Synthesis and Biological Evaluation of Amino Acid and Peptide Conjugates of 5-Bromovaleric Acid.

BACKGROUND: Among various carboxylic acid derivatives, valeric acid or pentanoic acid is found to be widely distributed in nature. It is a straight-chain alkyl carboxylic acid containing five carbon atoms. Due to the therapeutic value of valeric acid, it is used as a versatile nucleus in the pharmaceutical field. Valeric acid derivatives are associated with a broad spectrum of biological activities, like anticonvulsant, antiplatelet, antidiabetic, and plant growth activities. AIM: It has previously been revealed that peptide derivatives of carboxylic acids are accountable for enhanced antimicrobial activity. Therefore, it was hypothesized that coupling peptides with valeric acid would increase the antimicrobial properties of the target compounds. So, the objective of the present study was to synthesize peptide derivatives of 5-bromovaleric acid and evaluate their antibacterial and antifungal activities. METHODS: 5-bromovaleric acid was synthesized by the reaction of cyclopentanone and hydrogen peroxide in the presence of copper bromide and sodium bromide. Additionally, 5-bromovaleric acid was coupled with amino acid methyl esters, dipeptides, tripeptides, and tetrapeptides in the presence of dicyclohexylcarbodimide (DCC) and N-methylmorpholine (NMM) as a base under continuous stirring for 36 hours to produce its peptide derivatives. RESULTS: The results obtained showed that 5-bromovaleric acid possesses more potent antibacterial activity than N-terminal 5-bromovaleric acid conjugates of selected di-, tri, and tetra peptide Cterminal methyl esters against ciprofloxacin as a standard. The selected dipeptide and tripeptide Nterminal 5-bromovaleric acid-conjugated C-terminal methyl ester derivatives were more active than the selected tetrapeptide methyl ester analogue. Using fluconazole as a reference, the antifungal efficacy of 5-bromovaleric acid against C. albicans and A. niger declined as it was combined with C-terminal methyl esters of selected dipeptides, tripeptides, and tetrapeptides. CONCLUSION: The novel selected peptide derivatives had less antibacterial and antifungal action than the parent 5-bromovaleric acid. Antibacterial and antifungal investigations showed that 5- bromopentanoic acid peptide derivatives might impair antimicrobial efficacy. Further, attaching 5- bromopentanoic acid to di, tri, and tetra peptides did not boost their antibacterial potential.

Mammalian cell expressed recombinant trimeric spike protein is a potent vaccine antigen and confers near-complete protection against SARS-CoV-2 infection in Hamster.

Numerous vaccine candidates have emerged in the fight against SARS-CoV-2, yet the challenges posed by viral evolution and the evasion of vaccine-induced immunity persist. The development of broadly protective vaccines is essential in countering the threat posed by variants of concern (VoC) capable of eluding existing vaccine defenses. Among the diverse SARS-CoV-2 vaccine candidates, detailed characterization of those based on the expression of the entire spike protein in mammalian cells have been limited. In our study, we engineered a recombinant prefusion-stabilized trimeric spike protein antigen, IMT-CVAX, encoded by the IMT-C20 gene. This antigen was expressed utilizing a suspension mammalian cell line (CHO-S). The establishment of a stable cell line expressing IMT-CVAX involved the integration of the gene into the CHO genome, followed by the expression, purification, and characterization of the protein. To gauge the vaccine potential of adjuvanted IMT-CVAX, we conducted assessments in small animals. Analyses of blood collected from immunized animals included measurements of anti-spike IgG, SARS-CoV-2 neutralization, and responses from GC-B and Tfh cells. Furthermore, the protective efficacy of IMT-CVAX was evaluated using a Hamster challenge model. Our findings indicate that adjuvanted IMT-CVAX elicits an excellent immune response in both mice and hamsters. Notably, sera from animals immunized with IMT-CVAX effectively neutralize a diverse range of SARS-CoV-2 variants. Moreover, IMT-CVAX immunization conferred complete protection to hamsters against SARS-CoV-2 infection. In hACE2 transgenic mice, IMT-CVAX vaccination induced a robust response from GC-B and Tfh cells. Based on our preclinical model assessments, adjuvanted IMT-CVAX emerges as a highly efficacious vaccine candidate. This protein-subunit-based vaccine exhibits promise for clinical development, offering an affordable solution for both primary and heterologous immunization against SARS-CoV-2 variants.

Tailored Engineering of Layered Double Hydroxide Catalysts for Biomass Valorization: A Way Towards Waste to Wealth.

Layered double hydroxides (LDH) have significant attention in recent times due to their unique characteristic properties, including layered structure, variable compositions, tunable acidity and basicity, memory effect, and their ability to transform into various kinds of catalysts, which make them desirable for various types of catalytic applications, such as electrocatalysis, photocatalysis, and thermocatalysis. In addition, the upcycling of lignocellulose biomass and its derived compounds has emerged as a promising strategy for the synthesis of valuable products and fine chemicals. The current review focuses on recent advancements in LDH-based catalysts for biomass conversion reactions. Specifically, this review highlights the structural features and advantages of LDH and LDH-derived catalysts for biomass conversion reactions, followed by a detailed summary of the different synthesis methods and different strategies used to tailor their properties. Subsequently, LDH-based catalysts for hydrogenation, oxidation, coupling, and isomerization reactions of biomass-derived molecules are critically summarized in a very detailed manner. The review concludes with a discussion on future research directions in this field which anticipates that further exploration of LDH-based catalysts and integration of cutting-edge technologies into biomass conversion reactions hold promise for addressing future energy challenges, potentially leading to a carbon-neutral or carbon-positive future.

Spontaneous Pneumothorax, Pneumomediastinum, and Pneumopericardium in an HIV Patient With Tuberculosis: A Rare Trio.

A trio of spontaneous pneumomediastinum, pneumopericardium, and pneumothorax is a highly unusual presentation. The majority of reported cases are due to trauma, while the remaining cases are iatrogenic. Among infections, this trio has so far been reported in COVID-19 pneumonia and pneumocystis pneumonia in HIV-positive patients. There are case reports on pneumothorax and pneumomediastinum in tuberculosis, but the trio is not reported. Here, we present a case of a recently diagnosed HIV-positive patient with complaints of cough and shortness of breath whose initial workup was negative for Mycobacterium. The patient was, however, started on antitubercular drugs based on clinical radiological evidence. He developed spontaneous pneumothorax, pneumomediastinum, and pneumopericardium, and repeat bronchoalveolar lavage (BAL) came positive for Mycobacterium. The patient, however, could not be revived and succumbed to obstructive and septic shock.

Cell-Permeable Fluorescent Sensors Enable Rapid Live Cell Visualization of Plasma Membrane and Nuclear PIP3 Pools.

Phosphoinositides, phospholipids that are key cell-signal mediators, are present at very low levels in cellular membranes and within nuclei. Phosphatidylinositol-(3,4,5)-trisphosphate (PIP3), a phosphoinositide barely present in resting cell membranes, is produced when cells receive either growth, proliferation, or movement signals. Aberrant PIP3 levels are associated with the formation of cancers. PIP3 pools are also present in the nucleus, specifically in the nucleolus. However, questions related to the organization and function of this lipid in such membraneless intranuclear structures remain unanswered. Therefore, chemical sensors for tracking cellular PIP3 are invaluable not only for timing signal initiation in membranes but also for identifying the organization and function of membraneless nuclear PIP3 pools. Because PIP3 is present in the inner leaflet of cell membranes and in the nucleus, cell-permeable, rapid-response fluorescent sensors would be ideal. We have designed two peptide-based, water-soluble, cell-permeable, ratiometric PIP3 sensors named as MFR-K17H and DAN-NG-H12G. MFR-K17H rapidly entered into the cell cytoplasm, distinctly reporting rapid (<1 min) time scales of growth factor-stimulated PIP3 generation and depletion within cell membranes in living cells. Importantly, MFR-K17H lighted up inherently high levels of PIP3 in triple-negative breast cancer cell membranes, implying future applications in the detection of enhanced PIP3 levels in cancerous cells. On the other hand, DAN-NG-H12G targeted intranuclear PIP3 pools, revealing that within membraneless structures, PIP3 resided in a hydrophobic environment. Together, both probes form a unique orthogonally targeted combination of cell-permeable, ratiometric probes that, unlike previous cell-impermeable protein-based sensors, are easy to apply and provide an unprecedented handle into PIP3-mediated cellular processes.

Supraglottic Myxedema Presenting as a Complication of Hypothyroidism: A Case Report.

Myxedema is a medical emergency with high mortality rates if not treated aggressively. Here, we present a middle-aged female with complaints of generalized body swelling for one year, shortness of breath, hoarseness of voice, neck swelling, and cough for 20 days. The patient was diagnosed to be having severe hypothyroidism with polyserositis. Contrast-enhanced computed tomography (CECT) of the neck and thorax revealed extensive soft tissue edema causing airway narrowing, bilateral pleural effusion, moderate pericardial effusion, and features of atypical pneumonia. The patient was started on levothyroxine and antibiotics as per cultures to which she had initially improved; however, she developed ventilator-associated pneumonia leading to sepsis, acute respiratory distress syndrome followed by refractory type 1 respiratory failure and succumbed.

Continuous emission monitoring systems (CEMS) in India: Performance evaluation, policy gaps and financial implications for effective air pollution control.

Continuous Emission Monitoring Systems (CEMS) are devices used to measure and report real-time emission of air pollutants. Although CEMS have been extensively deployed in developed countries to ensure compliance with emission standards and enhance their environmental performance, their adoption in India is still in its early stages. The present study aims to evaluate the effectiveness of CEMS in India, identify obstacles in terms of policy, regulation, technology and finance that impede their adoption and suggest mechanisms and incentives to facilitate their expansion. The findings indicate that CEMS offer benefits for air pollution control in India by improving monitoring accuracy, transparency, accountability and enforcement. The study also highlights institutional challenges faced by CEMS, including the absence of a certification system, lack of quality assurance measures, issues with data validation and challenges in its calibration as well as integration concerns with existing regulatory framework. To address these challenges effectively it is recommended that India must develop a policy framework for CEMS along with regulations. Essential steps such as establishing a certification and accreditation system should be taken while enhancing stakeholders' capacity and awareness.

Barriers to Completing Preoperative Hair Removal for Penile Inversion Vaginoplasty.

Penile inversion vaginoplasty (PIV) is a gender-affirming surgical procedure where the skin of the penis and scrotum is reconstructed into the neovaginal lining. To prevent hair-bearing skin from becoming incorporated into the neovaginal canal, transgender patients are encouraged to undergo hair removal of their external genitalia. The goal of this preoperative hair removal is to minimize the risk of potential hair-related complications after vaginoplasty. To better support patients seeking preoperative hair removal and identify current treatment barriers, we surveyed patients about their progress and satisfaction with hair removal. A cross-sectional survey was constructed to assess patient experiences with hair removal in advance of PIV. Sixty-seven patients met the inclusion criteria, of which 46 participated (68.7%). Both laser hair removal (LHR) and electrolysis were used. Although all patients had completed some preoperative hair removal at the time of survey (average of 14 sessions), the cohort completed only two-thirds of their total expected hair clearance. Multiple peri-procedural pain management therapies were employed, but overall satisfaction with pain management was low (57.4 ± 5.0 out of 100). LHR was associated with significantly lower procedural pain compared to electrolysis (p < .001). The average global satisfaction with the hair removal process was 57.9 ± 5.7 and incidents of mistreatment were associated with a statistically significant reduction in overall satisfaction (p = .02). Most patients felt that hair removal was important prior to surgery. Overall, LHR and electrolysis were both utilized as effective preoperative hair removal modalities; however, LHR has better pain tolerability than electrolysis.

Burkholderia-associated polymyositis.

A diagnosis of polymyositis can readily be made when there is a typical history of proximal muscle weakness together with clinical findings, and there is corroboratory evidence in the form of elevated creatine kinase lactate dehydrogenase, aldolase, and serum glutamic-oxaloacetic transaminase (aspartate aminotransferase). A muscle biopsy usually helps in making the confirmatory diagnosis. A female in her 50s presented with non-healing multiple deep necrotic ulcers with muscle weakness. The initial possibility of vasculitis ulcers remained. Later, this proved to be a case of polymyositis with mildly elevated creatine kinase (which is usually not the case), atypical skin manifestations (usually there is no skin involvement), and negative extended myositis specific antibody panel with the growth of Burkholderia cepacia (perhaps the triggering factor). Hence, polymyositis can present with a myriad of atypical findings. Thus, thorough clinical examination and an integrated approach are necessary for early identification and treatment of the disease.

Interfacial nanoarchitectonics of nickel phosphide supported on activated carbon for transfer hydrogenation of nitroarenes under mild conditions.

Metal phosphides are promising catalysts for hydrogenation reactions due to their unique ability to generate active hydrogen species which are essential for desired reactions. In this work, the hydrogenation potential of nickel phosphide (Ni2P) is explored for the transfer hydrogenation of aromatic nitro compounds using hydrazine hydrate as hydrogen source. The Ni2P was supported on activated carbon (AC) to facilitate highly exposed active reaction sites. The as-synthesized Ni2P-AC catalyst showed excellent catalytic potential for the hydrogenation of nitro compounds to corresponding amines with 100% conversion efficiency and resulted in excellent yields. The reaction conditions were optimized by varying different reaction parameters, such as time, temperature, solvents, catalyst amount and hydrogen sources. The developed reaction protocol is highly selective for nitro compounds having reduction susceptible functional groups like -Cl, -Br, -CHO, etc. The structure-activity relationship of the Ni2P-AC was also examined which suggested that both acidic and basic sites present in Ni2P-AC catalyst plays crucial role in hydrogenation reaction. Besides, an in-depth insight into the reaction mechanism illustrates that the reaction proceeds via N-phenyl hydroxylamine as the reaction intermediate. In addition, decent recyclability and stability of Ni2P-AC catalyst demonstrates its highly versatile nature for potential large-scale applications. The use of highly efficient Ni2P-AC catalyst for hydrogenation reactions can lead the way towards sustainable and effective industrial organic catalysis.

Enhancing Immunogenicity of a Thermostable, Efficacious SARS-CoV-2 Vaccine Formulation through Oligomerization and Adjuvant Choice.

Currently deployed SARS-CoV-2 vaccines all require storage at refrigerated or sub-zero temperatures. We demonstrate that after month-long incubation at 37 °C, solubilization, and formulation with squalene-in-water emulsion adjuvant, a stabilized receptor binding domain retains immunogenicity and protective efficacy. We also examine the effects of trimerization of the stabilized RBD, as well as of additional adjuvants, on both B and T-cell responses. The additional emulsion or liposome-based adjuvants contained a synthetic TLR-4 ligand and/or the saponin QS-21. Trimerization enhanced immunogenicity, with significant antibody titers detectable after a single immunization. Saponin-containing adjuvants elicited enhanced immunogenicity relative to both emulsion and aluminum hydroxide adjuvanted formulations lacking these immunostimulants. Trimeric RBD formulated with liposomal based adjuvant containing both TLR-4 ligand and saponin elicited a strongly Th1 biased response, with ~10-fold higher neutralization titers than the corresponding aluminum hydroxide adjuvanted formulation. The SARS-CoV-2 virus is now endemic in humans, and it is likely that periodic updating of vaccine formulations in response to viral evolution will continue to be required to protect vulnerable individuals. In this context, it is desirable to have efficacious, thermostable vaccine formulations to facilitate widespread vaccine coverage, including in low- and middle-income countries, where global access rights to clinically de-risked adjuvants will be important moving forward.

A Recent Advance on Phytochemicals, Nutraceutical and Pharmacological Activities of Buckwheat.

Buckwheat, a member of the Fagopyrum genus in the Polygonaceae family, is an ancient pseudocereal with noteworthy nutraceutical properties that have been relatively less explored. This crop holds great promise for the future due to its gluten-free protein, wellbalanced amino acid profile, and the presence of bioactive flavonoids that promote good health. With its gluten-free nature and a combination of beneficial nutritional components, buckwheat shows significant potential for a variety of health benefits. The objective of the present review aims to explore various nutritional and pharmacological properties of buckwheat. With the help of various search engines Pubmed, Google and Semantic Scholar, research and review papers. Data were analyzed and summarized in a comprehensive review. A fascinating spectrum of nutritional and pharmacological activities of common buckwheat and Tartary buckwheat were explored such as antidiabetic, anti-inflammatory, neurological disorders, antiobesity, anticancer, cardiovascular agents and many more. This review provides a concise overview of the current understanding of the chemical composition of both common buckwheat and Tartary buckwheat and the captivating spectrum of pharmacological activity and also underscoring their immense potential for future advancements.

Enhanced protective efficacy of a thermostable RBD-S2 vaccine formulation against SARS-CoV-2 and its variants.

With the rapid emergence of variants of concern (VOC), the efficacy of currently licensed vaccines has reduced drastically. VOC mutations largely occur in the S1 subunit of Spike. The S2 subunit of SARS-CoV-2 is conserved and thus more likely to elicit broadly reactive immune responses that could improve protection. However, the contribution of the S2 subunit in improving the overall efficacy of vaccines remains unclear. Therefore, we designed, and evaluated the immunogenicity and protective potential of a stabilized SARS-CoV-2 Receptor Binding Domain (RBD) fused to a stabilized S2. Immunogens were expressed as soluble proteins with approximately fivefold higher purified yield than the Spike ectodomain and formulated along with Squalene-in-water emulsion (SWE) adjuvant. Immunization with S2 alone failed to elicit a neutralizing immune response, but significantly reduced lung viral titers in mice challenged with the heterologous Beta variant. In hamsters, SWE-formulated RS2 (a genetic fusion of stabilized RBD with S2) showed enhanced immunogenicity and efficacy relative to corresponding RBD and Spike formulations. Despite being based on the ancestral Wuhan strain of SARS-CoV-2, RS2 elicited broad neutralization, including against Omicron variants (BA.1, BA.5 and BF.7), and the clade 1a WIV-1 and SARS-CoV-1 strains. RS2 elicited sera showed enhanced competition with both S2 directed and RBD Class 4 directed broadly neutralizing antibodies, relative to RBD and Spike elicited sera. When lyophilized, RS2 retained antigenicity and immunogenicity even after incubation at 37 °C for a month. The data collectively suggest that the RS2 immunogen is a promising modality to combat SARS-CoV-2 variants.

Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity, and neutralization sensitivity.

IMPORTANCE: The Omicron subvariants have substantially evaded host-neutralizing antibodies and adopted an endosomal route of entry. The virus has acquired several mutations in the receptor binding domain and N-terminal domain of S1 subunit, but remarkably, also incorporated mutations in S2 which are fixed in Omicron sub-lineage. Here, we found that the mutations in the S2 subunit affect the structural and biological properties such as neutralization escape, entry route, fusogenicity, and protease requirement. In vivo, these mutations may have significant roles in tropism and replication. A detailed understanding of the effects of S2 mutations on Spike function, immune evasion, and viral entry would inform the vaccine design, as well as therapeutic interventions aiming to block the essential proteases for virus entry. Thus, our study has identified the crucial role of S2 mutations in stabilizing the Omicron spike and modulating neutralization resistance to antibodies targeting the S1 subunit.

Beneath the Layers: Deciphering the Molecular Pathways, Therapeutic Avenues, and Neurological Connections of Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are a heterogeneous group of malignancies that have long posed challenges in terms of diagnosis, treatment, and management. This narrative review provides a comprehensive exploration into the multifaceted realm of STS, spanning from its historical origins to the latest advancements in research and clinical care. We delve into the molecular intricacies of STS, highlighting the genetic and epigenetic aberrations that drive these tumors. The review emphasizes the neurological implications of STS, a relatively underexplored area, shedding light on the interplay between tumor biology and neural processes. The evolving therapeutic landscape is discussed, with a focus on the promise of targeted therapies, immunotherapy, and precision medicine. A significant portion is dedicated to the patient-centric approach, underscoring the importance of holistic care that addresses both the physical and psychological needs of STS patients. Furthermore, we highlight the gaps in current research and clinical practices, offering insights into potential avenues for future exploration. This review serves as a valuable resource for clinicians, researchers, and the broader scientific community, encapsulating the current state of STS knowledge and pointing toward future directions in this dynamic field.

Very high particulate pollution over northwest India captured by a high-density in situ sensor network.

Exposure to particulate matter less than 2.5 µm in diameter (PM2.5) is a cause of concern in cities and major emission regions of northern India. An intensive field campaign involving the states of Punjab, Haryana and Delhi national capital region (NCR) was conducted in 2022 using 29 Compact and Useful PM2.5 Instrument with Gas sensors (CUPI-Gs). Continuous observations show that the PM2.5 in the region increased gradually from < 60 µg m-3 in 6-10 October to up to 500 µg m-3 on 5-9 November, which subsequently decreased to about 100 µg m-3 in 20-30 November. Two distinct plumes of PM2.5 over 500 µg m-3 are tracked from crop residue burning in Punjab to Delhi NCR on 2-3 November and 10-11 November with delays of 1 and 3 days, respectively. Experimental campaign demonstrates the advantages of source region observations to link agricultural waste burning and air pollution at local to regional scales.

Schistosoma japonicum Associated Colorectal Cancer and Its Management.

BACKGROUND: An association between Schistosoma japonicum and colorectal cancer in humans has been known since a long time; however, this association remains understudied and lacks comprehensive experimentation support. OBJECTIVE: Various epidemiological and pathological studies have established the role of chronic inflammation as a major factor behind the induction of colorectal cancer. The aim of this review is to present the current knowledge on the association of Schistosoma japonicum with colorectal cancer. RESULT: Mechanisms which lead to induction and progression of colorectal cancer are highlighted along with diagnosis and treatment for the same. Further, various methodologies, including mass drug administration, use of new drugs and vaccines, role of apoptosis, and histone-modifying enzymes, have been described which can either prevent the schistosomal infection itself or can check it from reaching an advanced stage. CONCLUSIONS: Epidemiological, clinical, pathological and surgical studies suggest that Schistosoma japonicum is responsible for induction of colorectal cancer. However, thorough clinical studies are required to support and globally accept this notion. Further, methodologies highlighted in this work can be employed in order to take care of schistosomal infection or address the cancer induction and progression.