The endocrinologist gap: Managing diabetes patients in absence of a specialist.

The treatment of pediatric patients with diabetes is frequently orchestrated within a multidisciplinary framework at tertiary, specialized institutions. In situations where emergent surgery is indicated or when a procedure is scheduled in a facility devoid of an endocrinology service, the onus of managing perioperative glycemic levels may rest with the attending anesthesiologist. The objective of this review is to furnish a comprehensive examination of the anesthetic considerations and perioperative governance of pediatric patients with diabetes. Furthermore, this paper delineates a streamlined protocol for perioperative glycemic control, tailored to both major and minor surgical interventions.

ERAS following Gastrectomy for Octo- and Nonagenarians: A Single-Center Retrospective Analysis.

Background: The safety and efficacy of enhanced recovery after surgery (ERAS) following elective gastrectomy for gastric cancer in patients >80 years of age are not well described. The aim of this study was to explore whether an ERAS protocol following gastrectomy in this age group can be safely implemented and reduce postoperative length of stay. Methods: A retrospective, single-center analysis was performed. All patients >80 years of age with gastric cancer undergoing elective subtotal and total gastrectomy between January 2010 and December 2021 were identified. With the implementation of an ERAS protocol in January 2016, patients treated beforehand were allocated to Group A (pre-ERAS) and Group B (ERAS). The length of stay, incidence of postoperative complications and representation/readmission to the hospital were compared between the groups. Results: Of the 221 patients identified, 56 met the inclusion criteria with 22 patients (39.3%) allocated to Group A and 34 patients (60.7%) to Group B. There were no differences with regard to the type of resection and surgical approach. Length of stay was shorter in Group B (5 days, range 2-27 versus 10 days, 3-109, P = .040). A trend toward more discharges by postoperative day 3 was noted among patients in Group B (7/34, 20.6% versus 2/22, 9.1%, P = .253). There were no differences in the incidence of postoperative complications or readmission hospital between the groups. Conclusion: Among patients >80 years of age, ERAS following gastrectomy for cancer is associated with a reduced length of stay and can be safely implemented.

Cannabis Use Characteristics Associated with Self-Reported Cognitive Function in a Nationally Representative U.S. sample.

BACKGROUND: With increases in cannabis use and potency, there is a need to improve our understanding of the impact of use on cognitive function. Previous research indicates long-term cannabis use may have a negative effect on executive function. Few studies have examined persistence of it in protracted abstinence, and there is limited evidence of predictors of worse cognitive function in current and former users. In this study, we aim to evaluate the associations between cannabis use status (current, former, and never use) and self-report cognition. Further, we investigate if cannabis use characteristics predict self-report cognitive function. METHODS: Cross-sectional cannabis use data from the National Epidemiological Survey on Alcohol and Related Conditions-III (NESARC-III), a national survey (N = 36,309) conducted in the USA between 2012 and 2013 were used alongside the Executive Function Index scales. The data were analyzed by using Ordinary Least Squares regression. RESULTS: Current (N = 3,681, Female = 37.7%) and former users (N = 7,448, Female = 45.4%) reported poorer cognition than never users (N = 24,956, Female = 56.6%). Self-reported cognition of former users was in-between that of current and never users. Several cannabis use characteristics were associated with self-reported cognition in current and former users. CONCLUSION: While prospective studies are required to confirm, findings suggest cannabis use is linked to worse cognition. There may be some limited recovery of cognition in former users and some cannabis use characteristics predict impairment. These findings add to our understanding of the cognitive impact of cannabis use. As worse cognitive function may impact relapse, findings have implications for personalization of cannabis use disorder treatment.

Evaluation and assessment of the survival of tooth implant supported prosthesis in tooth and implant supported rehabilitation cases with metal frameworks.

INTRODUCTION: Over the years, implant therapy has been a commonly used treatment option for individuals who are partially or totally edentulous, with a long-term success rate of over 90%. With significant advancements in biomaterials and technology, implant dentistry can now conduct prosthetic rehabilitations in the majority of patients catering to all types of needs. However, in order to meet the demands of a patient base that is always growing, new trends in implantology are emerging in recent years that are focused on minimally invasive surgery and financial sustainability. In certain clinical scenarios, connecting teeth and implants to support fixed partial prosthesis (FPPs) may be a predictable and workable course of treatment. MATERIALS AND METHODS: 22 patients were selected for this study who had tooth and implant supported prosthesis placed as a final restoration. Out of these 22 patients; 12 were male and 10 were female patients. Implants were placed following proper protocol and if grafting procedures were required they were carried out. A second stage surgical procedure was carried out and delayed loading protocols were followed. The statistical analysis was done using the IBM SPSS 24.0, Chicago, USA. The survival of the implants and teeth were measured by the Kaplan Meier survival scale. Bone loss was assessed at baseline(upon loading), 12 months and 24 months. RESULTS: The implant survival rate was measured at 6 months, 12 months, 18 months and 24 months. At 24 months, one implant showed failure, so the survival rate of the implants were 95.4%. Bone loss of 1 mm was seen around one implant at 12 months. Bone loss of 1 and 2 mm was present around two implants and one implant respectively at 24 months. CONCLUSION: From the results of this study, we can conclude that tooth implant supported prosthesis show very good survival when used in rehabilitation cases.

Nanozymes and carbon-dots based nanoplatforms for cancer imaging, diagnosis and therapeutics: Current trends and challenges.

Cancer patients face a significant clinical and socio-economic burden due to increased incidence, mortality, and poor survival. Factors like late diagnosis, recurrence, drug resistance, severe side effects, and poor bioavailability limit the scope of current therapies. There is a need for novel, cost-effective, and safe diagnostic methods, therapeutics to overcome recurrence and drug resistance, and drug delivery vehicles with enhanced bioavailability and less off-site toxicity. Advanced nanomaterial-based research is aiding cancer biologists by providing solutions for issues like hypoxia, tumor microenvironment, low stability, poor penetration, target non-specificity, and rapid drug clearance. Currently, nanozymes and carbon-dots are attractive due to their low cost, high catalytic activity, biocompatibility, and lower toxicity. Nanozymes and carbon-dots are increasingly used in imaging, biosensing, diagnosis, and targeted cancer therapy. Integrating these materials with advanced diagnostic tools like CT scans and MRIs can aid in clinical decision-making and enhance the effectiveness of chemotherapy, photothermal, photodynamic, and sonodynamic therapies, with minimal invasion and reduced collateral effects.

Docetaxel-Based Neoadjuvant Chemotherapy Followed by En Bloc Resection for Esophageal Adenocarcinoma: A 15-Year Retrospective Analysis from a Regional Upper Gastrointestinal Cancer Network.

BACKROUND: Real-world, long-term survival outcomes of neoadjuvant, docetaxel-based therapy for esophageal and junctional adenocarcinoma are lacking. This study describes the long-term survival outcomes of patients with esophageal and junctional adenocarcinoma treated with neoadjuvant docetaxel-based chemotherapy and en bloc transthoracic esophagectomy. METHODS: A retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada, was performed. From January 2007 to December 2021, all patients with locally advanced (cT3 and/or N1) esophageal/Siewert I/II adenocarcinoma treated with neoadjuvant DCFx3 (Docetaxel/Cisplatin/5FU) or FLOTx4 (5FU/Leucovorin/Oxaliplatin/Docetaxel) and transthoracic en bloc esophagectomy were identified. Postoperative, pathological, and survival outcomes were compared. RESULTS: Overall, 236 of 420 patients met the inclusion criteria. Tumor location was esophageal/Siewert I/Siewert II (118/33/85), most were cT3-4 (93.6%) and cN+ (61.0%). DCF and FLOT were used in 127 of 236 (53.8%) and 109 of 236 (46.2%). All neoadjuvant cycles were completed in 87.3% with no difference between the regimens. Operative procedures included Ivor Lewis (81.8%), left thoraco-abdominal esophagectomy (10.6%) and McKeown (7.6%) with an R0 resection in 95.3% and pathological complete response in 9.7% (DCF 12.6%/FLOT 6.4%, p = 0.111). The median lymph node yield was 32 (range 4-79), and 60.6% were ypN+. Median follow-up was longer for the DCF group (74.8 months 95% confidence interval [CI] 4-173 vs. 37.8 months 95% CI 2-119, p <0.001. Overall survival was similar between the groups (FLOT 97.3 months, 78.6-115.8 vs. DCF 92.9, 9.2-106.5, p = 0.420). CONCLUSIONS: Neoadjuvant DCF and FLOT followed by transthoracic en bloc resection are both highly effective regimens for locally advanced esophageal adenocarcinoma with equivalent survival outcomes despite high disease load.

Incorporating mutational heterogeneity to identify genes that are enriched for synonymous mutations in cancer.

BACKGROUND: Synonymous mutations, which change the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations might be enriched in cancer has been explored in several recent studies. However, none of these studies control for all three types of mutational heterogeneity (patient, histology, and gene) that are known to affect the accurate identification of non-synonymous cancer-associated genes. Our goal is to adopt the current standard for non-synonymous mutations in an investigation of synonymous mutations. RESULTS: Here, we create an algorithm, MutSigCVsyn, an adaptation of MutSigCV, to identify cancer-associated genes that are enriched for synonymous mutations based on a non-coding background model that takes into account the mutational heterogeneity across these levels. Using MutSigCVsyn, we first analyzed 2572 cancer whole-genome samples from the Pan-cancer Analysis of Whole Genomes (PCAWG) to identify non-synonymous cancer drivers as a quality control. Indicative of the algorithm accuracy we find that 58.6% of these candidate genes were also found in Cancer Census Gene (CGC) list, and 66.2% were found within the PCAWG cancer driver list. We then applied it to identify 30 putative cancer-associated genes that are enriched for synonymous mutations within the same samples. One of the promising gene candidates is the B cell lymphoma 2 (BCL-2) gene. BCL-2 regulates apoptosis by antagonizing the action of proapoptotic BCL-2 family member proteins. The synonymous mutations in BCL2 are enriched in its anti-apoptotic domain and likely play a role in cancer cell proliferation. CONCLUSION: Our study introduces MutSigCVsyn, an algorithm that accounts for mutational heterogeneity at patient, histology, and gene levels, to identify cancer-associated genes that are enriched for synonymous mutations using whole genome sequencing data. We identified 30 putative candidate genes that will benefit from future experimental studies on the role of synonymous mutations in cancer biology.

Evaluation and Assessment of the Colour Stability of Modified Polymethyl Methacrylate Denture Base Materials and Polyether Ether Ketone in a Cast Partial Denture Framework: An In-Vitro Study.

Background One of the frequent aesthetic issues patients confront is the loss of colour and lifeless appearance of the dentures of the base materials of their dentures after regular use. This leads to a lack of motivation to use the denture regularly. Due to the drawbacks of conventional PMMA, polyether ether ketone (PEEK) and newer polymethyl methacrylate (PMMA)-based materials have now started being used in cast partial denture frameworks due to their superior physical and biological properties. The lack of long-lasting colour is one of the main reasons for the repeat of dental prostheses. Hence, the need for the study is to help clinicians decide which would be the most suitable denture base material to be used based on colour stability. Aim To assess and compare the colour stability of PEEK, polyan, and biodentaplast denture base materials (DBMs) upon staining with distilled water, tea, coffee, and turmeric solutions after one day, seven days, and 30 days. Methods A total of 20 cuboidal specimens were constructed and immersed in distilled water, tea, coffee, and turmeric (five specimens of each material in each solution, a total of 60 specimens): Group 1: PEEK, Group 2: polyan, Group 3: biodentaplast. All specimens were subjected to colour measurements before exposure to beverage solutions, after 24 hours, on the seventh day and 30th day with a colour reflectance spectrophotometer with computer software. A one-way ANOVA test followed by post hoc Tukey's honestly significant difference (HSD) was performed for comparison of colour stability between the DBMs, revealing a significant difference between PEEK and polyan and PEEK and biodentaplast. Polyan showed the highest delta E values, followed by biodentaplast and PEEK. A two-way ANOVA test, followed by Tukey's HSD post hoc, was done to compare the staining ability of various staining solutions. Turmeric had the highest delta E values, followed by coffee, tea, and distilled water. Data were assessed using Statistical Product and Service Solutions (SPSS, version 23) (IBM SPSS Statistics for Windows, Armonk, NY) software. Results The highest mean delta E value at T1 was seen in biodentaplast immersed in turmeric (12.3900+/-0.442), and the least value at T1 was obtained for PEEK immersed in distilled water (0.4460+/-0.036). The highest mean delta E value at T2 was seen in polyan immersed in turmeric (13.0160+/-0.28962), and the least value at T2 was obtained for PEEK immersed in distilled water (0.5860+/-0.051). At T3, the highest mean delta E value was seen in polyan immersed in turmeric (16.8600+/-0.49845), and the least value at T3 was obtained for PEEK immersed in distilled water (0.700+/-0.037). Conclusion PEEK had the highest colour stability when compared with polyan and biodentaplast.

Survival and perioperative outcomes of octo- and nonagenarians with resectable esophageal carcinoma.

The outcomes of different treatment modalities for patients aged 80 and above with locally advanced and resectable esophageal carcinoma are not well described. The aim of this study was to explore survival and perioperative outcomes among this specific group of patients. A retrospective, cohort analysis was performed on a prospectively maintained esophageal cancer database from the McGill regional upper gastroinestinal cancer network. Between 2010 and 2020, all patients ≥80 years with cT2-4a, Nany, M0 esophageal carcinoma were identified and stratified according to the treatment modality: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT); definitive CRT (dCRT); upfront surgery; palliative CT/RT; or best supportive care (BSC). Of the 162 patients identified, 79 were included in this study. The median age was 83 years (80-97), most were cT3 (73%), cN- (56%), and had adenocarcinoma (62%). Treatment included: nCT/nCRT (16/79, 20%); surgery alone (19/79, 24%); dCRT (12/29, 15%); palliative RT/CT (27/79, 34%); and BSC (5/79, 6%). Neoadjuvant treatment was completed in 10/16 (63%). Of the 35/79 who underwent surgery, major complications occurred in 13/35 (37%) and 90-day mortality in 3/35 (9%). Overall survival (OS) for the cohort at 1- and 3-years was 58% and 19%. Among patients treated with nCT/nCRT, this was 94% and 46% respectively. Curative intent treatment (nCT/nCRT/upfront surgery/dCRT) had significantly increased 1- and 3- year OS compared with non-curative treatment (76%/31% vs. 34%/3.3%). Multimodal standard of care treatment is feasible and safe in select octo/nonagenarians, and may be associated with improved OS. Age alone should not bias against treatment with curative intent.

Plant-Derived Bioactive Compounds in the Management of Neurodegenerative Disorders: Challenges, Future Directions and Molecular Mechanisms Involved in Neuroprotection.

Neurodegenerative disorders encompass a wide range of pathological conditions caused by progressive damage to the neuronal cells and nervous-system connections, which primarily target neuronal dysfunction and result in problems with mobility, cognition, coordination, sensation, and strength. Molecular insights have revealed that stress-related biochemical alterations such as abnormal protein aggregation, extensive generation of reactive oxygen and nitrogen species, mitochondrial dysfunction, and neuroinflammation may lead to damage to neuronal cells. Currently, no neurodegenerative disease is curable, and the available standard therapies can only provide symptomatic treatment and delay the progression of the disease. Interestingly, plant-derived bioactive compounds have drawn considerable attention due to their well-established medicinal properties, including anti-apoptotic, antioxidant, anti-inflammatory, anticancer, and antimicrobial properties, as well as neuroprotective, hepatoprotective, cardioprotective, and other health benefits. Plant-derived bioactive compounds have received far more attention in recent decades than synthetic bioactive compounds in the treatment of many diseases, including neurodegeneration. By selecting suitable plant-derived bioactive compounds and/or plant formulations, we can fine tune the standard therapies because the therapeutic efficacy of the drugs is greatly enhanced by combinations. A plethora of in vitro and in vivo studies have demonstrated plant-derived bioactive compounds' immense potential, as proven by their capacity to influence the expression and activity of numerous proteins implicated in oxidative stress, neuroinflammation, apoptosis, and aggregation. Thus, this review mostly focuses on the antioxidant, anti-inflammatory, anti-aggregation, anti-cholinesterase, and anti-apoptotic properties of several plant formulations and plant-derived bioactive compounds and their molecular mechanisms against neurodegenerative disorders.

Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review.

Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk of developing progressive fibrosis, cirrhosis, and hepatocellular carcinoma. As of now, there are no FDA-approved treatments for NAFLD/non-alcoholic steatohepatitis (NASH) or its associated fibrosis. Although many drugs are under clinical trial, both obeticholic acid (OCA) and semaglutide are among the few that have reached phase III clinical trials, but they were never compared. We decided to conduct a systematic review of randomized controlled trials and meta-analyses. A total of 6,589 articles were found after searching PubMed, OVID Embase, OVID Medline, PubMed Central, and clinicaltrials.gov. Only full-text peer-reviewed articles published in the past six years were put through the Cochrane bias assessment tool or the Assessment of Multiple Systematic Reviews (AMSTAR) tool to screen for bias. After strict quality assessment, data from five randomized controlled trials (n=2,694) and three systematic reviews/meta-analysis (n=8,898) was extracted and included. The data extraction from these studies showed that semaglutide and OCA cause histological improvement, but NASH resolution is exclusive to semaglutide. Although high doses of OCA can cause dyslipidemia and severe pruritus, it is the only therapeutic that causes improvement in NASH-associated hepatic fibrosis. Semaglutide is the safest option among the two and leads to significant weight loss compared to OCA; thus, a better outcome on hepatic steatosis follows. The indications of each of these drugs should be based on the NAFLD activity score and NASH fibrosis stage. OCA should be used with caution among patients with hyperlipidemia and ischemic heart disease as it may make these conditions worst.

Implications of Nerve Fiber Density on the Diagnosis and Treatment of Juvenile Fibromyalgia.

Juvenile fibromyalgia (JFM) is a condition that presents as chronic widespread musculoskeletal pain and affects children and adolescents. JFM remains a challenging diagnosis, as it is both based on subjective criteria and the pathogenesis is poorly understood. Small fiber neuropathy (SFN) is a distinct condition, which is characterized by pathology of small A-delta and C fibers, and can present similarly to JFM. Small fiber pathology is characterized by reduced intraepidermal nerve fiber density (IENFD) on skin biopsy. Recent studies have found that as many as half of patients with JFM can demonstrate decreased IENFD, in pattern similar to SFN. This phenomenon has been referred to as small fiber pathology. The meaning of these findings was disputed; however, the current consensus remains that fibromyalgia and SFN are distinct conditions. Additionally, among patients with fibromyalgia, there are two phenotypes: those with small fiber pathology and those without. The purpose of this review was to characterize the role assessment of IENFD plays in the clinical context. We conducted a narrative review of pertinent articles pertaining to JFM, SFN and small fiber pathology in fibromyalgia. We concluded that assessment of IENFD should be completed if SFN is suspected either when a patient first presents or in patients who were previously diagnosed with fibromyalgia and SFN is later suspected. Distinguishing between JFM and SFN is important because recommended therapies differ between the two conditions. However, there is no evidence to support the use of skin biopsy to distinguish between the two discussed fibromyalgia phenotypes. More studies are needed to elucidate whether IENFD varies with morbidity and if both fibromyalgia phenotypes vary in their response to different therapeutic regimens.

Awareness of usage of fentanyl in dental applications among dental students.

Opioids like fentanyl are used both alone and in combination with other drugs to induce anesthesia and treat pain. It is also combined with heroin or cocaine when used recreationally. It starts acting quickly, and its effects usually wear off within 2 h. A typical pharmaceutical strategy for controlling the physical pain and psychological discomfort related to dental treatments, including surgery, is moderate (conscious) sedation. This study aimed to assess knowledge and awareness about dental applications of fentanyl among dental students. A 15-question survey was sent through an online platform to about 150 dental students in Tamil Nadu. Data were collected over a 6-month period and compared using SPSS software by IBM. The results were statistically analyzed and graphically interpreted. From the results obtained, we can observe that from the respondents of the current survey, 52% were undergraduates and 48% were postgraduate dental students. About 93% of them were aware of the fact that fentanyl comes under opioid analgesics, and 82% were aware that it is mostly used in case of pediatric patients. About 81% of the participants were aware that apart from benzodiazepines, fentanyl can also be used in combination with general anesthesia in dentistry. This study revealed that most of the participants are aware of the commonly used anesthesia and analgesia such as fentanyl in dental practices. However, more continuing dental education programs and seminars must be conducted to further enhance the knowledge and understanding of dental students about drugs such as fentanyl in dental practice.

Awareness of usage of Vicryl suture material in oral surgical procedures.

Oral surgical procedures constitute a very important part in the broad scope of general dentistry. This necessitates a significant need for dental students to know about the suture materials. This study aims to assess the awareness of Vicryl suture material in dental surgical procedures. The descriptive survey was attended among 237 dental students. Results were analyzed using Microsoft Excel and using SPSS software version 23.0. The majority (96%) of the dental students were aware of Vicryl suture material. Approximately 75% and 66% knew that Vicryl suture was absorbable and braided, respectively. However, only 33% knew that Vicryl suture would get fall off in 2 weeks. According to the statistics, there is no significant difference between gender and awareness of Vicryl suture material (Chi-square; P = 0.14, not significant). Dental students have adequate knowledge about Vicryl suture material.

Comparative analysis of weld strength of nickel-chromium and cobalt-chromium base metal alloys when submitted to tungsten inert gas welding.

Long span base metal alloy fixed prosthesis and partial dental prosthesis frameworks most often require welding for better fit and adaptation. The type of metal alloys used and its effect on the weld strength of the prosthesis have to be investigated. The aim of the study is to comparatively analyze the weld strength of nickel-chromium (Ni-Cr) and cobalt-chromium (Co-Cr) base metal alloys when subjected to tungsten inert gas (TIG) welding. 10 nickel- and cobalt-based specimens were obtained by casting of castable resin patterns of dimension 25 mm × 3 mm × 1 mm. Welding of the samples was carried out using the Lampert PuK 2 welding equipment, and a three-point bend test using a universal testing machine was carried out to evaluate the weld strength of the specimens. Statistical analysis was carried out using the SPSS software version 23. Higher weld strength was observed in the Co-Cr alloy (mean = 898 MPa) than in the Ni-Cr alloy (mean = 690 MPa), when submitted to TIG welding (P < 0.05). TIG welding could be a better alternative for joining base metal alloys for long span edentulous cases, and cobalt-based alloys could be better alternatives to nickel-based alloys that usually tend to cause hypersensitivity reactions.

Current status of usage of ivermectin in the management of COVID.

The antibacterial, antiviral, and anticancer properties of ivermectin make it a wonder drug with a wide range of possible applications. It works against a variety of microorganisms, including viruses. Ivermectin has a wide range of antiviral effects, according to in vivo research in animal models. Because ivermectin is involved in a range of biological processes, it could be a promising therapeutic candidate for viruses such as COVID-19 and other positive-sense single-stranded RNA viruses. The study aims to analyze the awareness about the current status of usage of ivermectin in management of COVID among students studying in a private dental college. A study based on questionnaire was organized among students studying in a private dental college in Tamil Nadu. The subjects were asked a series of structural questions based on the usage of ivermectin in management of COVID. The questionnaire was prepared with 10 questions. 150 individuals completed the questionnaire; all of their answers were tallied in excel and imported into SPSS. For statistical analysis, the Chi-square test was performed. Excel was used to tabulate and enter the data, and the SPSS package software was used to analyze it. The study's threshold for statistical significance was set at P < 0.05. From this study, we found that the students had limited knowledge about the usage of ivermectin for management of COVID. More studies should be conducted to widen the knowledge among the students about the current affairs of the world.

DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha).

Withania somnifera, commonly known as Ashwagandha, is a medicinal plant used for thousands of years for various remedies. Extracts of Ashwagandha contain more than 200 metabolites, with withanone (win) being one of the major ones responsible for many of its medicinal properties. Recently, several cases of liver toxicity resulting from commercially available Ashwagandha products have been reported. The first report of Ashwagandha-related liver damage was from Japan, which was quickly resolved after drug-withdrawal. Later, similar cases of liver toxicity due to Ashwagandha consumption were reported from the USA and Iceland. Towards understanding the liver toxicity of Ashwagandha extracts, we studied win, a representative withanolide having toxicophores or structural alerts that are commonly associated with adverse drug reactions. We found that win can form non-labile adducts with the nucleosides dG, dA, and dC. Using various biochemical assays, we showed that win forms adducts in DNA and interfere with its biological property. Win also forms adducts with amines and this process is reversible. Based on the data presented here we concluded that win is detoxified by GSH but under limiting GSH levels it can cause DNA damage. The work presented here provides a potential mechanism for the reported Ashwagandha-mediated liver damage.

Protective Role of Glutathione against Peroxynitrite-Mediated DNA Damage During Acute Inflammation.

Inflammation is an immune response to protect against various types of infections. When unchecked, acute inflammation can be life-threatening, as seen with the current coronavirus pandemic. Strong oxidants, such as peroxynitrite produced by immune cells, are major mediators of the inflammation-associated pathogenesis. Cellular thiols play important roles in mitigating inflammation-associated macromolecular damage including DNA. Herein, we have demonstrated a role of glutathione (GSH) and other thiols in neutralizing the effect of peroxynitrite-mediated DNA damage through stable GSH-DNA adduct formation. Our observation supports the use of thiol supplements as a potential therapeutic strategy against severe COVID-19 cases and a Phase II (NCT04374461) open-label clinical trial launched in early May 2020 by the Memorial Sloan Kettering Cancer Center.

Comparative genomic analysis of collagen gene diversity.

Collagen gene family, comprising 30% of the total protein mass in mammals, is the major part of extracellular matrix. To understand the complexity of collagen gene family, detailed sequence, phylogenetic and synteny analyses of 44 collagen genes were performed. According to sequence analysis results, Fibril-associated collagen with interrupted triple helices (FACITs) were identified as the most recently evolved vertebrate-specific collagens while Fibril-forming collagens and Collagen VI, VII, XXVI, and XXVIII were the most ancient collagens, originating at the time of choanoflagellates. Network-forming collagens were entirely conserved from arthopods to homo sapiens, except one gene loss event. Of note, bird specific gene dispensability of COL1A1, COL3A1, COL5A3 and COL11A2 genes was observed in Fibril-forming collagens. According to phylogenetic analysis, gene duplications in collagen family occurred at variable time points during invertebrate to vertebrate evolution. However, majority of gene duplications in FACITs and network-forming collagens occurred at fish time point, suggesting large scale duplications at the root of vertebrate lineage. Lastly, synteny analysis identified 12 conserved blocks containing 27 collagen genes in vertebrate species. Interestingly, dysregulation of seven conserved blocks including block1 (COL11A1), block3 (COL3A1, COL5A2), block5 (COL6A5, COL6A6), block7 (COL1A2), block9 (COL4A1, COL4A2), block11 (COL6A1, COL6A2, COL18A1) and block12 (COL4A5, COL4A6) were also reported in different diseases including cancer. The current study revealed many critical insights into sequence, structural and functional diversity of collagen gene family. In future, by using this information we may be able to establish the clinical and pathological relevance of these conserved collagen blocks in different diseases.

Profiling Ssb-Nascent Chain Interactions Reveals Principles of Hsp70-Assisted Folding.

The yeast Hsp70 chaperone Ssb interacts with ribosomes and nascent polypeptides to assist protein folding. To reveal its working principle, we determined the nascent chain-binding pattern of Ssb at near-residue resolution by in vivo selective ribosome profiling. Ssb associates broadly with cytosolic, nuclear, and hitherto unknown substrate classes of mitochondrial and endoplasmic reticulum (ER) nascent proteins, supporting its general chaperone function. Ssb engages most substrates by multiple binding-release cycles to a degenerate sequence enriched in positively charged and aromatic amino acids. Timely association with this motif upon emergence at the ribosomal tunnel exit requires ribosome-associated complex (RAC) but not nascent polypeptide-associated complex (NAC). Ribosome footprint densities along orfs reveal faster translation at times of Ssb binding, mainly imposed by biases in mRNA secondary structure, codon usage, and Ssb action. Ssb thus employs substrate-tailored dynamic nascent chain associations to coordinate co-translational protein folding, facilitate accelerated translation, and support membrane targeting of organellar proteins.