Patterns of physical activity of people with COPD during participation in a pulmonary rehabilitation program.

INTRODUCTION: Very few studies have examined patterns of physical activity (PA) during a pulmonary rehabilitation (PR) program in people with COPD. AIMS: To compare the patterns of PA in: 1) the week before commencing PR (pre-PR) with a week during PR (PR week); 2) PR days and non-PR days during a PR week; 3) pre-PR and the week following PR completion (post-PR). METHODS: This was a multicenter, prospective cohort study. Participants attended twice weekly supervised PR for 8-12 weeks. Daily step count (primary outcome), time in light activities, time in moderate to vigorous PA (MVPA), total sedentary time and sit-to-stand (STS) transitions were measured using a thigh worn accelerometer for seven days, at each assessment time point: pre-PR, PR week and post-PR. RESULTS: 29 participants, mean age (SD) 69years(7), FEV1 53%pred(16). The PR week compared to pre-PR, showed higher daily: step count (mean difference (95%CI)), 941steps(388-1494); and MVPA, 11mins(6-15), with no difference in: time in light activities, -1min(-6-5); total sedentary time, 7mins(-21-36); or STS transitions, 0(-5-6). PR days compared to non-PR days showed higher: step count, 2810steps(1706-3913); time in light activities 11mins(1-20); time in MVPA, 27mins(17-35) and STS transitions, 8(4-12), with no difference in total sedentary time: -33mins(-80-15). There were no differences in any PA measures post-PR compared to pre-PR (p < 0.05). CONCLUSION: Daily step count and time spent in MVPA increased significantly during the PR week, solely due to increased PA on days participants attended PR.

Effect of a 4-Week Telerehabilitation Program for People with Post-COVID Syndrome on Physical Function and Symptoms: Protocol for a Randomized Controlled Trial.

OBJECTIVE: COVID-19 has led to significant morbidity and mortality globally. Post-COVID sequelae can persist beyond the acute and subacute phases of infection, often termed Post-COVID Syndrome (PCS). There is limited evidence on the appropriate rehabilitation for people with PCS. The aim of this study is to evaluate the effect on exercise capacity, symptoms, cognition, anxiety, depression, health-related quality of life (HRQoL), and fatigue, of a 4-week, twice-weekly supervised pulmonary telerehabilitation program compared to usual medical care for people with PCS with persistent respiratory symptoms. METHODS: The study will be a multi-site randomized controlled trial (RCT) with assessor blinding. Participants with confirmed previous COVID-19 infection and persistent respiratory symptoms who attend a post-COVID respiratory clinic will be randomized 1:1 to either an intervention group (IG) of 4 weeks, twice-weekly pulmonary telerehabilitation or a control group (CG) of usual medical care. Participants in the CG will be invited to cross-over into the IG after the week 4 assessment. Primary outcome: exercise capacity measured by the 1-minute sit-to-stand test. Secondary outcomes: 5 repetition sit-to-stand test; Montreal Cognitive Assessment; COVID-19 Yorkshire Rehabilitation Scale; COPD Assessment Test; 36-Item Short-Form Health Survey; Hospital Anxiety and Depression Scale; Fatigue Severity Scale; and the Kessler Psychological Distress Scale. Outcomes will be collected at baseline, after 4-weeks intervention or control period, after intervention in the cross-over group, and at 12-month follow-up. IMPACT STATEMENT: Research into effective rehabilitation programs is crucial given the substantial morbidity associated with PCS and the lack of long-term data for COVID-19 recovery. A short duration pulmonary telerehabilitation program, if effective compared to usual care, could inform practice guidelines and direct future clinical trials for the benefit of individuals with persistent respiratory symptoms post-COVID.

Changes in Exercise Capacity and Health-Related Quality of Life at Four and Eight Weeks of a Pulmonary Rehabilitation Program in People with COPD.

Pulmonary Rehabilitation (PR) is a key intervention in the management of people with chronic obstructive pulmonary disease (COPD), though few studies have assessed where changes in outcomes occur during a PR program. The aim of this study was to determine the changes in exercise capacity and health-related quality of life at four and eight weeks during a twice-weekly supervised PR program in people with COPD. Fifty participants with COPD were recruited and attended PR twice-weekly for eight weeks. The outcome measures were the endurance shuttle walk test (ESWT), six-minute walk distance (6MWD), St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT) and the Hospital Anxiety and Depression Scale (HADS) which were measured at baseline, four and eight weeks. Compared to baseline, at week four there were significant improvements in ESWT (mean difference [95%CI] 197 [89 to 305] seconds), 6MWD (22 [8 to 36] metres), SGRQ symptom score (-6 [-12 to -1] points) and SGRQ total score (-4 [-7 to -1] points). Between week four and eight there were further significant improvements in ESWT (94 [8 to 181] seconds) only. By week eight, ESWT, 6MWD, SGRQ symptoms and total score, and CAT had all improved significantly compared to baseline measures. This study demonstrated that participants with moderate to very severe COPD who participated in a twice weekly, eight-week PR program (16 sessions) had significant improvement in ESWT, 6MWD, SGRQ, and CAT score with the greatest improvements occurring in the first four weeks of the program.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.2013793 .

Identification and Mechanistic Characterization of a Peptide Inhibitor of Glycogen Synthase Kinase (GSK3ß) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein.

Glycogen synthase kinase 3-beta (GSK3ß) is a critical regulator of several cellular pathways involved in neurodevelopment and neuroplasticity and as such is a potential focus for the discovery of new neurotherapeutics toward the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3ß have been focused on developing small molecule inhibitors that compete with adenosine triphosphate (ATP) through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The disrupted in schizophrenia 1 (DISC1) protein has previously been shown to bind and inhibit GSK3ß activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3ß in a noncompetitive mode distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3ß: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3ß binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3ß.

Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo.

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3ß) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase Cγ1-calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.

Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects.

The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3's inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3ß, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in in vitro systems or in vivo models. A nonconventional analysis of data from a GSK3ß inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Despite the prevalence of HCC, there is no effective, systemic treatment. The transcription factor LSF is a promising protein target for chemotherapy; it is highly expressed in HCC patient samples and cell lines, and promotes oncogenesis in rodent xenograft models of HCC. Here, we identify small molecules that effectively inhibit LSF cellular activity. The lead compound, factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity both in vitro, as determined by electrophoretic mobility shift assays, and in cells, as determined by ChIP. Consistent with such inhibition, FQI1 eliminates transcriptional stimulation of LSF-dependent reporter constructs. FQI1 also exhibits antiproliferative activity in multiple cell lines. In LSF-overexpressing cells, including HCC cells, cell death is rapidly induced; however, primary or immortalized hepatocytes are unaffected by treatment with FQI1. The highly concordant structure-activity relationship of a panel of 23 quinolinones strongly suggests that the growth inhibitory activity is due to a single biological target or family. Coupled with the striking agreement between the concentrations required for antiproliferative activity (GI(50)s) and for inhibition of LSF transactivation (IC(50)s), we conclude that LSF is the specific biological target of FQIs. Based on these in vitro results, we tested the efficacy of FQI1 in inhibiting HCC tumor growth in a mouse xenograft model. As a single agent, tumor growth was dramatically inhibited with no observable general tissue cytotoxicity. These findings support the further development of LSF inhibitors for cancer chemotherapy.

Disc1 regulates both ß-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis.

Disc1 is a schizophrenia risk gene that engages multiple signaling pathways during neurogenesis and brain development. Using the zebrafish as a tool, we analyze the function of zebrafish Disc1 (zDisc1) at the earliest stages of brain and body development. We define a "tool" as a biological system that gives insight into mechanisms underlying a human disorder, although the system does not phenocopy the disorder. A zDisc1 peptide binds to GSK3ß, and zDisc1 directs early brain development and neurogenesis, by promoting ß-catenin-mediated Wnt signaling and inhibiting GSK3ß activity. zDisc1 loss-of-function embryos additionally display a convergence and extension phenotype, demonstrated by abnormal movement of dorsolateral cells during gastrulation, through changes in gene expression, and later through formation of abnormal, U-shaped muscle segments, and a truncated tail. These phenotypes are caused by alterations in the noncanonical Wnt pathway, via Daam and Rho signaling. The convergence and extension phenotype can be rescued by a dominant negative GSK3ß construct, suggesting that zDisc1 inhibits GSK3ß activity during noncanonical Wnt signaling. This is the first demonstration that Disc1 modulates the noncanonical Wnt pathway and suggests a previously unconsidered mechanism by which Disc1 may contribute to the etiology of neuropsychiatric disorders.

Enantioselective addition of boronates to acyl imines catalyzed by chiral biphenols.

On the big screen: A chiral biphenol catalyst screening protocol was developed for the rapid identification of enantioselective nucleophilic boronate reactions with acyl imines (see scheme). The approach successfully identified a unique catalyst for the reaction of aryl, vinyl, and alkynyl boronates. Mechanistic studies demonstrate boronate ligand exchange with the catalyst is necessary for activation towards nucleophilic addition.