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Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer’s disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14 C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the Tau P301L -BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies. Alzheimer’s disease: A tool for preventing toxic tangles The discovery that an already approved drug can disrupt tau protein aggregation in cultured cells and live mice could guide the development of new therapies for Alzheimer’s. Tau plays an important role in organizing the internal structure of neurons, but in neurodegenerative disease is seen to form abnormal assemblies that are toxic to cells. Researchers led by Ae Nim Pae and Yun Kyung Kim at the Korea Institute of Science and Technology, Seoul, South Korea have devised an assay that allowed them to identify agents that actively interfere with this process. Levosimendan, a drug approved for heart failure, broke up tau aggregates in cell culture and reduced cognitive symptoms in a mouse model of tau-induced neurodegeneration. Further investigation of levosimendan’s mode of action could yield interventions that slow or prevent Alzheimer’s progression.

Fluorescence imaging of amyloid beta (Aβ) polypeptide using a small‐molecule fluorophore is a practical system for Alzheimer's disease (AD) diagnosis in clinical and research fields. Herein, a molecular designing strategy for a new fluorogenic probe that equips bathochromic emission shift and enhanced binding affinity toward Aβ fibril through structural optimization is suggested. Thioflavin T (ThT)‐derived fluorescent dyes are developed by adjusting the hydrophobicity of electron donor moiety in D–π–A structures with biannulated ring expansion. Indeed, probes are tuned to have redshifted fluorescence emission wavelength and optimized binding affinities for Aβ fibrils in vitro and cortical imaging. Detection of background signal is minimized by maintaining the photophysical properties of twisted intramolecular charge transfer (TICT), resulting in significantly sensitive fluorogenic probes for outstanding bioimaging in AD. The synthesis and development of thioflavin T derivatives are suggested for tailoring hydrophobicity by substituting biannulated electron donor moieties, which enables the formation of a D–π–A molecular structure. In particular, a novel fluorophore, ThN, can detect amyloid beta fibrils as bathochromic emission and clear visualization of stained amyloid beta aggregates co‐occurrence with tau proteins in brain slice images.

Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer's disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the Tau -BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.

There is disagreement about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a living systematic review and meta-analysis to address three questions: (1) Amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) Amongst people with SARS-CoV-2 infection who are asymptomatic when diagnosed, what proportion will develop symptoms later? (3) What proportion of SARS-CoV-2 transmission is accounted for by people who are either asymptomatic throughout infection or presymptomatic? We searched PubMed, Embase, bioRxiv, and medRxiv using a database of SARS-CoV-2 literature that is updated daily, on 25 March 2020, 20 April 2020, and 10 June 2020. Studies of people with SARS-CoV-2 diagnosed by reverse transcriptase PCR (RT-PCR) that documented follow-up and symptom status at the beginning and end of follow-up or modelling studies were included. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with an adapted checklist for case series, and the relevance and credibility of modelling studies were assessed using a published checklist. We included a total of 94 studies. The overall estimate of the proportion of people who become infected with SARS-CoV-2 and remain asymptomatic throughout infection was 20% (95% confidence interval [CI] 17-25) with a prediction interval of 3%-67% in 79 studies that addressed this review question. There was some evidence that biases in the selection of participants influence the estimate. In seven studies of defined populations screened for SARS-CoV-2 and then followed, 31% (95% CI 26%-37%, prediction interval 24%-38%) remained asymptomatic. The proportion of people that is presymptomatic could not be summarised, owing to heterogeneity. The secondary attack rate was lower in contacts of people with asymptomatic infection than those with symptomatic infection (relative risk 0.35, 95% CI 0.10-1.27). Modelling studies fit to data found a higher proportion of all SARS-CoV-2 infections resulting from transmission from presymptomatic individuals than from asymptomatic individuals. Limitations of the review include that most included studies were not designed to estimate the proportion of asymptomatic SARS-CoV-2 infections and were at risk of selection biases; we did not consider the possible impact of false negative RT-PCR results, which would underestimate the proportion of asymptomatic infections; and the database does not include all sources. The findings of this living systematic review suggest that most people who become infected with SARS-CoV-2 will not remain asymptomatic throughout the course of the infection. The contribution of presymptomatic and asymptomatic infections to overall SARS-CoV-2 transmission means that combination prevention measures, with enhanced hand hygiene, masks, testing tracing, and isolation strategies and social distancing, will continue to be needed.

Hematologic malignancy outcomes have remarkably improved in the past decade with further advancement expected in future years. However, the detrimental effects of financial toxicity (FT) on patients with hematologic malignancies, because of both diagnoses and subsequent treatments, have not been studied comprehensively. We performed a systematic review of all studies reporting FT as a primary or secondary outcome among adult or pediatric patients with hematological malignancies. A total of 55 studies met the inclusion criteria for analysis. Across studies, 20–50% of patients reported some form of FT, including loss of work productivity, food and transportation costs, and depletion of savings. Younger age, lower-income level, unemployment, and rural residence were the most commonly identified risk factors for FT. Two studies looked at survival outcomes, with one reporting improvement in survival with a decrease in financial toxicity. However, significant heterogeneity in FT definitions was found between countries and payor systems. Only half of the studies (51%, n = 28) used validated survey instruments such as the COST assessment. The present systematic review identified that FT is common in patients with hematological malignancies and may be associated with poorer outcomes. However, studies of FT generally use non-standardized methods with cross-sectional analyses rather than longitudinal, prospective assessments. Further work is needed to standardize FT reporting and investigate measures to alleviate FT among patients with hematologic malignancies.

Eyesight is one of the most well-deserved blessings, amid all the five senses in the human body. It captures the raw signals from the outside world to create detailed visual images, granting the ability to witness and gain knowledge about the world. Eyes are exposed directly to the external environment; they are susceptible to the vicissitudes of diseases. The World Health Organization has predicted that the number of individuals affected by eye diseases will rise enormously in the next decades. However, the physical barriers of the eyes and the problems associated with conventional ocular formulations are significant challenges in ophthalmic drug development. This has generated the demand for a sustained ocular drug delivery system, which serves to deliver effective drug concentration at a reduced frequency for consistent therapeutic effect and better patient treatment adherence. Recent advancement in pharmaceutical dosage design has demonstrated that a stimuli-responsive in situ gel system exhibits the favorable characteristics for providing sustained ocular drug delivery and enhanced ocular bioavailability. Stimuli-responsive in situ gels undergo a phase transition (solution–gelation) in response to the ocular environmental temperature, pH, and ions. These stimuli transform the formulation into a gel at the cul de sac to overcome the shortcomings of conventional eye drops, such as rapid nasolacrimal drainage and short contact time with the ocular surface This review highlights the recent successful research outcomes of stimuli-responsive in situ gelling systems in treating in vivo models with glaucoma and various ocular infections. Additionally, it also presents the mechanism, recent development, and safety considerations of stimuli-sensitive in situ gel as the potential sustained ocular delivery system for treating common eye disorders.

Bionanotechnology is the combination of biotechnology and nanotechnology for the development of biosynthetic and environmentally friendly nanomaterial synthesis technology. The presented research work adopted a reliable and environmentally sustainable approach to manufacturing silver nanoparticles from Brachychiton populneus (BP-AgNPs) leaf extract in aqueous medium. The Brachychiton populneus-derived silver nanoparticles were characterized by UV–Vis spectroscopy, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and energy dispersive X-ray analysis (EDX). In addition, the antioxidant, anti-inflammatory, antidiabetic, and cytotoxic activities of AgNPs were brought to light. The synthesis of BP-AgNPs was verified at 453 nm wavelength by UV–Vis spectrum. FTIR analysis revealed that synthesis, stability, and capping of AgNPs depend on functional groups such as alkane, alkene, nitro, flouro, phenol, alcoholic, and flavones, present in plant extract. The SEM analysis revealed evenly distributed cubical-shaped nanoparticles. The average diameter of AgNPs was 12 nm calculated from SEM image through ImageJ software. EDX spectrum confirmed the presence of Ag at 3 keV and other trace elements such as oxygen and chlorine. The biosynthesized silver nanoparticles exhibited proven antioxidant (DPPH assay), antidiabetic (alpha amylase assay), anti-inflammatory (albumin denaturation assay), and cytotoxic (MTT assay) potential against U87 and HEK293 cell lines in comparison to standard drugs. In these assays, BP-AgNPs exhibited inhibition in a concentration-dependent manner and had lower IC50 values compared to standards. All these outcomes suggest that silver nanoparticles work as a beneficial biological agent. The salient features of biosynthesized silver nanoparticles propose their effective applications in the biomedical domain in the future.

Background The covid-19 pandemic has highlighted the role of living systematic reviews. The speed of evidence generated during the covid-19 pandemic accentuated the challenges of managing high volumes of research literature. Methods In this article, we summarise the characteristics of ongoing living systematic reviews on covid-19, and we follow a life cycle approach to describe key steps in a living systematic review. Results We identified 97 living systematic reviews on covid-19, published up to 7th November 2022, which focused mostly on the effects of pharmacological interventions ( n  = 46, 47%) or the prevalence of associated conditions or risk factors ( n  = 30, 31%). The scopes of several reviews overlapped considerably. Most living systematic reviews included both observational and randomised study designs ( n  = 45, 46%). Only one-third of the reviews has been updated at least once ( n  = 34, 35%). We address practical aspects of living systematic reviews including how to judge whether to start a living systematic review, methods for study identification and selection, data extraction and evaluation, and give recommendations at each step, drawing from our own experience. We also discuss when it is time to stop and how to publish updates. Conclusions Methods to improve the efficiency of searching, study selection, and data extraction using machine learning technologies are being developed, their performance and applicability, particularly for reviews based on observational study designs should improve, and ways of publishing living systematic reviews and their updates will continue to evolve. Finally, knowing when to end a living systematic review is as important as knowing when to start.

Background Outbreaks of infectious diseases generate outbreaks of scientific evidence. In 2016 epidemics of Zika virus emerged, and in 2020, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of coronavirus disease 2019 (COVID-19). We compared patterns of scientific publications for the two infections to analyse the evolution of the evidence. Methods We annotated publications on Zika virus and SARS-CoV-2 that we collected using living evidence databases according to study design. We used descriptive statistics to categorise and compare study designs over time. Results We found 2286 publications about Zika virus in 2016 and 21,990 about SARS-CoV-2 up to 24 May 2020, of which we analysed a random sample of 5294 (24%). For both infections, there were more epidemiological than laboratory science studies. Amongst epidemiological studies for both infections, case reports, case series and cross-sectional studies emerged first, cohort and case-control studies were published later. Trials were the last to emerge. The number of preprints was much higher for SARS-CoV-2 than for Zika virus. Conclusions Similarities in the overall pattern of publications might be generalizable, whereas differences are compatible with differences in the characteristics of a disease. Understanding how evidence accumulates during disease outbreaks helps us understand which types of public health questions we can answer and when.