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Diabetes mellitus (DM) is one of the leading causes of death by World Health Organization in 2019 and is considered a significant cause of other diseases including heart attack, stroke, kidney failure, blindness, and lower limb amputation. Sodium glucose co-transporter 2 (SGLT2) is a protein that reabsorbs around 90% of glucose from plasma glucose. SGLT2 is a recognised target for the treatment and management of diabetes. SGLT2 inhibitors (SGLT2-I) have entered in the market for managing glucose levels in diabetes. There are six SGLT proteins in the human body varying in their preference for sugar binding. The therapeutic approach focuses on the SGLT2 located in the intestine and early proximal tubule of the nephron that facilitates glucose reabsorption by approximately 90%. The expression of SGLT2, and tubular glucose load increases in the diabetic condition and hence the glucose reabsorption leads to hyperglycemia. SGLT2-I functions by inhibiting the reabsorption of glucose from renal tubule and enhancing the glucose excretion via urine. Discovery and development of selective SGLT2-I have a great potential for the treatment and maintenance of diabetes mellitus. This review provides an understanding of medicinal chemistry approaches toward the discovery of novel SGLT2-I over a decade. Compiled studies will help to describe the safety, efficacy, and benefits of various SGLT2-I in the management of blood glucose in diabetic patients.

Substituted coumarins are a very large family of naturally occurring compounds, and substituted coumarins are versatile scaffolds for the development of medicinally active compounds. Coumarins are extensively found in higher plant families such as Rutaceae and Umbelliferae, and are ingredients in various essential oils such as cinnamon bark oil, cassia leaf oil, and lavender oil. Coumarin-based compounds are obtained from nature and substituted coumarins synthesized by chemists demonstrate antitumor, antibacterial, antifungal, anticancer, anticoagulant, antimalarial, antiviral, anti-HIV and anti-inflammatory activities. They are also used as fluorescent dyes and probes and possess a variety of other bioactive properties. Coumarin and its derivatives might have diverse mechanisms of action on different targets for different activities depending on the substitution pattern on the coumarin scaffold. The important progress of natural and synthetic 4-substituted coumarin derivatives that are biologically active against many diseases is the subject of this review study. The research for more potent molecules begins with the substitution of the coumarin scaffold on the C-4 position, which showed anticancer activity against A549, ACHN, H727, MCF-7, and HL60 cancer cell lines. Overall, the expansion of anticancer, antibacterial, and antimalarial agents is covered by substitution at the C-4 position of the coumarin scaffold. This comprehensive study could aid in the development of more strong drug candidates for numerous diseases in the future, with broad and fascinating therapeutic applications.

Excellent characteristics of multi-walled carbon nanotubes (MWCNTs), such as higher toughness and stiffness, enlarged strength, and high thermal conductivity, make them an attractive choice to improve surface characteristics and machining performance. In the current study, MWCNTs mixed with dielectric fluid in the wire electrical discharge machining (WEDM) process was used to enhance the machining performance of Nitinol shape memory alloy (SMA). Significance of WEDM machining variables such as current, pulse-on time (Ton), pulse-off time (Toff), and variation in powder concentration of MWCNTs are studied on material removal rate (MRR) and surface roughness (SR). The addition of MWCNTs substantially improves the machining performance by increasing MRR and simultaneously reducing the SR. Improvement in the MRR of 75.42% and SR of 19.15% is achieved with the use of MWCNTs at 1 g/L in comparison to the conventional WEDM process. An advanced parameterless TLBO algorithm is used for simultaneous optimization of multiple responses. An advanced parameterless TLBO algorithm is used to find the optimal solution of multiple responses. Single objective optimization result has yielded maximum MRR of 0.5262 g/min at a current of 5 A, Ton 110 μs, Toff 1 μs and MWCNTs amount of 1 g/L while minimum SR of 1.27 μm at a current of 1 A, Ton 1 μs, Toff 24 μs and MWCNTs amount of 1 g/L. MOTLBO algorithm is used for simultaneous optimization of MRR and SR. Lastly, the surface integrity of machined surfaces using a field emission scanning electron microscope (FESEM) is also studied to evaluate the effect of MWCNTs on recast layer thickness (RLT) and other surface defects. The incorporation of MWCNTs has shown a substantial reduction in RLT and other surface defects such as reduction in globules of debris, melted material deposition, micro-crack-free, and micro-pores-free surfaces.

Abstract Population-based studies identified an association between a prior pregnancy complicated by gestational diabetes mellitus (GDM) and cardiac hypertrophy and dysfunction later in life. It is however unclear whether GDM initiates this phenotype and what are the underlying mechanisms. We addressed these questions by using female rats that express human amylin (HIP rats) as a GDM model and their wild-type (WT) littermates as the normal pregnancy model. Pregnant and two months postpartum HIP females had increased left-ventricular mass and wall thickness compared to non-pregnant HIP females, which indicates the presence of concentric hypertrophy. These parameters were unchanged in WT females during both pregnancy and postpartum periods. Hypertrophic Ca2+-dependent calcineurin/NFAT signaling was stimulated two months after giving birth in HIP females but not in the WT. In contrast, the CaMKII/HDAC hypertrophy pathway was active immediately after giving birth and returned to the baseline by two months postpartum in both WT and HIP females. Myocytes from two months postpartum HIP females exhibited slower Ca2+ transient relaxation and higher diastolic Ca2+ levels, which may explain calcineurin activation. No such effects occurred in the WT. These results suggest that a GDM-complicated pregnancy accelerates the development of pathological cardiac remodeling likely through activation of calcineurin/NFAT signaling.

Abstract An optimal mixture design was employed to optimize flour combination consisting of refined wheat flour (50%–75.9%), malted proso millet flour (20%–45.7%), and gluten (2%–5%) on responses, namely bread volume, hardness, springiness, L* value of crust, L* value of crumb, and overall acceptability of malted millet bread. The optimum level was found to be 73.3% of refined wheat flour, 24.7% of malted proso millet, and 2% of gluten, resulting in bread volume (773.33 cm3), hardness (79.08 N), springiness (0.054 mm), L* value crust (58.16), L* value crumb (64.08), and overall acceptability (7.89), respectively. The optimized bread showed significantly higher protein, ash, crude fiber, dietary fiber, and antioxidant activity than the control refined wheat flour bread. Therefore, optimized bread exhibited higher nutritional properties, making it appropriate for large‐scale production to improve consumers' nutrient delivery and protein requirements.

Global warming and changes in seasonal temperature can severely affect the general circulation and precipitation distribution of a region. Therefore, it becomes essential to analyze seasonal trends in air temperature with changing climate. The present study evaluates the troposphere temperature extremes over India during different seasons. We intend to identify significant trends in temperature distribution in different regions of India using the Mann–Kendall test. Further, we have calculated indices concerning temperature extremes to make inferences about the nature of this monotonicity at four pressure levels on a seasonal and annual basis. The temperature data being used in our analysis is obtained from the output of a Regional Climate Model version 4.6 (RegCM v4.6). The monthly temperature values are taken for 25 years (1982–2006) from the model output. We observed that the model captured temperature climatology is coherent with our theoretical analysis. Results of our study reveal a significant (p < 0.05) trend in TT during all the seasons in major parts of the country in the lower troposphere. The upper troposphere, on the other hand, does not show any significant trend during most of the seasons. The identification of these changes can be useful for analysis of coastal vulnerability and extreme weather conditions. HIGHLIGHTS Changes in seasonal temperature can severely affect general circulation and precipitation distribution of a region; therefore, it is essential to analyze seasonal trends in air temperature with changing climate.; We evaluate the troposphere temperature extremes over India during different seasons and trends in temperature distribution in different regions of India. Indices concerning temperature extremes to make inferences about the nature of this monotonicity at four pressure levels on a seasonal and annual basis are also calculated.; The monthly temperature values are taken for 25 years (1982–2006) from the model output of RegCM v4.6.; We observed a significant trend in TT during all the seasons in major parts of the country only in the lower troposphere and no such trend was observed in the upper troposphere during most of the seasons.; Findings can be useful in examining the perturbed state of the atmosphere, shifts in weather patterns and its impact on mean seasonal circulation in the near future.;

The security of web applications in an enterprise is of paramount importance. To strengthen the security of applications, the identification and mitigation of vulnerabilities through appropriate countermeasures becomes imperative. The Open Web Application Security Project (OWASP) Top 10 API Security Risks, 2023 Edition, indicates the prominent vulnerabilities of API security risks. Broken authentication, however, is placed in second position with level-3 exploitability, level-2 prevalence, level-3 detectability, and level-3 technical impact. To mitigate this vulnerability, many mitigation strategies have been proposed by using the cryptographic primitives wherein two techniques, namely hashing and PUF, are used. Some of the proposals have integrated the concepts of hashing and PUF. However, the unnecessarily lengthy and complex mathematics used in these proposals makes them unsuitable for current API-based application scenarios. Therefore, in this paper, the authors propose a privacy-preserving authentication protocol that incorporates the capability of both mechanisms in an easy and low-complexity manner. In addition to overcoming existing limitations, the proposed protocol is tested to provide more security properties over existing schemes. Analysis of their performance has demonstrated that the proposed solutions are secure, efficient, practical, and effective for API-based web applications in an enterprise environment.

Wire electrical discharge machining (WEDM) is widely preferred for machining difficult-to-cut materials like Ti6Al4V. In the present study, current, pulse-off-duration (Toff), and pulse-on-duration (Toff) were identified as vital input factors for the WEDM process of Ti6Al4V. Material removal rate (MRR) and surface roughness (SR) were selected as output measures for the study. The experiments were carried out by employing Taguchi’s L9 design at three levels. Empirical models were generated, which give the relationship between the input and output factors of the process. To check the acceptability of the model terms, analysis of variance (ANOVA) was used. The regression mode was observed to be significant for the output measures. For MRR, Toff was recorded as the highly significant factor affecting the response values with 74.95% impact, followed by Ton with 16.39%, and current with 6.56%. In the case of SR, Ton was found to be a highly significant factor with a 50.24% impact, followed by current with 43.99%, and Toff with 1.47%. Further, multi-objective optimization by using the HTS technique was performed. The effect of expanded graphite (EG) nano-powder has been studied on the output factors of MRR and SR. The use of EG nano-powder was found to improve WEDM operations as MRR was increased by 45.35%, and simultaneously, SR was reduced by 36.16%. Lastly, the surface morphology of the machined surface was investigated by employing SEM to understand the effect of EG nano-powder. The results have shown a reduction in surface defects by using EG nano-powder compared to the conventional WEDM process.

The objective of this study was to investigate the rhombohedral-structured, flower-like iron oxide (Fe2O3) nanoparticles that were produced using a cost-effective and environmentally friendly coprecipitation process. The structural and morphological characteristics of the synthesized Fe2O3 nanoparticles were analyzed using XRD, UV-Vis, FTIR, SEM, EDX, TEM, and HR-TEM techniques. Furthermore, the cytotoxic effects of Fe2O3 nanoparticles on MCF-7 and HEK-293 cells were evaluated using in vitro cell viability assays, while the antibacterial activity of the nanoparticles against Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) was also tested. The results of our study demonstrated the potential cytotoxic activity of Fe2O3 nanoparticles toward MCF-7 and HEK-293 cell lines. The antioxidant potential of Fe2O3 nanoparticles was evidenced by the 1,1-diphenyl-2-picrylhydrazine (DPPH) and nitric oxide (NO) free radical scavenging assays. In addition, we suggested that Fe2O3 nanoparticles could be used in various antibacterial applications to prevent the spread of different bacterial strains. Based on these findings, we concluded that Fe2O3 nanoparticles have great potential for use in pharmaceutical and biological applications. The effective biocatalytic activity of Fe2O3 nanoparticles recommends its use as one of the best drug treatments for future views against cancer cells, and it is, therefore, recommended for both in vitro and in vivo in the biomedical field.

Abstract The measurement of the optical transmission matrix (TM) of an opaque material is an advanced form of space-variant aberration correction. Beyond imaging, TM-based methods are emerging in a range of fields, including optical communications, micro-manipulation, and computing. In many cases, the TM is very sensitive to perturbations in the configuration of the scattering medium it represents. Therefore, applications often require an up-to-the-minute characterisation of the fragile TM, typically entailing hundreds to thousands of probe measurements. Here, we explore how these measurement requirements can be relaxed using the framework of compressive sensing, in which the incorporation of prior information enables accurate estimation from fewer measurements than the dimensionality of the TM we aim to reconstruct. Examples of such priors include knowledge of a memory effect linking the input and output fields, an approximate model of the optical system, or a recent but degraded TM measurement. We demonstrate this concept by reconstructing the full-size TM of a multimode fibre supporting 754 modes at compression ratios down to ∼5% with good fidelity. We show that in this case, imaging is still possible using TMs reconstructed at compression ratios down to ∼1% (eight probe measurements). This compressive TM sampling strategy is quite general and may be applied to a variety of other scattering samples, including diffusers, thin layers of tissue, fibre optics of any refractive profile, and reflections from opaque walls. These approaches offer a route towards the measurement of high-dimensional TMs either quickly or with access to limited numbers of measurements.

Abstract Reactive oxygen species (ROS) are implicated in triggering cell signalling events and pathways to promote and maintain tumorigenicity. Chemotherapy and radiation can induce ROS to elicit cell death allows for targeting ROS pathways for effective anti-cancer therapeutics. Coenzyme Q10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration. This study demonstrates that delivery of oxidized Coenzyme Q10 (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model. Consequent activation of cell death was observed in vitro in pancreatic cancer cells, and both human patient-derived organoids and tumour xenografts. The study is a first to demonstrate the effectiveness of oxidized ubidecarenone in targeting mitochondrial function resulting in an anti-cancer effect. Furthermore, these findings support the clinical development of proprietary formulation, BPM31510, for treatment of cancers with high ROS burden with potential sensitivity to ubidecarenone.

BackgroundApproximately 1 in 5 American adults experience mental illness every year. Thus, mobile phone–based mental health prediction apps that use phone data and artificial intelligence techniques for mental health assessment have become increasingly important and are being rapidly developed. At the same time, multiple artificial intelligence–related technologies (eg, face recognition and search results) have recently been reported to be biased regarding age, gender, and race. This study moves this discussion to a new domain: phone-based mental health assessment algorithms. It is important to ensure that such algorithms do not contribute to gender disparities through biased predictions across gender groups. ObjectiveThis research aimed to analyze the susceptibility of multiple commonly used machine learning approaches for gender bias in mobile mental health assessment and explore the use of an algorithmic disparate impact remover (DIR) approach to reduce bias levels while maintaining high accuracy. MethodsFirst, we performed preprocessing and model training using the data set (N=55) obtained from a previous study. Accuracy levels and differences in accuracy across genders were computed using 5 different machine learning models. We selected the random forest model, which yielded the highest accuracy, for a more detailed audit and computed multiple metrics that are commonly used for fairness in the machine learning literature. Finally, we applied the DIR approach to reduce bias in the mental health assessment algorithm. ResultsThe highest observed accuracy for the mental health assessment was 78.57%. Although this accuracy level raises optimism, the audit based on gender revealed that the performance of the algorithm was statistically significantly different between the male and female groups (eg, difference in accuracy across genders was 15.85%; P

With advancements in genomics technologies, a vast diversity of 'atypical' phages, that is, with single-stranded DNA or RNA genomes, are being uncovered from different ecosystems. Though these efforts have revealed the existence and prevalence of these nonmodel phages, computational approaches often fail to associate these phages with their specific bacterial host(s), while the lack of methods to isolate these phages has limited our ability to characterize infectivity pathways and new gene function. In this review, we call for the development of generalizable experimental methods to better capture this understudied viral diversity via isolation and study them through gene-level characterization and engineering. Establishing a diverse set of new 'atypical' phage model systems has the potential to provide many new biotechnologies, including potential uses of these atypical phages in halting the spread of antibiotic resistance and engineering of microbial communities for beneficial outcomes.

Abstract This study was undertaken to investigate the anticancer effects of organic extracts derived from the floral cones of Metasequoia glyptostroboides. Dried powder of M. glyptostroboides floral cones was subjected to methanol extraction, and the resulting extract was further partitioned by liquid–liquid extraction using the organic solvents n-hexane, dichloromethane (DME), chloroform, and ethyl acetate in addition to deionized water. HeLa cervical and COS-7 cells were used as a cancer cell model and normal cell control, respectively. The anticancer effect was evaluated by using the Cell Counting Kit-8 assay. The viability of COS-7 cells was found to be 12-fold higher than that of the HeLa cells under the administration of 50 µg/ml of the DME extract. Further, the sub-G1 population was determined by FACS analysis. The number of cells at the sub-G1 phase, which indicates apoptotic cells, was increased approximately fourfold upon treatment with the DME and CE extracts compared with that in the negative control. Furthermore, RT-qPCR and western blotting were used to quantitate the relative RNA and protein levels of the cell death pathway components, respectively. Our results suggest that the extracts of M. glyptostroboides floral cones, especially the DME extract, which possesses several anticancer components, as determined by GC–MS analysis, could a potential natural anticancer agent.

Background and Purpose: Occurrence of stroke has been reported among patients with COVID-19. The present study compares clinical features and outcomes of stroke patients with and without COVID-19. Methods: The COVID-19 Stroke Study Group (CSSG) is a multicentric study in 18 sites across India to observe and compare the clinical characteristics of patients with stroke admitted during the current pandemic period and a similar epoch in 2019. The present study reports patients of stroke with and without COVID-19 (CoVS and non-CoVS, respectively) seen between February 2020 and July 2020. Demographic, clinical, treatment, and outcome details of patients were collected. Results: The mean age and gender were comparable between the two groups. CoVS patients had higher stroke severity and extent of cerebral involvement on imaging. In-hospital complications and death were higher among CoVS patients (53.06% vs. 17.51%; P < 0.001) and (42.31% vs. 7.6%; P < 0.001), respectively. At 3 months, higher mortality was observed among CoVS patients (67.65% vs. 13.43%; P < 0.001) and good outcome (modified Rankin score [mRS]: 0–2) was seen more often in non-CoVS patients (68.86% vs. 33.33%; P < 0.001). The presence of COVID-19 and baseline stroke severity were independent predictors of mortality. Conclusions: CoVS is associated with higher severity, poor outcome, and increased mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and baseline stroke severity are independent predictors of mortality.

Parkinson’s disease (PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.

Non-line-of-sight imaging is typically limited by loss of directional information due to diffuse reflections scattering light in all directions. Here, the authors see around corners by using vertical edges and temporal response to pulsed light to obtain angular and longitudinal resolution, respectively.

Abstract Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable difference. Co-enzyme Q10 (CoQ10) an endogenous mitochondrial resident molecule, plays an important role in mitochondrial redox homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ10) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.

Abstract It is necessary to develop an understanding of the specific mechanisms involved in alpha-synuclein aggregation and propagation to develop disease modifying therapies for age-related synucleinopathies, including Parkinson’s disease and Dementia with Lewy Bodies. To adequately address this question, we developed a new transgenic mouse model of synucleinopathy that expresses human A53T SynGFP under control of the mouse prion protein promoter. Our characterization of this mouse line demonstrates that it exhibits several distinct advantages over other, currently available, mouse models. This new model allows rigorous study of the initial location of Lewy pathology formation and propagation in the living brain, and strongly suggests that aggregation begins in axonal structures with retrograde propagation to the cell body. This model also shows expeditious development of alpha-synuclein pathology following induction with small, in vitro-generated alpha-synuclein pre-formed fibrils (PFFs), as well as accelerated cell death of inclusion-bearing cells. Using this model, we found that aggregated alpha-synuclein somatic inclusions developed first in neurons, but later showed a second wave of inclusion formation in astrocytes. Interestingly, astrocytes appear to survive much longer after inclusion formation than their neuronal counterparts. This model also allowed careful study of peripheral-to-central spread of Lewy pathology after PFF injection into the hind limb musculature. Our results clearly show evidence of progressive, retrograde trans-synaptic spread of Lewy pathology through known neuroanatomically connected pathways in the motor system. As such, we have developed a promising tool to understand the biology of neurodegeneration associated with alpha-synuclein aggregation and to discover new treatments capable of altering the neurodegenerative disease course of synucleinopathies.

Abstract Background Severe acute respiratory syndrome (SARS) has been initiating pandemics since the beginning of the century. In December 2019, the world was hit again by a devastating SARS episode that has so far infected almost four million individuals worldwide, with over 200,000 fatalities having already occurred by mid-April 2020, and the infection rate continues to grow exponentially. SARS coronavirus 2 (SARS-CoV-2) is a single stranded RNA pathogen which is characterised by a high mutation rate. It is vital to explore the mutagenic capability of the viral genome that enables SARS-CoV-2 to rapidly jump from one host immunity to another and adapt to the genetic pool of local populations. Methods For this study, we analysed 2301 complete viral sequences reported from SARS-CoV-2 infected patients. SARS-CoV-2 host genomes were collected from The Global Initiative on Sharing All Influenza Data (GISAID) database containing 9 genomes from pangolin-CoV origin and 3 genomes from bat-CoV origin, Wuhan SARS-CoV2 reference genome was collected from GeneBank database. The Multiple sequence alignment tool, Clustal Omega was used for genomic sequence alignment. The viral replicating enzyme, 3-chymotrypsin-like cysteine protease (3CLpro) that plays a key role in its pathogenicity was used to assess its affinity with pharmacological inhibitors and repurposed drugs such as anti-viral flavones, biflavanoids, anti-malarial drugs and vitamin supplements. Results Our results demonstrate that bat-CoV shares > 96% similar identity, while pangolin-CoV shares 85.98% identity with Wuhan SARS-CoV-2 genome. This in-depth analysis has identified 12 novel recurrent mutations in South American and African viral genomes out of which 3 were unique in South America, 4 unique in Africa and 5 were present in-patient isolates from both populations. Using state of the art in silico approaches, this study further investigates the interaction of repurposed drugs with the SARS-CoV-2 3CLpro enzyme, which regulates viral replication machinery. Conclusions Overall, this study provides insights into the evolving mutations, with implications to understand viral pathogenicity and possible new strategies for repurposing compounds to combat the nCovid-19 pandemic.

This research was conducted to study the genetic relationship between eleven quantitative traits of 95 Indian mustard (Brassica juncea L.) genotypes. The experiment material was evaluated in paired rows of 4 m length at Research Area of Oilseeds Section, Department of Genetics and plant breeding, CCS HAU, Hisar during Rabi, 2017-18. All the recommended package of practices was followed to raise the healthy crop. Maximum variation was observed for seed yield per plant followed by the number of secondary branches per plant, the number of primary branches per plant, 1000-seed weight and the number of siliqua on main shoot. Correlation studies revealed that seed yield per plant was positively and significantly associated with plant height, the number of primary and secondary branches per plant, and the number of siliqua on main shoot length. Selection based on these traits would ultimately improve seed yield. Four ideal genotypes viz., DRMRIJ-14-261, DRMRIJ-15-52, DRMRIJ-15-148 and M 5 were identified for the traits such as medium maturity, the number of primary branches per plant, the number of seeds per siliqua and 1000-seed weight in this study. These genotypes can be used as source lines in breeding programme for obtaining desirable segregates.

Objective: It is well established that the liver-specific miR-122, a bona fide tumor suppressor, plays a critical role in lipid homeostasis. However, its role, if any, in amino acid metabolism has not been explored. Since glutamine (Gln) is a critical energy and anaplerotic source for mammalian cells, we assessed Gln metabolism in control wild type (WT) mice and miR-122 knockout (KO) mice by stable isotope resolved metabolomics (SIRM) studies. Methods: Six-to eight-week-old WT and KO mice and 12- to 15-month-old liver tumor-bearing mice were injected with [U–13C5,15N2]-L-Gln, and polar metabolites from the liver tissues were analyzed by nuclear magnetic resonance (NMR) imaging and ion chromatography-mass spectrometry (IC-MS). Gln-metabolism was also assessed in a Gln-dependent hepatocellular carcinoma (HCC) cell line (EC4). Expressions of glutaminases (Gls and Gls2) were analyzed in mouse livers and human primary HCC samples. Results: The results showed that loss of miR-122 promoted glutaminolysis but suppressed gluconeogenesis in mouse livers as evident from the buildup of 13C- and/or 15N-Glu and decrease in glucose-6-phosphate (G6P) levels, respectively, in KO livers. Enhanced glutaminolysis is consistent with the upregulation of expressions of Gls (kidney-type glutaminase) and Slc1a5, a neutral amino acid transporter in KO livers. Both Gls and Slc1a5 were confirmed as direct miR-122 targets by the respective 3′-UTR-driven luciferase assays. Importantly, expressions of Gls and Slc1a5 as well as glutaminase activity were suppressed in a Gln-dependent HCC (EC4) cell line transfected with miR-122 mimic that resulted in decreased 13C-Gln, 13C-á-ketoglutarate, 13C-isocitrate, and 13C-citrate levels. In contrast, 13C-phosphoenolpyruvate and 13C-G6P levels were elevated in cells expressing ectopic miR-122, suggesting enhanced gluconeogenesis. Finally, The Cancer Genome Atlas—Liver Hepatocellular Carcinoma (TCGA-LIHC) database analysis showed that expression of GLS is negatively correlated with miR-122 in primary human HCCs, and the upregulation of GLS RNA is associated with higher tumor grade. More importantly, patients with higher expressions of GLS or SLC1A5 in tumors exhibited poor survival compared with those expressing lower levels of these proteins. Conclusions: Collectively, these results show that miR-122 modulates Gln metabolism both in vitro and in vivo, implicating the therapeutic potential of miR-122 in HCCs that exhibit relatively high GLS levels. Keywords: Glutaminase, Glutaminolysis, Gluconeogenesis, Krebs cycle, miRNA-122, miR-122, SIRM, Slc1a5

Abstract The Global Carbon Project estimates that the terrestrial biosphere has absorbed about one‐third of anthropogenic CO2 emissions during the 1959–2019 period. This sink‐estimate is produced by an ensemble of terrestrial biosphere models and is consistent with the land uptake inferred from the residual of emissions and ocean uptake. The purpose of our study is to understand how well terrestrial biosphere models reproduce the processes that drive the terrestrial carbon sink. One challenge is to decide what level of agreement between model output and observation‐based reference data is adequate considering that reference data are prone to uncertainties. To define such a level of agreement, we compute benchmark scores that quantify the similarity between independently derived reference data sets using multiple statistical metrics. Models are considered to perform well if their model scores reach benchmark scores. Our results show that reference data can differ considerably, causing benchmark scores to be low. Model scores are often of similar magnitude as benchmark scores, implying that model performance is reasonable given how different reference data are. While model performance is encouraging, ample potential for improvements remains, including a reduction in a positive leaf area index bias, improved representations of processes that govern soil organic carbon in high latitudes, and an assessment of causes that drive the inter‐model spread of gross primary productivity in boreal regions and humid tropics. The success of future model development will increasingly depend on our capacity to reduce and account for observational uncertainties.

Summary: At its current rate, the rise of antimicrobial-resistant (AMR) infections is predicted to paralyze our industries and healthcare facilities while becoming the leading global cause of loss of human life. With limited new antibiotics on the horizon, we need to invest in alternative solutions. Bacteriophages (phages)—viruses targeting bacteria—offer a powerful alternative approach to tackle bacterial infections. Despite recent advances in using phages to treat recalcitrant AMR infections, the field lacks systematic development of phage therapies scalable to different applications. We propose a Phage Foundry framework to establish metrics for phage characterization and to fill the knowledge and technological gaps in phage therapeutics. Coordinated investment in AMR surveillance, sampling, characterization, and data sharing procedures will enable rational exploitation of phages for treatments. A fully realized Phage Foundry will enhance the sharing of knowledge, technology, and viral reagents in an equitable manner and will accelerate the biobased economy.

Drylands cover ca. 40% of the land surface and are hypothesised to play a major role in the global carbon cycle, controlling both long-term trends and interannual variation. These insights originate from land surface models (LSMs) that have not been extensively calibrated and evaluated for water-limited ecosystems. We need to learn more about dryland carbon dynamics, particularly as the transitory response and rapid turnover rates of semi-arid systems may limit their function as a carbon sink over multi-decadal scales. We quantified aboveground biomass carbon (AGC; inferred from SMOS L-band vegetation optical depth) and gross primary productivity (GPP; from PML-v2 inferred from MODIS observations) and tested their spatial and temporal correspondence with estimates from the TRENDY ensemble of LSMs. We found strong correspondence in GPP between LSMs and PML-v2 both in spatial patterns (Pearson’s r = 0.9 for TRENDY-mean) and in inter-annual variability, but not in trends. Conversely, for AGC we found lesser correspondence in space (Pearson’s r = 0.75 for TRENDY-mean, strong biases for individual models) and in the magnitude of inter-annual variability compared to satellite retrievals. These disagreements likely arise from limited representation of ecosystem responses to plant water availability, fire, and photodegradation that drive dryland carbon dynamics. We assessed inter-model agreement and drivers of long-term change in carbon stocks over centennial timescales. This analysis suggested that the simulated trend of increasing carbon stocks in drylands is in soils and primarily driven by increased productivity due to CO2 enrichment. However, there is limited empirical evidence of this 50-year sink in dryland soils. Our findings highlight important uncertainties in simulations of dryland ecosystems by current LSMs, suggesting a need for continued model refinements and for greater caution when interpreting LSM estimates with regards to current and future carbon dynamics in drylands and by extension the global carbon cycle.

Ochratoxin A (OTA) is one of the predominant mycotoxins that contaminate a wide range of food commodities. In the present study, a 36-mer aptamer was used as a molecular recognition element coupled with gold nanoparticles (AuNPs) for colorimetric detection of OTA in a microfluidic paper-based analytical device (μPADs). The μPADs consisted of three zones: control, detection, and sample, interconnected by channels. UV-vis spectroscopy (UV-vis), Dynamic Light Scattering (DLS), and Transmission Electron Microscopy (TEM) were used for characterization of AuNPs and AuNPs/Aptamer. According to the colorimetric assay, limit of detection (LOD) was found to be 242, 545.45, and 95.69 ng/mL in water, corn, and groundnut, respectively. The HPLC detection method achieved acceptable coefficient in standard curves (r2 = 0.9995), improved detection range, and recovery rates in spiked corn and groundnut samples as 43.61 ± 2.18% to 87.10 ± 1.82% and 42.01 ± 1.31% to 86.03 ± 2.64% after multiple sample extractions and cleanup steps. However, the developed μPADs analytical device had the potent ability to rapidly detect OTA without any extraction pre-requirement, derivatization, and cleanup steps, thus illustrating its feasibility in the animal health sector, agricultural, and food industries.

Existing drugs have limited success in managing obesity in human due to their low efficacy and severe side-effects. Surface-modified gold nanoparticles have now received considerable attention of researchers for efficient biomedical applications owing to their superior uptake by cells, biocompatibility, hydrophilicity and non-immunogenicity. Here we prepared Cinnamomum verum derived bioactives-functionalized gold nanoparticles (Au@P-NPs) and assessed their impact on obesity and related immune-metabolic complications in high-fat diet (HFD)-induced obese mice using metabolic experiments along with 16S RNA gene-based gut microbial profiling and faecal microbiota transplantation (FMT). Au@P-NPs treatment prevented weight gain, decreased fat deposition, reduced metabolic inflammation and endotoxaemia in HFD-fed mice. Au@P-NPs-treated group exhibited better glucose tolerance and insulin sensitivity than HFD-fed control mice, and got completely protected against hepatic steatosis. These impacts were related to increased energy expenditure and enhanced Ucp1 expression in the brown adipose tissues of Au@P-NPs-administered animals, which strongly linked with the mRNA expression of the membrane bile acid receptor TGR5. Treatment of HFD-fed animals with Au@P-NPs altered plasma bile acid profile, and increased Akkermansia muciniphila and decreased Lactobacillus populations in the faeces. Au@P-NPs-treated animals revealed altered plasma bile acid profile, and increased Akkermansia muciniphila and decreased Lactobacillus populations in the faeces. FMT experiments showed lesser weight gain and greater energy expenditure in the mice fed with faecal suspension from Au@P-NPs-treated animals than that from HFD-fed mice. These results clearly establish that gold nanoparticles functionalized with bioactive compounds of C. verum have high potential to be an anti-obesity drug.

To examine the relationships of retinal structural (optical coherence tomography) and visual functional (multifocal visual evoked potentials, mfVEP) indices with neuropsychological and brain structural measurements in healthy older subjects. 95 participants (mean (SD) age 68.1 (9.0)) years were recruited in the Optic Nerve Decline and Cognitive Change (ONDCC) study in this observational clinical investigation. OCT was conducted for retinal nerve fibre layer (RNFL) and mfVEP for amplitude and latency measurements. Participants undertook neuropsychological tests for cognitive performance and MRI for volumetric evaluation of various brain regions. Generalised estimating equation models were used for association analysis (p

Nickel-based superalloys find their main use in missile engines, atomic devices, investigational aircraft, aerospace engineering, industrial applications, and automotive gas turbines, spacecraft petrochemical tools, steam power, submarines, and broader heating applications. These superalloys impose certain difficulties during the process fabrication owing to their levels of higher hardness. In the current study, the precise machining of Waspaloy was attempted through the wire electrical discharge machining (WEDM) technique. A multi-objective optimization has been performed, and the influence of multi-walled carbon nanotubes (MWCNTs) has been assessed using the passing vehicle search (PVS) algorithm. The effects of machining variables like current, Toff, and Ton were studied using the output measures of material removal rate (MRR), recast layer thickness (RLT), and surface roughness (SR). The Box–Behnken design was applied to generate the experimental matrix. Empirical models were generated which show the interrelationship among the process variables and output measures. The analysis of variance (ANOVA) method was used to check the adequacy, and suitability of the models and to understand the significance of the parameters. The PVS technique was executed for the optimization of MRR, SR, and RLT. Pareto fronts were derived which gives a choice to the user to select any point on the front as per the requirement. To enhance the machining performance, MWCNTs mixed dielectric fluid was utilized, and the effect of these MWCNTs was also analyzed on the surface defects. The use of MWCNTs at 1 g/L enhanced the performance of MRR, SR, and RLT by 65.70%, 50.68%, and 40.96%, respectively. Also, the addition of MWCNTs has shown that the machined surface largely reduces the surface defects.

Intelligent fault diagnosis gives timely information about the condition of mechanical components. Since rolling element bearings are often used as rotating equipment parts, it is crucial to identify and detect bearing faults. When there are several defects in components or machines, early fault detection becomes necessary to avoid catastrophic failure. This work suggests a novel approach to reliably identifying compound faults in bearings when the availability of experimental data is limited. Vibration signals are recorded from single ball bearings consisting of compound faults, i.e., faults in the inner race, outer race, and rolling elements with a variation in rotational speed. The measured vibration signals are pre-processed using the Hilbert–Huang transform, and, afterward, a Kurtogram is generated. The multiscale-SinGAN model is adapted to generate additional Kurtogram images to effectively train machine-learning models. To identify the relevant features, metaheuristic optimization algorithms such as teaching–learning-based optimization, and Heat Transfer Search are applied to feature vectors. Finally, selected features are fed into three machine-learning models for compound fault identifications. The results demonstrate that extreme learning machines can detect compound faults with 100% Ten-fold cross-validation accuracy. In contrast, the minimum ten-fold cross-validation accuracy of 98.96% is observed with support vector machines.

Meiosis in angiosperm plants is followed by mitotic divisions to form multicellular haploid gametophytes. Termination of meiosis and transition to gametophytic development is, in Arabidopsis, governed by a dedicated mechanism that involves SMG7 and TDM1 proteins. Mutants carrying the smg7-6 allele are semi-fertile due to reduced pollen production. We found that instead of forming tetrads, smg7-6 pollen mother cells undergo multiple rounds of chromosome condensation and spindle assembly at the end of meiosis, resembling aberrant attempts to undergo additional meiotic divisions. A suppressor screen uncovered a mutation in centromeric histone H3 (CENH3) that increased fertility and promoted meiotic exit in smg7-6 plants. The mutation led to inefficient splicing of the CENH3 mRNA and a substantial decrease of CENH3, resulting in smaller centromeres. The reduced level of CENH3 delayed formation of the mitotic spindle but did not have an apparent effect on plant growth and development. We suggest that impaired spindle re-assembly at the end of meiosis limits aberrant divisions in smg7-6 plants and promotes formation of tetrads and viable pollen. Furthermore, the mutant with reduced level of CENH3 was very inefficient haploid inducer indicating that differences in centromere size is not the key determinant of centromere-mediated genome elimination.

AbstractThe spindle assembly checkpoint protects the integrity of the genome by ensuring that chromosomes are properly attached to the mitotic spindle before they are segregated during anaphase. Activation of the spindle checkpoint results in inhibition of the Anaphase-Promoting Complex (APC), an E3 ubiquitin ligase that triggers the metaphase–anaphase transition. Here, we show that levels of Ubc1, an E2 enzyme that functions in complex with the APC, modulate the response to spindle checkpoint activation in Saccharomyces cerevisiae

The generation mean analysis was carried out to estimate nature and magnitude of gene effect for yield traits and oil content in two crosses RH 0749 × RLC-3 and RH 0749 × PDZ-1 of Indian mustard [Brassica juncea (L.) Czern & Coss]. Significance of scaling test as well as χ2 in joint scaling test showed the presence of digenic or higher order interactions for all characters except for days to maturity in cross RH 0749 × RLC-3. Additive gene effects (d) were important for days to maturity, number of secondary branches per plant, number of seeds per siliqua, 1000-seed weight and seed yield per plant. Both additive (d) and dominance (h) gene effect were important for plant height, number of primary branches per plant, main shoot length, number of siliquae on main shoot, siliqua length and oil content. The dominant × dominant (l) type of gene interaction and duplicate epistasis was observed for most of the character in two crosses except for seed yield per plant in cross RH0749 × PDZ-1 for which complementary epistasis was observed. These results suggested that substantial improvement in yield may be achieved through recurrent selection and heterosis breeding.

Considering the significance of sunflower (Helianthus annuus L.) cultivation under diverse agro-climatic conditions, present study was done to recognize assorted parental lines utilizing RAPD and ISSR markers to lessen environmental effects or test blunders at Rajasthan College of Agriculture, MPUA & T, Udaipur, Rajasthan during 2016. In the present study, RAPD primers produced 334 polymorphic band and ISSR primers produced 160 polymorphic bands. RAPD primers detected more polymorphic loci (56.88%) than the ISSR primers (52.24%). The dendrograms constructed by RAPD, ISSR primers and pooled data were associated with each other, indicating the efficacy of both marker systems in genetic diversity study of sunflower. Based on RAPD, ISSR and pooled data analysis, the restorer line EC 623023, R 16 and seed parental line CMS 234B, PET 2-7-1B were found to be genetically most diverse and fall into different groups. Therefore, their genetic origin seems to be different and could be efficiently used in sunflower breeding programs.

Background: An acute respiratory disease (COVID-19), caused by a novel coronavirus (SARS-CoV-2,), has been declared a pandemic by WHO. A surgery on COVID-19 patients not only involves a risk of spread of the disease but also there is a serious concern for the patient's surgical outcomes and resources requirement. Aim: The retrospective study is aimed to provide a protocol for pre-operative testing of SARS CoV-2 using RT-PCR in the patient undergoing cardio-thoracic surgeries. Material and Methods: To analyze the impact of pre-operative testing of SARS- CoV-2 using RT-PCR in the patient undergoing elective cardio-thoracic surgeries. The patient who underwent surgical interventions during the COVID-19 lockdown period was divided into two phases. Phase I (without COVID-19 RT-PCR testing) and Phase II (with pre-operative COVID-19 RT-PCR testing). The retrospective comparison between the two study groups was done using Student t-test, Mann–Whitney U, and Chi square (χ2) test depending upon the clinical variable to be analyzed. Results: During the early phase (phase I), 26 patients underwent cardio-thoracic surgery without COVID-19 RT-PCR test. Whereas, during phase II, all patients were tested for COVID-19 using RT-PCR, preoperatively and a total of 64 surgeries were performed during this phase. One patient planned for CABG was positive on RT-PCR for COVID-19 and was sent to the quarantine ward. The difference in the pre-operative hospital stay between two groups was found to be statistically significant and a significant decrease in the number of PPE kits used, during the phase I. Conclusion: All asymptomatic patients should be tested for COVID-19 using RT-PCR prior to cardio-thoracic surgeries not only to contain the disease but to avoid potential implications of COVID-19 on the perioperative course, without added financial implications.

Extracellular deposits of the amyloid-beta peptide (Aβ) are known as the main pathological hallmark of Alzheimer’s disease. In Alzheimer’s disease, neurons are injured and die throughout the brain, a process in which Aβ neurotoxicity is considered to play an important role. However, the molecular mechanisms underlying Aβ toxicity that lead to neurodegeneration are not clearly established. Here we have elucidated the molecular pathways and networks which are impacted by Aβ in neurons using SH-SY5Y human neuroblastoma cells as a model. These cells were treated with Aβ1–42 peptides to study changes in biochemical networks using tandem mass tag labeled quantitative proteomic technique followed by computational analysis of the data. The molecular impacts of Aβ on cells were evident in a time- and dose-dependent manner, albeit the duration of treatment induced greater differential changes in cellular proteome compared to the effects of concentration. Aβ induced early changes in proteins associated with lysosomes, collagen chain trimerization and extracellular matrix receptor interaction, complement and coagulation cascade, oxidative stress induced senescence, ribosome biogenesis, regulation of insulin-like growth factor transport and uptake by insulin-like growth factor-binding protein. These novel findings provide molecular insights on the effects of Aβ on neurons, with implications for better understanding the impacts of Aβ on early neurodegeneration in Alzheimer’s disease pathology.