‘Kinesinopathies’: emerging role of the kinesin family member genes in birth defects

Motor kinesins are a family of evolutionary conserved proteins involved in intracellular trafficking of various cargoes, first described in the context of axonal transport. They were discovered to have a key importance in cell-cycle dynamics and progression, including chromosomal condensation and alignment, spindle formation and cytokinesis, as well as ciliogenesis and cilia function. Recent evidence suggests that impairment of kinesins is associated with a variety of human diseases consistent with their functions and evolutionary conservation. Through the advent of gene identification using genome-wide sequencing approaches, their role in monogenic disorders now emerges, particularly for birth defects, in isolated as well as multiple congenital anomalies. We can observe recurrent phenotypical themes such as microcephaly, certain brain anomalies, and anomalies of the kidney and urinary tract, as well as syndromic phenotypes reminiscent of ciliopathies. Together with the molecular and functional data, we suggest understanding these ‘kinesinopathies’ as a recognisable entity with potential value for research approaches and clinical care.

Ozenoxacin: A Novel Drug Discovery for the Treatment of Impetigo

Objective: Ozenoxacin is one of the potent quinolone antibiotics, recently approved by the United States Food and Drug Administration (USFDA) with reported pharmacology to treat the impetigo. The demand for better acting topical formulation is increasing day by day. The present review is an attempt to summarize the facts behind the chemistry and biological applications of Ozenoxacin. Mechanism of Action: This novel drug being a quinolone antibiotic compound, acts by inhibiting DNA gyrase A and topoisomerase IV and affects supercoiling, supercoil relaxation, chromosomal condensation, chromosomal decatenation and many others. Mechanism of Action: This novel drug being a quinolone antibiotic compound, acts by inhibiting DNA gyrase A and topoisomerase IV and affects supercoiling, supercoil relaxation, chromosomal condensation, chromosomal decatenation and many others. Pharmacology: Ozenoxacin has demonstrated to have a bactericidal activity against organisms, such as Staphylococcus aureus and Staphylococcus pyogenes. Ozenoxacin is non-fluorinated quinolone and being developed for the other dermatological bacterial infections as well. No sign of genotoxicity was observed when tested experimentally. Conclusion: The present review also covers the complete picture of pharmacokinetics, clinical trials, toxicity and future scope and possible avenues in this arena.

Chromosomal condensation leads to a preference for peripheral heterochromatin

ABSTRACTA layer of dense heterochromatin is found at the periphery of the nucleus. Because this peripheral heterochromatin functions as a repressive phase, mechanisms that relocate genes to the periphery play an important role in regulating transcription. Using Monte-Carlo simulations, we show that an interaction between chromatin and the nuclear boundary need not be specific to heterochromatin in order to preferentially locate heterochromatin to the nuclear periphery. This observation considerably broadens the class of possible interactions that result in peripheral positioning to include boundary interactions that either weakly attract all chromatin or strongly bind to a randomly chosen small subset of loci. The key distinguishing feature of heterochromatin is its high chromatin density with respect to euchromatin. In our model this densification is caused by HP1’s preferential binding to H3K9me3 marked histone tails. We conclude that factors that are themselves unrelated to the nuclear periphery can determine which genomic regions condense to form heterochromatin and thereby control which regions are relocated to the periphery.

Non-Toxic and Ultra-Small Biosilver Nanoclusters Trigger Apoptotic Cell Death in Fluconazole-Resistant Candida albicans via Ras Signaling

Silver-based nanostructures are suitable for many biomedical applications, but to be useful therapeutic agents, the high toxicity of these nanomaterials must be eliminated. Here, we biosynthesize nontoxic and ultra-small silver nanoclusters (rsAg@NCs) using metabolites of usnioid lichen (a symbiotic association of algae and fungi) that exhibit excellent antimicrobial activity against fluconazole (FCZ)-resistant Candida albicans that is many times higher than chemically synthesized silver nanoparticles (AgNPs) and FCZ. The rsAg@NCs trigger apoptosis via reactive oxygen species accumulation that leads to the loss of mitochondrial membrane potential, DNA fragmentation, chromosomal condensation, and the activation of metacaspases. The proteomic analysis clearly demonstrates that rsAg@NCs exposure significantly alters protein expression. Most remarkable among the down-regulated proteins are those related to glycolysis, metabolism, free radical scavenging, anti-apoptosis, and mitochondrial function. In contrast, proteins involved in plasma membrane function, oxidative stress, cell death, and apoptosis were upregulated. Eventually, we also established that the apoptosis-inducing potential of rsAg@NCs is due to the activation of Ras signaling, which confirms their application in combating FCZ-resistant C. albicans infections.