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Nature possesses an inexhaustible reservoir of agents that could serve as alternatives to combat the growing threat of antimicrobial resistance (AMR). While some of the most effective drugs for treating bacterial infections originate from natural sources, they have predominantly been derived from fungal and bacterial species. However, a substantial body of literature is available on the promising antibacterial properties of plant-derived compounds. In this comprehensive review, we address the major challenges associated with the discovery and development of plant-derived antimicrobial compounds, which have acted as obstacles preventing their clinical use. These challenges encompass limited sourcing, the risk of agent rediscovery, suboptimal drug metabolism, and pharmacokinetics (DMPK) properties, as well as a lack of knowledge regarding molecular targets and mechanisms of action, among other pertinent issues. Our review underscores the significance of these challenges and their implications in the quest for the discovery and development of effective plant-derived antimicrobial agents. Through a critical examination of the current state of research, we give valuable insights that will advance our understanding of these classes of compounds, offering potential solutions to the global crisis of AMR. © 2017 Elsevier Inc. All rights reserved.
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Granular materials show inhomogeneous flows characterized by strain localization. When strain is localized in a sheared granular material, rigid regions of a nearly undeformed state are separated by shear bands, where the material yields and flows. The characteristics of the shear bands are determined by the geometry of the system, the micromechanical material properties, and the kinematics at the particle level. For a split-bottom shear cell, recent experimental work has shown that mixtures of hard, frictional and soft, nearly frictionless particles exhibit wider shear zones than samples with only one of the two components. To explain this finding, we investigate the shear zone properties and the stress response of granular mixtures using discrete element simulations. We show that both interparticle friction and elastic modulus determine the shear-band properties and packing density of granular mixtures of various mixing ratios, but their stress response depends strongly on the interparticle friction. Our study provides a fundamental understanding of the micromechanics of shear band formation in granular mixtures.
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Decentralised clinical trials (DCTs) encompass various terms such as virtual, home-based, remote and siteless trials. The objectives of DCTs are to enhance the ease of participation for patients in clinical trials by minimising or removing the necessity for trial subjects to travel to the trial sites. This approach has been shown to reduce drop-out rates, increase study effectiveness and ultimately get life-altering drugs to market faster-saving sponsors billions. At the outset, DCTs deploy a wide range of digital technologies to collect safety and efficacy data from study participants, providing study treatments and performing investigations from the comfort of the patient's own home. The aim of decentralised trials includes patient centricity, enhanced efficacy in clinical trial conduct and generating real-world data. This is done by not only making it convenient for the patient to participate in the trial execution, but also involving them from the planning stage and taking their inputs during designing of trials and consenting documentation, understanding their treatment requirements and designing the studies accordingly. Various regulatory authorities have published guidelines governing DCT principles, especially after the coronavirus disease 2019 (COVID-19) experience of undertaking multicentric clinical trials. Both United States Food and Drug Administration (USFDA) and European Medicines Agency (EMA) have newer, recently updated guidelines to capture this growing reality to undertake clinical trials using patient technology or patient-centric technologies. Other regulatory agencies are accepting data generated using decentralised and patient-centric technologies and making an effort to include elements of decentralised trials in their regulatory guidelines. Decentralised trials follow a hybrid approach to have a balanced mix of remote and in-person data collection and trial procedures. Decentralised and patient-centric approaches are the future of any organisation for the conduct of clinical trials. Globally, all sponsor pharmaceutical companies must start undertaking drug development and clinical trials using a decentralised approach while keeping patient centricity in mind.
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COVID-19 , Humanos , Pacientes , Política , Estados Unidos , Ensayos Clínicos como AsuntoRESUMEN
Here, we report the first transition-metal-free defluorinative cycloaddition of gem-difluoroalkenes with organic azides in morpholine as a solvent to construct fully decorated morpholine-substituted 1,2,3-triazoles. Mechanistic studies revealed the formation of an addition-elimination intermediate of morpholine and gem-difluoroalkenes prior to the triazolization reaction via two plausible pathways. Attractive elements include the regioselective and straightforward direct synthesis of fully substituted 1,2,3-triazoles, which are otherwise difficult to access, from readily available starting materials.
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The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against Mtb. The potent analogs demonstrated no cytotoxicity in mammalian cells at over 100 times the effective concentration required in Mtb and were bactericidal against Mtb during infection of macrophages. In the exploratory ADME investigations, we observed suboptimal ADME characteristics, which prompted us to identify potential metabolic liabilities for further optimization. Our preliminary investigations into the mechanism of action suggest that this series is not engaging the promiscuous targets that arise from many phenotypic screens. We selected for resistant mutants with the nanomolar potent nitro-containing compound 20 and identified resistant isolates with mutations in genes required for coenzyme F420 biosynthesis and the nitroreductase Ddn. This suggests that the aromatic nitro-1,2,4-triazolyl pyridines are activated by F420-dependent Ddn activity, similar to the nitro-containing TB drug pretomanid. We were able to circumvent the requirement for F420-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.
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Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Animales , Antituberculosos/farmacología , Mamíferos , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
The RNA-binding protein Hu antigen R (HuR) is a post-transcriptional regulator critical in several types of diseases, including cancer, making it a promising therapeutic target. We have identified small-molecule inhibitors of HuR through a screening approach used in combination with fragment analysis. A total of 36 new compounds originating from fragment linking or structural optimization were studied to establish structure-activity relationships in the set. Two top inhibitors, 1c and 7c, were further validated by binding assays and cellular functional assays. Both block HuR function by directly binding to the RNA-binding pocket, inhibit cancer cell growth dependence of HuR, and suppress cancer cell invasion. Intraperitoneal administration of inhibitor 1c inhibits tumor growth as a single agent and shows a synergistic effect in combination with chemotherapy docetaxel in breast cancer xenograft models. Mechanistically, 1c interferes with the HuR-TGFB/THBS1 axis.
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Neoplasias , Humanos , Xenoinjertos , Transformación Celular Neoplásica , Línea Celular TumoralRESUMEN
Myocardial ischemia/reperfusion (I/R) injury and the resulting cardiac remodeling is a common cause of heart failure. The RNA binding protein Human Antigen R (HuR) has been previously shown to reduce cardiac remodeling following both I/R and cardiac pressure overload, but the full extent of the HuR-dependent mechanisms within cells of the myocardium have yet to be elucidated. In this study, we applied a novel small molecule inhibitor of HuR to define the functional role of HuR in the acute response to I/R injury and gain a better understanding of the HuR-dependent mechanisms during post-ischemic myocardial remodeling. Our results show an early (two hours post-I/R) increase in HuR activity that is necessary for early inflammatory gene expression by cardiomyocytes in response to I/R. Surprisingly, despite the reductions in early inflammatory gene expression at two hours post-I/R, HuR inhibition has no effect on initial infarct size at 24-hours post-I/R. However, in agreement with previously published work, we do see a reduction in pathological remodeling and preserved cardiac function at two weeks post-I/R upon HuR inhibition. RNA-sequencing analysis of neonatal rat ventricular myocytes (NRVMs) at two hours post-LPS treatment to model damage associated molecular pattern (DAMP)-mediated activation of toll like receptors (TLRs) demonstrates a broad HuR-dependent regulation of pro-inflammatory chemokine and cytokine gene expression in cardiomyocytes. We show that conditioned media from NRVMs pre-treated with HuR inhibitor loses the ability to induce inflammatory gene expression in bone marrow derived macrophages (BMDMs) compared to NRVMs treated with LPS alone. Functionally, HuR inhibition in NRVMs also reduces their ability to induce endocrine migration of peripheral blood monocytes in vitro and reduces post-ischemic macrophage infiltration to the heart in vivo. In summary, these results suggest a HuR-dependent expression of pro-inflammatory gene expression by cardiomyocytes that leads to subsequent monocyte recruitment and macrophage activation in the post-ischemic myocardium.
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Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts to active myofibroblasts, which have extracellular matrix (ECM) remodeling and contractile functions which play a central role in cardiac remodeling in response to injury. Here, we show that expression and activity of the RNA binding protein HuR is increased in cardiac fibroblasts upon transformation to an active myofibroblast. Pharmacological inhibition of HuR significantly blunts the TGFß-dependent increase in ECM remodeling genes, total collagen secretion, in vitro scratch closure, and collagen gel contraction in isolated primary cardiac fibroblasts, suggesting a suppression of TGFß-induced myofibroblast activation upon HuR inhibition. We identified twenty-four mRNA transcripts that were enriched for HuR binding following TGFß treatment via photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Eleven of these HuR-bound mRNAs also showed significant co-expression correlation with HuR, αSMA, and periostin in primary fibroblasts isolated from the ischemic-zone of infarcted mouse hearts. Of these, WNT1-inducible signaling pathway protein-1 (Wisp1; Ccn4), was the most significantly associated with HuR expression in fibroblasts. Accordingly, we found Wisp1 expression to be increased in cardiac fibroblasts isolated from the ischemic-zone of mouse hearts following ischemia/reperfusion, and confirmed Wisp1 expression to be HuR-dependent in isolated fibroblasts. Finally, addition of exogenous recombinant Wisp1 partially rescued myofibroblast-induced collagen gel contraction following HuR inhibition, demonstrating that HuR-dependent Wisp1 expression plays a functional role in HuR-dependent MF activity downstream of TGFß. In conclusion, HuR activity is necessary for the functional activation of primary cardiac fibroblasts in response to TGFß, in part through post-transcriptional regulation of Wisp1.
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Proteínas CCN de Señalización Intercelular , Proteína 1 Similar a ELAV , Miofibroblastos , Factor de Crecimiento Transformador beta , Animales , Ratones , Colágeno/metabolismo , Fibroblastos/metabolismo , Corazón , Miofibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteína 1 Similar a ELAV/metabolismo , Proteínas CCN de Señalización Intercelular/metabolismoRESUMEN
Background: The paper aims to identify the factors for effective implementation and adherence to the behavioural intervention package by women experiencing domestic violence (DV) and attending ANC in a public hospital. Methods: A qualitative study was undertaken with 211 pregnant women experiencing DV and attending antenatal care (ANC) at the LN Hospital, New Delhi. The intervention was given to women recruited under the RCT study. The narratives were analysed under two broad themes, impeding and facilitating factors, with nine sub-themes. Findings: Impeding factors are external factors generated by the structural interaction of the participants, whereas facilitating factors are supplied internally in the trial to eliminate the influence of impeding factors and singulate the factors under study. Our results show that despite the plethora of impeding factors (nine), the overall sum impact of impeding factors falls short of the positive impact of facilitating factors (nine), which were minor adjustments but reinforce participation in the trial and adherence with 97% follow-up rates. Interpretation: Our study findings are expected to reset the treatment protocol, which entails converting impeding factors into facilitating factors for appropriate adherence and compliance and adequate access and utilization of public services. The sensitization of healthcare providers to the impact of the quality of human interaction on the patient and its impact on the uptake of healthcare services and adherence is needed, particularly in the public hospitals of India. Funding: Funds received for the research are from the Indian Council of Medical Research (ICMR), New Delhi, Government of India.
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India has approximately 23 million children without parental care, who need alternative forms of care (MOSPI, 2018). Udayan Care, an NGO, designed an innovative group care model for children and youth in need of care and protection, implementing the indigenously developed LIFE (Living in Family Environment) strategy in 17 Udayan Ghars. (Sunshine Homes). With child participation as a core pillar, Udayan Care developed a Questionnaire to Assess the Needs of Children in Care (QANCC) in 2011, which is to be filled up by children annually, as a longitudinal study. The tool is conceived to ascertain whether children in the Ghars perceived if their rights were being fulfilled and that their needs were being addressed. With "meaningful participation" of children stipulated by the United Nations Convention on the Rights of the Child (UNCRC), the objective was to develop an evidence-based tool to assess the views of children on the services meted out to them, from their standpoint, and inform actual care practices annually. The self-assessment tool consists of questions, assessing the four dimensions of basic/fundamental, emotional, educational, and interpersonal needs, on a four-point Likert rating scale. A convenient purposive sampling is done on children, aged 10 to 18 years, who receive care and protection at the Ghars, and have resided there for a minimum of 6 months. This paper has two objectives, where at one end, the deductions of the previous years' data are made (2011-12 to 2016-17) with demarcating the differences with year 2018-19 data and at the second level, there is an update on the efforts made to establish the reliability and validity of the tool and create a standardized tool that can be implemented by other child care organizations in India. The paper illustrates how listening to direct voices of children and incorporating their inputs into actual care practice, can go a long way in improving the holistic wellness of children living in an alternative care setting. The results indicate that all needs of the majority of the children in Udayan Ghars.
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Domestic Violence (DV) during the antenatal period has major effects on the mother and pregnancy outcome and is associated with stress and mental health problems. The paper aims to examine the association of DV with stress and depression (S&D) during the first trimester of pregnancy attending antenatal care (ANC) at the Lok Nayak (LN) hospital, a tertiary healthcare hospital in New Delhi, India and address the response of the women. A mixed method was used to gain an in-depth understanding of the participants. A total of 921 women were screened from November 2018 to March 2020 using standard tools for the presence of incidents of DV and S&D. 517 pregnant women with up to 20 weeks of pregnancy who met the inclusion criteria and came to receive ANC at the facility were considered. The prevalence of DV in various forms (psychological, physical and sexual) during pregnancy (49.5%), stress (82%), and depression (33%) have an association that reflects the importance of acknowledging both of them as having a significant implication for the health of pregnant women in India. Analysis suggest that women who experienced DV during pregnancy are 4.9 times and 5.3 times more likely to suffer from stress and depressive symptoms than non-victims of DV respectively. The strong association reinforces the need to conduct routine screening during pregnancy to identify and respond to women with DV and S&D.
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Violencia Doméstica , Atención Prenatal , Estudios Transversales , Depresión/epidemiología , Violencia Doméstica/psicología , Femenino , Hospitales , Humanos , India/epidemiología , Masculino , Embarazo , Atención Prenatal/psicología , Prevalencia , Factores de RiesgoRESUMEN
The efforts to limit the spread of the tuberculosis epidemic have been challenged by the rise of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. It is critical to discover new chemical scaffolds acting on novel or unexploited targets to beat this drug-resistant pathogen. MraY (phospho-MurNAc-pentapeptide translocase or translocase I) is an in vivo validated target for antibacterials-discovery. MraY is inhibited by nucleoside-based natural products that suffer from poor in vivo efficacy. The current study is focused on discovering novel chemical entities, particularly, non-nucleoside small molecules, as MraYMtb inhibitors possessing antituberculosis activity. In the absence of any reported X-ray crystal structures of MraYMtb, we used a homology model-based virtual screening approach combined with the ligand-based e-pharmacophore screening. We screened â¼12 million commercially available compounds from the ZINC15 database using GOLD software. The resulting hits were filtered using a 2-pronged screening method comprising e-pharmacophore hypotheses and docking against the MraYMtb homology model using Glide. Further clustering based on Glide scores and optimal binding interactions resulted in 15 in silico hits. We performed molecular dynamics (MD) simulations for the three best-ranking compounds and one other poorer-ranking compound, out of the 15 in silico hits, to analyze the interaction modes in detail. The MD simulations indicated stable interactions between the compounds and key residues in the MraY active site that are crucial for maintaining the enzymatic activity. These in silico hits could advance the antibacterial drug discovery campaign to find new MraY inhibitors for tuberculosis treatment.Communicated by Ramaswamy H. Sarma.
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Mycobacterium tuberculosis , Tuberculosis , Antituberculosos/química , Antituberculosos/farmacología , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Tuberculosis/tratamiento farmacológicoRESUMEN
The similarity in mechanical properties of dense active matter and sheared amorphous solids has been noted in recent years without a rigorous examination of the underlying mechanism. We develop a mean-field model that predicts that their critical behavior-as measured by their avalanche statistics-should be equivalent in infinite dimensions up to a rescaling factor that depends on the correlation length of the applied field. We test these predictions in two dimensions using a numerical protocol, termed "athermal quasistatic random displacement," and find that these mean-field predictions are surprisingly accurate in low dimensions. We identify a general class of perturbations that smoothly interpolates between the uncorrelated localized forces that occur in the high-persistence limit of dense active matter and system-spanning correlated displacements that occur under applied shear. These results suggest a universal framework for predicting flow, deformation, and failure in active and sheared disordered materials.
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Molecular assessments at the single cell level can accelerate biological research by providing detailed assessments of cellular organization and tissue heterogeneity in both disease and health. The human kidney has complex multi-cellular states with varying functionality, much of which can now be completely harnessed with recent technological advances in tissue proteomics at a near single-cell level. We discuss the foundational steps in the first application of this mass spectrometry (MS) based proteomics method for analysis of sub-sections of the normal human kidney, as part of the Kidney Precision Medicine Project (KPMP). Using ~30-40 laser captured micro-dissected kidney cells, we identified more than 2,500 human proteins, with specificity to the proximal tubular (PT; n = 25 proteins) and glomerular (Glom; n = 67 proteins) regions of the kidney and their unique metabolic functions. This pilot study provides the roadmap for application of our near-single-cell proteomics workflow for analysis of other renal micro-compartments, on a larger scale, to unravel perturbations of renal sub-cellular function in the normal kidney as well as different etiologies of acute and chronic kidney disease.
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Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 Mpro), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 Mpro active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 Mpro crystal structures. Several key preferences for strong binding to the four subsites (S1, S1', S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 -log10(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 Mpro inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 -log10(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 Mpro [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals.
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Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Cisteína Endopeptidasas/metabolismo , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/metabolismo , Antivirales/química , Betacoronavirus/enzimología , Sitios de Unión , COVID-19 , Dominio Catalítico , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/química , Diseño de Fármacos , Reposicionamiento de Medicamentos , Humanos , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , Pandemias , Inhibidores de Proteasas/química , Conformación Proteica , SARS-CoV-2 , Proteínas no Estructurales Virales/químicaRESUMEN
Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is upregulated in breast cancer, and elevated cytoplasmic HuR correlates with high-grade tumors and poor clinical outcome of breast cancer. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, and cytokines that support major tumor hallmarks including invasion and metastasis. Here, we report a HuR inhibitor KH-3, which potently suppresses breast cancer cell growth and invasion. Furthermore, KH-3 inhibits breast cancer experimental lung metastasis, improves mouse survival, and reduces orthotopic tumor growth. Mechanistically, we identify FOXQ1 as a direct target of HuR. KH-3 disrupts HuR-FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion. Our study suggests that inhibiting HuR is a promising therapeutic strategy for lethal metastatic breast cancer.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proteína 1 Similar a ELAV/antagonistas & inhibidores , Factores de Transcripción Forkhead/metabolismo , Neoplasias Pulmonares/prevención & control , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína 1 Similar a ELAV/genética , Proteína 1 Similar a ELAV/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
α-Fluoroalkynes are elusive molecules due to their instability and inaccessibility. Here, we show that α-fluoronitroalkenes can serve as synthetic surrogates of α-fluoroalkynes in [3+2] cycloaddition reactions with organic azides facilitated by a catalytic amount of trifluoroacetic acid (TFA). This work provides the first regioselective method to access 4-fluoro-1,5-disubstituted-1,2,3-triazoles.
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[This corrects the article DOI: 10.3389/fmed.2020.00499.].
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Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), ARID1A enhances DNA repair. Consequently, ARID1A has been proposed as a promising therapeutic target to sensitize cancer cells to chemotherapy and radiation. Here, we report that ARID1A is regulated by human antigen R (HuR), an RNA-binding protein that is highly expressed in a wide range of cancers and enables resistance to chemotherapy and radiation. Our results indicate that HuR binds ARID1A mRNA, thereby increasing its stability in breast cancer cells. We further find that ARID1A expression suppresses the accumulation of DNA double-strand breaks (DSBs) caused by radiation and can rescue the loss of radioresistance triggered by HuR inhibition, suggesting that ARID1A plays an important role in HuR-driven resistance to radiation. Taken together, our work shows that HuR and ARID1A form an important regulatory axis in radiation resistance that can be targeted to improve radiotherapy in breast cancer patients.