Precision Colorectal Cancer Fecal Immunological Test Screening With Fecal-Hemoglobin-Concentration-Guided Interscreening Intervals.

Importance: Given a gradient relationship between fecal hemoglobin (f-Hb) concentration and colorectal neoplasia demonstrated previously, using f-Hb-guided interscreening interval has increasingly gained attention in population-based fecal immunological test (FIT), but it is very rare to address how to implement such a precision strategy and whether it can economize the use of FIT and colonoscopy. Objective: To demonstrate the applicability of personalized colorectal cancer (CRC) screening with f-Hb-guided screening intervals to reduce the number of FITs and colonoscopy with as equivalent efficacy as universal biennial screening equivalent efficacy as universal biennial screening. Design, Setting, and Participants: A retrospective cohort study for developing f-Hb-guided precision interscreening interval was conducted using data on a Taiwanese biennial nationwide FIT screening program that enrolled more than 3 million participants aged 50 to 74 years between 2004 and 2014. The cohort was followed up over time until 2019 to ascertain colorectal neoplasia and causes of death. A comparative study was further designed to compare the use of FIT and colonoscopy between the personalized f-Hb-guided group and the universal biennial screening group given the equivalent efficacy of reducing CRC-related outcomes. Main Outcomes and Measurements: A spectrum of f-Hb-guided intervals was determined by using the Poisson regression model given the equivalent efficacy of a universal biennial screening. The use of FIT and colonoscopy for the pragmatic f-Hb-guided interval group was measured compared with the universal biennial screening group. Data analysis was performed from September 2022 to October 2023. Results: Using data from the 3 500 250 participants (mean [SD] age, 57.8 [6.0] years) enrolled in the Taiwanese biennial nationwide FIT screening program, an incremental increase in baseline f-Hb associated with colorectal neoplasia and CRC mortality consistently was observed. Participants with different f-Hb levels were classified into distinct risk categories. Various screening intervals by different f-Hb levels were recommended. Using the proposed f-Hb-guided screening intervals, it was found that the personalized method was imputed to reduce the number of FIT tests and colonoscopies by 49% and 28%, respectively, compared with the universal biennial screening. Conclusion and Relevance: The gradient relationship between f-Hb and colorectal neoplasia and CRC mortality was used to develop personalized FIT screening with f-Hb-guided screening intervals. Such a precision interscreening interval led to the reduced use of FIT test and colonoscopy without compromising the effectiveness of universal biennial screening.

Exploring Temporal and Intensity Effects of Resistance Exercise on Inhibition: A Four-Arm Crossover Randomized Controlled Trial.

Objective: Given the recognized benefits of resistance exercise on both physical and cognitive domains, elucidating how to maximize its benefit is pivotal. This study aims to evaluate these effects in terms of their timing and intensity on cognitive performance. Methods: This was a four-arm, crossover randomized controlled trial. Healthy college-aged male adults with recreational resistance training experience participated in this study. Participants completed three separate sessions of circuit barbell resistance exercises, including back squat, press, and deadlift. Each session corresponded to a different intensity level: 65% 1RM, 72% 1RM, and 78% 1RM. Each session consisted of 5 repetitions across 3 sets, with a 3-minute rest between exercises and sets. For the control condition, participants engaged in a reading activity for the same duration. The subjective exercise intensity was measured using the rating of perceived exertion and repetitions in reserve immediately after each set. The primary outcome was the temporal effect of acute resistance exercise on inhibition, measured by the Stroop color-word task. The secondary outcome was the effect of different intensities. Results: 30 out of 31 recruited participants were randomized, with 28 completing all experiment sessions. Using repeated measures correlation (rrm), a linear temporal effect was observed on accuracy-adjusted congruent reaction time: rrm = 0.114, p = 0.045, 95% CI [0.002, 0.223]. Participants responded 19.1 ms faster than the control condition approximately 10 minutes post-intervention. This advantage, however, gradually declined at a rate of 4.3 ms every 15 minutes between 10-55 minutes post-intervention. In contrast, no significant effects were detected for incongruent trials or the Stroop effect. When examining the linear relationship across exercise intensities, no significant correlations emerged for congruent trials. Conclusion: Resistance exercise demonstrates a temporal effect on cognitive performance, particularly in reaction speed for congruent trials, without significant changes in incongruent trials or the overall Stroop effect. The findings highlight the importance of timing in leveraging the cognitive benefits of acute resistance exercise, suggesting a window of enhanced cognitive performance following exercise. However, this study has a limitation regarding Type I error inflation, due to multiple measurements of cognitive performance being undertaken, suggesting caution in interpreting the observed temporal effects. Practically, scheduling crucial, cognitively demanding tasks within 10-60 minutes post-exercise may maximize benefits, as positive effects diminish after this period.

The intrinsic substrate specificity of the human tyrosine kinome.

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.

Enhancing Overhead Throwing Ball Velocity after Core Muscle Training in Athletes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the influence of core muscle training (CMT) on throwing ball velocity among overhead throwing athletes. DESIGN: A literature search was performed from inception to July 2023 for randomized controlled trials (RCTs) investigating the effects of CMT on overhead throwing ball velocity. The primary outcome was the change in standing throwing ball velocity. The secondary outcome focused on the enhancement of step/jump throwing ball velocity. RESULTS: Seven RCTs were included, revealing a significant improvement in standing throwing ball-velocity in the group undergoing CMT (Hedges' g = 0.701, 95% confidence interval [CI] = 0.339 to 1.063, p < 0.001). Longer treatment duration and a higher frequency of CMT sessions per week contributed to improved standing throwing ball velocity. However, CMT did not show significant benefits for step (Hedge's g = 0.463, 95% CI = -0.058 to 0.985, p = 0.082) and jump throwing ball-velocity (Hedges' g = 0.550, 95% CI = -0.051 to 1.152, p = 0.073). CONCLUSION: CMT significantly enhanced standing ball throwing velocity. However, its effect on step/jump-throwing ball velocity was less certain. Further research is needed to explore the impact of CMT (especially its long-term effects) on throwing ball velocity.

Effectiveness of Lumbar Segmental Stabilization Exercises in Managing Disability and Pain Intensity Among Patients with Lumbar Spondylolysis and Spondylolisthesis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: This study aims to assess the effectiveness of lumbar segmental stabilization exercises (LSSE) in managing spondylolysis and spondylolisthesis. SUMMARY OF BACKGROUND DATA: Spondylolysis and spondylolisthesis are spinal disorders associated with lumbar segmental instability. LSSE have shown positive effects in treating these conditions; however, systematic reviews and meta-analyses are lacking. METHODS: A systematic search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, including studies from the inception of the databases used up to January 2024, was conducted. Disability improvement and pain intensity change were the primary and secondary outcomes, respectively, standardized using Hedges' g. Eligible articles underwent independent scrutiny by two authors, who also performed data extraction and quality assessment. Data pooling was accomplished using a random-effects model. RESULTS: In total, five randomized controlled trials comprising 198 participants were included, revealing a trend effect toward disability improvement in the LSSE group (Hedges' g=-0.598, 95% CI=-1.211 to 0.016, P=0.056, I2=75.447%). When the LSSE was administered as a single treatment, disability improvement became significant (Hedges' g=-1.325, 95% CI=-2.598 to -0.053, P=0.041, I2=80.020%). No significant effect of LSSE on pain reduction was observed (Hedges' g=-0.496, 95% CI=-1.082 to 0.090, P=0.097, I2=73.935%). CONCLUSION: In summary, our meta-analysis suggests that LSSE can potentially improve disability, especially when used as a single treatment. LSSE appears more beneficial in reducing disability than alleviating pain. Future research on different patient groups is needed to understand comprehensively LSSE's effects on other musculoskeletal disorders.

The relevance of motor sequence and visual perception skills in learning Chinese handwriting.

This study explored visual perception skills and the ability to write according to standard stroke order and their links to the learning of Chinese handwriting. Thirty-seven children (aged 6-8) (15 boys and 22 girls) participated in a handwriting test and visual perception evaluation (Test of Visual Perceptual Skills-3rd Edition, TVPS-3). A computerized system was used to evaluate the stroke order accuracy, legibility, and automation of stroke movements. The stroke order accuracy was found to positively correlate with the scores of TVPS-3 (r = .498, p < .05) and to significantly correlate with handwriting legibility (r = .435, p < .05) as well as the automation of stroke movements (r = .494, p < .01). This study revealed that visual perception skill is related to stroke order accuracy and provides directions to assist students who encounter difficulties in learning Chinese handwriting.

New insights into three trajectories of omicron-related all-cause death reduced by COVID-19 booster vaccination.

BACKGROUND: The trajectories of all-cause deaths linked to omicron infections are rarely studied, especially in relation to the efficacy of booster shots. For assessing three epidemiological death trajectories, including dying from COVID-19, dying with COVID-19, and non-COVID-19 death, we offer a new COVID-19-and-death competing risk model that deals with the primary pathway (e.g., dying from COVID-19) competing with two other pathways. METHODS: We applied this model to track three trajectories: deaths directly from COVID-19, deaths with COVID-19 as a contributing factor, and indirect non-COVID-19 deaths. The study used data from a Taiwanese cohort, covering periods of Omicron subvariants BA.2, BA.5, and BA.2.75. It focused on the effectiveness of monovalent and bivalent booster vaccines against these death trajectories. RESULTS: The highest mortality was observed during the BA.2 phase, which decreased in the BA.5 period and increased again in the BA.2.75 period. Analyzing each trajectory, we noted similar trends in deaths directly from and with COVID-19, while non-COVID-19 deaths remained stable across subvariants. Booster vaccines reduced all-cause mortality by 58% (52%-62%) for BA.2, 70% (65%-75%) for BA.5%, and 75% (70%-80%) for BA.2.75, compared to incomplete vaccination. The reduction in deaths directly from COVID-19 was 66% (61%-72%) for BA.2, 78% (72%-84%) for BA.5%, and 85% (76%-93%) for BA.2.75. For deaths with COVID-19, the figures were 46% (36%-55%), 76% (68%-84%), and 90% (86%-95%). Additionally, the booster shots decreased non-COVID-19 deaths by 64% (63%-66%) for BA.2, 38% (36%-40%) for BA.5, and 19% (17%-21%) for BA.2.75. CONCLUSION: Our competing risk analysis is effective for monitoring all-cause death trajectories amidst various Omicron infections. It provides insights into the impact of booster vaccines, especially bivalent ones, and highlights the consequences of inadequate healthcare for vulnerable groups.

Different Impacts of Traffic-Related Air Pollution on Early-Onset and Late-Onset Asthma.

Background: Early-onset asthma (EOA) and late-onset asthma (LOA) are two distinct phenotypes. Air pollution has been associated with an increase in poorer asthma outcomes. The objective of this study was to examine the effects of traffic-related air pollution (TRAP) on asthma outcomes in EOA and LOA patients. Methods: A cross-sectional study was conducted on 675 asthma patients (LOA: 415) recruited from a major medical center in Taiwan. The land-use regression (LUR) model was used to estimate the level of exposure to PM10, PM2.5, NO2, and O3 on an individual level. We investigated the association between TRAP and asthma outcomes in EOA and LOA patients, stratified by allergic sensitization status, using a regression approach. Results: An increase in PM10 was associated with younger age of onset, increased asthma duration, and decreased lung function in EOA patients (p<0.05). An increase in PM10 was associated with older age of onset, and decreased asthma duration, eosinophil count, and Asthma Control Test (ACT) score in LOA patients. An increase in PM2.5 was associated with younger age of onset, increased asthma duration, decreased eosinophil count, and lung function in EOA patients (p<0.05). An increase in PM2.5 was associated with decreased lung function and ACT score in LOA patients. An increase in NO2 was associated with increased eosinophil count and decreased lung function in EOA patients (p<0.05). An increase in O3 was associated with decreased lung function in LOA patients (p<0.05). In addition, associations of TRAP with age of onset and eosinophil counts were mainly observed in both EOA and LOA patients with allergic sensitization, and an association with ACT was mainly observed in LOA patients without allergic sensitization. Conclusion: The impact of TRAP on age of onset, eosinophil count, and lung function in EOA patients, and ACT in LOA patients, was affected by the status of allergic sensitization.

Structure of the p53 degradation complex from HPV16.

Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.

A systematic review on sonoelastography for rotator-cuff post-repair assessment.

Surgical repair of rotator cuff tears is performed routinely; however, the risks of re-tears and the associated consequences are significant. Sonoelastography, an imaging modality that evaluates the mechanical properties of tissues, can examine the dynamic transitions in rotator cuff stiffness following retear and investigate the relationship between these changes and the occurrences of retears. This systematic review aimed to summarize the role of perioperative sonoelastography in repaired rotator cuffs. A comprehensive search of the PubMed, Embase, and Cochrane databases was conducted, covering studies published until June 19, 2023. The Newcastle-Ottawa scale was used for quality assessment. The key information extracted from each study included the injury/surgery type, follow-up duration, sonoelastography mode, and main sonoelastographic findings. Eleven eligible studies comprising 355 patients were included. All studies focused on supraspinatus muscles and tendons with previous arthroscopic repairs. During the postoperative 1st - 6th months, muscle stiffness increased in the supraspinatus and decreased in the ipsilateral deltoid. Failure to recover supraspinatus muscle elasticity might be indicative of potential tendon re-tear; however, it is imperative to first establish correlations with other imaging modalities. Conflicting findings have been observed regarding stiffening or softening of the supraspinatus tendon after surgical repair. The preoperative stiffness of the supraspinatus tendon did not correlate with postoperative tendon integrity or function.

Effects of resistance exercises on inhibitory control and plasma epinephrine levels: A registered report of a crossover randomized controlled trial.

According to the locus coeruleus-norepinephrine (LC-NE) theory, activity of the LC, the major releaser of NE in the brain, regulates inhibitory control. As there is reciprocal communication between circulating epinephrine and the LC, plasma epinephrine is used as the index of LC-NE activity. The aim of this crossover randomized controlled trial is to expand on previous findings by investigating the effects of free-weight, multiple-joint, and structural barbell resistance exercises. Previous studies have had some methodological limitations, such as failure to report the process of randomization, absence of resistance exercise familiarization before the maximal strength testing, and lack of protocol publication. To address these issues, this study incorporates resistance exercise familiarization, transparent reporting of randomization, and submission as a registered report. The results suggest that a single session of resistance exercise (barbell squat, press, and deadlift) with an intensity of 65%-78% 1RM for five repetitions (70%-90% relative intensity) and three sets with 3-min rest intervals improved Stroop congruent reaction time (RT) only (t(27) = -2.663, mean reduction = -15 ms, p = .013, 95% CI [-26, -3]). No significant enhancements were observed in Stroop incongruent RT, inhibitory control as indexed by Stroop effect, or inhibitory control as indexed by the RT difference between the Stroop task and the simple reaction task. Moreover, the alterations in plasma epinephrine levels did not significantly associate with changes in any measure of cognitive performance.

Using the Diabetes Care System for a County-Wide Hepatitis C Elimination: An Integrated Community-Based Shared Care Model in Taiwan.

INTRODUCTION: Despite the serious risks of diabetes with hepatitis C virus (HCV) infection, this preventable comorbidity is rarely a priority for HCV elimination. We aim to examine how a shared care model could eliminate HCV in patients with diabetes (PwD) in primary care. METHODS: There were 27 community-based Diabetes Health Promotion Institutes in each township/city of Changhua, Taiwan. PwD from these institutes from January 2018 to December 2020 were enrolled. HCV screening and treatment were integrated into diabetes structured care through collaboration between diabetes care and HCV care teams. Outcome measures included HCV care continuum indicators. Township/city variation in HCV infection prevalence and care cascades were also examined. RESULTS: Of the 10,684 eligible PwD, 9,984 (93.4%) underwent HCV screening, revealing a 6.18% (n = 617) anti-HCV seroprevalence. Among the 597 eligible seropositive individuals, 507 (84.9%) completed the RNA test, obtaining 71.8% positives. Treatment was initiated by 327 (89.8%) of 364 viremic patients, and 315 (86.5%) completed it, resulting in a final cure rate of 79.4% (n = 289). Overall, with the introduction of antivirals in this cohort, the prevalence of viremic HCV infection dropped from 4.44% to 1.34%, yielding a 69.70% (95% credible interval 63.64%-77.03%) absolute reduction. DISCUSSION: Although HCV prevalence varied, the care cascades achieved consistent results across townships/cities. We have further successfully implemented the model in county-wide hospital-based diabetes clinics, eventually treating 89.6% of the total PwD. A collaborative effort between diabetes care and HCV elimination enhanced the testing and treatment in PwD through an innovative shared care model.

Pain neuroscience education for reducing pain and kinesiophobia in patients with chronic neck pain: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Chronic neck pain (CNP) is a common musculoskeletal disorder. Pain neuroscience education (PNE) is a promising nonpharmacological intervention for CNP, however, its effectiveness remains unclear. This systematic review and meta-analysis aimed to evaluate the effectiveness of PNE in treating CNP. METHODS: Electronic databases from inception to February 2023 were searched for randomized controlled trials (RCTs) on the effects of PNE on CNP. The primary outcome was the change in pain intensity, and the secondary outcome was improvement in kinesiophobia, standardized using Hedges' g. Two authors independently scrutinized eligible articles, extracted data and assessed quality; a random-effects model was employed for data pooling. RESULTS: In total, seven RCTs comprising 479 participants were included and demonstrated that PNE significantly reduced pain intensity (Hedges' g = -0.730, 95% CI = -1.340 to -0.119, p = 0.019, I2 = 89.288%). Subgroup analysis revealed that the adult group experienced significant pain reduction after PNE, whereas the adolescent group did not. PNE also reduced kinesiophobia which was evaluated in four of seven RCTs (Hedges' g = -0.444, 95% CI = -0.735 to -0.154, p = 0.003, I2 = 36.822%). The meta-regression analysis indicated that an increased intervention duration contributed to greater pain reduction. No adverse events were reported following PNE or the control treatment. CONCLUSIONS: PNE effectively reduced pain intensity and kinesiophobia in patients with CNP. A longer PNE time leads to greater pain reduction and is more effective in adults than in adolescents. Further studies are required to examine the long-term effects on CNP management. SIGNIFICANCE: This is the first meta-analysis evaluating the effectiveness of treating chronic neck pain with pain neuroscience education. Pain neuroscience education is successful in reducing pain and decreasing kinesiophobia in the chronic neck pain population. Longer treatment time leads to greater pain reduction.

Cardiac contraction and relaxation are regulated by distinct subcellular cAMP pools.

Cells interpret a variety of signals through G-protein-coupled receptors (GPCRs) and stimulate the generation of second messengers such as cyclic adenosine monophosphate (cAMP). A long-standing puzzle is deciphering how GPCRs elicit different physiological responses despite generating similar levels of cAMP. We previously showed that some GPCRs generate cAMP from both the plasma membrane and the Golgi apparatus. Here we demonstrate that cardiomyocytes distinguish between subcellular cAMP inputs to elicit different physiological outputs. We show that generating cAMP from the Golgi leads to the regulation of a specific protein kinase A (PKA) target that increases the rate of cardiomyocyte relaxation. In contrast, cAMP generation from the plasma membrane activates a different PKA target that increases contractile force. We further validated the physiological consequences of these observations in intact zebrafish and mice. Thus, we demonstrate that the same GPCR acting through the same second messenger regulates cardiac contraction and relaxation dependent on its subcellular location.

Assessment of the carpal tunnel and associated neural structures with superb microvascular imaging: a scoping review.

INTRODUCTION: Superb microvascular imaging (SMI) is an advanced ultrasound technique that portrays microcirculation. Its clinical applications have been studied in various diseases, including carpal tunnel syndrome (CTS) i.e. the most common entrapment neuropathy. This scoping review explores the role of SMI in diagnosing CTS or the assessment of relevant neural structures. METHODS: We conducted a comprehensive search of electronic databases (PubMed, Embase and Web of Science) up to 26 September 2023. Two independent authors conducted the literature search, quality assessment, and data extraction. RESULTS: This review includes seven studies comprising 385 wrists. SMI consistently revealed increased intraneural vascularity in the median nerves of patients with CTS compared to healthy individuals. While SMI demonstrated higher sensitivity than traditional Doppler methods for detecting CTS, its specificity was somewhat lower. Combining SMI with B-mode ultrasound appears to enhance the diagnostic accuracy for CTS. However, the relationship between SMI findings and CTS severity remains unclear. CONCLUSIONS: This review highlighted the ability of SMI to provide detailed vascular structures in both healthy wrists and those with CTS. Additional research is crucial to determine the typical SMI findings of the carpal tunnel and within that context, tailor more precise diagnostic/therapeutic applications for the CTS population.

Planning, implementing, and evaluating Hepatitis C virus elimination via collaborative community-based care cascade: age-period-cohort model for estimating demand from antecedent anti-HCV survey.

BACKGROUND: Estimating the demand for HCV care cascade plays an important role in planning, monitoring, and assessing the performance of introducing a new community-based hepatitis C virus (HCV) elimination program but such an analytic and systematic approach has been barley addressed. METHODS: A new collaborative care program for HCV elimination in the Changhua Community of Taiwan has been offered to a total of 895,353 residents since 2018. To grasp the variation of demand for HCV care cascade across demographic and geographic features in the planning stage, we applied the age-period-cohort spatial model to the antecedent anti-HCV survey enrolling 123,617 participants aged 30 years or older between 2005 and 2018. Based on this precise denominator, we then employed a "before-and-after" study design to routinely evaluate whether the WHO criteria of 90% RNA positive diagnosis and 80% successful treatments could be reached. RESULTS: The overall demand for HCV care cascade was 4.28% (HCV infection) of the underlying population but a declining trend was noted. The early cohort had a higher demand, whereas the demand of the young cohort decreased with each passing year. The demand also differed by township. The demand, allowing for these variations, for antiviral treatment was 22,362, yielding the WHO target of 12,880 for achieving HCV elimination. With 11,844 successful treatments, the effectiveness of elimination has already reached 92% (11,844/12,880) by the end of 2022. CONCLUSIONS: The demand for HCV care cascade allows health care decision-makers to timely and properly assess the performance of a novel community-based collaborative care program in achieving HCV elimination.

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.

Selective activation of intracellular ß1AR using a spatially restricted antagonist.

G-protein-coupled receptors (GPCRs) regulate several physiological and pathological processes and represent the target of approximately 30% of FDA-approved drugs. GPCR-mediated signaling was thought to occur exclusively at the plasma membrane. However, recent studies have unveiled their presence and function at subcellular membrane compartments. There is a growing interest in studying compartmentalized signaling of GPCRs. This requires development of novel tools to separate GPCRs signaling at the plasma membrane from the ones initiated at intracellular compartments. We took advantage of the structural and pharmacological information available for ß1-adrenergic receptor (ß1AR), an exemplary GPCR that functions at subcellular compartments, and rationally designed spatially restricted antagonists. We generated a cell impermeable ß1AR antagonist by conjugating a suitable pharmacophore to a sulfonate-containing fluorophore. This cell-impermeable antagonist only inhibited ß1AR on the plasma membrane. In contrast, a cell permeable ß1AR agonist containing a non-sulfonated fluorophore, efficiently inhibited both the plasma membrane and Golgi pools of ß1ARs. Furthermore, the cell impermeable antagonist selectively inhibited the phosphorylation of downstream effectors of PKA proximal to the plasma membrane in adult cardiomyocytes while ß1AR intracellular pool remained active. Our tools offer promising avenues for investigating compartmentalized ß1AR signaling in various context, potentially advancing our understanding of ß1AR-mediated cellular responses in health and disease. They also offer a general strategy to study compartmentalized signaling for other GPCRs in various biological systems.

Preferred Reporting Items for Resistance Exercise Studies (PRIRES): A Checklist Developed Using an Umbrella Review of Systematic Reviews.

BACKGROUND: The issues of replication and scientific transparency have been raised in exercise and sports science research. A potential means to address the replication crisis and enhance research reliability is to improve reporting quality and transparency. This study aims to formulate a reporting checklist as a supplement to the existing reporting guidelines, specifically for resistance exercise studies. METHODS: PubMed (which covers Medline) and Scopus (which covers Medline, EMBASE, Ei Compendex, World Textile Index, Fluidex, Geobase, Biobase, and most journals in Web of Science) were searched for systematic reviews that comprised the primary studies directly comparing different resistance training methods. Basic data on the selected reviews, including on authors, publication years, and objectives, were summarized. The reporting items for the checklist were identified based on the objective of the reviews. Additional items from an existing checklist, namely the Consensus on Exercise Reporting Template, a National Strength and Conditioning Association handbook, and an article from the EQUATOR library were incorporated into the final reporting checklist. RESULTS: Our database search retrieved 3595 relevant records. After automatic duplicate removal, the titles and abstracts of the remaining 2254 records were screened. The full texts of 137 records were then reviewed, and 88 systematic reviews that met the criteria were included in the umbrella review. CONCLUSION: Developed primarily by an umbrella review method, this checklist covers the research questions which have been systematically studied and is expected to improve the reporting completeness of future resistance exercise studies. The PRIRES checklist comprises 26 reporting items (39 subitems) that cover four major topics in resistance exercise intervention: 1) exercise selection, performance, and training parameters, 2) training program and progression, 3) exercise setting, and 4) planned vs actual training. The PRIRES checklist was designed specifically for reporting resistance exercise intervention. It is expected to be used with other reporting guidelines such as Consolidated Standards of Reporting Trials and Standard Protocol Items: Recommendations for Interventional Trials. This article presents only the development process and resulting items of the checklist. An accompanying article detailing the rationale for, the importance of, and examples of each item is being prepared. REGISTRATION: This study is registered with the EQUATOR Network under the title "Preferred Reporting Items for Resistance Exercise Studies (PRIRES)." PROSPERO registration number: CRD42021235259.