598 research outputs found

    Exploring the DNA2-PNA heterotriplex formation in targeting the Bcl-2 gene promoter: A structural insight by physico-chemical and microsecond-scale MD investigation

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    Peptide Nucleic Acids (PNAs) represent a promising tool for gene modulation in anticancer treatment. The uncharged peptidyl backbone and the resistance to chemical and enzymatic degradation make PNAs highly advantageous to form stable hybrid complexes with complementary DNA and RNA strands, providing higher stability than the corresponding natural analogues. Our and other groups’ research has successfully shown that tailored PNA sequences can effectively downregulate the expression of human oncogenes using antigene, antisense, or anti-miRNA approaches. Specifically, we identified a seven bases-long PNA sequence, complementary to the longer loop of the main G-quadruplex structure formed by the bcl2midG4 promoter sequence, capable of downregulating the expression of the antiapoptotic Bcl-2 protein and enhancing the anticancer activity of an oncolytic adenovirus. Here, we extended the length of the PNA probe with the aim of including the double-stranded Bcl-2 promoter among the targets of the PNA probe. Our investigation primarily focused on the structural aspects of the resulting DNA2-PNA heterotriplex that were determined by employing conventional and accelerated microsecond-scale molecular dynamics simulations and chemical-physical analysis. Additionally, we conducted preliminary biological experiments using cytotoxicity assays on human A549 and MDA-MB-436 adenocarcinoma cell lines, employing the oncolytic adenovirus delivery strategy

    Discovery of a Novel Class of Dual GPBAR1 Agonists-RORγt Inverse Agonists for the Treatment of IL-17-Mediated Disorders

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    Retinoic acid receptor-related orphan receptor γ-t (RORγt) and GPBAR1, a transmembrane G-protein-coupled receptor for bile acids, are attractive drug targets to develop clinically relevant small modulators as potent therapeutics for autoimmune diseases. Herein, we designed, synthesized, and evaluated several new bile acid-derived ligands with potent dual activity. Furthermore, we performed molecular docking and MD calculations of the best dual modulators in the two targets to identify the binding modes as well as to better understand the molecular basis of the inverse agonism of RORγt by bile acid derivatives. Among these compounds, 7 was identified as a GPBAR1 agonist (EC50 5.9 μM) and RORγt inverse agonist (IC50 0.107 μM), with excellent pharmacokinetic properties. Finally, the most promising ligand displayed robust anti-inflammatory activity in vitro and in vivo in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis

    Directionality for nuclear recoils in a LAr TPC

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    In the direct searches for Weakly Interacting Massive Particles (WIMPs) as Dark Matter candidates, the sensitivity of the detector to the incom- ing particle direction could provide a smoking gun signature for an interesting event. The SCENE collaboration firstly suggested the possible directional de- pendence of a dual-phase argon Time Projection Chamber through the columnar recombination effect. The Recoil Directionality project (ReD) within the Global Argon Dark Matter Collaboration aims to characterize the light and charge re- sponse of a liquid Argon dual-phase TPC to neutron-induced nuclear recoils to probe for the hint by SCENE. In this work, the directional sensitivity of the de- tector in the energy range of interest for WIMPs (20-100 keV) is investigated with a data-driven analysis involving a Machine Learning algorithm

    Undertreatment of opioid use disorder in patients hospitalized with injection drug use associated infections

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    OBJECTIVE: To evaluate the association between medication for opioid use disorder (MOUD) initiation and addiction consultation and outcomes for patients hospitalized with infectious complications of injecting opioids. DESIGN: Retrospective cohort study. SETTING: Four academic medical centers in the United States. PARTICIPANTS: 322 patients hospitalized with infectious complications of injecting opioids in 2018. EXPOSURES: Inpatient receipt of MOUD, initiation of MOUD, and addiction consultation. MEASUREMENTS: The main outcomes of interest were: 1) premature discharge; 2) MOUD on discharge; 3) linkage to outpatient MOUD; 4) one-year readmission; 5) death. RESULTS: 322 patients were predominately male (59%), white (66%), and median age 38, with 36% unstably housed, and 30% uninsured. 145 (45%) patients received MOUD during hospitalization, including only 65 (28%) patients not on baseline MOUD. Discharge was premature for 64 (20%) patients. In the year following discharge, 27 (9%) patients were linked to MOUD, and 159 (50%) patients had at least one readmission. Being on MOUD during hospitalization was significantly associated with higher odds of planned discharge (OR 3.87, P \u3c 0.0001), MOUD on discharge (OR 129.7, P \u3c 0.0001), and linkage to outpatient MOUD (OR 1.25, p \u3c 0.0001), however was not associated with readmission. LIMITATIONS: Retrospective study. Post-discharge data are likely underestimated. CONCLUSIONS: There was dramatic undertreatment with MOUD from inpatient admission to outpatient linkage, and high rates of premature discharge and readmission. Engagement in addiction care during hospitalization is a critical first step in improving the care continuum for individuals with opioid use disorder, however additional interventions may be needed to impact long-term outcomes like readmission

    Use of nonstigmatizing language is associated with improved outcomes in hospitalized people who inject drugs

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    BACKGROUND: Stigma surrounding opioid use disorder (OUD) is a barrier to treatment. The use of stigmatizing language may be evidence of negative views toward patients. OBJECTIVE: We aimed to identify associations between language and clinical outcomes in patients admitted for infectious complications of OUD. DESIGNS: We performed a retrospective medical record review. SETTINGS AND PARTICIPANTS: Four U.S. academic health systems. Participants were patients with OUD admitted for infectious complications of injection opioid use from January 1, 2018, to December 31, 2018, identified through international classification of diseases, 10th revision codes consistent with OUD and acute bacterial/fungal infection. MAIN OUTCOME AND MEASURES: Discharge summaries were reviewed for language, specifically: abuse, addiction, dependence, misuse, use disorder, intravenous drug use, and others. Binary outcomes including medication for OUD, planned discharge, naloxone provision, and an OUD treatment plan were evaluated using logistic regressions and admission duration was evaluated using Gamma regression. RESULTS: A total of 1285 records were reviewed and 328 met inclusion criteria. Of those, 191 (58%) were male, with a median age of 38 years. The most common term was abuse (219, 67%), whereas use disorder was recorded in 75 (23%) records. Having use disorder in the discharge summary was associated with increased odds of having a documented plan for ongoing OUD treatment (adjusted odds ratio [AOR]: 4.11, 95% confidence interval [CI]: 1.89-8.93) and having a documented plan for addiction-specific follow-up care (AOR: 2.31, 95% CI: 1.30-4.09). CONCLUSIONS: Stigmatizing language was common in this study of patients hospitalized for infectious complications of OUD. Best-practice language was uncommon, but when used was associated with increased odds of addiction treatment and specialty care referrals

    Directionality for nuclear recoils in a LAr TPC

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    In the direct searches for Weakly Interacting Massive Particles (WIMPs) as Dark Matter candidates, the sensitivity of the detector to the incom- ing particle direction could provide a smoking gun signature for an interesting event. The SCENE collaboration firstly suggested the possible directional de- pendence of a dual-phase argon Time Projection Chamber through the columnar recombination effect. The Recoil Directionality project (ReD) within the Global Argon Dark Matter Collaboration aims to characterize the light and charge re- sponse of a liquid Argon dual-phase TPC to neutron-induced nuclear recoils to probe for the hint by SCENE. In this work, the directional sensitivity of the de- tector in the energy range of interest for WIMPs (20-100 keV) is investigated with a data-driven analysis involving a Machine Learning algorithm

    Temperature-dependent cutting physics in orthogonal cutting of carbon fibre reinforced thermoplastic (CFRTP) composite

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    The global commitment towards reducing carbon emissions drives the implementation of sustainable carbon-fibre-reinforced-thermoplastic composites (CFRTPs). However, the machining of CFRTPs presents challenges due to the material's ductile–brittle composition and sensitivity to machining-induced high temperatures. For the first time, we conducted temperature-controlled orthogonal cutting of CFRTP (using CF/PEKK as a demonstrator) to unveil its temperature-dependent cutting physics. Three representative cutting temperatures, 23 ℃ (ambient temperature),100 ℃ (Tg) and four typical fibre cutting orientations (0°, 45°, 90°, and 135°) have been investigated. The evolution of chip microstructural morphology and surface/subsurface damage have been analysed by advanced microscopy to reveal temperature-dependent material removal mechanisms. The experimental results were elucidated through a novel microscale finite-element-analysis (FEA) model considering thermal softening of the matrix and interface. Results show the transition of the cutting physics with increasing temperature is associated to the degradation of the thermoplastic matrix stiffness/ultimate strength and interface bonding strength and fracture toughness, especially when > Tg

    Ventilatory associated barotrauma in COVID-19 patients: A multicenter observational case control study (COVI-MIX-study)

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    Background: The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. Methods: This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. Results: We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients; these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). Conclusions: C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma; otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. Trial registration: this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021)

    Nighttime resident supervision and education: results of a national survey of internal medicine residency program directors

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    Over the past several years, the Accreditation Council for Graduate Medical Education (ACGME) has issued new restrictions on resident duty hours while calling for increased supervision to ensure patient safety. To meet these requirements, some hospitals have hired overnight in-house hospitalist physicians, also called nocturnists, while others have continued a traditional model wherein a resident in-house can access a supervisor at home by phone as needed. This study examines the current state of internal medicine resident supervision and teaching at night.Christopher Bruti (Rush University Medical Center), Mathhew Tuck (Veterans Affairs Medical Center), Rebecca Harrison (Oregon Health and Science University School of Medicine), Dustin Smith (Atlanta VA Medical Center), Michael Kisielewski (Alliance for Academic Internal Medicine), Jillian S. Catalanotti (The George Washington University School of Medicine and Health Sciences), Alfred Burger (Icahn School of Medicine)Includes bibliographical reference
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