The frontal cortex adjusts striatal integrator dynamics for flexible motor timing.

Flexible control of motor timing is crucial for behavior. Before movement begins, the frontal cortex and striatum exhibit ramping spiking activity, with variable ramp slopes anticipating movement onsets. This activity may function as an adjustable 'timer,' triggering actions at the desired timing. However, because the frontal cortex and striatum share similar ramping dynamics and are both necessary for timing behaviors, distinguishing their individual roles in this timer function remains challenging. To address this, we conducted perturbation experiments combined with multi-regional electrophysiology in mice performing a lick-timing task. Following transient silencing of the frontal cortex, cortical and striatal activity swiftly returned to pre-silencing levels and resumed ramping, leading to a shift in lick timing close to the silencing duration. Conversely, briefly inhibiting the striatum caused a gradual decrease in ramping activity in both regions, with ramping resuming from post-inhibition levels, shifting lick timing beyond the inhibition duration. Thus, inhibiting the frontal cortex and striatum effectively paused and rewound the timer, respectively. Additionally, the frontal cortex, but not the striatum, encodes trial-history information guiding lick timing. These findings suggest specialized functional allocations within the forebrain: the striatum temporally integrates input from the frontal cortex to generate ramping activity that regulates motor timing.

Comparison of falls and risk factors among older adults in urban villages, urban and rural areas of Shantou, China.

Objective: To investigate and compare the differences between the incidence of falls, balance and living environment among older persons in urban villages and other types of residential areas. Methods: We surveyed 580 older adults living in different types of residential areas in Shantou, China, surveying basic information, fall incidence, balance ability testing of older persons, home environment safety assessment. Results: The incidence of falls among older people in urban villages (19.54 %) was between urban areas(26.63 %) and rural areas(16.91 %). The influencing factors of falls in different residential types were different. Near-fall, abnormal bowel movement, and impaired balance ability were the risk factors of falls among older persons in urban villages. Divorce/single, fair and poor hearing loss and near-fall were the risk factors of falls in urban older adults. Frailty and impaired balance ability were the risk factors of falls in rural older people. Conclusions: Risk factors for falls in older people vary according to the characteristics of their living areas and relevant interventions should be targeted according to the characteristics of falls occurring in different residential areas.

Association Between Hyperuricemia and Ultrasound-Detected Hand Synovitis.

OBJECTIVE: Although hand synovitis is prevalent in the older population, the etiology remains unclear. Hyperuricemia, a modifiable metabolic disorder, may serve as an underlying mechanism of hand synovitis, but little is known about their relationship. We assessed the association between hyperuricemia and hand synovitis in a large population-based sample. METHODS: We performed a cross-sectional study in Longshan County, Hunan Province, China. Hyperuricemia was defined as a serum urate level >420 µmol/L in men and >360 µmol/L in women. Ultrasound examinations were performed on both hands of 4,080 participants, and both gray-scale synovitis and the Power Doppler signal (PDS) were assessed using semiquantitative scores (grades 0-3). We evaluated the association of hyperuricemia with hand gray-scale synovitis (grade ≥2) and PDS (grade ≥1), respectively, adjusting for age, sex, and body mass index. RESULTS: All required assessments for analysis were available for 3,286 participants. The prevalence of hand gray-scale synovitis was higher among participants with hyperuricemia (30.0%) than those with normouricemia (23.3%), with an adjusted odds ratio (aOR) of 1.28 (95% confidence interval [CI] 1.00-1.62). Participants with hyperuricemia also had a higher prevalence of PDS (aOR 2.36; 95% CI 1.15-4.81). Furthermore, hyperuricemia positively associated, both at the hand and joint levels, with the presence of gray-scale synovitis (aOR 1.27; 95% CI 1.00-1.60 and adjusted prevalence ratio [aPR] 1.26; 95% CI 1.10-1.44, respectively) and PDS (aOR 2.35; 95% CI 1.15-4.79 and aPR 2.34; 95% CI 1.28-4.30, respectively). CONCLUSION: This population-based study provides more evidence for a positive association between hyperuricemia and prevalent hand synovitis.

Associations between hyperuricemia and ultrasound-detected knee synovial abnormalities in middle-aged and older population: a cross-sectional study.

OBJECTIVES: Knee synovial abnormalities, potentially treatment targets for knee pain and osteoarthritis, are common in middle-aged and older population, but its etiology remains unclear. We examined the associations between hyperuricemia and knee synovial abnormalities detected by ultrasound in a general population sample. METHODS: Participants aged ≥ 50 years were from a community-based observational study. Hyperuricemia was defined as serum urate (SU) level > 416 µmol/L in men and > 357 µmol/L in women. Ultrasound of both knees was performed to determine the presence of synovial abnormalities, i.e., synovial hypertrophy, effusion, or Power Doppler signal (PDS). We examined the relation of hyperuricemia to prevalence of knee synovial abnormalities and its laterality, and the dose-response relationships between SU levels and the prevalence of knee synovial abnormalities. RESULTS: In total, 3,405 participants were included in the analysis. Hyperuricemia was associated with higher prevalence of knee synovial abnormality (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI]: 1.02 to 1.43), synovial hypertrophy (aOR = 1.33, 95% CI: 1.05 to 1.68), and effusion (aOR = 1.21, 95% CI: 1.02 to 1.44), respectively. There were dose-response relationships between SU levels and synovial abnormalities. Additionally, the hyperuricemia was more associated with prevalence of bilateral than with that of unilateral knee synovial abnormality, synovial hypertrophy, or effusion; however, no significant association was observed between hyperuricemia and PDS. CONCLUSION: In this population-based study we found that hyperuricemia was associated with higher prevalence of knee synovial abnormality, synovial hypertrophy and effusion, suggesting that hyperuricemia may play a role in pathogenesis of knee synovial abnormalities.

The influence of cortical activity on perception depends on behavioral state and sensory context.

The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.

Association between hyperuricaemia and hand osteoarthritis: data from the Xiangya Osteoarthritis Study.

OBJECTIVE: The pathogenesis of hand osteoarthritis (OA) remains unknown. Hyperuricaemia, which is related to inflammation, may play a role in hand OA, but evidence is lacking. In a large population-based study, we examined the association between hyperuricaemia and hand OA. METHODS: Participants were from the Xiangya OA Study, a community-based observational study. Hyperuricaemia was defined as serum urate >416 µmol/L in men and >357 µmol/L in women. Radiographic hand OA (RHOA) was defined as presence of the modified Kellgren-Lawrence grade ≥2 in any hand joint. Symptomatic hand OA (SHOA) was defined as presence of both self-reported symptoms and RHOA in the same hand. The associations of hyperuricaemia with RHOA or SHOA were examined using generalised estimating equations. RESULTS: Among 3628 participants, the prevalence of RHOA was higher in participants with hyperuricaemia than those with normouricaemia (26.9% vs 20.9%), with an adjusted OR (aOR) of 1.34 (95% CI 1.11 to 1.61). The associations were consistent in men (aOR 1.33, 95% CI 1.01 to 1.74) and women (aOR 1.35, 95% CI 1.05 to 1.74). Hyperuricaemia was mainly associated with bilateral RHOA (aOR 1.54, 95% CI 1.18 to 2.01) but not unilateral RHOA (aOR 1.13, 95% CI 0.89 to 1.45). Prevalence of SHOA was higher, although statistically insignificant, in participants with hyperuricaemia (aOR 1.39, 95% CI 0.94 to 2.07). CONCLUSION: In this population-based study, hyperuricaemia was associated with a higher prevalence of hand OA. Future prospective studies are required to investigate the temporal relationship. TRIAL REGISTRATION NUMBER: NCT04033757.

Gut-joint axis in knee synovitis: gut fungal dysbiosis and altered fungi-bacteria correlation network identified in a community-based study.

OBJECTIVES: Knee synovitis is a highly prevalent and potentially curable condition for knee pain; however, its pathogenesis remains unclear. We sought to assess the associations of the gut fungal microbiota and the fungi-bacteria correlation network with knee synovitis. METHODS: Participants were derived from a community-based cross-sectional study. We performed an ultrasound examination of both knees. A knee was defined as having synovitis if its synovium was ≥4 mm and/or Power Doppler (PD) signal was within the knee synovium area (PD synovitis). We collected faecal specimens from each participant and assessed gut fungal and bacterial microbiota using internal transcribed spacer 2 and shotgun metagenomic sequencing. We examined the relation of α-diversity, ß-diversity, the relative abundance of taxa and the interkingdom correlations to knee synovitis. RESULTS: Among 977 participants (mean age: 63.2 years; women: 58.8%), 191 (19.5%) had knee synovitis. ß-diversity of the gut fungal microbiota, but not α-diversity, was significantly associated with prevalent knee synovitis. The fungal genus Schizophyllum was inversely correlated with the prevalence and activity (ie, control, synovitis without PD signal and PD synovitis) of knee synovitis. Compared with those without synovitis, the fungi-bacteria correlation network in patients with knee synovitis was smaller (nodes: 93 vs 153; edges: 107 vs 244), and the average number of neighbours was fewer (2.3 vs 3.2). CONCLUSION: Alterations of gut fungal microbiota and the fungi-bacteria correlation network are associated with knee synovitis. These novel findings may help understand the mechanisms of the gut-joint axis in knee synovitis and suggest potential targets for future treatment.

Association between gut microbiome-related metabolites and symptomatic hand osteoarthritis in two independent cohorts.

BACKGROUND: Since gut microbiome dysbiosis can cause inflammatory disorders by affecting host metabolism, we postulate that the gut microbiome and related metabolites could play a role in hand osteoarthritis. We characterised gut microbiome-related metabolites in people with symptomatic hand osteoarthritis (SHOA) in two independent cohorts. METHODS: Using data collected from a large-sample community-based observational study (discovery cohort), we assessed the relations of the microbial function and plasma key metabolites related to altered microbial function with SHOA. Finally, we verified the relations of plasma metabolites to SHOA in an independent observational study (validation cohort). FINDINGS: In the discovery cohort (n = 1359), compared to those without SHOA, participants with SHOA had significantly altered microbial functions related to tryptophan metabolism (Q = 0.025). Therefore we measured the plasma tryptophan metabolites and found that participants with SHOA had higher levels of 5-hydroxyindoleacetic acid (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.09-1.42) and 5-hydroxytryptophol (OR = 1.13, 95% CI: 1.04-1.23), but lower levels of indole-3-lactic acid (ILA) (OR = 0.85, 95% CI: 0.72-1.00), skatole (OR = 0.93, 95% CI: 0.88-0.99) and 3-hydroxyanthranilic acid (OR = 0.90, 95% CI: 0.85-0.96). Findings from the validation cohort (n = 142) verified that lower levels of ILA were related to SHOA (OR = 0.70, 95% CI: 0.53-0.92). INTERPRETATION: Alterations of the microbial function of tryptophan biosynthesis and tryptophan metabolites, especially lower levels of ILA, are associated with SHOA. These findings suggest the role of the microbiome and tryptophan metabolites in developing of SHOA and may contribute to future translational opportunities. FUNDING: National Key Research and Development Plan and National Natural Science Foundation of China.

Cell-type-specific plasticity shapes neocortical dynamics for motor learning.

Neocortical spiking dynamics control aspects of behavior, yet how these dynamics emerge during motor learning remains elusive. Activity-dependent synaptic plasticity is likely a key mechanism, as it reconfigures network architectures that govern neural dynamics. Here, we examined how the mouse premotor cortex acquires its well-characterized neural dynamics that control movement timing, specifically lick timing. To probe the role of synaptic plasticity, we have genetically manipulated proteins essential for major forms of synaptic plasticity, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Cofilin, in a region and cell-type-specific manner. Transient inactivation of CaMKII in the premotor cortex blocked learning of new lick timing without affecting the execution of learned action or ongoing spiking activity. Furthermore, among the major glutamatergic neurons in the premotor cortex, CaMKII and Cofilin activity in pyramidal tract (PT) neurons, but not intratelencephalic (IT) neurons, is necessary for learning. High-density electrophysiology in the premotor cortex uncovered that neural dynamics anticipating licks are progressively shaped during learning, which explains the change in lick timing. Such reconfiguration in behaviorally relevant dynamics is impeded by CaMKII manipulation in PT neurons. Altogether, the activity of plasticity-related proteins in PT neurons plays a central role in sculpting neocortical dynamics to learn new behavior.

The association between selenium and bone health: a meta-analysis.

Aims: Previous studies have suggested that selenium as a trace element is involved in bone health, but findings related to the specific effect of selenium on bone health remain inconclusive. Thus, we performed a meta-analysis by including all the relevant studies to elucidate the association between selenium status (dietary intake or serum selenium) and bone health indicators (bone mineral density (BMD), osteoporosis (OP), or fracture). Methods: PubMed, Embase, and Cochrane Library were systematically searched to retrieve relevant articles published before 15 November 2022. Studies focusing on the correlation between selenium and BMD, OP, or fracture were included. Effect sizes included regression coefficient (ß), weighted mean difference (WMD), and odds ratio (OR). According to heterogeneity, the fixed-effect or random-effect model was used to assess the association between selenium and bone health. Results: From 748 non-duplicate publications, 19 studies were included. We found a significantly positive association between dietary selenium intake (ß = 0.04, 95% confidence interval (CI) 0.00 to 0.07, p = 0.029) as well as serum selenium (ß = 0.13, 95% CI 0.00 to 0.26, p = 0.046) and BMD. Consistently, those with higher selenium intake had a lower risk of OP (OR = 0.47, 95% CI 0.31 to 0.72, p = 0.001), and patients with OP had a significantly lower level of serum selenium than healthy controls (WMD = -2.01, 95% CI -3.91 to -0.12, p = 0.037). High dietary selenium intake was associated with a lower risk of hip fracture (OR = 0.44, 95% CI 0.37 to 0.52, p < 0.001). Conclusion: Selenium was positively associated with BMD and inversely associated with OP; dietary selenium intake was negatively associated with hip fracture. The causality and therapeutic effect of selenium on OP needs to be investigated in future studies.

Prevalence and distribution of ultrasound-detected hand synovial abnormalities in a middle-aged and older population.

OBJECTIVE: Synovial abnormalities are modifiable targets for hand pain and osteoarthritis. We examined the prevalence and distribution of ultrasound-detected hand synovial abnormalities in a community-derived sample of older people in China. METHODS: Within the Xiangya Osteoarthritis Study, a community-based study, we assessed synovial hypertrophy (SH), joint effusion, and Power Doppler signal (PDS) on all fingers and thumbs of both hands using standardized ultrasound examinations (score: 0-3). We assessed distribution patterns of SH and effusion using χ2-test and interrelationships of SH and effusion in different joints and hands by generalized estimating equations. RESULTS: Among 3,623 participants (mean age: 64.4 years; women: 58.1%), prevalence of SH, effusion and PDS were 85.5%, 87.3% and 1.5%, respectively. Prevalence of SH, effusion and PDS increased with age, was higher in the right hand than in the left hand and was more common in proximal than in distal hand joints. SH and effusion often occurred in multiple joints (P < 0.001). SH in one joint was strongly associated with presence of SH in the same joint of the opposite hand (odds ratio [OR]= 6.60, 95% confidence interval [CI]: 6.19-7.03) followed by SH in other joints in the same row, (OR=5.70, 95%CI: 5.32-6.11), and then other joints in the same ray of the same hand (OR=1.49, 95%CI: 1.39-1.60). Similar patterns were observed for effusion. CONCLUSION: Hand synovial abnormalities are common among older people, often affect multiple hand joints and present a unique pattern. These findings suggest both systemic and mechanical factors play roles in their occurrence.

Generalized anxiety disorder among rural primary and middle school students during the outbreak of COVID-19: a multicenter study in three southern Chinese cities.

BACKGROUND: The major public health crisis caused by the rapid spread of the coronavirus disease 2019 (COVID-19) and the large-scale public health measures such as social isolation and school closures enforced by some countries have severely affected on the physical and mental wellbeing of children and adolescents globally. This study aimed to estimate the prevalence of the psychological impact and investigate the similarities and differences in the influential factors for generalized anxiety disorder among rural adolescents as a relatively lesser noticed population the outbreak of COVID-19. METHODS: From May 11 to 22, 2020, a total of 1,179 adolescents, including Grade 5-6 in primary school and Grade 7-8 in middle school, were selected by multistage sampling in three Southern Chinese cities (Shantou, Guangdong Province; Hezhou, Guangxi Province; Nanchong, Sichuan Province), and completed the questionnaires including sociodemographic, generalized anxiety disorder, academic stress, coronaphobia, knowledge of COVID-19, and precautionary measures. ANOVA, Chi-square test, Kruskalwallis H test and multivariate linear regression were performed in the statistical analysis. RESULTS: The average scores of generalized anxiety disorder during the past two weeks were 3.43 (SD 4.46), 4.47 (SD 5.15), and 4.10 (SD 4.94) in Shantou, Hezhou and Nanchong, respectively. For the pooled data, academic stress (P < 0.001), coronaphobia (P < 0.001), and precautionary measures (P = 0.002) contributed to the prediction of anxiety scores. Academic stress was significantly associated to anxiety symptoms in all cities (P all < 0.001). Coronaphobia was also significantly associated to anxiety symptoms in all cities (P all < 0.001). CONCLUSION: This study highlights the urgent need for researchers and policymakers to focus on the mental health of rural children and adolescents during the COVID-19 epidemic. The adolescents with academic stress and coronaphobia, the greater the risk that adolescents will suffer from anxiety, suggesting mental health counseling and professional family support are needed.

Dysbiosis of gut microbiota, a potential mediator of bile acid compositions, and prevalence of hand synovitis: a community-based study.

OBJECTIVES: Hand synovitis, a potentially modifiable pathological lesion, is common and associated with pain and hand OA; nevertheless, its pathogenesis remains uncertain. This study investigated the relationship between gut microbiota dysbiosis and hand synovitis prevalence and evaluated whether bile acids mediate the association. METHODS: Participants were derived from a community-based observational study. Synovitis in each hand joint was assessed using US. Gut microbiota was evaluated using 16S ribosomal RNA amplicon sequencing on faeces, and plasma bile acids were measured by HPLC mass spectrometry. We examined the relationship between gut microbiota dysbiosis and hand synovitis prevalence, as well as the extent to which bile acids were involved in the association. RESULTS: Among 1336 participants (mean age: 63.2 years; women: 58.8%), 18.3% had prevalent hand synovitis (unilateral in 13.6% and bilateral in 4.7%). ß-diversity, but not α-diversity, of gut microbiota was significantly associated with prevalent hand synovitis. Higher relative abundance of the genus Prevotella and lower relative abundance of the genus Blautia were significantly associated with the prevalence of hand synovitis. Similar associations were also observed for laterality and the number of joints affected by hand synovitis. The association between Prevotella and hand synovitis was partially mediated through its effect on tauroursodeoxycholic acid and glycoursodeoxycholic acid, the mediation proportions being 25.7% and 21.6%, respectively. CONCLUSION: Our findings suggest that gut microbiota dysbiosis is associated with the prevalence of hand synovitis. Such an association appears to be partially mediated by plasma bile acids.

Short-term effects of extreme meteorological factors on daily outpatient visits for anxiety in Suzhou, Anhui Province, China: a time series study.

Anxiety disorders are a major public health concern in China. Previous studies have provided evidence for associations between ambient temperature and anxiety outpatient visits, but no studies have examined short-term effects of other meteorological factors such as sunshine duration, wind speed, and precipitation on increased anxiety outpatient visits. We aimed to assess the association between climatic factors and outpatient visits for anxiety in Suzhou, a city with a temperate climate in Anhui Province, China. Daily anxiety outpatient visits, meteorological factors, and air pollutants from 2017 to 2019 were collected. A quasi-Poisson generalized linear regression model combined with distributed lag non-linear model (DLNM) was used to quantify the effects of extreme meteorological factors (sunshine duration, wind speed, and precipitation) on anxiety outpatient visits. All effects were presented as relative risk (RR), with the 90th and 10th percentiles of meteorological factors compared to the median. Subgroup analyses by age and gender were performed to identify susceptible subgroups. A total of 11,323 anxiety outpatient visits were reported. Extremely low sunshine duration and low and high wind speed increased the risk of anxiety outpatient visits. The strongest cumulative effects occurred at lag 0-14 days, and the corresponding RRs of extremely low sunshine duration and low and high wind speed were 1.417 (95% CI: 1.056-1.901), 1.529 (95% CI: 1.028-2.275), and 1.396 (95% CI: 1.007-1.935), respectively. Subgroup analyses showed that males and people aged ≥45 years appeared to be more susceptible to the cumulative effects of extremely low sunshine duration. In addition, the adverse effects of extreme wind speed were more pronounced in the cold season. This study provides evidence that extreme climatic factors have a lagged effect on anxiety outpatient visits. In the context of climate change, these findings may help develop weather-based early warning systems to minimize the effects of extreme meteorological factors on anxiety.

Anteromedial Portal Technique, but Not Outside-in Technique, Is Superior to Standard Transtibial Technique in Knee Stability and Functional Recovery After Anterior Cruciate Ligament Reconstruction: A Network Meta-analysis.

PURPOSE: To compare the postoperative outcomes of 4 different femoral drilling techniques in anterior cruciate ligament reconstruction. METHODS: Three databases were searched for randomized controlled trials comparing any 2 or more of the following femoral drilling techniques in anterior cruciate ligament reconstruction: standard transtibial (sTT), anteromedial portal (AMP), outside-in (OI), or modified transtibial (mTT) technique. A Bayesian network meta-analysis was performed to assess postoperative stability and functional recovery in terms of the side-to-side difference (measured by arthrometry), Lachman test, pivot-shift test, International Knee Documentation Committee subjective and objective scores, Lysholm score, and Tegner score. The Fisher exact probability test and χ2 test were used to compare the incidences of infection and graft rupture, respectively. RESULTS: We included 20 randomized controlled trials involving 1,515 patients. The AMP technique showed a lower side-to-side difference (standardized mean difference, -0.33; 95% credible interval [CrI], -0.53 to -0.12), higher negative rate on the pivot-shift test (odds ratio, 2.19; 95% CrI, 1.38 to 3.44), and higher International Knee Documentation Committee objective score (odds ratio, 3.13; 95% CrI, 1.42 to 7.82) than the sTT technique. However, knee stability and functional outcomes did not differ significantly between the OI and sTT techniques. Safety outcomes of the mTT technique were unavailable. The incidence of graft rupture was 5.20% for the OI technique, 2.27% for the AMP technique, and 1.51% for the sTT technique. The OI technique had a significantly higher incidence of graft rupture than the sTT technique (χ2 = 4.421, P = .035). No significant difference in the incidence of infection was found between the sTT, AMP, and OI techniques (P = .281). CONCLUSIONS: The AMP technique, but not the OI technique, was superior to the sTT technique in knee stability and functional recovery. The OI technique had a higher incidence of graft rupture than the sTT technique. There was no significant difference between the AMP and OI techniques or between the mTT technique and any other femoral drilling technique. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies.

14-3-3 proteins regulate photomorphogenesis by facilitating light-induced degradation of PIF3.

14-3-3s are highly conserved phosphopeptide-binding proteins that play important roles in various developmental and signaling pathways in plants. However, although protein phosphorylation has been proven to be a key mechanism for regulating many pivotal components of the light signaling pathway, the role of 14-3-3 proteins in photomorphogenesis remains largely obscure. PHYTOCHROME-INTERACTING FACTOR3 (PIF3) is an extensively studied transcription factor repressing photomorphogenesis, and it is well-established that upon red (R) light exposure, photo-activated phytochrome B (phyB) interacts with PIF3 and induces its rapid phosphorylation and degradation. PHOTOREGULATORY PROTEIN KINASES (PPKs), a family of nuclear protein kinases, interact with phyB and PIF3 in R light and mediate multisite phosphorylation of PIF3 in vivo. Here, we report that two members of the 14-3-3 protein family, 14-3-3λ and κ, bind to a serine residue in the bHLH domain of PIF3 that can be phosphorylated by PPKs, and act as key positive regulators of R light-induced photomorphogenesis. Moreover, 14-3-3λ and κ preferentially interact with photo-activated phyB and promote the phyB-PIF3-PPK complex formation, thereby facilitating phyB-induced phosphorylation and degradation of PIF3 upon R light exposure. Together, our data demonstrate that 14-3-3λ and κ work in close concert with the phyB-PIF3 module to regulate light signaling in Arabidopsis.

The association between violent video game exposure and sub-types of school bullying in Chinese adolescents.

Background: School bullying among adolescents has been a worldwide public health issue. It has been observed that adolescents who are exposed to violent video games (VVGs) are often more aggressive. However, research on the association between violent video game exposure (VVGE) and different types of school bullying is limited in the Chinese context. Objective: The purpose of this study was to explore whether VVGE is linked to school bullying behaviors among Chinese adolescents and to examine the relationship between different levels of violent game exposure and four sub-types (physical, verbal, relational, and cyber) of school bullying involvement. Methods: This was a cross-sectional study of 1,992 Chinese students (55.02% boys and 44.98% girls) with the average age of 15.84 ± 1.62 years. Sub-types of school bullying victimization and perpetration, Internet addiction, and VVGE were measured by using a self-administrated questionnaire. The association was examined by multiple logistic regression analysis, adjusting for covariates. Results: Physical, verbal, relational, and cyber school bullying victimization were reported by 18.12, 60.34, 11.75, and 12.05% of the adolescents, and physical, verbal, relational, and cyber school bullying perpetration were reported by 16.62, 54.62, 21.49, and 8.23% of them. Of the students, 1,398 (70.18%) were normal Internet users, 514 (25.80%) showed moderate Internet addictive behaviors, and 31 (1.56%) of the students showed severe Internet addictive behaviors. The prevalence of no VVGE, low-level VVGE, medium-level VVGE, and high-level of VVGE were 27.70, 24.10, 24.20, and 24.00%, respectively. The risk of physical victimization and physical perpetration significantly increased with the increasing degree of violent video game exposure (P for trend < 0.001), with the highest adjusted odds ratios (ORs) of 2.251 (95% CI 1.501-3.375) and 2.554 (95% CI 1.685-3.870), when comparing high-level VVGE with no VVGE. Conclusion: These findings highlight the specific association between different sub-types of school bullying involvement and violent video game exposure. Physical school bullying prevention and intervention programs should be conducted after adolescents are exposed to violent video games.

Comparative risk-benefit profiles of weak opioids in the treatment of osteoarthritis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Despite their poor tolerance, weak opioids are still the most commonly-prescribed medicine for osteoarthritis (OA)-related pain. The objective of this network meta-analysis was to comparatively examine the efficacy and safety of weak opioids in OA treatment. METHODS: Databases including PubMed, Embase, Cochrane Library and Web of Science were searched from inception to 4 April 2022 to retrieve randomized controlled trials (RCTs) comparing weak opioids with placebo or between one another in OA patients. Bayesian network meta-analysis was performed on the following outcomes of interest, namely the change-from-baseline score in pain relief, gastrointestinal (GI) adverse events (AEs), central nervous system (CNS) AEs, and total number of AEs (i.e. the number of subjects experiencing any AE for at least once) during follow-up. The surface under the cumulative ranking curve (SUCRA) was used to rank the effectiveness of each treatment and identify the best treatment. RESULTS: A total of 14 RCTs invoving four types of weak opioids were included in this meta-analysis. Compared to placebo, tramadol (standardized mean difference [SMD] = -0.34, 95% credible interval [CrI]: -0.53 to -0.18) and codeine (SMD = -0.39, 95% CrI: -0.79 to -0.04) were effective for pain relief, but involved a higher risk of GI AEs, CNS AEs and total number of AEs. Dextropropoxyphene demonstrated a significantly lower risk of GI AEs (OR = 0.28, 95%CrI: 0.17 to 0.51), CNS AEs (OR = 0.29, 95%CrI: 0.11 to 0.78) and total number of AEs (OR = 0.35, 95%CrI: 0.15 to 0.82) compared to codeine. Dihydrocodeine had a better safety profile in CNS AEs (SUCRA = 64.8%) and total number of AEs (SUCRA = 66.6%). CONCLUSIONS: The results of the present study confirmed that tramadol and codeine were effective drugs for the treatment of OA, but involved considerable safety issues. Dextropropoxyphene and dihydrocodeine exhibited a relatively good safety profile but their efficacy still warrant further investigation.