Changbin Lei

Neurite outgrowth is critically controlled by calcium influx-mediated cytoskeleton dynamics. Spastin, a AAA ATPase microtubule-severing protein, also plays an important role in neurite outgrowth. However, the detailed mechanisms underlying posttranscriptional fine-tuning spastin activity, particularly in the context of calcium signaling, remain elusive. Here, we identified that the Ca ²⁺ /calmodulin-dependent protein kinase II beta (CaMKIIβ) isoform acted as an upstream kinase to mediate the phosphorylation of spastin. CaMKIIβ interacted with and phosphorylated spastin on Ser233 and Ser562 amino acids. Moreover, CaMKIIβ-mediated phosphorylation reduced the polyubiquitination level of spastin and suppressed its proteasomal degradation. This enhanced protein stability by CaMKIIβ increased the microtubule-severing activity of spastin and coordinately promoted the neurite outgrowth in hippocampal neurons. Inhibition of spastin or CaMKIIβ impaired synaptic activity, as evidenced by reduced frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Behaviorally, treatment with spastin or CaMKIIβ inhibitors led to deficits in short-term working memory and spatial learning, as assessed by Y-maze and Morris water maze tests in male mice, respectively. In general, this study unveils a novel mechanism whereby CaMKIIβ-mediated phosphorylation of spastin connects extracellular calcium signaling to the regulation of cytoskeleton dynamics and neurite outgrowth.

Background: The Visceral Adiposity Index (METS-VF) has emerged as a novel obesity assessment metric. However, research exploring the relationship between METS-VF and rheumatoid arthritis (RA) remains limited. The objective of this investigation was to examine the correlation between the prevalence of RA and METS-VF.Methods: The NHANES data collected between 2011 and 2018 were used in this investigation. To determine the association between METS-VF and the prevalence of RA, logistic regression analysis was used. Sensitivity and subgroup analysis were done to test how reliable the results were. Finally, the predictive power of BMI, waist circumference, and METS-VF for RA was compared using ROC curve analysis.Results: This research had 8,626 individuals in total. The findings showed that compared to those without RA, persons with the condition had noticeably greater METS-VF levels. METS-VF and the prevalence of RA were significantly positively correlated, according to a logistic regression analysis (OR = 1.50, 95% CI = 1.12–2.00). The results of the sensitivity and subgroup analyses agreed with the primary conclusions. ROC analysis indicated that METS-VF possessed a superior ability to predict RA compared to BMI and waist circumference.Conclusion: This study indicates that elevated METS-VF levels are positively correlated with an increased risk of RA in the US population. Monitoring this metric might aid in the early detection of high-risk patients.

Hyperuricemia is a metabolic disorder that is essential to the development of inflammatory gout, with increasing prevalence over recent years. Emerging clinical findings has evidenced remarkable tendon damage in individuals with longstanding asymptomatic hyperuricemia, yet the impact of hyperuricemia on tendon homeostasis and associated repercussions is largely unknown. Here, we investigated whether asymptomatic hyperuricemia was associated with spontaneous ruptures in the Achilles tendon and the pathological effect of hyperuricemia on the tendon stem/progenitor cells (TSPCs). Significantly higher serum uric acid (SUA) levels were found in 648 closed Achilles tendon rupture (ATR) patients comparing to those in 12559 healthy volunteers. In vitro study demonstrated that uric acid (UA) dose dependently reduced rat Achilles TSPC viability, decreased the expressions of tendon collagens, and deformed their structural organization while significantly increased the transcript levels of matrix degradative enzymes and proinflammatory factors. Consistently, marked disruptions in Achilles tendon tissue structural and functional integrity were found in a rat model of hyperuricemia, together with enhanced immune cell infiltration. Transcriptome analysis revealed a significant elevation in genes involved in metabolic stress and tissue degeneration in TSPCs challenged by hyperuricemia. Specifically, reduced activity of the AKT-mTOR pathway with enhanced autophagic signaling was confirmed. Our findings indicate that asymptomatic hyperuricemia may be a predisposition of ATR by impeding the normal functions of TSPCs. This information may provide theoretical and experimental basis for exploring the early prevention and care of ATR.

Introduction: Ubiquitously found in all life forms, inorganic polyphosphates (polyP) are linear polymers of repeated orthophosphate units. Present in intervertebral disc tissue, polyP was previously shown to increase extracellular matrix production in nucleus pulposus (NP) cells. However, the effects of polyP on human annulus fibrosus (hAF) cell metabolism is not known.Methods and Results: Here, hAF cells cultured in the presence of 0.5 to 1 mM polyP, chain length 22 (polyP‐22), showed an increase in glycosaminoglycan content, proteoglycan and collagen synthesis, and aggrecan and collagen type 1 gene expression. Gene expression level of matrix metalloproteinases 1 was reduced while matrix metalloproteinases 3 level was increased in hAF cells treated with 1 mM polyP. Adenosine triphosphate (ATP) synthesis was also significantly increased in hAF cell culture 72 hours after the exposure to 1 mM polyP‐22.Conclusions: PolyP thus has both anabolic and bioenergetic effects in AF cells, similar to that observed in NP cells. Together, these results suggest polyP as a potential energy source and a metabolic regulator of disc cells.

Purpose: This study aimed to assess the psychological impact of the COVID-19 pandemic among the general public in Hunan Province, China, which could help develop psychological interventions and mental health programs. Participants and Methods: This online cross-sectional study recruited 571 participants through snowball sampling between February 2 and February 5, 2020. Data were collected through a general information questionnaire, the Public Emergency Psychological State Questionnaire, the Simple Coping Style Questionnaire, and the Public Disease Awareness on COVID-19 Scale. Results: The total mean score of the public emergency psychological state of the sample was 0.27 (0.31) points, with only 5.78% of participants (n = 33) developing psychological distress. Avoidant coping style and disease awareness were weakly positively correlated (r_s = 0.257, p < 0.01) and weakly negatively correlated (r_s = − 0.124, p < 0.01) with psychological responses, respectively. There were significant psychological differences among the following variables: occupation, symptoms of fever or fatigue, discernment of the authenticity of COVID-19 information, and level of concern regarding COVID-19 (p < 0.05). Conclusion: The COVID-19 pandemic appears to have had a minor psychological impact on the general population in Hunan Province. However, psychological health promotion in the general public is still required, especially for employees (such as company employees, migrant workers, and businessmen), individuals with COVID-19-like symptoms, limited discernment competence and unconcerned attitudes. Implications: The initiatives for improving psychological health among the general public could focus on delivering COVID-19 knowledge and alleviating avoidant coping styles. Our findings could provide important insight for the development of psychological support strategies in China, as well as in other places affected by the epidemic.

Suppression of the insulin‐like growth factor‐1 (IGF‐1) signaling pathway reduces age‐related disorders and increases lifespan across species, making the IGF‐1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro‐anabolic effect of exogenously adding IGF‐1 on matrix production. However, the overall effects of suppressing IGF‐1 signaling on age‐related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF‐1 signaling on age‐related IDD in vivo were examined using PAPPA^−/− mice. These are animals with targeted deletion of pregnancy‐associated plasma protein A (PAPPA), the major protease that cleaves inhibitory IGF binding proteins that control bioavailability of IGF‐1 for cell signaling. Compared to age‐matched wild‐type (Wt) littermates, reduced levels of matrix proteoglycan (PG) and aggrecan were seen in discs of 23‐month old PAPPA^−/− mice. Decreased aggrecanolysis and expression of two key catabolic markers, matrix metalloproteinase‐3 and a disintegrin and metalloproteinase with thrombospondin motifs‐4, were also observed in discs of old PAPPA^−/− mice compared to Wt littermates. Suppressing IGF‐1 signaling has been implicated to shift cellular metabolism toward maintenance rather than growth and decreasing cellular senescence. Along this line, discs of old PAPPA^−/− mice also exhibited lower cellular senescence, assessed by p53 and lamin B1 markers. Collectively, the data reveal complex regulation of disc matrix homeostasis by PAPPA/IGF‐1 signaling during chronologic aging, that is, reduced IGF‐1 bioavailability confers the benefit of decreasing disc cellular senescence and matrix catabolism but also the disadvantage of decreasing disc PG matrix anabolism. This pathway requires further mechanistic elucidation before IGF‐1 could be considered as a therapeutic growth factor for treating IDD.