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Background The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation. Results HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate with APOBEC3 mutagenesis in vivo . HER2-enriched breast carcinomas display evidence of elevated levels of replication stress-associated DNA damage in vivo . Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro . APOBEC3B activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation. Conclusion These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.

Rice metabolomics is widely used for biomarker research in the fields of pharmacology. As a consequence, characterization of the variations of the pigmented and non-pigmented traditional rice varieties of Tamil Nadu is crucial. These varieties possess fatty acids, sugars, terpenoids, plant sterols, phenols, carotenoids and other compounds that plays a major role in achieving sustainable development goal 2 (SDG 2). Gas-chromatography coupled with mass spectrometry was used to profile complete untargeted metabolomics of Kullkar (red colour) and Milagu Samba (white colour) for the first time and a total of 168 metabolites were identified. The metabolite profiles were subjected to data mining processes, including principal component analysis (PCA), Orthogonal Partial Least Square Discrimination Analysis (OPLS-DA) and Heat map analysis. OPLS-DA identified 144 differential metabolites between the 2 rice groups, variable importance in projection (VIP) ≥ 1 and fold change (FC) ≥ 2 or FC ≤ 0.5. Volcano plot (64 down regulated, 80 up regulated) was used to illustrate the differential metabolites. OPLS-DA predictive model showed good fit (R2X = 0.687) and predictability (Q2 = 0.977). The pathway enrichment analysis revealed the presence of three distinct pathways that were enriched. These findings serve as a foundation for further investigation into the function and nutritional significance of both pigmented and non-pigmented rice grains thereby can achieve the SDG 2.

Background COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. Methods In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. Results Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-β1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. Conclusion Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.

Naive CD4 + T cells differentiate into effector (Th1, Th2, Th17) cells and immunosuppressive (Treg) cells upon antigenic stimulation in the presence of a specific cytokine milieu. The T cell in vitro culture system provides a very efficient model to study compounds’ therapeutic activity and mechanism of action. Tinospora cordifolia (Willd.) Hook.f. & Thomson (Family. Menispermaceae) is one of the widely used drugs in Ayurveda (ancient Indian system of medicine) for various ailments such as inflammatory conditions, autoimmune disorders, and cancer as well as for promoting general health. In vitro and in vivo studies on immune cells comprising dendritic cells, macrophages, and B cells suggest its immune-modulating abilities. However, to date, the effect of T. cordifolia on individual purified and polarized T cell subsets has not been studied. Studying drug effects on T cell subsets is needed to understand their immunomodulatory mechanism and to develop treatments for diseases linked with T cell abnormalities. In this study, we examined the immunomodulatory activity of T. cordifolia on primary CD4 + T cells, i.e., Th1, Th17, and iTreg cells. An aqueous extract of T. cordifolia was non-cytotoxic at concentrations below 1500 µg/ml and moderately inhibited the proliferation of naive CD4 + T cells stimulated with anti-CD3ε and anti-CD28 for 96 h. T. cordifolia treatment of naive CD4 + T cells differentiated under Th17-polarizing conditions exhibited reduced frequency of IL-17 producing cells with inhibition of differentiation and proliferation. For the first time, in-depth genome-wide expression profiling of T. cordifolia treated naive CD4 + T cells, polarized to Th17 cells, suggests the broad-spectrum activity of T. cordifolia . It shows inhibition of the cytokine-receptor signaling pathway, majorly via the JAK-STAT signaling pathway, subsequently causing inhibition of Th17 cell differentiation, proliferation, and effector function. Additionally, the molecular docking studies of the 69 metabolites of T. cordifolia further substantiate the inhibitory activity of T. cordifolia via the cytokine-receptor signaling pathway. Furthermore, in vitro polarized Th1 and iTreg cells treated with T. cordifolia extract also showed reduced IFN-γ production and FoxP3 expression, respectively. This study provides insight into the plausible mechanism/s of anti-inflammatory activity of T. cordifolia involving T cells, mainly effective in Th17-associated autoimmune and inflammatory diseases.

The process of angiogenesis is a vital step towards the formation of malignant tumors. Anti-angiogenic peptides are therefore promising candidates in the treatment of cancer. In this study, we have collected anti-angiogenic peptides from the literature and analyzed the residue preference in these peptides. Residues like Cys, Pro, Ser, Arg, Trp, Thr and Gly are preferred while Ala, Asp, Ile, Leu, Val and Phe are not preferred in these peptides. There is a positional preference of Ser, Pro, Trp and Cys in the N terminal region and Cys, Gly and Arg in the C terminal region of anti-angiogenic peptides. Motif analysis suggests the motifs \"CG-G\", \"TC\", \"SC\", \"SP-S\", etc., which are highly prominent in anti-angiogenic peptides. Based on the primary analysis, we developed prediction models using different machine learning based methods. The maximum accuracy and MCC for amino acid composition based model is 80.9% and 0.62 respectively. The performance of the models on independent dataset is also reasonable. Based on the above study, we have developed a user-friendly web server named \"AntiAngioPred\" for the prediction of anti-angiogenic peptides. AntiAngioPred web server is freely accessible at http://clri.res.in/subramanian/tools/antiangiopred/index.html (mirror site: http://crdd.osdd.net/raghava/antiangiopred/).

BRCA2 plays a critical role in stabilizing stalled replication forks, yet critical gaps remain in understanding how BRCA2 deficiency triggers fork collapse and drives genomic instability. Here, we identify cytidine deaminase APOBEC3B as a key driver of this process. Using a unique uracil-in-DNA probe, we show that BRCA2 loss promotes APOBEC3B-mediated uracil accumulation in single-stranded DNA (U-ssDNA) at stalled forks. These lesions when processed by UNG2 and APE1, trigger fork collapse and release ssDNA fragments into the cytoplasm, activating NF-κB signaling. This in turn upregulates APOBEC3B expression, establishing a self-reinforcing loop that amplifies cytidine deamination at stalled forks and exacerbates genomic instability. Depletion of APOBEC3B, UNG2, or APE1 rescues these defects. Notably, BRCA1-deficient cells do not accumulate U-ssDNA or induce APOBEC3B under replication stress, highlighting a BRCA2-specific vulnerability. Clinically, low APE1 expression correlates with poor survival in patients with BRCA2 -mutant tumors, with high APOBEC3 levels further worsening outcomes. Together, our findings establish that replication stress, whether intrinsic or therapy induced, triggers APOBEC3B overexpression and potentially activates an APOBEC3B-driven mutagenic loop in BRCA2-deficient cells. These results position APOBEC3B, UNG2 and APE1 as critical regulators of BRCA2 -mutant tumor evolution and therapy resistance. Here the authors reveal how replication stress in BRCA2-deficient cells triggers a mutagenic cycle of APOBEC3B upregulation, uracil accumulation at stalled forks, and DNA damage, uncovering a self-reinforcing loop that fuels genomic instability.

The effect of drupe size on in vivo and in vitro germination and its dormancy mechanism in teak have been studied in this paper. Teak drupes were size graded to five categories namely very large with more than 15 mm, large with 13 to <15 mm, medium with 11 to <13 mm, small with 9 to <11 mm and very small with less than 9 mm of diameter. Under in vivo pot culture condition very low germination percent of drupes was observed. It was observed that very large size drupe had highest 100 drupe weight, 100 true seed weight and seed filling capacity, but it was negatively correlated with in vivo germination of teak drupes. When true seeds isolated from the drupes were grown under in vitro condition in half strength MS medium the germination percent was significantly increased up to 54.1. True seeds obtained from small size graded drupes recorded highest germination per cent in MS media. This showed that the drupe size did not play major role in the germination and early growth in teak. Very small size graded drupes have low seed filling capacity, and it leads to decrease the germination percent. Poor germination of drupes showed the presence of mechanical and physiological dormancy in drupes. Similarly, the presence of morphological and embryo dormancy in teak may limit the true seed germination potential to 54.1 per cent. In addition, in vitro germination of true seeds will be a promising approach to obtain large number of saplings in teak.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the regulation of the extracellular signaling and structural matrix environment of cells and tissues. MMPs are considered as promising targets for the treatment of many diseases. Therefore, creation of database on the inhibitors of MMP would definitely accelerate the research activities in this area due to its implication in above-mentioned diseases and associated limitations in the first and second generation inhibitors. In this communication, we report the development of a new MMpI database which provides resourceful information for all researchers working in this field. It is a web-accessible, unique resource that contains detailed information on the inhibitors of MMP including small molecules, peptides and MMP Drug Leads. The database contains entries of ~3000 inhibitors including ~72 MMP Drug Leads and ~73 peptide based inhibitors. This database provides the detailed molecular and structural details which are necessary for the drug discovery and development. The MMpI database contains physical properties, 2D and 3D structures (mol2 and pdb format files) of inhibitors of MMP. Other data fields are hyperlinked to PubChem, ChEMBL, BindingDB, DrugBank, PDB, MEROPS and PubMed. The database has extensive searching facility with MMpI ID, IUPAC name, chemical structure and with the title of research article. The MMP inhibitors provided in MMpI database are optimized using Python-based Hierarchical Environment for Integrated Xtallography (Phenix) software. MMpI Database is unique and it is the only public database that contains and provides the complete information on the inhibitors of MMP. Database URL: http://clri.res.in/subramanian/databases/mmpi/index.php.

The emergence of the recent COVID-19 pandemic has rendered mandatory wearing of respiratory masks by infected persons, frontline workers, security personnel and members of the public. This has caused a sudden shift of focus, and significant demand on availability, effectiveness, reuse after sterilisation and development of facemask. Toward this, three types of masks viz. N95, non-woven fabric and double layer cotton cloth are being used by the majority of the population across the world as an essential inhalation protective measure for suppressing the entry of virus-laden respiratory droplets. The Filtering Efficiency ( FE ) of these masks are tested for atmospheric and laboratory-generated aerosols of size 1.0 µm and 102.7 nm particles before and after sterilisation and the two flow rate conditions corresponding to normal breath rate and during sneezing/coughing. Sterilisation is carried out using a gamma irradiator containing Co-60 source for the two-dose exposures viz. 15 kGy and 25 kGy. The FE of surgical and cloth masks is found to be in the range of 15.76 ± 0.22 to 22.48 ± 3.92%, 49.20 ± 8.44 to 60 ± 7.59% and 73.15 ± 3.73 to 90.36 ± 4.69% for aerosol sizes 0.3–5.0, 1.0–5.0 and 3.0–5.0 µm atmospheric aerosols respectively. The FE of cloth and surgical masks ranges from 45.07 ± 6.69% to 63.89 ± 4.44% and 56.58 ± 1.69% to 83.95 ± 1.04% for 1.0 µm laboratory-generated aerosol for two flow rate, control and irradiated conditions. The FE of N95 mask is found to be more than 95% for atmospheric aerosol, and 1.0 µm laboratory-generated aerosol. However, FE reduced to about 70% for most penetrating particle size after sterilisation. Further, FE reduced to 84% for the particle > 0.3 µm and to 87% for the particle < 0.3 µm after sterilisation. The reduction in FE for N95 mask after sterilization is associated with the reduction of electrostatic interaction of filter medium with particles laden in the air stream. Instead of disposing of N95 masks after a single use, they can be reused a few times as N70 mask during this pandemic crisis after sterilisation. The use of cotton cloth masks in the general public serves fit for the purpose than surgical masks.

Poor seed germination is a major issue in teak (Tectona grandis) propagation. Teak seed dormancy is thought to be the reason for delayed germination. So far, specific dormancy mechanisms have not yet been identified. In order to study the influence of presowing treatments on germination, seedling vigour, and biochemical attributes of fresh teak drupes collected from the seed production area of Top Slip in Tamil Nadu. The collected drupes were subjected to different presowing treatments viz., T1 - control, T2 - soaking and drying for 6 days, T3 – T18 (soaking and drying for 5 days + soaking in different concentrations of thiourea, potassium nitrate, hydrogen peroxide and calcium oxychloride for 12 hours). Treated drupes were placed for germination in earthen pots and kept in open sunlight. In parallel, true seeds extracted from untreated drupes were also subjected to germination under in vitro conditions as a check. A higher percentage of germination (40%) was recorded in true seeds under in vitro conditions when compared to the treated and untreated drupes under in vivo conditions. Among the treated drupes sown under in vivo conditions, the drupes given soaking + drying for 5 days + soaking in 2% calcium oxychloride (CaOCl2) recorded higher germination (17.16) with better seedling vigour. Analysis of teak true seeds and mesocarp extract in high-performance liquid chromatography showed that gibberellic acid was found only in true seeds, whereas the other compounds, viz., indole-3-acetic acid, indole butyric acid, abscisic acid and coumarin, were not present in the true seed or mesocarp.