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In this paper, an efficient design of FIR digital differentiator using the L1-optimality criterion is proposed. We present a technique based on the modified Newton method to solve the design problem so that the optimal differentiator coefficients are obtained by minimizing the absolute error The novel L1-errorfunction leads to aflat response at low-frequencies. Extensive simulations are carried out to validate the proposed design. The superiority of the proposed design is evident by comparing it with other conventional design techniques such as, windowing, minimax and the least-squares approach. [ABSTRACT FROM AUTHOR]

The present paper focused on the fluency component of scientific creative talent of elementary stage students of Himachal Pradesh with respect to area, type of school and gender. The researcher has taken the sample of 1120 elementary stage students of classes VII and VIII studying in Govt. and Private schools of Himachal affiliated to HP board of School Education, Dharamshala from five selected districts. To collect the requisite data for the present study, the investigator used Verbal Test of Scientific Creativity constructed by V. P. Sharma, retired professor and head Department of Psychology, R. S. University, Raipur (C. G.) and J. P. Shukla, Department of Psychology, R. S. University, Raipur, (C. G.). The researcher has employed the technique of three way ANOVA (2×2×2) to analyse the data. The results revealed that elementary stage students of urban area are more fluent in scientific creative talent as compared to the elementary stage students of rural area. Also there exists a significance difference between the two. The elementary stage boys exhibited slightly more Fluency than the elementary stage girls with a significant difference at highest level of significance. It is found in the study that Area and School, School and Gender interact significantly. The paper discusses certain suggestions for productive thinking and studies in respective areas in the field of science. [ABSTRACT FROM AUTHOR]

A fast track "Hot Start" process was implemented to launch the European Bank for Induced Pluripotent Stem Cells (EBiSC) to provide early release of a range of established control and disease linked human induced pluripotent stem cell (hiPSC) lines. Established practice amongst consortium members was surveyed to arrive at harmonised and publically accessible Standard Operations Procedures (SOPs) for tissue procurement, bio-sample tracking, iPSC expansion, cryopreservation, qualification and distribution to the research community. These were implemented to create a quality managed foundational collection of lines and associated data made available for distribution. Here we report on the successful outcome of this experience and work flow for banking and facilitating access to an otherwise disparate European resource, with lessons to benefit the international research community. ETOC: The report focuses on the EBiSC experience of rapidly establishing an operational capacity to procure, bank and distribute a foundational collection of established hiPSC lines. It validates the feasibility and defines the challenges of harnessing and integrating the capability and productivity of centres across Europe using commonly available resources currently in the field., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Estrogen Receptor-β (ER-β), a tumor-suppressor in prostate cancer, is epigenetically repressed by hypermethylation of its promoter. DNA-methyltransferases (DNMTs), which catalyze the transfer of methyl-groups to CpG islands of gene promoters, are overactive in cancers and can be inhibited by DNMT-inhibitors to re-express the tumor suppressors. The FDA-approved nucleoside DNMT-inhibitors like 5-Azacytidine and 5-Aza-deoxycytidine carry notable concerns due to their off-target toxicity, therefore non-nucleoside DNMT inhibitors are desirable for prolonged epigenetic therapy. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ER-β. To increase the DNMT-inhibitory activity of DSF, its chemical scaffold was optimized and compound-339 was discovered as a doubly potent DSF-derivative with similar off-target toxicity. It potently and selectively inhibited cell proliferation of prostate cancer (PC3/DU145) cells in comparison to normal (non-cancer) cells by promoting cell-cycle arrest and apoptosis, accompanied with inhibition of total DNMT activity, and re-expression of ER-β (mRNA/protein). Bisulfite-sequencing of ER-β promoter revealed that compound-339 demethylated CpG sites more efficaciously than DSF, restoring near-normal methylation status of ER-β promoter. Compound-339 docked on to the MTase domain of DNMT1 with half the energy of DSF. In xenograft mice-model, the tumor volume regressed by 24% and 50% after treatment with DSF and compound-339, respectively, with increase in ER-β expression. Apparently both compounds inhibit prostate cancer cell proliferation by re-expressing the epigenetically repressed tumor-suppressor ER-β through inhibition of DNMT activity. Compound-339 presents a new lead for further study as an anti-prostate cancer agent. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Trichomoniasis and candidiasis are amongst the most common morbidity-causing reproductive tract infections, generally treated by Metronidazole and Fluconazole respectively. Poor vaginal efficacy, drug-resistance and non-spermicidal nature limit their use as topical microbicidal contraceptives. Bis(dialkylaminethiocarbonyl)disulfides (4-38) were designed as dually active, non-surfactant molecules capable of eliminating Trichomonas vaginalis and Candida strains as well as irreversibly immobilizing 100% human sperm instantly, at doses non-cytotoxic to human cervical epithelial cells and vaginal microflora in vitro. Compounds 12, 16, 17 were fifty times more active than nonoxynol-9, OTC vaginal spermicide, and compounds 12 and 17 have shown remarkable in vivo activity in rabbit model. Most promising compound 17 has shown promise for further development as a double-edged vaginal microbicide due to their improved activity and safety along with notable in vivo trichomonicidal activity. Role of disulfide group was established by loss of spermicidal activity on chemical modifications (39-56). These disulfides might be targeting thiol groups present over cell membrane of human sperm and Trichomonas as shown by fluorescence labeling of free thiols., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Dithiocarbamates (DTC), a sulfhydryl group containing compounds, are extensively used by humans that include metam and thiram due to their pesticide properties, and disulfiram (DSF) as an alcohol deterrent. We screened these DTC in an osteoblast viability assay. DSF exhibited the highest cytotoxicity (IC50 488nM). Loss in osteoblast viability and proliferation was due to induction of apoptosis via G1 arrest. DSF treatment to osteoblasts reduced glutathione (GSH) levels and exogenous addition of GSH prevented DSF-induced reactive oxygen species generation and osteoblast apoptosis. DSF also inhibited osteoblast differentiation in vitro and in vivo, and the effect was associated with inhibition of aldehyde dehydrogenase (ALDH) activity. Out of various ALDH isozymes, osteoblasts expressed only ALDH2 and DSF downregulated its transcript as well as activity. Alda-1, a specific activator of ALDH2, stimulated osteoblast differentiation. Subcutaneous injection of DSF over the calvarium of new born rats reduced the differentiation phenotype of calvarial osteoblasts but increased the mRNA levels of Runx-2 and osteocalcin. DSF treatment at a human-equivalent dose of 30 mg/kg p.o. to adult Sprague Dawley rats caused trabecular osteopenia and suppressed the formation of mineralized nodule by bone marrow stromal cells. Moreover, DSF diminished bone regeneration at the fracture site. In growing rats, DSF diminished growth plate height, primary and secondary spongiosa, mineralized osteoid and trabecular strength. Substantial decreased bone formation was also observed in the cortical site of these rats. We conclude that DSF has a strong osteopenia inducing effect by impairing osteoblast survival and differentiation due to the inhibition of ALDH2 function.

Study Question: Can a specifically acting synthetic spermicide (DSE-37) be combined with a natural microbicide (saponins) for safe, prophylactic contraception?, Summary Answer: A 1:1 (w/w) combination of DSE-37 and Sapindus saponins can target sperm and Trichomonas vaginalis precisely without any noticeable off-target effects on somatic cells at effective concentrations., What Is Known Already: Broad-spectrum vaginal agents like nonoxynol-9 (N-9) and cellulose sulfate have failed clinically as microbicides due to non-specific off-target effects, whereas agents that specifically target retroviruses have shown promise in clinical trials. DSE-37 and Sapindus saponins, respectively, specifically target human sperm and T. vaginalis in vitro., Study Design, Size, Duration: A comprehensive study of efficacy and safety was undertaken using in vitro (human cells) and in vivo (rabbit) models. The 1:1 combination of DSE-37 and Sapindus saponins was based on the in vitro spermicidal and anti-Trichomonal activities of the two components. N-9, the spermicide in clinical use, served as reference control. Free sperm thiols were fluorescently glinted to reveal differences in the targets of the test agents., Participants/materials, Setting, Methods: On/off-target effects were evaluated in vitro against human sperm, T. vaginalis, HeLa, Vk2/E6E7, End1/E6E7 and Lactobacillus jensenii, using standard assays of drug susceptibility, cell viability, flow cytometric assessment of cell apoptosis and qPCR for expression of pro-inflammatory cytokine mRNAs. The spermicidal effect was also recorded live and free thiols on sperm were fluorescently visualized using a commercial kit. In vivo contraceptive efficacy (pregnancy/fertility rates) and safety (vaginal histopathology and in situ immune-labeling of inflammation markers VCAM-1, E-selectin and NFkB) were evaluated in rabbits., Main Results and the Role of Chance: A 0.003% drug 'combination' containing 0.0015% each of DSE-37 and Sapindus saponins in physiological saline irreversibly immobilized 100% human sperm in ∼30 s and eliminated 100% T. vaginalis in 24 h, without causing any detectable toxicity to human cervical (HeLa) cells and Lactobacilli in 24-48 h, in vitro. N-9 at 0.003% exhibited lower microbicidal activity against Trichomonas but failed in spermicidal assays while causing severe toxicity to HeLa cells and Lactobacilli in 12-24 h. The 'combination' of DSE-37 and Sapindus saponins completely prevented pregnancy in rabbits at a vaginal dose of 20 mg (1% in K-Y Jelly), while application of 5% 'combination' in K-Y Jelly for 4 consecutive days caused negligible alterations in epithelial lining of rabbit vagina with only minor changes in levels of inflammation markers. N-9 at a 20 mg vaginal dose prevented pregnancy in 33% animals and a 4-day repeat application of 2% N-9 gel caused severe local toxicity to vaginal epithelium with molecular expression of acute inflammation markers., Limitations, Reasons for Caution: The number of animals used for the in vivo efficacy study was limited by the approval of the animal ethics committee., Wider Implications of the Findings: Anti-Trichomonal contraceptives with specifically acting synthetic component and clinically-proven safe natural component may define a new concept in empowering women to control their fertility and reproductive health., Study Funding/competing Interest(s): The study was funded by CSIR-Network Project 'PROGRAM' (BSC0101) and partly by the Ministry of Health and Family Welfare, Government of India (GAP0001). The funding agencies did not play any role in this study and none of the authors had any competing interest(s).

Unlike somatic cells, sperm have several-fold more available-thiols that are susceptible to redox-active agents. The present study explains the mechanism behind the instant sperm-immobilizing and trichomonacidal activities of pyrrolidinium pyrrolidine-1-carbodithioate (PPC), a novel thiol agent rationally created for prophylactic contraception by minor chemical modifications of some known thiol drugs. PPC, and its three derivatives (with potential active-site blocked by alkylation), were synthesized and evaluated against live human sperm and metronidazole-susceptible and resistant Trichomonas vaginalis, in vitro. Sperm hexokinase activity was evaluated by coupled enzyme assay. PPC irreversibly immobilized 100% human sperm in ∼30 seconds and totally eliminated Trichomonas vaginalis more efficiently than nonoxynol-9 and metronidazole. It significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. However, the molecule completely lost all its biological activities once its thiol group was blocked by alkylation. PPC was subsequently formulated into a mucoadhesive vaginal film using GRaS excipients and evaluated for spermicidal and microbicidal activities (in vitro), and contraceptive efficacy in rabbits. PPC remained fully active in quick-dissolving, mucoadhesive vaginal-film formulation, and these PPC-films significantly reduced pregnancy and fertility rates in rabbits. The films released ∼90% of PPC in simulated vaginal fluid (pH 4.2) at 37°C in 5 minutes, in vitro. We have thus discovered a common target (reactive thiols) on chiefly-anaerobic, redox-sensitive cells like sperm and Trichomonas, which is susceptible to designed chemical interference for prophylactic contraception. The active thiol in PPC inactivates sperm and Trichomonas via interference with crucial sulfhydryl-disulfide based reactions, e.g. hexokinase activation in human sperm. In comparison to non-specific surfactant action of OTC spermicide nonoxynol-9, the action of thiol-active PPC is apparently much more specific, potent and safe. PPC presents a proof-of-concept for prophylactic contraception via manipulation of thiols in vagina for selective targeting of sperm and Trichomonas, and qualifies as a promising lead for the development of dually protective vaginal-contraceptive.

Background: There is a paucity of data on end-of-life decisions (EOLD) for patients in Indian intensive care units (ICUs)., Objective: To document the end-of-life and full-support (FS) decisions among patients dying in an ICU, to compare the respective patient characteristics and to describe the process of decision-making., Design: Retrospective, observational., Patients: Consecutive patients admitted to a 12-bed closed medical-surgical ICU., Exclusions: Patients with EOLD discharged home or transferred to another hospital., Measurements and Results: Demographic profile, APACHE IV at 24 h, ICU outcome, type of limitation, disease category, pre-admission functional status, reasons for EOLD, interventions and therapies within 3 days of death, time to EOLD, time to death after EOLD and ICU length of stay. Out of 88 deaths among 830 admissions, 49% were preceded by EOLD. Of these 58% had withholding of treatment, 35% had do-not-resuscitate orders (DNR) and 7% had a withdrawal decision. Mean age and APACHE IV scores were similar between EOLD and FS groups. Functional dependence before hospitalization favored EOLD. Patients receiving EOLD as opposed to FS had longer stays. Fifty-three percent of limitations were decided during the first week of ICU stay well before the time of death. Escalation of therapy within 3 days of death was less frequent in the EOLD group., Conclusions: Despite societal and legal barriers, half the patients dying in the ICU received a decision to limit therapy mostly as withholding or DNR orders. These decisions evolved early in the course of stay and resulted in significant reduction of therapeutic burdens.

Introduction: Medical colleges both in public and private sector in Nepal have been supporting national TB control program (NTP) in its effort to control TB and its eventual elimination. Official collaboration between Nepalganj Medical College (NGMC), a private sector medical college and NTP was developed in 2000; a joint private-public initiative to contain TB., Objectives: This study has been done with the objectives a) to review the TB cases diagnosed/managed at NGMC Teaching Hospital (TH), Kohalpur, in Financial Year 2063/2064 (Shrawan 63 Asad 64) and b) to assess the contribution of NGMC, TH, Kohalpur towards TB control., Methodology: This is record based review of TB cases diagnosed, categorized, treated at NGMC TH, Kohalpur and referred to respective health facilities in Financial Year 2063/2064 (Shrawan 63 Asad 64). And case detection with respect to detected TB cases in Midwestern Region and entire country., Results: Around 13% of detected TB cases for Mid Western Region and 1.5 % of detected TB cases at national level were diagnosed at NGMC, TH, Kohalpur. 35% of cases were of pediatric TB; lymph node TB, pleural effusion & abdominal TB were common form of extra pulmonary (EP) TB seen in children. 20.8%, 44.8% and 34.4% of cases in adults were of sputum smear (SS) + pulmonary TB (PTB), SS- PTB & EPTB respectively; pleural effusion, lymph node TB, Miliary & abdominal TB were common form of EPTB seen in adults., Conclusion: Contribution of NGMC, TH, Kohalpur towards case detection seems to be significant. The role of medical colleges in TB control can not be underestimated.