Nuclear localization signal in nuclear receptor VDR facilitates the mitotic genome bookmarking by involving distinct amino acid residues.

Mitotic genome-bookmarking preserves epigenetic information, re-establishing progenitor's gene expression profile through transcription factors, chromatin remodelers, and histone modifiers, thereby regulating cell fate and lineage commitment post-mitotically in progeny cells. Our recent study revealed that the constitutive association of VDR with mitotic chromatin involves its DNA-binding domain. However, amino acid residues in this domain, crucial for genome bookmarking, remain elusive. This study demonstrates that nuclear localization signal (NLS) residues between 49 and 55 amino acids in VDR are essential for receptor-chromatin interaction during mitosis. Furthermore, it is revealed that both bipartite nature of VDR-NLS region and N-terminally located positively charged arginine residues are critical for its 'genome-bookmarking' property. Since mitotic chromatin association of heterodimeric partner RXR depends on VDR-chromatin association, interventions in VDR binding also abort RXR-chromatin interaction. Overall, this study documents the mechanistic details underlying VDR-chromatin interactions in genome-bookmarking behavior, potentially aiding in comprehending VDR-mediated diseases attributed to certain SNPs.

Truncated variants of thyroid hormone receptor beta display disease-inflicting malfunctioning at cellular level.

Thyroid hormone receptor ß (THRß) is a member of the nuclear receptor superfamily of ligand-modulated transcription factors. Upon ligand binding, THRß sequentially recruits the components of transcriptional machinery to modulate target gene expression. In addition to regulating diverse physiological processes, THRß plays a crucial role in hypothalamus-pituitary-thyroid axis feedback regulation. Anomalies in THRß gene/protein structure are associated with onset of diverse disease states. In this study, we investigated disease-inflicting truncated variants of THRß using in-silico analysis and cell-based assays. We examined the THRß truncated variants on multiple test parameters, including subcellular localization, ligand-receptor interactions, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions. Moreover, molecular dynamic simulation approaches predicted that shortened THRß-LBD due to point mutations contributes proportionally to the loss of structural integrity and receptor stability. Deviant subcellular localization and compromised transcriptional function were apparent with these truncated variants. Present study shows that 'mitotic bookmarking' property of some THRß variants is also affected. The study highlights that structural and conformational attributes of THRß are necessary for normal receptor functioning, and any deviations may contribute to the underlying cause of the inflicted diseases. We anticipate that insights derived herein may contribute to improved mechanistic understanding to assess disease predisposition.

Hereditary Vitamin D-Resistant Rickets (HVDRR) associated SNP variants of vitamin D receptor exhibit malfunctioning at multiple levels.

Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. It is a primary regulator of calcium and phosphate homeostasis required for skeleton and bone mineralization. Vitamin D in active form 1α,25 dihydroxyvitamin-D3 mediates its cellular functions by binding to VDR. Active VDR forms heterodimers with partner RXR (retinoid X receptor) to execute its physiological actions. HVDRR (Hereditary Vitamin D-Resistant Rickets) is a rare genetic disorder that occurs because of generalized resistance to the 1α,25(OH)2D3. HVDRR is caused by the polymorphic variations in VDR gene leading to defective intestinal calcium absorption and mineralization of newly forming bones. Using point and deletion SNPs of VDR we have studied several HVDRR-associated SNP variants for their subcellular dynamics, transcriptional functions, 'genome bookmarking', heterodimeric interactions with RXR, and receptor stability. We previously reported that VDR is a 'mitotic bookmarking factor' that remains constitutively associated with the mitotic chromatin to inherit 'transcriptional memory', however the mechanistic details remained unclear. We document that 'genome bookmarking' property by VDR is critically impaired by naturally occurring HVDRR-associated point and deletion variants found in patients. Furthermore, these HVDRR-associated SNP variants of VDR were found to be compromised in transcriptional function, nuclear translocation, protein stability and intermolecular interactions with its heterodimeric partner RXR. Intriguingly, majority of these disease-allied functional defects failed to be rescued by RXR. Our findings suggest that the HVDRR-associated SNP variations influence the normal functioning of the receptor, and this derived understanding may help in the management of disease with precisely designed small molecule modulators.

Cardio-Oncology: Managing Cardiovascular Complications of Cancer Therapies.

This narrative review explores the complex relationship between cancer medicines and cardiovascular health in the junction of oncology and cardiology, known as cardio-oncology. The study examines the historical development of cancer treatments and highlights the growing importance of cardiovascular problems in patient care. This text delves into the topic of cardiotoxicity, examining both conventional chemotherapeutic drugs like anthracyclines and more recent tyrosine kinase and immune checkpoint inhibitors. The complex molecular and cellular mechanisms that control cardiovascular problems are explained, including an understanding of how genetic predisposition influences an individual's sensitivity. The narrative expands into the crucial realm of risk stratification and evaluation, revealing advanced instruments for identifying cardiovascular risk in cancer patients. The importance of non-invasive imaging methods and biomarkers in early detection and continuous monitoring is emphasized. The prioritization of preventive tactics emphasizes the need to take proactive measures incorporating therapies to protect the heart throughout cancer treatment. It also highlights the significance of making lifestyle improvements to reduce risk factors. The narrative emphasizes the changing collaborative treatment environment, advocating for merging oncologists and cardiologists in a coordinated endeavor to maximize patient outcomes. In addition to clinical factors, the review explores the critical domain of patient education and support, acknowledging its crucial role in promoting informed decision-making and improving overall patient well-being. The latter portions of the text anticipate and consider upcoming treatments and existing research efforts that offer the potential for the future of cardio-oncology. This review seeks to provide a detailed viewpoint on the intricate connection between cancer treatments and cardiovascular well-being. Its objective is to encourage a more profound comprehension of the subject and prompt careful contemplation regarding the comprehensive care of cancer patients who confront the intricate difficulties presented by their treatment plans.

Neurological Manifestations of Infectious Diseases: Insights From Recent Cases.

This narrative review examines the complex connection between infectious diseases and their neurological effects. It provides a detailed analysis of recent instances and insights derived from various pathogens. As we explore the realm of infectious agents, including viruses, bacteria, parasites, and fungi, a thorough and diverse analysis reveals the intricacies of neurological problems. The review begins by examining viral infections, specifically focusing on how viruses invade the neurological system and its subsequent effects. Significant instances from recent widespread disease outbreaks function as instructive benchmarks, highlighting the progressing comprehension of these ever-changing interconnections. The article examines the complex pathophysiology of neurological problems caused by bacterial infections. It presents current cases that illustrate the various ways these complications might manifest and the difficulties faced in their therapeutic management. Parasitic and fungal infections, which are typically overlooked, are being carefully examined to emphasize their distinct role in causing neurological complications. The mentioned cases highlight the importance of being thoroughly aware of these less-explored areas ranging from protozoan parasites to opportunistic fungal infections. In addition to the immediate effects caused by infectious agents, the review investigates autoimmune responses activated by infections. It provides a detailed examination of specific instances that shed light on the complex relationship between viral triggers and future neurological problems. This text elaborates on the intricacy of autoimmune-related neurological issues, highlighting the necessity for a comprehensive approach to diagnosing and treating them. The narrative next redirects its attention to the diagnostic difficulties that arise when interpreting the neurological symptoms of viral disorders. This article provides a thorough examination of existing diagnostic tools, along with an investigation into new technologies that have the potential to improve our capacity to identify and comprehend complex presentations. This debate connects to the following examination of treatment methods, where current cases that showcase successful interventions are carefully examined to extract valuable insights into good clinical management. The discussion focuses on the public health implications of preventive efforts against infectious infections, including their neurological consequences. The story emphasizes the link between infectious diseases and overall societal health, advocating for a proactive strategy to reduce the impact of neurological complications. The abstract concludes by providing a prospective viewpoint, highlighting areas of research that still need to be addressed, and suggesting potential future avenues. This narrative review seeks to provide a comprehensive resource for physicians, researchers, and public health professionals dealing with the complex field of neurological manifestations in infectious diseases. It combines recent examples, synthesizes current information, and offers a holistic perspective.

Isolation and characterization of a novel choline degrading Citrobacter amalonaticus strain from the human gut.

Gut microbiota metabolism can have profound effects on human health. Choline, a quaternary amine (QA) highly abundant in our diet, is canonically cleaved by a glycyl radical enzyme, choline trimethylamine lyase (CutC), and its SAM-dependent radical activator, CutD. CutC cleaves choline to form trimethylamine (TMA) and acetaldehyde. TMA is oxidized to TMAO by FMO3 in the liver, which plays a role in causing atherosclerosis. We hypothesized that alternative pathways for choline degradation occur within gut microbes and that certain gut microbiota can anaerobically respire or ferment QAs, such as choline. Based on this prediction we established QA-supplemented enrichment cultures using fecal material from healthy volunteers as the inocula. We have isolated, from a choline-supplemented enrichment of a human fecal sample, a strain of Citrobacter amalonaticus, that we have designated CJ25. This strain is capable of anaerobically utilizing choline as its sole carbon and energy source. Its genome does not contain the cutCD genes or genes encoding any COG5598 methyltransferases. We have confirmed the degradation of choline and production of acetate by the organism during growth of the strain. However, we used multiple analytical methods to confirm that no TMA accumulated in the medium during growth. Hence, strain CJ25 is a unique bacterium that degrades choline without the production of the proatherogenic metabolite TMA.

Mitotic genome bookmarking by nuclear receptor VDR advocates transmission of cellular transcriptional memory to progeny cells.

Mitosis is an essential process for the self-renewal of cells that is accompanied by dynamic changes in nuclear architecture and chromatin organization. Despite all the changes, the cell manages to re-establish all the parental epigenetic marks, post-mitotically. Recent reports suggest that some sequence-specific transcription factors remain attached to mitotic chromatin during cell division to ensure timely reactivation of a subset of transcription factors necessary to maintain cell identity. These mitotically associated factors are suggested to act as 'genome bookmarking factors' and the phenomenon is termed 'genome bookmarking'. Here, we studied this phenomenon with Vitamin D Receptor (VDR), a key regulator of calcium and phosphate homeostasis and a member of the nuclear receptor superfamily. This study, for the first time, has confirmed VDR as a mitotic bookmarking factor that may be playing a crucial role in the maintenance of cell identity and genome bookmarking. Full 'DNA binding domain (DBD)' present in VDR was identified as essential for enrichment of VDR on mitotic chromatin. Furthermore, the study also demonstrates that VDR evokes mitotic chromatin binding behaviour in its heterodimeric partner Retinoid X receptor (RXR). Interestingly, for promoting bookmarking behaviour in RXR, both DBD and/or ligand-binding domain (LBD) in conjunction with hinge region of VDR were required. Additionally, ChIP analysis showed that VDR remains associated with DR3 (direct repeat 3) region of its specific target gene promoter CYP24A1(Cytochrome P450 family 24 subfamily A member1), during mitosis. Altogether, our study illustrates a novel function of VDR in the epigenetic transmission and control of expression of target proteome for maintenance of cell identity and traits in progeny cells.

Major chemical constituents from Illicium griffithii Hook. f. & Thoms of North East India and their cytotoxicity and antimicrobial activities.

Illicium griffithii Hook. f. & Thoms is an endemic medicinal plant of North East India found in the Eastern Himalayan region of biodiversity mega centre. Herein, chemical investigation of I. griffithii, afforded five compounds and their structures were determined through extensive use of NMR, HRMS, and FT-IR spectroscopy. The complete proton-proton, proton-carbon coupling network of compound 1 was determined using 1H-1H COSY, HSQC and NOESY NMR experiments. All the compounds were evaluated for their cytotoxic activity by MTT assay and antimicrobial activity by Agar well diffusion method. Compound 1 exhibited significant cytotoxicity activity against Lung cancer (A549) and pancreatic cancer (MIAPaCa2) cell lines with IC50 values of 15.01 ± 2.69 µg/mL and 47.77 ± 2.38 µg/mL, respectively. Further, the compound 1 exhibited good antimicrobial activities against Escherichia coli and Candida albicans with MIC 7.50 ± 0.28 µg/mL and 7.50 ± 0.86 µg/mL, respectively. The other isolated compounds along with the extracts of I. griffithii also displayed moderate anticancer and antimicrobial activities against respective strains. To the best of our knowledge, this is the first study of isolation of compounds from bark, wood, and leaf along with cytotoxicity and antimicrobial activities of I. griffithii from the North Eastern region of India and could be a potential herbal medicine in near future.

Prototype of a Smart Microfluidic Platform for the Evaluation of SARS-Cov-2 Pathogenesis, Along with Estimation of the Effectiveness of Potential Drug Candidates and Antigen-Antibody Interactions in Convalescent Plasma Therapy.

Originating in China during December 2019, the novel corona-virus, SARS-CoV-2, has created mayhem worldwide in a very short time. The outbreak has been so rapid and widespread that the only option to treat the patients was administering drugs already available in the market like chloroquine/hydroxychloroquine (an antimalarial drug) and remedesivir. A large number of patients have been cured but the attribution to survival by these drugs has been controversial. Till date, we do not have any specific drug or vaccine available for COVID-19 and the pandemic seems to be far from over. To handle the current challenges posed by the outbreak effectively, we need to employ innovative interdisciplinary approaches. Organ-on-chip (OOC), particularly lung-on-chip, is one such approach which combines the potential of microfluidics, cell culture and molecular biology into a single miniaturised platform. The device is realized to be capable of simulating in-vivo physiological responses of an organ. In the current study, an OOC, which is a multichannel 3D cell culture microfluidic device, is made via soft lithography technique, using polydimethylsiloxane-polymer and diverse polymeric porous/semipermeable membranes. Several polymer membranes i.e. PDMS, polyvinylidene fluoride (PVDF), nitrocellulose, polyester etc., integrated into the microdevices, were efficiently explored to realize their better cell-adhesion and viability property. We also propose for the application of a simple, smart and cost-effective lung-on-chip platform to study the SARS-CoV-2 pathogenesis in humans, drug toxicity testing and provide insights into antigen-antibody interactions. This platform will enable us to study multiple phenomena at a micro-level generating more reliable data and a better understanding of the underlying mechanisms of SARS-CoV-2 infection and pathogenesis.

Facile synthesis of novel polypyrrole dispersed AgFeO2 nanohybrid with highly efficient photocatalytic activity towards 2,4,6-trichlorophenol degradation.

With the aim to develop a visible light driven eco-friendly photocatalyst, the present work reports for the first time the synthesis of polypyrrole/AgFeO2 nanohybrids synthesized via in situ polymerization of pyrrole (by varying the mol ratios) in AgFeO2 dispersions. The nanohybrids were characterized using Fourier transform infrared (FT-IR) spectroscopy, ultra-violet visible near infrared (UV/VIS/NIR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA) and transmission electron microscopy (TEM) measurements. The TGA measurements confirmed 20%, 60%, and 80% loading of pyrrole in AgFeO2 and hence the nanohybrids were designated as 20%-Ppy/AgFeO2, 60%-Ppy/AgFeO2, 80%-Ppy/AgFeO2 respectively. IR and X-ray photoelectron spectroscopy (XPS) studies confirmed polymerization of pyrrole and formation of the nanohybrids while XRD reflected high crystallinity of the nanohybrids. The photocatalytic activity of Ppy/AgFeO2 nanohybrids was investigated against 2,4,6-trichlorophenol (2,4,6-TCP) under sonophotocatalytic conditions using visible light irradiation. The nanohybrids were observed to completely degrade the organic pollutant within a short span of 40 min. The degradation kinetics fitted the pseudo-first order model. The fragments were analyzed using LCMS studies which revealed the formation of diols as degraded products. The nanohybrids revealed immense potential for rapid as well as eco-friendly destruction of organic pollutants in wastewater.

Highly Efficient Photocatalytic Degradation of Amido Black 10B Dye Using Polycarbazole-Decorated TiO2 Nanohybrids.

The present study reports the synthesis of polycarbazole (PCz)-decorated TiO2 nanohybrids via in situ chemical polymerization of carbazole monomers in TiO2 dispersions. The ratio of the polymer in the nanohybrid varied between 0.5 and 2 wt %. The synthesized nanohybrids were characterized using infrared and diffuse reflectance spectroscopies, whereas the morphology was analyzed using X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. XRD revealed changes in the peak corresponding to the d(001) plane of TiO2 owing to the interaction between the two components. TEM confirmed the formation of PCz-decorated nanohybrids. Amido Black 10B (AB-10B) was chosen as a model dye for the degradation studies. Sonophotocatalytic degradation of the dye was studied by varying the catalyst and dye concentrations. Results showed that PCz/TiO2 nanohybrids exhibited a complete degradation of AB-10B dye within a short span of 60-90 min, which was faster than pure TiO2 and the reported decorated TiO2 nanohybrids synthesized by other authors. The degraded dye fragments were identified using liquid chromatography-mass spectrometry (LCMS). By varying the loading of PCz in TiO2, the nanohybrids could be tuned to achieve visible light-driven degradation.