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The mostly aggressive and extremely malignant type of central nervous system is Glioblastoma (GBM), which is characterized by an extremely short average survival time of lesser than 16 months. The primary cause of this phenomenon can be attributed to the extensively altered genome of GBM, which is characterized by the dysregulation of numerous critical signaling pathways and epigenetics regulations associated with proliferation, cellular growth, survival, and apoptosis. In light of this, different genetic alterations in critical signaling pathways and various epigenetics regulation mechanisms are associated with GBM and identified as distinguishing markers. Such GBM prognostic alterations are identified in PI3K/AKT, p53, RTK, RAS, RB, STAT3 and ZIP4 signaling pathways, metabolic pathway (IDH1/2), as well as alterations in epigenetic regulation genes (MGMT, CDKN2A-p16INK4aCDKN2B-p15INK4b). The exploration of innovative diagnostic and therapeutic approaches that specifically target these pathways is utmost importance to enhance the future medication for GBM. This study provides a comprehensive overview of dysregulated epigenetic mechanisms and signaling pathways due to mutations, methylation, and copy number alterations of in critical genes in GBM with prevalence and emphasizing their significance. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial‐mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self‐renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in‐depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC‐mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)‐T cell therapy, cytokine‐induced killer (CIK) cell therapy, natural killer (NK) cell‐mediated CSC‐targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions. [ABSTRACT FROM AUTHOR]

RGS (Regulator of G protein signaling) proteins have long captured the fascination of researchers due to their intricate involvement across a wide array of signaling pathways within cellular systems. Their diverse and nuanced functions have positioned them as continual subjects of scientific inquiry, especially given the implications of certain family members in various cancer types. Of particular note in this context is RGS20, whose clinical relevance and molecular significance in hepatocellular carcinoma we have recently investigated. These investigations have prompted questions into the prevalence of pathogenic mutations within the RGS20 gene and the intricate network of interacting proteins that could contribute to the complex landscape of cancer biology. In our study, we aim to unravel the mutations within the RGS20 gene and the multifaceted interplay between RGS20 and other proteins within the context of cancer. Expanding on this line of inquiry, our research is dedicated to uncovering the intricate mechanisms of RGS20 in various cancers. In particular, we have redirected our attention to examining the role of RGS20 within hematological malignancies, with a specific focus on multiple myeloma and follicular lymphoma. These hematological cancers hold significant promise for further investigation, as understanding the involvement of RGS20 in their pathogenesis could unveil novel therapeutic strategies and treatment avenues. Furthermore, our exploration has extended to encompass the latest discoveries concerning the potential involvement of RGS20 in diseases affecting the central nervous system, thereby broadening the scope of its implications beyond oncology to encompass neurobiology and related fields. [ABSTRACT FROM AUTHOR]

The role of messenger RNA (mRNA) in biological systems is extremely versatile. However, it’s extremely short half-life poses a fundamental restriction on its application. Moreover, the translation efficiency of mRNA is also limited. On the contrary, circular RNAs, also known as circRNAs, are a common and stable form of RNA found in eukaryotic cells. These molecules are synthesized via back-splicing. Both synthetic circRNAs and certain endogenous circRNAs have the potential to encode proteins, hence suggesting the potential of circRNA as a gene expression machinery. Herein, we aim to summarize all engineering aspects that allow exogenous circular RNA (circRNA) to prolong the time that proteins are expressed from full-length RNA signals. This review presents a systematic engineering approach that have been devised to efficiently assemble circRNAs and evaluate several aspects that have an impact on protein production derived from. We have also reviewed how optimization of the key components of circRNAs, including the topology of vector, 5′ and 3′ untranslated sections, entrance site of the internal ribosome, and engineered aptamers could be efficiently impacting the translation machinery for molecular and metabolic reprogramming. Collectively, molecular and metabolic reprogramming present a novel way of regulating distinctive cellular features, for instance growth traits to neoplastic cells, and offer new possibilities for therapeutic inventions. [ABSTRACT FROM AUTHOR]

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people and claimed thousands of lives. Starting in China, it is arguably the most precipitous global health calamity of modern times. The entire world has rocked back to fight against the disease and the COVID-19 vaccine is the prime weapon. Even though the conventional vaccine development pipeline usually takes more than a decade, the escalating daily death rates due to COVID-19 infections have resulted in the development of fast-track strategies to bring in the vaccine under a year’s time. Governments, companies, and universities have networked to pool resources and have come up with a number of vaccine candidates. Also, international consortia have emerged to address the distribution of successful candidates. Herein, we summarize these unprecedented developments in vaccine science and discuss the types of COVID-19 vaccines, their developmental strategies, and their roles as well as their limitations.

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients. [ABSTRACT FROM AUTHOR]

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X‐linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X‐linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X‐linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X‐linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X‐linked TSGs in sex chromosome–autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X‐linked TSG in immunomodulation and in gender‐based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X‐linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarizes the pivotal role of tumor-infiltrating immune cells (TIICs) within the tumor microenvironment (TME) and their impact on cancer prognosis and treatment response. By analyzing TIICs alongside tumor mutation burden (TMB) and immune checkpoint inhibitor (ICI) scores, this study reveals insights into cancer's immune landscapes. Understanding TIICs' influence enables tailored cancer treatments, aiding postoperative care, therapy decisions, and personalized medicine choices. We effectively examined the predictive and prognostic value of TIICs alongside TMB and ICI scores in identifying the diverse immunological environments of cancer. Several approaches discussed in this review provide more accurate predictions of patient outcomes and treatment responses. These models can help identify individuals who may derive greater benefit from adjuvant or neoadjuvant treatment. In summary, we believe that the major contribution of TIICs in cancer will have a substantial positive impact on postoperative follow-up, therapy, interventions, and the ability to make educated decisions regarding personalized cancer treatments. This comprehensive study underscores the significant role of TIICs in combating tumor-mediated immunosuppression and fostering antitumor immune responses, promising improved cancer prognosis and therapeutic outcomes. TIICs are critical components of the TME and are used to estimate prognostic and treatment responses in many malignancies. TIICs in the tumor microenvironment are assessed and quantified by categorizing immune cells into three subtypes: CD66b+ tumor-associated neutrophils (TANs), FoxP3+ regulatory T cells (Tregs), and CD163+ tumor-associated macrophages (TAMs). In addition, many cancers have tumor-infiltrating M1 and M2 macrophages, neutrophils (Neu), CD4+ T cells (T-helper), CD8+ T cells (T-cytotoxic), eosinophils, and mast cells. A variety of clinical treatments have linked tumor immune cell infiltration (ICI) to immunotherapy receptivity and prognosis. To improve the therapeutic effectiveness of immune-modulating drugs in a wider cancer patient population, immune cells and their interactions in the TME must be better understood. This study examines the clinicopathological effects of TIICs in overcoming tumor-mediated immunosuppression to boost antitumor immune responses and improve cancer prognosis. We successfully analyzed the predictive and prognostic usefulness of TIICs alongside TMB and ICI scores to identify cancer's varied immune landscapes. Traditionally, immune cell infiltration was quantified using flow cytometry, immunohistochemistry, gene set enrichment analysis (GSEA), CIBERSORT, ESTIMATE, and other platforms that use integrated immune gene sets from previously published studies. We have also thoroughly examined traditional limitations and newly created unsupervised clustering and deconvolution techniques (SpatialVizScore and ProTICS). These methods predict patient outcomes and treatment responses better. These models may also identify individuals who may benefit more from adjuvant or neoadjuvant treatment. Overall, we think that the significant contribution of TIICs in cancer will greatly benefit postoperative follow-up, therapy, interventions, and informed choices on customized cancer medicines. [ABSTRACT FROM AUTHOR]

Medicinal plants are a major source of numerous therapeutic agents, and the emergence of pathogenic bacteria has rekindled interest in traditional medicine systems as an alternative approach to overcoming resistance. The dried plant material of four medicinal plants, namely Terminalia arjuna (bark), Terminalia bellirica (fruit), Aegle marmelos (leaves), and Bacopa monnieri (leaves), was powdered, and aqueous extracts were prepared. The antimicrobial activity of the extracts was evaluated against three clinically important strains: Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli 385. As E. coli 385 was resistant to the broadest spectrum of antibiotics tested, it was classified as (MDR multi-drug resistant). E. coli, Bacillus subtilis, Mycobacterium smegmatis (MTTC), and Vibrio alginolyticus (ATCC) were also assessed using the agar well diffusion method for zones of inhibition and minimum inhibitory/bactericidal concentration (MIC/MBC). Clinically important strains were found to be sensitive to the aqueous extract of T. bellerica (19.51 ± 0.61 mm) with MICs ranging from 0.31 to 0.62 mg/ml. The MDR strain was also sensitive to Bellirica monnieri (16.10 ± 0.31 mm) aqueous extract. To determine the potential for a wide range of applications, the antioxidant activities of the extracts were evaluated using DPPH, ABTS, and FRAP assays. The T. arjuna plant extract exhibited the highest radical scavenging activity with the lowest EC50 values for DPPH (1.15 ± 0.061 mg/ml) and ABTS (1.02 ± 0.07 mg/ml). The plant extracts were characterized by UV-visible spectroscopy, Fourier-transform infrared spectroscopy, and LC-MS/MS. [ABSTRACT FROM AUTHOR]

The therapeutic application of flavonoids in the management of infectious diseases, cancers, chronic wounds, aging, and neurodegenerative disorders has been well documented in scientific literature. The citric flavonoid naringenin comes under the category of flavanone and exhibits a plethora of health benefits. Very few flavonoids such as curcumin, resveratrol, catechin, quercetin, and kaempferol have been studied to exert their anti-aging properties in humans. The effect of naringenin in the context of age-associated disorders in detail has not been elucidated yet. The databases used for the literature search were Science Direct, Google Scholar, and PubMed. More emphasis has been put on the recent literature on "naringenin" and its effect on "age-associated disorders." Almost all chronic degenerative disorders are characterized by oxidative stress and inflammatory response. The study aims at highlighting the reactive oxygen species-mediated activity of naringenin and the underlying molecular mechanism leading to the prevention of various age-associated disorders. Altogether, the review presents a systematic comprehension of the pharmaceutical and clinicopathological benefits of naringenin in age-associated disorders. [ABSTRACT FROM AUTHOR]

Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in PKD1L1 in two of the five case–parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of Pkd1l1 mutant mouse embryos revealed about 20% of Pkd1l1−/− embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in Pkd1l1−/− embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of PKD1L1 in congenital lymphatic anomalies, including CCTs. [ABSTRACT FROM AUTHOR]

Cold-inducible RNA-binding protein (CIRP) is an intracellular stress-response protein and a type of damage-associated molecular pattern (DAMP) that responds to various stress stimulus by altering its expression and mRNA stability. Upon exposure to ultraviolet (UV) light or low temperature, CIRP get translocated from the nucleus to the cytoplasm through methylation modification and stored in stress granules (SG). During exosome biogenesis, which involves formation of endosomes from the cell membrane through endocytosis, CIRP also gets packaged within the endosomes along with DNA, and RNA and other proteins. Subsequently, intraluminal vesicles (ILVs) are formed following the inward budding of the endosomal membrane, turning the endosomes into multi-vesicle bodies (MVBs). Finally, the MVBs fuse with the cell membrane to form exosomes. As a result, CIRP can also be secreted out of cells through the lysosomal pathway as Extracellular CIRP (eCIRP). Extracellular CIRP (eCIRP) is implicated in various conditions, including sepsis, ischemia-reperfusion damage, lung injury, and neuroinflammation, through the release of exosomes. In addition, CIRP interacts with TLR4, TREM-1, and IL-6R, and therefore are involved in triggering immune and inflammatory responses. Accordingly, eCIRP has been studied as potential novel targets for disease therapy. C23 and M3, polypeptides that oppose eCIRP binding to its receptors, are beneficial in numerous inflammatory illnesses. Some natural molecules such as Luteolin and Emodin can also antagonize CIRP, which play roles similar to C23 in inflammatory responses and inhibit macrophagemediated inflammation. This review aims to provide a better understanding on CIRP translocation and secretion from the nucleus to the extracellular space and the mechanisms and inhibitory roles of eCIRP in diverse inflammatory illnesses. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinical and molecular advances have improved knowledge and treatment prospects for cancer, yet hepatocellular carcinoma (HCC), the most common form of liver cancer, still ranks significantly higher in terms of the global cancer burden. Herein, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancers with a particular focus on HCC. Hepatocellular carcinoma (HCC) is at the forefront of the global cancer burden, and biomarkers for HCC are constantly being sought. Interestingly, RGS (Regulators of G protein signaling) proteins, which negatively regulate GPCR signaling, have been associated with various cancers, with some members of the RGS family being associated with liver cancer as well. Considering this, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancer types with special emphasis on HCC. By using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, our analysis revealed that (a) RGS20 was strongly upregulated in tumor tissue compared with adjacent normal tissue of HCC patients; (b) RGS20 was strongly associated with some important clinical parameters such as alpha-fetoprotein and tumor grade in the HCC patients; (c) besides HCC (p < 0.001), RGS20 was found to be an important factor for survival in four other cancers (clear renal cell carcinoma: p < 0.001, lung adenocarcinoma: p = 0.004, mesothelioma: p = 0.039, ovarian serous cystadenocarcinoma: p = 0.048); (d) RGS20 was found to be significantly associated with some tumor-related signaling pathways and long intergenic non-coding RNAs (lincRNAs: LINC00511, PVT1, MIR4435-2HG, BCYRN1, and MAPKAPK5-AS1) that exhibit oncogenic potential. Taken together, we showed that RGS20 correlates with a few HCC-associated lincRNAs harboring oncogenic potential and is markedly upregulated in HCC patients. Our analysis further supports the putative function of RGS proteins, particularly RGS20, in cancer. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, β-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of β-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in β-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting β-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shβ-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as β-catenin knockdown. When investigating the effect of CCL2 on β-catenin activity, we found that CCL2 modulates components of the Wnt/β-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological β-catenin inhibitor MSAB reduces active β-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that β-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between β-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence. [ABSTRACT FROM AUTHOR]

Objectives: Rheumatoid arthritis (RA) is an autoimmune disease, associated with chronic inflammation of synoviocytes. Tumor necrosis factor α (TNF-α) plays a crucial role in the pathogenesis of RA through pro-inflammatory cytokines. Nicotine, an alkaloid used as herbal medicine, often worked as an anti-inflammatory agent. In the present study, we tried to uncover the anti-inflammatory impact of nicotine against RA. Materials and methods: Nicotine was isolated from Brassica oleracea, purified by high profile/phase liquid chromatography (HPLC). In-silico docking was carried out using bioinformatics tools SwissADME (absorption, distribution, metabolism and excretion), PASS, and Drug-induced Gene Expression Profile (DIGEP)-Pred to determine drug likeliness of nicotine. The in-vitro study was performed in TNFα-induced SW982 synoviocytes by qPCR. mRNA expression of pro-inflammatory cytokines (TNF, IL6, IL1β) and proteins (TRAF2, P50, P65) were analyzed followed by validation of P65 (RELA), pP65, IkBα by Western blot analysis. Results: Nicotine compound was extracted from Brassica oleracea and purified by HPLC method (Rt values at 2.67 min). The physicochemical, pharmacokinetic properties and drug-likeliness of nicotine were studied by in-silico analysis. In-vitro studies revealed that nicotine lowers the expression of inflammatory cytokines (TNF, IL6, IL1β) and proteins (TNF receptor-associated factor 2 (TRAF2), P50, P65) at 1 μg/ml in TNFα-induced SW982 cells. Conclusion: Nicotine from natural sources (Brassica oleracea) has been found to be an effective anti-inflammatory compound at a low dosage; thus, identifying the role of nicotine present in the natural sources as a therapeutic option for RA, may be recommended as remedial drug instead of synthetic drug. [ABSTRACT FROM AUTHOR]

Since the human genome contains about 6% of tumor suppressor genes (TSGs) and the X chromosome alone holds a substantial share (2%), herein, we have discussed exclusively the relative contribution of X-linked human TSGs that appear to be primarily involved in 32 different cancer types. Our analysis showed that, (a) the majority of X-linked TSGs are primarily involved in the dysregulation of breast cancer, followed by prostate cancer, (b) Despite being escaped from X chromosome inactivation (XCI), a clear pattern of altered promoter methylation linked to the mutational burden was observed among them. (c) X-linked TSGs (mainly on the q-arm) maintain spatial and genetic interactions with certain autosomal loci. Corroborating our previous findings that loss/gain of entire sex chromosomes (in XO and XXY syndromes) can profoundly affect the epigenetic status of autosomes we herein suggest that X-linked TSGs alone can also contribute significantly in the dynamics this sex chromosome-autosome crosstalk to restructure the cancer genome. [ABSTRACT FROM AUTHOR]

Zygosaccharomyces rouxii is an osmo/halo-tolerant yeast species which are used in beneficiary industrial productions such as beverages, sauces. Not all yeast species can survive osmotic stress and therefore, these species establish an advantageous aspect of beneficial industrial products. The property of tolerance is due to the presence of various genes and proteins. In this study, we have focused on ZrFPS1p, an aquaglyceroporin channel protein that belongs to the Major Intrinsic Protein (MIP) family that is majorly involved in the efflux of glycerol accumulated during osmotic stress condition. Various studies have been done on the protein but, the mechanism is not fully understood due to the unavailability of the crystal structure of the protein due to its high fragment delicacy. Therefore, in this study, we have done the 3D structural modelling of the protein using I-TASSER and the model validation was done using 3Drefine. ZrFPS1p comprehend six transmembrane domains and a highly conserved NPS (Asn-Pro-Ser) and NMA (Asn-Met-Ala) motifs that are responsible for the opening and closure of the carrier protein. It was found that these motifs are different from model organisms which have NPS and NLA(Asn-Leu-Ala) motifs. So, to determine the role of these motifs, we have done multiple sequence alignment of FPS1p in eleven different yeast including high and mild osmo/halo-tolerant species. As anticipated, it is found that the NPS motif is present in both Zygosaccharomyces and Saccharomyces (highly tolerant and moderately tolerant) species, whereas the NMA motif is present only in highly tolerant yeast species namely Zygosaccharomyces and Candida. Therefore, it can be concluded that the NMA motif plays an important role during high osmotic stress conditions. Further studies can be done on the regulation by the protein on the structural and functional aspects for a better understanding of this channel protein during stress conditions. [ABSTRACT FROM AUTHOR]

In the present study, in silico predictions and molecular docking were performed on five clerodane diterpenes (1–5) from Polyalthia longifolia seeds to evaluate their potential as xanthine oxidase (XO) inhibitors. The initial screening was conducted by target prediction using TargetNet web server application and only compounds 3 and 4 showed a potential interaction with XO. Compounds 3 and 4 were subsequently subjected to in silico analyses on XO protein structure (PDB: 1N5X) using Schrödinger Release 2020–3 followed by structural modeling & molecular simulation studies to confirm the initial prediction result and identify the binding mode of these compounds to the XO. Molecular docking results revealed that compounds 3 (-37.3 kcal/mol) and 4 (-32.0 kcal/mol) binds more stably to XO than the reference drug allopurinol (-27.0 kcal/mol). Interestingly, two residues Glu 802 and Thr 1010 were observed as the two main H-bond binding sites for both tested compounds and the allopurinol. The center scaffold of allopurinol was positioned by some π-π stacking with Phe 914 and Phe 1009, while that of compounds 3 and 4 were supported by many hydrophobic interactions mainly with Leu 648, Phe 649, Phe 1013, and Leu 1014. Additionally, the docking simulation predicted that the inhibitory effect of compounds 3 and 4 was mediated by creating H-bond with particularly Glu 802, which is a key amino acid for XO enzyme inhibition. Altogether, in vitro studies showed that compounds 3 and 4 had better inhibitory capacity against XO enzyme with IC50 values significantly (p < 0.001) lower than that of allopurinol. In short, the present study identified cleroda-4(18),13-dien-15,16-olide as novel potential XO inhibitors, which can be potentially used for the treatment of gout. [ABSTRACT FROM AUTHOR]

Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF. [ABSTRACT FROM AUTHOR]

Molecular typing techniques are key tools in surveillance of food spoilage yeasts, in investigations on intra-species population diversity, and in tracing selected starters during fermentation. Unlike previous works on strain typing of Zygosaccharomyces spoilage species, here Zygosaccharomyces mellis and the Zygosaccharoymces rouxii complex yeasts, which include Z. rouxii , Zygosaccharomyces sapae , and a mosaic lineage (ML) of putatively hybrids, were evaluated by three typing methods for intra- and inter-species resolution. Overall these yeasts are relevant for food fermentation and spoilage, but are quite difficult to discriminate at strain and species level as they evolved by reticulation. A pool of 76 strains from different sources were typed by M13 and (GTG) 5 MSP-PCR fingerprinting and PCR-RFLP of ribosomal intergenic spacer region (IGS). We demonstrated that M13 overcame (GTG) 5 fingerprinting to group Z. sapae, Z. rouxii , Z. mellis and the ML isolates in congruent distinct clusters. Even if (GTG) 5 primer yielded a number of DNA fingerprints comparable with those obtained by M13 primer, it failed to discriminate Z. sapae , Z. mellis and Z. rouxii at species level. Clustering of IGS RFLP patterns obtained with three endonucleases produced groups congruent with species assignment and highlighted intra-species diversity similar to that observed by M13 fingerprinting. However, IGS PCR amplification failed for 14 ML and 6 Z. mellis strains under the experimental conditions tested here, indicating that this marker could be less easy to use in fast typing protocol. Finally, our results posit that the genetic diversity within Z. sapae and Z. mellis could be shaped by isolation source. The information generated in this study would facilitate the monitoring of these yeasts during food processing and storage, and provides preliminary evidences about Z. sapae and Z. mellis intra-species diversity. [ABSTRACT FROM AUTHOR]

Multidrug resistance of the pathogenic microorganisms to the antimicrobial drugs has become a major impediment toward successful diagnosis and management of infectious diseases. Recent advancements in nanotechnology-based medicines have opened new horizons for combating multidrug resistance in microorganisms. In particular, the use of silver nanoparticles (AgNPs) as a potent antibacterial agent has received much attention. The most critical physico-chemical parameters that affect the antimicrobial potential of AgNPs include size, shape, surface charge, concentration and colloidal state. AgNPs exhibits their antimicrobial potential through multifaceted mechanisms. AgNPs adhesion to microbial cells, penetration inside the cells, ROS and free radical generation, and modulation of microbial signal transduction pathways have been recognized as the most prominent modes of antimicrobial action. On the other side, AgNPs exposure to human cells induces cytotoxicity, genotoxicity, and inflammatory response in human cells in a cell-type dependent manner. This has raised concerns regarding use of AgNPs in therapeutics and drug delivery. We have summarized the emerging endeavors that address current challenges in relation to safe use of AgNPs in therapeutics and drug delivery platforms. Based on research done so far, we believe that AgNPs can be engineered so as to increase their efficacy, stability, specificity, biosafety and biocompatibility. In this regard, three perspectives research directions have been suggested that include (1) synthesizing AgNPs with controlled physico-chemical properties, (2) examining microbial development of resistance toward AgNPs, and (3) ascertaining the susceptibility of cytoxicity, genotoxicity, and inflammatory response to human cells upon AgNPs exposure. [ABSTRACT FROM AUTHOR]

The Zygosaccharomyces rouxii complex comprises three distinct lineages of halotolerant yeasts relevant in food processing and spoilage, such as Z. sapae, Z. rouxii and a mosaic group of allodiploid strains. They manifest plastic genome architecture (variation in karyotype, ploidy level and Na+/H+ antiporter-encoding gene copy number), and exhibit diverse tolerances to salt concentrations. Here, we investigated accumulation of compatible osmolytes and transcriptional regulation of Na+/H+ antiporter-encoding ZrSOD genes during salt exposure in strains representative for the lineages, namely Z. sapae ABT301T (low salt tolerant), Z. rouxii CBS 732T (middle salt tolerant) and allodiploid strain ATCC 42981 (high salt tolerant). Growth curve modelling in 2 M NaCl-containing media supplemented with or without yeast extract as nitrogen source indicates that moderate salt tolerance of CBS 732T mainly depends on nitrogen availability rather than intrinsic inhibitory effects of salt. All the strains produce glycerol and not mannitol under salt stress and use two different glycerol balance strategies. ATCC 42981 produces comparatively more glycerol than Z. sapae and Z. rouxii under standard growth conditions and better retains it intracellularly under salt injuries. Conversely, Z. sapae and Z. rouxii enhance glycerol production under salt stress and intracellularly retain glycerol less efficiently than ATCC 42981. Expression analysis shows that, in diploid Z. sapae and allodiploid ATCC 42981, transcription of gene variants ZrSOD2-22/ZrSOD2 and ZrSOD22 is constitutive and salt unresponsive. [ABSTRACT FROM AUTHOR]

Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. Here, GWAS (Genome wide association studies) discovery and replication studies, as well as the re-sequencing of ISL1, identified sequence variants (rs9291768, rs6874700, c.137C > G (p.Ala46Gly)) associated with CBE. Here, we aimed to determine the molecular and functional consequences of these sequence variants and estimate the dependence of ISL1 protein on other predicted candidates. We used: (i) computational analysis of conserved sequence motifs to perform an evolutionary conservation analysis, based on a Bayesian algorithm, and (ii) computational 3D structural modeling. Furthermore, we looked into long non-coding RNAs (lncRNAs) residing within the ISL1 region, aiming to predict their targets. Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C > G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor α interactions. In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder. [ABSTRACT FROM AUTHOR]

• Intracellular adhesion molecule 1 (ICAM-1) is one of the most extensively studied inducible cell adhesion molecule which is responsible for several immune functions. • The molecule is constitutively expressed over the cell surface and is regulated up / down in response to inflammatory mediators. • The presence of various binding sites for NF-κB, AP-1, SP-1 and many other transcription factors, architecture of ICAM-1 promoter become complex. • Transcription factors in union with other transcription factors, coactivators and suppressors promote their assembly in stereospecific manner on ICAM-1 promoter which mediates ICAM-1 regulation in response to different stimuli. • In this review, we summarize the regulation of ICAM-1 expression both at transcriptional as well as post transcriptional level. Intracellular adhesion molecule 1 (ICAM-1) is one of the most extensively studied inducible cell adhesion molecules which is responsible for several immune functions like T cell activation, extravasation, inflammation, etc. The molecule is constitutively expressed over the cell surface and is regulated up / down in response to inflammatory mediators like cellular stress, proinflammatory cytokines, viral infection. These stimuli modulate the expression of ICAM-1 primarily through regulating the ICAM-1 gene transcription. On account of the presence of various binding sites for NF-κB, AP-1, SP-1, and many other transcription factors, the architecture of the ICAM-1 promoter become complex. Transcription factors in union with other transcription factors, coactivators, and suppressors promote their assembly in a stereospecific manner on ICAM-1 promoter which mediates ICAM-1 regulation in response to different stimuli. Along with transcriptional regulation, epigenetic modifications also play a pivotal role in controlling ICAM-1 expression on different cell types. In this review, we summarize the regulation of ICAM-1 expression both at the transcriptional as well as post-transcriptional level with an emphasis on transcription factors and signaling pathways involved. [ABSTRACT FROM AUTHOR]