Temporal analysis of melanogenesis identifies fatty acid metabolism as key skin pigment regulator.

Therapeutic methods to modulate skin pigmentation has important implications for skin cancer prevention and for treating cutaneous hyperpigmentary conditions. Towards defining new potential targets, we followed temporal dynamics of melanogenesis using a cell-autonomous pigmentation model. Our study elucidates 3 dominant phases of synchronized metabolic and transcriptional reprogramming. The melanogenic trigger is associated with high MITF levels along with rapid uptake of glucose. The transition to pigmented state is accompanied by increased glucose channelisation to anabolic pathways that support melanosome biogenesis. SREBF1-mediated up-regulation of fatty acid synthesis results in a transient accumulation of lipid droplets and enhancement of fatty acids oxidation through mitochondrial respiration. While this heightened bioenergetic activity is important to sustain melanogenesis, it impairs mitochondria lately, shifting the metabolism towards glycolysis. This recovery phase is accompanied by activation of the NRF2 detoxication pathway. Finally, we show that inhibitors of lipid metabolism can resolve hyperpigmentary conditions in a guinea pig UV-tanning model. Our study reveals rewiring of the metabolic circuit during melanogenesis, and fatty acid metabolism as a potential therapeutic target in a variety of cutaneous diseases manifesting hyperpigmentary phenotype.

Sustained pigmentation causes DNA damage and invokes translesion polymerase Polκ for repair in melanocytes.

Melanin protects skin cells from ultraviolet radiation-induced DNA damage. However, intermediates of eumelanin are highly reactive quinones that are potentially genotoxic. In this study, we systematically investigate the effect of sustained elevation of melanogenesis and map the consequent cellular repair response of melanocytes. Pigmentation increases γH2AX foci, DNA abasic sites, causes replication stress and invokes translesion polymerase Polκ in primary human melanocytes, as well as mouse melanoma cells. Confirming the causal link, CRISPR-based genetic ablation of tyrosinase results in depigmented cells with low Polκ levels. During pigmentation, Polκ activates replication stress response and keeps a check on uncontrolled proliferation of cells harboring melanin-damaged DNA. The mutational landscape observed in human melanoma could in part explain the error-prone bypass of DNA lesions by Polκ, whose absence would lead to genome instability. Thereby, translesion polymerase Polκ is a critical response of pigmenting melanocytes to combat melanin-induced DNA alterations. Our study illuminates the dark side of melanin and identifies (eu)melanogenesis as a key missing link between tanning response and mutagenesis, mediated via the necessary evil translesion polymerase, Polκ.

Kupyaphores are zinc homeostatic metallophores required for colonization of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) endures a combination of metal scarcity and toxicity throughout the human infection cycle, contributing to complex clinical manifestations. Pathogens counteract this paradoxical dysmetallostasis by producing specialized metal trafficking systems. Capture of extracellular metal by siderophores is a widely accepted mode of iron acquisition, and Mtb iron-chelating siderophores, mycobactin, have been known since 1965. Currently, it is not known whether Mtb produces zinc scavenging molecules. Here, we characterize low-molecular-weight zinc-binding compounds secreted and imported by Mtb for zinc acquisition. These molecules, termed kupyaphores, are produced by a 10.8 kbp biosynthetic cluster and consists of a dipeptide core of ornithine and phenylalaninol, where amino groups are acylated with isonitrile-containing fatty acyl chains. Kupyaphores are stringently regulated and support Mtb survival under both nutritional deprivation and intoxication conditions. A kupyaphore-deficient Mtb strain is unable to mobilize sufficient zinc and shows reduced fitness upon infection. We observed early induction of kupyaphores in Mtb-infected mice lungs after infection, and these metabolites disappeared after 2 wk. Furthermore, we identify an Mtb-encoded isonitrile hydratase, which can possibly mediate intracellular zinc release through covalent modification of the isonitrile group of kupyaphores. Mtb clinical strains also produce kupyaphores during early passages. Our study thus uncovers a previously unknown zinc acquisition strategy of Mtb that could modulate host-pathogen interactions and disease outcome.

Amyloid-Beta Peptides 40 and 42 Employ Distinct Molecular Pathways for Cell Entry and Intracellular Transit at the Blood-Brain Barrier Endothelium.

The blood-brain barrier (BBB) plays a critical role in maintaining the equilibrium between amyloid beta (Aß) levels in blood and the brain by regulating Aß transport. Our previous publications demonstrated that BBB trafficking of Aß42 and Aß40 is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle Aß40 and Aß42 have not been clearly elucidated. In this study, we identified mechanisms of Aß endocytosis in polarized human cerebral microvascular endothelial cell monolayers. Our studies demonstrated that Aß peptides with fluorescent label (F-Aß) were internalized by BBB endothelial cells via energy, dynamin, and actin-dependent endocytosis. Interestingly, endocytosis of F-Aß40 but not F-Aß42 was substantially reduced by clathrin inhibition, whereas F-Aß42 but not F-Aß40 endocytosis was reduced by half after inhibiting the caveolae-mediated pathway. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. Although Aß42 was shown to accumulate more in the lysosomes, which could lead to its higher degradation and/or aggregation at lower lysosomal pH, Aß40 demonstrated robust accumulation in recycling endosomes, which may facilitate its exocytosis by the endothelial cells. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport Aß40 versus Aß42. This knowledge contributes to the understanding of molecular pathways underlying Aß accumulation in the BBB endothelium and associated BBB dysfunction. Moreover, it allows us to establish mechanistic rationale for altered Aß40:Aß42 ratios and anomalous amyloid deposition in the cerebral vasculature as well as brain parenchyma during Alzheimer's disease progression. SIGNIFICANCE STATEMENT: Differential interaction of Aß40 and Aß42 isoforms with the blood-brain barrier (BBB) endothelium may contribute to perturbation in Aß42:Aß40 ratio, which is associated with Alzheimer's disease (AD) progression and severity. The current study identified distinct molecular pathways by which Aß40 and Aß42 are trafficked at the BBB, which regulates equilibrium between blood and brain Aß levels. These findings provide molecular insights into mechanisms that engender BBB dysfunction and promote Aß accumulation in AD brain.

Histone variant dictates fate biasing of neural crest cells to melanocyte lineage.

In the neural crest lineage, progressive fate restriction and stem cell assignment are crucial for both development and regeneration. Whereas fate commitment events have distinct transcriptional footprints, fate biasing is often transitory and metastable, and is thought to be moulded by epigenetic programmes. Therefore, the molecular basis of specification is difficult to define. In this study, we established a role for a histone variant, H2a.z.2, in specification of the melanocyte lineage from multipotent neural crest cells. H2a.z.2 silencing reduces the number of melanocyte precursors in developing zebrafish embryos and from mouse embryonic stem cells in vitro We demonstrate that this histone variant occupies nucleosomes in the promoter of the key melanocyte determinant mitf, and enhances its induction. CRISPR/Cas9-based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby, our study establishes the role of a histone variant upstream of the core gene regulatory network in the neural crest lineage. This epigenetic mark is a key determinant of cell fate and facilitates gene activation by external instructive signals, thereby establishing melanocyte fate identity.

Rheometric and stability analysis of additive infused magnetorheological fluids: a comparative study.

Magnetorheological fluid (MRF) is a smart responsive fluid, when exposed to the magnetic field, reflects a noticeable transformation in fluid viscosity due to the presence of field responsive particles in the fluid. MRF has been utilized in variety of applications, which despite possess significant concerns regarding on sedimentation due to the density mismatch between the carrier fluid and the suspended magnetic particles. To improve the resistance of rapid sedimentation, this research aims to incorporate one of the component (additive/surfactants) blended into the fluid. The objective of the study focuses to determine the efficient incorporate-infused fluid for further application and sedimentation resistance. In this study, MRF is infused with siloxane, lithium, oleic acid and SDBS (Sodium Dodecyl Benzene Sulfonate) as additive and surfactants along with silicon oil as a carrier fluid. The significant repercussion parameters such as rheology behavior of the samples, temperature and particle sedimentation has been examined and interpreted. Substantially, the effective sample and performance has been comprehended with the insightful comparative results obtained.

Polyketide Quinones Are Alternate Intermediate Electron Carriers during Mycobacterial Respiration in Oxygen-Deficient Niches.

Mycobacterium tuberculosis (Mtb) adaptation to hypoxia is considered crucial to its prolonged latent persistence in humans. Mtb lesions are known to contain physiologically heterogeneous microenvironments that bring about differential responses from bacteria. Here we exploit metabolic variability within biofilm cells to identify alternate respiratory polyketide quinones (PkQs) from both Mycobacterium smegmatis (Msmeg) and Mtb. PkQs are specifically expressed in biofilms and other oxygen-deficient niches to maintain cellular bioenergetics. Under such conditions, these metabolites function as mobile electron carriers in the respiratory electron transport chain. In the absence of PkQs, mycobacteria escape from the hypoxic core of biofilms and prefer oxygen-rich conditions. Unlike the ubiquitous isoprenoid pathway for the biosynthesis of respiratory quinones, PkQs are produced by type III polyketide synthases using fatty acyl-CoA precursors. The biosynthetic pathway is conserved in several other bacterial genomes, and our study reveals a redox-balancing chemicocellular process in microbial physiology.

Effects of cyclic loading on loss of abutment screw torque of angled screw channel single implant crowns on narrow diameter implants.

STATEMENT OF PROBLEM: Screw access channels that emerge on the facial aspect of anterior screw-retained implant crowns can compromise esthetics. Recently, angled screw channels (ASCs) have been developed that can alter screw access channel angulations to improve esthetics. While ASCs can be used on narrow-diameter implants, information is limited on the loss of abutment screw torque on narrow-diameter implants with ASCs. PURPOSE: The purpose of this in vitro study was to compare the loss of abutment screw torque after thermocycling and the cyclic loading of ASCs from 3 different companies connected to narrow-diameter implants. MATERIAL AND METHODS: A total of 40 narrow-diameter implants (NobelReplace Conical Connection 3.5×11.5 mm) were mounted individually in acrylic resin blocks and divided equally into 4 groups. The first group, NB-0 (Control), consisted of screw-retained zirconia crowns fabricated on ASCs at 0-degree angulation (n=10). The other 3 groups consisted of a total of 30 screw-retained zirconia crowns fabricated on ASCs at 20-degree angulation: NB-20 (Angulated Screw Channel Solutions), ATL-20 (Atlantis Custom Base Solution with angulated screw access), and DA-20 (Dynamic TiBase). Each crown was secured on the mounted implant with its corresponding titanium base insert and screw and then tightened to the manufacturer's recommended torque with a digital torque gauge. The initial reverse torque value (RTVI) was obtained and recorded at baseline. Subsequently, a new set of screws were tightened to recommended values, and each specimen underwent thermocycling and then cyclic loading at 0 to 100 N at 10 Hz for 1 million cycles to simulate 1year of functional loading. After cyclic loading, the final reverse torque values (RTVF) were recorded and compared with the RTVI to evaluate the percentage torque loss (PTLF). Statistical analysis was performed using the Kruskal-Wallis analysis, Rank base analysis of covariance (ANCOVA), and the Tukey HSD post hoc comparisons (α=.05). RESULTS: Significant differences were found for the PTLF among all groups after cyclic loading (P<.001). The PTLF in ATL-20 (51.4%) was significantly higher than in NB-0 (22.2%) (P<.001) and NB-20 (29.2%) (P=.010). No significant difference was found in the PTLF among other groups (P>.05). CONCLUSIONS: The abutment screw torque loss after cyclic loading of the ASCs on narrow diameter implants among the 4 groups did not perform comparably. The largest percentage torque loss was recorded for the ATL-20 group. The NB-20 group demonstrated the lowest percentage torque loss. DA-20 showed percentage torque loss less than ATL-20; however, its RTVF was the lowest.

Comparison of different QT correction methods for nonclinical safety assessment in ketamine-anesthetized Indian rhesus monkeys (Macaca mulatta).

Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs. As heart rate and QT interval have an inverse relationship, any change in heart rate causes a subsequent change in QT interval. This warrants for calculation of a corrected QT interval. This study aimed to identify an appropriate formula that best corrected QT for change in heart rate. We employed seven formulas based on source-species type, clinical relevance, and requirements of various international regulatory guidelines. Data showed that corrected QT interval values varied drastically for different correction formulas. Equations were compared on their slope values based on QTc versus RR plots. The rank order of the slope for different formulas was (closest to farthest from zero) QTcNAK, QTcHAS, QTcBZT, QTcFRD, QTcVDW, QTcHDG, and QTcFRM. QTcNAK emerged to be the best correcting formula in this study. It showed the least correlation with the RR interval (r = -0.01) and displayed no significant difference amongst the sexes. As there is no universally recognized formula for preclinical use, the authors recommend developing a best-case scenario model for specific study designs and individual organizations. The data from this research will be helpful in deciding an appropriate QT correction formula for the safety assessment of new pharmaceuticals and biologics.

Assessment of Toxicity of Green Synthesized Silver Nanoparticle-coated Titanium Mini-implants with Uncoated Mini-implants: Comparison in an Animal Model Study.

AIM: To assess the potential for systemic toxicity when silver nanoparticle-coated mini-implants were implanted in Wistar albino rats conducted as a comparative study in the animal model by assessing the blood biochemistry, liver and kidney function, and histology of the implanted site. MATERIALS AND METHODS: The surface of the mini-implant was coated with a green-mediated silver nanoparticle. Uncoated mini-implants were placed in two groups of eight Wistar albino rats, and silver nanoparticle-coated mini-implants were placed in another eight rats. The bone's general conditions, blood biochemistry assessing for ALT, AST, GPT, GOT, and histological sections using H and E stain and Masson's Trichrome stain were examined at 7, 14, and 28-day intervals. RESULTS: The creatinine, urea, ALP, and ALT showed no signs of systemic toxicity during the 28-day follow-up period in the Wistar rats both in the test and control groups. The histological evaluation, which was conducted using HE and MTS stain, revealed osteogenesis and adequate healing of the insertion site in the group where coated mini-implant was placed. The bone sample revealed no abnormalities in the control group with uncoated mini-implants. CONCLUSION: Green synthesized silver nanoparticle-coated mini-implant does not cause systemic toxicity as indicated by no abnormalities in the levels of creatinine, urea, ALT, ALP, GPT, and GOT. The bone histology indicates that the coated mini-implants placed in animal bone healed with adequate osteogenesis. CLINICAL SIGNIFICANCE: Silver nanoparticles have potential for antimicrobial activity. Mini-implants placed as temporary anchorage devices in orthodontics often fail due to inflammation and plaque. Silver nanoparticle-coated mini-implants would reduce the risk of mini-implant failure as it would have antimicrobial potential and eliminate this cause for failure of mini-implants. How to cite this article: Sreenivasagan S, Subramanian AK, Mohanraj KG, et al. Assessment of Toxicity of Green Synthesized Silver Nanoparticle-coated Titanium Mini-implants with Uncoated Mini-implants: Comparison in an Animal Model Study. J Contemp Dent Pract 2023;24(12):944-950.

A comprehensive update on the use of optical coherence tomography angiography in glaucoma.

PURPOSE: The primary purpose of this review is to provide a comprehensive summary on the technical principles of OCTA and to enumerate vascular parameters being explicated for glaucoma diagnosis and progression with emphasis on recent studies. In addition, the authors also summarize the future clinical potentials of OCTA in glaucoma and enumerate the limitations of this imaging modality in the present-day scenario. METHODS: The index study is a narrative review on OCTA in glaucoma. The authors searched the PubMed database using the key phrases ''optical coherence tomography angiography" AND "glaucoma,'' AND/OR "vascular parameters" AND/OR "ocular perfusion." Being a relatively recent development in ocular imaging, studies in which OCTA imaging had been used for glaucoma evaluation since 2012 were included until March 2022. The literature search included original studies and previous review articles, while case reports were excluded. Preliminary search was based on relevant articles with search keywords in the title and abstract. The second screening was performed by reading the full text of the literature. RESULTS: Recent studies indicate reduction in microcirculation in glaucomatous eyes compared to the normal subjects. The area of interest for glaucoma evaluation using OCTA varies among the different studies. Based on the literature reviewed here, (1) OCTA parameters measured in the peripapillary; ONH and macular area have been shown to differentiate between glaucoma and normal eyes with a discriminatory power comparable to OCT parameters used routinely in clinics, (2) monitoring of peripapillary and macular vessel density may provide important information to the evaluation of glaucoma progression and prediction of rates of disease worsening, (3) studies suggest strong correlation between the OCTA parameters, the OCT parameters and visual function, measured by visual field testing, in glaucomatous eyes, (4) future prospects of OCTA in glaucoma evaluations using AI predicting structural and functional features and prognosis based on early vascular findings would open up scope for early detection of high-risk suspects and fast progressors in glaucoma. CONCLUSION: OCTA can be useful in quantifying vascular parameters in the optic disc, peripapillary and the macular regions for glaucoma evaluation. OCTA shows potential to become a part of everyday glaucoma management.

Suppression of perioperative stress response in elective abdominal surgery: A randomized comparison between dexmedetomidine and epidural block.

Background and Aims: Stress response after surgery induces local and systemic inflammation which may be detrimental if it goes unchecked. Blockade of afferent neurons or inhibition of hypothalamic function may mitigate the stress response. Material and Methods: A total of 50 consenting adult ASA I/II patients undergoing elective abdominal surgery were randomized to receive either dexmedetomidine (Group D) or epidural bupivacaine (Group E) in addition to balanced general anesthesia. Laparoscopic surgery, contraindications to epidural administration, history of psychiatric disorders, obesity (BMI >30 kg/m2), on beta blockers or continuous steroid therapy for >5 days over last 1 year, and known case of endocrine abnormalities or malignancy were excluded. Serum cortisol, blood glucose, and blood urea were estimated. Hemodynamic parameters, total dose of dexmedetomidine, bupivacaine, emergence characteristics, and analgesic consumption over 24 h postoperatively were recorded. Statistical comparisons were done using Student's t-test, repeated measure analysis of variance followed by Dunnett's test, generalized linear model and Chi-square/Fisher's exact test. A P value <0.05 was considered significant. Results: Serum cortisol levels were significantly lower in group E than group D 24 h after surgery (P = 0.029). Intraoperative and postoperative glucose level was lower in group E compared with group D. Time to request of first rescue analgesic was longer in group E than group D (P = 0.040). There was no significant difference between the number of doses of paracetamol required in the postoperative period (P = 0.198). Conclusion: Epidural bupivacaine was more effective than intravenous dexmedetomidine for suppression of neuroendocrine and metabolic response to surgery. Dexmedetomidine provided better hemodynamic stability at the time of noxious stimuli and postoperatively.

STIM1 activation of adenylyl cyclase 6 connects Ca2+ and cAMP signaling during melanogenesis.

Endoplasmic reticulum (ER)-plasma membrane (PM) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca2+ levels has been uncovered in recent years, the functional significance of ER-PM junctions in non-excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM1 (stromal interaction molecule 1) interacts with the plasma membrane-localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis. The physiological stimulus α-melanocyte-stimulating hormone (αMSH) depletes ER Ca2+ stores, thus recruiting STIM1 to ER-PM junctions, which in turn activates ADCY6. Using zebrafish as a model system, we further established STIM1's significance in regulating pigmentation in vivo STIM1 domain deletion studies reveal the importance of Ser/Pro-rich C-terminal region in this interaction. This mechanism of cAMP generation creates a positive feedback loop, controlling the output of the classical αMSH-cAMP-MITF axis in melanocytes. Our study thus delineates a signaling module that couples two fundamental secondary messengers to drive pigmentation. Given the central role of calcium and cAMP signaling pathways, this module may be operative during various other physiological processes and pathological conditions.

The Singapore Asymptomatic Narrow Angles Laser Iridotomy Study: Five-Year Results of a Randomized Controlled Trial.

PURPOSE: To examine the efficacy of laser peripheral iridotomy (LPI) in patients who received a diagnosis of primary angle-closure suspect (PACS). DESIGN: Prospective, randomized controlled trial. PARTICIPANTS: This multicenter, randomized controlled trial (ClinicalTrials.gov identifier, NCT00347178) enrolled 480 patients older than 50 years from glaucoma clinics in Singapore with bilateral asymptomatic PACS (defined as having ≥2 quadrants of appositional angle closure on gonioscopy). METHODS: Each participant underwent prophylactic LPI in 1 randomly selected eye, whereas the fellow eye served as a control. Patients were followed up yearly for 5 years. MAIN OUTCOME MEASURES: The primary outcome measure was development of primary angle closure (PAC; defined as presence of peripheral anterior synechiae, intraocular pressure [IOP] of >21 mmHg, or both or acute angle closure [AAC]) or primary angle-closure glaucoma (PACG) over 5 years. RESULTS: Of the 480 randomized participants, most were Chinese (92.7%) and were women (75.8%) with mean age of 62.8 ± 6.9 years. Eyes treated with LPI reached the end point less frequently after 5 years (n = 24 [5.0%]; incidence rate [IR], 11.65 per 1000 eye-years) compared with control eyes (n = 45 [9.4%]; IR, 21.84 per 1000 eye-years; P = 0.001). The adjusted hazard ratio (HR) for progression to PAC was 0.55 (95% confidence interval [CI], 0.37-0.83; P = 0.004) in LPI-treated eyes compared with control eyes. Older participants (per year; HR, 1.06; 95% CI, 1.03-1.10; P < 0.001) and eyes with higher baseline IOP (per millimeter of mercury; HR, 1.35; 95% CI, 1.22-1.50; P < 0.0001) were more likely to reach an end point. The number needed to treat to prevent an end point was 22 (95% CI, 12.8-57.5). CONCLUSIONS: In patients with bilateral asymptomatic PACS, eyes that underwent prophylactic LPI reached significantly fewer end points compared with control eyes over 5 years. However, the overall incidence of PAC or PACG was low.

pH-controlled histone acetylation amplifies melanocyte differentiation downstream of MITF.

Tanning response and melanocyte differentiation are mediated by the central transcription factor MITF. This involves the rapid and selective induction of melanocyte maturation genes, while concomitantly the expression of other effector genes is maintained. In this study, using cell-based and zebrafish model systems, we report on a pH-mediated feed-forward mechanism of epigenetic regulation that enables selective amplification of the melanocyte maturation program. We demonstrate that MITF activation directly elevates the expression of the enzyme carbonic anhydrase 14 (CA14). Nuclear localization of CA14 leads to an increase of the intracellular pH, resulting in the activation of the histone acetyl transferase p300/CBP. In turn, enhanced H3K27 histone acetylation at selected differentiation genes facilitates their amplified expression via MITF. CRISPR-mediated targeted missense mutation of CA14 in zebrafish results in the formation of immature acidic melanocytes with decreased pigmentation, establishing a central role for this mechanism during melanocyte differentiation in vivo. Thus, we describe an epigenetic control system via pH modulation that reinforces cell fate determination by altering chromatin dynamics.

Neuroprotective effect of quercetin against rotenone-induced neuroinflammation and alterations in mice behavior.

Various studies suggested that neuroinflammation leads to the development of several neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Rotenone is an organic pesticide and potent inhibitor of complex I of electron transport chain widely used to develop the PD model. Numerous studies reported rotenone toxicity in the dopaminergic system but very few studies are available on rotenone-induced glial cell activation and subsequent neurodegeneration and alterations in various types of behavior. Therefore, the present study was designed to explore the effect of rotenone on neuroinflammation and its deleterious effect on the behavior of mice, and also how these effects can be protected through quercetin. Quercetin, a natural flavonoid having strong antioxidant and anti-inflammatory properties, is found in vegetables and fruits. The finding of the study indicated that rotenone 5 mg/kg body weight for 60 days through oral gavage leads to the release of inflammatory markers in blood serum, astrocytes activation in substantia nigra and hippocampus, and subsequently decreased density of dopaminergic fibers in the striatum. Rotenone also altered the memory of the mice as indicated by decreased spontaneous alteration in Y-maze and T-maze tests and reduction in exploration time in novel object recognition, increased immobility time in the forced swim test and reduced muscular strength. Co-treatment of quercetin 30 mg/kg/day through oral gavage for 60 days along with rotenone significantly reversed all these adverse effects, suggesting that quercetin could reduce neuroinflammation, and improve memory, and cognitive function.

Biomimetic synthesis of silver nanoparticles for treatment of N-Nitrosodiethylamine-induced hepatotoxicity.

The development of bioengineered nanoparticles has attracted considerable universal attention in the field of medical science and disease treatment. Current studies were executed to evaluate the hepatoprotective activity of biosynthesized silver nanoparticles (AgNPs). Their characterization was performed by UV-Visible analysis, fourier transform infrared spectroscopy, transmission electron microscopy (TEM), scanning electron microscope (SEM), and Zeta analyses. In in vivo studies, albino rats (180 ± 10 g) were persuaded with model hepatic toxicant N-nitrosodiethylamine (NDEA) and subsequently cotreated with Morus multicaulis at 100 mg/kg and AgNPs at 100 µg/kg dose. NDEA administration elevates the levels of liver function test biomarkers, which were reinstated to normal by cotreatment of test drugs. The oxidative stress and concentration of drug-metabolizing enzyme increase after induction of toxicant (NDEA), these markers are restored toward normal after cotreatment of nano-drug. Treatments of M. multicaulis extract did not show such significant protection. The NDEA-treated groups showed a significant rise in the level of cytokines (interleukin [IL-6] and IL-10) and reached normal with subsequent treatment with AgNPs. Histopathological studies also exhibited the curative effect of AgNPs in the same manner. Thus current results strongly suggest that biomimetic AgNPs could be used as an effective drug against hepatic alteration.

The role of ultra-low-dose computed tomography in the detection of pulmonary pathologies: a prospective observational study.

Purpose: The aim of the study was to compare the image noise, radiation dose, and image quality of ultra-low-dose computed tomography (CT) and standard CT in the imaging of pulmonary pathologies. Material and methods: This observational study was performed between July 2020 and August 2021. All enrolled patients underwent both ultra-low-dose and standard CTs. The image noise, image quality for normal pulmonary structures, presence or absence of various pulmonary lesions, and radiation dose were recorded for each of the scans. The findings of standard-dose CT were regarded as the gold standard and compared with that of ultra-low-dose CT. Results: A total of 124 patients were included in the study. The image noise was higher in the ultra-low-dose CT compared to standard-dose CT. The overall image quality was determined to be diagnostic in 100% of standard CT images and in 96.77% of ultra-low-dose CT images with proportional worsening of the image quality as the body mass index (BMI) range was increased. Ultra-low-dose CT offered higher (> 90%) sensitivity for lesions like consolidation (97%), pleural effusion (95%), fibrosis (92%), and solid pulmonary nodules (91%). The effective radiation dose (mSv) was many times lower in ultra-low-dose CT when compared to standard-dose CT (mean ± SD: 0.50 ± 0.005 vs. 3.99 ± 1.57). Conclusions: The radiation dose of ultra-low-dose chest CT was almost equal to that of a chest X-ray. It could be used for the screening and/or follow-up of patients with solid pulmonary nodules (> 3 mm) and consolidation.

ANTI-INFLAMMATORY AND MOLECULAR DOCKING ANALYSIS OF LEUCAS VESTITA Wall. Ex. Benth. EXTRACT AGAINST CYCLO-OXYGENASE-2.

Leucas vestita Wall. ex. Benth., is an endemic species restricted to Western Ghats, India. In this study, the carrageenan-induced anti-inflammatory model was used to evaluate the influence of L. vestita ethanol extract on inflammation. The Ethanol extract was tested for its anti-inflammatory property at a dose of 200mg/kg po. and 400mg/kg po. The paw volume was reduced gradually, three hours after administration of the extract. The extract showed a dosage dependant activity. The compounds present in the ethanol extract were identified by using HPLC and the binding affinity of these compounds against Cyclo-oxygenase-2 (COX-2, the enzyme involved in the perception of pain) was analyzed by using FlexX molecular docking suite.

Myg1 exonuclease couples the nuclear and mitochondrial translational programs through RNA processing.

Semi-autonomous functioning of mitochondria in eukaryotic cell necessitates coordination with nucleus. Several RNA species fine-tune mitochondrial processes by synchronizing with the nuclear program, however the involved components remain enigmatic. In this study, we identify a widely conserved dually localized protein Myg1, and establish its role as a 3'-5' RNA exonuclease. We employ mouse melanoma cells, and knockout of the Myg1 ortholog in Saccharomyces cerevisiae with complementation using human Myg1 to decipher the conserved role of Myg1 in selective RNA processing. Localization of Myg1 to nucleolus and mitochondrial matrix was studied through imaging and confirmed by sub-cellular fractionation studies. We developed Silexoseqencing, a methodology to map the RNAse trail at single-nucleotide resolution, and identified in situ cleavage by Myg1 on specific transcripts in the two organelles. In nucleolus, Myg1 processes pre-ribosomal RNA involved in ribosome assembly and alters cytoplasmic translation. In mitochondrial matrix, Myg1 processes 3'-termini of the mito-ribosomal and messenger RNAs and controls translation of mitochondrial proteins. We provide a molecular link to the possible involvement of Myg1 in chronic depigmenting disorder vitiligo. Our study identifies a key component involved in regulating spatially segregated organellar RNA processing and establishes the evolutionarily conserved ribonuclease as a coordinator of nucleo-mitochondrial crosstalk.