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.

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.

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.

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.

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.

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.

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.

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.

An individual-based model of transmission of resistant bacteria in a veterinary teaching hospital.

Veterinary nosocomial infections caused by antibiotic resistant bacteria cause increased morbidity, higher cost and length of treatment and increased zoonotic risk because of the difficulty in treating them. In this study, an individual-based model was developed to investigate the effects of movements of canine patients among ten areas (transmission points) within a veterinary teaching hospital, and the effects of these movements on transmission of antibiotic susceptible and resistant pathogens. The model simulates contamination of transmission points, healthcare workers, and patients as well as the effects of decontamination of transmission points, disinfection of healthcare workers, and antibiotic treatments of canine patients. The model was parameterized using data obtained from hospital records, information obtained by interviews with hospital staff, and the published literature. The model suggested that transmission resulting from contact with healthcare workers was common, and that certain transmission points (housing wards, diagnostics room, and the intensive care unit) presented higher risk for transmission than others (lobby and surgery). Sensitivity analyses using a range of parameter values demonstrated that the risk of acquisition of colonization by resistant pathogens decreased with shorter patient hospital stays (P<0.0001), more frequent decontamination of transmission points and disinfection of healthcare workers (P<0.0001) and better compliance of healthcare workers with hygiene practices (P<0.0001). More frequent decontamination of heavily trafficked transmission points was especially effective at reducing transmission of the model pathogen.

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.

Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1ß monoclonal antibody.

Canakinumab is a high-affinity human monoclonal anti-interleukin-1ß (IL-1ß) antibody of the IgG1/κ isotype designed to bind and neutralize the activity of human IL-1ß, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1ß. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS®, as well as diseases such as rheumatoid arthritis, asthma and psoriasis. Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70 kg, slow serum clearance (0.174 L/day) was observed with a low total volume of distribution at steady state (6.0 L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70%). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex- or age-related pharmacokinetic differences were observed after correction for body weight. An increase in total IL-1ß was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1ß. The kinetics of total IL-1ß along with the pharmacokinetics of canakinumab were characterized by a population-based pharmacokinetic-binding model, where the apparent in vivo dissociation constant, signifying binding affinity of canakinumab to circulating IL-1ß, was estimated at 1.07 ± 0.173 nmol/L in CAPS patients. During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokinetic/pharmacodynamic properties of canakinumab.

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.

A network control theory approach to modeling and optimal control of zoonoses: case study of brucellosis transmission in sub-Saharan Africa.

BACKGROUND: Developing control policies for zoonotic diseases is challenging, both because of the complex spread dynamics exhibited by these diseases, and because of the need for implementing complex multi-species surveillance and control efforts using limited resources. Mathematical models, and in particular network models, of disease spread are promising as tools for control-policy design, because they can provide comprehensive quantitative representations of disease transmission. METHODOLOGY/PRINCIPAL FINDINGS: A layered dynamical network model for the transmission and control of zoonotic diseases is introduced as a tool for analyzing disease spread and designing cost-effective surveillance and control. The model development is achieved using brucellosis transmission among wildlife, cattle herds, and human sub-populations in an agricultural system as a case study. Precisely, a model that tracks infection counts in interacting animal herds of multiple species (e.g., cattle herds and groups of wildlife for brucellosis) and in human subpopulations is introduced. The model is then abstracted to a form that permits comprehensive targeted design of multiple control capabilities as well as model identification from data. Next, techniques are developed for such quantitative design of control policies (that are directed to both the animal and human populations), and for model identification from snapshot and time-course data, by drawing on recent results in the network control community. CONCLUSIONS/SIGNIFICANCE: The modeling approach is shown to provide quantitative insight into comprehensive control policies for zoonotic diseases, and in turn to permit policy design for mitigation of these diseases. For the brucellosis-transmission example in particular, numerous insights are obtained regarding the optimal distribution of resources among available control capabilities (e.g., vaccination, surveillance and culling, pasteurization of milk) and points in the spread network (e.g., transhumance vs. sedentary herds). In addition, a preliminary identification of the network model for brucellosis is achieved using historical data, and the robustness of the obtained model is demonstrated. As a whole, our results indicate that network modeling can aid in designing control policies for zoonotic diseases.

Displaced middle-third fractures of the clavicle-operative management.

Displaced midclavicular fractures resulting in malunion with shortening and rotational deformity does not remodel in adults and incidence of non-union in displaced midshaft clavicular fractures is between 10-15% especially in those with an initial shortening of >20 mm.We have treated 10 patients of displaced middle-third clavicle fracture by open reduction and internal fixation with plate and screws and found it to be very effective in respect to rehabilitation, union and cosmesis.

An evaluation of flexible intramedullary nail fixation in femoral shaft fractures in paediatric age group.

Sixty-two femoral shaft fractures in 60 patients treated by elastic intramedullary nailing with mean age of the patients being 9.2 years (range 5 years to 12 years) and average follow-up of 15 months (range 7 months to 60 months) are evaluated. Twenty-eight fractures were fixed with titanium elastic nail while 34 fractures were fixed with Enders nail. There were 40 midshaft fractures, 18 proximal femoral and 4 were fractures of distal third. Fracture patterns were transverse in 35, short oblique in 14 cases and 13 were spiral fractures. Mean age of union in this series was 17 weeks (range 12 weeks to 28 weeks). Ten cases had complications, 5 had nail tip irritation, 3 varus or valgus malalignment and 2 had delayed union. In this series, we did not have any non-union, refracture, limb length discrepancy or any major infection. The result demonstrates 100% union rate irrespective of the age, weight and height of the patient. Regardless of the site of fracture and their pattern, it united every time with elastic nail fixation. We did not find and mismatch in the results of fractures stabilised with titanium elastic nail with that of elastic stainless steel nail.

Operative management of closed intra-articular fractures of distal end of humerus in adults.

This is a study of 60 patients with mean age of 30 years having intra-articular fracture of distal humerus of type C (AO classification). We treated these fractures by open reduction and internal fixation through transolecranon approach. Mean duration of operative time with that of injury was 10 days. In all the cases 1st the intracondylar fracture was fixed followed by reconstruction and stabilisation of medial and lateral pillar by 1/3 tubular plate and 3.5 mm dynamic compressent plate (DCP) or recon plate respectively. Minimum follow-up was of 1 year duration with average follow-up of 3 years. We could achieve 100% union with mean range of movement at the and of 1 year was 20 degree to 110 degree. Two fractures had delayed union, 5 patients had skin complications for which extended dressing was required. None of these patients required SSG or secondary suture.