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Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca 2+ -dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) technology-mediated genome editing has significantly improved the targeted inactivation of genes in vitro and in vivo in many organisms. Neuropilins play crucial roles in zebrafish heart regeneration, heart failure in mice, and electrical remodeling after myocardial infarction in rats. But the cell-specific functions of nrp1 have not been described before. In this study, we have investigated the role of nrp1 isoforms, including nrp1a and nrp1b , in cardiomyocytes during cardiac injury and regeneration in adult zebrafish hearts., Methods: In this study, we have reported a novel CRISPR-based vector system for conditional tissue-specific gene ablation in zebrafish. Specifically, the cardiac-specific cmlc2 promoter drives Cas9 expression to silence the nrp1 gene in cardiomyocytes in a heat-shock inducible manner. This vector system establishes a unique tool to regulate the gene knockout in both the developmental and adult stages and hence widens the possibility of loss-of-function studies in zebrafish at different stages of development and adulthood. Using this approach, we investigated the role of neuropilin isoforms nrp1a and nrp1b in response to cardiac injury and regeneration in adult zebrafish hearts., Results: We observed that both the isoforms ( nrp1a and nrp1b ) are upregulated after the cryoinjury. Interestingly, the nrp1b knockout significantly delayed heart regeneration and impaired cardiac function in the adult zebrafish after cryoinjury, demonstrated by reduced heart rate, ejection fractions, and fractional shortening. In addition, we show that the knockdown of nrp1b but not nrp1a induces activation of the cardiac remodeling genes in response to cryoinjury., Conclusions: To our knowledge, this study is novel where we have reported a heat-shock-mediated conditional knockdown of nrp1a and nrp1b isoforms using CRISPR/Cas9 technology in the cardiomyocyte in zebrafish and furthermore have identified a crucial role for the nrp1b isoform in zebrafish cardiac remodeling and eventually heart function in response to injury., Competing Interests: Disclosures None.

Mean arterial pressure (MAP) is often estimated from cuff systolic (S) and diastolic (D) blood pressure (BP) using a fixed arterial form factor (FF, usually 0.33). If MAP is measured directly, a true FF can be calculated: FF = [MAP-DBP]/[SBP-DBP]. Because waveform shapes vary, true FF should also vary and MAP accuracy will be affected. We studied factors affecting FF using radial tonography (SphygmoCor, n = 376) or brachial oscillometry (Mobil-O-Graph, n = 157) and to compare devices, 101 pairs were matched precisely for SBP and DBP. SphygmoCor brachioradial FF correlated strongly with central FF (r 2  = 0.75), central augmentation index (cAI, r 2  = 0.39), and inversely with pulse pressure amplification (PPA) ratio (r 2  = 0.44) [all p < 0.000]; brachioradial FF was lower than central (c) FF (0.34 vs. 0.44, 95% CI's [0.23,0.46] and [0.34,0.54], p < 0.000). On forward stepwise regression, brachioradial FF correlated with PPA ratio, age, heart rate, and cAI (multiple-r 2 0.63, p < 0.000). With Mobil-O-Graph: brachial FF was fixed, lower than the corresponding cFF [mean(SD)] 0.46(0.00098) vs. 0.57(0.048), p < 0.000], and uncorrelated with clinical characteristics; MAP and cSBP were higher than SphygmoCor by 6.3 and 2.2 mmHg (p < 0.005) at the midpoint with systematic negative biases. We conclude that FF derived from radial tonometry (SphygmoCor) varies with pulse wave morphology within and between individuals and by measurement site, age, and heart rate. With oscillometry (Mobil-O-Graph), brachial FF was fixed and high and unrelated to other clinical variables; MAP and cSBP were higher than tonometry, with systematic negative biases., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Priya Srinivas1,2, Chitta Ranjan Patra2,4, Santanu Bhattacharya2, Debabrata Mukhopadhyay2,31Integrated Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala, India; 2Department of Biochemistry and Molecular Biology; 3Department of Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Department of Chemical Biology, Indian Institute of Chemical Technology, Hyderabad, IndiaAbstract: Several reports have demonstrated the anticancer activities of plumbagin, a naphthoquinone derivative isolated from plants belonging to Plumbaginaceae family. However, to the best of our knowledge, there are no reports which describe gold nanoconjugation with plumbagin, even though plumbagin is considered to be a promising therapeutic agent. In this report, we demonstrate the fabrication and characterization of gold nanoparticles conjugated with plumbagin (AuPB) that can reduce the toxicity of the latter, and their capacity for cellular localization and generation of reactive oxygen species. The anticancer activity and ability of plumbagin to produce reactive oxygen species was studied and compared with that of bromoderivatives of 1,4 naphthoquinones such as 2-bromo-1,4-naphthoquinone (2-BNQ) and 2,3-dibromo-1, 4-naphthoquinone (2,3-DBNQ) and their gold nanoconjugates. Plumbagin and bromoderivatives of 1,4 naphthoquinones in the form of gold nanoconjugates showed reduced cytotoxicity and apoptosis compared with the pristine compounds, ie, plumbagin, 2-BNQ, and 2,3-DBNQ. Interestingly, we observed that the gold nanoparticles could quench the reactive oxygen species-generating capacity of plumbagin, 2-BNQ, and 2,3-BNQ, which is one of the main mechanisms of action of the naphthoquinones. Therefore, it can be concluded that conjugation with gold nanoparticles can reduce the cytotoxicity of these compounds.Keywords: plumbagin, gold nanoparticles, reactive oxygen species, naphthoquinones, breast cancer

Catalysis by trivalent nucleophilic organophosphines has emerged as an essential tool in organic synthesis. Several new organic transformations promoted by phosphines substantiate and complement the existing synthetic chemistry tools. Mere design of the substrate and reagent combinations has introduced new modes of reactivity patterns, which are otherwise difficult to achieve. These design considerations have led to the rapid build-up of complex molecular entities and laid a solid foundation to synthesise bioactive natural products and pharmaceuticals. This article presents an overview of some of the conceptual advances, including our contributions to nucleophilic organophosphine chemistry. The scope, limitations, mechanistic insights, and applications of these metal-free transformations are discussed elaborately.

Objectives: The presentation and outcomes of acute decompensated heart failure (ADHF) during COVID times (June 2020 to Dec 2020) were compared with the historical control during the same period in 2019., Methods: Data of 4806 consecutive patients of acute HF admitted in 22 centres in the country were collected during this period. The admission patterns, aetiology, outcomes, prescription of guideline-directed medical therapy (GDMT) and interventions were analysed in this retrospective study., Results: Admissions for acute heart failure during the pandemic period in 2020 decreased by 20% compared to the corresponding six-month period in 2019, with numbers dropping from 2675 to 2131. However, no difference in the epidemiology was seen. The mean age of presentation in 2019 was 61.75 (±13.7) years, and 59.97 (±14.6) years in 2020. There was a significant decrease in the mean age of presentation (p = 0.001). Also. the proportion of male patients decreased significantly from 68.67% to 65.84% (p = 0.037). The in-hospital mortality for acute heart failure did not differ significantly between 2019 and 2020 (4.19% and 4.,97%) respectively (p = 0.19). The proportion of patients with HFrEF did not change in 2020 compared to 2019 (76.82% vs 75.74%, respectively). The average duration of hospital stay was 6.5 days., Conclusion: The outcomes of ADHF patients admitted during the Covid pandemic did not differ significantly. The length of hospital stay remained the same. The study highlighted the sub-optimal use of GDMT, though slightly improving over the last few years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ALL PARTICIPATING CENTRE CO INVESTIGATORS reports financial support was provided by Cardiological Society of India., (Copyright © 2023 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

Background: Globally, patients with diabetes suffer from increased disease severity and mortality due to coronavirus disease 2019 (COVID-19). Old age, high body mass index (BMI), comorbidities, and complications of diabetes are recognized as major risk factors for infection severity and mortality., Aim: To investigate the risk and predictors of higher severity and mortality among in-hospital patients with COVID-19 and type 2 diabetes (T2D) during the first wave of the pandemic in Dubai (March-September 2020)., Methods: In this cross-sectional nested case-control study, a total of 1083 patients with COVID-19 were recruited. This study included 890 men and 193 women. Of these, 427 had T2D and 656 were non-diabetic. The clinical, radiographic, and laboratory data of the patients with and without T2D were compared. Independent predictors of mortality in COVID-19 non-survivors were identified in patients with and without T2D., Results: T2D patients with COVID-19 were older and had higher BMI than those without T2D. They had higher rates of comorbidities such as hypertension, ischemic heart disease, heart failure, and more life-threatening complications. All laboratory parameters of disease severity were significantly higher than in those without T2D. Therefore, these patients had a longer hospital stay and a significantly higher mortality rate. They died from COVID-19 at a rate three times higher than patients without. Most laboratory and radiographic severity indices in non-survivors were high in patients with and without T2D. In the univariate analysis of the predictors of mortality among all COVID-19 non-survivors, significant associations were identified with old age, increased white blood cell count, lym-phopenia, and elevated serum troponin levels. In multivariate analysis, only lymphopenia was identified as an independent predictor of mortality among T2D non-survivors., Conclusion: Patients with COVID-19 and T2D were older with higher BMI, more comorbidities, higher disease severity indices, more severe proinflammatory state with cardiac involvement, and died from COVID-19 at three times the rate of patients without T2D. The identified mortality predictors will help healthcare workers prioritize the management of patients with COVID-19., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

We aimed to understand the crosstalk between mismatch repair (MMR) and FA-BRCA pathway in primary bladder carcinoma (BlCa) samples as well as in chemotolerant cell line. We analysed the genetic alterations of MLH1 and MSH2 (MMR-related genes) and after that we correlated it with the nuclear translocation of FANCD2 protein. Next, we evaluated this crosstalk in T24 BlCa cell line in response to doxorubicin treatment. In primary BlCa tumors, infrequent genetic deletion (17-20%) but frequent promoter methylation (28-55%) of MLH1 and MSH2 was observed, where MLH1 was significantly (p < 0.05) more methylated among the early staged samples (NMIBC). However, MSH2 was significantly more altered among the NMIBC samples, signifying the importance of MMR pathway during the early pathogenesis of the disease. Furthermore, BlCa samples with underexpressed MLH1/MSH2 protein possessed cytoplasmic FANCD2 protein; encouraging that inefficiency of MMR proteins might restrict FANCD2 nuclear translocation. Next, we analysed publicly available data in GEO2R tool where we observed that in response to chemotherapeutic drugs, expression of MLH1, MSH2 and FANCD2 were diminishing. Validating this result in doxorubicin tolerant T24 cells, we found that expression of MLH1 and MSH2 was gradually decreased with increasing dose of doxorubicin. Interestingly, FANCD2 mono-ubiquitination (L-form) was also reduced in chemotolerant T24 cells. The crosstalk between MMR and FA-BRCA pathway was substantiated in the primary BlCa tumors. Further, in response to doxorubicin, this crosstalk was found to be hampered due to under-expression of MLH1 and MSH2 gene, thereby rendering chemotolerance., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2's known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2., (© 2023. The Author(s).)

Toxoplasma virulence depends on its ability to evade or survive the toxoplasmacidal mechanisms induced by interferon gamma (IFNγ). While many Toxoplasma genes involved in the evasion of the murine IFNγ response have been identified, genes required to survive the human IFNγ response are largely unknown. In this study, we used a genome-wide loss-of-function screen to identify Toxoplasma genes important for parasite fitness in IFNγ-stimulated primary human fibroblasts. We generated gene knockouts for the top six hits from the screen and confirmed their importance for parasite growth in IFNγ-stimulated human fibroblasts. Of these six genes, three have homology to GRA32, localize to dense granules, and coimmunoprecipitate with each other and GRA32, suggesting they might form a complex. Deletion of individual members of this complex leads to early parasite egress in IFNγ-stimulated cells. Thus, prevention of early egress is an important Toxoplasma fitness determinant in IFNγ-stimulated human cells. IMPORTANCE Toxoplasma infection causes serious complications in immunocompromised individuals and in the developing fetus. During infection, certain immune cells release a protein called interferon gamma that activates cells to destroy the parasite or inhibit its growth. While most Toxoplasma parasites are cleared by this immune response, some can survive by blocking or evading the IFNγ-induced restrictive environment. Many Toxoplasma genes that determine parasite survival in IFNγ-activated murine cells are known but parasite genes conferring fitness in IFNγ-activated human cells are largely unknown. Using a Toxoplasma adapted genome-wide loss-of-function screen, we identified many Toxoplasma genes that determine parasite fitness in IFNγ-activated human cells. The gene products of four top hits play a role in preventing early parasite egress in IFNγ-stimulated human cells. Understanding how IFNγ-stimulated human cells inhibit Toxoplasma growth and how Toxoplasma counteracts this, could lead to the development of novel therapeutics.

Layered anorthosite, chromiferous pyroxenite, and spatially associated mafic and felsic rocks of the 2.9 Ga Sittampundi layered complex (SLC), South India, underwent high-grade metamorphism at ca. 2.5 Ga and were subjected to amphibolite-facies metamorphism accompanied by intrusion of granitoid plutons during late-Neoproterozoic tectonothermal activity (0.72-0.45 Ga). During the latter event, anorthosite developed millimeter- to centimeter-thick compositional layers rich in clinopyroxene+amphibole+clinozoisite+chlorite [+ or -] chromite and corundum+spinel+chlorite. Tiny grains of hogbomite replaced only the grains of corundum and spinel and are in textural equilibrium with chlorite. The studied hogbomite contains appreciable Ti[O.sub.2] (>4.4 wt%) but insignificant NiO and ZnO. [Cr.sub.2][O.sub.3] content reaches up to 0.35 wt% only in chromite-bearing samples. Systematic partitioning of Fe and Mg between hogbomite and associated Fe-Mg minerals demonstrate attainment of chemical equilibrium among these phases. Integrating textural relations and algebraic analyses of the phase compositions, several reactions were constructed involving the associated oxide phases (spinel, corundum, hogbomite), calcite, and silicates (amphibole, chlorite, anorthite, clinozoisite). Interpretation of the reaction reveals that (1) [Mg.sup.2+] and [Ti.sup.4+] were mobile for more than 2 cm during the formation of hogbomite and chlorite, and (2) chloritization of amphibole in the clinopyroxene+amphibole-bearing layers released Ti that was transported to the spinel+corundum-bearing layers to develop hogbomite. Stability fields of some critical mineral assemblages in [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.] space combined with geothermobarometry in the associated rocks tightly constrain the growth of hogbomite in the presence of aqueous fluids ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.] < 0.15) to the P- Trange of 7 [+ or -] 1 kbar, 650 [+ or -] 50[degrees]C. These aqueous fluids, presumably derived from the Pan-African granitoid batholiths, chloritized amphibole grains, and transported the released [Ti.sup.4+] to the spinel+corundum-bearing layers to develop hogbomite. Topological relations in isothermal-isobaric fugacity diagrams ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) in the system FeO-[A1.sub.2][O.sub.3]Ti[O.sub.2]-[O.sub.2]-[S.sub.2]-[H.sub.2]0-C[O.s (+MgO, [Cr.sub.2][O.sub.3]) indicate that the stability and compositional characteristics of natural h6gbomite are strongly influenced by [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.], and concentrations of other soluble species (Ti, Mg, Cr, etc.) in the metamorphic fluids. Keywords: Hogbomite, corundum, spinel, anorthosite, Ti-mobility, Sittampundi, South India DOI: 10.2138/am.2009.3121

The paper evaluates the impact of Foreign Direct Investment (FDI) on small-scale retailers. The study operationalizes the constructs with the variables: Backend infrastructure in less developed market, employment opportunity, investment capacity of neighborhood stores, investment capacity of big stores of Indian companies, investment capacity of FDI stores, investment capacity of online retailers, growth of neighborhood stores, growth of big stores of Indian companies, growth of FDI stores, growth of online retailers, and Business Environment Factors (BEF). The study was conducted on a sample of 500 respondents in Delhi National Capital Region (NCR). In retrospective, coefficient of investment capacity of FDI stores and growth of FDI stores show significantly negative impact on backend infrastructure in less developed market and employment opportunity. [ABSTRACT FROM AUTHOR]