The DNA repair pathway as a therapeutic target to synergize with trastuzumab deruxtecan in HER2-targeted antibody-drug conjugate-resistant HER2-overexpressing breast cancer.

BACKGROUND: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo. METHODS: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations. RESULTS: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents. CONCLUSIONS: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.

Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer.

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. Cleavage of full-length cyclin E (FL-cycE) to low molecular weight isoforms (LMW-E) dramatically alters the substrate specificity, promoting G1/S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. Here, analysis of TNBC patient tumor samples revealed that co-expression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared to FL-cycE, LMW-E specifically upregulated PKMYT1 expression and protein stability, elevating CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breaks, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and LMW-E-high TNBC patient-derived xenografts but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

Any better? A follow-up content analysis of adolescent sexual and reproductive health inclusion in Global Financing Facility country planning documents.

BACKGROUND: The Global Financing Facility (GFF) supports national reproductive, maternal, newborn, child, adolescent health, and nutrition needs. Previous analysis examined how adolescent sexual and reproductive health was represented in GFF national planning documents for 11 GFF partner countries. OBJECTIVES: This paper furthers that analysis for 16 GFF partner countries as part of a Special Series. METHODS: Content analysis was conducted on publicly available GFF planning documents for Afghanistan, Burkina Faso, Cambodia, CAR, Côte d'Ivoire, Guinea, Haiti, Indonesia, Madagascar, Malawi, Mali, Rwanda, Senegal, Sierra Leone, Tajikistan, Vietnam. Analysis considered adolescent health content (mindset), indicators (measure) and funding (money) relative to adolescent sexual and reproductive health needs, using a tracer indicator. RESULTS: Countries with higher rates of adolescent pregnancy had more content relating to adolescent reproductive health, with exceptions in fragile contexts. Investment cases had more adolescent content than project appraisal documents. Content gradually weakened from mindset to measures to money. Related conditions, such as fistula, abortion, and mental health, were insufficiently addressed. Documents from Burkina Faso and Malawi demonstrated it is possible to include adolescent programming even within a context of shifting or selective priorities. CONCLUSION: Tracing prioritisation and translation of commitments into plans provides a foundation for discussing global funding for adolescents. We highlight positive aspects of programming and areas for strengthening and suggest broadening the perspective of adolescent health beyond the reproductive health to encompass issues, such as mental health. This paper forms part of a growing body of accountability literature, supporting advocacy work for adolescent programming and funding.

Main findings: Adolescent health content is inconsistently included in the Global Financing Facility country documents, and despite strong or positive examples, the content is stronger in investment cases than project appraisal documents, and diminishes when comparing content, indicators and financing.Added knowledge: Although adolescent health content is generally strongest in countries with the highest proportion of births before age 18, there are exceptions in fragile contexts and gaps in addressing important issues related to adolescent health.Global health impact for policy and action: Adolescent health programming supported by the Global Financing Facility should build on examples of strong country plans, be more consistent in addressing adolescent health, and be accompanied by public transparency to facilitate accountability work such as this.

A rare case of acantholytic squamous cell carcinoma presenting on non-sun exposed palpebral conjunctiva.

Purpose: This report describes the clinical and histological characteristics and management of a keratinized lesion of the palpebral conjunctiva in a 59-year-old male. The lesion was identified as a rare acantholytic variant of squamous cell carcinoma that atypically arose from a non-sun exposed region of palpebral conjunctiva. Management was complete excision via Mohs surgery. Observations: A 59-year-old male presented with ocular irritation and chronic foreign body sensation in the right eye. Exam revealed a keratinized lesion in the right lower tarsal conjunctiva, and an initial shave biopsy was non-diagnostic. 12 months later, the patient presented with similar symptoms and a larger, more irregular lesion for which histopathology of a tarsal-involving excisional biopsy was consistent with acantholytic squamous cell carcinoma with involved margins. The patient subsequently underwent complete excision via Mohs surgery and a secondary reconstruction. Conclusions and importance: Acantholytic variants of squamous cell carcinoma are rare and are described as arising from areas with routine sun exposure. This case reports such a lesion arising from non-sun exposed tarsal conjunctiva, as identified by histopathology of a full-thickness excisional biopsy. The lesion was successfully managed with complete excision via Mohs surgery and secondary reconstruction. Given that this histologic variant may be more aggressive and have higher rates of recurrence than other forms of squamous cell carcinoma, this case highlights the importance of complete excisional biopsy and accurate histopathology of concerning periocular lesions and offers a template for management of similar lesions. The unique presenting location should bring awareness to consideration of this type of malignancy developing on palpebral conjunctiva.

Long-term follow-up of kidney transplant recipients admitted to a tertiary care transplant center with SARS-CoV-2.

BACKGROUND: Kidney transplant recipients (KTR) are at risk of severe coronavirus disease 2019 (COVID-19) disease and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We predicted that hospitalization for COVID-19 and subsequent admission to the intensive care unit (ICU) would yield worse outcomes in KTRs. AIM: To investigate outcomes among KTRs hospitalized at our high-volume transplant center either on the general hospital floor or the ICU. METHODS: We retrospectively describe all adult KTRs who were hospitalized at our center with their first SARS-CoV-2 infection between 04/2020 and 04/2022 and had at least 12 months follow-up (unless they experienced graft failure or death). The cohort was stratified by ICU admission. Outcomes of interest included risk factors for ICU admission and mortality, length of stay (LOS), respiratory symptoms at admission, all-cause graft failure at the last follow-up, and death related to COVID-19. RESULTS: 96 KTRs were hospitalized for SARS-COV-2 infection. 21 (22%) required ICU admission. The ICU group had longer hospital LOS (21.8 vs 8.6 days, P < 0.001) and were more likely to experience graft failure (81% vs 31%, P < 0.001). Of those admitted to the ICU, 76% had death at last-follow up, and 71% had death related to COVID-19. Risk factors for ICU admission included male sex (aHR: 3.11, 95%CI: 1.04-9.34; P = 0.04). Risk factors for all-cause mortality and COVID-19-related mortality included ICU admission and advanced age at SARS-CoV-2 diagnosis. Mortality was highest within a month of COVID-19 diagnosis, with the ICU group having increased risk of all-cause (aHR: 11.2, 95%CI: 5.11-24.5; P < 0.001) and COVID-19-related mortality (aHR: 27.2, 95%CI: 8.69-84.9; P < 0.001). CONCLUSION: ICU admission conferred an increased risk of mortality, graft failure, and longer LOS. One-fifth of those hospitalized died of COVID-19, reflecting the impact of COVID-19-related morbidity and mortality among KTRs.

Cinnamon essential oil induced microbial stress metabolome indicates its active food packaging efficiency when incorporated into poly vinyl alcohol, engineered with zinc oxide nanoparticles and nanocellulose.

In the study, Poly Vinyl Alcohol (PVA) films engineered with the nanoparticles and essential oils have been developed as efficient alternative to the currently used food packaging materials. For this, impact of cinnamon essential oil (CEO), on the metabolomic profile of Staphylococcus aureus, Escherichia coli and Aspergillus flavus was analysed. Subsequently, PVA based nanocomposite films CEO, zinc oxide nanoparticles (ZnONPs), and nanocellulose (NC) were synthesised and characterized by FT-IR analysis. By the GC-MS analysis. The presence of ZnONPs enhanced the release of cinnamaldehyde from 31.16 to 44.23 and further enhancement to 71.82 was seen the presence of nanocellulose. The incorporation of NPs was found to enhance the hydrodynamic and mechanical properties of the prepared films. The final developed films, PZNCCEO, showed the least values for WHC and MC which were 56.31 ±â€¯2.12 % and 13.30 ±â€¯0 % respectively. Antimicrobial efficacy could also be demonstrated through the observation on changes in the morphological features of treated S. aureus and E. coli by the FE-SEM. Finally, the developed nanocomposite film was found to have the potential for food packaging as demonstrated through the protection of corn kernals and Vigna unguiculata.

Anticancer Effects of Ethanolic Extracts of Macaranga Peltata Leaves on Human Oral Squamous Carcinoma Cell Lines: An In Vitro Study.

Cancer is a disease resulting from the disruption of cell cycle regulation, leading to the abnormal and unchecked proliferation of cells. Medicinal plants are rich in various bioactive phytochemicals or nutritional compounds. The aim is to determine the cytotoxic and genotoxic effects of ethanolic extracts of Macaranga peltata leaves on human oral cancer cell lines. The study setting was centre for Research on Molecular and Applied Sciences, Azeezia College of Dental Sciences and Research. The study design is a Comparative In Vitro study. Shade dried leaves of Macaranga peltata were subjected to Soxhlet extraction, and ethanolic extract was prepared. In vitro cytotoxic effects on human oral cancer cell lines were evaluated by (3-(4,5-dimethyl thiazole-2yl)-2,5-diphenyl tetrazolium bromide) MTT assay, and genotoxic effect was evaluated by comet assay. Untreated cell lines were used as control, and 5-fluorouracil was used as positive control. All experiments were performed in triplicates, and results were represented as Mean+/- SE. One-way ANOVA and Dunnet test were performed to analyze data. ***P < 0.001 compared with the control group. The ethanolic extract of Macaranga peltata exhibited cytotoxicity against oral cancer cells (LC50: 40.193089 µg/ml). There was a concentration-dependent increase in cell death, and at 100 µg/ml, the extract was most effective, causing 50% inhibition of viability. The comet assay showed significant genotoxic effects compared with 5-fluorouracil and untreated oral cancer cell lines. The ethanolic extract of Macaranga peltata leaves was subjected to MTT assay and comet using KB cell lines. The study concludes that the extract gave promising result for the anticancer activity on the KB cell lines producing cytotoxicity and genotoxicity.

Form and functioning: contextualising the start of the global financing facility policy processes in Burkina Faso.

BACKGROUND: Burkina Faso joined the Global Financing Facility for Women, Children and Adolescents (GFF) in 2017 to address persistent gaps in funding for reproductive, maternal, newborn, child, and adolescent health and nutrition (RMNCAH-N). Few empirical papers deal with how global funding mechanisms, and specifically GFF, support resource mobilisation for health nationally. OBJECTIVE: This study describes the policy processes of developing the GFF planning documents (the Investment Case and Project Appraisal Document) in Burkina Faso. METHODS: We conducted an exploratory qualitative policy analysis. Data collection included document review (N = 74) and in-depth semi-structured interviews (N = 23). Data were analysed based on the components of the health policy triangle. RESULTS: There was strong national political support to RMNCAH-N interventions, and the process of drawing up the investment case (IC) and the project appraisal document was inclusive and multi-sectoral. Despite high-level policy commitments, subsequent implementation of the World Bank project, including the GFF contribution, was perceived by respondents as challenging, even after the project restructuring process occurred. These challenges were due to ongoing policy fragmentation for RMNCAH-N, navigation of differing procedures and perspectives between stakeholders in the setting up of the work, overcoming misunderstandings about the nature of the GFF, and weak institutional anchoring of the IC. Insecurity and political instability also contributed to observed delays and difficulties in implementing the commitments agreed upon. To tackle these issues, transformational and distributive leaderships should be promoted and made effective. CONCLUSIONS: Few studies have examined national policy processes linked to the GFF or other global health initiatives. This kind of research is needed to better understand the range of challenges in aligning donor and national priorities encountered across diverse health systems contexts. This study may stimulate others to ensure that the GFF and other global health initiatives respond to local needs and policy environments for better implementation.

Main findings: There was a high level of political commitment to the Global Financing Facility in Burkina Faso, but its implementation has been hindered by policy fragmentation, competing interests, weak institutional anchoring, and misunderstandings.Added knowledge: This study documents the initiation of a global health initiative, specifically the Global Financing Facility, including the development and implementation of its planning documents, namely the Investment Case and Project Appraisal Document.Global health impact for policy and action: An understanding of the factors that facilitated or impeded the policy processes of developing and implementing the Global Financing Facility can inform the design and implementation of future initiatives.

Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection among Kidney Transplant Recipients: A Large Single-Center Experience.

Background: Kidney transplant recipients (KTRs) are a vulnerable immunocompromised population at risk of severe COVID-19 disease and mortality after SARS-CoV-2 infection. We sought to characterize the post-infection sequelae in KTRs at our center. Methods: We studied all adult KTRs (with a functioning allograft) who had their first episode of SARS-CoV-2 infection between 04/2020 and 04/2022. Outcomes of interest included risk factors for hospitalization, all-cause mortality, COVID-19-related mortality, and allograft failure. Results: Of 979 KTRs with SARS-CoV-2 infection, 381 (39%) were hospitalized. In the multivariate analysis, risk factors for hospitalization included advanced age/year (HR: 1.03, 95% CI: 1.02-1.04), male sex (HR: 1.29, 95% CI: 1.04-1.60), non-white race (HR: 1.48, 95% CI: 1.17-1.88), and diabetes as a cause of ESKD (HR: 1.77, 95% CI: 1.41-2.21). SARS-CoV-2 Vaccination was associated with decreased risk of hospitalization (HR: 0.73, 95% CI: 0.59-0.90), all-cause mortality (HR: 0.52, 95% CI: 0.37-0.74), and COVID-19-related mortality (HR: 0.47, 95% CI: 0.31-0.71) in the univariate and multivariate analyses. Risk factors for both all-cause and COVID-19-related mortality in the multivariate analyses included advanced age, hospitalization, and respiratory symptoms for hospital admission. Furthermore, additional risk factors for all-cause mortality in the multivariate analysis included being a non-white recipient and diabetes as a cause of ESKD, with being a recipient of a living donor as protective. Conclusions: Hospitalization due to COVID-19-associated symptoms is associated with increased mortality. Vaccination is a protective factor against hospitalization and mortality.

Towards a better tomorrow: addressing intersectional gender power relations to eradicate inequities in maternal health.

An equity lens to maternal health has typically focused on assessing the differences in coverage and use of healthcare services and critical interventions. While this approach is important, we argue that healthcare experiences, dignity, rights, justice, and well-being are fundamental components of high quality and person-centred maternal healthcare that must also be considered. Looking at differences across one dimension alone does not reflect how fundamental drivers of maternal health inequities-including racism, ethnic or caste-based discrimination, and gendered power relations-operate. In this paper, we describe how using an intersectionality approach to maternal health can illuminate how power and privilege (and conversely oppression and exclusion) intersect and drive inequities. We present an intersectionality-informed analysis on antenatal care quality to illustrate the advantages of this approach, and what is lost in its absence. We reviewed and mapped equity-informed interventions in maternal health to existing literature to identify opportunities for improvement and areas for innovation. The gaps and opportunities identified were then synthesised to propose recommendations on how to apply an intersectionality lens to maternal health research, programmes, and policies.

Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response.

Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.

LSD1 Regulates Neurogenesis in Human Neural Stem Cells Through the Repression of Human-Enriched Extracellular Matrix and Cell Adhesion Genes.

Neurogenesis begins with neural stem cells undergoing symmetric proliferative divisions to expand and then switching to asymmetric differentiative divisions to generate neurons in the developing brain. Chromatin regulation plays a critical role in this switch. Histone lysine-specific demethylase LSD1 demethylates H3K4me1/2 and H3K9me1/2 but the mechanisms of its global regulatory functions in human neuronal development remain unclear. We performed genome-wide ChIP-seq of LSD1 occupancy, RNA-seq, and Histone ChIP-seq upon LSD1 inhibition to identify its repressive role in human neural stem cells. Novel downstream effectors of LSD1 were identified, including the Notch signaling pathway genes and human-neural progenitor-enriched extracellular matrix (ECM) pathway/cell adhesion genes, which were upregulated upon LSD1 inhibition. LSD1 inhibition led to decreased neurogenesis, and overexpression of downstream effectors mimicked this effect. Histone ChIP-seq analysis revealed that active and enhancer markers H3K4me2, H3K4me1, and H3K9me1 were upregulated upon LSD1 inhibition, while the repressive H3K9me2 mark remained mostly unchanged. Our work identifies the human-neural progenitor-enriched ECM pathway/cell adhesion genes and Notch signaling pathway genes as novel downstream effectors of LSD1, regulating neuronal differentiation in human neural stem cells.

Nonmeningothelial Dural-Based Lesions: A Histopathological Analysis.

Introduction We report 30 cases of nonmeningothelial dural-based lesions encountered during a 3-year study period. Materials and Methods We retrospectively reviewed pathology records of patients operated for extra-axial, dural-based lesions during the years 2016 to 2018 and included nonmeningothelial lesions as a part of this study. Results Among the 3,243 neurosurgical specimens for histopathologic examination, only 30 (0.93%) were "nonmeningothelial dural-based lesions." Six (20%) patients were in the pediatric age group. Pathologic assessment identified 13 cases of solitary fibrous tumor/hemangiopericytoma (43.3%) and 7 cases of Ewing's sarcoma/primitive neuroectodermal tumor (23.3%). Two cases (6.7%) were of metastasis. Other lesions included a single case each of non-Hodgkin's lymphoma, undifferentiated sarcoma, solitary plasmacytoma, and granulocytic sarcoma. Nonneoplastic lesions included two cases each of Rosai-Dorfman disease and nonspecific inflammatory lesions. Conclusion Nonmeningothelial dural-based lesions being rare, thorough examination of morphological features is a must by the pathologist, to arrive at the accurate diagnosis. Ancillary tests, if required, should be employed in the context of the morphologic picture.

Rapid scan white light two-dimensional electronic spectroscopy with 100 kHz shot-to-shot detection.

We demonstrate an approach to two-dimensional electronic spectroscopy (2DES) that combines the benefits of shot-to-shot detection at high-repetition rates with the simplicity of a broadband white light continuum input and conventional optical elements to generate phase-locked pump pulse pairs. We demonstrate this through mutual synchronization between the laser repetition rate, the acousto-optical deflector, the pump delay stage, and the CCD line camera, which allows for rapid scanning of pump optical delay synchronously with the laser repetition rate, while the delay stage is moved at a constant velocity. The resulting shot-to-shot detection scheme is repetition rate scalable and only limited by the CCD line rate and the maximum stage velocity. Using this approach, we demonstrate the measurement of an averaged 2DES absorptive spectrum in as much as 1.2 s of continuous sample exposure per 2D spectrum. We achieve a signal-to-noise ratio of 6.8 for optical densities down to 0.05 with 11.6 s of averaging at 100 kHz laser repetition rate. Combining rapid scanning of mechanical delay lines with shot-to-shot detection as demonstrated here provides a viable alternative to acousto-optic pulse shaping approaches that is repetition-rate scalable, has comparable throughput and sensitivity, and minimizes sample exposure per 2D spectrum with promising micro-spectroscopy applications.

Microrchidia 2/histone deacetylase 1 complex regulates E-cadherin gene expression and function.

Although Microrchidia 2 (MORC2) is widely overexpressed in human malignancies and linked to cancer cell proliferation, metabolism, and metastasis, the mechanism of action of MORC2 in cancer cell migration and invasion is yet undeciphered. Here, we identified for the first time that MORC2, a chromatin remodeler, regulates E-cadherin expression and, subsequently regulates breast cancer cell migration and invasion. We observed a negative correlation between the expression levels of MORC2 and E-cadherin in breast cancer. Furthermore, the overexpression of MORC2 resulted in decreased expression levels of E-cadherin. In addition, co-immunoprecipitation and chromatin immunoprecipitation assays revealed that MORC2 interacts with HDAC1 and gets recruited onto the E-cadherin promoter to inhibit its transcription, thereby suppress its expression. Consequently, knockdown of HDAC1 in MORC2-overexpressing cells led to reduced cancer cell migration and invasion. Interestingly, we noticed that MORC2-regulated glucose metabolism via c-Myc, and LDHA, also modulates the expression of E-cadherin. Collectively, these results demonstrate for the first time a mechanistic role for MORC2 as an upstream regulator of E-cadherin expression and its associated functions in breast cancer.

Insights on the structural characteristics and molecular dynamic studies of methyl vanillin Schiff base bio-compounds.

A new crystalline form of Schiff base, N-cyclohexyl-1-(3,4-dimethoxyphenyl)methanimine (CHADMB) was obtained from methanolic solution of cylohexylamine and (methylvanillin) 3,4dimethoxybenzaldehyde. Single crystal X-ray diffraction study reveals that the compound crystallized in monoclinic crystal system with P21/c space group having four molecules per unit cell (Z = 4). Hirshfeld surface (HS) analysis and 2D fingerprint plots reveals that weak non-covalent interactions are responsible for crystal packing. The UV-Vis spectroscopy study reveals that the optical band gap of the compound is 4.25 eV. The dielectric properties were studied as a function of frequency at room temperature and the results show that these properties can be exploited for optoelectronic applications. Thermal stability of the compound is revealed by thermogravimetric and differential thermogravimetric analysis. The in vitro antimicrobial activity against Gram negative (E. coli and P. aeruginosa and Gram positive (S. aureus ) bacterial strains and two fungal strains (C. albicans and A. niger) were studied by agar well diffusion method. It is found that the Schiff base is inhibiting the growth of the tested species to varying degrees. Molecular docking studies indicate that alkyl-pi and pi-pi weak interactions enhance the binding affinity of Schiff base-protein complexes. Molecular dynamics study reveals interaction of CHADMB complexed with bacterial protein, EC showed maximum stability which is in agreement with experimental result.Communicated by Ramaswamy H. Sarma.

New crystalline form of (N-cyclohexyl-1-(3,4-dimethoxyphenyl)methanimine Schiff base is synthesized.Synthesized compound is characterized by elemental analysis, SXRD, Raman, FT-IR, Mass, ¹H and ¹³C NMR spectroscopy.Band gap of the compound is calculated from absorption data.The dielectric properties of the compound are tested.Biological activity of the compound is tested against three bacterial and two fungal strains.Molecular docking and molecular dynamics studies were carried out to study the interaction of synthesized compound with various bacterial and fungal proteins.

Ethyl Gallate: Promising Cytoprotective against HIV-1-Induced Cytopathy and Antiretroviral-Induced Cytotoxicity.

Introduction: HIV-1 infection in cell culture is typically characterized by certain cytopathic effects such as vacuolization of cells and development of syncytia, which further lead to cell death. In addition, the majority of drugs during HIV treatment exhibit serious adverse effects in patients, apart from their beneficial role. During the screening of cytoprotective agents to protect the cells from HIV-1-associated cell death and also drug-associated toxicity, antioxidants from a natural source are assumed to be a choice. A well-known antioxidant, ethyl gallate (EG), was selected for cytoprotection studies which have already been proven as an anti-HIV agent. Objective: The main objective of the study was to explore the cytoprotective potential of EG against HIV-1-induced cytopathic effect and antiretroviral drug toxicity. Methods: DPPH free radical scavenging assay was performed with EG to find the effective concentration for antioxidant activity. HIV-1infection-associated cytopathic effects and further rescue by EG were studied in MT-2 lymphocytes by the microscopic method and XTT cytopathic assays. The cellular toxicity of different antiretroviral drugs in different cell lines and the consequent cytoprotective effectiveness of EG were investigated using an MTT cell viability assay. Results: Like ascorbic acid, EG exhibited promising antioxidant activity. HIV-1 infection of MT2 cells induces cell death often referred to as the cytopathic effect. In addition, the usage of antiretroviral drugs also causes severe adverse effects like cytotoxicity. In this context, EG was tested for its cytoprotective properties against HIV-1-induced cytopathic effect and drug-mediated cellular toxicity. EG reclaimed back the MT2 cells from HIV-1-induced cell death. Antiretroviral drugs, such as ritonavir, efavirinz, AZT, and nevirapine, were tested for their toxicity and induced more cell death at higher concentrations in different tissue models such as the liver (THLE-3), lung (AEpiCM), colorectal (HT-29), and brain (U87 MG). Pretreated cells with EG were rescued from the toxic doses of ART. Conclusion: EG was found to be exhibited cytoprotection not only from HIV-1-linked cell death but also from the chemotoxicity of antiretroviral drugs. Evidently, EG could be a cytoprotective supplement in the management of AIDS along with its enormous antioxidant benefits.

Prenatal socioenvironmental exposures and autism spectrum disorder: A web of confusion.

Although evidence of heritability for autism spectrum disorder (ASD) is strong, studies of twin pairs suggest that at least some portion of the etiology is attributable to environmental factors, either directly or through interaction with genes. Given the multitude of environmental and psychosocial exposures that have been reported to increase atypical neurodevelopment in offspring, in this article, we summarize what prenatal air pollutant, chemical, and occupational exposures and psychosocial stressors have been reportedly associated with ASD and co-occurring neurodevelopmental disorders. We highlight consistencies in reported associations and recommend areas for research to close gaps in our understanding of environmental risk for ASD. Because this issue is of particular importance in historically marginalized communities and low- and middle-income countries, we also discuss the importance of environmental justice issues and exposure disparities in research, and we advocate for prioritizing policies to reduce disparities and improve service provision in vulnerable populations.

A shared agenda for gender and COVID-19 research: priorities based on broadening engagement in science.

While the acute and collective crisis from the pandemic is over, an estimated 2.5 million people died from COVID-19 in 2022, tens of millions suffer from long COVID and national economies still reel from multiple deprivations exacerbated by the pandemic. Sex and gender biases deeply mark these evolving experiences of COVID-19, impacting the quality of science and effectiveness of the responses deployed. To galvanise change by strengthening evidence-informed inclusion of sex and gender in COVID-19 practice, we led a virtual collaboration to articulate and prioritise gender and COVID-19 research needs. In addition to standard prioritisation surveys, feminist principles mindful of intersectional power dynamics underpinned how we reviewed research gaps, framed research questions and discussed emergent findings. The collaborative research agenda-setting exercise engaged over 900 participants primarily from low/middle-income countries in varied activities. The top 21 research questions included the importance of the needs of pregnant and lactating women and information systems that enable sex-disaggregated analysis. Gender and intersectional aspects to improving vaccine uptake, access to health services, measures against gender-based violence and integrating gender in health systems were also prioritised. These priorities are shaped by more inclusive ways of working, which are critical for global health as it faces further uncertainties in the aftermath of COVID-19. It remains imperative to address the basics in gender and health (sex-disaggregated data and sex-specific needs) and also advance transformational goals to advance gender justice across health and social policies, including those related to global research.