The role of Rnd3 in keratinocytes

The skin is continuously being shed and therefore it is vital that it is renewed. Epidermal self-renewal is dependent on a population of keratinocyte stem cells (KSC) that reside in the basal layer. During epidermal regeneration, KSC divide asymmetrically giving rise to more stem cells as well as committed progenitors. Committed progenitors exit the cell cycle before going on to differentiate to form the highly resilient cells that make up the outermost layer. It is thought that committed progenitors and KSC are differentially regulated therefore allowing for such different behaviors. Rnd3 is an atypical GTPase that is constitutively active and has been previously shown to regulate keratinocyte differentiation. However, the identification of the molecular mechanism is currently unknown. The work presented here shows that Rnd3 depletion enriches for keratinocytes with a number of ‘stem-like’ phenotypes including reduced differentiation, reduced cell size, increased adhesion to ECM proteins and a deregulation of putative stem cell markers. Furthermore, using a quantitative proteomic approach, it can be seen that Rnd3 regulated the abundance of proteins involved in regulating stem cell function. This work proposes a function for Rnd3 in the regulation of key proteins involved keratinocyte differentiation and self-renewal

Antioxidants in the Management of Fluoride Induced Neural Oxidative Stress in Developing Rats

Fluoride (F) is highly electronegative anion with cumulative toxic effects, from prolonged ingestion that can lead to the pathogenesis known as fluorosis, a condition especially persistent in third world countries, where populations have little choice as to the main source of F-contaminated drinking. In recent times many neurological problems among children are being addressed in endemic areas. Thereby reasons for the neurotoxicity have to be explicated thoroughly. In this study premated Wistar albino rats were exposed to 50 and 150 ppm fluoride in drinking water during gestation and pups born to them were used to analyze the extent of neurotoxicity imposed in discrete brain areas. Dose dependent toxicity was evident in different brain regions and fluoride exposure has significantly enhanced the levels of malondialdehyde (P>0.05), glutathione (P>0.05) and decreased the activities of superoxide dismutase (P>0.05), catalase (P>0.05), glutathione peroxidase (P>0.05) and glutathione- S-transferase (P>0.05). Alterations were region specific and oral supplementation of dietary antioxidants viz., vitamin-C (20mg), vitamin-E (400.g), zinc (200.g) and selenium (40.g) not only inhibited oxidative stress but also enhanced the activity of antioxidant enzymes. Thereby supplementation of antioxidants to toxicated animals significantly overcame toxic burden imposed by fluoride and therefore may be a therapeutic strategy for fluorotic victims

Permethrin induced neuronal inefficiency in the supraoesophageal ganglion of mulberry silkworm, Bombyx mori. L

The primary target for pyrethroid insecticides is the nervous system. Available literature on the toxicity of pyrethroids to mulberry silkworm, are confined to specific tissues like haemolymph, fat body, eggs of silk moth and no study is indicated on supraoesophageal ganglion tissue, hence this study was conducted. In this study the changes occurring in the level of cholinergic and GABAergic transmitters (ACh and GABA)​; their connected enzymes viz., ChAT, AChE, GAD were studied in the supraoesophageal ganglionic tissue of silkworm Bombyx mori upon permithrin intoxication. Findings indicate that suppression of acetyl cholinesterase has led to the accumulation of ACh in greater quantities. Contrary to the cholinesterase suppression, a profound increase in GABAergic system was evident in the nervous tissue suggesting existence of an imbalance of excitatory-​inhibitory interplay in the supraoesophageal ganglia due to the toxic insult caused by permethrin; this substantially affects the growth, development, fecundity and silk prodn. In conclusion, the permethrin induced neurotoxicity resulted a series of perturbations in silkworm neurotransmitter metab

Evaluation of Fluoride-​Induced Oxidative Stress in Rat Brain: A Multigeneration Study

Multigenerational evaluation was made in rats on exposure to high fluoride (100 and 200 ppm) to assess neurotoxic potential of fluoride in discrete areas of the brain in terms of lipid peroxidn. and the activity of antioxidant enzyme system. The rats were given fluoride through drinking water (100 and 200 ppm) and maintained subsequently for three generations. Fluoride treatment significantly increased the lipid peroxidn. and decreased the activity of antioxidant enzymes viz, catalase, superoxide dismutase, glutathione peroxidase, glutathione S-​transferase, and glutathione level in first-​generation rats and these alterations were more pronounced in the subsequent second and third-​generation rats in both the doses tested. Decreased feed and water consumption, litter size and organ (brain) somatic index, marginal drop in body growth rate and mortality were obsd. in all three generations. Decreased antioxidant enzyme activity and increased malondialdehyde levels found in the present study might be related to oxidative damage that occurs variably in discrete regions of the brain. Results of this study can be taken as an index of neurotoxicity in rats exposed to water fluoridation over several generations

On your marks, get SET(D1A)::the race to protect stalled replication forks

We recently identified that methylation of lysine 4 of histone H3 (H3K4) by SETD1A (SET domain containing 1A) maintains genome stability by protecting newly-replicated DNA from degradation. Mechanistically, SETD1A-dependent histone methylation regulates nucleosome mobilisation by FANCD2 (FA complementation group D2), a crucial step in maintaining genome integrity with important implications in chemo-sensitivity

CYBER SECURITY AND RISK MANAGEMENT: SAFEGUARDING ORGANIZATIONS IN THE DIGITAL AGE

Cyber security helps the organization to protect the organizational data from external users. The development of an effective cyber security system is important as this helps the organization to enhance the data safety system. The secondary data collection process has been used for analyzing the most affected factors that affect the security system of an organization. On the other hand, qualitative analysis helps to know the all interrelated factors related to the data safety and risk management system. System theory helps to analyze the ways to develop a better protective system for enhancing the protection of organizational data. The use of centralized servers, double-protected passwords and network security and access control is important for developing a stronger security system in an organization.&nbsp

Quantitative Phosphoproteomics Reveals a Role for Collapsin Response Mediator Protein 2 in PDGF-Induced Cell Migration

AbstractThe Platelet Derived Growth Factor (PDGF) family of ligands have well established functions in the induction of cell proliferation and migration during development, tissue homeostasis and interactions between tumours and stroma. However, the mechanisms by which these actions are executed are incompletely understood. Here we report a differential phosphoproteomics study, using a SILAC approach, of PDGF-stimulated mouse embryonic fibroblasts (MEFs). 116 phospho-sites were identified as up-regulated and 45 down-regulated in response to PDGF stimulation. These encompass proteins involved in cell adhesion, cytoskeleton regulation and vesicle-mediated transport, significantly expanding the range of proteins implicated in PDGF signalling pathways. Included in the down-regulated class was the microtubule bundling protein Collapsin Response Mediator Protein 2 (CRMP2). In response to stimulation with PDGF, CRMP2 was dephosphorylated on Thr514, an event known to increase CRMP2 activity. This was reversed in the presence of micromolar concentrations of the protein phosphatase inhibitor okadaic acid, implicating PDGF-induced activation of protein phosphatase 1 (PP1) in CRMP2 regulation. Depletion of CRMP2 resulted in impairment of PDGF-mediated cell migration in an in vitro wound healing assay. These results show that CRMP2 is required for PDGF-directed cell migration in vitro.</jats:p

Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks

Immunological imprinting of humoral immunity to SARS-CoV-2 in children

Omicron variants of SARS-CoV-2 are globally dominant and infection rates are very high in children. We measure immune responses following Omicron BA.1/2 infection in children aged 6-14 years and relate this to prior and subsequent SARS-CoV-2 infection or vaccination. Primary Omicron infection elicits a weak antibody response with poor functional neutralizing antibodies. Subsequent Omicron reinfection or COVID-19 vaccination elicits increased antibody titres with broad neutralisation of Omicron subvariants. Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primes for robust antibody responses following Omicron infection but these remain primarily focussed against ancestral variants. Primary Omicron infection thus elicits a weak antibody response in children which is boosted after reinfection or vaccination. Cellular responses are robust and broadly equivalent in all groups, providing protection against severe disease irrespective of SARS-CoV-2 variant. Immunological imprinting is likely to act as an important determinant of long-term humoral immunity, the future clinical importance of which is unknown