant rats: amelioration by Catharanthus roseus treatments

High intake of dietary fructose has been shown to exert a number of adverse metabolic effects in humans and experimental animals. The present study was proposed to elucidate the effect of Catharanthus roseus (C. roseus) leaf powder treatment on alterations in carbohydrate and lipid metabolisms in rats fed with high-fructose diet. Male Wistar rats of body weight around 180 g were divided into four groups, two of these groups (groups C and C+CR) were fed with standard pellet diet and the other two groups (groups F and F+CR) were fed with high-fructose (66 %) diet. C. roseus leaf powder suspension in water (100 mg/kg body weight/day) was administered orally to group C+CR and group F+CR. At the end of a 60-day experimental period, biochemical parameters related to carbohydrate and lipid metabolisms were assayed. C. roseus treatment completely prevented the fructose-induced increased body weight, hyperglycemia, and hypertriglyceridemia. Hyperinsulinemia and insulin resistance observed in group F was significantly decreased with C. roseus treatment in group F+CR. The alterations observed in the activities of enzymes of carbohydrate and lipid metabolisms and contents of hepatic tissue lipids in group F rats were significantly restored to near normal values by C. roseus treatment in group F+CR. In conclusion, our study demonstrates that C. roseus treatment is effective in preventing fructose-induced insulin resistance and hypertriglyceridemia while attenuating the fructose-induced alterations in carbohydrate and lipid metabolisms. This study suggests that the plant can be used as an adjuvant for the prevention and/or management of insulin resistance and disorders related to it.     

Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers

The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses −1 programmed ribosomal frameshifting (−1 PRF) to control the relative expression of viral proteins. As modulating −1 PRF can inhibit viral replication, the RNA pseudoknot stimulating −1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through junctions formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting −1 PRF in SARS-CoV-2.     

The ApoE gene of Alzheimer's disease (AD)

The ApoE gene responsible for the Alzheimer's disease has been examined to identify functional consequences of single-nucleotide polymorphisms (SNPs). Eighty-eight SNPs have been identified in the ApoE gene in which 31 are found to be nonsynonymous, 8 of them are coding synonymous, 33 are found to be in intron, and 3 are in untranslated region. The SNPs found in the untranslated region consisted of two SNPs from 5′ and one SNP from the 3′. Twenty-nine percent of the identified nsSNPs have been reported as damaging. In the analysis of SNPs in the UTR regions, it has been recognized that rs72654467 from 5′ and rs71673244 from 5′ and 3′ are responsible for the alteration in levels of expression. Both native and mutant protein structures were analyzed along with the stabilization residues. It has been concluded that among all SNPs of ApoE, the mutation in rs11542041 (R132S) has the most significant effect on functional variation.     

Ligand-based and structure-based approaches in identifying ideal pharmacophore against c-Jun N-terminal kinase-3

Structure and ligand based pharmacophore modeling and docking studies carried out using diversified set of c-Jun N-terminal kinase-3 (JNK3) inhibitors are presented in this paper. Ligand based pharmacophore model (LBPM) was developed for 106 inhibitors of JNK3 using a training set of 21 compounds to reveal structural and chemical features necessary for these molecules to inhibit JNK3. Hypo1 consisted of two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), and a hydrophobic (HY) feature with a correlation coefficient (r²) of 0.950. This pharmacophore model was validated using test set containing 85 inhibitors and had a good r² of 0.846. All the molecules were docked using Glide software and interestingly, all the docked conformations showed hydrogen bond interactions with important hinge region amino acids (Gln155 and Met149) and these interactions were compared with Hypo1 features. The results of ligand based pharmacophore model (LBPM) and docking studies are validated each other. The structure based pharmacophore model (SBPM) studies have identified additional features, two hydrogen bond donors and one hydrogen bond acceptor. The combination of these methodologies is useful in designing ideal pharmacophore which provides a powerful tool for the discovery of novel and selective JNK3 inhibitors.