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Increased lung vascular permeability and neutrophilic inflammation are hallmarks of acute lung injury. Alveolar macrophages (AMϕ), the predominant sentinel cell type in the airspace, die in massive numbers while fending off pathogens. Recent studies indicate that the AMϕ pool is replenished by airspace-recruited monocytes, but the mechanisms instructing the conversion of recruited monocytes into reparative AMϕ remain elusive. Cyclic AMP (cAMP) is a vascular barrier protective and immunosuppressive second messenger in the lung. Here, we subjected mice expressing GFP under the control of the Lysozyme-M promoter (LysM-GFP mice) to the LPS model of rapidly resolving lung injury to address the impact of mechanisms determining cAMP levels in AMϕ and regulation of mobilization of the reparative AMϕ-pool. RNA-seq analysis of flow-sorted Mϕ identified phosphodiesterase 4b (PDE4b) as the top LPS-responsive cAMP-regulating gene. We observed that PDE4b expression markedly increased at the time of peak injury (4 h) and then decreased to below the basal level during the resolution phase (24 h). Activation of transcription factor NFATc2 was required for the transcription of PDE4b in Mϕ. Inhibition of PDE4 activity at the time of peak injury, using intratracheal rolipram, increased cAMP levels, augmented the reparative AMϕ pool, and resolved lung injury. This response was not seen following conditional depletion of monocytes, thus establishing airspace-recruited PDE4b-sensitive monocytes as the source of reparative AMϕ. Interestingly, adoptive transfer of rolipram-educated AMϕ into injured mice resolved lung edema. We propose suppression of PDE4b as an effective approach to promote reparative AMϕ generation from monocytes for lung repair.

Avalanche forecasting is carried out using physical as well as statistical models. All these models have certain limitations associated with their mathematical formulation that enable them to perform variably with respect to forecast of an avalanche event and associated danger. To overcome limitations of each individual model, a multi-model decision support system (MM-DSS) has been developed for forecasting of avalanche danger in Chowkibal–Tangdhar (C-T) region of North-West Himalaya. The MM-DSS has been developed for two different altitude zones of the C-T region by integrating four avalanche forecasting models-Hidden Markov model (HMM), nearest neighbour (NN), artificial neural network (ANN) and snow cover model-HIM-STRAT to deliver avalanche forecast with a lead time of three days. Weather variables for these models have been predicted using ANN. Root mean square error of predicted weather variables is computed by using leave one out cross-validation method. Snow and meteorological data of 22 winters (1992–2014) of the lower C-T region and 8 winters (2008–2016) of the higher C-T region have been used to develop avalanche forecasting models for these two sub-regions. All the avalanche forecasting models have been validated by true skill score (TSS), Heidke skill score (HSS), per cent correct (PC), probability of detection (POD), bias and false alarm rate (FAR) using data of five winters (2014–19) for the lower C-T region and three winters (2016–19) for the upper C-T region. In both the C-T regions, for day-1, day-2 and day-3, the HSS of MM-DSS lies between 0.26 and 0.4 and the POD between 0.64 and 0.86.

Objective Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of pathological event's revealed that increased myocardial tissue oxygen demand and energy dysregulation exist early during Iso-induced cardiac toxicity. Later, tissue hypoxia results in increased oxidative stress, inflammation and fibrosis along with cardiac dysfunction in this model. The canonical Wnt/β-catenin pathway has been reported to directly implicate in inducing cardiomyocyte hypertrophy and remodelling. However, less is known about the role of non-canonical Wnt signalling in cardiac diseases. Method Certain evidences have suggested that the activation of Wnt could up-regulate key energy sensor and cell growth regulator mTOR (Mechanistic target of rapamycin) by inhibition of GSK-3β mediator. Result The GSK-3β could negatively influence the mTOR activity and produce energy dysregulation during stress or hypoxic conditions. This suggests that the inhibition of GSK-3β by Wnt signalling could up-regulate mTOR levels and thereby restore early myocardial tissue energy balance and prevent cardiac toxicity in rodents. Conclusion We hereby discuss a novel therapeutic role of the β-catenin independent, Wnt-GSK3-mTOR axis in attenuation of Iso-induced cardiotoxicity in rodents.

High resolution meteorological fields have been found potentially useful for hydrological and agricultural applications and mitigation of hydro-meteorological hazards such as landslide and snow avalanches. These meteorological fields are being generated for Himalaya using Weather Research and Forecast (WRF) model with spatial resolution up to 3 km. However, gridded meteorological data of sub-kilometer resolution is not available for the Himalayan region. In the present study, Numerical Weather Prediction model-WRF has been configured for North-West (N-W) Himalayan region with spatial resolution of 2 km and run in hind cast mode to generate meteorological data of 11 winters (2009-19). Artificial neural networks (ANNs) have been developed for post-processing of maximum temperature, minimum temperature, wind speed, relative humidity, snow depth and snowfall in 24h generated by the WRF model using observed surface weather data of five different locations in Chowkibal-Tangdhar (C-T) region. Post-processed WRF output has been spatially interpolated to a grid resolution of 90 m using quasi-physical relations and inverse distance weighing scheme. The ultra-high resolution meteorological fields generated over the C-T domain have been validated at five locations in the C-T region for two winters (2017-19). For all five stations, the Nash-Sutcliffe Efficiency (NSE) scores of the model for maximum and minimum temperature, relative humidity and snow depth has been found at “very good” level (> 0.75) with considerably high Heidke Skill Score (HSS) (> 0.4). A comparison of observed and simulated cumulative snowfall during major snow storms during 2017-19 has also been discussed.

Increased endothelial permeability leads to excessive exudation of plasma proteins and leukocytes in the interstitium, which characterizes several vascular diseases including acute lung injury. The myosin light chain kinase long (MYLK‐L) isoform is canonically known to regulate the endothelial permeability by phosphorylating myosin light chain (MLC‐P). Compared to the short MYLK isoform, MYLK‐L contains an additional stretch of ~919 amino acid at the N‐terminus of unknown function. We show that thapsigargin and thrombin‐induced SOCE was markedly reduced in Mylk‐L –/– endothelial cells (EC) or MYLK‐L‐depleted human EC. These agonists also failed to increase endothelial permeability in MYLK‐L‐depleted EC and Mylk‐L –/– lungs, thus demonstrating the novel role of MYLK‐L‐induced SOCE in increasing vascular permeability. MYLK‐L augmented SOCE by increasing endoplasmic reticulum (ER)‐plasma membrane (PM) junctions and STIM1 translocation to these junctions. Transduction of N‐MYLK domain (amino acids 1‐919 devoid of catalytic activity) into Mylk‐L –/– EC rescued SOCE to the level seen in control EC in a STIM1‐dependent manner. N‐MYLK‐induced SOCE augmented endothelial permeability without MLC‐P via an actin‐binding motif, DVRGLL. Liposomal‐mediated delivery of N‐MYLK mutant but not ∆DVRGLL‐N‐MYLK mutant in Mylk‐L –/– mice rescued vascular permeability increase in response to endotoxin, indicating that targeting of DVRGLL motif within MYLK‐L may limit SOCE‐induced vascular hyperpermeability.

Artificial neural network (ANN)-based models have been developed for simulation of snowpack parameters—RAM hardness, shear strength, temperature, density, thickness and settlement of snowpack layers using manually observed weather data. The simulated snowpack parameters have been used for development of ANN for avalanche prediction. The complete scheme of simulation of snowpack parameters and avalanche prediction has been named as HIM-STRAT and developed for Chowkibal–Tangdhar region in North-West Himalaya using weather and snow stratigraphy data collected at a representative observatory in that region. Weather and snowpack data collected during the period from 1992 to 2016 have been analysed to generate the database of prominent snowpack layers and associated weather variables. Snowpack parameters have been simulated using randomly selected 490 (80%) data points and tested with 123 (20%) data points. Simulated snowpack parameters—RAM hardness, shear strength of the weakest snowpack layer and overburden pressure on the weakest layer—have been used to derive stability index of snowpack (SIS). The SIS and other snowpack parameters such as snowpack height, RAM hardness, shear strength, storm snow and snow temperature have been derived for past 22 winters (1992–2014) and used for prediction of avalanches. The HIM-STRAT has been validated through computation of root-mean-square error of simulated snowpack parameters and accuracy, bias, false alarm rate and Heidke Skill Score of avalanche prediction for five winters from 2014 to 2019. The performance of HIM-STRAT for simulation of snowpack parameters and prediction of avalanches has been found reasonably good and discussed in detail.

Extracellular vesicles (EVs) are cell-secreted particles with broad potential to treat tissue injuries by delivering cargo to program target cells. However, improving the yield of functional EVs on a per cell basis remains challenging due to an incomplete understanding of how microenvironmental cues regulate EV secretion at the nanoscale. We show that mesenchymal stromal cells (MSCs) seeded on engineered hydrogels that mimic the elasticity of soft tissues with a lower integrin ligand density secrete ~10-fold more EVs per cell than MSCs seeded on a rigid plastic substrate, without compromising their therapeutic activity or cargo to resolve acute lung injury in mice. Mechanistically, intracellular CD63(+) multivesicular bodies (MVBs) transport faster within MSCs on softer hydrogels, leading to an increased frequency of MVB fusion with the plasma membrane to secrete more EVs. Actin-related protein 2/3 complex but not myosin-II limits MVB transport and EV secretion from MSCs on hydrogels. The results provide a rational basis for biomaterial design to improve EV secretion while maintaining their functionality.

[Figure: see text].

Summary: Alveolar macrophages (AMs), upon sensing pathogens, trigger host defense by activating toll-like receptor 4 (TLR4), but the counterbalancing mechanisms that deactivate AM inflammatory signaling and prevent lethal edema, the hallmark of acute lung injury (ALI), remain unknown. Here, we demonstrate the essential role of AM protease-activating receptor 2 (PAR2) in rapidly suppressing inflammation to prevent long-lasting injury. We show that thrombin, released during TLR4-induced lung injury, directly activates PAR2 to generate cAMP, which abolishes Ca2+ entry through the TRPV4 channel. Deletion of PAR2 and thus the accompanying cAMP generation augments Ca2+ entry via TRPV4, causing sustained activation of the transcription factor NFAT to produce long-lasting TLR4-mediated inflammatory lung injury. Rescuing thrombin-sensitive PAR2 expression or blocking TRPV4 activity in PAR2-null AMs restores their capacity to resolve inflammation and reverse lung injury. Thus, activation of the thrombin-induced PAR2-cAMP cascade in AMs suppresses TLR4 inflammatory signaling to reinstate tissue integrity. : Alveolar macrophages trigger inflammatory signaling upon TLR4 activation by pathogens, and this signaling, if unchecked, can lead to pulmonary edema, the hallmark of acute lung injury. Rayees et al. demonstrate that thrombin ligation of the alveolar macrophage protease-activating receptor 2 post-injury suppresses inflammatory lung injury via a cAMP blockade of the TRPV4 channel. Keywords: protease-activating receptor 2, alveolar macrophages, cAMP, TRPV4, NFAT, acute lung injury, Ca2+ entry

Polymorphonuclear neutrophils (PMN) are highly dynamic innate immune cells which are essential for lung host defense. However, in vivo intravital imaging in moving organs such as the lung remains challenging due to motion artifacts. Here we describe a novel intravital imaging method with high-throughput analytical capability based on a computer vision stabilization algorithm, Computer-vision-Assisted STabilized intravital imaging (CASTii). The sub-micron precision of this approach enables analysis of compartmentalized intravital PMN dynamics. We quantified in real-time a novel patrolling function of lung intracapillary circulating PMN. We also describe the dynamics of intracapillary PMN pooling (marginated PMN pool) using direct imaging of PMNs. The pool was formed by repeated catch-and-release kinetics involving PMN deformation inside microvessels during the passage of PMNs in vessels. We observed rapid PMN recruitment into the lung tissue compartments from pooled PMNs in response to alveolar chemoattract exposure. In contrast, endotoxemia-induced intracapillary sequestration of PMN impaired PMN transmigration into the alveolar space and defective phagocytosis of live bacteria. Intravital imaging of PMN dynamics with CASTii provides fundamental insights into host-defense functions of lung capillary PMN.

Acute respiratory distress syndrome (ARDS) is the major cause of mortality among hospitalized acute lung injury (ALI) patients. Lung macrophages play an important role in maintaining the tissue-fluid homeostasis following injury. We recently showed that circulating monocytes recruited into the alveolar space suppressed the stimulator of type 1 interferon genes (STING) signaling in alveolar macrophages through sphingosine-1-phosphate (S1P). We used CD11b-DTR mice to deplete CD11b+ monocytes following LPS or Pseudomonas aeruginosa infection. Depletion of CD11b+ monocytes leads to the persistent inflammatory injury, infiltration of neutrophils, activation of STING signaling and mortality following lung infection. We demonstrated that adoptively transferred SPHK2-CD11b+ monocytes into CD11b-DTR mice after pathogenic infection rescue lung inflammatory injury.

Nutraceuticals are the bioactive substances and constituents of herbs and minerals or those dietary supplements which have therapeutic activity. They are supplied as dosage formulations, in addition to the basic nutritional value found in foodstuffs, and have emerged as an essential component of the diet for the common consumer. Vitamins, minerals, fatty acids, pre- and probiotics, herbal supplements, etc. are now widely consumed globally for prophylactic and therapeutic purposes, and this has made the maintenance of safety and quality standards extremely important. The rapidly expanding global nutraceutical industry has further emphasized the need for development of such regulatory guidelines. Though regulations in the United States, United Kingdom, and Europe are streamlined and have become conducive to the development of nutraceutical products, the Indian industry and regulatory scenario are relatively nascent and has great potential to develop to compete with the other international agencies. This is a rapidly growing industry in India and several initiatives have been taken in this direction to make India one of the key players in the area of nutraceuticals in the years to come.

Introduction: Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate the endothelial cell (EC) regenerative programs facilitating thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Hypothesis: We postulate that S1PR1 + EC serve as an endogenous means to prevent endothelial injury. Methods: Studies were made using EC-S1PR1 null mice and S1PR1-GFP reporter mice to trace the generation and characteristics of S1PR1 + EC by exploiting immuno-histochemical analysis and FACS. RNA-seq analysis was performed to identify the genetic signature of S1PR1 + EC. Combination of genetic and pharmacological strategies were included for mechanistic study. Transplantation of S1PR1 + EC and edema measurement was performed in EC-S1PR1 null mice. Results: We observed in a mouse model of endotoxemia that LPS via generation of S1P induced the programming of S1PR1 lo EC to S1PR1 + EC, comprising 80% of lung EC. Their generation preceded the vascular repair phase and these cells were required for reestablishing the endothelial barrier function. Thus, conditional deletion of S1PR1 in EC spontaneously increased lung vascular permeability. RNA-seq analysis of S1PR1 + EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively, as well as transcription factors EGR1 and STAT3. EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively to increase S1P concentration that served to amplify S1PR1 + EC transition. Transplantation of S1PR1 + EC into injured lung vasculature of EC-S1PR1 -/- mice restored endothelial integrity. Conclusions: Findings illustrate that generation of a specialized S1PR1 + EC population has the potential to activate key endothelial regenerative program mediating vascular endothelial repair raising the possibility of activating this pathway to restore vascular homeostasis in inflammatory lung injury.

Macrophages play a central role in dictating the tissue response to infection and orchestrating subsequent repair of the damage. In this context, macrophages residing in the lungs continuously sense and discriminate among a wide range of insults to initiate the immune responses important to host-defense. Inflammatory tissue injury also leads to activation of proteases, and thereby the coagulation pathway, to optimize injury and repair post-infection. However, long-lasting inflammatory triggers from macrophages can impair the lung's ability to recover from severe injury, leading to increased lung vascular permeability and neutrophilic injury, hallmarks of Acute Lung Injury (ALI). In this review, we discuss the roles of toll-like receptor 4 (TLR4) and protease activating receptor 2 (PAR2) expressed on the macrophage cell-surface in regulating lung vascular inflammatory signaling.

Hidden Markov Model (HMM) has been developed for avalanche warning on 10 different road sectors in Pir-Panjal and Great Himalayan mountain ranges of North-West Himalaya. The model uses a data set of nine snow and meteorological variables—average air temperature, snow temperature index, snow drift index, snowfall in 24 h, snowfall in 48 h, snow water equivalent, snowfall intensity, standing snow and snowpack settlement collected during past 20 winters (1992–2012). The HMM is composed of four observations derived from the model input variables and four state variables. The state variables of the model are four levels of avalanche danger (No, Low, Medium and High). Single HMM has been developed to provide avalanche warning for both direct and delayed/wet avalanches with a lead time of two days. The HMM has been validated with (Case-1) and without (Case-2) incorporating delayed/wet avalanches using data collected during four winters (2012–2016) and compared with official Avalanche Warning Bulletin issued by Snow and Avalanche Study Establishment during these winters. The model has been validated through computation of accuracy measures such as percent correct (PC), bias, false alarm rate, probability of detection and Heidke Skill Score. The PC of the HMM for different stations for Case-1 varies from 80.1 to 98.6% for day-1 and 81.2 to 98.3% for day-2 and that for Case-2 from 82.2 to 98.6% for day-1 and 83.3 to 98.3% for day-2.

Objective: To assess the effect of 4-hydroxy-3,5-di-tret-butyl cinnamic acid on the state of endothelial function under conditions of experimental cerebral ischemia. Materials and Methods: Antioxidant properties of 4-hydroxy-3,5-di-tret-butyl cinnamic acid and the effect of this compound on NO-synthase system activity and ADMA concentration were evaluated. Results: As a result, it has been found that the use of 4-hydroxy-3,5-di-tretbutyl cinnamic acid promotes reduction activity of catalase, glutathione peroxidase, superoxide dismutase and a decrease in the concentration of MDA and DC. In addition, the ability to modulate NO synthase system activity was established for this compound: an increase in eNOS activity by 114.2% (p Key words: Experimental ischemic stroke, Cinnamic acid derivatives, Antioxidants, Endothelium

BACKGROUND AND OBJECTIVE Nanoparticles have special properties, such as higher surface-to-volume ratio and higher reactivity, which increases cell penetrability and enhance their applicability in the field of medicine, especially in the case where other drugs are ineffective. Calcium phosphate nanoparticles (CPNP) and their encapsulation with therapeutic and/or diagnostic agents is such an agent synthesized. However, there are concerns related to the colloidal stability of these nanoparticles, which are reflected in their tendency to form aggregates in the physiological milieu. Therefore, successful translation of these nanoparticles from laboratory to the clinic requires studies of biodistribution and biocompatibility of nanoparticles for in vivo biomedical applications. METHOD Calcium phosphate nanoparticles synthesized and were tagged with a fluorophore and surface stabilized with trisilanol for stable aqueous dispersion. The in vivo biodistribution and sub-acute toxicological studies were done for orally-administered calcium phosphate nanoparticles. RESULTS The biodistribution studies indicated that these nanoparticles were not prone to rapid degradation or excretion in the body, were long-circulating, and could appreciably permeate to the brain. Body/organ weight and biochemical analyses did not reveal much difference between nanoparticle-administered and saline-administered (control) groups. Finally, histopathological analyses of major organs such as liver, lungs, heart, stomach and kidney, did not reveal significant abnormalities in the treatment groups. CONCLUSION Thus, it is evident from these sub-acute toxicity studies that the nanoparticles appear to be non-toxic to rats following oral administration. These observations can have significant implications in calcium-phosphate nanoparticle-mediated non-toxic drug delivery to target organs, such as brain, via non-invasive, oral route.

Summary: Acute lung injury (ALI) is a lethal inflammatory lung disorder whose incidence is on the rise. Alveolar macrophages normally act to resolve inflammation, but when dysregulated they can provoke ALI. We demonstrate that monocyte-derived macrophages (CD11b+ macrophages) recruited into the airspace upregulate the anti-inflammatory function of alveolar macrophages by suppressing their stimulator of type 1 interferon gene (STING) signaling. Depletion of CD11b+ macrophages in mice (macrophagedep mice) after endotoxin or after Pseudomonas aeruginosa causes expansion of the inflammatory alveolar macrophage population, leading to neutrophil accumulation, irreversible loss of lung vascular barrier function, and lethality. We show that CD11b+ macrophages suppress alveolar macrophage-STING signaling via sphingosine kinase-2 (SPHK2) generation of sphingosine-1-phosphate (S1P). Thus, adoptive transfer of wild-type (WT) or STING−/−, but not SPHK2−/−, CD11b monocytes from murine bone marrow into injured macrophagedep mice rescue anti-inflammatory alveolar macrophages and reverse lung vascular injury. SPHK2-induced S1P generation in CD11b+ macrophages has the potential to educate alveolar macrophages to resolve ALI. : Joshi et al. demonstrate an essential role of SPHK2+ monocyte-derived CD11b+ macrophages, which are recruited to the airspace, in promoting anti-inflammatory function of alveolar macrophages during lung injury. They show that S1P generated by recruited SPHK2+-CD11b+ macrophages suppresses STING signaling in alveolar macrophages to resolve inflammatory injury. Keywords: acute lung injury, sting, sphingosine kinase 2, alveolar macrophages, recruited macrophages, CD11b+ macrophages, S1P, inflammation, cGAMP

Alveolar macrophages (AMs), upon sensing pathogens, trigger host defense by activating toll-like receptor 4 (TLR4), but the counterbalancing mechanisms that deactivate AM inflammatory signaling and prevent lethal edema, the hallmark of acute lung injury (ALI), remain unknown. Here, we demonstrate the essential role of AM protease-activating receptor 2 (PAR2) in rapidly suppressing inflammation to prevent long-lasting injury. We show that thrombin, released during TLR4-induced lung injury, directly activates PAR2 to generate cAMP, which abolishes Ca(2+) entry through the TRPV4 channel. Deletion of PAR2 and thus the accompanying cAMP generation augments Ca(2+) entry via TRPV4, causing sustained activation of the transcription factor NFAT to produce long-lasting TLR4-mediated inflammatory lung injury. Rescuing thrombin-sensitive PAR2 expression or blocking TRPV4 activity in PAR2-null AMs restores their capacity to resolve inflammation and reverse lung injury. Thus, activation of the thrombin-induced PAR2-cAMP cascade in AMs suppresses TLR4 inflammatory signaling to reinstate tissue integrity.

The present study evaluated the effects of morphine on acute and chronic restraint stress (RS) induced anxiety modulation and the possible involvement of nitric oxide (NO) and heat shock proteins (Hsp70) during such effects. Acute RS (×1) induced anxiogenesis in the elevated plus maze (EPM) test which was associated with lowered brain NO metabolites (NOx) and elevated Hsp70 levels. Pretreatment with morphine (1 and 5 mg/kg) and L-arginine (500 mg/kg) attenuated the RS effects on EPM activity and brain NOx, whereas, Hsp70 levels were further augmented. Co-administration of both agents showed synergistic effects. By contrast, repeated RS (×15) did not induce any significant changes in EPM activity or brain NOx, but brain Hsp70 levels stayed elevated. Administration of morphine or L-arginine prior to chronic RS did not influence such chronic stress induced changes in behavioral and biochemical markers, but appreciably attenuated chronic RS induced elevation in Hsp70 levels. These results suggest that acute and chronic RS induced anxiety modulations were differentially influenced by morphine and L-arginine and that complex interactions involving brain NO and unregulated Hsp70 could regulate such effects.

A Hidden Markov Model (HMM) has been developed for prediction of quantitative snowfall in Pir-Panjal and Great Himalayan mountain ranges of Indian Himalaya. The model predicts snowfall for two days in advance using daily recorded nine meteorological variables of past 20 winters from 1992–2012. There are six observations and six states of the model. The most probable observation and state sequence has been computed using Forward and Viterbi algorithms, respectively. Baum–Welch algorithm has been used for optimizing the model parameters. The model has been validated for two winters (2012–2013 and 2013–2014) by computing root mean square error (RMSE), accuracy measures such as percent correct (PC), critical success index (CSI) and Heidke skill score (HSS). The RMSE of the model has also been calculated using leave-one-out cross-validation method. Snowfall predicted by the model during hazardous snowfall events in different parts of the Himalaya matches well with the observed one. The HSS of the model for all the stations implies that the optimized model has better forecasting skill than random forecast for both the days. The RMSE of the optimized model has also been found smaller than the persistence forecast and standard deviation for both the days.

Maximum and minimum temperatures are used in avalanche forecasting models for snow avalanche hazard mitigation over Himalaya. The present work is a part of development of Hidden Markov Model (HMM) based avalanche forecasting system for Pir-Panjal and Great Himalayan mountain ranges of the Himalaya. In this work, HMMs have been developed for forecasting of maximum and minimum temperatures for Kanzalwan in Pir-Panjal range and Drass in Great Himalayan range with a lead time of two days. The HMMs have been developed using meteorological variables collected from these stations during the past 20 winters from 1992 to 2012. The meteorological variables have been used to define observations and states of the models and to compute model parameters (initial state, state transition and observation probabilities). The model parameters have been used in the Forward and the Viterbi algorithms to generate temperature forecasts. To improve the model forecasts, the model parameters have been optimised using Baum–Welch algorithm. The models have been compared with persistence forecast by root mean square errors (RMSE) analysis using independent data of two winters (2012–13, 2013–14). The HMM for maximum temperature has shown a 4–12% and 17–19% improvement in the forecast over persistence forecast, for day-1 and day-2, respectively. For minimum temperature, it has shown 6–38% and 5–12% improvement for day-1 and day-2, respectively.

The present study evaluated the effects of morphine treatments on elevated plus maze test parameters, oxidative stress markers and Hsp70 expression in normal and stressed rats. Acute and chronic stress caused neurobehavioral suppression, altered prooxidant–antioxidant balance and increased Hsp70 expression in brain homogenates in a differential manner. Morphine (1 and 5 mg/kg) attenuated RS induced anxiogenesis, changes in MDA and GSH but further enhanced Hsp70 expression. Similar anxiolytic and Hsp70 enhancing effects were seen after morphine in normal rats (no RS). Exposure to chronic RS did not elicit any appreciable neurobehavioral response in EPM but enhanced MDA, lowered GSH and exaggerated the Hsp70 expression. Pretreatment with morphine did not affect the neurobehavioral response to chronic RS, but reverted the GSH and Hsp70 expression. The results suggest that morphine differentially influences acute and chronic stress induced changes in anxiety behavior and complex interactions between oxidative stress markers and Hsp70 expression which may contribute to these effects.

We report the synthesis of optically doped calcium phosphate nanoparticles (CPs), with and without surface coating with the biocompatible polymer chitosan. Trisilanol was used to restrict the size of calcium phosphate in the nano-dimension. The diameter of the nanoparticles was found to be less than 200 nm. A powder X-ray diffraction (XRD) study demonstrated the crystalline nature of the nanoparticles, largely matching with the XRD pattern of hydroxyapatite, which is the most common crystalline form of calcium phosphate. Upon fluorophore encapsulation in these nanoparticles, the optical properties of the fluorophore not only remained preserved, but also had enhanced stability against chemical quenching in comparison to its free form. In vitro analysis showed that these nanoparticles are taken up by cells, the uptake being enhanced upon coating with chitosan. No sign of in vitro cytotoxicity was observed in the dosages tested. Preliminary in vivo studies showed that oral administration of these nanoparticles in healthy Wistar rats, at a dose of 2000 mg kg−1, did not result in any visible sign of acute toxicity. These results highlight the potential for CPs to be used as safe and efficient agents for optical bioimaging and drug delivery.

Frequent avalanche activity and poor route visibility due to bad weather make snow bound mountainous regions quite unsafe for travel during the winter months. Hence, there is a need for an accurate navigation device that can help in the safe movement of mountain travellers in avalanche prone areas. This paper presents the design and implementation of a portable GPS-based warning and navigation system, capable of providing safe navigation to mountain travellers in avalanche-prone regions. The system uses a hand-held GPS with a positional accuracy of 2–5 m. A customized application has been developed for the visualization of maps, navigation, positioning, tracking and issuing avalanche path warning. On the basis of registered avalanche path data, this application updates the traveller at predefined time intervals on whether the current position of the traveller is inside or outside an avalanche path. When the traveller enters an avalanche prone area, a warning in the form of text and voice messages is gener...

Cytokines are small, non-structural proteins with low molecular weights which have a complex regulatory influence on inflammation and immunity. It has long been considered that development of immune and inflammatory response involves hematopoietic cells, lymphoid cell, and various pro-inflammatory and anti-inflammatory cells, and cytokines mediate the complex interactions of these cells. Cytokines are the intercellular messengers in the immune system where they integrate function of several cell types in various body compartments into a coherent immune response. They have evolved over the years and now include the interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. Earlier known as `soluble factors`, cytokines are produced by and elicit a response from every cell, with the lone exception of the red blood cell. In response to various stimulus cytokines are secreted from various cells including white blood cells. Pleiotropism is the hallmark of a cytokine and there are failures and successes of cytokines and related agents as therapeutic agents. In the membrane of target cells they have specific receptors for their signal transduction and regulatory functions. Beyond the innate and adaptive immunity, cytokines has a major role in many diverse functions including immune cell differentiation, inflammation, angiogenesis, tumorigenesis, neurobiology, viral pathogenesis etc. In addition to inflammation, immunity and infections, cytokines have now expanded their domain to atherosclerosis and cancer. Thus, cytokines may be useful biomarkers for health and disease and act as diagnostic, prognostic and therapeutic agents. This review will highlight the impact of cytokines in various physiological actions, pathophysiological states, therapeutics and the complex interactions between brain and immune cells.

Nutraceuticals provide benefits in the prevention and treatment of various diseases. With increasing incidences of lifestyle-related health problems, they have emerged as an essential component of the diet for the common consumer. Vitamins, minerals, fatty acids, prebiotics and probiotics, and herbal supplements are now widely consumed globally for prophylactic and therapeutic purposes, and this has made the maintenance of safety and quality standards extremely important. The rapidly expanding global nutraceutical industry has further emphasized the need for development of such regulatory guidelines. Although regulations in the United States, the United Kingdom, and Europe are streamlined and have become conducive to the development of nutraceutical products, the Indian industry and regulatory scenario are relatively nascent and have great potential to develop and compete with other international agencies. This is a rapidly growing industry in India and several initiatives have been taken in this direction to make India one of the key future players in the area of nutraceuticals.

Temperature and fresh snow are essential inputs in an avalanche forecasting model. Without these parameters, prediction of avalanche occurrence for a region would be very difficult. In the complex terrain of Himalaya, nonavailability of snow and meteorological data of the remote locations during snow storms in the winter is a common occurrence. In view of this persistent problem present study estimates maximum temperature, minimum temperature, ambient temperature and precipitation intensity on different regions of Indian western Himalaya by using similar parameters of the neighbouring regions. The location at which parameters are required and its neighbouring locations should all fall in the same snow climatic zone. Initial step to estimate the parameters at a location, is to shift the parameters of neighbouring regions at a reference height corresponding to the altitude of the location at which parameters are to be estimated. The parameters at this reference height are then spatially interpolated by using Barnes objective analysis. The parameters estimated on different locations are compared with the observed one and the Root Mean Square Errors (RMSE) of the observed and estimated values of the parameters are discussed for the winters of 2007–2008.

Stress and stress related disorders are a major cause of morbidity and mortality and understanding stress mechanisms is of great importance for devising appropriate therapeutic measures in such situations. The brain and its complex neurotransmitter systems regulate physiological and behavioral responses to a variety of stressors. Several other factors like age, gender and emotionality of the organism, as well as type, intensity and duration of the stressor may decide the nature and extent of stress effects. Nitric oxide (NO) is widely distributed in the brain and its role in Central nervous system (CNS) pathophysiology has been suggested. Recent studies have shown that free radicals and in particular NO may play a crucial role in the regulation of stress effects. All the various factors, mentioned above, that might influence stress responsiveness have been discussed with reference to regulatory role of NO during stress and it appears that NO may act as a therapeutic target for development of novel strategies against stress related disorders.