Automatic HighThroughput Fluorescence Lifetime Image Microscopy to identify ProteinProtein Relationships

Starting from our previous finding of 14 known drugs as inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. this website 20 nM IC50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for Mpro-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to Mpro. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.Hypertension in kidney transplant (KTx) recipients is common, affecting both patient and graft survival. Annual data from the Norwegian Renal Registry reveal that
In conjunction with the 2018 annual data reporting, additional questions were added for recipients with BP >130/80 mm Hg (treating physician´s target BP for each patient, reasons for not achieving target, method of measurement).
Annual forms were received from 98% (3407 of 3486) of KTx recipients, with 1787 (52%) reporting a BP >130/80 mm Hg ("above-target" group). These recipients were older, mostly male, with higher body mass index and serum creatinine levels (
 < 0.05) compared with patients with controlled hypertension ("on-target" group). Valid survey answers were available for 84% of the "above-target" group (Surv
) with no significant demographic differences versus nonresponders (Surv
). Among Surv
, 32% were under antihypertensive dose titration, whereas dose-limiting side effects were reported in 7%. Target BP was confirmed to 130/80 mm Hg for 60% of Surv
. In recipients for whom the treating physician set target BP >130/80 mm Hg, 51% did not reach these individual targets. The number of antihypertensive drugs was significantly higher in the "above-target" group versus "on-target" group (mean 2.1 ± 1.2 versus 1.8 ± 1.3) and 36% versus 25% used ≥3 antihypertensive drugs (
 < 0.05). Automatic attended BP measurement was utilized by 51%.
In KTx recipients, a higher BP target achievement seems possible, potentially in the range of 75%-80%.
In KTx recipients, a higher BP target achievement seems possible, potentially in the range of 75%-80%.During the global outbreak of COVID-19 pandemic, "cytokine storm" conditions are regarded as the fatal step resulting in most mortality. Hemoperfusion is widely used to remove cytokines from the blood of severely ill patients to prevent uncontrolled inflammation induced by a cytokine storm. This article discoveres, for the first time, that 2D Ti3C2T x MXene sheet demonstrates an ultrahigh removal capability for typical cytokine interleukin-6. In particular, MXene shows a 13.4 times higher removal efficiency over traditional activated carbon absorbents. Molecular-level investigations reveal that MXene exhibits a strong chemisorption mechanism for immobilizing cytokine interleukin-6 molecules, which is different from activated carbon absorbents. MXene sheet also demonstrates excellent blood compatibility without any deleterious side influence on the composition of human blood. This work can open a new avenue to use MXene sheets as an ultraefficient hemoperfusion absorbent to eliminate the cytokine storm syndrome in treatment of severe COVID-19 patients.Dementia-related behavioral and psychology symptoms (BPSD) are undertreated and have negative consequences. However, families do not have access to disease information, tailored problem-solving and effective management strategies, and with COVID-19, are more socially isolated and distressed. To address this dementia care gap, we describe a Phase III efficacy trial testing an online platform, WeCareAdvisor, and design modifications necessitated by COVID-19. WeCareAdvisor provides caregivers with disease information, daily tips, and a systematic approach for describing behaviors, investigating underlying causes, creating tailored strategies, and evaluating their effectiveness (DICE). The trial will enroll 326 caregivers nationwide, randomly assign them to immediately receive WeCareAdvisor (treatment), or a 3-month waitlist (control) and evaluate short (1- and 3-month) and long-term (6-month) outcomes for caregiver distress with and confidence managing BPSD, and BPSD occurrences. We will also evaluate utilization patterns with different prompting conditions high-intensity (telephone and email reminders), low-intensity (email reminders), or no reminders to use WeCareAdvisor. COVID-19 necessitated design modifications resulting in greater inclusivity of caregivers from diverse races, ethnicities, and geographic areas. Key modifications include shifting from in-home, in-person interviewing to telephone; adjusting tool functionality from operating on a grant-funded iPad to caregivers' personal internet-capable devices; and expanding recruitment from one metropolitan area to nationwide. Study modifications necessitated by COVID-19 facilitate national outreach, easier tool adoption, and enable more diverse caregivers to participate. This study addresses a critical dementia care need, and design modifications may shorten timeline from efficacy testing to commercialization.SARS-CoV-2 caused the emerging epidemic of coronavirus disease in 2019 (COVID-19). To date, there are more than 82.9 million confirmed cases worldwide, there is no clinically effective drug against SARS-CoV-2 infection. The conserved properties of the membrane fusion domain of the spike (S) protein across SARS-CoV-2 make it a promising target to develop pan-CoV therapeutics. Herein, two clinically approved drugs, Itraconazole (ITZ) and Estradiol benzoate (EB), are found to inhibit viral entry by targeting the six-helix (6-HB) fusion core of SARS-CoV-2 S protein. Further studies shed light on the mechanism that ITZ and EB can interact with the heptad repeat 1 (HR1) region of the spike protein, to present anti-SARS-CoV-2 infections in vitro, indicating they are novel potential therapeutic remedies for COVID-19 treatment. Furthermore, ITZ shows broad-spectrum activity targeting 6-HB in the S2 subunit of SARS-CoV and MERS-CoV S protein, inspiring that ITZ have the potential for development as a pan-coronavirus fusion inhibitor.Hexavalent sulfoglycodendrimers (SGDs) are synthesized as mimics of host cell heparan sulfate proteoglycans (HSPGs) to inhibit the early stages in viral binding/entry of HIV-1 and SARS-CoV-2. Using an HIV neutralization assay, the most promising of the seven candidates are found to have sub-micromolar anti-HIV activities. Molecular dynamics simulations are separately implemented to investigate how/where the SGDs interacted with both pathogens. link2 The simulations revealed that the SGDs 1) develop multivalent binding with polybasic regions within and outside of the V3 loop on glycoprotein 120 (gp120) for HIV-1, and consecutively bind with multiple gp120 subunits, and 2) interact with basic amino acids in both the angiotensin-converting enzyme 2 (ACE2) and HSPG binding regions of the Receptor Binding Domain (RBD) from SARS-CoV-2. These results illustrate the considerable potential of SGDs as inhibitors in viral binding/entry of both HIV-1 and SARS-CoV-2 pathogens, leading the way for further development of this class of molecules as broad-spectrum antiviral agents.
Poly(ethylene glycol) (PEG) is a nontoxic, hydrophilic polymer that is often covalently attached to proteins, drugs, tissues, or materials; a procedure commonly referred to as PEGylation. PEGylation improves solubility, circulation time, and reduces immunogenicity of therapeutic molecules. Currently, there are 21 PEGylated drugs approved by the Food and Drug Administration (FDA), and more in the developmental stage. In addition to the polymer's applications in the clinic, PEG is widely used as a solvent and emulsifying agent in the formulation of cosmetics, cleaning, and personal care products. Due to the ubiquitous presence of the polymer in everyday products, patients can develop antibodies against PEG (αPEG Abs) that can be problematic when a PEGylated drug is administered. These αPEG Abs can provoke hypersensitivity reactions, accelerated drug clearance, and decreased therapeutic efficacy. Herein, we review how the prevalence of PEG in everyday products has induced αPEG Abs within the general public as p antibodies (αPEG Abs) against the polymer, which recognize PEG as foreign. Of note, PEG is frequently incorporated into drug formulations to improve therapeutic efficacy. Complications can arise when a patient receiving a PEGylated drug has previously developed αPEG Abs from interactions with PEG in everyday products. The presence of high concentrations of αPEG Abs in blood can result in decreased treatment efficacy and allergic reactions to a wide range of therapeutics.
The timely management of cancer surgery suffered due to COVID-19 and nationwide lockdown. Continuing cancer surgery was a challenge faced by all. We present our experience on cancer surgery in a cancer centre with high volume of patients and limited resources during early pandemic.
We retrospectively analysed our operation theatre database on surgery and anaesthesia from 1st April to 30th June 2020.
A total of 457 surgeries were done-complex major, major, intermediate and minor surgeries constituted 43%, 25%, 12% and 20%, respectively. Median age of patient was 50years, and 76% were below 60. The median ASA class was I (I-IV), and 97% were ASA I and II. link3 The median Eastern Cooperative Oncology Group score was 0 (0-3), and 92% had score 0 and 1. Major cases done under regional anaesthesia were 30.7%. Median length of intensive care unit stay was 1 (1-6) days, and length of hospital stay was 7 (7-15) days. Clavien-Dindo Grade II complication in patients above 60years was 16.4% and below 60years was 17.6% (
 = 0.76). 10% in ASA I compared to 26% of ASA II (
 = 0.00) and 15.9% with ECOG 0 and 1 compared to 30.9% with ECOG 3 and 4 (
 = 0.01) had grade II complication. Four (1%) patients had Grade ≥ III CD complication. Covid testing was undertaken in 52% patients pre-operatively, and there was no positive case in post-operative period.
Adopting and implementing institutional policy catering to limited resource available at our centre, we facilitated cancer surgery.
Adopting and implementing institutional policy catering to limited resource available at our centre, we facilitated cancer surgery.
Total cavopulmonary connection (TCPC) is associated with a lower risk of incident atrial arrhythmias as compared to atriopulmonary Fontan, but the risk of recurrent atrial arrhythmias is unknown in this population. The purpose of this study was to determine the incidence and risk factors for recurrent atrial arrhythmias and thromboembolic complications in patients with TCPC.
This is a retrospective multicenter study conducted by the Alliance for Adult Research in Congenital Cardiology (AARCC), 2000-2018. The inclusion criteria were TCPC patients (age>15years) with prior history of atrial arrhythmia.
A total of 103 patients (age 26±7years; male 58 [56%]) met inclusion criteria. The mean age at initial arrhythmia diagnosis was 13±5years, and atrial arrhythmias were classified as atrial flutter/tachycardia in 85 (83%) and atrial fibrillation in 18 (17%). The median duration of follow-up from the first episode of atrial arrhythmia was 14.9 (12.1-17.3) years, and during this period 64 (62%) patients had recurrent atrial arrhythmias (atrial flutter/tachycardia 51 [80%] and atrial fibrillation 13 [20%]) with annual incidence of 4.