Prestroke Physical Activity Matters for Functional Limitations: A Longitudinal Case-Control Study of 12,860 Participants.

OBJECTIVE: In the chronic phase after a stroke, limitations in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) initially plateau before steadily increasing. The benefits of prestroke physical activity on these limitations remain unclear. To clarify this relationship, the effect of physical activity on the long-term evolution of functional limitations in a cohort of people with stroke compared to a cohort of matched adults without stroke was examined. METHODS: Longitudinal data from 2143 people with stroke and 10,717 adults without stroke aged 50 years and older were drawn from a prospective cohort study based on the Survey of Health, Ageing and Retirement in Europe (2004-2022; 8 data collection waves). Physical activity was assessed in the prestroke wave. Functional limitations were assessed in the poststroke waves. Each person with stroke was matched with 5 adults without stroke who had similar propensity scores computed on the basis of key covariates, including baseline age, sex, body mass index, limitations in ADLs and IADLs, chronic conditions, and country of residence, before any of the participants from either cohort had experienced a stroke. RESULTS: Results showed an interaction between stroke status and physical activity on ADL limitations (b = -0.076; 95% CI = -0.142 to -0.011), with the effect of physical activity being stronger in people with stroke (b = -0.345; 95% CI = -0.438 to -0.252) than in adults without stroke (b = -0.269; 95% CI = -0.269 to -0.241). CONCLUSION: The beneficial effect of prestroke physical activity on ADL limitations after stroke is stronger than its effect in matched adults without stroke followed for a similar number of years. IMPACT: Physical activity, an intervention within the physical therapist's scope of practice, is effective in reducing the risk of functional dependence after stroke. Moreover, prestroke levels of physical activity can inform the prognosis of functional dependence in people with stroke.

Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway.

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimer's disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that plays a key role in synaptic plasticity, learning, and memory. Arc has been implicated in AD pathogenesis and regulates the release of amyloid-beta. We found that decreased Arc levels correlate with AD status and disease severity. Importantly, Arc protein was upregulated in the hippocampus of Tau KO mice and dendrites of Tau KO primary hippocampal neurons. Overexpression of tau decreased Arc stability in an activity-dependent manner, exclusively in neuronal dendrites, which was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The tau-dependent decrease in Arc was found to be proteasome-sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. These observations provide a potential molecular basis for synaptic dysfunction mediated through the accumulation of tau in dendrites. Our findings confirm that Arc is misregulated in AD and further show a physiological role for tau in regulating Arc stability and AMPA receptor targeting.

Single Live Cell Imaging of Multidrug Resistance Using Silver Ultrasmall Nanoparticles as Biosensing Probes in Triple-Negative Breast Cancer Cells.

Silver ultrasmall nanoparticles (Ag UNPs) (size < 5 nm) were used as biosensing probes to analyze the efflux kinetics contributing to multidrug resistance (MDR) in single live triple-negative breast cancer (TNBC) cells by using dark-field optical microscopy to follow their size-dependent localized surface plasmon resonance. TNBC cells lack expression of estrogen (ER-), progesterone (PR-), and human epidermal growth factor 2 (HER2-) receptors and are more likely to acquire resistance to anticancer drugs due to their ability to transport harmful substances outside the cell. The TNBC cells displayed greater nuclear and cytoplasmic efflux, resulting in less toxicity of Ag UNPs in a concentration-independent manner. In contrast, more Ag UNPs and an increase in cytotoxic effects were observed in the receptor-positive breast cancer cells that have receptors for ER+, PR+, and HER2+ and are known to better respond to anticancer therapies. Ag UNPs accumulated in receptor-positive breast cancer cells in a time-and concentration-dependent mode and caused decreased cellular growth, whereas the TNBC cells due to the efflux were able to continue to grow. The TNBC cells demonstrated a marked increase in survival due to their ability to have MDR determined by efflux of Ag UNPs outside the nucleus and the cytoplasm of the cells. Further evaluation of the nuclear efflux kinetics of TNBC cells with Ag UNPs as biosensing probes is critical to gain a better understanding of MDR and potential for enhancement of cancer drug delivery.

Arc ubiquitination regulates endoplasmic reticulum-mediated Ca2+ release and CaMKII signaling.

Synaptic plasticity relies on rapid, yet spatially precise signaling to alter synaptic strength. Arc is a brain enriched protein that is rapidly expressed during learning-related behaviors and is essential for regulating metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD). We previously showed that disrupting the ubiquitination capacity of Arc enhances mGluR-LTD; however, the consequences of Arc ubiquitination on other mGluR-mediated signaling events is poorly characterized. Here we find that pharmacological activation of Group I mGluRs with S-3,5-dihydroxyphenylglycine (DHPG) increases Ca2+ release from the endoplasmic reticulum (ER). Disrupting Arc ubiquitination on key amino acid residues enhances DHPG-induced ER-mediated Ca2+ release. These alterations were observed in all neuronal subregions except secondary branchpoints. Deficits in Arc ubiquitination altered Arc self-assembly and enhanced its interaction with calcium/calmodulin-dependent protein kinase IIb (CaMKIIb) and constitutively active forms of CaMKII in HEK293 cells. Colocalization of Arc and CaMKII was altered in cultured hippocampal neurons, with the notable exception of secondary branchpoints. Finally, disruptions in Arc ubiquitination were found to increase Arc interaction with the integral ER protein Calnexin. These results suggest a previously unknown role for Arc ubiquitination in the fine tuning of ER-mediated Ca2+ signaling that may support mGluR-LTD, which in turn, may regulate CaMKII and its interactions with Arc.

Reducing touching eyes, nose and mouth ('T-zone') to reduce the spread of infectious disease: A prospective study of motivational, volitional and non-reflective predictors.

BACKGROUND: The route into the body for many pathogens is through the eyes, nose and mouth (i.e., the 'T-zone') via inhalation or fomite-based transfer during face touching. It is important to understand factors that are associated with touching the T-zone to inform preventive strategies. PURPOSE: To identify theory-informed predictors of intention to reduce facial 'T-zone' touching and self-reported 'T-zone' touching. METHODS: We conducted a nationally representative prospective questionnaire study of Canadians. Respondents were randomized to answer questions about touching their eyes, nose, or mouth with a questionnaire assessing 11 factors from an augmented Health Action Process Approach at baseline: intention, outcome expectancies, risk perception, individual severity, self-efficacy, action planning, coping planning, social support, automaticity, goal facilitation and stability of context. At 2-week follow-up, we assessed HAPA-based indicators of self-regulatory activities (awareness of standards, effort, self-monitoring) and self-reported behaviour (primary dependent variable). RESULTS: Of 656 Canadian adults recruited, 569 responded to follow-up (87% response rate). Across all areas of the 'T-zone', outcome expectancy was the strongest predictor of intention to reduce facial 'T-zone' touching, while self-efficacy was a significant predictor for only the eyes and mouth. Automaticity was the strongest predictor of behaviour at the 2-week follow-up. No sociodemographic or psychological factors predicted behaviour, with the exception of self-efficacy, which negatively predicted eye touching. CONCLUSION: Findings suggest that focusing on reflective processes may increase intention to reduce 'T-zone' touching, while reducing actual 'T-zone' touching may require strategies that address the automatic nature of this behaviour.

The mevalonate suppressor δ-tocotrienol increases AMPA receptor-mediated neurotransmission.

Synaptic dysfunction is a hallmark of aging and is found in several neurological disorders such as Alzheimer's disease. A common mechanism related to synaptic dysfunction is dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which mediate excitatory neurotransmission and synaptic plasticity. Accumulating evidence suggests that tocotrienols, vitamin E molecules that contain an isoprenoid side chain, may promote cognitive improvement in hippocampal-dependent learning tasks. Tocotrienols have also been shown to reduce the secretion of ß-amyloid (Aß) and cholesterol biosynthesis in part by downregulating 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that controls flux of the mevalonate pathway and cholesterol biosynthesis. We hypothesized that tocotrienols might promote cognitive improvement by increasing AMPA receptor-mediated synaptic transmission. Here, we found that δ-tocotrienol increased surface levels of GluA1 but not the GluA2 AMPA receptor subunit in primary hippocampal neurons. Unexpectedly, δ-tocotrienol treatment caused a decrease in the phosphorylation of GluA1 at Serine 845 with no significant changes in GluA1 at Serine 831. Moreover, δ-tocotrienol increased spontaneous excitatory postsynaptic current (sEPSC) amplitude and reduced the secretion of Aß40 in primary hippocampal neurons. Taken together, our findings suggest that δ-tocotrienol increases AMPA receptor-mediated neurotransmission via noncanonical changes in GluA1 phosphorylation status. These findings suggest that δ-tocotrienol may be beneficial in ameliorating synaptic dysfunction found in aging and neurological disease.

Disproportionate Burden of COVID-19 Infection Among Hispanic Patients During the First COVID-19 Surge in South Texas.

Introduction: The morbidity and mortality of the COVID-19 pandemic have disproportionately burdened Hispanic populations in the United States. While health equity research is typically conducted in populations where Hispanics are the minority, this project analyzes COVID-19 racioethnic transmission trends over the first 6 months of the pandemic within a large majority-minority city in South Texas. Methods: Patients diagnosed with COVID-19 across inpatient, emergency department, and outpatient settings of a large county health system were included in a clinical registry. For 4644 COVID-19-positive patients between March 16 and August 31, 2020, demographic and clinical data were abstracted from the registry. Race/ethnicity trends over time were compared for patients with and without COVID-19 diagnoses. Logistic regressions identified predictors of inpatient diagnosis by age, race/ethnicity, and testing delay. Results: The proportion of patients with COVID-19 identifying as Hispanic increased rapidly during the pandemic's first months: from 55.6% in March to 85.7% in June. A significantly greater proportion of patients identified as Hispanic within the COVID-19 cohort compared to other diagnoses cohort. Testing delay was 11.6% longer for Hispanic patients, with each day of testing delay associated with 7% increased odds of inpatient COVID-19 diagnosis. Conclusion: These findings highlight the disproportionate impact of COVID-19 on Hispanic populations even within a majority-minority community. In the United States, Hispanic persons are more likely to work frontline jobs, live in multigenerational homes in poverty, and be uninsured. The burden of COVID-19 cases within Bexar County's largest hospital system reflects this systemic inequity. Identifying racioethnic health disparities supports efforts toward mitigating structural factors that predispose minority groups to illness and death.

Fluorogenic monomer activation for protein-initiated atom transfer radical polymerization.

Fluorogenic atom transfer radical polymerization (ATRP) directly detects initiator-dependent polymer formation, as initially non-fluorescent polycyclic aromatic probe monomers reveal visible fluorescence upon polymerization in real time. Advancement of this initial proof-of-concept toward biodetection applications requires both a more detailed mechanistic understanding of probe fluorescence activation, and the ability to initiate fluorogenic polymerization directly from a biomolecule surface. Here, we show that simple monomer hydrogenation, independent of polymerization, reveals probe fluorescence, supporting the critical role of covalent enone attachment in fluorogenic probe quenching and subsequent fluorescence activation. We next demonstrate bioorthogonal, protein-initiated fluorogenic ATRP by the surface conjugation and characterization of protein-initiator conjugates of a model protein, bovine serum albumin (BSA). Fluorogenic ATRP from initiator-modified protein allows for real-time visualization of polymer formation with negligible background fluorescence from unmodified BSA controls. We further probe the bioorthogonality of this fluorogenic ATRP assay by assessing polymer formation in a complex biological environment, spiked with fetal bovine serum. Taken together, we demonstrate the potential of aqueous fluorogenic ATRP as a robust, bioorthogonal method for biomolecular-initiated polymerization by real-time fluorescence activation.

Brief interventions targeting long-term benzodiazepine and Z-drug use in primary care: a systematic review and meta-analysis.

AIMS: To assess the effectiveness of brief interventions in primary care aimed at reducing or discontinuing long-term benzodiazepine/Z-drug (BZRA) use. METHOD: Systematic review of randomized controlled trials of brief interventions in primary care settings aimed at reducing or discontinuing long-term BZRA use in adults taking BZRAs for ≥ 3 months. Four electronic databases were searched: PubMed, EMBASE, PsycINFO and CENTRAL. The primary outcome was BZRA use, classified as discontinuation or reduction by ≥ 25%. The Theoretical Domains Framework (TDF) was used to retrospectively code behavioural determinants targeted by the interventions. The Behaviour Change Technique (BCT) Taxonomy was used to identify the interventions' active components. Study-specific estimates were pooled, where appropriate, to yield summary risk ratios (RRs) and 95% confidence intervals (CIs). Pearson's correlations were used to determine the relationship between intervention effect size and the results of both the TDF and BCT coding. RESULTS: Eight studies were included (n = 2071 patients). Compared with usual care, intervention patients were more likely to have discontinued BZRA use at 6 months (eight studies, RR = 2.73, 95% CI = 1.84-4.06) and 12 months post-intervention (two studies, RR = 3.41, 95% CI = 2.22-5.25). TDF domains 'knowledge', 'memory, attention and decision processes', 'environmental context and resources' and 'social influences' were identified as having been included in every intervention. Commonly identified BCTs included 'information about health consequences', 'credible source' and 'adding objects to the environment'. There was no detectable relationship between effect size and the results of either the TDF or BCT coding. CONCLUSION: Brief interventions delivered in primary care are more effective than usual care in reducing and discontinuing long-term benzodiazepine/Z-drug use.

Fluorogenic atom transfer radical polymerization in aqueous media as a strategy for detection.

The development of novel approaches to signal amplification in aqueous media could enable new diagnostic platforms for the detection of water-soluble analytes, including biomolecules. This paper describes a fluorogenic polymerization approach to amplify initiator signal by the detection of visible fluorescence upon polymerization in real-time. Fluorogenic monomers were synthesized and co-polymerized by atom transfer radical polymerization (ATRP) in water to reveal increasing polymer fluorescence as a function of both reaction time and initiator concentration. Optimization of the fluorogenic ATRP reaction conditions allowed for the quantitative detection of a small-molecule initiator as a model analyte over a broad linear concentration range (pM to mM). Raising the reaction temperature from 30 °C to 60 °C facilitated sensitive initiator detection at sub-picomolar concentrations in as little as 1 h of polymerization. This method was then applied to the detection of streptavidin as a model biological analyte by fluorogenic polymerization from a designed biotinylated ATRP initiator. Taken together, these studies represent the first example of a fluorogenic ATRP reaction and establish fluorogenic polymerization as a promising approach for the direct detection of aqueous analytes and biomolecular recognition events.

Testing Trait-State Isomorphism in a New Domain: An Exploratory Manipulation of Openness to Experience.

The trait-state isomorphism hypothesis holds that personality traits and states (i.e., trait-related behavior) are characterized by similar outcomes (Fleeson, 2001). Openness is associated with creative thinking, personal growth, and positive affect. Engaging in behavior associated with openness has also been found to covary with feelings of authenticity. In the present experiment, participants (N = 210) completed a pre-test assessment, five daily exercises designed to either be inert (control condition) or engage the behaviors and cognitions associated with openness (experimental condition), a post-test assessment, and a 2 week follow up assessment. Results supported the isomorphism hypothesis for positive affect but not creative thinking ability or personal growth. Furthermore, open behavior was only associated with authenticity for individuals high on trait openness.

The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility.

Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.

The morbidity of transperineal template-guided prostate mapping biopsy.

OBJECTIVE: To evaluate the effect of transperineal template-guided prostate mapping biopsy (TTMB) on urinary, bowel and erectile function. PATIENTS AND METHODS: In all, 129 men had TTMB; a median of 56 biopsy cores were obtained per patient. Tamsulosin (0.8 mg daily) was initiated 2 days before TTMB and continued for 2 weeks. The International Prostate Symptom Score (IPSS), Rectal Function Assessment Score (R-FAS), International Index of Erectile Function (IIEF)-6 and the postvoid residual volume (PVR) were assessed at baseline and after 30 days, except for the IPSS, which was also assessed at 7 days. Several variables were evaluated as predictors of TTMB-induced morbidity. RESULTS: The mean patient age was 64.7 years with a mean prostate volume of 74.3 mL; 60 men (46.5%) were diagnosed with prostate cancer. After TTMB, 39.4%, 7.1% and 1.6% of patients remained catheter-dependent at 0, 3 and 6 days. The median catheter-dependency was 0, 1, 2 and 3 days for prostate volumes of <60, 60-90, 90-120 and >120 mL, respectively. No patient remained catheter- dependent for >12 days or required a transurethral resection secondary to TTMB. The mean IPSS before TTMB was 10.4, and was 4.6 and 3.8 at 7 and 30 days. At baseline and 30 days the mean PVR was 35 and 40 mL, and the median R-FAS and IIEF scores for patients potent before TTMB were 2.0 and 2.2, and 27.0 and 26.0, respectively. CONCLUSIONS: TTMB is a promising procedure for diagnosing prostate cancer. TTMB-related morbidity differs from that of standard TRUS biopsy primarily in the incidence of temporary urinary retention, and is comparable in terms of urinary, bowel and erectile function.