A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk.

BackgroundTumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway.ResultTo develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior.ConclusionThese results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance

Transcriptomic and functional analyses of mitochondrial dysfunction in pressure overload-induced right ventricular failure

Background In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods and Results We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 versus RV hypertrophy 334.3±30.65 versus RV failure 165.4±36.72 pmol/(s×mL)

Coconut-growing soils of Kerala: 1. Characteristics and classification

Coconut plantations are the major land use systems in Kerala state. The tropical hot humid climate and soils of the state are considered suitable for the palm, with the exception of highlands occurring 600 m above MSL. However, the productivity of coconut is abysmally low in the state with an average productivity of around 40 nuts per year per palm. To find out whether the highly weathered and leached low activity clay soils developed in tropical hot humid climate is responsible for the low yield, an assessment of soil qualities in the coconut-growing soils of the state was made. Six distinct regions of coconut cultivation in the state were identified and delineated based on the variability of agro-climate and soils, viz., Central and Eastern Palakkad, Northern Kerala, Central Kerala, Southern Kerala, Onattukara sandy plains and coastal sandy plains. Soil profiles were studied at representative sites in each region. Investigated morphological features and sampled horizon-wise for the analysis of physical and chemical properties of the soil. Coconut-growing soils of Kerala state are in general deep and well drained, clayey or sandy having good structure permitting rapid transmission of water. The soils of Palakkad, Southern Kerala and Coastal Sandy Plains have near neutral reaction whereas the extensive areas of laterite soils of Northern and Central Kerala and sandy soils of Onattukara were strongly acid and had high levels of KCl extractable aluminium. The acid soils also analysed for low levels of basic cations, potassium, calcium and magnesium. Soils from all regions except Palakkad have low CEC. Surface and sub-soils base status were extremely low for soils of Northern and Central Kerala and Onattukara sandy plain. The soils of Central and Eastern Palakkad were classified as Typic Haplustalfs, Northern Kerala as Plinthic Humults, Central Kerala as Typic Plinthustults, Southern Kerala as Rhodic Kandiustults and the soils of sandy plains as Ustipsamments, according to soil taxonomy

Performance of the ocean state forecast system at Indian National Centre for Ocean Information Services

The reliability of the operational Ocean State Forecast system at the Indian National Centre for Ocean Information Services (INCOIS) during tropical cyclones that affect the coastline of India is described in this article. The performance of this system during cyclone Thane that severely affected the southeast coast of India during the last week of December 2011 is reported here. Spec-tral wave model is used for forecasting the wave fields generated by the tropical cyclone and vali-dation of the same is done using real-time automated observation systems. The validation results indicate that the forecasted wave parameters agree well with the measurements. The feedback from the user community indicates that the forecast was reliable and highly useful. Alerts based on this operational ocean state forecast system are thus useful for protecting the property and lives of the coastal communities along the coastline of India. INCOIS is extending this service for the benefit of the other countries along the Indian Ocean rim

Prospective nutritional, therapeutic, and dietary benefits of camel milk making it a viable option for human consumption: Current state of scientific knowledge

For over five thousand years, people in Asia and Africa have known about the health benefits of camel milk. Thus, it is used not only as a food source but also as a medicine. The similarities between camel milk and human milk have been scientifically proven. Camel milk is unique among ruminant milk because it is high in vitamins C and E and low in sugar and cholesterol. Still, it contains a wide variety of beneficial minerals (including sodium, potassium, iron, copper, zinc, and magnesium), besides being rich in several nutrients, including monounsaturated and polyunsaturated fatty acids, serum albumin, lactoferrin, immunoglobulins, lysozyme and the hormone insulin. Because of these components, many medical professionals now recommend camel milk as a treatment for various human ailments. It has been demonstrated to be effective in treating gastrointestinal issues, Type 1 diabetes, and food allergies. As a bonus, camel milk has been utilized to cure autism, lower cholesterol, prevent psoriasis, heal inflammation, aid tuberculosis patients, boost the body's natural defences, and impede the spread of cancer cells. Those who have problems digesting lactose may still be able to tolerate it. Conversely, camel milk can also help reduce an excessively high bilirubin, globulin, and granulocyte count. Drinking camel milk does not affect the erythrocyte sedimentation rate, hemoglobin concentration, and leukocyte count. The proteins in camel milk have an adequate ratio of critical amino acids. Immunoglobulins, which fight disease, are contained inside, and their small size allows antigens to penetrate and boosts the immune system's efficacy. This article highlights the health benefits and medicinal uses of camel milk

Wave forecasting and monitoring during very severe cyclone Phailin in the Bay of Bengal

Wave fields, both measured and forecast during the very severe cyclone Phailin, are discussed in this communication. Waves having maximum height of 13.54 m were recorded at Gopalpur, the landfall point of the cyclone. The forecast and observed significant wave heights matched well at Gopalpur with correlation coefficient of 0.98, RMS error of 0.35 m and scatter index of 14%. Forecasts were also validated in the open ocean and found to be reliable (scatter index < 15%). The study also revealed the presence of Southern Ocean swells with a peak period of 20-22 sec hitting Gopalpur coast along with the cyclone-generated waves

Islet-Like Cell Aggregates Generated from Human Adipose Tissue Derived Stem Cells Ameliorate Experimental Diabetes in Mice

BACKGROUND: Type 1 Diabetes Mellitus is caused by auto immune destruction of insulin producing beta cells in the pancreas. Currently available treatments include transplantation of isolated islets from donor pancreas to the patient. However, this method is limited by inadequate means of immuno-suppression to prevent islet rejection and importantly, limited supply of islets for transplantation. Autologous adult stem cells are now considered for cell replacement therapy in diabetes as it has the potential to generate neo-islets which are genetically part of the treated individual. Adopting methods of islet encapsulation in immuno-isolatory devices would eliminate the need for immuno-suppressants. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we explore the potential of human adipose tissue derived adult stem cells (h-ASCs) to differentiate into functional islet like cell aggregates (ICAs). Our stage specific differentiation protocol permit the conversion of mesodermic h-ASCs to definitive endoderm (Hnf3β, TCF2 and Sox17) and to PDX1, Ngn3, NeuroD, Pax4 positive pancreatic endoderm which further matures in vitro to secrete insulin. These ICAs are shown to produce human C-peptide in a glucose dependent manner exhibiting in-vitro functionality. Transplantation of mature ICAs, packed in immuno-isolatory biocompatible capsules to STZ induced diabetic mice restored near normoglycemia within 3-4 weeks. The detection of human C-peptide, 1155±165 pM in blood serum of experimental mice demonstrate the efficacy of our differentiation approach. CONCLUSIONS: h-ASC is an ideal population of personal stem cells for cell replacement therapy, given that they are abundant, easily available and autologous in origin. Our findings present evidence that h-ASCs could be induced to differentiate into physiologically competent functional islet like cell aggregates, which may provide as a source of alternative islets for cell replacement therapy in type 1 diabetes

Integrative miRNA-mRNA Profiling of Adipose Tissue Unravels Transcriptional Circuits Induced by Sleep Fragmentation

Obstructive sleep apnea (OSA) is a prevalent condition and strongly associated with metabolic disorders. Sleep fragmentation (SF) is a major consequence of OSA, but its contribution to OSA-related morbidities is not known. We hypothesized that SF causes specific perturbations in transcriptional networks of visceral fat cells, leading to systemic metabolic disturbances. We simultaneously profiled visceral adipose tissue mRNA and miRNA expression in mice exposed to 6 hours of SF during sleep, and developed a new computational framework based on gene set enrichment and network analyses to merge these data. This approach leverages known gene product interactions and biologic pathways to interrogate large-scale gene expression profiling data. We found that SF induced the activation of several distinct pathways, including those involved in insulin regulation and diabetes. Our integrative methodology identified putative controllers and regulators of the metabolic response during SF. We functionally validated our findings by demonstrating altered glucose and lipid homeostasis in sleep-fragmented mice. This is the first study to link sleep fragmentation with widespread disruptions in visceral adipose tissue transcriptome, and presents a generalizable approach to integrate mRNA-miRNA information for systematic mapping of regulatory networks

Clinical and molecular characterisation of KCNT1-related severe early onset epilepsy

Objective: To characterise the phenotypic spectrum, molecular genetic findings and functional consequences of pathogenic variants in early onset KCNT1-epilepsy. Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple gene next generation sequencing panel and whole exome sequencing. Additional patients with non-EIMFS early onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. Where possible, we performed homology modelling to predict putative effects of variants on protein structure and function. We undertook electrophysiological assessment of mutant KCNT1 channels in a Xenopus oocyte model system. Results: We identified pathogenic variants in KCNT1 in 12 patients, four of which are novel. Most variants occurred de novo. Ten had a clinical diagnosis of EIMFS and the other two presented with early onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in one. Computational modelling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain-of-function, with significantly increased channel amplitude and variable blockade by quinidine. Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, though clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy