Fluoride export is required for the competitive fitness of pathogenic microorganisms in dental biofilm models.

Microorganisms resist fluoride toxicity using fluoride export proteins from one of several different molecular families. Cariogenic species Streptococcus mutans and Candida albicans extrude intracellular fluoride using a CLCF F-/H+ antiporter and FEX fluoride channel, respectively, whereas oral commensal eubacteria, such as Streptococcus gordonii, export fluoride using a Fluc fluoride channel. In this work, we examine how genetic knockout of fluoride export impacts pathogen fitness in single-species and three-species dental biofilm models. For biofilms generated using S. mutans with the genetic knockout of the CLCF transporter, exposure to low fluoride concentrations decreased S. mutans counts, synergistically reduced the populations of C. albicans, increased the relative proportion of oral commensal S. gordonii, and reduced properties associated with biofilm pathogenicity, including acid production and hydroxyapatite dissolution. Biofilms prepared with C. albicans with genetic knockout of the FEX channel also exhibited reduced fitness in the presence of fluoride but to a lesser degree. Imaging studies indicate that S. mutans is highly sensitive to fluoride, with the knockout strain undergoing complete lysis when exposed to low fluoride for a moderate amount of time. Biochemical purification of the S. mutans CLCF transporter and functional reconstitution establishes that the functional protein is a dimer encoded by a single gene. Together, these findings suggest that fluoride export by oral pathogens can be targeted by specific inhibitors to restore biofilm symbiosis in dental biofilms and that S. mutans is especially susceptible to fluoride toxicity. IMPORTANCE: Dental caries is a globally prevalent condition that occurs when pathogenic species, including Streptococcus mutans and Candida albicans, outcompete beneficial species, such as Streptococcus gordonii, in the dental biofilm. Fluoride is routinely used in oral hygiene to prevent dental caries. Fluoride also has antimicrobial properties, although most microbes possess fluoride exporters to resist its toxicity. This work shows that sensitization of cariogenic species S. mutans and C. albicans to fluoride by genetic knockout of fluoride exporters alters the microbial composition and pathogenic properties of dental biofilms. These results suggest that the development of drugs that inhibit fluoride exporters could potentiate the anticaries effect of fluoride in over-the-counter products like toothpaste and mouth rinses. This is a novel strategy to treat dental caries.

Measurement and analysis of microbial fluoride resistance in dental biofilm models.

The interactions between communities of microorganisms inhabiting the dental biofilm is a major determinant of oral health. These biofilms are periodically exposed to high concentrations of fluoride, which is present in almost all oral healthcare products. The microbes resist fluoride through the action of membrane export proteins. This chapter describes the culture, growth and harvest conditions of model three-species dental biofilm comprised of cariogenic pathogens Streptococcus mutans and Candida albicans and the commensal bacterium Streptococcus gordonii. In order to examine the role of fluoride export by S. mutans in model biofilms, procedures for generating a strain of S. mutans with a genetic knockout of the fluoride exporter are described. We present a case study examining the effects of this mutant strain on the biofilm mass, acid production and mineral dissolution under exposure to low levels of fluoride. These general approaches can be applied to study the effects of any gene of interest in physiologically realistic multispecies oral biofilms.

Prescription-based cost analysis of medicines for cardiovascular risk factors at Indian Council of Medical Research-Rational Use of Medicine Centre Hospitals of India.

OBJECTIVES: India has taken several initiatives to provide health care to its population while keeping the related expenditure minimum. Since cardiovascular diseases are the most prevalent chronic conditions, in the present study, we aimed to analyze the difference in prices of medicines prescribed for three cardiovascular risk factors, based on (a) listed and not listed in the National List of Essential Medicines (NLEM) and (b) generic and branded drugs. MATERIALS AND METHODS: Outpatient prescriptions for diabetes mellitus, hypertension, and dyslipidemia were retrospectively analyzed from 12 tertiary centers. The prices of medicines prescribed were compared based on presence or absence in NLEM India-2015 and prescribing by generic versus brand name. The price was standardized and presented as average price per medicine per year for a given medicine. The results are presented in Indian rupee (INR) and as median (range). RESULTS: Of the 4,736 prescriptions collected, 843 contained oral antidiabetic, antihypertensive, and/or hypolipidemic medicines. The price per medicine per year for NLEM oral antidiabetics was INR 2849 (2593-3104) and for non-NLEM was INR 5343 (2964-14364). It was INR 806 (243-2132) for generic and INR 3809 (1968-14364) for branded antidiabetics. Antihypertensives and hypolipidemics followed the trend. The price of branded non-NLEM medicines was 5-22 times higher compared to generic NLEM which, for a population of 1.37 billion, would translate to a potential saving of 346.8 billion INR for statins. The variability was significant for sulfonylureas, angiotensin receptor blockers, beta-blockers, diuretics, and statins (P < 0.0001). CONCLUSION: The study highlights an urgent need for intervention to actualize the maximum benefit of government policies and minimize the out-of-pocket expenditure on medicines.

Evaluation of prescriptions from tertiary care hospitals across India for deviations from treatment guidelines & their potential consequences.

BACKGROUND OBJECTIVES: Irrational prescribing practices have major consequences on patient safety and also increase the economic burden. Real-life examples of impact of irrational prescription have potential to improve prescribing practices. In this context, the present study aimed to capture and evaluate the prevalence of deviations from treatment guidelines in the prescriptions, potential consequence/s of the deviations and corrective actions recommended by clinicians. METHODS: It was a cross-sectional observational study conducted in the outpatient departments of tertiary care hospitals in India wherein the 13 Indian Council of Medical Research Rational Use of Medicines Centres are located. Prescriptions not compliant with the standard treatment guidelines and incomplete prescriptions with respect to formulation, dose, duration and frequency were labelled as 'prescriptions having deviations'. A deviation that could result in a drug interaction, lack of response, increased cost, preventable adverse drug reaction (ADR) and/or antimicrobial resistance was labelled as an 'unacceptable deviation'. RESULTS: Against all the prescriptions assessed, about one tenth of them (475/4838; 9.8%) had unacceptable deviations. However, in 2667/4838 (55.1%) prescriptions, the clinicians had adhered to the treatment guidelines. Two thousand one hundred and seventy-one prescriptions had deviations, of which 475 (21.9%) had unacceptable deviations with pantoprazole (n=54), rabeprazole+domperidone (n=35) and oral enzyme preparations (n=24) as the most frequently prescribed drugs and upper respiratory tract infection (URTI) and hypertension as most common diseases with unacceptable deviations. The potential consequences of deviations were increase in cost (n=301), ADRs (n=254), drug interactions (n=81), lack of therapeutic response (n=77) and antimicrobial resistance (n=72). Major corrective actions proposed for consideration were issuance of an administrative order (n=196) and conducting online training programme (n=108). INTERPRETATION CONCLUSIONS: The overall prevalence of deviations found was 45 per cent of which unacceptable deviations was estimated to be 9.8 per cent. To minimize the deviations, clinicians recommended online training on rational prescribing and administrative directives as potential interventions.

Fluoride export is required for competitive fitness of pathogenic microorganisms in dental biofilm models.

Microorganisms resist fluoride toxicity using fluoride export proteins from one of several different molecular families. Cariogenic species Streptococcus mutans and Candida albicans extrude intracellular fluoride using a CLCF F-/H+ antiporter and FEX fluoride channel, respectively, whereas commensal eubacteria, such as Streptococcus gordonii, export fluoride using a Fluc fluoride channel. In this work, we examine how genetic knockout of fluoride export impacts pathogen fitness in single-species and three-species dental biofilm models. For biofilms generated using S. mutans with genetic knockout of the CLCF transporter, exposure to low fluoride concentrations decreased S. mutans counts, synergistically reduced the populations of C. albicans, increased the relative proportion of commensal S. gordonii, and reduced properties associated with biofilm pathogenicity, including acid production and hydroxyapatite dissolution. Biofilms prepared with C. albicans with genetic knockout of the FEX channel also exhibited reduced fitness in the presence of fluoride, but to a lesser degree. Imaging studies indicate that S. mutans is highly sensitive to fluoride, with the knockout strain undergoing complete lysis when exposed to low fluoride for a moderate amount of time, and biochemical purification the S. mutans CLCF transporter and functional reconstitution establishes that the functional protein is a dimer encoded by a single gene. Together, these findings suggest that fluoride export by oral pathogens can be targeted by specific inhibitors to restore biofilm symbiosis in dental biofilms, and that S. mutans is especially susceptible to fluoride toxicity.

Conceptualization of the comprehensive phyto-radiotoxicity incurred by radiocesium and strategies to expunge the metal using biotechnological and phytoremediative approaches.

Agricultural pollution with 137Cs is an ecological threat due to its sustained half-life and radioactivity. Release of radiocesium isotopes after major nuclear power plant accidents like the Fukushima Dai-ichi and the Chernobyl nuclear power plant disasters have severely affected the surrounding growth of agricultural crops and vegetables cultivated across extensive areas. Even years after the nuclear accidents, biosafety in these agricultural fields is still questionable. Due to similarity in charge and ionic radius between radiocesium and K+, the radionuclides are promiscuously uptaken via K+ channels expressed in plants. Bioaccumulation of radiocesium reportedly promotes physiological and anatomical anomalies in crops due to radiation and also affects the rhizospheric architecture. Due to radiation hazard, the ecological balance and quality are compromised and ingestion of such contaminated food results in irreversible health hazards. Recently, strategies like exogenous supplementation of K+ or genetic engineering of K+ channels were able to reduce radiocesium bioaccumulation in plants taking the advantage of competition between radiocesium and K+ translocation. Furthermore, bioremediation strategies like phycoremediation, mycoremediation, phytoremediation and rhizofiltration have also showed promising results for removing radiocesium from polluted sites. It has been proposed that these eco-friendly ways can be adopted to de-pollute the contaminated sites prior to subsequent cultivation of crops and vegetables. Hence it is essential to: 1) understand the basic radiotoxic effects of radiocesium on agricultural crops and surrounding vegetation and, 2) design sustainable ameliorative strategies to promote radiocesium tolerance for ensuring food and social security of the affected population.

The 100 Top-Cited Studies on Loneliness: A Bibliometric Analysis.

The present study explores characteristics of the top 100 most-cited articles on loneliness. A systematic search was carried out using the Thomson Reuters Web of Science Core Collection to collect studies on loneliness from inception to June 1, 2022. The initial search resulted in 6,250 search results, which included articles, book chapters, conference proceedings, editorials, and letters. Two authors independently screened the literature and extracted the data. The study supervisor removed any discrepancies. Top 100 papers (articles and reviews) on loneliness published in English were extracted. Data analysis and visualization were performed on Excel, Web of Science (WoS) Data Analyzer, and VOSviewer 1.6.16. The total number of citations of the 100 top-cited articles was 42,044, ranging from 203 to 2,201 per article. All of the studies were published from 1989 to 2021, and the years with the highest number of top-cited articles published were 2003 and 2008. Most publications were from the following journals: Computers in Human Behavior, Developmental Psychology, Psychological Science, Psychology, and Aging (n=4 each). The most cited article was titled "UCLA Loneliness Scale (Version 3): Reliability, validity, and factor structure" by Russell, DW, in the Journal of Personality Assessment. The most productive institute was the University of Chicago. The two most productive authors were Cacioppo, JT, and Hawkley, LC. Of the 100 top-cited publications, 87 were original articles and 13 were reviews. The top three WoS categories were psychology multidisciplinary, gerontology, and psychiatry. In total, 37 author keywords were elicited and further clubbed into eight distinct clusters. The study provides new insight into loneliness research, which may help doctors, researchers, and stakeholders achieve a more comprehensive understanding of trends and influential contributions to the field and highlight under-researched areas, which could be the basis for future investigation.

Bio-priming with a Novel Plant Growth-Promoting Acinetobacter indicus Strain Alleviates Arsenic-Fluoride Co-toxicity in Rice by Modulating the Physiome and Micronutrient Homeostasis.

Sustainable remediation of arsenic-fluoride from rice fields through efficient bio-extraction is the need of the hour, since these toxicants severely challenge safe cultivation of rice and food biosafety. In the present study, we screened an arsenic-fluoride tolerant strain AB-ARC of Acinetobacter indicus from the soil of a severely polluted region of West Bengal, India, which was capable of efficiently removing extremely high doses of arsenate and fluoride from the media. The strain also behaved as a plant growth-promoting rhizobacterium, since it could produce indole-3-acetic acid and solubilize phosphate, zinc, and starch. Due to these properties of the identified strain, it was used for bio-priming the seeds of the arsenic-fluoride susceptible rice cultivar, Khitish for testing the efficacy of the AB-ARC strain to promote combined arsenic-fluoride tolerance in the rice genotype. Bio-priming with AB-ARC led to accelerated uptake of crucial elements like iron, copper, and nickel which behave as co-factors of physiological and antioxidative enzymes. Thus, the activation of superoxide dismutase, catalase, guaiacol peroxidase, glutathione peroxidase, and glutathione-S-transferase enabled detoxification of reactive oxygen species (ROS) and reduction of the oxidative injuries like malondialdehyde and methylglyoxal generation. Overall, due to ameliorated molecular damages and low uptake of the toxic xenobiotics, the plants were able to maintain improved growth vigor and photosynthesis, as evident from the elevated levels of Hill activity and chlorophyll content. Hence, bio-priming with the A. indicus AB-ARC strain may be advocated for sustainable rice cultivation in arsenic-fluoride co-polluted fields.

Use of baricitinib in treatment of COVID-19: a systematic review.

OBJECTIVE: To assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19. METHODS: Systematic literature search was conducted in the WHO COVID-19 coronavirus disease database to find clinical studies on use of baricitinib for treatment of COVID-19 between December 1, 2019 and September 30, 2021. Two independent set of reviewers identified the eligible studies fulfilling the inclusion criteria, relevant data was extracted and a qualitative synthesis of evidence performed. The risk of bias was evaluated with validated tools. RESULTS: A total of 267 articles were found to be eligible after primary screening of titles and abstracts. Following assessment of full texts, 19 studies were finally included for this systematic review, out of which 16 are observational, and 3 are interventional studies. Collating the results from these observational and interventional studies, baricitinib used as add-on to standard therapy, either alone or in combination with other drugs, was found to have favorable outcomes in hospitalized patients with moderate to severe COVID-19. Furthermore, ongoing trials indicate that the drug is being extensively studied across the world for its safety and efficacy in COVID-19. CONCLUSION: Baricitinib significantly improves clinical outcomes in hospitalized patients with COVID-19 pneumonia, and further evidence will establish the drug as a standard treatment among such patients.

Dissecting the biochemical and molecular-genetic regulation of diverse metabolic pathways governing aroma formation in indigenous aromatic indica rice varieties.

BACKGROUND: Aromatic rice is characterized by its distinct flavor and fragrance, imparted by more than 200 volatile organic compounds. The desirable trait of aroma relies on the type of the variety, with some varieties exhibiting considerably higher aroma content. This prompted us to undergo an exhaustive study of the aroma-associated biochemical pathways and expression of related genes, encoding the enzymes involved in those pathways in indigenous aromatic rice cultivars. METHODS AND RESULTS: The higher aroma level in aromatic rice varieties was attributed to higher transcript levels of PDH, P5CS, OAT, ODC, DAO and TPI, but lower P5CDH and BADH2, as revealed by comparative expression profiling of genes in 11 aromatic and four non-aromatic varieties. Some of the high-aroma containing varieties exhibited lower expression of SPDS and SPMS genes, concomitant with higher PAO expression. Protein immunoblot analyses showed lesser BADH2 protein accumulation in the aromatic varieties. The involvement of shikimate pathway in aroma formation was justified by higher levels of shikimic and ferulic acids due to higher expression of SK1, SK2 and ARD genes. The aromatic varieties exhibited higher expression of LOX3 and HPL, with higher corresponding enzyme activity, accompanied with lower accumulation of lipid hydroperoxides and higher level of total terpenoids, signifying the role of oxylipin pathway and terpene-related volatiles in aroma formation. The pattern of transcript level and metabolite accumulation followed the same trend in both vegetative (seedling) and reproductive (seed) tissues. Sequence analyses revealed several mutations in the upstream region and different exons and introns of BADH2 in the examined aromatic varieties. The allele specific marker system acted as fingerprint to distinguish the selected aromatic rice varieties. The cleaved amplified polymorphic sequence marker established the absence of any mutation in the 14th exon of BADH2 in the aromatic varieties. CONCLUSION: The present work clearly highlighted the biochemical and molecular-genetic mechanism of differential aroma levels which could be attributed to differential regulation of metabolites and genes, belonging to 2-acetyl-1-pyrroline, shikimate, oxylipin and terpenoid metabolic pathways in the indigenous aromatic rice varieties.

Internet Use and Autism Spectrum Disorders.

N/A.

An observational multi-centric COVID-19 sequelae study among health care workers.

Background: India has seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any. Methods: This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12 and 52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire. Finding: Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46-12.23) and lower among males (OR 0.55; 95% CI 0.39-0.76). Besides these, other predictors for having sequelae were age (≥45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19. Interpretation: Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae. Funding: This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Medicines network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.

Robotic Arm-Assisted versus Manual Total Knee Arthroplasty: A Propensity Score-Matched Analysis.

The purpose of this study was to compare (1) operative time, (2) in-hospital pain scores, (3) opioid medication use, (4) length of stay (LOS), (5) discharge disposition at 90-day postoperative, (6) range of motion (ROM), (7) number of physical therapy (PT) visits, (8) emergency department (ED) visits, (9) readmissions, (10) reoperations, (11) complications, and (12) 1-year patient-reported outcome measures (PROMs) in propensity matched patient cohorts who underwent robotic arm-assisted (RA) versus manual total knee arthroplasty (TKA). Using a prospectively collected institutional database, patients who underwent RA- and manual TKA were the nearest neighbor propensity score matched 3:1 (255 manual TKA:85 RA-TKA), accounting for various preoperative characteristics. Data were compared using analysis of variance (ANOVA), Kruskal-Wallis, Pearson's Chi-squared, and Fisher's exact tests, when appropriate. Postoperative pain scores, opioid use, ED visits, readmissions, and 1-year PROMs were similar between the cohorts. Manual TKA patients achieved higher maximum flexion ROM (120.3 ± 9.9 versus 117.8 ± 10.2, p = 0.043) with no statistical differences in other ROM parameters. Manual TKA had shorter operative time (105 vs.113 minutes, p < 0.001), and fewer PT visits (median [interquartile range] = 10.0 [8.0-13.0] vs. 11.5 [9.5-15.5] visits, p = 0.014). RA-TKA had shorter LOS (0.48 ± 0.59 vs.1.2 ± 0.59 days, p < 0.001) and higher proportion of home discharges (p < 0.001). RA-TKA and manual TKA had similar postoperative complications and 1-year PROMs. Although RA-TKA patients had longer operative times, they had shorter LOS and higher propensity for home discharge. In an era of value-based care models and the steady shift to outpatient TKA, these trends need to be explored further. Long-term and randomized controlled studies may help determine potential added value of RA-TKA versus manual TKA. This study reflects level of evidence III.

Rhizofiltration of combined arsenic-fluoride or lead-fluoride polluted water using common aquatic plants and use of the 'clean' water for alleviating combined xenobiotic toxicity in a sensitive rice variety.

Groundwater co-contamination with toxic pollutants like arsenic-fluoride or lead-fluoride is a serious threat for safe rice cultivation, since major stretches of land, involved in cultivation of this staple food crop are presently experiencing severe endemic pollution from these xenobiotic combinations. Preliminary investigations established that the combined pollutants together exerted more phytotoxicity in the widely cultivated indica rice variety Khitish, compared with that exerted by the individual contaminants. Thus, an ecologically sustainable and economically viable phytoremediative strategy was designed where three aquatic plants, viz., Azolla (water fern), Pistia (water lettuce) and Eichhornia (water hyacinth) (commonly located across the co-polluted regions) were tested for their ability to rhizofiltrate the water samples that had been polluted with arsenic-fluoride or lead-fluoride. Water lettuce exhibited the highest ability to 'clean' both arsenic-fluoride and lead-fluoride polluted water due to its capacity of efficient phytoextraction and phytostabilization. Irrigation of Khitish seedlings with this de-polluted water appreciably reduced malondialdehyde formation, electrolyte leakage and irreversible protein carbonylation due to suppression in NADPH oxidase activity and reactive oxygen species production, compared with those in sets grown with non-treated, arsenic-fluoride or lead-fluoride contaminated water. Oxidative injuries, cytotoxic methylglyoxal synthesis and inhibition of biomass growth were ameliorated, and chlorophyll synthesis and Hill activity were increased due to reduced bioaccumulation of xenobiotics, along with the improved uptake of vital micronutrients like iron, copper and nickel. Overall, the current investigation illustrated a cheap, farmer-friendly blueprint which could be easily promulgated to ensure safe rice cultivation even across territories that are severely co-polluted with the mixed contaminants.

Fluoride tolerance in rice is negatively regulated by the 'stress-phytohormone' abscisic acid (ABA), but promoted by ABA-antagonist growth regulators, melatonin, and gibberellic acid.

The present manuscript aimed at investigating whether abscisic acid (ABA) promotes fluoride tolerance, similar to inciting salt adaptation in rice. Seeds of three salt-tolerant rice genotypes were maintained at 32 °C under 16/8 h light/dark photoperiodic cycle with 700 µmol photons m-2 s-1 intensity and 50% relative humidity in a plant growth chamber for 20 days. Suppressed ABA biosynthesis, and downregulated expression of ABA-inducible genes like Rab16A, Osem, and TRAB1 triggered NaCl-induced growth inhibition and physiological injuries like chlorophyll degradation, electrolyte leakage, formation of H2O2, malondialdehyde, and methylglyoxal in Matla. Reduced ABA accumulation increased the levels of melatonin and gibberellic acid in NaF (50 mg L-1)-stressed Nonabokra and Matla, which altogether promoted fluoride tolerance. Higher ABA content in NaF-stressed Jarava stimulated fluoride uptake via chloride channels, thus exhibiting severe fluoride susceptibility, in spite of higher production of ABA-associated osmolytes like proline, glycine-betaine and polyamines via the concerted action of genes like PDH, ADC, ODC, SAMDC, SPDS, SPMS, DAO, and PAO. Increased accumulation of compatible solutes in presence of high endogenous ABA promoted salt tolerance in Jarava; the same was insufficient to ameliorate fluoride-induced injuries in this cultivar. Treatment with ABA biosynthetic inhibitor, Na2WO4 promoted fluoride tolerance in Jarava, whereas further supplementation with exogenous ABA resulted in reversion back to fluoride-susceptible phenotype. Our work clearly established that ABA cannot always be considered as a 'universal' stress hormone as known in literature, since it acts as a negative regulator of fluoride tolerance which is more tightly regulated in rice via melatonin- and gibberellic acid-dependent pathways in ABA-independent manner.

Explicating the cross-talks between nanoparticles, signaling pathways and nutrient homeostasis during environmental stresses and xenobiotic toxicity for sustainable cultivation of cereals.

Precision farming using nanoparticles is a cutting-edge technology for safe cultivation of crop plants in marginal areas afflicted with environmental/climatic stresses like salinity, drought, extremes of temperature, ultraviolet B stress or polluted with xenobiotics like toxic heavy metals and fluoride. Major cereal crops like rice, wheat, maize, barley, sorghum and millets which provide the staple food for the entire global population are mainly glycophytes and are extremely susceptible to abiotic stress-induced oxidative injuries. Nanofertilization/exogenous spraying of beneficial nanoparticles alleviates the oxidative damages in cereals by altering the homeostasis of phytohormones like abscisic acid, gibberellins, cytokinins, auxins, salicylic acid, jasmonic acid and melatonin and by triggering the synthesis of gasotransmitter nitric oxide. Signaling cross-talks of nanoparticles with plant growth regulators enable activation of the defence machinery, comprising of antioxidants, thiol-rich compounds and glyoxalases and restrict xenobiotic mobilization by suppressing the expression of associated transporters. Accelerated nutrient uptake and grain biofortification under the influence of nanoparticles result in optimum crop productivity under sub-optimal conditions. However, over-dosing of even beneficial nanoparticles promotes severe phytotoxicity. Hence, the concentration of nanoparticles and mode of administering need to be thoroughly standardized before large-scale field applications, to ensure sustainable cereal cultivation with minimum ecological imbalance.

Use of drugs not listed in the National List of Essential Medicines: Findings from a prescription analysis by the Indian Council of Medical Research-Rational Use of Medicines Centres Network in tertiary care hospitals across India.

BACKGROUND: The concept of listing essential medicines can lead to improved supply and access, more rational prescribing, and lower costs of drugs. However, these benefits hinge on the prescription of drugs from an Essential Medicines List (EML). Several studies have highlighted the problem of underutilization of EMLs by prescribers. Therefore, as part of prescription research by the Indian Council of Medical Research-Rational Use of Medicines Centres Network, we evaluated the extent of prescription of drugs not listed in the National List of Essential Medicines (NLEM). MATERIALS AND METHODS: Prescriptions of outpatients from participating centers were included after obtaining verbal/written informed consent as approved by the Ethics Committee, and evaluated for prescription of drugs from the NLEM 2015. RESULTS: Analysis of 4838 prescriptions from 13 tertiary health-care institutes revealed that 2677 (55.33%) prescriptions had at least one non-NLEM drug prescribed. In all, 5215 (31.12%) of the total 16,758 drugs prescribed were not in NLEM. Of these, 2722 (16.24%) were single drugs and 2493 (14.88%) were fixed-dose combinations (FDCs). These comprised 700 different drug products - 346 single drugs and 354 FDCs. The average number of non-NLEM drugs prescribed per prescription was 1.08, while the average number of all drugs prescribed was 3.35 per prescription. It was also found that some of the non-NLEM drugs prescribed had the potential to result in increased cost (for example, levocetirizine), increased adverse effects (dextromethorphan), and less effectiveness (losartan) when compared to their NLEM counterparts. Nonavailability of an essential drug (oral hydroxocobalamin) was another important finding of our study. CONCLUSION: This study highlights the extent and pattern of drugs prescribed from outside the NLEM at the tertiary health-care level and the need for training and enhanced awareness among prescribers for greater utilization of the NLEM.

Relevance in the Renormalization Group and in Information Theory.

The analysis of complex physical systems hinges on the ability to extract the relevant degrees of freedom from among the many others. Though much hope is placed in machine learning, it also brings challenges, chief of which is interpretability. It is often unclear what relation, if any, the architecture- and training-dependent learned "relevant" features bear to standard objects of physical theory. Here we report on theoretical results which may help to systematically address this issue: we establish equivalence between the field-theoretic relevance of the renormalization group, and an information-theoretic notion of relevance we define using the information bottleneck (IB) formalism of compression theory. We show analytically that for statistical physical systems described by a field theory the relevant degrees of freedom found using IB compression indeed correspond to operators with the lowest scaling dimensions. We confirm our field theoretic predictions numerically. We study dependence of the IB solutions on the physical symmetries of the data. Our findings provide a dictionary connecting two distinct theoretical toolboxes, and an example of constructively incorporating physical interpretability in applications of deep learning in physics.

Functional and molecular characterization of fluoride exporter (FEX) from rice and its constitutive overexpression in Nicotiana benthamiana to promote fluoride tolerance.

KEY MESSAGE: Early induction of OsFEX was insufficient for fluoride adaptation in IR-64. Overexpression of OsFEX in yeast and Nicotiana benthamiana enhanced fluoride tolerance. The present study delineates the regulation of fluoride exporter (FEX) in the fluoride-sensitive rice cultivar, IR-64 and its efficacy in generating high fluoride tolerance in transgenic Nicotiana benthamiana. Gene and protein expression profiling revealed that OsFEX exhibited early induction during fluoride stress in the vegetative and reproductive tissues of IR-64, although the expression was suppressed upon prolonged stress treatment. Analysis of OsFEX promoter in transgenic N. benthamiana, using ß-glucuronidase reporter assay confirmed its early inducible nature, since the reporter expression and activity peaked at 12 h of NaF stress, after which it was lowered. OsFEX expression was up regulated in the presence of gibberellic acid (GA) and melatonin, while it was suppressed by abscisic acid (ABA). Complementation of ΔFEX1ΔFEX2 yeast mutants with OsFEX enabled high fluoride tolerance, thus validating the functional efficiency of the transgene. Bioassay of transgenic N. benthamiana lines, expressing OsFEX either under its own promoter or under CaMV35S promoter, established that constitutive overexpression, rather than early induction of OsFEX was essential and crucial for generating fluoride tolerance in the transgenics. Overall, the suppression of OsFEX in the later growth phases of stressed IR-64 due to enhanced ABA conservation and lowered synthesis of GA, as supported by the application of the respective phytohormone biosynthetic inhibitors, such as sodium tungstate and paclobutrazol, accounted for the fluoride-hyperaccumulative nature of the rice cultivar.