Drug-sensitive FGFR3 mutations in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.

NGS-based approach to determine the presence of HPV and their sites of integration in human cancer genome.

BACKGROUND: Human papilloma virus (HPV) accounts for the most common cause of all virus-associated human cancers. Here, we describe the first graphic user interface (GUI)-based automated tool 'HPVDetector', for non-computational biologists, exclusively for detection and annotation of the HPV genome based on next-generation sequencing data sets. METHODS: We developed a custom-made reference genome that comprises of human chromosomes along with annotated genome of 143 HPV types as pseudochromosomes. The tool runs on a dual mode as defined by the user: a 'quick mode' to identify presence of HPV types and an 'integration mode' to determine genomic location for the site of integration. The input data can be a paired-end whole-exome, whole-genome or whole-transcriptome data set. The HPVDetector is available in public domain for download: http://www.actrec.gov.in/pi-webpages/AmitDutt/HPVdetector/HPVDetector.html. RESULTS: On the basis of our evaluation of 116 whole-exome, 23 whole-transcriptome and 2 whole-genome data, we were able to identify presence of HPV in 20 exomes and 4 transcriptomes of cervical and head and neck cancer tumour samples. Using the inbuilt annotation module of HPVDetector, we found predominant integration of viral gene E7, a known oncogene, at known 17q21, 3q27, 7q35, Xq28 and novel sites of integration in the human genome. Furthermore, co-infection with high-risk HPVs such as 16 and 31 were found to be mutually exclusive compared with low-risk HPV71. CONCLUSIONS: HPVDetector is a simple yet precise and robust tool for detecting HPV from tumour samples using variety of next-generation sequencing platforms including whole genome, whole exome and transcriptome. Two different modes (quick detection and integration mode) along with a GUI widen the usability of HPVDetector for biologists and clinicians with minimal computational knowledge.

Journey through the spectacular landscape of melanocortin 1 receptor.

The physiological role of α-melanocyte stimulating hormone in regulating integumental pigmentation of many vertebrate species has been recognized since the 1960's. However, its physiological significance for human pigmentation remained enigmatic until the 1990's. α-Melanocyte stimulating hormone and related melanocortins are synthesized locally in the skin, primarily by keratinocytes, in addition to the pituitary gland, and therefore act as paracrine factors for melanocytes. Human melanocytes express the melanocortin 1 receptor, which recognizes α-melanocyte stimulating hormone and the related adrenocorticotropic hormone as agonists. This review summarizes the current knowledge of the pleotropic effects of the activated melanocortin 1 receptor that maintain human melanocyte homeostasis by regulating melanogenesis and the response to environmental stressors, mainly solar radiation. Certain allelic variants of the melanocortin 1 receptor gene are associated with specific pigmentary phenotypes in various human populations. Variants associated with red hair phenotype compromise the function of the encoded receptor. Activation of the human melanocortin 1 receptor regulates eumelanin synthesis and enhances DNA damage response of melanocytes to solar radiation and oxidative stressors. We describe how synthetic selective melanocortin 1 receptor agonists can be efficacious as sunless tanning agents, for treatment of vitiligo and photosensitivity disorders, and for prevention of skin cancer, including melanoma.

A fundamental asymmetry in human memory: Old ≠ not-new and new ≠ not-old.

In recognition memory, anything that is objectively new is necessarily not-old, and anything that is objectively old is necessarily not-new. Therefore, judging whether a test item is new is logically equivalent to judging whether it is old, and conversely. Nevertheless, a series of 10 experiments showed that old? and new? judgments did not produce equivalent recognition accuracy. In Experiments 1-4, wherein subjects made old? or new? judgments about test items, new? judgments yielded more accurate performance for old items than old? judgments did, and old? judgments yielded more accurate performance for new items than new? judgments did. This same violation of logical equivalence was observed in Experiments 5-10, wherein subjects made similar? judgments as well as old? and new? ones. In short, old? and new? judgments displayed consistent Judgment × Item crossovers, rather than equivalence. Response latencies were used to test the hypothesis that Judgment × Item crossovers were due to certain judgment-item combinations provoking more deliberate, thorough retrieval than other combinations. There was no support for that hypothesis, but the data were consistent with an earlier theory, which posits that latency depends on the extent to which judgments or items slant retrieval toward accessing verbatim traces. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Effect of Inner Engineering Online (IEO) Program on Reducing Stress for Information Technology Professionals: A Randomized Control Study.

In recent years, mindfulness-based interventions (MBIs) are rapidly growing in the workplace. Several meta-analyses conclude that overall MBIs have a moderate effect of alleviating deficit-based experiences, such as burnout and stress, but a small to no effect of promoting asset-based experiences, such as positive affect and well-being. While workplace MBIs vary greatly in their content, format, and duration, the dominant format is still face to face in a group setting, which limits scalability. Our study introduces an emerging workplace intervention called Inner Engineering Online (IEO) and evaluates its effect on reducing stress, burnout, depression, and anxiety and increasing mindfulness and joy. Drawing on the classical yogic science, IEO is a comprehensive web-based multicomponent intervention that utilizes dialectic discourse, meditation, and yogic practices designed to improve physical, mental, and emotional health. Utilizing a randomized active control cross-over experimental design with a sample of 71 employees of an Information Technology company, we tested our hypothesis that IEO training and regular daily yogic practice are likely to lower the stress levels, prevent burnout, and alleviate anxiety and depression, while at the same time promotes positive affect for employees. The results show that IEO program significantly reduces stress only among those who adhere to recommended daily yogic practices. The study is limited by its small sample size. Future research using a large sample is recommended to reexamine the effect of IEO training on occupational health. This trial is registered with NCT04126564.

Integrated agroforestry systems improve soil carbon storage, water productivity, and economic returns in the marginal land of the semi-arid region.

Environmental crises, land degradation, and frequent crop failure threaten the livelihoods of millions of the populace in the semi-arid agroecosystems. Therefore, different combinations of annual crops with perennial fruit trees were assessed to restore the soil carbon, and enhance farm productivity and profitability in a semi-arid climate. The study hypothesized that the integration of perennial fruit trees with seasonal crops may enhance farm productivity, economic returns, and environmental sustainability. Integration of phalsa (Grewia asiatica) with mung bean (Vigna radiata) - potato (Solanum tuberosum) system recorded the highest system productivity (25.9 Mg/ha) followed by phalsa with cowpea (Vigna unguiculata) -mustard (Brassica juncea) systems (21.2 Mg/ha). However, Karonda (Carissa sp.) with mung bean - potato system recorded maximum net return (3529.1 US$/ha), and water use efficiency (33.0 kg/ha-mm). Concerning the benefit-cost (B:C) ratio, among the agroforestry systems, the karonda + cowpea - mustard system registered a maximum BC ratio (3.85). However, SOC density remained higher (9.10 Mg/ha) under the phalsa + cowpea - mustard and Moringa + mung bean - potato system (9.16 Mg/ha) over other systems. Similarly, phalsa + mung bean - potato system had the highest C sustainability index (27.6), carbon sequestration potential (0.6-0.67 Mg/ha/year), and water use efficiency (33.0 kg/ha-mm). Hence, the study suggested that the integration of short-duration leguminous and oilseeds with fruit trees offer a myriad of benefits and an efficient system for restoring the soil C without compromising the food and livelihood security of the rural populace in semiarid regions.

Nanofertilizers for agricultural and environmental sustainability.

Indiscriminate use of chemical fertilizers in the agricultural production systems to keep pace with the food and nutritional demand of the galloping population had an adverse impact on ecosystem services and environmental quality. Hence, an alternative mechanism is to be developed to enhance farm production and environmental sustainability. A nanohybrid construct like nanofertilizers (NFs) is an excellent alternative to overcome the negative impact of traditional chemical fertilizers. The NFs provide smart nutrient delivery to the plants and proves their efficacy in terms of crop productivity and environmental sustainability over bulky chemical fertilizers. Plants can absorb NFs by foliage or roots depending upon the application methods and properties of the particles. NFs enhance the biotic and abiotic stresses tolerance in plants. It reduces the production cost and mitigates the environmental footprint. Multitude benefits of the NFs open new vistas towards sustainable agriculture and climate change mitigation. Although supra-optimal doses of NFs have a detrimental effect on crop growth, soil health, and environmental outcomes. The extensive release of NFs into the environment and food chain may pose a risk to human health, hence, need careful assessment. Thus, a thorough review on the role of different NFs and their impact on crop growth, productivity, soil, and environmental quality is required, which would be helpful for the research of sustainable agriculture.

Microbes-mediated integrated nutrient management for improved rhizo-modulation, pigeonpea productivity, and soil bio-fertility in a semi-arid agro-ecology.

Excessive dependence on chemical fertilizers and ignorance to organic and microbial inputs under intensive cropping systems are the basic components of contemporary agriculture, which evolves several sustainability issues, such as degraded soil health and sub-optimal crop productivity. This scenario urges for integrated nutrient management approaches, such as microbes-mediated integrated plant nutrition for curtailing the high doses as chemical fertilizers. Rationally, experiment has been conducted in pigeonpea at ICAR-IARI, New Delhi, with the aim of identifying the appropriate nutrient management technique involving microbial and organic nutrient sources for improved rhizo-modulation, crop productivity, and soil bio-fertility. The randomized block-designed experiment consisted nine treatments viz. Control, Recommended dose of fertilizers (RDF), RDF+ Microbial inoculants (MI), Vermicompost (VC), Farm Yard Manure (FYM), Leaf Compost (LC), VC + MI, FYM + MI, and LC + MI. Rhizobium spp., Pseudomonas spp., Bacillus spp., and Frateuria aurantia were used as seed-inoculating microbes. The results indicated the significant response of integration following the trend VC + MI > FYM + MI > LC + MI > RDF + MI for various plant shoot-root growth attributes and soil microbial and enzymatic properties. FYM + MI significantly improved the water-stable aggregates (22%), mean weight diameter (1.13 mm), and geometric mean diameter (0.93 mm), soil organic carbon (SOC), SOC stock, and SOC sequestration. The chemical properties viz. available N, P, and K were significantly improved with VC + MI. The study summarizes that FYM + MI could result in better soil physico-chemical and biological properties and shoot-root development; however; VC + MI could improve available nutrients in the soil and may enhance the growth of pigeonpea more effectively. The outcomes of the study are postulated as a viable and alternative solution for excessive chemical fertilizer-based nutrient management and would also promote the microbial consortia and organic manures-based agro-industries. This would add to the goal of sustainable agricultural development by producing quality crop produce, maintaining agro-biodiversity and making the soils fertile and healthy that would be a "gift to the society."

Perceived stress, resilience, well-being, and COVID 19 response in Isha yoga practitioners compared to matched controls: A research protocol.

OBJECTIVES: The COVID-19 pandemic has been a significant stressor worldwide and reports of psychological distress, depression, sedentary lifestyles, and overall decreased wellbeing are increasing. Yoga practices have been found to improve mental and physical health. The purpose of this randomized controlled trial is to compare Isha yoga practitioners to controls on perceived stress, resilience, wellbeing, and protection and recovery from COVID-19. Trial Design. In this prospective randomized control trial, the effects of yoga practices are being compared between seasoned yoga practitioners with two controls who are age (±3 years), gender matched, and living in the same neighborhood. METHODS: Participants will be asked to complete a series of web-based surveys at baseline, six weeks, and 12 weeks. These surveys include validated scales and objective questions on COVID-19 infection and medical history. The validated questionnaires assess stress, mood states, resilience, and overall wellbeing. Questionnaires, weekly activity diaries, and medical history, will be collected using REDCap. RESULTS: We hypothesize that routine yoga practice during the COVID-19 pandemic will reduce stress, enhance well-being, and provide protective effects against COVID-19. CONCLUSION: With the growing concern about the physical and mental impacts of COVID-19 and increased interest in alternative practices such as yogic practices, this study will contribute to the growing body of evidence about the safety and efficacy of yoga for emotional, mental, and physical health conditions.

Involvement of atrial natriuretic peptide in abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart.

BACKGROUND: Nitric oxide (NO) is an effective mediator of ischemic preconditioning (IPC)-induced cardioprotection. Atrial natriuretic peptide (ANP) is downregulated after ovariectomy, which results in reduction in the level of NO. The present study deals with the investigation of the role of ANP in abrogated cardioprotective effect of IPC in the ovariectomized rat heart. METHODS: Heart was isolated from ovariectomized rat and mounted on Langendorff's apparatus, subjected to 30 min of ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Krebs-Henseleit solution. The myocardial infract size was estimated employing triphenyltetrazolium chloride stain, and coronary effluent was analyzed for creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release to consider the degree of myocardial injury. The cardiac release of NO was estimated by measuring the level of nitrite in coronary effluent. RESULTS: IPC-mediated cardioprotection was significantly attenuated in ovariectomized rat as compared to normal rat, which was restored by perfusion with ANP. However, this observed cardioprotection was significantly attenuated by perfusion with L-NAME, an endothelial nitric oxide synthase inhibitor, and Glibenclamide, a KATP channel blocker, alone or in combination noted in terms of increase in myocardial infract size, release of CK-MB and LDH, and also decrease in release of NO. CONCLUSION: Thus, it is suggested that ANP restores the attenuated cardioprotective effect of IPC in the ovariectomized rat heart which may be due to increase in the availability of NO and consequent increase activation of mitochondrial KATP channels.

Visual detection of IS6110 of Mycobacterium tuberculosis in sputum samples using a test based on colloidal gold and latex beads.

The IS6110 sequence was detected visually in sputum samples of tuberculosis patients using a bi-probe system. One of the probes was an oligonucleotide conjugated to colloidal gold particles, complementary to one end of the target strand. The other probe was an oligonucleotide conjugated to latex beads complementary to the other end of the target strand. In a reaction mix, these two probes bind to the target strand, and the latex beads are then separated by filtration. Bound latex beads have gold colloid particles at the other end of the target strand. These gold colloid particles were made visible to the naked eye by silver autometallography on the 'invisible' colloidal gold particles. The lower detection limit was 50 ng of genomic DNA of Mycobacterium tuberculosis. This new test, together with conventional PCR, was performed on DNA extracted from sputum samples of suspected tuberculosis patients. The new test was simple to perform, the results were visible to the naked eye, and the test was highly specific, as even single point mutations in the target strand sequence could be differentiated. The test could be useful in field-level laboratories because it requires no sophisticated equipment.

Biological studies of azadirachtin and its derivatives against polyphagous pest, Spodoptera litura.

Azadirachtin-A (Aza-A, figure 1) was subjected to a variety of synthetic transformations and the antifeedant activity and toxicity of the azadirachtin derivatives were assessed against second instar larvae Spodoptera litura on castor leaves in comparison with the crude material containing 9.14% Aza-A, as well as relatively pure 91% Aza-A. A probable mechanism for the base initiated fragmentation of the diketocarbonate into a decalin fragment and a spiroketal moiety has been proposed. The present study indicates that the combination of insect toxicity and antifeedancy of azadirachtin provides good crop protection.

Real time monitoring of lymphocyte proliferation by an impedance method.

Impedance methods are routinely used to estimate the concentration of viable bacteria in a culture. We have adapted an impedance method to monitor the growth of lymphocytes and used it to monitor lymphocyte proliferation in real time. In this method lymphocytes were cultured in modified micro-well strips with transparent indium-titanium oxide coated electrodes at the bottom. The assay was totally automated and did not involve handling of radioactive chemicals. As the method uses a non destructive method of recording the proliferation, the cells could be used for other studies after the proliferation assay. Due to the real time monitoring of proliferation, results could be obtained within 30 h and additional information such as the rate of proliferation and the limiting rate at time-->0 could also be calculated instantly.

Acquired colour deficiency in patients with Parkinson's disease.

The blue cone pathway is reported to be affected early in Parkinson's disease (PD) and acquired type three (tritan) defects may occur. Sixty-one patients attending a treatment and rehabilitation centre for PD were examined with clinical colour vision tests. Seven of 13 patients, for whom the diagnosis of PD was equivocal or who had other medical conditions, were identified as having tritan colour deficiency. Results for the remaining 44 PD patients were compared with 40 age matched controls. Ten PD patients (22.7%) had tritan defects. Tritan defects were not found in the control group but performance on some tests was age related. We conclude that clinical tests for tritan colour deficiency are unlikely to be helpful in identifying PD.

Electroporation of the skin to deliver antigen by using a piezo ceramic gas igniter.

The static electricity generated by triggering a piezo gas igniter is shown to cause electroporation of the skin to deliver antigen. Mice were immunized with chicken albumin by electroporation using a piezo gas igniter and in another experiment, the gas igniter was replaced by a power supply. In both the groups identical immune responses were generated. The change in impedance of the skin of a mice after applying high voltage electrical pulses from a power supply and that with a gas igniter were found to be similar. The piezo gas igniter is an inexpensive and easily available device. It is much more user 'friendly' than a power supply used for electroporation and it may be viewed as a replacement for a syringe with a needle.

Hepatobiliary scintigraphy in congenital cystic dilatation of biliary tract.

Six preoperative and five postoperative hepatobiliary scans in children having cystic dilatation of the biliary tract were analyzed. The preoperative hepatobiliary scans revealed three distinct patterns. The type 1 pattern showed, in early scans, good hepatic uptake of radioactivity, and photon deficient area(s) around the porta hepatis or in the subhepatic region. These area(s) showed progressive accumulation of radio activity in the delayed scans. The type 2 pattern revealed poor hepatic uptake, nonvisualization of major biliary channels, and photon deficient area(s) in the porta hepatis or subhepatic region which persisted throughout the study. Preoperatively, it was possible to diagnose cystic dilatation of biliary tract in cases that showed type 1 and type 2 patterns. No preoperative diagnosis was possible when the scans showed a type 3 pattern. Analysis of results revealed a correct pre-operative diagnostic rate of 83.3% for the cystic dilatation of biliary tract. It was also possible to provide correct functional information regarding the patency of the bile outflow tract in all 11 cases, both pre- and postoperatively, with a diagnostic rate of 100%. On the basis of the overall accuracy of results obtained in this series, hepatobiliary scintigraphy is strongly advocated in suspected cases of cystic dilatation of the biliary tract for the initial diagnosis and for the assessment of the status of the bilioenteric bypass postoperatively.

Effect of ultraviolet light absorbers on photostabilization of azadirachtin-A in solution (part: II).

The effect of photostabilization of azadirachtin-A (Aza-A) was examined in solutions when exposed to UV radiation, in the presence of four structurally different UV absorbers namely, p-aminobenzoic acid, 2,4-dihydroxybenzophenone, 4,4'-dihydroxybenzophenone and phenyl salicylate. The percentages of Aza-A recovered from the solutions after 6 h exposed to UV radiation in the presence and absence of UV absorbers indicated that the order of stabilization of Aza-A by these absorbers was similar to that obtained in the solid phase experiments in accordance with our previous observations. It is observed that the addition of phenyl salicylate in Aza-A (in 1:1 mole ratio) provides the excellent photostabilization of Aza-A molecule in solid phase as well as in solution among the four absorbers studied.

Heat stroke in long distance runners.

Four cases of young cadets who developed severe heat stroke while on a cross country run in Doon Valley are reported. Physical exertion alone caused the episode in a homeothermic environment. One patient continued to have left facial nerve palsy.