Publications by authors named "Rohit Sharma"

363 Publications

A study on chemical exfoliation and structural and optical properties of two-dimensional layered titanium diselenide.

Dalton Trans 2021 Feb 26. Epub 2021 Feb 26.

Amity Institute of Nanotechnology, Amity University UP, Noida, UP, India.

Titanium diselenide (TiSe2) is the least studied member of the transition metal dichalcogenide family due to a lack of available synthesis methodology, controlled bandgap engineering, and rapid characterization of layers. In this paper, we report the chemical exfoliation of TiSe2 platelets synthesized by the chemical vapor transport route in ortho-dichlorobenzene (o-DCB) functionalized with oleylamine (OLA), for the first time to the best of our knowledge. It is found that the addition of OLA supports the formation of a stable dispersion of a large area of the TiSe2 sheets due to surface capping with the OLA molecules indicating the importance of the ligand in dispersion behavior. The X-ray diffraction pattern confirms the hexagonal structure of the TiSe2 platelets with the space group P3[combining macron]m1 while Raman spectroscopy reveals that two modes of vibration i.e. A1g and E2g exist with layered structures having dimensions in micrometers as confirmed by scanning electron microscopy. Fourier transform infrared spectroscopy confirms the successful functionalization of chemically exfoliated TiSe2 nanosheets. Field-emission scanning electron microscopy reveals that exfoliated TiSe2 has a thickness of 15-55 nm whereas high-resolution transmission electron microscopy indicates thicker sheets for ligand-free exfoliated TiSe2 which are crystalline. Atomic force microscopy confirms the formation of nanosheets. UV-Visible, photoluminescence, and time-resolved PL spectroscopy showed an enhanced effect and better average lifetime of excitation for the exfoliated sheets with OLA than those without OLA. The C-V studies reveal that with increasing scan rate, the corresponding current also increases. The present study offers the possibility of their utilization in optoelectronics, advanced low-power electronics, voltage-controlled oscillators, ultra-fast electronics, and electrochemical devices.
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http://dx.doi.org/10.1039/d0dt03689gDOI Listing
February 2021

spp.: A Review on Its Immune-Stimulatory and Other Biological Potentials.

Front Pharmacol 2020 8;11:602364. Epub 2021 Feb 8.

Research Institute of Biotechnology and Medical Converged Science, Dongguk University-Seoul, Goyangsi, South Korea.

In recent decades, interest in the genus has amplified due to its immunostimulatory potential. species, its extracts, and bioactive constituents have been related with cytokine production such as interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor (TNF)-α, phagocytosis stimulation of immune cells, nitric oxide production by increasing inducible nitric oxide synthase activity, and stimulation of inflammatory response via mitogen-activated protein kinase pathway. Other pharmacological activities like antioxidant, anti-cancer, antihyperlipidemic, anti-diabetic, anti-fatigue, anti-aging, hypocholesterolemic, hypotensive, vasorelaxation, anti-depressant, aphrodisiac, and kidney protection, has been reported in pre-clinical studies. These biological activities are correlated with the bioactive compounds present in including nucleosides, sterols, flavonoids, cyclic peptides, phenolic, bioxanthracenes, polyketides, and alkaloids, being the cyclic peptides compounds the most studied. An organized review of the existing literature was executed by surveying several databanks like PubMed, Scopus, etc. using keywords like , cordycepin, immune system, immunostimulation, immunomodulatory, pharmacology, anti-cancer, anti-viral, clinical trials, ethnomedicine, pharmacology, phytochemical analysis, and different species names. This review collects and analyzes state-of-the-art about the properties of species along with ethnopharmacological properties, application in food, chemical compounds, extraction of bioactive compounds, and various pharmacological properties with a special focus on the stimulatory properties of immunity.
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http://dx.doi.org/10.3389/fphar.2020.602364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898063PMC
February 2021

The public health implications of the Paris Agreement: a modelling study.

Lancet Planet Health 2021 Feb;5(2):e74-e83

Institute for Global Health, University College London, London, UK.

Background: nationally determined contributions (NDCs) serve to meet the goals of the Paris Agreement of staying "well below 2°C", which could also yield substantial health co-benefits in the process. However, existing NDC commitments are inadequate to achieve this goal. Placing health as a key focus of the NDCs could present an opportunity to increase ambition and realise health co-benefits. We modelled scenarios to analyse the health co-benefits of NDCs for the year 2040 for nine representative countries (ie, Brazil, China, Germany, India, Indonesia, Nigeria, South Africa, the UK, and the USA) that were selected for their contribution to global greenhouse gas emissions and their global or regional influence.

Methods: Modelling the energy, food and agriculture, and transport sectors, and mortality related to risk factors of air pollution, diet, and physical activity, we analysed the health co-benefits of existing NDCs and related policies (ie, the current pathways scenario) for 2040 in nine countries around the world. We compared these health co-benefits with two alternative scenarios, one consistent with the goal of the Paris Agreement and the Sustainable Development Goals (ie, the sustainable pathways scenario), and one in line with the sustainable pathways scenario, but also placing health as a central focus of the policies (ie, the health in all climate policies scenario).

Findings: Compared with the current pathways scenario, the sustainable pathways scenario resulted in an annual reduction of 1·18 million air pollution-related deaths, 5·86 million diet-related deaths, and 1·15 million deaths due to physical inactivity, across the nine countries, by 2040. Adopting the more ambitious health in all climate policies scenario would result in a further reduction of 462 000 annual deaths attributable to air pollution, 572 000 annual deaths attributable to diet, and 943 000 annual deaths attributable to physical inactivity. These benefits were attributable to the mitigation of direct greenhouse gas emissions and the commensurate actions that reduce exposure to harmful pollutants, as well as improved diets and safe physical activity.

Interpretation: A greater consideration of health in the NDCs and climate change mitigation policies has the potential to yield considerable health benefits as well as achieve the "well below 2°C" commitment across a range of regional and economic contexts.

Funding: This work was in part funded through an unrestricted grant from the Wellcome Trust (award number 209734/Z/17/Z) and supported by an Engineering and Physical Sciences Research Council grant (grant number EP/R035288/1).
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http://dx.doi.org/10.1016/S2542-5196(20)30249-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887663PMC
February 2021

Treatment of orbital venous malformation type 2 with a bleomycin injection.

BMJ Case Rep 2021 Feb 4;14(2). Epub 2021 Feb 4.

Ophthalmology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK.

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http://dx.doi.org/10.1136/bcr-2020-240633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868239PMC
February 2021

Silencing of Double-Stranded Ribonuclease Improves Oral RNAi Efficacy in Southern Green Stinkbug .

Insects 2021 Jan 28;12(2). Epub 2021 Jan 28.

Department of Plants and Crops, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.

Variability in RNA-interference (RNAi) efficacy among different insect orders poses a big hurdle in the development of RNAi-based pest control strategies. The activity of double-stranded ribonucleases (dsRNases) in the digestive canal of insects can be one of the critical factors affecting oral RNAi efficacy. Here, the involvement of these dsRNases in the southern green stinkbug was investigated. First, the full sequence of the only dsRNase () in the transcriptome of . was obtained, followed by an oral feeding bioassay to evaluate the effect of -silencing on oral RNAi efficacy. The was first silenced in nymphs by -dsRNA injections, followed by exposure to an artificial diet containing a lethal -specific dsRNA. A significantly higher mortality was observed in the silenced nymphs when placed on the ds-containing diet (65%) than in the ds injected and ds fed control (46.67%). Additionally, an ex vivo dsRNA degradation assay showed a higher stability of dsRNA in the saliva and midgut juice of silenced adults. These results provide evidence for the involvement of in the reduction of oral RNAi efficacy in . . This information will be useful in further improving potential RNAi-based strategies to control this pest.
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http://dx.doi.org/10.3390/insects12020115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912330PMC
January 2021

A prospective, population-based, surveillance (BOSU) study of uveal effusion syndrome in the UK.

Eur J Ophthalmol 2021 Jan 26:1120672120969369. Epub 2021 Jan 26.

Faculty of Life Science and Medicine, King's College London, London, UK.

Purpose: To determine the incidence and demographic profile of uveal effusion syndrome (UES), and to describe the visual and anatomic outcome following deep sclerectomy or vortex vein decompression.

Methods: The British Ophthalmological Surveillance Unit (BOSU) mails reporting cards monthly to 1149 senior UK ophthalmologists, who are requested to report incident cases of specified rare diseases. UES was included in the reporting system from October 2009 to October 2011. If UES was identified, ophthalmologists were mailed a questionnaire to collect anonymized clinical data at baseline, and 12 months after.

Results: Over 2 years, 29 cases were reported. Two cases were duplicates and 12 failed to meet the eligibility criteria. Of the 15 eligible cases, age ranged from 11 to 91 years (mean 62) and nine were males (60%). Ten patients were hypermetropic; three had an axial length of 19.0 mm or less. Estimated annual incidence was 1.2 per 10 million population. Seven cases were managed nonsurgically, including observation (one case), topical steroids (two cases), systemic steroids (three cases), and cyclodiode laser (one case). Eight cases (11 eyes) underwent full-thickness sclerectomy; the elevated flap was retained in four. The sclera was noted to be thick and rigid during surgery in five cases. Median preoperative visual acuity was 6/18, changing slightly to 6/21.5 at final review, with three eyes showing complete anatomic response, five showing some improvement, and three failing to respond.

Conclusions: UES is extremely rare. It occurs in a range of ages, but is most common in middle-aged, hypermetropic men. Visual acuity can be materially reduced. The most commonly used surgical treatment in the UK is deep sclerectomy.
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http://dx.doi.org/10.1177/1120672120969369DOI Listing
January 2021

Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity.

J Clin Invest 2021 01;131(2)

Howard Hughes Medical Institute, Department of Molecular Biology, and.

Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, α-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, β-hydroxy acylcarnitines, and β-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease.
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http://dx.doi.org/10.1172/JCI136055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810486PMC
January 2021

Dose-dependent cell cycle arrest and apoptosis in HER2 breast cancer cells byLu-CHX-A"-DTPA-Trastuzumab.

J Cancer Res Ther 2020 Oct-Dec;16(6):1426-1434

Radiopharmaceuticals Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai, Maharashtra, India.

Background: Trastuzumab is a Food and Drug Administration-approved humanized monoclonal antibody which targets the extracellular domain of human epidermal growth factor receptor 2 (HER2) receptor overexpressed on HER2-positive breast cancer cells. The combination of Lutetium-177 ( Lu) (t= 6.7 days, E497 keV (78.6%) and trastuzumab makes it a suitable targeting agent for radioimmunotherapy. In preclinical and clinical studies, Lu-Trastuzumab has proven to be effective for the treatment of HER2-positive malignancies such as breast and ovarian cancer.

Objectives: In this study, we report the mechanism of action of Lu-CHX-A"-diethylenetriaminepentaacetic acid (DTPA)-trastuzumab at the cellular and molecular level by performing various in vitro assays in HER2-positive MDA-MB-453 breast cancer cells.

Materials And Methods: Trastuzumab was conjugated to the bifunctional chelating agent (BFCA) para-isothiocyanatobenzyl-DTPA and radiolabeled with Lu. In vitro cell binding studies were carried out in MDA-MB-453 cells to confirm the specificity of the complex toward the receptor. Cellular toxicity, cell cycle, and cell death analysis were also performed for exploring the potential of the radioimmunoconjugate at cellular and molecular level.

Results: In vitro cell binding studies showed a maximum binding of 10.7 ± 0.1% which reduced to 2.9 ± 0.1% on coincubation with unlabeled antibody. Our study revealed that the cellular toxicity was dose dependent, and mode of cell death was predominantly by apoptosis. The radioimmunoconjugate retarded the cell in the S phase of cell cycle with two-fold increase in G2/M arrest which justifies the enhanced apoptosis at higher doses.

Conclusions: The study revealed that the formulation can execute a dose-dependent cellular toxicity through induction of apoptosis.
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http://dx.doi.org/10.4103/jcrt.JCRT_20_19DOI Listing
December 2020

The Long Pentraxin 3 (PTX3) Suppresses Immunity to Cutaneous Leishmaniasis by Regulating CD4 T Helper Cell Response.

Cell Rep 2020 Dec;33(11):108513

Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Electronic address:

The long pentraxin 3 (PTX3) plays a critical role in inflammation, tissue repair, and wound healing. Here, we show that PTX3 regulates disease pathogenesis in cutaneous leishmaniasis (CL). PTX3 expression increases in skin lesions in patients and mice during CL, with higher expression correlating with severe disease. PTX3-deficient (PTX3) mice are highly resistant to L. major and L. braziliensis infections. This enhanced resistance is associated with increases in Th17 and IL-17A responses. The neutralization of IL-17A abolishes this enhanced resistance, while rPTX3 treatment results in decrease in Th17 and IL-17A responses and increases susceptibility. PTX3 CD4 T cells display increased differentiation to Th17 and expression of Th17-specific transcription factors. The addition of rPTX3 suppresses the expression of Th17 transcription factors, Th17 differentiation, and IL-17A production by CD4 T cells from PTX3 mice. Collectively, our results show that PTX3 contributes to the pathogenesis of CL by negatively regulating Th17 and IL-17A responses.
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http://dx.doi.org/10.1016/j.celrep.2020.108513DOI Listing
December 2020

Quercetin acts as a P-gp modulator via impeding signal transduction from nucleotide-binding domain to transmembrane domain.

J Biomol Struct Dyn 2020 Dec 11:1-9. Epub 2020 Dec 11.

Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

The inherent ability of the cancer cells to resist chemotherapeutic agents is a major challenge in drug discovery. Chemotherapy is one of the most widely used treatment methods for cancer, but due to multidrug resistance (MDR) development in cancer cells, the healing procedure often fails. Various factors impart cancer resistance to cells; among them, P-glycoprotein (P-gp) overexpression is directly linked to MDR in cancer cells. P-gp leads to the efflux of drug molecules to the extracellular space. Several molecules have been reported to inhibit the P-gp activity. Among them, quercetin has revealed a great potential to modulate P-gp activity. However, the mechanistic understanding of quercetin induced modulation is not entirely elucidated. In the present work, we showed that quercetin binds in the interacting region between the transmembrane domain and nucleotide-binding domain out of the three plausible binding sites of P-gp and restrict the conformational change from inward- to outward-facing conformation of P-gp. Due to the absence of the inward-facing structure of human P-gp, we first modeled an inward-facing P-gp structure. Using molecular docking, the interacting residues of P-gp were identified, and the stability and interaction dynamics of the complex were studied using molecular dynamics simulation. Our work reveals the mechanistic understanding of quercetin induced modulation of P-gp and indicates its importance in cancer treatment. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1858966DOI Listing
December 2020

Sarcoidosis Mimicking Chronic Sialadenitis of Parotid Gland.

J Craniofac Surg 2020 Dec 1. Epub 2020 Dec 1.

MH Jaipur, India.

Non-specific Chronic sialadenitis of the Parotid gland is an inflammatory disorder that leads to several anatomical and functional changes within the glandular structure. The exact etiopathogenesis of this disorder is unknown due to its relatively rare occurrence. Primary sarcoidosis of the Parotid gland masquerading the peripheral changes of Chronic sialadenitis has never been reported in literature. We report such a case of Primary Sarcoidosis of the Parotid gland presenting with non-specific chronic sialadenitis along with ipsilateral non-reducing disc displacement of the Temporomandibular joint along with its management.
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http://dx.doi.org/10.1097/SCS.0000000000007289DOI Listing
December 2020

A Patient with Asymptomatic SARS-CoV-2 Infection Who Presented 86 Days Later with COVID-19 Pneumonia Possibly Due to Reinfection with SARS-CoV-2.

Am J Case Rep 2020 Dec 1;21:e927154. Epub 2020 Dec 1.

Department of Infectious Diseases, Hamad Medical Corporation, Doha, Qatar.

BACKGROUND Coronavirus disease 2019 (COVID-19) has radically changed the world, and promising vaccine trials are currently underway. The immune responses in asymptomatic and symptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still under investigation, and data are evolving. While it is known that humoral and cell-mediated immune responses against SARS-CoV-2 are elicited, it is uncertain whether these responses protect against reinfection or that they provide definitive evidence of viral clearance. Very few cases have been reported in the literature regarding reinfection with SARS-CoV-2. CASE REPORT We present a case of a middle-aged man with asymptomatic SARS-CoV-2 infection who later developed mild symptomatic COVID-19 after a period of 3 months. The source of reinfection was likely from the community, which had a soaring burden of infection with the highest number of COVID-19 cases per million in the world at that time. The patient had 2 negative COVID-19 polymerase chain reaction (PCR) tests 2 weeks after the initial infection. During the second infection, a nasopharyngeal reverse-transcription PCR test and tests for the presence of COVID-19 immunoglobulin (Ig)M and IgG antibodies were all positive. CONCLUSIONS Reinfection with SARS-CoV-2 is a strong possibility. This case raises concerns that asymptomatic infections may not provide long-term protective immunity to all patients, which could make them susceptible to reinfection. Possible explanations for reinfection include an interval decrease in protective antibodies titers after SARS-CoV-2 infection that may be more prevalent in patients who had an asymptomatic infection. Other possibilities include viral reactivation after a prolonged carriage of the virus or delayed immune response.
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http://dx.doi.org/10.12659/AJCR.927154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718490PMC
December 2020

Novel hypotheses related to Temporomandibular joint derived from Ankylosing spondylitis.

Med Hypotheses 2020 Nov 2;144:110225. Epub 2020 Sep 2.

Consultant (Oral and Maxillofacial Pathology), Sri Ramachandra Dental Specialty Clinic, Vallal Pachayappa Street, Kancheepuram, Tamilnadu, India.

Ankylosing spondylitis (AS) is a seronegative arthropathy that affects fibrocartilaginous joints leading to arthritis and eventually ankylosis. Temporomandibular joint (TMJ), a fibrocartilaginous joint is affected to a lesser extent than the other joints, very rarely precipitating TMJ ankylosis. No explanation exists for the same in the present literature. Several hypothesis have been presented to explain this phenomenon of rarity of TMJ ankylosis in AS. The presence of an intraarticular disc acts as a physical barrier to the ankylotic process. However, in cases with AS, that present with TMJ ankylosis, this hypothesis needs several clarifications since the intraarticular disc is a constant phenomenon in TMJ. The cause of TMJ ankylosis in these cases might be explained by two hypotheses. Firstly, Pathological condylar loading in some cases; secondly, an application of the orthopaedic concept of functional enthesis to the TMJ disc and thirdly, an application of the concept of enthesis organ to TMJ. Using these hypotheses, important concepts on the anatomy and evolution of TMJ can be derived with evidence from literature. The intraarticular disc may be considered as an involuted tendon of the lateral pterygoid muscle which not only attaches to the mandibular condyle but also to the temporal bone via a elastic fiber mediated enthesis extending to the malleus through the discomalleolar ligament. The fibrocartilaginous changes that occur on the undersurface of the disc may support the concept of functional enthesis and provide a reverse evidence for the disc being a tendon. The evidence presented from extant monotremes may also throw light on the embryological development of the articular disc. These evidences are more of an anecdote than being focussed. Several scientific experiments, studies and data collection needs to be carried out to validate them. The proof of these hypotheses will be of use in establishing the development and role of the articular disc in TMJ function and TMJ disorders, including AS. The understanding of the role of the articular disc is important since many firstly, TMJ disorders are being treated by discectomy with good results, apparently rendering the disc vestigial and secondly, in the era of tissue engineering where efforts are being made to artificially produce articular disc and its analogues.
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http://dx.doi.org/10.1016/j.mehy.2020.110225DOI Listing
November 2020

Towards a more intelligent model of providing pediatric trauma care: identifying temporal variations in trauma team activations.

Trauma Surg Acute Care Open 2020 11;5(1):e000448. Epub 2020 Nov 11.

Pediatric Surgery, Santa Barbara Cottage Hospital, Santa Barbara, California, USA.

Background: Trauma centers are resource-intensive environments, and pediatric-specific personnel are often limited resources. Identifying the temporal patterns of pediatric traumas can help guide resource allocation strategies to optimize patient care.

Methods: We conducted a retrospective, single-institution analysis of 575 injured patients less than 18 years old that triggered a trauma team activation (TTA). TTA volume according to time of day and day of the week was analyzed using a mixed Poisson regression model and monthly patterns were analyzed using an analysis of variance. Subset analyses were conducted for children and teenagers.

Results: Across all days, the 6-hour time frame between 15:00 and 21:00 had significantly more activations than average, encompassing nearly half (47.2%) of all pediatric TTAs (p=0.01). Saturdays had significantly more activations than the daily average (Saturdays: 26.0/year, Other: 14.8/year, p<0.01). A pediatric TTA was 3.6 times more likely to occur between 15:00 and 21:00 on a Saturday than any other time. Volume of activation did not significantly differ by month (p=0.880).

Conclusion: The volume of pediatric trauma activations varies significantly according to time of day and day of the week. These findings can direct or validate resource allocation strategies such as staffing physicians, nurses, and ancillary personnel according to TTA volume.

Type Of Study: Retrospective cohort study.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1136/tsaco-2020-000448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661376PMC
November 2020

Optic neuropathy as a presenting feature of vitamin B-12 deficiency: A systematic review of literature and a case report.

Ann Med Surg (Lond) 2020 Dec 5;60:316-322. Epub 2020 Nov 5.

Department of Internal Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.

Introduction: Vitamin B12 (VitB12) deficiency rarely manifests with visual symptoms. Optic nerve damage in VitB12 deficiency is thought to be via degeneration. However, optic neuritis, though infrequent, has been reported secondary to VitB12 deficiency.

Material And Methods: We conducted a systematic review of all the reported cases of VitB12 deficiency with optic nerve involvement in Pubmed, Cochrane, and Google Scholar any date up to September 6, 2020. We have discussed the findings and compiled the available information on ophthalmological manifestations of VitB12 deficiency. We aim to provide a unified knowledge about the evidence related to types of optic neuropathies reported to date secondary to VitB12 deficiency. We also present a case of bilateral optic neuritis secondary to VitB12 deficiency.

Presentation Of Case: We present a 29-year-old previously healthy male with progressive, painful, bilateral, but asymmetric visual deterioration for forty-five days. A detailed history, examination, and laboratory workup were carried out. He was diagnosed as having optic neuritis secondary to VitB12 deficiency. He showed partial improvement with the replacement of VitB12.

Conclusion: We suggest promptly identifying and replacing VitB12 in patients with optic neuritis with proven VitB12 deficiency to prevent permanent damage to the optic nerve. Patients with VitB12 deficiency should have a baseline fundoscopic exam to rule out subclinical optic nerve damage. Moreover, patients who present with visual disturbances should be screened for VitB12 deficiency, especially the vegan population.
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http://dx.doi.org/10.1016/j.amsu.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653199PMC
December 2020

Global Forecasting Confirmed and Fatal Cases of COVID-19 Outbreak Using Autoregressive Integrated Moving Average Model.

Front Public Health 2020 29;8:580327. Epub 2020 Oct 29.

Institute of Research and Development, Duy Tan University, Da Nang, Vietnam.

The world health organization (WHO) formally proclaimed the novel coronavirus, called COVID-19, a worldwide pandemic on March 11 2020. In December 2019, COVID-19 was first identified in Wuhan city, China, and now coronavirus has spread across various nations infecting more than 198 countries. As the cities around China started getting contaminated, the number of cases increased exponentially. As of March 18 2020, the number of confirmed cases worldwide was more than 250,000, and Asia alone had more than 81,000 cases. The proposed model uses time series analysis to forecast the outbreak of COVID-19 around the world in the upcoming days by using an autoregressive integrated moving average (ARIMA). We analyze data from February 1 2020 to April 1 2020. The result shows that 120,000 confirmed fatal cases are forecasted using ARIMA by April 1 2020. Moreover, we have also evaluated the total confirmed cases, the total fatal cases, autocorrelation function, and white noise time-series for both confirmed cases and fatalities in the COVID-19 outbreak.
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http://dx.doi.org/10.3389/fpubh.2020.580327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658382PMC
October 2020

MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.

Nucleic Acids Res 2021 01;49(D1):D1541-D1547

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.
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http://dx.doi.org/10.1093/nar/gkaa1011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778944PMC
January 2021

Sensing platform for pico-molar level detection of ethyl parathion using Au-Ag nanoclusters based enzymatic strategy.

Talanta 2021 Jan 21;221:121267. Epub 2020 Jun 21.

Department of Chemistry & Centre for Advanced Studies in Chemistry, Panjab University, Sector-14, Chandigarh, 160014, India. Electronic address:

This work demonstrates a simple, cost effective and ultrasensitive detection of ethyl parathion, an organophosphorus (OPs) pesticide, using enzyme based fluorometric sensing strategy by employing bimetallic BSA@AuAg nanoclusters (NC). The sensing assay is based on the "quenched off" state of bimetallic NC with the addition of Cu ions that can be "switched on" due to generation of thiocholine (TCh), a catalytic product of enzymatic reaction of acetylthiocholine (ATCh) using acetylcholinesterase (AChE) enzyme. The generated TCh preferably seize Cu ions from BSA@AuAg NC-Cu ensemble and recovered the fluorescence of BSA@AuAg NC. The presence of ethyl parathion can be monitored optically due to its inhibitory action towards AChE enzyme leading to suppression of thiocholine (TCh) formation and subsequently decreases TCh-Cu interaction that ultimately retrieved quenched off state of bimetallic NC. The synthesized biosensor is appropriate for the ultrasensitive sensing of ethyl parathion in pM range, exhibiting 2.40 pM as lowest limit of detection (LOD) which is the least known so far. Further, the real sample analysis adds on for the appropriateness of the synthesized nanoprobe by depicting excellent reproducibility and robustness. The designed assay proved its specificity towards pesticides in general and ethyl parathion in particular when employed with other commonly used non-OPs pesticides.
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http://dx.doi.org/10.1016/j.talanta.2020.121267DOI Listing
January 2021

Facial Fractures After Geriatric Ground-Level Falls Are a Marker of Functional Decline and Warrant Trauma Center Admission.

Am Surg 2020 Oct 19;86(10):1302-1306. Epub 2020 Oct 19.

Santa Barbara Cottage Hospital, Santa Barbara, CA, USA.

Ground-level falls (GLFs) are a frequent source of injury in the geriatric population. Facial fractures (FFs) are one subsequent injury that can occur and may be an important marker of functional decline. We conducted a retrospective analysis over a 6-year period of patients 65 years and older sustaining one or more FFs due to a GLF (n = 28). Demographics, comorbidities, FF patterns, concomitant injuries, procedures, and outcomes were analyzed. The mean age was 80.0 ± 8.2 years, 64% were male, 12 patients (43%) were on oral anticoagulants prior to injury, and mean injury severity score was 8.3 ± 7.0. Five patients (18%) had LeFort fractures (1 with LeFort I, 4 with LeFort II), and 5 (18%) had isolated mandible fractures (2 were bilateral). Nearly half of all patients suffered neurological injury (concussion: 18%, intracranial hemorrhage: 29%). Average hospital length of stay (LOS) was 4.0 ± 2.9 days. Eight patients (29%) required intensive care unit (ICU) admission with an average ICU-LOS of 2.8 ± 1.2 days. Surgical management was required in 4 patients (14%). More than half of the patients returned home (54%), 25% were discharged to a skilled nursing facility, 4% to rehabilitation, 7% to hospice, and 7% expired. Nearly one-third of patients required discharge to a higher level of care facility than their location prior to injury. GLF-induced FFs are often associated with significant injuries and serve as an indicator of functional decline. These injuries warrant trauma center admission for comprehensive evaluation and management.
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http://dx.doi.org/10.1177/0003134820964228DOI Listing
October 2020

Photodynamic inactivation of Leishmania braziliensis doubly sensitized with uroporphyrin and diamino-phthalocyanine activates effector functions of macrophages in vitro.

Sci Rep 2020 10 13;10(1):17065. Epub 2020 Oct 13.

Instituto Gonçalo Moniz, FIOCRUZ, Salvador, BA, Brazil.

Photodynamic inactivation of Leishmania has been shown to render them non-viable, but retain their immunological activities. Installation of dual photodynamic mechanisms ensures complete inactivation of species in the Leishmania subgenus, raising the prospect of their safe and effective application as whole-cell vaccines against leishmaniasis. Here, we report the successful extension of this approach to L. braziliensis in the Viannia subgenus, viz. genetic engineering of promastigotes for cytosolic accumulation of UV-sensitive uroporphyrin (URO) and their loading with red light excitable phthalocyanines (PC) that was cationized by chemical engineering. The transgenic strategy used previously produced L. braziliensis transfectants, which gave the same phenotype of aminolevulinate (ALA)-inducible uroporphyria as found in Leishmania subgenus, indicative of pre-subgenus evolutionary origin for similar genetic deficiencies in porphyrin/heme biosynthesis. In the present study, 12 independent clones were obtained and were invariably ALA-responsive, albeit to different extent for uroporphyrinogenesis and UV-inactivation. In a separate study, L. braziliensis was also found, like other Leishmania spp., to take up diamino-PC (PC2) for red light inactivation. In vitro interactions of a highly uroporphyrinogenic clone with primary macrophages were examined with the intervention of URO/PC2-medated double-photodynamic inactivation to ascertain its complete loss of viability. Doubly sensitized L. braziliensis transfectants were photo-inactivated before (Strategy #1) or after (Strategy #2) loading of macrophages. In both cases, macrophages were found to take up L. braziliensis and degrade them rapidly in contrast to live Leishmania infection. The effector functions of macrophages became upregulated following their loading with L. braziliensis photodynamically inactivated by both strategies, including CD86 expression, and IL6 and NO production. This was in contrast to the immunosuppressive infection of macrophages with live parasites, marked by IL10 production. The results provide evidence that photodynamically inactivated L. braziliensis are susceptible to the degradative pathway of macrophages with upregulation of immunity relevant cytokine and co-stimulatory markers. The relative merits of the two loading strategies with reference to previous experimental vaccination were discussed in light of the present findings with L. braziliensis.
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http://dx.doi.org/10.1038/s41598-020-74154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555832PMC
October 2020

IMA Genome - F13: Draft genome sequences of , and .

IMA Fungus 2020 24;11:19. Epub 2020 Sep 24.

Department of Biochemistry, Genetics and Microbiology, Forestry and Agricultural Biotechnology Institute (FABI), University of Pretoria, Private Bag x20, Hatfield, Pretoria, 0028 South Africa.

Draft genomes of the fungal species , and are presented. is an important lichen forming fungus and is an ambrosia beetle symbiont. and are agriculturally relevant plant pathogens that cause leaf-spots in brassicaceous vegetables and cucurbits respectively. causes severe leaf blight and defoliation of trees. These genomes provide a valuable resource for understanding the molecular processes in these economically important fungi.
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http://dx.doi.org/10.1186/s43008-020-00039-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513301PMC
September 2020

Neuroprotective potential of Myrica esulenta in Haloperidol induced Parkinson's disease.

J Ayurveda Integr Med 2020 Oct-Dec;11(4):448-454. Epub 2020 Sep 8.

Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India.

Background: Myrica esculenta is a notable therapeutic plant widely utilized in Indian system of medicine. Ayurvedic literature reported fruit and bark of this plant is used in gulma, jvara, arsa, grahani, pandu roga, hrillasa, mukha roga, kasa, svasa, agnimandhya, aruchi, meha, and kantharoga.

Objective: The present study aimed to investigate the neuroprotective potential of "Himalayan Bayberry" (Myrica esculenta Buch.-Ham. ex D. Don) leaves methanol extract in Parkinson's disease induced by haloperidol.

Materials And Methods: The present investigation was completed in wistar rats, in which Parkinson's disease (PD) was induced with haloperidol 1 mg/kg, intraperitoneally. The rats were randomly divided into six gatherings and the test animals received the methanolic extract of M. esculenta (MEME) at a dose of 50, 100 and 200 mg/kg, orally for one week. Various behavioural, biochemical and histopathological parameters were estimated in haloperidol exposed rats.

Results: MEME demonstrated significant and dose-dependent increment in behavioural activity and improved muscle coordination. The significant diminution in malonaldehyde level while improved the level of antioxidant enzymes like catalase, superoxide dismutase and reduced glutathione in extract treated group were observed as compared to the control group. Histopathological changes revealed MEME significantly reduced haloperidol-induced damage in the substantia nigra and there was very little neuronal atrophy.

Conclusion: The outcomes showed the defensive role of M. esculenta against PD. The mechanism of protection may be due to an escalation of cellular antioxidants.
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http://dx.doi.org/10.1016/j.jaim.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772500PMC
September 2020

The Relationship Between Surgeon Faculty Emotional Intelligence and Medical Student Evaluations.

J Surg Educ 2021 Mar-Apr;78(2):604-611. Epub 2020 Sep 6.

Department of Surgery, University of Texas Southwestern, Dallas, Texas. Electronic address:

Objective: We sought to measure the emotional intelligence (EI) of surgical faculty and the relationship between faculty EI and medical student (MS) evaluations of faculty.

Design: Faculty completed the Emotional Intelligence Appraisal. Aggregate, anonymous MS evaluations were collected from the Program Director's office. Parametric and nonparametric tests were used for analysis.

Setting: This study was first performed in a single surgical division at 1 center which informed an expanded study including the entire General Surgery Department at a single academic institution.

Participants: A pilot study was conducted in 1 surgical division which was then expanded to all clinical faculty in the Department of Surgery. All clinical faculty in the Department of Surgery were eligible for enrollment.

Results: Pilot study faculty EI scores were positively correlated with MS evaluations (r = 0.92, p < 0.001). The follow-up study enrolled 41 surgeons with a median age of 48 (inter-quartile range 12). The sample was mostly white (70.7%). Mean EI for the group was 76 (standard deviation ± 7.8). Total faculty EI scores were not significantly correlated with MS evaluations (r = 0.30, p = 0.06).

Conclusions: MS evaluations of surgeon faculty were not related to EI in the larger sample. However, EI did correlate to MS evaluations in 2 surgical specialties. Further exploration into the utility of EI training in surgical departments should be conducted to determine the true value of such endeavors.
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http://dx.doi.org/10.1016/j.jsurg.2020.08.010DOI Listing
September 2020

Degloving Approach for the Management of Extensive Mandibular Osteomyelitis.

J Craniofac Surg 2020 Aug 28. Epub 2020 Aug 28.

Dept of Anesthesiology, Military Hospital Jaipur, India.

Extensive osteomyelitis of the mandible is usually managed using elaborate procedures including resection and reconstruction of the affected part of the mandible. This brief clinical report, the authors present a case of 75-year old male with extensive osteomyelitis of the mandible, incidentally diagnosed with anemia of chronic disease and Type I diabetes mellitus and managed using an intraoral degloving approach exclusively. This has proved to be a procedure ensuring better blood supply, decreased morbidity, precluding an elaborate reconstruction procedure and an overall reduction in cost. The advantages, scientific basis, rationale and pitfalls have been discussed briefly.
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http://dx.doi.org/10.1097/SCS.0000000000006960DOI Listing
August 2020

Intraoperative tragal and conchal cartilage thickness: Comparative study for cartilage tympanoplasty.

Am J Otolaryngol 2020 Nov - Dec;41(6):102690. Epub 2020 Aug 20.

Department of Community Medicine, Rohilkhand Medical College and Hospital, Bareilly, UP, India.

Introduction: In conditions like recurrent perforations, atelectatic tympanic membrane and poor eustachian tube function, temporalis fascia graft fails to give the desired result. In such cases cartilage is used for tympanoplasty. It was demonstrated that if the thickness of cartilage is reduced to around 0.5 mm, the sound conduction is comparable to that of normal tympanic membrane with excellent mechanical stability.

Aim: To intra-operatively measure the mean thickness of tragal and conchal cartilage and compare it for age and sex variations.

Material & Methods: A total of 114 tragal and conchal cartilage samples of 86 patients were included in the study. Thickness of cartilages was measured intra-operatively after removing the perichondrium from both sides.

Results: Out of 58 tragal cartilages, 32 were from males and 26 from females. Mean thickness was 1.18 ± 0.11 mm among males and 1.12 ± 0.14 mm among females. Out of 56 conchal cartilage taken, 29 were from males and 27 females. Mean thickness among males were 1.38 ± 0.13 mm and 1.35 ± 0.08 mm in females. In 28 patients both tragal and conchal cartilage was taken. Mean thickness of both tragal (1.22 mm) and conchal cartilage (1.36 mm) increased with increase in age. Among 16 males in whom both cartilages were taken, mean thickness of tragal cartilage was 1.25 ± 0.11 mm and conchal cartilage was 1.41 ± 0.12 mm. Similarly among 12 females where both cartilages were taken, mean thickness of tragal cartilage was 1.20 ± 0.13 mm and conchal cartilage was 1.35 ± 0.07 mm.

Conclusion: Sliced cartilage tympanoplasty is a relatively better technique. When using cartilage splitter to get sliced cartilage, ideally thickness of every graft should be known. As it is difficult to measure the exact thickness in every case, so knowing the mean for age and sex for cartilage thickness is important to have an idea of which plates to use for a successful outcome of slicing. We concluded that thickness of tragal cartilage is significantly less than the thickness of conchal cartilage. Also there is significant age related difference between mean thickness of cartilages, both for tragal and conchal cartilage. Surprisingly the difference between thickness in male and female is not statistically different.
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http://dx.doi.org/10.1016/j.amjoto.2020.102690DOI Listing
January 2021

Rifampicin-Induced Pneumonitis Mimicking Severe COVID-19 Pneumonia Infection.

Am J Case Rep 2020 Aug 25;21:e927586. Epub 2020 Aug 25.

Department of Internal Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.

BACKGROUND Rifampicin-induced pneumonitis is an infrequent occurrence, with only a few cases reported in the literature. Furthermore, this condition constitutes a diagnostic challenge, particularly in the era of COVID-19 infection. Here, we report a case of rifampicin-induced pneumonitis with clinical, imaging, and histological features of acute respiratory distress syndrome (ARDS), which required severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to exclude a diagnosis of coronavirus disease 2019 (COVID-19) pneumonia. CASE REPORT A 43-year-old man on anti-TB treatment for TB meningitis developed new-onset fever, fatigue, hypoxemic respiratory failure, and bilateral pulmonary opacities. His clinical, chest X-ray, and CT thorax findings of ARDS were similar to both rifampicin-induced pneumonitis and severe COVID-19 pneumonia. However, reverse transcription polymerase chain reaction (RT-PCR) testing from a nasopharyngeal swab and bronchoalveolar lavage (BAL) via the GeneXpert system was negative for SARS-CoV-2. A detailed workup, including lung biopsy, revealed drug-induced pneumonitis as the cause of his presentation. His pneumonitis improved after discontinuation of rifampicin and recurred following the rifampicin challenge. CONCLUSIONS This case highlights the importance of early, rapid, and accurate testing for SARS-CoV-2 during the COVID-19 pandemic for patients presenting with acute respiratory symptoms, so that accurate diagnosis and early patient management are not delayed for patients with treatable causes of acute and severe lung diseases. Timely identification of rifampicin-induced pneumonitis via a high clinical suspicion, detailed workup, and histopathological analysis is required to avoid permanent damage to the lungs.
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http://dx.doi.org/10.12659/AJCR.927586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478429PMC
August 2020

Nutraceuticals-Based Immunotherapeutic Concepts and Opportunities for the Mitigation of Cellular Senescence and Aging: A Narrative Review.

Ageing Res Rev 2020 11 15;63:101141. Epub 2020 Aug 15.

Pharmacology and Toxicology Laboratory, Food and Nutraceutical Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, India.

The role of increased tissue senescent cell (SC) burden in driving the process of ageing and associated disorders is rapidly gaining attention. Amongst various plausible factors, impairment in immune functions is emerging as a critical regulator of known age-associated accumulation of SC. Immune cells dysfunctions with age are multi-faceted and are uniquely attributed to the independent processes of immunosenescence and cellular senescence which may collectively impair immune system mediated clearance of SC. Moreover, being functionally and phenotypically heterogenic, immune cells are also liable to be affected by senescence microenvironment in other tissues. Therefore, strategies aimed at improving immunosenescence and cellular senescence in immune cells can have pleiotropic effects on ageing physiology including the accumulation of SC. In this regard, nutraceutical's immunomodulatory attributes are well documented which may have implications in developing nutrition-oriented immunotherapeutic approaches against SC. In particular, the three diverse sources of bioactive ingredients, viz., phytochemicals, probiotic bacteria and omega-3-fatty acids have shown promising anti-immunosenescence and anti-cellular senescence potential in immune cells influencing aging and immunity in ways beyond modest stimulation of immune responses. The present narrative review describes the preventive and therapeutic attributes of phytochemicals such as polyphenols, probiotic microbes and omega-3-fatty acids in influencing the emerging nexus of immunosenescence, cellular senescence and SC during aging. Outstanding questions and nutraceuticals-based pro-longevity and niche research areas have been deliberated. Further research using integrative approaches is recommended for developing nutrition-based holistic immunotherapeutic strategies for 'healthy ageing'.
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http://dx.doi.org/10.1016/j.arr.2020.101141DOI Listing
November 2020

Intersection of the ATF6 and XBP1 ER stress pathways in mouse islet cells.

J Biol Chem 2020 10 11;295(41):14164-14177. Epub 2020 Aug 11.

Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, New York, USA

Success or failure of pancreatic beta cell adaptation to ER stress is a determinant of diabetes susceptibility. The ATF6 and IRE1/XBP1 pathways are separate ER stress-response effectors important to beta cell health and function. ATF6α. and XBP1 direct overlapping transcriptional responses in some cell types. However, the signaling dynamics and interdependence of ATF6α and XBP1 in pancreatic beta cells have not been explored. To assess pathway-specific signal onset, we performed timed exposures of primary mouse islet cells to ER stressors and measured the early transcriptional response. Comparing the time course of induction of ATF6 and XBP1 targets suggested that the two pathways have similar response dynamics. The role of ATF6α in target induction was assessed by acute knockdown using islet cells from α mice transduced with adenovirus expressing Cre recombinase. Surprisingly, given the mild impact of chronic deletion in mice, acute ATF6α knockdown markedly reduced ATF6-pathway target gene expression under both basal and stressed conditions. Intriguingly, although ATF6α knockdown did not alter splicing dynamics or intensity, it did reduce induction of XBP1 targets. Inhibition of splicing did not decrease induction of ATF6α targets. Taken together, these data suggest that the XBP1 and ATF6 pathways are simultaneously activated in islet cells in response to acute stress and that ATF6α is required for full activation of XBP1 targets, but XBP1 is not required for activation of ATF6α targets. These observations improve understanding of the ER stress transcriptional response in pancreatic islets.
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http://dx.doi.org/10.1074/jbc.RA120.014173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549035PMC
October 2020

Telomeres, DNA Damage and Ageing: Potential Leads from Ayurvedic Rasayana (Anti-Ageing) Drugs.

J Clin Med 2020 Aug 6;9(8). Epub 2020 Aug 6.

Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal.

Ageing, while a relentless, unidirectional and pleiotropic phenomenon of life, is a key trigger for several age-related disorders, such as cancer, cataract, osteoporosis, hypertension, cardiovascular (CV), metabolic and even neurodegenerative ailments, including Alzheimer's (AD) and Parkinson's (PD) disease [1] [...].
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http://dx.doi.org/10.3390/jcm9082544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465058PMC
August 2020

Merkel Cell Polyomavirus Small T Antigen Activates Noncanonical NF-κB Signaling to Promote Tumorigenesis.

Mol Cancer Res 2020 11 4;18(11):1623-1637. Epub 2020 Aug 4.

Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas.

Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT-expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth and in xenografts. We identify MCPyV sT-induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. IMPLICATIONS: This work is the first to identify the activation of ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641980PMC
November 2020