Transition from rectal to intranasal route among mostly pediatric patients with repeated prescriptions of rescue benzodiazepines for seizure emergencies.

OBJECTIVE: To describe the changes in Food and Drug Administration (FDA)-approved non-intravenous rescue benzodiazepine (non-IV-rBZD) use and cost after the introduction of intranasal midazolam and intranasal diazepam. METHODS: Retrospective descriptive study using the MarketScan Database between the years 2016 and 2022. We considered patients who had at least one non-IV-rBZD prescription before the introduction of intranasal rescue medications and at least one non-IV-rBZD prescription after the introduction of intranasal rescue medications. RESULTS: There were 4,444 patients (45.8 % female, median (p25-p75) age of 10.0 (5.0-15.0) years). 2,255 of 4,444 (50.7 %) patients switched from rectal diazepam to either intranasal midazolam (1,110 (25.0 %)) or intranasal diazepam (1,145 (25.8 %)) as their last non-IV-rBZD. The change from rectal to intranasal non-IV-rBZDs has been increasing over the years from 2019 to 2022. On multivariable analysis, having a non-IV-rBZD for epilepsy (rather than for other reasons including febrile seizures), the year of the last rescue medication, urban (non-rural) patient's residence, and certain regions of the United States were the factors most strongly associated with a change from rectal diazepam to intranasal non-IV-rBZDs. After adjusting for inflation, the median (p25-p75) average wholesale price (AWP) of the last non-IV-rBZD was higher than that of the first non-IV-rBZD [702 (406-748) versus 417 (406-426), Wilcoxon signed rank test p < 0.0001)]. This difference was mainly driven by the patients who changed from rectal diazepam to intranasal non-IV-rBZD [748 (714-755) versus 417 (406-426), Wilcoxon signed rank test p < 0.0001)]. After adjusting for inflation, the median (p25-p75) patient cost of the last non-IV-rBZD was higher than that of the first non-IV-rBZD [16 (3-55) versus 12 (6-31), Wilcoxon signed rank test p < 0.0001)]. This difference was mainly driven by the patients who changed from rectal diazepam to intranasal non-IV-rBZD [41 (6-83) versus 12 (6-30), Wilcoxon signed rank test p < 0.0001)]. CONCLUSION: Approximately half of patients changed from rectal diazepam to intranasal midazolam or intranasal diazepam and that transition has been progressively increasing from the year 2019 to the year 2022. The inflation-adjusted AWP and patient cost increased, especially among those patients who changed from rectal to intranasal rescue medication.

Prescription patterns of home rescue benzodiazepines for febrile seizures.

OBJECTIVE: To describe the prescription patterns of home, non-intravenous rescue benzodiazepines (non-IV-rBZDs) for febrile seizures and the factors associated with their prescription. METHODS: Retrospective descriptive study using the MarketScan Commercial Database, a large database of employer-sponsored privately insured patients in the United States. We used data from January 1st 2006 to December 31st 2022. We studied patients with febrile seizures as the main code for the healthcare encounter (identified with International Classification of Diseases codes) with age from 6 months to 5 years of age and with at least 1 month of follow-up. RESULTS: There were a total of 82,835 patients [median (p25-p75) age 1.0 (1.0-2.0) years, 56.7 % males] with at least one febrile seizure, of whom 9,737 (11.8 %) filled at least one non-IV-rBZD prescription. Among the 9,737 patients who filled at least one prescription, the median (p25-p75) time from first febrile seizure to non-IV-rBZD prescription was 27 (2-186) days. Among the factors known at the time of the first febrile seizure, complex febrile seizure (OR: 3.51, 95 % CI: 3.24-3.79), and an initial inpatient hospitalization for febrile seizure (OR: 3.53, 95 % CI: 3.29-3.79) were the factors most strongly associated with filling a non-IV-rBZD prescription. In contrast, sex, rural patient's residence, and salary employment (versus other employment class) were not independently associated with filling a non-IV-rBZD prescription. Among the factors known at the end of follow-up, complex febrile seizures, type of initial encounter, and an eventual diagnosis of epilepsy were major independent factors associated with filling a non-IV-rBZD prescription. CONCLUSION: Only approximately 12 % of children with a febrile seizure filled a prescription for a home non-IV-rBZD. The major factors independently associated with prescription were complex febrile seizure, hospital admission, recurrent febrile seizures, and an eventual diagnosis of epilepsy.

Remediation of lead toxicity with waste-bio materials from aqueous solutions in fixed-bed column using response surface methodology.

Heavy metal ions pose significant risks to human health, pelagic, and several other life forms due to perniciousness, tendency to accumulate, and resistance to biodegradation. Waste bio-materials extend a budding alternative as low-cost adsorbent to address the removal of noxious pollutants from wastewater on account of being cost-effective and exhibiting exceptional adsorption capacities. The current exploration was accomplished to gauge the performance of raw and modified human hair concerning lead scavenging in a down-flow fixed bed column. The appraisal of column performance under varying operational parameters encompassing bed height (15-45 cm), influent metal ion concentration (60-140 mg L-1), and a solution flow rate (20-40 mL min-1) was performed by breakthrough curve analysis. The consequences acquired were evaluated using the Yoon Nelson, Thomas, Adam-Bohart, and Bed Depth Service Time (BDST) model. Among these employed models, Bed Depth Service Time (BDST) and Thomas models exhibited the highest R-squared value compared to the Yoon Nelson and Adam-Bohart's model for most cases. In addition, the optimization of lead adsorption was followed using the Box-Behnken design of response surface methodology (RSM). The optimal conditions (desirability-1.00) for achieving a goal of maximum percent removal of lead ions were marked to be a bed height of 42.79 cm, solution flow rate of 20.92 mL min-1, and an initial metal concentration of 139.51 mg L-1. Under these optimized conditions, the percent amputation of lead in a fixed bed was observed to be 82.31 %, while the results of the experiment performed approximately under these optimized conditions revealed a percent removal of 85.05 %, reflecting a reasonable conformity with values acquired through Box-Behnken design.

2D MXene-Based Nanoscale Materials for Electrochemical Sensing Toward the Detection of Hazardous Pollutants: A Perspective.

MXenes (Mn+1XnTx), a subgroup of 2-dimensional (2D) materials, specifically comprise transition metal carbides, nitrides, and carbonitrides. They exhibit exceptional electrocatalytic and photocatalytic properties, making them well-suited for the detection and removal of pollutants from aqueous environments. Because of their high surface area and remarkable properties, they are being utilized in various applications, including catalysis, sensing, and adsorption, to combat pollution and mitigate its adverse effects. Different characterization techniques like XRD, SEM, TEM, UV-Visible spectroscopy, and Raman spectroscopy have been used for the structural elucidation of 2D MXene. Current responses against applied potential were measured during the electrochemical sensing of the hazardous pollutants in an aqueous system using a variety of electroanalytical techniques, including differential pulse voltammetry, amperometry, square wave anodic stripping voltammetry, etc. In this review, a comprehensive discussion on structural patterns, synthesis, properties of MXene and their application for electrochemical detection of lethal pollutants like hydroquionone, phenol, catechol, mercury and lead, etc. are presented. This review will be helpful to critically understand the methods of synthesis and application of MXenes for the removal of environmental pollutants.

Potential Development of Porous Carbon Composites Generated from the Biomass for Energy Storage Applications.

Creating an innovative and environmentally friendly energy storage system is of vital importance due to the growing number of environmental problems and the fast exhaustion of fossil fuels. Energy storage using porous carbon composites generated from biomass has attracted a lot of attention in the research community. This is primarily due to the environmentally friendly nature, abundant availability in nature, accessibility, affordability, and long-term viability of macro/meso/microporous carbon sourced from a variety of biological materials. Extensive information on the design and the building of an energy storage device that uses supercapacitors was a part of this research. This study examines both porous carbon electrodes (ranging from 44 to 1050 F/g) and biomasses with a large surface area (between 215 and 3532 m2/g). Supposedly, these electrodes have a capacitive retention performance of about 99.7 percent after 1000 cycles. The energy density of symmetric supercapacitors is also considered, with values between 5.1 and 138.4 Wh/kg. In this review, we look at the basic structures of biomass and how they affect porous carbon synthesis. It also discusses the effects of different structured porous carbon materials on electrochemical performance and analyzes them. In recent developments, significant steps have been made across various fields including fuel cells, carbon capture, and the utilization of biomass-derived carbonaceous nanoparticles. Notably, our study delves into the innovative energy conversion and storage potentials inherent in these materials. This comprehensive investigation seeks to lay the foundation for forthcoming energy storage research endeavors by delineating the current advancements and anticipating potential challenges in fabricating porous carbon composites sourced from biomass.

Nontypeable Haemophilus influenzae challenge during gammaherpesvirus infection enhances viral reactivation and latency.

Gammaherpesviruses are ubiquitous, lifelong pathogens associated with multiple cancers that infect over 95% of the adult population. Increases in viral reactivation, due to stress and other unknown factors impacting the immune response, frequently precedes lymphomagenesis. One potential stressor that could promote viral reactivation and increase viral latency would be the myriad of infections from bacterial and viral pathogens that we experience throughout our lives. Using murine gammaherpesvirus 68 (MHV68), a mouse model of gammaherpesvirus infection, we examined the impact of bacterial challenge on gammaherpesvirus infection. We challenged MHV68 infected mice during the establishment of latency with nontypeable Haemophilus influenzae (NTHi) to determine the impact of bacterial infection on viral reactivation and latency. Mice infected with MHV68 and then challenged with NTHi, saw increases in viral reactivation and viral latency. These data support the hypothesis that bacterial challenge can promote gammaherpesvirus reactivation and latency establishment, with possible consequences for viral lymphomagenesis.

Threatening language detection from Urdu data with deep sequential model.

The Urdu language is spoken and written on different social media platforms like Twitter, WhatsApp, Facebook, and YouTube. However, due to the lack of Urdu Language Processing (ULP) libraries, it is quite challenging to identify threats from textual and sequential data on the social media provided in Urdu. Therefore, it is required to preprocess the Urdu data as efficiently as English by creating different stemming and data cleaning libraries for Urdu data. Different lexical and machine learning-based techniques are introduced in the literature, but all of these are limited to the unavailability of online Urdu vocabulary. This research has introduced Urdu language vocabulary, including a stop words list and a stemming dictionary to preprocess Urdu data as efficiently as English. This reduced the input size of the Urdu language sentences and removed redundant and noisy information. Finally, a deep sequential model based on Long Short-Term Memory (LSTM) units is trained on the efficiently preprocessed, evaluated, and tested. Our proposed methodology resulted in good prediction performance, i.e., an accuracy of 82%, which is greater than the existing methods.

Global perspective of municipal solid waste and landfill leachate: generation, composition, eco-toxicity, and sustainable management strategies.

Globally, more than 2 billion tonnes of municipal solid waste (MSW) are generated each year, with that amount anticipated to reach around 3.5 billion tonnes by 2050. On a worldwide scale, food and green waste contribute the major proportion of MSW, which accounts for 44% of global waste, followed by recycling waste (38%), which includes plastic, glass, cardboard, and paper, and 18% of other materials. Population growth, urbanization, and industrial expansion are the principal drivers of the ever-increasing production of MSW across the world. Among the different practices employed for the management of waste, landfill disposal has been the most popular and easiest method across the world. Waste management practices differ significantly depending on the income level. In high-income nations, only 2% of waste is dumped, whereas in low-income nations, approximately 93% of waste is burned or dumped. However, the unscientific disposal of waste in landfills causes the generation of gases, heat, and leachate and results in a variety of ecotoxicological problems, including global warming, water pollution, fire hazards, and health effects that are hazardous to both the environment and public health. Therefore, sustainable management of MSW and landfill leachate is critical, necessitating the use of more advanced techniques to lessen waste production and maximize recycling to assure environmental sustainability. The present review provides an updated overview of the global perspective of municipal waste generation, composition, landfill heat and leachate formation, and ecotoxicological effects, and also discusses integrated-waste management approaches for the sustainable management of municipal waste and landfill leachate.

On Application of Lightweight Models for Rice Variety Classification and Their Potential in Edge Computing.

Rice is one of the fundamental food items that comes in many varieties with their associated benefits. It can be sub-categorized based on its visual features like texture, color, and shape. Using these features, the automatic classification of rice varieties has been studied using various machine learning approaches for marketing and industrial use. Due to the outstanding performance of deep learning, several models have been proposed to assist in vision tasks like classification and detection. Regardless of their best results on accuracy metrics, they have been observed as overly excessive for computational resources and expert supervision. To address these challenges, this paper proposes three deep learning models that offer similar performance with 10% lighter computational overhead in comparison to existing best models. Moreover, they have been trained for end-to-end flow to demonstrate minimum expert supervision for pre-processing and feature engineering sub-tasks. The results can be observed as promising for classifying rice among five varieties, namely Arborio, Basmati, Ipsala, Jasmine, and Karacadag. The process and performance of the trained models can be extended for edge and mobile devices for field-specific tasks autonomously.

Transition metal doped CeO2 for photocatalytic removal of 2-chlorophenol in the exposure of indoor white light and antifungal activity.

Besides natural sunlight and expensive artificial lights, economical indoor white light can play a significant role in activating a catalyst for photocatalytic removal of organic toxins from contaminated water. In the current effort, CeO2 has been modified with Ni, Cu, and Fe through doping methodology to study the removal of 2-chlorophenol (2-CP) in the illumination of 70 W indoor LED white light. The absence of additional diffractions due to the dopants and few changes such as reduction in peaks' height, minor peak shift at 2θ (28.525°) and peaks' broadening in XRD patterns of modified CeO2 verifies the successful doping of CeO2. The solid-state absorption spectra revealed higher absorbance of Cu-doped CeO2 whereas a lower absorption response was observed for Ni-doped CeO2. An interesting observation regarding the lowering of indirect bandgap energy of Fe-doped CeO2 (∼2.7 eV) and an increase in Ni-doped CeO2 (∼3.0 eV) in comparison to pristine CeO2 (∼2.9 eV) was noticed. The process of e -- h + recombination in the synthesized photocatalysts was also investigated through photoluminescence spectroscopy. The photocatalytic studies revealed the greater photocatalytic activity of Fe-doped CeO2 with a higher rate (∼3.9 × 10-3 min-1) among all other materials. Moreover, kinetic studies also revealed the validation of the Langmuir-Hinshelwood kinetic model (R2 = 0.9839) while removing 2-CP in the exposure of indoor light with a Fe-doped CeO2 photocatalyst. The XPS analysis revealed the existence of Fe3+, Cu2+ and Ni2+ core levels in doped CeO2. Using the agar well-diffusion method, the antifungal activity was assessed against the fungus M. fructicola and F. oxysporum. Compared to CeO2, Ni-doped CeO2, and Cu-doped CeO2 nanoparticles, the Fe-doped CeO2 nanoparticles have outstanding antifungal properties.

MTORC2 is a physiological hydrophobic motif kinase of S6 Kinase 1.

Ribosomal protein S6 kinase 1 (S6K1), a major downstream effector molecule of mTORC1, regulates cell growth and proliferation by modulating protein translation and ribosome biogenesis. We have recently identified eIF4E as an intermediate in transducing signals from mTORC1 to S6K1 and further demonstrated that the role of mTORC1 is restricted to inducing eIF4E phosphorylation and interaction with S6K1. This interaction relieves S6K1 auto-inhibition and facilitates its hydrophobic motif (HM) phosphorylation and activation as a consequence. These observations underscore a possible involvement of mTORC1 independent kinase in mediating HM phosphorylation. Here, we report mTORC2 as an in-vivo/physiological HM kinase of S6K1. We show that rapamycin-resistant S6K1 truncation mutant ∆NH∆CT continues to display HM phosphorylation with selective sensitivity toward Torin-1. We also show that HM phosphorylation of wildtype S6K1and ∆NH∆CT depends on the presence of mTORC2 regulatory subunit-rictor. Furthermore, truncation mutagenesis and molecular docking analysis reveal the involvement of a conserved 19 amino acid stretch of S6K1 in mediating interaction with rictor. We finally show that deletion of the 19 amino acid region from wildtype S6K1 results in loss of interaction with rictor, with a resultant loss of HM phosphorylation regardless of the presence of functional TOS motif. Our data demonstrate that mTORC2 acts as a physiological HM kinase that can activate S6K1 after its auto-inhibition is overcome by mTORC1. We, therefore, propose a novel mechanism for S6K1 regulation where mTOR complexes 1 and 2 act in tandem to activate the enzyme.

Temporal trends in the cost and use of first-line treatments for infantile epileptic spasms syndrome.

OBJECTIVE: To describe the temporal trends in the cost and use of adrenocorticotropic hormone (ACTH), oral prednisolone, and vigabatrin, the first-line treatments for infantile epileptic spasms syndrome (IESS). METHODS: Retrospective observational study using the MarketScan Commercial database from 2006 to 2020. We identified patients with IESS diagnosed between birth and 18 months of age who received at least one of the first-line treatments within 60 days of diagnosis. Costs were adjusted for inflation using the Gross Domestic Product Implicit Price Deflator. RESULTS: A total of 1131 patients received at least one first-line treatment (median [p25 -p75 ] age: 6.3 [4.5-8.3] months, 55% male), of whom 592 patients received ACTH, 363 patients received oral prednisolone, and 355 patients received vigabatrin. After adjusting for inflation, the median average wholesale price of a 14-day course of treatment increased for ACTH from $3718 in 2006 to $100 457 in 2020, ~2700% (by a factor of 27), whereas it decreased for oral prednisolone from $169 in 2006 to $89 in 2020, ~50% (by a factor of 0.5), and increased for vigabatrin from $1206 in 2009 (first year with data on vigabatrin used for IESS) to $4102 in 2020, ~340% (by a factor of 3.4). During the first 60 days after diagnosis, inpatient admission days and costs where higher for ACTH than for oral prednisolone and vigabatrin-5.0 (3.0-8.3) days vs 2.0 (0.0-5.0) days vs 2.0 (0.0-6.0) days, p < .0001; and $32 828 ($14 711-$67 216) vs $16 227 ($0-$35 829) vs $17 844 ($0-$47 642), p < .0001. ACTH use decreased from representing 78% of first-line treatments in 2006 to 18% in 2020 (p < .0001). Sensitivity analyses confirmed the robustness of the results. SIGNIFICANCE: The gap between the cost of ACTH and the cost of oral prednisolone or vigabatrin has widened markedly from 2006 to 2020, whereas the relative proportion of ACTH use has decreased.

Synthesis and Micromechanistic Studies of Sensitized Bentonite for Methyl Orange and Rhodamine-B Adsorption from Wastewater: Experimental and DFT-Based Analysis.

This work reports the formation of a novel adsorbent, prepared by activating bentonite with cinnamic acid, which is highly efficient to remove dyes from wastewater. The adsorption efficiency of the cinnamic acid activated bentonite was compared with unmodified bentonite by removing methyl orange and rhodamine-B from polluted water. The characterization was performed through X-ray diffraction (XRD) Fourier transform infrared (FTIR) and scanning electron microscopy (SEM). The results indicated that acidic pH and low temperature were more suitable for the selected dyes adsorption. The analysis of the data was done by the Langmuir and Freundlich isotherms; the Freundlich isotherm showed more suitability for the equilibrium data. The data were further analyzed by pseudo-first and pseudo-second-order models to study adsorption kinetics. The results showed that methyl orange and rhodamine-B adsorption obeyed pseudo-order kinetics. The results obtained from this research suggested that acid activation of bentonite with cinnamic acid increased the surface area of the clay and hence enhanced its adsorption efficiency. The maximum adsorption efficiency for the removal of methyl orange and rhodamine-B was up to 99.3 mg g-1 and 44.7 mg g-1, respectively, at 25 °C. This research provides an economical modification technique of bentonite, which makes it cost-effective and a good adsorbent for wastewater treatment.

Expanding the view of the molecular mechanisms of autophagy pathway.

Autophagy is an evolutionarily conserved multistep degradation mechanism in eukaryotes, that maintains cellular homoeostasis by replenishing cells with nutrients through catabolic lysis of the cytoplasmic components. This critically coordinated pathway involves sequential processing events that begin with initiation, nucleation, and elongation of phagophores, followed by the formation of  double-membrane vesicles known as autophagosomes. Finally, autophagosomes migrate towards and fuse with lysosomes in mammals and vacuoles in yeast and plants, for the eventual degradation of the intravesicular cargo. Here, we review the recent advances in our understanding of the molecular events that define the process of autophagy.

Deciphering waste bound nitrogen by employing psychrophillic Aporrectodea caliginosa and priming of coprolites by associated heterotrophic nitrifiers under high altitude Himalayas.

Himalayan ecosystem is characterized by its fragile climate with rich repositories of biodiversity. Waste collection and disposal are becoming increasingly difficult due to topographical variations. Aporrectodea caligenosa, a versatile psychrophillic soil dweller, is a useful biocatalyst with potent bio-augmented capability for waste treatment at low temperatures. Microcosm experiments were conducted to elucidate the comprehensive nature of biogenic nitrogen transformation to NH4+ and NO3- produced by coupling of earthworm-microbes. Higher biogenic recovery of NH4+-N from coprolites of garden soil (47.73 ± 1.16%) and Himalayan goat manure (86.32 ± 0.92%) with an increment of 14.12 and 47.21% respectively over their respective control (without earthworms) with a linear decline beyond 4th week of incubation was reported. NO3--N recovery progressively sustained in garden soil and goat manure coprolites during entire incubation with highest 81.81 ± 0.45 and 87.20 ± 1.08 µg-N g-1dry weight recorded in 6th and 5th week of incubation respectively and peak increments as 38.58 and 53.71% relative to respective control (without earthworms). Declined NH4+-N in coprolites at low temperature (15.0 ± 2.0 °C) evidenced increased nitrification rates by taking over the process by abundant nitrifying microbes. Steady de-nitrification with progressive incubation on an average was 16.95 ± 0.46 ng-N g-1 per week and 21.08 ± 0.87 ng-N g-1 per week compared to 14.03 ± 0.58 ng-N g-1 per week and 4.50 ± 0.31 ng-N g-1 per week in respective control treatments. Simultaneous heterotrophic nitrification and aerobic denitrification (SHNAD) was found to be a prominent bioprocess at low temperature that resulted in high and stable total nitrogen and nitrate accumulation from garden soil and goat manure with relative recovery efficiency of 11.12%, 14.97% and 14.20%; 19.34%. A. caligenosa shows promising prospects for mass applicability in biogenic N removal from manure of Himalayan goat.

A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma.

PURPOSE: Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma. PATIENTS AND METHODS: In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib. RESULTS: Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch. CONCLUSIONS: The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.

Psychrotolerant Mesorhizobium sp. Isolated from Temperate and Cold Desert Regions Solubilizes Potassium and Produces Multiple Plant Growth Promoting Metabolites.

Soil potassium (K) supplement depends intensively on the application of chemical fertilizers, which have substantial harmful environmental effects. However, some bacteria can act as inoculants by converting unavailable and insoluble K forms into plant-accessible forms. Such bacteria are an eco-friendly approach for enhancing plant K absorption and consequently reducing utilization of chemical fertilization. Therefore, the present research was undertaken to isolate, screen, and characterize the K solubilizing bacteria (KSB) from the rhizosphere soils of northern India. Overall, 110 strains were isolated, but only 13 isolates showed significant K solubilizing ability by forming a halo zone on solid media. They were further screened for K solubilizing activity at 0 °C, 1 °C, 3 °C, 5 °C, 7 °C, 15 °C, and 20 °C for 5, 10, and 20 days. All the bacterial isolates showed mineral K solubilization activity at these different temperatures. However, the content of K solubilization increased with the upsurge in temperature and period of incubation. The isolate KSB (Grz) showed the highest K solubilization index of 462.28% after 48 h of incubation at 20 °C. The maximum of 23.38 µg K/mL broth was solubilized by the isolate KSB (Grz) at 20 °C after 20 days of incubation. Based on morphological, biochemical, and molecular characterization (through the 16S rDNA approach), the isolate KSB (Grz) was identified as Mesorhizobium sp. The majority of the strains produced HCN and ammonia. The maximum indole acetic acid (IAA) (31.54 µM/mL) and cellulase (390 µM/mL) were produced by the isolate KSB (Grz). In contrast, the highest protease (525.12 µM/mL) and chitinase (5.20 µM/mL) activities were shown by standard strain Bacillus mucilaginosus and KSB (Gmr) isolate, respectively.

Growth Inhibition and Induction of Innate Immune Signaling of Chondrosarcomas with Epigenetic Inhibitors.

Chondrosarcomas are inherently resistant to chemotherapy and radiotherapy, pointing to an unmet need for new treatment options. Immune checkpoint inhibitors, which have shown remarkable promise in multiple solid cancer types, have limited efficacy in chondrosarcomas. Mutations in IDH1/2 genes, which result in progressive increases in DNA and histone methylation, are observed in 50% of conventional chondrosarcomas, suggesting that epigenetic dysregulation represents a potential barrier for tumor progression and target for therapeutic intervention. Here, we demonstrated that combined treatment of FDA-approved inhibitors of DNA methyltransferases (DNMTs) 5-aza-2'-deoxycytidine (5-aza), and histone deacetylases (HDACs) suberanilohydroxamic acid (SAHA) impaired the proliferation of chondrosarcoma cell lines in vitro and in xenograft studies. Transcriptomic analysis reveals that chondrosarcoma cells treated with 5-aza and SAHA markedly elevated the expression of IFN-stimulated genes including PD-L1, indicating that these epigenetic drugs induced a potent innate immune response. We demonstrated that 5-aza and SAHA resulted in both genomic and epigenomic instability, as shown by elevated DNA damage response and derepression of retrotransposons, respectively, which in turn activated pattern recognition receptors (PRRs) and the downstream IFN signaling pathways. Importantly, the cytotoxic effects of 5-aza and SAHA can be rescued by depletion of PRRs such as cGAS and MAVS, and potentiated by depletion of the RNA-editing enzyme ADAR1. Together, our results demonstrate preclinical activity of combined DNMT and HDAC inhibition against chondrosarcomas and suggest that targeted epigenetic therapies could represent a new therapeutic approach in the treatment of chondrosarcomas, and this is being tested in an ongoing clinical trial (NCT04340843).

Ectopic expression of a novel cold-resistance protein 1 from Brassica oleracea promotes tolerance to chilling stress in transgenic tomato.

Cold stress is considered as one of the major environmental factors that adversely affects the plant growth and distribution. Therefore, there arises an immediate need to cultivate effective strategies aimed at developing stress-tolerant crops that would boost the production and minimise the risks associated with cold stress. In this study, a novel cold-responsive protein1 (BoCRP1) isolated from Brassica oleracea was ectopically expressed in a cold susceptible tomato genotype Shalimar 1 and its function was investigated in response to chilling stress. BoCRP1 was constitutively expressed in all the tissues of B. oleracea including leaf, root and stem. However, its expression was found to be significantly increased in response to cold stress. Moreover, transgenic tomato plants expressing BoCRP1 exhibited increased tolerance to chilling stress (4 °C) with an overall improved rate of seed germination, increased root length, reduced membrane damage and increased accumulation of osmoprotectants. Furthermore, we observed increased transcript levels of stress responsive genes and enhanced accumulation of reactive oxygen species scavenging enzymes in transgenic plants on exposure to chilling stress. Taken together, these results strongly suggest that BoCRP1 is a promising candidate gene to improve the cold stress tolerance in tomato.

mTORC1 induces eukaryotic translation initiation factor 4E interaction with TOS-S6 kinase 1 and its activation.

Eukaryotic translation initiation factor 4E was recently shown to be a substrate of mTORC1, suggesting it may be a mediator of mTORC1 signaling. Here, we present evidence that eIF4E phosphorylated at S209 interacts with TOS motif of S6 Kinase1 (S6K1). We also show that this interaction is sufficient to overcome rapamycin sensitivity and mTORC1 dependence of S6K1. Furthermore, we show that eIF4E-TOS interaction relieves S6K1 from auto-inhibition due to carboxy terminal domain (CTD) and primes it for hydrophobic motif (HM) phosphorylation and activation in mTORC1 independent manner. We conclude that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif to influence its state of HM phosphorylation and inducing its activation.