Development of pH-Sensitive hydrogel for advanced wound Healing: Graft copolymerization of locust bean gum with acrylamide and acrylic acid.

Wounds pose a formidable challenge in healthcare, necessitating the exploration of innovative tissue-healing solutions. Traditional wound dressings exhibit drawbacks, causing tissue damage and impeding natural healing. Using a Microwave (MW)-)-assisted technique, we envisaged a novel hydrogel (Hg) scaffold to address these challenges. This hydrogel scaffold was created by synthesizing a pH-responsive crosslinked material, specifically locust bean gum-grafted-poly(acrylamide-co-acrylic acid) [LBG-g-poly(AAm-co-AAc)], to enable sustained release of c-phycocyanin (C-Pc). Synthesized LBG-g-poly(AAm-co-AAc) was fine-tuned by adjusting various synthetic parameters, including the concentration of monomers, duration of reaction, and MW irradiation intensity, to maximize the yield of crosslinked LBG grafted product and enhance encapsulation efficiency of C-Pc. Following its synthesis, LBG-g-poly(AAm-co-AAc) was thoroughly characterized using advanced techniques, like XRD, TGA, FTIR, NMR, and SEM, to analyze its structural and chemical properties. Moreover, the study examined the in-vitro C-Pc release profile from LBG-g-poly(AAm-co-AAc) based hydrogel (HgCPcLBG). Findings revealed that the maximum release of C-Pc (64.12 ±â€¯2.69 %) was achieved at pH 7.4 over 48 h. Additionally, HgCPcLBG exhibited enhanced antioxidant performance and compatibility with blood. In vivo studies confirmed accelerated wound closure, and ELISA findings revealed reduced inflammatory markers (IL-6, IL-1ß, TNF-α) within treated skin tissue, suggesting a positive impact on injury repair. A low-cost and eco-friendly approach for creating LBG-g-poly(AAm-co-AAc) and HgCPcLBG has been developed. This method achieved sustained release of C-Pc, which could be a significant step forward in wound care technology.

Assessing the Correlation of Periodontal Inflamed Surface Area (PISA) With Systemic Inflammatory Markers.

Background Periodontitis has a vital role in eliciting a cross-reactivity or systemic inflammatory response, making periodontal inflamed surface area (PISA) a primary contributor to the inflammatory burden posed by periodontitis. PISA helps in the quantification of the amount of inflamed periodontal tissue. However, the existing literature data concerning PISA as an indicator of inflammatory burden are scarce, with limited research on the relationship between systemic inflammatory markers and PISA. Aim The present clinic-hematological cross-sectional study aimed to correlate PISA with systemic inflammatory markers. The study also aimed to assess serum concentrations of inflammatory markers such as erythrocyte sedimentation rates (ESR), C-reactive protein (CRP), and peripheral blood markers such as neutrophils and monocytes and to correlate these markers with PISA. Methods The study assessed 62 subjects, who were divided into two groups of 31 subjects, each following bleeding on probing (BOP) criteria. Group I consisted of subjects with generalized chronic gingivitis, and Group II included subjects with generalized chronic periodontitis. In two groups, BOP, probing pocket depth, clinical attachment level, and gingival recession were assessed along with PISA by a custom-made R function derived from a pre-existing, freely available MS Excel spreadsheet (Microsoft Corporation, Redmond, Washington). The results of the assessment were then compared. Results A statistically highly significant positive correlation was seen in PISA and CRP with a correlation coefficient of 0.4875 and p-value of 0.000059. A similar statistically significant positive correlation was seen in ESR and PISA with a correlation coefficient of 0.4089 and p-value of 0.000968. A statistically non-significant correlation was seen in neutrophils and PISA with p=0.576018. However, a moderate and positive statistically significant association was seen in monocyte and PISA with a correlation coefficient of 0.3258 and p-value of 0.009956. Conclusions The present study concludes that most of the common systemic inflammatory markers have a positive correlation with PISA. However, more studies are required to establish this correlation.

A Unique mRNA Vaccine Elicits Protective Efficacy against the SARS-CoV-2 Omicron Variant and SARS-CoV.

The highly pathogenic coronaviruses SARS-CoV-2 and SARS-CoV have led to the COVID-19 pandemic and SARS outbreak, respectively. The receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2, particularly the Omicron variant, has frequent mutations, resulting in the reduced efficiency of current COVID-19 vaccines against new variants. Here, we designed two lipid nanoparticle-encapsulated mRNA vaccines by deleting the mutant RBD of the SARS-CoV-2 Omicron variant (SARS2-S (RBD-del)) or by replacing this mutant RBD with the conserved and potent RBD of SARS-CoV (SARS2-S (SARS-RBD)). Both mRNA vaccines were stable at various temperatures for different time periods. Unlike SARS2-S (RBD-del) mRNA, SARS2-S (SARS-RBD) mRNA elicited effective T-cell responses and potent antibodies specific to both SARS-CoV-2 S and SARS-CoV RBD proteins. It induced strong neutralizing antibodies against pseudotyped SARS-CoV-2 and SARS-CoV infections and protected immunized mice from the challenge of the SARS-CoV-2 Omicron variant and SARS-CoV by significantly reducing the viral titers in the lungs after Omicron challenge and by completely preventing SARS-CoV-induced weight loss and death. SARS2-S (SARS-RBD)-immunized serum antibodies protected naïve mice from the SARS-CoV challenge, with its protective efficacy positively correlating with the neutralizing antibody titers. These findings indicate that this mRNA vaccine has the potential for development as an effective vaccine against current and future SARS-CoV-2 variants and SARS-CoV.

Antiproliferative effect of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues on IL-6 mediated STAT3 and role of the apoptotic pathway in albino Wistar rats of ethyl carbamate-induced lung carcinoma: In-silico, In-vitro, and In-vivo study.

Lung cancer (LC) ranks second most prevalent cancer in females after breast cancer and second in males after prostate cancer. Based on the GLOBOCAN 2020 report, India represented 5.9% of LC cases and 8.1% of deaths caused by the disease. Several clinical studies have shown that LC occurs because of biological and morphological abnormalities and the involvement of altered level of antioxidants, cytokines, and apoptotic markers. In the present study, we explored the antiproliferative activity of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues against LC using in-vitro, in-silico, and in-vivo models. In-vitro screening against A549 cells revealed compounds 9B (8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) and 12B (5-(4-chlorophenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) as potential pyrimidine analogues against LC. Compounds 9B and 12B were docked with different molecular targets IL-6, Cyt-C, Caspase9, and Caspase3 using AutoDock Vina 4.1 to evaluate the binding affinity. Subsequently, in-vivo studies were conducted in albino Wistar rats through ethyl-carbamate (EC)- induced LC. 9B and 12B imparted significant effects on physiological (weight variation), and biochemical (anti-oxidant [TBAR's, SOD, ProC, and GSH), lipid (TC, TG, LDL, VLDL, and HDL)], and cytokine (IL-2, IL-6, IL-10, and IL-1ß) markers in EC-induced LC in albino Wistar rats. Morphological examination (SEM and H&E) and western blotting (IL-6, STAT3, Cyt-C, BAX, Bcl-2, Caspase3, and caspase9) showed that compounds 9B and 12B had antiproliferative effects. Accordingly, from the in-vitro, in-silico, and in-vivo experimental findings, we concluded that 9B and 12B have significant antiproliferative potential and are potential candidates for further evaluation to meet the requirements of investigation of new drug application.

Multifunctional polymeric nanofibrous scaffolds enriched with azilsartan medoxomil for enhanced wound healing.

A prolonged and compromised wound healing process poses a significant clinical challenge, necessitating innovative solutions. This research investigates the potential application of nanotechnology-based formulations, specifically nanofiber (NF) scaffolds, in addressing this issue. The study focuses on the development and characterization of multifunctional nanofibrous scaffolds (AZL-CS/PVA-NF) composed of azilsartan medoxomil (AZL) enriched chitosan/polyvinyl alcohol (CS/PVA) through electrospinning. The scaffolds underwent comprehensive characterization both in vitro and in vivo. The mean diameter and tensile strength of AZL-CS/PVA-NF were determined to be 240.42 ± 3.55 nm and 18.05 ± 1.18 MPa, respectively. A notable drug release rate of 93.86 ± 2.04%, was observed from AZL-CS/PVA-NF over 48 h at pH 7.4. Moreover, AZL-CS/PVA-NF exhibited potent antimicrobial efficacy for Staphylococcus aureus and Pseudomonas aeruginosa. The expression levels of Akt and CD31 were significantly elevated, while Stat3 showed a decrease, indicating a heightened tissue regeneration rate with AZL-CS/PVA-NF compared to other treatment groups. In vivo ELISA findings revealed reduced inflammatory markers (IL-6, IL-1ß, TNF-α) within treated skin tissue, implying a beneficial effect on injury repair. The comprehensive findings of the present endeavour underscore the superior wound healing activity of the developed AZL-CS/PVA-NF scaffolds in a Wistar rat full-thickness excision wound model. This indicates their potential as novel carriers for drugs and dressings in the field of wound care.

A predominately pulmonary activation of complement in a mouse model of severe COVID-19.

Evidence from in vitro studies and observational human disease data suggest the complement system plays a significant role in SARS-CoV-2 pathogenesis, although how complement dysregulation develops in patients with severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of severe COVID-19, we identify significant serologic and pulmonary complement activation following infection. We observed C3 activation in airway and alveolar epithelia, and in pulmonary vascular endothelia. Our evidence suggests that while the alternative pathway is the primary route of complement activation, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia in response to cytokine exposure. This locally generated complement response appears to precede and subsequently drive lung injury and inflammation. Results from this mouse model recapitulate findings in humans, which suggest sex-specific variance in complement activation, with predilection for increased C3 activity in males, a finding that may correlate with more severe disease. Our findings indicate that complement activation is a defining feature of severe COVID-19 in mice and lay the foundation for further investigation into the role of complement in COVID-19.

Antiproliferative, apoptotic and anti-inflammatory potential of 5H-benzo[h]thiazolo[2,3-b]quinazoline analogues: Novel series of anticancer compounds.

Lung cancer (LC) is the most common cancer in males. As per GLOBOCAN 2020, 8.1 % of deaths and 5.9 % of cases of LC were reported in India. Our laboratory has previously reported the significant anticancer potential of 5H-benzo[h]thiazolo[2,3-b]quinazoline analogues. In this study, we have explored the anticancer potential of 7A {4-(6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)phenol} and 9A {7-(4-chlorophenyl)-9-methyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline}by using in-vitro and in-vivo models of LC. In this study, we investigated the antiproliferative potential of quinazoline analogues using A549 cell line to identify the best compound of the series. The in-vitro and molecular docking studies revealed 7A and 9A compounds as potential analogues. We also performed acute toxicity study to determine the dose. After that, in-vivo studies using urethane-induced LC in male albino Wistar rats carried out further physiological, biochemical, and morphological evaluation (SEM and H&E) of the lung tissue. We have also evaluated the antioxidant level, inflammatory, and apoptotic marker expressions. 7A and 9A did not demonstrate any signs of acute toxicity. Animals treated with urethane showed a significant upregulation of oxidative stress. However, treatment with 7A and 9A restored antioxidant markers near-normal levels. SEM and H&E staining of the lung tissue demonstrated recovered architecture after treatment with 7A and 9A. Both analogues significantly restore inflammatory markers to normal level and upregulate the intrinsic apoptosis protein expression in the lung tissue. These experimental findings demonstrated the antiproliferative potential of the synthetic analogues 7A and 9A, potentially due to their anti-inflammatory and apoptotic properties.

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations.

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

A Unique Case of Eight Fetuses in a Single Fetu.

Fetus in fetu is a rare congenital anomaly in which a malformed parasitic twin is found within the body of a living child or adult. In this case report, a 1-day-old child presented with a large firm abdominal mass on the left side of the upper abdomen. Imaging studies misdiagnosed the mass as an intraperitoneal benign dermoid cyst displacing the bowel loops and internal viscera. A surgical resection was performed on 21 days of life, and pathology confirmed eight fetuses inside the cyst.

MOSARIX: Multi-crystal spectrometer in the tender x-ray range at SOLEIL synchrotron.

We have built and commissioned a novel standalone multi-crystal x-ray spectrometer (MOSARIX) in the von Hamos configuration based on highly annealed pyrolytic graphite crystals. The spectrometer is optimized for the energy range of 2-5 keV, but this range can be extended up to 20 keV by using higher reflection orders. With its nine crystals and a Pilatus detector, MOSARIX achieves exceptional detection efficiency with good resolving power (better than 4000), opening the door to study small cross section phenomena and perform fast in situ measurements. The spectrometer operates under a He atmosphere, which provides a flexible sample environment for measurements in gas, liquid, and solid phases.

Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike.

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding domain of spike protein. In contrast, whether antigenic drift occurs in the S2 domain remains largely elusive. Here, we perform a deep mutational scanning experiment to identify S2 mutations that affect binding of SARS-CoV-2 spike to three S2 apex public antibodies. Our results indicate that spatially diverse mutations, including D950N and Q954H, which are observed in Delta and Omicron variants, respectively, weaken the binding of spike to these antibodies. Although S2 apex antibodies are known to be nonneutralizing, we show that they confer protection in vivo through Fc-mediated effector functions. Overall, this study indicates that the S2 domain of SARS-CoV-2 spike can undergo antigenic drift, which represents a potential challenge for the development of more universal coronavirus vaccines.

CRISPR and Gene Editing: A Game-changer in Drug Development.

CRISPR and gene editing technologies have emerged as transformative tools in medicine, offering unprecedented precision in targeting genetic disorders and revolutionizing drug development. This review explores the multifaceted impact of CRISPR across various medical domains, from hereditary diseases to infectious diseases and cancer. The potential of CRISPR in personalized medicine, therapeutic innovation, and pandemic prevention is highlighted, along with its role in reshaping traditional drug development processes. However, alongside its promise, ethical considerations loom large, particularly regarding germline editing and equitable access to treatments. The commercialization of CRISPR poses further challenges, raising questions about affordability and healthcare equity. Collaboration among scientists, policymakers, and the public is emphasized to navigate the ethical and societal implications of CRISPR responsibly. As the field advances, it is essential to ensure that the benefits of CRISPR are realized while addressing potential risks and maintaining a commitment to the well-being of future generations.

A T cell-based SARS-CoV-2 spike protein vaccine provides protection without antibodies.

SARS-CoV-2 spike-based vaccines are used to control the COVID-19 pandemic. However, emerging variants have become resistant to antibody neutralization and further mutations may lead to full resistance. We tested whether T cells alone could provide protection without antibodies. We designed a T cell-based vaccine in which SARS-CoV-2 spike sequences were rearranged and attached to ubiquitin. Immunization of mice with the vaccine induced no specific antibodies, but strong specific T cell responses. We challenged mice with SARS-CoV-2 wild-type strain or an Omicron variant after the immunization and monitored survival or viral titers in the lungs. The mice were significantly protected against death and weight loss caused by the SARS-CoV-2 wild-type strain, and the viral titers in the lungs of mice challenged with the SARS-CoV-2 wild-type strain or the Omicron variant were significantly reduced. Importantly, depletion of CD4+ or CD8+ T cells led to significant loss of the protection. Our analyses of spike protein sequences of the variants indicated that fewer than one-third presented by dominant HLA alleles were mutated and that most of the mutated epitopes were in the subunit 1 region. As the subunit 2 region is conservative, the vaccines targeting spike protein are expected to protect against future variants due to the T cell responses.

Innovative Strategies to Enhance mRNA Vaccine Delivery and Effectiveness: Mechanisms and Future Outlook.

The creation of mRNA vaccines has transformed the area of vaccination and allowed for the production of COVID-19 vaccines with previously unheard-of speed and effectiveness. The development of novel strategies to enhance the delivery and efficiency of mRNA vaccines has been motivated by the ongoing constraints of the present mRNA vaccine delivery systems. In this context, intriguing methods to get beyond these restrictions include lipid nanoparticles, self-amplifying RNA, electroporation, microneedles, and cell-targeted administration. These innovative methods could increase the effectiveness, safety, and use of mRNA vaccines, making them more efficient, effective, and broadly available. Additionally, mRNA technology may have numerous and far-reaching uses in the field of medicine, opening up fresh avenues for the diagnosis and treatment of disease. This paper gives an overview of the existing drawbacks of mRNA vaccine delivery techniques, the creative solutions created to address these drawbacks, and their prospective public health implications. The development of mRNA vaccines for illnesses other than infectious diseases and creating scalable and affordable manufacturing processes are some of the future directions for research in this area that are covered in this paper.

BREATH-Net: a novel deep learning framework for NO2 prediction using bi-directional encoder with transformer.

Air pollution poses a significant challenge in numerous urban regions, negatively affecting human well-being. Nitrogen dioxide (NO2) is a prevalent atmospheric pollutant that can potentially exacerbate respiratory ailments and cardiovascular disorders and contribute to cancer development. The present study introduces a novel approach for monitoring and predicting Delhi's nitrogen dioxide concentrations by leveraging satellite data and ground data from the Sentinel 5P satellite and monitoring stations. The research gathers satellite and monitoring data over 3 years for evaluation. Exploratory data analysis (EDA) methods are employed to comprehensively understand the data and discern any discernible patterns and trends in nitrogen dioxide levels. The data subsequently undergoes pre-processing and scaling utilizing appropriate techniques, such as MinMaxScaler, to optimize the model's performance. The proposed forecasting model uses a hybrid architecture of the Transformer and BiLSTM models called BREATH-Net. BiLSTM models exhibit a strong aptitude for effectively managing sequential data by adeptly capturing dependencies in both the forward and backward directions. Conversely, transformers excel in capturing extensive relationships over extended distances in temporal data. The results of this study will illustrate the proposed model's efficacy in predicting the levels of NO2 in Delhi. If effectively executed, this model can significantly enhance strategies for controlling urban air quality. The findings of this research show a significant improvement of RMSE = 9.06 compared to other state-of-the-art models. This study's primary objective is to contribute to mitigating respiratory health issues resulting from air pollution through satellite data and deep learning methodologies.

In silico and structural investigation of sulfonamides targeting VraSR two component system in methicillin-resistant Staphylococcus aureus.

Drug-resistant Staphylococcus aureus strains are global health concerns. Several studies have shown that these strains can develop defences against cell wall antibiotics such as ß-lactams, glycopeptides and daptomycin which target cell wall biosynthesis. The coordination of these responses have been associated with two component system (TCS) regulated by histidine kinase protein (VraS) and its cognate regulator VraR which influences the target DNA upon signal recognition. Computer-based screening methods, predictions and simulations have emerged as more efficient and quick ways to identify promising new compound leads from large databases against emerging drug targets thus allowing prediction of small select set of molecules for further validations. These combined approaches conserve valuable time and resources. Due to methicillin resistance, sulfonamide-derivative medications have been found to be effective treatment strategy to treat S. aureus infections. The current study used ligand-based virtual screening (LBVS) to identify powerful sulfonamide derivative inhibitors from an antibacterial compound library against VraSR signaling components, VraS and VraR. We identified promising sulfonamide derivative [compound 5: (4-[(1-{[(3,5-Dimethoxyphenyl)Carbamoyl]Methyl}-2,4-Dioxo-1,2,3,4-Tetrahydroquinazolin-3-Yl)Methyl]-N-[(Furan-2-Yl)Methyl]Benzamide)] with reasonable binding parameters of -31.38 kJ/mol and ΔGbind score of -294.32 kJ/mol against ATP binding domain of sensor kinase VraS. We further identified four compounds N1 (PCID83276726), N3 (PCID83276757), N9 (PCID3672584), and N10 (PCID20900589) against VraR DNA binding domain (VraRC) with ΔGbind energies of -190.27, -237.54, -165.21, and -190.88 kJ/mol, respectively. Structural and simulation analyses further suggest their stable interactions with DNA interacting residues and potential to disrupt DNA binding domain dimerization; therefore, it is prudent to further investigate and characterize them as VraR dimer disruptors and inhibit other promoter binding site. Interestingly, the discovery of drugs that target VraS and VraR may open new therapeutic avenues for drug-resistant S. aureus. These predictions based on screening, simulations and binding affinities against VraSR components hold promise for opening novel therapeutic avenues against drug-resistant S. aureus and present opportunities for repositioning efforts. These efforts aim to create analogs with enhanced potency and selectivity against two-component signaling systems that significantly contribute to virulence in MRSA or VRSA. These analyses contribute valuable insights into potential avenues for combating antibiotic-resistant S. aureus through computationally driven drug discovery strategies.Communicated by Ramaswamy H. Sarma.

Neurocognitive Functions After 6-Month Buprenorphine (Naloxone)-Based Opioid Agonist Maintenance Treatment: A Controlled Prospective Study.

BACKGROUND: Medications for opioid use disorder (OUD) may influence neurocognitive functions. Inadequate power, confounders, and practice effects limit the validity of the existing research. We examined the change in cognitive functions in patients with OUD at 6-month buprenorphine (naloxone) posttreatment and compared the cognitive performance of the buprenorphine-treated group with control subjects. METHODS: We recruited 498 patients with OUD within a week of initiating buprenorphine. Assessments were done twice-at baseline and 6 months. Those abstinent from illicit opioids and adherent to treatment (n = 199) underwent follow-up assessments. Ninety-eight non-substance-using control subjects were recruited from the community. The neurocognitive assessments comprised the Wisconsin Card Sorting Test, Iowa Gambling Task, Trail-Making Tests A and B (TMT-A and TMT-B), and verbal and visual N-Back Test. We controlled for potential effect modifiers. RESULTS: Twenty-five of the 32 test parameters significantly improved with 6 months of buprenorphine treatment; 20 parameters withstood corrections for multiple comparisons (P < 0.001). The improved test domains spread across cognitive tests: Wisconsin Card Sorting Test (perseverative errors and response, categories completed, conceptual responses), TMTs (time to complete), verbal and visual N-Back Tests (hits, omission, and total errors). After treatment, OUD (vs control subjects) had less perseverative response and error (P < 0.001) and higher conceptual response (P = 0.004) and took lesser time to complete TMT-A (P < 0.001) and TMT-B (P = 0.005). The baseline neurocognitive functions did not differ between those who retained and those who discontinued the treatment. CONCLUSION: Cognitive functions improve in patients with OUD on buprenorphine. This improvement is unlikely to be accounted for by the practice effect, selective attrition, and potential confounders.