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1.
Microbiol Res ; 237: 126478, 2020 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-32361340

RESUMO

The emergence of resistance among fungal phytopathogens poses a biggest threat across the world. Streptomyces are a group of spore-forming Gram + ve bacteria and prolific producers of secondary bioactive metabolites which have been used as biocontrol agents against phytopathogens and also known for plant growth promotion. The current study identified a potent isolate M4 from soil with broad spectrum antifungal activity against different fungal phytopathogens. The isolate was identified as a Streptomyces sp. on the basis of cultural, morphological, physiological, biochemical and phylogenetic characteristics. 16S rRNA gene sequence of M4 showed 100 % similarity with three Streptomyces spp. i.e. Streptomyces plicatus NBRC 13071 T (AB184291), Streptomyces rochei NBRC 12908 T AB184237 and Streptomyces enissocaesilis NRRL-B-16365 T (DQ026641). However, phenotypic and phylogenetic analysis concluded that M4 represents a novel sp. within the genus Streptomyces. One of the two antifungal compounds purified from Streptomyces M4 was identified as salvianolic acid B. To our knowledge, the present study is the first work reporting purification and characterization of salvianolic acid B from Streptomyces and its broad spectrum antifungal activity against different fungal phytopathogens viz. Alternaria spp., Fusarium spp., Colletotrichum spp., Cladosporium herbarum and Botrytis cineria. Salvianolic acid B was found to be photostable, thermostable (up to 70 °C) and non-mutagenic in nature and might be developed as safe biofungicide to control phytopathogens.

2.
Comput Biol Med ; 119: 103691, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32339125

RESUMO

Sleep is one of the most important body mechanisms responsible for the proper functioning of human body. Cyclic alternating patterns (CAP) play an indispensable role in the analysis of sleep quality and related disorders like nocturnal front lobe epilepsy, insomnia, narcolepsy etc. The traditional manual segregation methods of CAP phases by the medical experts are prone to human fatigue and errors which may lead to inaccurate diagnosis of sleep stages. In this paper, we present an automated approach for the classification of CAP phases (A and B) using Wigner-Ville Distribution (WVD) and Rényi entropy (RE) features. The WVD provides a high-resolution time-frequency analysis of the signals whereas RE provides least time-frequency uncertainty with WVD. The classification is performed using medium Gaussian kernel-based support vector machine with 10-fold cross-validation technique. We have presented the results for randomly sampled balanced data sets. The proposed approach does not require any pre-processing or post-processing stages, making it simple as compared to the existing techniques. The proposed method is able to achieve an average classification accuracy of 72.35% and 87.45% for balanced and unbalanced data sets respectively. The proposed method can aid the medical experts to analyze the cerebral stability as well as the sleep quality of a person.

3.
Am Soc Clin Oncol Educ Book ; 40: 1-17, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32315240

RESUMO

Antibody drug conjugates (ADCs) are an emerging class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody, which is directed toward a specific cell surface target expressed by tumor cells and/or the microenvironment. ADCs leverage the specificity of the antibody such that it functions as a carrier to deliver the cytotoxic payload into the tumor. Four parameters are considered critical for this class of complex engineered therapeutics: target selection, antibody, cytotoxic payload, as well as conjugation and linker technology. The development of this class of drugs has proven more complex than expected. Several challenges have arisen, including a lack of true tumor antigen specificity, early release of the cytotoxic payload into the bloodstream due to linker instability, and low potency of the payload, resulting in either greater toxicity or lack of improved efficacy compared with unconjugated cytotoxics. The approval of trastuzumab emtansine in 2013 for HER2-positive breast cancer served as a proof of concept that ADCs have therapeutic application in solid tumors. Two novel ADCs have recently been approved: trastuzumab deruxtecan for HER2-positive breast cancer and enfortumab vedotin for locally advanced or metastatic urothelial cancer. Trastuzumab deruxtecan is distinguished by a unique biochemical structure with a novel cytotoxic payload, deruxtecan-a highly potent, topoisomerase I inhibitor. Enfortumab vedotin is directed toward nectin-4 and represents an example of successful and strategic target selection. This review focuses on the concepts underlying the choice of suitable targets and novel payloads, discusses specific examples of ADCs in preclinical and clinical development, and provides future directions related to this unique class of therapeutics.

4.
Biochim Biophys Acta Mol Basis Dis ; 1866(7): 165769, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32184133

RESUMO

Brain is well known for its disproportionate oxygen consumption and high energy-budget for optimal functioning. The decrease in oxygen supply to brain, thus, necessitates rapid activation of adaptive pathways - the absence of which manifest into vivid pathological conditions. Amongst these, oxygen sensing in glio-vascular milieu and H2S-dependent compensatory increase in cerebral blood flow (CBF) is a major adaptive response. We had recently demonstrated that the levels of H2S were significantly decreased during chronic hypobaric hypoxia (HH)-induced neuro-pathological effects. The mechanistic basis of this phenomenon, however, remained to be deciphered. We, here, describe experimental evidence for marked limitation of cysteine during HH - both in animal model as well as human volunteers ascending to high altitude. We show that the preservation of brain cysteine level, employing cysteine pro-drug (N-acetyl-L-cysteine, NAC), markedly curtailed effects of HH - not only on endogenous H2S levels but also, impairment of spatial reference memory in our animal model. We, further, present multiple lines of experimental evidence that the limitation of cysteine was causally governed by physiological propensity of brain to utilize cysteine, in cystathionine beta synthase (CBS)-dependent manner, past its endogenous replenishment potential. Notably, decrease in the levels of brain cysteine manifested despite positive effect (up-regulation) of HH on endogenous cysteine maintenance pathways and thus, qualifying cysteine as a conditionally essential nutrient (CEN) during HH. In brief, our data supports an adaptive, physiological role of CBS-mediated cysteine-utilization pathway - activated to increase endogenous levels of H2S - for optimal responses of brain to hypobaric hypoxia.

5.
Indian J Cancer ; 57(1): 76-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32129298

RESUMO

Introduction: Squamous cell carcinoma of head and neck (SCCHN) account for approximately 30-33% of all cancer and the median survival for recurrent and metastatic(R/M) SCCHN remains less than 1 year despite modern advances in therapy. Chemotherapy, usually single agent remains the backbone of therapy in these patients. EGFR antibodies are being used in (R/M) SCCHN. Nimotuzumab is one such agent that has anti-EGFR action similar to other agents without similar skin toxicity. Methods: Prospective, interventional, non-randomized study done at Rajiv Gandhi Cancer Institute and Research Centre. A total 124 patients were enrolled and divided into Arm A (Chemotherapy + Nimotuzumab) and Arm B (Chemotherapy) in a ratio of 1:1 i.e., 62 in each arm. They were evaluated and treated as per protocol after a written informed consent. Statistical analysis was done using the SPSS software. Quantitative variables were compared using Unpaired t-test/Mann-Whitney Test. Qualitative variables were compared using Chi-Square test /Fisher's exact test. Kaplan-Meier analysis was used to assess the PFS, with log rank test for comparison between the groups. A p value of < 0.05 was considered statistically significant. Results: The most frequent primary location of tumor was oral cavity (n=38, 69%) and (n=33, 56.9%) in both arms. The overall response rate in Arm A was 38.2% and 19% in Arm B (p= 0.023). The disease control rate in Arm A was 74.5% and 43.1% Arm B (p= 0.0007). The median PFS in Arm A was 5.2 months whereas it was 3.2 months in Arm B (p= 0.009). Conclusion: In this study, the combination of Nimotuzumab plus platinum/taxane based chemotherapy was active and well tolerated in Indian patients in R/M SCCHN. Addition of Nimotuzumab to chemotherapy had a response rate of 38.2% and median PFS of 5.2 months are strong arguments for clinically testing this combination.

6.
Biomed Chromatogr ; 34(6): e4825, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32166756

RESUMO

Treatment through a combination of drugs involving cyclin D-dependent kinase inhibitors like abemaciclib and aromatase inhibitor like letrozole proved to be a potential therapeutic regimen and first-line treatment in estrogen receptor-positive breast cancer. In this study, we developed a simple and simultaneous RP-HPLC bioanalytical method for quantifying abemaciclib and letrozole in rat plasma. Abemaciclib and letrozole were separated on Zorbax Eclipse C18 column employing a gradient elution method comprising 10 mM ammonium acetate (pH 5) and acetonitrile as mobile phase. The method was found to have acceptable selectivity, accuracy (97.20-118.17%), precision (1.10-9.39%) and stability in the validation experiment performed as per the US Food and Drug Administration guidelines. The method sensitivity was low at a concentration level of 100 ng/ml. The applicability of the method has been verified through a single-dose oral pharmacokinetic study in rat. The developed method will be useful to quantitate the analytes in rat plasma samples of different preclinical studies including their pharmacokinetic drug-drug interactions in the future. To date, no method has been reported for the quantification of abemaciclib and letrozole simultaneously in any type of biological matrices. Therefore, this study makes a definite significant contribution in the field of bioanalytical research.

7.
Acta Neurochir (Wien) ; 162(5): 1147-1151, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32193725

RESUMO

Herpes viruses have been described as markers of occult cancer and have also been implicated in oncogenesis. This group of viruses includes varicella-zoster virus (VZV) which is well-known for its ability to evade the immune response by lying dormant in the dorsal root ganglion of peripheral nerves. Although it is common knowledge that VZV reactivation causes herpes zoster (shingles), there have been no reports in literature of herpes zoster manifesting in the dermatomal territory of peripheral nerves involved by either benign or malignant tumors. We report two cases of patients with peripheral nerve tumors who presented with herpes zoster in the dermatomal distribution of the involved nerves. One patient had primary neurolymphomatosis, whereas the other had a sacral schwannoma. We believe these are the first cases to be reported that demonstrate herpes zoster at clinical presentation in patients with peripheral nerve tumors. This suggests that VZV may have the potential to cause peripheral nerve tumors via a complex interplay of viral oncogenes and alterations in host immunological responses.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32004940

RESUMO

Flibanserin (FLB) is the first FDA approved drug showed to have significant activity against sexual desire disorder of premenopausal and postmenopausal women. Unfortunately, FLB is used as an adulterant in dietary supplement products as a performance enhancer in sports. Identification of FLB and its metabolites in the biological samples requires an authenticated analytical technique. The aim of this study was to identify N-oxide metabolite of FLB in microsomal and S9 human liver enzyme fractions, rat urine and feces. There are several N-oxide reported as genotoxic impurity or reactive metabolites based on position of N-oxide in piperazine ring. This study also describes the strategy to utilize degradation chemistry for isolation of N-oxide and its step-wise characterization. An LC-MS method has been developed and employed for identifying the N-oxide metabolite of FLB. The targeted N-oxide metabolite in the extracted ion chromatogram of the in vitro and in vivo samples has been confirmed by analyzing the changes in observed mass at m/z 407.1693. Major distinguished abundant ions at m/z 243.1104, 190.0974, 161.0705, 119.0601 confirmed the structure of the metabolite. This study will help to understand the oxidative potential of FLB in toxicokinetic study. The developed method can be useful to identify FLB or its N-oxide metabolite in dope testing in future. This is the first time to report a strategy to utilize degradation chemistry for N-oxide metabolite characterization. In this study, isolated N-oxidative degradation product was used to confirm N-oxide metabolite which was characterized by LC-MS through H/D exchange and structure was ensured by NMR spectroscopy (1H, COSY).


Assuntos
Benzimidazóis , Medição da Troca de Deutério/métodos , Fezes/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/análise , Benzimidazóis/química , Benzimidazóis/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
9.
J Phys Chem Lett ; : 2092-2100, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32073268

RESUMO

Sodium batteries have emerged as a promising alternative for large-scale energy storage applications due to the low cost and high abundance of sodium. Sodium batteries require safe, high-voltage, and cost-effective electrolytes and cathode materials for their practical applications to be realized. In the present study, Na metal cells with a mixed-phase electrolyte comprising a high concentration of Na salt in an organic ionic plastic crystal (OIPC), namely, triisobutylmethylphosphonium bis(fluorosulfonyl)imide, are investigated-coupled with either a sodium vanadium phosphate-carbon composite (NVP/C) or a sodium iron pyrophosphate (NFpP) cathode. The performance of the Na/NVP/C and Na/NFpP cells are evaluated using cyclic voltammetry, electrochemical impedance spectroscopy, and galvanostatic cycling at 60 °C and room temperature. The results reported herein indicate the performance improvement in terms of cycling stability, with high Coulombic efficiency at 60 °C granted by the OIPC and ionic liquid mixtures, compared to a conventional organic solvent electrolyte.

10.
J Anal Toxicol ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020175

RESUMO

Flibanserin (FLB) is the first USFDA approved serotonin modulator recently marketed to treat acquired generalized women hypoactive sexual desire disorder. The scope of this study was to develop and validate a sensitive, selective and reliable ultra-performance-liquid chromatography-mass spectroscopy/mass spectroscopy based quantification method for FLB in rat plasma as well as brain tissue samples. The method includes a simple liquid-liquid sample extraction procedure. FLB was subjected to chromatographic separation using a poroshell C18 column with the mobile phase comprising a mixture of acetonitrile, 10 mM ammonium acetate and acetic acid (90:10:0.1, v/v/v). Detection and quantification of FLB after positive electrospray ionization was carried out in selective ion monitoring mode. The fragment ion (m/z) of FLB (parent ion: 391.1741) and IS (parent ion: 448.1550) were monitored at 161.0704 and 285.0917, respectively. A linear response of FLB was observed over a concentration range of 2.5 to 600 ng/mL in plasma and 5 to 500 ng/mL in brain tissue homogenate. The intra and inter-day precision and accuracy of the method was met the acceptable limits specified in the USFDA bioanalytical method validation guideline. The analyte was found to be stable in benchtop, freeze-thaw, auto-injector, and dry extract stability studies. The developed method was used to quantitate FLB in the plasma and brain tissue of a single dose oral pharmacokinetic and brain tissue distribution study in female rats. Maximum FLB concentration in plasma and brain were achieved within an hour, however the total amount of the drug that reached the brain was significantly less than in plasma. Rate of elimination of FLB from brain was also faster resulting in a lesser half-life in brain compared to the plasma.

11.
Clin Cancer Res ; 26(1): 18-24, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31558477

RESUMO

PURPOSE: 5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. RESULTS: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. CONCLUSIONS: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.

12.
Cancer ; 126(2): 281-292, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31639217

RESUMO

BACKGROUND: Metastasectomy of isolated colorectal liver metastases (CRLM) requires significant clinical expertise and may not be readily available or offered. The authors hypothesized that hospitals that treat a greater percentage of patients from higher income catchment areas are more likely to perform metastasectomies regardless of patient or tumor characteristics. METHODS: Using the National Cancer Data Base, the authors classified facilities into facility income quartiles (FIQs) based on the percentage of patients from the wealthiest neighborhoods (by zip code). Quartile 1 included facilities with <2.1% of the patients residing within the highest income zip codes, quartile 2 included facilities with 2.2% to 15.6% of patients residing within the highest income zip codes, quartile 3 included facilities with 15.7% to 40.2% of patients residing within the highest income zip codes, and quartile 4 included facilities with 40.3% to 90.5% of patients residing within the highest income ZIP codes. Patient, tumor, and facility characteristics were analyzed using a multivariate logistic regression to identify associations between metastasectomy and FIQ. RESULTS: Patients with CRLM were more likely to undergo metastasectomy at facilities in the highest FIQ compared with the lowest FIQ (18% vs 11% in FIQ4; P = .001). This trend was not observed in the resection of primary tumors for nonmetastatic CRLM (rates of 95% vs 93%; P = .94). After adjusting for individual insurance status, distance traveled, zip code-level individual income, tumor, and host, patients who were treated at the highest FIQ facilities were found to be more likely to undergo metastasectomy (odds ratio, 1.29; 95% CI, 1.02-1.72 [P = .03]). CONCLUSIONS: Metastasectomy for CRLM is more likely to occur at facilities that serve a greater percentage of patients from high-income catchment areas, regardless of individual patient characteristics. This disparity uniquely affects those patients with advanced cancers for which specialized expertise for therapy is necessary.

13.
J Clin Pharmacol ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31802506

RESUMO

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

14.
Proc Natl Acad Sci U S A ; 116(47): 23760-23771, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31676548

RESUMO

Elimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here, we find that striatal-enriched protein, Rhes, is a critical regulator of mitophagy and striatal vulnerability in brain. In vivo interactome and density fractionation reveal that Rhes coimmunoprecipitates and cosediments with mitochondrial and lysosomal proteins. Live-cell imaging of cultured striatal neuronal cell line shows Rhes surrounds globular mitochondria, recruits lysosomes, and ultimately degrades mitochondria. In the presence of 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, Rhes disrupts mitochondrial membrane potential (ΔΨ m ) and promotes excessive mitophagy and cell death. Ultrastructural analysis reveals that systemic injection of 3-NP in mice promotes globular mitochondria, accumulation of mitophagosomes, and striatal lesion only in the wild-type (WT), but not in the Rhes knockout (KO), striatum, suggesting that Rhes is critical for mitophagy and neuronal death in vivo. Mechanistically, Rhes requires Nix (BNIP3L), a known receptor of mitophagy, to disrupt ΔΨ m and promote mitophagy and cell death. Rhes interacts with Nix via SUMO E3-ligase domain, and Nix depletion totally abrogates Rhes-mediated mitophagy and cell death in the cultured striatal neuronal cell line. Finally, we find that Rhes, which travels from cell to cell via tunneling nanotube (TNT)-like cellular protrusions, interacts with dysfunctional mitochondria in the neighboring cell in a Nix-dependent manner. Collectively, Rhes is a major regulator of mitophagy via Nix, which may determine striatal vulnerability in the brain.

15.
mSystems ; 4(6)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690592

RESUMO

Basal autophagy is crucial for maintenance of cellular homeostasis. ATG5 is an essential protein for autophagosome formation, and its depletion has been extensively used as a tool to disrupt autophagy. Here, we characterize the impact of Atg5 deficiency on the cellular proteome of mouse embryonic fibroblasts (MEFs). Using a tandem mass tagging (TMT)-based quantitative proteomics analysis, we observe that 14% of identified proteins show dysregulated levels in atg5-/- MEFs. These proteins were distributed across diverse biological processes, such as cell adhesion, development, differentiation, transport, metabolism, and immune responses. Several of the upregulated proteins were receptors involved in transforming growth factor ß (TGF-ß) signaling, JAK-STAT signaling, junction adhesion, and interferon/cytokine-receptor interactions and were validated as autophagy substrates. Nearly equal numbers of proteins, including several lysosomal proteins and enzymes, were downregulated, suggesting a complex role of autophagy/ATG5 in regulating their levels. The atg5-/- MEFs had lower levels of key immune sensors and effectors, including Toll-like receptor 2 (TLR2), interferon regulatory factor 3 (IRF3), IRF7, MLKL, and STAT1/3/5/6, which were restored by reexpression of ATG5. While these cells could efficiently mount a type I interferon response to the double-stranded RNA (dsRNA) mimic poly(I·C), they were compromised in their inflammatory response to the bacterial pathogen-associated molecular patterns (PAMPs) lipopolysaccharide (LPS) and Pam3CSK4. Transcriptional activation and secretion of interleukin-6 (IL-6) in these cells could be recovered by ATG5 expression, supporting the role of autophagy in the TLR2-induced inflammatory response. This study provides a key resource for understanding the effect of autophagy/ATG5 deficiency on the fibroblast proteome.IMPORTANCE Autophagy performs housekeeping functions for cells and maintains a functional mode by degrading damaged proteins and organelles and providing energy under starvation conditions. The process is tightly regulated by the evolutionarily conserved Atg genes, of which Atg5 is one such crucial mediator. Here, we have done a comprehensive quantitative proteome analysis of mouse embryonic fibroblasts that lack a functional autophagy pathway (Atg5 knockout). We observe that 14% of the identified cellular proteome is remodeled, and several proteins distributed across diverse cellular processes with functions in signaling, cell adhesion, development, and immunity show either higher or lower levels under autophagy-deficient conditions. These cells have lower levels of crucial immune proteins that are required to mount a protective inflammatory response. This study will serve as a valuable resource to determine the role of autophagy in modulating specific protein levels in cells.

16.
J Biomol Struct Dyn ; : 1-10, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31590614

RESUMO

Chemical entities targeting kinase signalling pathways serve as a potential strategy to combat malignancies. Protein Kinase B or Akt is a validated target for various malignancies and Akt3 remains the least explored isoform among all its isoforms. Initially, homology modelling technique was used for generating protein structure and further validation was performed using molecular dynamics simulation and Ramachandran plot. The validated protein structure was then subjected for active site analysis which led to identification of active site residues based on metrics provided by site score. The important residues in binding site were identified as Thr81, Asp271 and Asp289 for binding energetics and inhibition. Subsequently, virtual screening methodologies were used for identification of novel hits for inhibition of Protein Kinase B or Akt3. This led to the identification of two hits, i.e. thiophene derivative and thieno-pyridine derivative which were selected on the basis of their binding affinity and drug likeliness. These identified hits were subjected for molecular dynamics simulations, quantum mechanical and synthetic accessibility studies. The role of crucial residues in binding site stood validated as suggested by molecular dynamics simulations studies. Abbreviations PknB Protein Kinase B mTOR Mammalian target of Rapamycin OPLS Optimized potential for liquid simulations RMSD root mean square deviation RMSF root mean square fluctuation MMGB/SA Molecular Mechanics generalized Born and surface area XP Extra Precision SP Simple Precision DFT Density Functional Theory SPC Simple point charge HOMO Highest occupied molecular orbital LUMO Lowest unoccupied molecular orbital ESP electrostatic potential ALIE Average local ionization energy B3LYP Becke 3-parameter Lee-Yang-Parr Communicated by Ramaswamy H. Sarma.

17.
Phys Chem Chem Phys ; 21(40): 22456-22466, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31580343

RESUMO

Lithium borohydride is a promising lithium ion conductor for all-solid-state batteries. However, the compound only exhibits high ionic conductivity at elevated temperatures, typically above 110 °C. It was shown that the addition of oxides such as silica or alumina increases the room temperature ionic conductivity by 3 orders of magnitude. The origin of this remarkable effect is not yet well understood. Here, we investigate the influence of oxide surface groups on the ionic conductivity of LiBH4/SiO2 nanocomposites. We systematically varied the density and nature of the surface groups of mesoporous silica by heat treatment at different temperatures, or surface functionalization, and subsequently prepared LiBH4/SiO2 nanocomposites by melt infiltration. The ionic conductivity is strongly influenced by the heat treatment temperature, hence the density of the free surface silanol groups. Replacing some of the silanol groups with hydrophobic surface groups resulted in an order of magnitude reduction of the room temperature ionic conductivity, suggesting that their presence is crucial to obtain high ionic conductivity in the nanocomposites. This systematic study and insight provide a basis for further exploration of the impact of surface groups, and for the rational design of novel solid-state nanocomposite electrolytes via interface engineering.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31652712

RESUMO

Hypertension (HT) is an extreme increment in blood pressure that can prompt a stroke, kidney disease, and heart attack. HT does not show any symptoms at the early stage, but can lead to various cardiovascular diseases. Hence, it is essential to identify it at the beginning stages. It is tedious to analyze electrocardiogram (ECG) signals visually due to their low amplitude and small bandwidth. Hence, to avoid possible human errors in the diagnosis of HT patients, an automated ECG-based system is developed. This paper proposes the computerized segregation of low-risk hypertension (LRHT) and high-risk hypertension (HRHT) using ECG signals with an optimal orthogonal wavelet filter bank (OWFB) system. The HRHT class is comprised of patients with myocardial infarction, stroke, and syncope ECG signals. The ECG-data are acquired from physionet's smart health for accessing risk via ECG event (SHAREE) database, which contains recordings of a total 139 subjects. First, ECG signals are segmented into epochs of 5 min. The segmented epochs are then decomposed into six wavelet sub-bands (WSBs) using OWFB. We extract the signal fractional dimension (SFD) and log-energy (LOGE) features from all six WSBs. Using Student's t-test ranking, we choose the high ranked WSBs of LOGE and SFD features. We develop a novel hypertension diagnosis index (HDI) using two features (SFD and LOGE) to discriminate LRHT and HRHT classes using a single numeric value. The performance of our developed system is found to be encouraging, and we believe that it can be employed in intensive care units to monitor the abrupt rise in blood pressure while screening the ECG signals, provided this is tested with an extensive independent database.

19.
AMB Express ; 9(1): 168, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641879

RESUMO

Meloidogyne spp. are microscopic, obligatory endoparasites with worldwide distribution which cause severe damage to agricultural crops. The present study revealed the nematicidal activity of Streptomyces antibioticus strain M7 against Meloidogyne incognita. The culture supernatant of the isolate caused 100% J2 mortality after 24 h and inhibited egg hatching (only 3%). In addition, the nematicidal activity of actinomycins V, X2 and D purified from strain M7 was also checked. In vitro studies displayed 97.0-99.0% juvenile mortality and 28.0-44.0% egg hatching after 168 h at 240 µg/ml of actinomycin, with LD50 (lethal dose) values of 28-120 µg/ml. In vivo study further validated the nematicidal activity of strain M7, where nematode infested tomato plants treated with culture supernatant/cells/solvent extract showed reduction in root galls and egg masses per plant by 50.0-62.06% and 53.48-76.74%, respectively, and significantly enhanced the shoot length (54.67-76.39%), root length (36.45-64.88%), shoot fresh weight (111-171.77%), root fresh weight (120-163.33%), shoot dry weight (54.45-145.45%), and root dry weight (100-133.3%) over the nematode infested plants treated with water. Furthermore, tomato plants treated with cells/culture supernatant/extract of strain M7 without nematode infestation also showed significant increase in various plant growth parameters. Thus, the outcome of the study revealed the potential of S. antibioticus strain M7 and actinomycins produced from it to be developed as safe nematicidal agents to control the root knot nematodes, and to increase the crop yield.

20.
Comput Biol Med ; 115: 103446, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31627019

RESUMO

Malignant arrhythmia can lead to sudden cardiac death (SCD). Shockable arrhythmia can be terminated with device electrical shock therapies. Ventricular-tachycardia (VT) and ventricular fibrillation (VF) are responsive to electrical anti-tachycardia pacing therapy and defibrillation which help to restore normal electrical and mechanical function of the heart. In contrast, non-shockable arrhythmia like asystole and bradycardia are not responsive to electric shock therapy. Distinguishing between shockable and non-shockable arrhythmia is an important diagnostic challenge that has practical clinical relevance. It is difficult to accurately differentiate between these two types of arrhythmia by manual inspection of electrocardiogram (ECG) segments within the short time duration before triggering the device for electrical therapy. Automated defibrillators are equipped with automatic shockable arrhythmia detection algorithms based on ECG morphological features, which may possess variable diagnostic performance depending on machine models. In our work, we have designed a robust system using wavelet decomposition filter banks for extraction of features from the ECG signal and then classifying the features. We believe this method will improve the accuracy of discriminating between shockable and non-shockable arrhythmia compared with existing conventional algorithms. We used a novel three channel orthogonal wavelet filter bank, which extracted features from ECG epochs of duration 2 s to distinguish between shockable and non-shockable arrhythmia. The fuzzy, Renyi and sample entropies are extracted from the various wavelet coefficients and fed to support vector machine (SVM) classifier for automated classification. We have obtained an accuracy of 98.9%, sensitivity and specificity of 99.08% and 97.11.9%, respectively, using 10-fold cross validation. The area under the receiver operating characteristic has been found to be 0.99 with F1-score of 0.994. The system developed is more accurate than the existing algorithms. Hence, the proposed system can be employed in automated defibrillators inside and outside hospitals for emergency revival of patients suffering from SCD. These automated defibrillators can also be implanted inside the human body for automatic detection of potentially fatal shockable arrhythmia and to deliver an appropriate electric shock to the heart.

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