Establishment of risk acceptance criteria using Life Quality Index: Application to the Indian context.

The formulation of risk acceptance criteria may be coupled gainfully with a prediction of the of investment required to comply with it, an exercise which can benefit from the application of socioeconomic indicators. The Life Quality Index (LQI) is one such indicator which amalgamates human mortality and wealth creation and places an implicit economic value on reduction of life risk. While there have been a number of studies to demonstrate the application of LQI pertaining to various technological systems, the present work extends it to estimate the sectoral level investment needed to reduce public risks to within the As Low As Reasonably Predictable region for the chemical industry, with specific illustration of the methodology for India. The potential reduction in public individual risk is computed as a function of percentage increase in safety investment expressed as a fraction of the industry's contribution to the nation's GDP. In addition, using a new, more accurate expression, estimates of a related parameter, the implied cost of averting a fatality (ICAF), are obtained for a number of developed economies and India. The ICAF estimates show reasonable agreement with the value of statistical life (VSL), a parameter which is integral to cost-benefit analysis of safety and environmental regulations.

Mathematical modelling for decision making of lockdown during COVID-19.

Due to the recent worldwide outbreak of COVID-19, there has been an enormous change in our lifestyle and it has a severe impact in different fields like finance, education, business, travel, tourism, economy, etc., in all the affected countries. In this scenario, people must be careful and cautious about the symptoms and should act accordingly. Accurate predictions of different factors, like the end date of the pandemic, duration of lockdown and spreading trend can guide us through the pandemic and precautions can be taken accordingly. Multiple attempts have been made to model the virus transmission, but none of them has investigated it at a global level. The novelty of the proposed work lies here. In this paper, first, authors have analysed spreading of the said disease using data collected from various platforms and then, have presented a predictive mathematical model for fifteen countries from first, second and third world for probable future projections of this pandemic. The prediction can be used by planning commission, healthcare organizations and the government agencies as well for creating suitable arrangements against this pandemic.

A wake-like state in vitro induced by transmembrane TNF/soluble TNF receptor reverse signaling.

Tumor necrosis factor alpha (TNF) has sleep regulatory and brain development roles. TNF promotes sleep in vivo and in vitro while TNF inhibition diminishes sleep. Transmembrane (tm) TNF and the tmTNF receptors (Rs), are cleaved by tumor necrosis factor alpha convertase to produce soluble (s) TNF and sTNFRs. Reverse signaling occurs in cells expressing tmTNF upon sTNFR binding. sTNFR administration in vivo inhibits sleep, thus we hypothesized that a wake-like state in vitro would be induced by sTNFR-tmTNF reverse signaling. Somatosensory cortical neuron/glia co-cultures derived from male and female mice lacking both TNFRs (TNFRKO), or lacking TNF (TNFKO) and wildtype (WT) mice were plated onto six-well multi-electrode arrays. Daily one-hour electrophysiological recordings were taken on culture days 4 through 14. sTNFR1 (0.0, 0.3, 3, 30, 60, and 120 ng/µL) was administered on day 14. A final one-hour recording was taken on day 15. Four measures were characterized that are also used to define sleep in vivo: action potentials (APs), burstiness index (BI), synchronization of electrical activity (SYN), and slow wave power (SWP; 0.25-3.75 Hz). Development rates of these emergent electrophysiological properties increased in cells from mice lacking TNF or both TNFRs compared to cells from WT mice. Decreased SWP, after the three lowest doses (0.3, 3 and 30 ng/µL) of the sTNFR1, indicate a wake-like state in cells from TNFRKO mice. A wake-like state was also induced after 3 ng/µl sTNFR1 treatment in cells from TNFKO mice, which express the TNFR1 ligand, lymphotoxin alpha. Cells from WT mice showed no treatment effects. Results are consistent with prior studies demonstrating involvement of TNF in brain development, TNF reverse signaling, and sleep regulation in vivo. Further, the current demonstration of sTNFR1 induction of a wake-like state in vitro is consistent with the idea that small neuronal/glial circuits manifest sleep- and wake-like states analogous to those occurring in vivo. Finally, that sTNF forward signaling enhances sleep while sTNFR1 reverse signaling enhances a wake-like state is consistent with other sTNF/tmTNF/sTNFR1 brain actions having opposing activities.

Tumor necrosis factor enhances the sleep-like state and electrical stimulation induces a wake-like state in co-cultures of neurons and glia.

We characterise sleep-like states in cultured neurons and glia during development in vitro as well as after electrical stimulation, the addition of tumor necrosis factor alpha (TNF), and the combination of TNF plus electrical stimulation. We also characterise optogenetic stimulation-induced ATP release and neuronal interleukin-1 and TNF expression in vitro demonstrating the activity dependence of these putative sleep-regulatory substances. Action potential (AP) burstiness, expressed as the burstiness index (BI), synchronization of slow electrical potentials between recording electrodes (SYN), and slow wave (SW) power (0.25-3.75 Hz) determined using fast Fourier analyses emerged as network properties, maturing after 2 weeks in culture. Homologous in vivo measures are used to characterise sleep. Electrical stimulation reduced the BI, SYN and SW power values during and/or after the stimulus period. One day later, homeostasis was evident from rebounds of SYN and SW power values to above baseline levels; the magnitude of the rebound was stimulus pattern-dependent. The addition of TNF enhanced BI, SYN and SW power values, suggesting the induction of a deeper sleep-like state. Electrical stimulation reversed these TNF effects, suggesting the network state was more wake-like. The day after TNF plus electrical stimulation, the changes in SYN and SW power values were dependent upon the stimulus patterns the cells received the day before. We conclude that sleep and wake states in cultured in vitro networks can be controlled and they share molecular regulatory mechanisms with local in vivo networks. Further, sleep is an activity-dependent emergent local network property.

Emergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing.

Tip-links in the inner ear convey force from sound and trigger mechanotransduction. Here, we present evidence that tip-links (collectively as heterotetrameric complexes of cadherins) function as force filters during mechanotransduction. Our force-clamp experiments reveal that the tip-link complexes show slip-ideal-slip bond dynamics. At low forces, the lifetime of the tip-link complex drops monotonically, indicating slip-bond dynamics. The ideal bond, rare in nature, is seen in an intermediate force regime where the survival of the complex remains constant over a wide range. At large forces, tip-links follow a slip bond and dissociate entirely to cut-off force transmission. In contrast, the individual tip-links (heterodimers) display slip-catch-slip bonds to the applied forces. While with a phenotypic mutant, we showed the importance of the slip-catch-slip bonds in uninterrupted hearing, our coarse-grained Langevin dynamics simulations demonstrated that the slip-ideal-slip bonds emerge as a collective feature from the slip-catch-slip bonds of individual tip-links.

Cancer mortality in India: a nationally representative survey.

BACKGROUND: The age-specific mortality rates and total deaths from specific cancers have not been documented for the various regions and subpopulations of India. We therefore assessed the cause of death in 2001-03 in homes in small areas that were chosen to be representative of all the parts of India. METHODS: At least 130 trained physicians independently assigned causes to 122,429 deaths, which occurred in 1·1 million homes in 6671 small areas that were randomly selected to be representative of all of India, based on a structured non-medical surveyor's field report. FINDINGS: 7137 of 122,429 study deaths were due to cancer, corresponding to 556,400 national cancer deaths in India in 2010. 395,400 (71%) cancer deaths occurred in people aged 30-69 years (200,100 men and 195,300 women). At 30-69 years, the three most common fatal cancers were oral (including lip and pharynx, 45,800 [22·9%]), stomach (25,200 [12·6%]), and lung (including trachea and larynx, 22,900 [11·4%]) in men, and cervical (33,400 [17·1%]), stomach (27,500 [14·1%]), and breast (19,900 [10·2%]) in women. Tobacco-related cancers represented 42·0% (84,000) of male and 18·3% (35,700) of female cancer deaths and there were twice as many deaths from oral cancers as lung cancers. Age-standardised cancer mortality rates per 100,000 were similar in rural (men 95·6 [99% CI 89·6-101·7] and women 96·6 [90·7-102·6]) and urban areas (men 102·4 [92·7-112·1] and women 91·2 [81·9-100·5]), but varied greatly between the states, and were two times higher in the least educated than in the most educated adults (men, illiterate 106·6 [97·4-115·7] vs most educated 45·7 [37·8-53·6]; women, illiterate 106·7 [99·9-113·6] vs most educated 43·4 [30·7-56·1]). Cervical cancer was far less common in Muslim than in Hindu women (study deaths 24, age-standardised mortality ratio 0·68 [0·64-0·71] vs 340, 1·06 [1·05-1·08]). INTERPRETATION: Prevention of tobacco-related and cervical cancers and earlier detection of treatable cancers would reduce cancer deaths in India, particularly in the rural areas that are underserved by cancer services. The substantial variation in cancer rates in India suggests other risk factors or causative agents that remain to be discovered. FUNDING: Bill & Melinda Gates Foundation and US National Institutes of Health.

Sleep as a fundamental property of neuronal assemblies.

Sleep is vital to cognitive performance, productivity, health and well-being. Earlier theories of sleep presumed that it occurred at the level of the whole organism and that it was governed by central control mechanisms. However, evidence now indicates that sleep might be regulated at a more local level in the brain: it seems to be a fundamental property of neuronal networks and is dependent on prior activity in each network. Such local-network sleep might be initiated by metabolically driven changes in the production of sleep-regulatory substances. We discuss a mathematical model which illustrates that the sleep-like states of individual cortical columns can be synchronized through humoral and electrical connections, and that whole-organism sleep occurs as an emergent property of local-network interactions.

Solar photothermochemical reaction and supercritical CO2 work up for a fully green process of preparation of pure p-nitrobenzyl bromide.

It has been reported by us recently that p-nitrobenzyl bromide (PNBBr) can be synthesized from p-nitrotoluene (PNT) in high isolated yield with respect to available bromine in 2:1 Br(-)-BrO3(-) employed as brominating reagent. The reaction was conducted in ethylene dichloride (EDC) and the substrate was taken in excess to suppress dibromo impurity formation. The product was "cold crystallized" from the reaction mass and the mother liquor was recycled in the subsequent batch thereby eliminating organic discharge. The present work attempts to further advance the synthesis of this commercially important molecule employed in protection-deprotection strategies. Herein its successful synthesis employing neat substrate and solar radiation as the sole energy source to drive this photothermochemical reaction is reported. Further, 100% pure PNBBr could be isolated from the solid reaction mass in 87% yield by leaching out the excess substrate through supercritical CO2 (Sc-CO2) extraction. The reaction was therefore accomplished cleanly in all respects and with low carbon footprint.

Enhancing Data Security of Cloud Based LMS.

Around the world, the educational system is evolving. The new trend can be found in traditional classroom systems as well as digitalization systems. Cloud-based Learning Management Systems (LMS) will accelerate the educational industry forward in the next years because they can provide end-user with a versatile, convenient, secure, and cost-effective learning process. The cloud-based LMS approach is the most effective and proper learning model in the worldwide educational sector, particularly if the organization is in a state of depression owing to a global pandemic. It can be utilized over the internet with several users on the same platform. As a result, the initial requirement is important to enable to the LMS model. Despite its many advantages, LMS confronts challenges such as confidentiality, user acceptance, and traffic. In a pandemic like Covid 19, the entire planet depends on a safe LMS platform to establish student and instructor trust. Therefore, with this work, the attempt has been made to explain one LMS model that may provide its users with optimal security, a user-friendly environment, and quick access. This paper discusses the use of the cloud attack, and also cryptographic and steganographic security models and techniques to address these issues. There's also information on what kinds of security vulnerabilities or operations on cloud data are feasible, and also how to deal with them using various algorithms.

A spirocyclohexyl nitroxide amino acid spin label for pulsed EPR spectroscopy distance measurements.

Site-directed spin labeling and EPR spectroscopy offer accurate, sensitive tools for the characterization of structure and function of macromolecules and their assemblies. A new rigid spin label, spirocyclohexyl nitroxide alpha-amino acid and its N-(9-fluorenylmethoxycarbonyl) derivative, have been synthesized, which exhibit slow enough spin-echo dephasing to permit accurate distance measurements by pulsed EPR spectroscopy at temperatures up to 125 K in 1:1 water/glycerol and at higher temperatures in matrices with higher glass transition temperatures. Distance measurements in the liquid nitrogen temperature range are less expensive than those that require liquid helium, which will greatly facilitate applications of pulsed EPR spectroscopy to the study of structure and conformation of peptides and proteins.

Comparison of the pharmacokinetics, safety and tolerability of daptomycin in healthy adult volunteers following intravenous administration by 30 min infusion or 2 min injection.

OBJECTIVES: Two randomized Phase I studies in separate populations of healthy adult volunteers investigated the pharmacokinetics, safety and tolerability of daptomycin (Cubicin; Novartis Pharma AG, Basel, Switzerland) administered as a 2 min intravenous (iv) injection, relative to the currently licensed 30 min iv infusion. METHODS: Study 1 was an open-label, single-dose, two-period, crossover study in which each subject received 6 mg/kg daptomycin administered as a 30 min iv infusion (n = 15) and as a 2 min iv injection (n = 16). In Study 2, a single-blind, multiple-dose, parallel-group study, subjects received a once-daily 2 min iv injection of 6 mg/kg daptomycin (n = 12), 4 mg/kg daptomycin (n = 8) or placebo (n = 4) for 7 days. Single-dose pharmacokinetics were assessed at various timepoints up to 36 and 24 h post-dose in Study 1 and Study 2, respectively, and multiple-dose pharmacokinetics were assessed in Study 2 at day 7 for 48 h post-dose. RESULTS: In Study 1, pharmacokinetic comparability between the two administration regimens was demonstrated by meeting the bioequivalence criteria for the exposure parameters, AUC(0-t), AUC(0-infinity) and C(max). In Study 2, time-invariant pharmacokinetic properties as well as dose-proportional pharmacokinetics were demonstrated for the daptomycin 2 min iv injection regimen. In both studies, daptomycin was well tolerated and the majority of treatment-emergent adverse events were of mild intensity and considered to be unrelated to daptomycin. CONCLUSIONS: The similar pharmacokinetic and safety profiles of the two administration regimens suggest that the 2 min iv injection may be a convenient treatment option for both patients and healthcare professionals.

The neuron-specific interleukin-1 receptor accessory protein alters emergent network state properties in Vitro.

Small in vitro neuronal/glial networks exhibit sleep-like states. Sleep regulatory substance interleukin-1ß (IL1) signals via its type I receptor and a receptor accessory protein (AcP). AcP has a neuron-specific isoform called AcPb. After sleep deprivation, AcPb, but not AcP, upregulates in brain, and mice lacking AcPb lack sleep rebound. Herein we used action potentials (APs), AP burstiness, synchronization of electrical activity (SYN), and delta wave (0.5-3.75 Hz) power to characterize cortical culture network state. Homologous parameters are used in vivo to characterize sleep. Cortical cells from 1-2-day-old pups from AcP knockout (KO, lacking both AcP and AcPb), AcPb KO (lacking only AcPb), and wild type (WT) mice were cultured separately on multi-electrode arrays. Recordings of spontaneous activity were taken each day during days 4-14 in vitro. In addition, cultures were treated with IL1, or in separate experiments, stimulated electrically to determine evoked response potentials (ERPs). In AcP KO cells, the maturation of network properties accelerated compared to those from cells lacking only AcPb. In contrast, the lack of AcPb delayed spontaneous network emergence of sleep-linked properties. The addition of IL1 enhanced delta wave power in WT cells but not in AcP KO or AcPb KO cells. The ontology of electrically-induced ERPs was delayed in AcP KO cells. We conclude IL1 signaling has a critical role in the emergence of sleep-linked network behavior with AcP playing a dominant role in the slowing of development while AcPb enhances development rates of sleep-linked emergent network properties.

A network model for activity-dependent sleep regulation.

We develop and characterize a dynamical network model for activity-dependent sleep regulation. Specifically, in accordance with the activity-dependent theory for sleep, we view organism sleep as emerging from the local sleep states of functional units known as cortical columns; these local sleep states evolve through integration of local activity inputs, loose couplings with neighboring cortical columns, and global regulation (e.g. by the circadian clock). We model these cortical columns as coupled or networked activity-integrators that transition between sleep and waking states based on thresholds on the total activity. The model dynamics for three canonical experiments (which we have studied both through simulation and system-theoretic analysis) match with experimentally observed characteristics of the cortical-column network. Most notably, assuming connectedness of the network graph, our model predicts the recovery of the columns to a synchronized state upon temporary overstimulation of a single column and/or randomization of the initial sleep and activity-integration states. In analogy with other models for networked oscillators, our model also predicts the possibility for such phenomena as mode-locking.

Chemistry of enediynyl azides: activation through a novel pathway.

The spontaneous activation of a nonaromatic enediynyl azide under ambient conditions has been demonstrated. The aromatic enediyne followed the expected cycloaddition with the alkene in the neighbouring arm to form a stable bridged bicyclic enediyne.

Synthesis and reactivity of a 9-membered azaenediyne: importance of proximity effect in N-alkylation.

Synthesis of a 9-membered azaenediyne has been achieved for the first time via intramolecular N-alkylation; the importance of proximity of the reacting centres via cobalt carbonyl complexation of the acetylenic moiety and not the activation of propargylic carbon has been demonstrated.

Sleep function: Toward elucidating an enigma.

Sleep function remains controversial. Individual perspectives frame the issue of sleep function differently. We briefly illustrate how sleep measurement and the evolution, tissue organization levels, molecular mechanisms, and regulation of sleep could influence one's view of sleep function. Then we discuss six viable theories of sleep function. Sleep serves host-defense mechanisms and conserves caloric expenditures, but these functions likely are opportunistic functions evolving later in evolution. That sleep replenishes brain energy stores and that sleep serves a glymphatic function by removing toxic byproducts of waking activity are attractive ideas, but lack extensive supporting experimental evidence. That sleep restores performance is experimentally demonstrated and has obvious evolutionary value. However, this hypothesis lacks experimentally verified mechanisms although ideas relating to this issue are presented. Finally, the ideas surrounding the broad hypothesis that sleep serves a connectivity/plasticity function are many and attractive. There is experimental evidence that connectivity changes with sleep, sleep loss, and with changing afferent input, and that those changes are linked to sleep regulatory mechanisms. In our view, this is the leading contender for the primordial function of sleep. However, much refinement of ideas and innovative experimental approaches are needed to clarify the sleep-connectivity relationship.

First-line anti-tubercular drug resistance of mycobacterial strains from re-treatment cases that were smear-positive at 4(th) month onwards under the Revised National Tuberculosis Control Program.

BACKGROUND: Programmatic management of drug-resistant TB (PMDT) under the RNTCP is being implemented in West Bengal in a phased manner since 2011. During the initial years MDR-TB cases were identified based on criteria A. This study examines the first line anti-tubercular drug resistance pattern of mycobacteria cultured from sputum samples of MDR suspects who were retreatment cases smear positive from 4(th) month onwards. MATERIALS AND METHODS: In the following retrospective record based study, data on Drug Sensitivity Testing (DST) of sputum samples of MDR suspects between September 2011 and August 2012 were collected from the IRL Kolkata and analysed. Sputum samples, collected in the districts maintaining adequate aseptic containment measures, were decontaminated and centrifuged and the sediment inoculated on LJ medium. Probable M. tuberculosis colonies were identified by typical colony characteristics and Ziehl-Neelsen (ZN) staining. Sensitivity of the four 1(st) line drugs (Streptomycin, Isoniazid, Ethambutol and Rifampicin) was deduced by the economic variant of the proportion method. RESULTS: Of all the 917 MDR suspects whose sputum was examined, 64 mycobacteria culture positive strains (6.98%) were mono-resistant to any of the four first line anti-tubercular drugs. Among the mono-resistant strains 43 (4.69%) were resistant to Rifampicin while 12 (1.31%) were resistant to INH. There were a total 78 (8.51%) poly drug-resistant strains. MDR-TB strains were seen in 741 (80.81%) samples. CONCLUSION: The magnitude of drug resistance were very high among retreatment patients that were smear positive from 4(th) months onwards probably because of repeated courses of anti-tubercular drugs prior to drug sensitivity testing (DST). The decision of the PMDT to enlist all retreatment patients as MDR suspects at initiation will result in early identification and treatment of MDR-TB patients.

Mini-ISES identifies promising carbafructopyranose-based salens for asymmetric catalysis: Tuning ligand shape via the anomeric effect.

This study introduces new methods of screening for and tuning chiral space and in so doing identifies a promising set of chiral ligands for asymmetric synthesis. The carbafructopyranosyl-1,2-diamine(s) and salens constructed therefrom are particularly compelling. It is shown that by removing the native anomeric effect in this ligand family, one can tune chiral ligand shape and improve chiral bias. This concept is demonstrated by a combination of (i) x-ray crystallographic structure determination, (ii) assessment of catalytic performance, and (iii) consideration of the anomeric effect and its underlying dipolar basis. The title ligands were identified by a new mini version of the in situ enzymatic screening (ISES) procedure through which catalyst-ligand combinations are screened in parallel, and information on relative rate and enantioselectivity is obtained in real time, without the need to quench reactions or draw aliquots. Mini-ISES brings the technique into the nanomole regime (200 to 350 nmol catalyst/20 µml organic volume) commensurate with emerging trends in reaction development/process chemistry. The best-performing ß-d-carbafructopyranosyl-1,2-diamine-derived salen ligand discovered here outperforms the best known organometallic and enzymatic catalysts for the hydrolytic kinetic resolution of 3-phenylpropylene oxide, one of several substrates examined for which the ligand is "matched." This ligand scaffold defines a new swath of chiral space, and anomeric effect tunability defines a new concept in shaping that chiral space. Both this ligand set and the anomeric shape-tuning concept are expected to find broad application, given the value of chiral 1,2-diamines and salens constructed from these in asymmetric catalysis.