pH-sensitive semi-interpenetrating network of microcrystalline cellulose and methacrylic acid hydrogel for the oral delivery of insulin.

Insulin is commonly administered to diabetic patients subcutaneously and has shown poor patient compliance. Due to this, research has been carried out extensively to find molecules that could deliver insulin orally. In this context, a new type of pH-responsive hydrogel, composed of microcrystalline cellulose and methacrylic acid-based hydrogels, has been developed and studied for the oral delivery of insulin. These hydrogels were prepared by free radical polymerization using potassium persulphate as initiator and N, N'-methylenebisacrylamide as a cross-linker. These pH-sensitive hydrogels showed swelling in distilled water as high as 5800 %. The hydrogels were investigated for swelling in saline and glucose solutions, and pH sensitivity was confirmed by swelling in solutions of different pH. The morphological shape was established by SEM, and the structure was analyzed by FTIR. Thermal degradation was investigated by TGA. In vitro release studies have confirmed pH sensitivity, showing lower insulin release at pH 1.2 than at pH 6.8. The encapsulation efficiency was determined to be 56.00 ±â€¯0.04 %. It was further validated by in-vivo investigations for which insulin was loaded into hydrogels and administered orally to healthy and diabetic Wistar rats at 40 IU/kg, showing maximum hypoglycemic effect at 6 h, which was sustained for 24 h. In the stomach's acidic environment, the gels remained unaffected due to the formation of intermolecular polymer complexes. Insulin remained in the gel and was protected from proteolytic degradation. Thus, pH-responsive methacrylic acid-based hydrogels are promising for biomedical applications, especially oral drug delivery.

Optimal allocation of distributed energy resources to cater the stochastic E-vehicle loading and natural disruption in low voltage distribution grid.

The everyday extreme uncertainties become the new normal for our world. Critical infrastructures like electrical power grid and transportation systems are in dire need of adaptability to dynamic changes. Moreover, stringent policies and strategies towards zero carbon emission require the heavy influx of renewable energy sources (RES) and adoption of electric transportation systems. In addition, the world has seen an increased frequency of extreme natural disasters. These events adversely impact the electrical grid, specifically the less hardened distribution grid. Hence, a resilient electrical network is the demand of the future to fulfill critical loads and charging of emergency electrical vehicles (EV). Therefore, this paper proposes a two-dimensional methodology in planning and operational phase for a resilient electric distribution grid. Initially stochastic modelling of EV load has been performed duly considering the geographical feature and commute pattern to form probability distribution functions. Thenceforth, the impact assessment of extreme natural events like earthquakes using damage state classification has been done to model the impact on distribution grid. The efficacy of the proposed methodology has been tested by simulating an urban Indian distribution grid with mapped EV on DigSILENT PowerFactory integrated with supervised learning tools on Python. Subsequently 24-h load profile before event and after event have been compared to analyze the impact.

Decolourization and detoxification of Reactive Red-195 azo dye by Staphylococcus caprae isolated from textile effluent.

Azo dyes are used as coloring agent in textile industries at larger scale. As a result, large quantity of dye-enriched waste water is generated which subsequently poses environmental problems. Biological tool involving bacteria having azoreductase enzyme has proved to be more effective and efficient in dye effluent treatment. Current work focuses on Staphylococcus caprae (S. caprae) for degradation and decolorization of Reactive Red-195 (RR-195) azo dye. For this purpose, factors such as pH, temperature, inoculums, carbon and nitrogen sources, and dye concentrations have been optimized for maximum decolorization and degradation. S. caprae (4 mg/mL) efficiently resulted into 90% decolorization of RR-195 dye under static condition at 100 µg/mL concentration, 30 °C and pH 7.0 at a 12-h contact period. FTIR analysis has revealed the formation of new functional groups in the treated dye such as O-H stretch at 3370 cm-1, C-H band stretching at 2928 cm-1, and new band at 1608 cm-1 which specify the degradation of aromatic ring, 1382 and 1118 cm-1 represents desulfonated peaks. Biodegraded metabolites of RR-195 dye such as phenol, 3, 5-di-tert-butylphenol, and phthalic acid have been identified respectively that find industrial applications. Phytotoxicity test has shown non-toxic effects of treated dye on germination of Vigna radiata and Triticum aestivum seeds. Further, antibiotic diffusion assay has confirmed the biosafety of S. caprae.

Fisetin induces G2/M phase arrest and caspase-mediated cleavage of p21Cip1 and p27Kip1 leading to apoptosis and tumor growth inhibition in HNSCC.

The anticancer potential and associated mechanisms of flavonoid fisetin are yet to be fully investigated on human head and neck squamous cell carcinoma (HNSCC). In the present study, fisetin (25-75 µM for 24-48 h) dose-dependently inhibited growth and induced death in HNSCC Cal33 and UM-SCC-22B cells, without showing any death in normal cells. Fisetin (25-50 µM) induced G2/M phase arrest via decrease in Cdc25C, CDK1, cyclin B1 expression, and an increase in p53(S15). A concentration-dependent increase in fisetin-induced DNA damage and apoptosis in HNSCC cells was authenticated by comet assay, gamma-H2A.X(S139) phosphorylation, and marked cleavage of PARP protein. Interestingly, fisetin-induced cell death occurred independently of p53 and reactive oxygen species production. The activation of JNK and inhibition of PI3K/Akt, ERK1/2, EGFR, and STAT-3 signaling were identified. Further, fisetin-induced apoptosis was mediated, in part, via p21Cip1 and p27Kip1 cleavage by caspase, which was reversed by z-VAD-FMK, a pan-caspase inhibitor. Subsequently, fisetin was also found to induce autophagy; nevertheless, autophagy attenuation exaggerated apoptosis. Oral fisetin (50 mg/kg body weight) treatment to establish Cal33 xenograft in mice for 19 days showed 73% inhibition in tumor volume (p < 0.01) along with a decrease in Ki67-positive cells and an increase in cleaved caspase-3 level in tumors. Consistent with the effect of 50 µM fisetin in vitro, the protein levels of p21Cip1 and P27Kip1 were also decreased by fisetin in tumors. Together, these findings showed strong anticancer efficacy of fisetin against HNSCC with downregulation of EGFR-Akt/ERK1/2-STAT-3 pathway and activation of JNK/c-Jun, caspases and caspase-mediated cleavage of p21Cip1 and p27Kip1.

Correlation of severity & clinical outcomes of COVID-19 with virus variants: A prospective, multicentre hospital network study.

BACKGROUND OBJECTIVES: The clinical course of COVID-19 and its prognosis are influenced by both viral and host factors. The objectives of this study were to develop a nationwide platform to investigate the molecular epidemiology of SARS-CoV-2 (Severe acute respiratory syndrome Corona virus 2) and correlate the severity and clinical outcomes of COVID-19 with virus variants. METHODS: A nationwide, longitudinal, prospective cohort study was conducted from September 2021 to December 2022 at 14 hospitals across the country that were linked to a viral sequencing laboratory under the Indian SARS-CoV-2 Genomics Consortium. All participants (18 yr and above) who attended the hospital with a suspicion of SARS-CoV-2 infection and tested positive by the reverse transcription-PCR method were included. The participant population consisted of both hospitalized as well as outpatients. Their clinical course and outcomes were studied prospectively. Nasopharyngeal samples collected were subjected to whole genome sequencing to detect SARS-CoV-2 variants. RESULTS: Of the 4972 participants enrolled, 3397 provided samples for viral sequencing and 2723 samples were successfully sequenced. From this, the evolution of virus variants of concern including Omicron subvariants which emerged over time was observed and the same reported here. The mean age of the study participants was 41 yr and overall 49.3 per cent were female. The common symptoms were fever and cough and 32.5 per cent had comorbidities. Infection with the Delta variant evidently increased the risk of severe COVID-19 (adjusted odds ratio: 2.53, 95% confidence interval: 1.52, 4.2), while Omicron was milder independent of vaccination status. The independent risk factors for mortality were age >65 yr, presence of comorbidities and no vaccination. INTERPRETATION CONCLUSIONS: The authors believe that this is a first-of-its-kind study in the country that provides real-time data of virus evolution from a pan-India network of hospitals closely linked to the genome sequencing laboratories. The severity of COVID-19 could be correlated with virus variants with Omicron being the milder variant.

Exploration of P1 and P4 modifications of nirmatrelvir: Design, synthesis, biological evaluation, and X-ray structural studies of SARS-CoV-2 Mpro inhibitors.

We report the synthesis, biological evaluation, and X-ray structural studies of a series of SARS-CoV-2 Mpro inhibitors based upon the X-ray crystal structure of nirmatrelvir, an FDA approved drug that targets the main protease of SARS-CoV-2. The studies involved examination of various P4 moieties, P1 five- and six-membered lactam rings to improve potency. In particular, the six-membered P1 lactam ring analogs exhibited high SARS-CoV-2 Mpro inhibitory activity. Several compounds effectively blocked SARS-CoV-2 replication in VeroE6 cells. One of these compounds maintained good antiviral activity against variants of concern including Delta and Omicron variants. A high-resolution X-ray crystal structure of an inhibitor bound to SARS-CoV-2 Mpro was determined to gain insight into the ligand-binding properties in the Mpro active site.

Molecular surface-dependent light harvesting and photo charge separation in plant-derived carbon quantum dots for visible-light-driven OH radical generation for remediation of aromatic hydrocarbon pollutants and real wastewater.

Despite the growing emphasis on eco-friendly nanomaterials as energy harvesters, scientists are actively searching for metal-free photocatalysts to be used in environmental remediation strategies. Developing renewable resource-based carbon quantum dots (CQDs) as the sole photocatalyst to harvest visible light for efficient pollutant degradation is crucial yet challenging, particularly for addressing the escalating issue of water deterioration. Moreover, the photocatalytic decomposition of H2O2 under visible light irradiation remains an arduous task. Based on this, we designed two types of CQDs, C-CQDs (carboxylic-rich) and A-CQDs (amine-rich) with distinct molecular surfaces. Owing to the higher amount of upward band bending induced by amine-rich molecular surface, A-CQDs efficiently harvest the visible light and prevent recombination kinetics resulting in prolonged lifetimes (25 ps), and augmented charge carrier density (35.7 × 1018) of photoexcited charge carriers. A-CQDs enabled rapid visible-light-driven photolysis of H2O2 (k = 0.058 min-1) and produced higher quantity of •OH radicals (0.158 µmol/sec) for the mineralization of petroleum waste, BETX (i.e. Benzene, Ethylbenzene, Toluene and Xylene) (k = 0.017-0.026 min-1) and real textile wastewater (k = 0.026 min-1). To assess comparative toxicities of both remediated and non-remediated real wastewater samples in a time and dose depended manner, Drosophila melanogaster was used as a model organism. The findings unequivocally demonstrate the potential of remediated wastewater for watering urban forestry.

Reagent-controlled chemo/stereoselective glycosylation of ʟ-fucal to access rare deoxysugars.

2,6-Dideoxy sugars constitute an important class of anticancer antibiotics natural products and serve as essential medicinal tools for carbohydrate-based drug discovery and vaccine development. In particular, 2-deoxy ʟ-fucose or ʟ-oliose is a rare sugar and vital structural motif of several potent antifungal and immunosuppressive bioactive molecules. Herein, we devised a reagent-controlled stereo and chemoselective activation of ʟ-fucal, enabling the distinctive glycosylation pathways to access the rare ʟ-oliose and 2,3-unsaturated ʟ-fucoside. The milder oxo-philic Bi(OTf)3 catalyst induced the direct 1,2-addition predominantly, whereas B(C6F5)3 promoted the allylic Ferrier-rearrangement of the enol-ether moiety in ʟ-fucal glycal donor, distinguishing the competitive mechanisms. The reagent-tunable modular approach is highly advantageous, employing greener catalysts and atom-economical transformations, expensive ligand/additive-free, and probed for a diverse range of substrates comprising monosaccharides, amino-acids, bioactive natural products, and drug scaffolds embedded with susceptible or labile functionalities.

3D printable, injectable amyloid-based composite hydrogel of bovine serum albumin and aloe vera for rapid diabetic wound healing.

Protein-based biomaterials, particularly amyloids, have sparked considerable scientific interest in recent years due to their exceptional mechanical strength, excellent biocompatibility and bioactivity. In this work, we have synthesized a novel amyloid-based composite hydrogel consisting of bovine serum albumin (BSA) and aloe vera (AV) gel to utilize the medicinal properties of the AV gel and circumvent its mechanical frangibility. The synthesized composite hydrogel demonstrated an excellent porous structure, self-fluorescence, non-toxicity, and controlled rheological properties. Moreover, this hydrogel possesses inherent antioxidant and antibacterial properties, which accelerate the rapid healing of wounds. The in vitro wound healing capabilities of the synthesized composite hydrogel were evaluated using 3T3 fibroblast cells. Moreover, the efficacy of the hydrogel in accelerating chronic wound healing via collagen crosslinking was investigated through in vivo experiments using a diabetic mouse skin model. The findings indicate that the composite hydrogel, when applied, promotes wound healing by inducing collagen deposition and upregulating the expression of vascular endothelial growth factor (VEGF) and its receptors. We also demonstrate the feasibility of the 3D printing of the BSA-AV hydrogel, which can be tailored to treat various types of wound. The 3D printed hydrogel exhibits excellent shape fidelity and mechanical properties that can be utilized for personalized treatment and rapid chronic wound healing. Taken together, the BSA-AV hydrogel has great potential as a bio-ink in tissue engineering as a dermal substitute for customizable skin regeneration.

Nanoparticles for combined photo- and chemo-dynamic therapy of cancer cells involving endogenous glutathione depletion.

Background: Reactive oxygen species (ROS) are powerful weapons for various anticancer therapies. However, high glutathione (GSH) levels in cancer cells can significantly reduce the efficacy of such therapies. Methods: In this study, pH-responsive fluorescein-encapsulated zeolitic imidazolate framework-8 nanoparticles were synthesized for ROS-mediated combination therapy. Results: Upon blue light activation, fluorescein displayed a high singlet oxygen photogeneration ability for photodynamic therapy. Concurrently, accumulated Zn2+ from degraded zeolitic imidazolate framework-8 stimulated simultaneous ROS generation and GSH depletion, thereby successfully inducing chemodynamic therapy. This triggered a cascade of photo-physical and chemical processes culminating in the localized generation of ROS, ultimately breaking the intracellular redox equilibrium. Conclusion: This nanoformulation can potentially be used for light-activated ROS-mediated therapy for the management of superficial tumors.

Highly reactive molecules called reactive oxygen species (ROS) are known to be present in excess in cancer cells. As a result, cancer cells are more susceptible to death by any further rise in levels of these species. In the current study, fluorescein-encapsulated zeolitic imidazolate nanoparticles were prepared for blue light-activated ROS-enhancing combination therapy. The nanoparticles displayed significant toxicity against a breast cancer cell line and simultaneously induced glutathione depletion, an antioxidant known to reduce the efficacy of various cancer therapies. Thus, this study reveals the potential of fluorescein-encapsulated zeolitic imidazolate nanoparticles for light-activated ROS-mediated therapy for the treatment of superficial tumors.

Synthesis of optically active SARS-CoV-2 Mpro inhibitor drug nirmatrelvir (Paxlovid): an approved treatment of COVID-19.

Nirmatrelvir (Paxlovid) is an FDA approved drug that targets SARS-COV-2 3CLprotease. We report an optically active synthesis of nirmatrelvir that avoids a critical epimerization step. Our initial coupling of gem-dimethyl bicyclo[3.1.0]proline methyl ester with tert-leucine-trifluoroacetamide using standard coupling reagents, EDC and HOBt, provided the corresponding dipeptide derivative in excellent yield, however, a significant epimerization was observed at the tert-leucine bearing chiral center. To circumvent this epimerization problem, we developed a ZnCl2-mediated direct N-trifluroacetylation of Boc-derivatives for the synthesis of nirmatrelvir. This protocol has been utilized for N-acyl bond formation with other anhydrides without epimerization. The present synthetic route can be useful for the synthesis of structural variants of nirmatrelvir without significant epimerization.

Comparative analysis of cobalt ferrite and iron oxide nanoparticles using bimodal hyperthermia, along with physical and in silico interaction with human hemoglobin.

Magnetic nanoparticles (MNPs) have captivated the scientific community towards biomedical applications owing to their numerous distinctive physio-chemical properties. In this work, cobalt ferrite (CFNPs) and iron oxide nanoparticles (IONPs) were synthesized using the thermal decomposition method and then functionalized with polyacrylic acid (PAA) for aqueous dispersion. Associated techniques, namely TEM, FESEM, DLS, XRD, and VSM, were used to characterize the synthesized nanoparticles. We also investigated the light-induced and magnetic-field-induced hyperthermia properties of the PAA-functionalized MNPs. It was found that the PAA-CFNPs show a high specific absorption rate (SAR) compared with the PAA-IONPs. Since blood plasma is essential for the delivery and targeting of drugs, studying biological interactions is crucial for effective therapeutic use. Therefore, we performed physical and in silico studies to probe into the mechanistic interaction of CFNPs and IONPs with human hemoglobin. From these studies, we inferred the successful binding between the nanoparticles and protein. Preliminary in vitro cytocompatibility and photothermal toxicity studies in breast cancer (MCF-7) cells treated with the nanoparticles revealed a low dark toxicity and significant laser-induced photothermal toxicity.

Cherenkov Radiation in Optical Fibres as a Versatile Machine Protection System in Particle Accelerators.

Machine protection systems in high power particle accelerators are crucial. They can detect, prevent, and respond to events which would otherwise cause damage and significant downtime to accelerator infrastructure. Current systems are often resource heavy and operationally expensive, reacting after an event has begun to cause damage; this leads to facilities only covering certain operational modes and setting lower limits on machine performance. Presented here is a new type of machine protection system based upon optical fibres, which would be complementary to existing systems, elevating existing performance. These fibres are laid along an accelerator beam line in lengths of ∼100 m, providing continuous coverage over this distance. When relativistic particles pass through these fibres, they generate Cherenkov radiation in the optical spectrum. This radiation propagates in both directions along the fibre and can be detected at both ends. A calibration based technique allows the location of the Cherenkov radiation source to be pinpointed to within 0.5 m with a resolution of 1 m. This measurement mechanism, from a single device, has multiple applications within an accelerator facility. These include beam loss location monitoring, RF breakdown prediction, and quench prevention. Detailed here are the application processes and results from measurements, which provide proof of concept for this device for both beam loss monitoring and RF breakdown detection. Furthermore, highlighted are the current challenges for future innovation.

TeV/m catapult acceleration of electrons in graphene layers.

Recent nanotechnology advances enable fabrication of layered structures with controllable inter-layer gap, giving the ultra-violet (UV) lasers access to solid-state plasmas which can be used as medium for electron acceleration. By using a linearly polarized 3 fs-long laser pulse of 100 nm wavelength and 10[Formula: see text] W/cm[Formula: see text] peak intensity, we show numerically that electron bunches can be accelerated along a stack of ionized graphene layers. Particle-In-Cell (PIC) simulations reveal a new self-injection mechanism based on edge plasma oscillations, whose amplitude depends on the distance between the graphene layers. Nanometre-size electron ribbons are electrostatically catapulted into buckets of longitudinal electric fields in less than 1 fs, as opposed to the slow electrostatic pull, common to laser wakefield acceleration (LWFA) schemes in gas-plasma. Acceleration then proceeds in the blowout regime at a gradient of 4.79 TeV/m yielding a 0.4 fs-long bunch with a total charge in excess of 2.5 pC and an average energy of 6.94 MeV, after travelling through a graphene target as short as 1.5 [Formula: see text]m. These parameters are unprecedented within the LWFA research area and, if confirmed experimentally, may have an impact on fundamental femtosecond research.

Evaluation of Congo red dye decolorization and degradation potential of an endophyte Colletotrichum gloeosporioides isolated from Thevetia peruviana (Pers.) K. Schum.

Decolorization and degradation of textile dye by endophytic fungi stand to be a profitable and viable alternative over conventional methods with respect to eco-friendliness, cost-effectiveness, and non-hazardous nature. One of the active fungal endophytes Colletotrichum gloeosporioides isolated from plant Thevetia peruviana (Pers.) K. Schum. was screened for laccase production and Congo red dye decolorization. Various physicochemical parameters like dye concentration, carbon sources, nitrogen sources, temperature, and pH were optimized, and the maximum decolorization (%) was achieved at 100 mg/L of dye concentration (82%), yeast extract (80%), 30 °C temp (80%), glucose (79%), and 7 pH (78%), respectively. SEM image and fungal biomass changes represent that fungus actively participated in the dye decolorization and had less significant effect on biomass. The regenerative ability of fungus C. gloeosporioides after dye decolorization indicated tolerance against the dye and was found to be more advantageous over previous reports of dye decolorization by other endophytic fungi. UV-Vis spectra, TLC, FTIR, and HPLC results confirmed the decolorization and degradation process due to absorption and biodegradation. Phytotoxicity assay depicted that degraded products are less toxic to Phaseolus mungo compared to Congo red. The overall findings showed that C. gloeosporioides possesses a good decolorization and degradation potential against Congo red and this endophyte can be profitably used for dye-containing wastewater treatment.

Measuring the Economic Burden of Health Conditions among White-Collar Employees: A Cross-Sectional Study from Delhi-NCR.

Background: In the past few decades, there has been a significant increase in healthcare expenditure due to the prevalence of health issues across the globe. This is primarily seen among white-collar employees due to the sedentary nature of their jobs, which affects their current earnings (Purchasing Power) directly due to the reallocation of their real income towards healthcare expenditure (Economic Burden) and indirectly by impacting work productivity through sick leaves. Aim: To measure the economic burden of disease(s) among white-collar employees, and to study the same across different socio-demographic variables. Methods: A cross-sectional study has been conducted in the region of Delhi-NCR among 357 white-collar employees. A random sampling method was adopted using a structured questionnaire. The questionnaire collected information regarding the direct and indirect costs of health conditions with a recall period of one month. The cumulative score of these monthly costs was converted to annual data to estimate the economic burden of the health conditions among the employees over a year. Results: As compared to Communicable diseases (16.24%), Non-communicable diseases (27.17%) were more prevalent among the respondents. Compared to other diseases, the employees suffering from Heart diseases (INR 7,62,237.50), Spinal health issues (INR 1,73,625.00), and Diabetes (INR 1,64,535.71) incurred more economic burden. At a 5% significance level, no significant difference was observed in economic burden for Gender and BMI. However, the economic burden was significantly different across the categories of Age and Monthly income. A positive association can be observed in economic burden with the increasing categories of age and monthly income. Conclusion: With the nature of sedentary work (desk jobs), white-collar employees are at a greater risk of exposure to various NCDs than CDs and incur a significant amount of out-of-pocket expenditure to manage their health status.

Role of gut-microbiota in disease severity and clinical outcomes.

A delicate balance of nutrients, antigens, metabolites and xenobiotics in body fluids, primarily managed by diet and host metabolism, governs human health. Human gut microbiota is a gatekeeper to nutrient bioavailability, pathogens exposure and xenobiotic metabolism. Human gut microbiota starts establishing during birth and evolves into a resilient structure by adolescence. It supplements the host's metabolic machinery and assists in many physiological processes to ensure health. Biotic and abiotic stressors could induce dysbiosis in gut microbiota composition leading to disease manifestations. Despite tremendous scientific advancements, a clear understanding of the involvement of gut microbiota dysbiosis during disease onset and clinical outcomes is still awaited. This would be important for developing an effective and sustainable therapeutic intervention. This review synthesizes the present scientific knowledge to present a comprehensive picture of the role of gut microbiota in the onset and severity of a disease.

Current status of pesticide effects on environment, human health and it's eco-friendly management as bioremediation: A comprehensive review.

Pesticides are either natural or chemically synthesized compounds that are used to control a variety of pests. These chemical compounds are used in a variety of sectors like food, forestry, agriculture and aquaculture. Pesticides shows their toxicity into the living systems. The World Health Organization (WHO) categorizes them based on their detrimental effects, emphasizing the relevance of public health. The usage can be minimized to a least level by using them sparingly with a complete grasp of their categorization, which is beneficial to both human health and the environment. In this review, we have discussed pesticides with respect to their global scenarios, such as worldwide distribution and environmental impacts. Major literature focused on potential uses of pesticides, classification according to their properties and toxicity and their adverse effect on natural system (soil and aquatic), water, plants (growth, metabolism, genotypic and phenotypic changes and impact on plants defense system), human health (genetic alteration, cancer, allergies, and asthma), and preserve food products. We have also described eco-friendly management strategies for pesticides as a green solution, including bacterial degradation, myco-remediation, phytoremediation, and microalgae-based bioremediation. The microbes, using catabolic enzymes for degradation of pesticides and clean-up from the environment. This review shows the importance of finding potent microbes, novel genes, and biotechnological applications for pesticide waste management to create a sustainable environment.