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In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria. In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686. Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal. Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria. Mitsubishi Tanabe Pharma Corporation.

Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.

The Creole architecture of New Orleans is one of the city’s most-recognized features, but studies of it largely have focused on architectural typology. In Building Antebellum New Orleans, Tara A. Dudley examines the architectural activities and influence of gens de couleur libres—free people of color—in a city where the mixed-race descendants of whites and other free Blacks could own property.Between 1820 and 1850 New Orleans became an urban metropolis and industrialized shipping center with a growing population. Amidst dramatic economic and cultural change in the mid-antebellum period, the gens de couleur libres thrived as property owners, developers, building artisans, and patrons. Dudley writes an intimate microhistory of two prominent families of Black developers, the Dollioles and Souliés, to explore how gens de couleur libres used ownership, engagement, and entrepreneurship to construct individual and group identity and stability. With deep archival research, Dudley re-creates in fine detail the material culture, business and social history, and politics of the built environment for free people of color and adds new, revelatory information to the canon on New Orleans architecture.

The use of F. religiosa might be beneficial in inflammatory illnesses and can be used for a variety of health conditions. In this article, we studied the identification of antioxidants using (DPPH) 2,2-Diphenyl-1-picrylhydrazylradical scavenging activity in Ficus religiosa, as F. religiosa is an important herbal plant, and every part of it has various medicinal properties such as antibacterial properties that can be used by the researchers in the development and design of various new drugs. The 2,2-Diphenyl-1-picrylhydrazyl (DPPH) is a popular, quick, easy, and affordable approach for the measurement of antioxidant properties that includes the use of the free radicals used for assessing the potential of substances to serve as hydrogen providers or free-radical scavengers (FRS). The technique of DPPH testing is associated with the elimination of DPPH, which would be a stabilized free radical. The free-radical DPPH interacts with an odd electron to yield a strong absorbance at 517 nm, i.e., a purple hue. An FRS antioxidant, for example, reacts to DPPH to form DPPHH, which has a lower absorbance than DPPH because of the lower amount of hydrogen. It is radical in comparison to the DPPH-H form, because it causes decolorization, or a yellow hue, as the number of electrons absorbed increases. Decolorization affects the lowering capacity significantly. As soon as the DPPH solutions are combined with the hydrogen atom source, the lower state of diphenylpicrylhydrazine is formed, shedding its violet color. To explain the processes behind the DPPH tests, as well as their applicability to Ficus religiosa (F. religiosa) in the manufacture of metal oxide nanoparticles, in particular MgO, and their influence on antioxidants, a specimen from the test was chosen for further study. According to our findings, F. religiosa has antioxidant qualities and may be useful in the treatment of disorders caused by free radicals.

Plasma circulating cell‐free nucleic acids (ccfNAs) provide an exceptional source of information about an individual's health, yet their biology in healthy individuals during aging remains poorly understood. Here, we present the first integrative multiparametric analysis of the major types of plasma ccfNAs, including nuclear (ccfnDNA) and mitochondrial (ccfmtDNA) DNA, as well as ribosomal (ccfrRNA), messenger (ccfmRNA) and micro‐RNA (ccfmiRNA) in 139 healthy donors aged 19–66 years. We focused on quantity, integrity, and DNA methylation using an optimized experimental workflow that combines highly sensitive analytical methods with the detection of highly repetitive DNA and highly abundant RNA sequences, thereby reducing the required amount of ccfNAs per analysis. We showed a highly significant increase in ccfnDNA levels during aging (p < 0.001), associated with a decrease in its integrity (p < 0.05), while no significant changes were detected in ccfmtDNA levels and ccfDNA methylation. Moreover, a significant increase in ccfmRNA and ccfrRNA (p < 0.05), as well as miR‐483‐5p (p < 0.001) levels was detected during aging, but without any changes in ccfRNA integrity. Finally, we also showed that ccfDNA and ccfRNA levels were correlated (p < 0.001), and a similar pattern was observed for ccfmtDNA and ccfRNA levels, suggesting a possible common release, maintenance, and/or clearance mechanism. Therefore, our study provides an optimized workflow for the global analysis of ccfNAs, enhances the understanding of their biology during aging, and identifies several potential ccfNA‐based biomarkers of aging. We performed the first integrative multiparametric analysis of plasma circulating cell‐free nucleic acids, including nuclear and mitochondrial DNA, as well as ribosomal, messenger, and micro‐RNAs, in a cohort of 139 healthy individuals. We focused on quantity, integrity, and DNA methylation using assays targeting highly repetitive DNA and highly abundant RNA.

In this study of antebellum African American print culture in transnational perspective, Erica L. Ball explores the relationship between antislavery discourse and the emergence of the northern black middle class. Through innovative readings of slave narratives, sermons, fiction, convention proceedings, and the advice literature printed in forums like Freedom's Journal, the North Star, and the Anglo-African Magazine, Ball demonstrates that black figures such as Susan Paul, Frederick Douglass, and Martin Delany consistently urged readers to internalize their political principles and to interpret all their personal ambitions, private familial roles, and domestic responsibilities in light of the freedom struggle. Ultimately, they were admonished to embody the abolitionist agenda by living what the fugitive Samuel Ringgold Ward called an \"antislavery life.\" Far more than calls for northern free blacks to engage in what scholars call \"the politics of respectability,\" African American writers characterized true antislavery living as an oppositional stance rife with radical possibilities, a deeply personal politics that required free blacks to transform themselves into model husbands and wives, mothers and fathers, self-made men, and transnational freedom fighters in the mold of revolutionary figures from Haiti to Hungary. In the process, Ball argues, antebellum black writers crafted a set of ideals-simultaneously respectable and subversive-for their elite and aspiring African American readers to embrace in the decades before the Civil War. Published in association with the Library Company of Philadelphia's Program in African American History. A Sarah Mills Hodge Fund Publication.

Liquid biopsy recently became a very promising diagnostic method that has several advantages over conventional invasive methods. Liquid biopsy may serve as a source of several important biomarkers including cell-free nucleic acids (cf-NAs). Cf-DNA is widely used in prenatal testing in order to characterize fetal genetic disorders. Analysis of cf-DNA may provide information about the mutation profile of tumor cells, while cell-free non-coding RNAs are promising biomarker candidates in the diagnosis and prognosis of cancer. Many of these markers have the potential to help clinicians in therapy selection and in the follow-up of patients. Thus, cf-NA-based diagnostics represent a new path in personalized medicine. Although several reviews are available in the field, most of them focus on a limited number of cf-NA types. In this review, we give an overview about all known cf-NAs including cf-DNA, cf-mtDNA and cell-free non-coding RNA (miRNA, lncRNA, circRNA, piRNA, YRNA, and vtRNA) by discussing their biogenesis, biological function and potential as biomarker candidates in liquid biopsy. We also outline possible future directions in the field.

High-quality, gluten-free doughs and bakery products are clearly more difficult to produce than wheat flour-based products. The poor quality of the breads that are currently available demonstrates that manufacturing remains a significant technological problem. This is mainly due to the absence of gluten, which has a huge negative impact on dough rheology and bread characteristics. Gluten replacement is still the major challenge in the development of doughs and baked goods. The literature documents various improvement strategies. The most active approach seeks to identify alternative ingredients that can mimic the viscoelastic properties of the gluten network, notably hydrocolloids, enzymes, emulsifiers, and alternative sources of protein. However, other innovative strategies, such as high pressure, using heat to dry flour, and sourdough fermentation, have been investigated. In this context, the first aim of this review is to summarize current knowledge regarding gluten-free doughs, breads, and bakery products. Secondly, as it is clear that the manufacture of gluten-free products remains a key challenge, it suggests some improvement strategies that can boost their nutritional, technological, and sensorial characteristics.

A newly synthesized nitroxide-based probe containing a fluorophore with high quantum yield at relatively long wavelengths can detect endogenously derived lipid-derived radicals and has therapeutic potential in a model of hepatocellular carcinoma. Lipids and their metabolites are easily oxidized in chain reactions initiated by lipid radicals, forming lipid peroxidation products that include the electrophiles 4-hydroxynonenal and malondialdehyde. These markers can bind cellular macromolecules, causing inflammation, apoptosis and other damage. Methods to detect and neutralize the initiating radicals would provide insights into disease mechanisms and new therapeutic approaches. We describe the first high-sensitivity, specific fluorescence probe for lipid radicals, 2,2,6-trimethyl-4-(4-nitrobenzo[1,2,5]oxadiazol-7-ylamino)-6-pentylpiperidine-1-oxyl (NBD-Pen). NBD-Pen directly detected lipid radicals in living cells by turn-on fluorescence. In a rat model of hepatic carcinoma induced by diethylnitrosamine (DEN), NBD-Pen detected lipid radical generation within 1 h of DEN administration. The lipid radical scavenging moiety of NBD-Pen decreased inflammation, apoptosis and oxidative stress markers at 24 h after DEN, and liver tumor development at 12 weeks. Thus, we have developed a novel fluorescence probe that provides imaging information about lipid radical generation and potential therapeutic benefits in vivo .

Free energy calculations based on molecular dynamics simulations show considerable promise for applications ranging from drug discovery to prediction of physical properties and structure-function studies. But these calculations are still difficult and tedious to analyze, and best practices for analysis are not well defined or propagated. Essentially, each group analyzing these calculations needs to decide how to conduct the analysis and, usually, develop its own analysis tools. Here, we review and recommend best practices for analysis yielding reliable free energies from molecular simulations. Additionally, we provide a Python tool, alchemical-analysis.py , freely available on GitHub as part of the pymbar package (located at http://github.com/choderalab/pymbar ), that implements the analysis practices reviewed here for several reference simulation packages, which can be adapted to handle data from other packages. Both this review and the tool covers analysis of alchemical calculations generally, including free energy estimates via both thermodynamic integration and free energy perturbation-based estimators. Our Python tool also handles output from multiple types of free energy calculations, including expanded ensemble and Hamiltonian replica exchange, as well as standard fixed ensemble calculations. We also survey a range of statistical and graphical ways of assessing the quality of the data and free energy estimates, and provide prototypes of these in our tool. We hope this tool  and discussion will serve as a foundation for more standardization of and agreement on best practices for analysis of free energy calculations.