Ethnic-specific genetic susceptibility loci for endometriosis in Taiwanese-Han population: a genome-wide association study.

Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies.

Distinguishing risk of curve progression in adolescent idiopathic scoliosis with bone microarchitecture phenotyping - a 6-year longitudinal study.

Low bone mineral density and impaired bone qualities have been shown to be important prognostic factors for curve progression in Adolescent Idiopathic Scoliosis (AIS). There is no evidence-based integrative interpretation method to analyse high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (a) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in AIS girls, (b) assess the phenotypes' risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (c) investigate risk of curve progression in a separate cohort of mild AIS girls whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (N = 101). Three bone microarchitecture phenotypes were clustered by Fuzzy C-Means at time of peripubertal peak height velocity (PHV). Phenotype-1 had normal bone characteristics. Phenotype-2 was characterized by low bone volume and high cortical bone density, and Phenotype-3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone qualities amongst the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype-3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (Odd Ratios (OR) = 4.88; 95% Confidence Interval (CI): 1.03-28.63). In the secondary cohort (N = 106), both Phenotype-2 (adjusted OR = 5.39; 95%CI: 1.47-22.76) and Phenotype-3 (adjusted OR = 3.67; 95%CI: 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, three distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT generated bone parameters at peripubertal PHV in AIS. The bone qualities reflected by these phenotypes were found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS.

Adolescent Idiopathic Scoliosis (AIS) is an abnormal spinal curvature commonly presents during puberty growth. Evidence has shown that low bone mineral density and impaired bone qualities are important risk factors for curve progression in AIS. High-resolution peripheral quantitative computed tomography (HR-pQCT) has improved our understanding of bone qualities in AIS. It generates a large amount of quantitative and qualitative bone parameters from a single measurement, but the data are not easy for clinicians to interpret and analyse. This study enrolled AIS girls and used unsupervised machine learning model to analyse their HR-pQCT data at first clinic visit. The model clustered the patients into 3 bone microarchitecture phenotypes (i.e. Phenotype-1: normal, Phenotype-2: low bone volume and high cortical bone density, and Phenotype-3: low cortical and trabecular bone density and impaired trabecular microarchitecture). They were longitudinally followed up for 6 years until skeletal maturity. We observed the three phenotypes were persistent, and Phenotype-3 had a significantly increased risk of curve progression to severity that requires invasive spinal surgery (Odds Ratio = 4.88, P = 0.029). The difference in bone qualities reflected by these 3 distinct phenotypes could aid clinicians to differentiate risk of curve progression and surgery at early stages of AIS.

Clinical Outcomes of 111 Patients with Early Onset Idiopathic Scoliosis (EOIS) Receiving Brace Treatment: A Longitudinal Retrospective Cohort Study.

Introduction: Bracing is one of the first-line treatment for early-onset idiopathic scoliosis (EOIS) to control curves from progression. This study aimed to explore the determinants that govern bracing effectiveness in EOIS. Methods: One hundred and eleven patients with EOIS (mean age of 8.6 ± 1.25 at diagnosis) received bracing treatment and had a final follow-up beyond skeletal maturity were identified from records between 1988 and 2021. Demographic data and clinical features of spinal curvature were obtained for correlation analyses to determine the associations between curve outcomes and clinical features. Results: Most patients were female (85.6%) and had a major curve on the left side (67%). The mean baseline Cobb angle of major curves was 21.73 ± 7.92°, with a mean Cobb angle progression of 18.05 ± 19.11°. The average bracing duration was 5.3 ± 1.9 years. Only 26 (23.4%) of them underwent surgery. The final Cobb angle and curve progression at the final follow-up with a Cobb angle of ≥50° were positively correlated with the initial Cobb angle (r = 0.206 and r = 0.313, respectively) and negatively correlated with maturity parameters. The lumbar curve type was found to correlate with a smaller final Cobb angle. Conclusions: The majority of patients had a final Cobb angle < 50°, which was considered a successful bracing outcome. The final Cobb angle correlated with the initial Cobb angle and curve types observed in EOIS.

Assessment of malalignment at early stage in adolescent idiopathic scoliosis: a longitudinal cohort study.

INTRODUCTION: Our objective was to assess abnormalities of the odontoid-hip axis (OD-HA) angle in a mild scoliotic population to determine whether screening for malalignment would help predict the distinction between progressive and stable adolescent idiopathic scoliosis (AIS) at early stage. MATERIALS AND METHODS: All patients (non-scoliotic and AIS) underwent a biplanar X-ray between 2013 and 2020. In AIS, inclusion criteria were Cobb angle between 10° and 25°; Risser sign lower than 3; age higher than 10 years; and no previous treatment. A 3D spine reconstruction was performed, and the OD-HA was computed automatically. A reference corridor for OD-HA values in non-scoliotic subjects was calculated as the range [5th-95th percentiles]. A severity index, helping to distinguish stable and progressive AIS, was calculated and weighted according to the OD-HA value. RESULTS: Eighty-three non-scoliotic and 205 AIS were included. The mean coronal and sagittal OD-HA angles in the non-scoliotic group were 0.2° and -2.5°, whereas in AIS values were 0.3° and -0.8°, respectively. For coronal and sagittal OD-HA, 27.5% and 26.8% of AIS were outside the reference corridor compared with 10.8% in non-scoliotic (OR = 3.1 and 3). Adding to the severity index a weighting factor based on coronal OD-HA, for thoracic scoliosis, improved the positive predictive value by 9% and the specificity by 13%. CONCLUSION: Analysis of OD-HA suggests that AIS patients are almost three times more likely to have malalignment compared with a non-scoliotic population. Furthermore, analysis of coronal OD-HA is promising to help the clinician distinguish between stable and progressive thoracic scoliosis.

Completion thyroidectomy: A safe option for high-volume surgeons.

BACKGROUND: The risk of complication in patients undergoing completion thyroidectomy (cT) is mixed. Several studies report increased risk in comparison to total thyroidectomy (TT) and still others reporting a comparatively decreased risk. We compared the rates of complication in patients at our institution undergoing thyroid lobectomy (TL), (TT), and cT by a single high-volume surgeon. METHODS: We performed a single-institution retrospective cohort study. Patients undergoing TL, TT, or cT by a high-volume surgeon were included. Rates of complication were collected and compared between the three cohorts. RESULTS: A total of 310 patients were included. The overall rate of complication was 4.2%. The complication rates in the TL, TT, and cT cohorts were 1%, 7.1%, and 4.5%, respectively (p = 0.10). Transient hypocalcemia was slightly more common in the TT cohort (6.1%) as opposed to the TL (0%) or cT (0.9%) cohort (p = 0.01). The cohorts also had similar rates of recurrent laryngeal nerve signal loss leading to transient dysphonia (TL: 0% vs. TT: 1% vs. cT: 3.6%, p = 0.10). CONCLUSIONS: While rates of complication tended to predictably decrease as approaches became less extensive, there were no significant differences in complication rates among the three surgical approaches when performed by a high-volume surgeon. Considering the low rates of complication overall, patient counseling and preference should be emphasized to provide appropriate and tailored treatment plans.

Monitoring of Curve Progression in Patients with Adolescent Idiopathic Scoliosis Using 3-D Ultrasound.

OBJECTIVE: The aim of the work described here was to determine whether 3-D ultrasound can provide results comparable to those of conventional X-ray examination in assessing curve progression in patients with adolescent idiopathic scoliosis (AIS). METHODS: One hundred thirty-six participants with AIS (42 males and 94 females; age range: 10-18 y, mean age: 14.1 ± 1.9 y) with scoliosis of different severity (Cobb angle range: 10º- 85º, mean: of 24.3 ± 14.4º) were included. Each participant underwent biplanar low-dose X-ray EOS and 3-D ultrasound system scanning with the same posture on the same date. Participants underwent the second assessment at routine clinical follow-up. Manual measurements of scoliotic curvature on ultrasound coronal projection images and posterior-anterior radiographs were expressed as the ultrasound curve angle (UCA) and radiographic Cobb angle (RCA), respectively. RCA and UCA increments ≥5º represented a scoliosis progression detected by X-ray assessment and 3-D ultrasound assessment, respectively. RESULTS: The sensitivity and specificity of UCA measurement in detecting scoliosis progression were 0.93 and 0.90, respectively. The negative likelihood ratio of the diagnostic test for scoliosis progression by the 3-D ultrasound imaging system was 0.08. CONCLUSION: The 3-D ultrasound imaging method is a valid technique for detecting coronal curve progression as compared with conventional radiography in follow-up of AIS. Substituting conventional radiography with 3-D ultrasound is effective in reducing the radiation dose to which AIS patients are exposed during their follow-up examinations.

Handgrip strength assessment at baseline in addition to bone parameters could potentially predict the risk of curve progression in adolescent idiopathic scoliosis.

Introduction: Adolescent idiopathic scoliosis (AIS) is characterized by deranged bone and muscle qualities, which are important prognostic factors for curve progression. This retrospective case-control study aims to investigate whether the baseline muscle parameters, in addition to the bone parameters, could predict curve progression in AIS. Methods: The study included a cohort of 126 female patients diagnosed with AIS who were between the ages of 12 and 14 years old at their initial clinical visit. These patients were longitudinally followed up every 6 months (average 4.08 years) until they reached skeletal maturity. The records of these patients were thoroughly reviewed as part of the study. The participants were categorized into two sub-groups: the progressive AIS group (increase in Cobb angle of ≥6°) and the stable AIS group (increase in Cobb angle <6°). Clinical and radiological assessments were conducted on each group. Results: Cobb angle increase of ≥6° was observed in 44 AIS patients (34.9%) prior to skeletal maturity. A progressive AIS was associated with decreased skeletal maturity and weight, lower trunk lean mass (5.7%, p = 0.027) and arm lean mass (8.9%, p < 0.050), weaker dominant handgrip strength (8.8%, p = 0.027), deranged cortical compartment [lower volumetric bone mineral density (vBMD) by 6.5%, p = 0.002], and lower bone mechanical properties [stiffness and estimated failure load lowered by 13.2% (p = 0.005) and 12.5% (p = 0.004)]. The best cut-off threshold of maximum dominant handgrip strength is 19.75 kg for distinguishing progressive AIS from stable AIS (75% sensitivity and 52.4% specificity, p = 0.011). Discussion: Patients with progressive AIS had poorer muscle and bone parameters than patients with stable AIS. The implementation of a cut-off threshold in the baseline dominant handgrip strength could potentially be used as an additional predictor, in addition to bone parameters, for identifying individuals with AIS who are at higher risk of experiencing curve progression.

Tyrosine Metabolism Pathway Is Downregulated in Dopaminergic Neurons with LRRK2 Overexpression in Drosophila.

LRRK2 mutations are the leading cause of familial Parkinson's disease (PD) and are a significant risk factor for idiopathic PD cases. However, the molecular mechanisms underlying the degeneration of dopaminergic (DA) neurons in LRRK2 PD patients remain unclear. To determine the translatomic impact of LRRK2 expression in DA neurons, we employed gene set enrichment analysis (GSEA) to analyze a translating ribosome affinity purification (TRAP) RNA-seq dataset from a DA-neuron-specific-expressing Drosophila model. We found that the tyrosine metabolism pathway, including tyrosine hydroxylase (TH), is downregulated in DA neurons with LRRK2 overexpression; in contrast, the Hippo signaling pathway is downregulated in the G2019S mutant compared to wild-type LRRK2 in the DA neurons. These results imply that the downregulation of tyrosine metabolism occurs before pronounced DA neuron loss and that LRRK2 may downregulate the tyrosine metabolism in a DA-neuron-loss-independent way.

miRNA profiling as a complementary diagnostic tool for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), the most prevalent motor neuron disease characterized by its complex genetic structure, lacks a single diagnostic test capable of providing a conclusive diagnosis. In order to demonstrate the potential for genetic diagnosis and shed light on the pathogenic role of miRNAs in ALS, we developed an ALS diagnostic rule by training the model using 80% of a miRNA profiling dataset consisting of 253 ALS samples and 103 control samples. Subsequently, we validated the diagnostic rule using the remaining 20% of unseen samples. The diagnostic rule we developed includes miR-205-5p, miR-206, miR-376a-5p, miR-412-5p, miR-3927-3p, miR-4701-3p, miR-6763-5p, and miR-6801-3p. Remarkably, the rule achieved an 82% true positive rate and a 73% true negative rate when predicting the unseen samples. Furthermore, the identified miRNAs target 21 genes in the PI3K-Akt pathway and 27 genes in the ALS pathway, including notable genes such as BCL2, NEFH, and OPTN. We propose that miRNA profiling may serve as a complementary diagnostic tool to supplement the clinical presentation and aid in the early recognition of ALS.

Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study.

Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10-5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10-10), collagen binding (GO:0005518, p = 8.6 × 10-5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10-5). Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism.

In Silico and In Vitro Screening of Serine Racemase Agonist and In Vivo Efficacy on Alzheimer's Disease Drosophila melanogaster.

The NMDA receptor hypofunction has been implicated in schizophrenia, memory impairment, and Alzheimer's disease. Modulating the abundance of D-serine, a co-agonist of the NMDA receptor, is a strategy to treat symptoms of the NMDA receptor hypofunction. In contrast to D-amino acid oxidase (DAAO) inhibitors, which aim at decreasing the loss of D-serine, this study tried to identify serine racemase (SRR) agonists, which boost the conversion of L-serine to D-serine. We used holo and apo structures of human SRR for the molecular docking against the National Cancer Institute (NCI) and ZINC compound databases and validated their efficacy by in vitro SRR activity assay. We identified NSC294149 (2-amino-3-(3-nitroimidazo[1,2-a]pyridin-2-yl)sulfanylpropanoic acid) as a potential SRR agonist and confirmed its amelioration of the hazard ratio of survival of the AD model of fruit fly (Drosophila melanogaster). These results suggest that the SRR agonist could be a drug design target against the NMDA receptor hypofunction symptoms.

More Prevalent and Severe Low Bone-Mineral Density in Boys with Severe Adolescent Idiopathic Scoliosis Than Girls: A Retrospective Study of 798 Surgical Patients.

INTRODUCTION: A total of 0.1-0.8% of AIS patients progress to severe stages without clear mechanisms, and AIS girls are more prone to curve progression than boys. Recent studies suggest that AIS girls have systemic and persistent low bone-mineral density (BMD), which has been shown to be a significant prognostic factor of curve progression in AIS. The present study aimed to (a) investigate the prevalence of low BMD in patients with severe AIS and (b) assess the sexual dimorphism and independent risk factors of low BMD in severe AIS patients. MATERIALS AND METHODS: A total of 798 patients (140 boys vs. 658 girls) with AIS who reached surgical threshold (Cobb ≥ 40°) were recruited. BMD were assessed using BMD Z-scores from dual-energy X-ray absorptiometry (DXA). Demographic, clinical, and laboratory values of the subjects were collected from their medical records. Logistic regression analysis was performed to identify independent risk factors of low BMD. RESULTS: The overall prevalence of BMD Z-score ≤ -2 and ≤ -1 were 8.1% and 37.5%, respectively. AIS boys had significantly lower BMD Z-scores (-1.2 ± 0.96 vs. -0.57 ± 0.92) and higher prevalence of low BMD (Z-score ≤ -2: 22.1% vs. 5.2%, p < 0.001; Z-score ≤ -1: 59.3% vs. 32.8%, p < 0.001) than girls. Sex, BMI, serum alkaline phosphatase, and potassium were independent factors of low BMD in the severe AIS patients. CONCLUSIONS: The present large cohort of surgical AIS patients revealed that low BMD is more prevalent and severe in boys than in girls with severe curves. Low BMD may serve as a more valuable predictive factor for curve progression to the surgical threshold in boys than girls with AIS.

Enhancing BIM security in emergency construction projects using lightweight blockchain-as-a-service.

Rapid design and construction of mobile cabin hospitals (MCHs) have become imperative in the COVID-19 response. However, due to unique design specifications (e.g., parallel design and model pre-revision), collaboration in emergency construction projects (ECPs) like MCHs presents data security vulnerabilities, including a lack of traceability and transparency. These hazards invariably reduce design effectiveness, leading to undesirable rework and project delay. Blockchain technology is a potential solution to address the aforementioned security issues in ECPs because it offers immutable and traceable data storage. Nevertheless, directly implementing blockchain in ECPs is impractical, for the blockchain has a complex deployment process and provides limited functions supporting BIM-based design. Therefore, this paper develops a lightweight blockchain-as-a-service (LBaaS) prototype to enhance the ECPs design efficiency by securing and automating information exchange while eliminating the difficulties of deploying and using blockchain. This paper contributes three elements: (1) Security vulnerabilities of design in ECP are identified. Taking an MCH in Hong Kong as an example, this paper investigates its design process and determines two design characteristics and associated security flaws. (2) Key technologies to support easy deployment and usage of blockchain in ECPs are developed. New technical elements, including a Multi-to-One mapping (MtOM) kit for easy blockchain registration, an integrated workflow retaining existing design practices, and smart contracts for secure interaction with blockchain, are developed to support LBaaS functionality. (3) An LBaaS prototype is validated and evaluated. The prototype is illustrated and evaluated using design examples based on actual MCH project data. Results show that the LBaaS is a feasible and secure approach for ECPs collaboration. This paper deepens the understanding of data security issues in ECPs and offers technical guidance in establishing blockchain solutions.

Patients with Adolescent Idiopathic Scoliosis Have Higher Metabolic Cost during High-Intensity Interval Training.

BACKGROUND: Patients with adolescent idiopathic scoliosis (AIS) are found to have a lower level of physical activity, and may have reduced exercise capacity due to spinal deformity. Previous study showed the benefits of high-intensity interval training (HIIT), named E-Fit, which is specifically designed for patients with AIS to improve musculoskeletal health and psychological well-being. To optimize the beneficial effects of training, the current study aimed to investigate the appropriate exercise intensity and metabolic demand in patients with AIS when performing E-Fit. METHODS: In all, 22 female subjects, 10 diagnosed with AIS and 12 gender-matched healthy controls, aged between 10 and 16 years, were recruited. Subjects were instructed to perform two trials of a seven min E-Fit. Breath-by-breath gas exchange parameters including oxygen consumption (VO2), heart rate (HR) and the rate of perceived exertion (PRE) were measured during exercise. Demographic data and clinical features of AIS and body composition were obtained. Metabolic demand between AIS and control groups was compared using MANOVA with covariates adjustment. RESULTS: Patients with AIS had an earlier onset of menarche (p = 0.01), higher visceral adipose tissue (p = 0.04) and percentage body fat (p = 0.03) as compared to controls. Patients with AIS showed a significantly higher adjusted means of VO2 average in both the first (p = 0.014) and second trials (p = 0.011) of E-Fit. The adjusted mean of the highest measured VO2 was higher than healthy controls and reached statistical significance in the second trial (p = 0.004). Both the AIS and control group exercised at a similar percentage of VO2 peak (64.26% vs. 64.60%). CONCLUSION: Patients with AIS showed higher oxygen consumption during E-Fit than heathy controls, which might indicate a higher metabolic cost. Patients with AIS could carry out exercise at a moderate exercise intensity similar to that of healthy controls, but special considerations in designing an exercise program, such as frequent rest intervals, would be useful to avoid fatigue among patients with AIS.

Osthole Antagonizes Microglial Activation in an NRF2-Dependent Manner.

Microglia are neuroglia in the brain with an innate immune function and participate in the progress of neurodegenerative diseases. Osthole (OST) is a coumarin derivative extracted from Cnidium monnieri and bears a microglia-antagonizing ability. However, the underlying mechanism of the antagonism is not clear. The lipopolysaccharides-induced microglial BV2 cell line and amyloid-overexpressing fruit fly were used as models to study OST treatment. We found that OST treatment is sufficient to evoke NRF2 cascade under an LPS-induced inflammatory environment, and silencing NRF2 is sufficient to abolish the process. Moreover, we found that OST is sufficient to antagonize microglial activation in both LPS-induced BV2 cells and Aß-overexpressing fruit flies, and silencing NRF2 abolishes OST's antagonism. Furthermore, OST treatment rescued survival, climbing, and the learning ability of Aß-overexpressing fruit flies and relieved oxidative stress. In conclusion, we proved that OST antagonizes microglial activation induced by either LPS or Aß and that NRF2 is necessary for OST's antagonism.

Sirt3 mediates the benefits of exercise on bone in aged mice.

Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.

Convex-concave and anterior-posterior spinal length discrepancies in adolescent idiopathic scoliosis with major right thoracic curves versus matched controls.

PURPOSE: The apical deformation in adolescent idiopathic scoliosis (AIS) is a combination of rotation, coronal deviation and passive anterior lengthening of the spine. In AIS surgery, posterior-concave lengthening or anterior-convex shortening can be part of the corrective maneuver, as determined by the individual surgeon's technique. The magnitude of convex-concave and anterior-posterior length discrepancies, and how this needs to be modified to restore optimal spinal harmony, remains unknown. METHODS: CT-scans of 80 pre-operative AIS patients with right convex primary thoracic curves were sex- and age-matched to 80 healthy controls. The spinal length parameters of the main thoracic curves were compared to corresponding levels in controls. Vertebral body endplates and posterior elements were semi-automatically segmented to determine the length of the concave and convex side of the anterior column and along the posterior pedicle screw entry points while taking the 3D-orientation of each individual vertebra into account. RESULTS: The main thoracic curves showed anterior lengthening with a mean anterior-posterior length discrepancy of + 3 ± 6%, compared to a kyphosis of - 6 ± 3% in controls (p < 0.01). In AIS, the convex side was 20 ± 7% longer than concave (0 ± 1% in controls; p < 0.01). The anterior and posterior concavity were 7 and 22 mm shorter, respectively, while the anterior and posterior convexity were 21 and 8 mm longer compared to the controls. CONCLUSIONS: In thoracic AIS, the concave shortening is more excessive than the convex lengthening. To restore spinal harmony, the posterior concavity should be elongated while allowing for some shortening of the posterior convexity.

Abnormal morphological features of osteocyte lacunae in adolescent idiopathic scoliosis: A large-scale assessment by ultra-high-resolution micro-computed tomography.

AIM: Abnormal osteocyte lacunar morphology in adolescent idiopathic scoliosis (AIS) has been reported while the results were limited by the number of osteocyte lacunae being quantified. The present study aimed to validate previous findings through (a) comparing morphological features of osteocyte lacunae between AIS patients and controls in spine and ilium using a large-scale assessment, and (b) investigating whether there is an association between the acquired morphological features of osteocyte lacunae and disease severity in AIS. METHOD: Trabecular bone tissue of the facet joint of human vertebrae on both concave and convex sides at the apex of the scoliotic curve were collected from 4 AIS and 5 congenital scoliosis (CS) patients, and also at the same anatomic site from 3 non-scoliosis (NS) subjects intraoperatively. Trabecular bone tissue from ilium was obtained from 12 AIS vs 9 NS subjects during surgery. Osteocyte lacunae were assessed using ultra-high-resolution micro-computed tomography. Clinical information such as age, body mass index (BMI) and radiological Cobb angle of the major curve were collected. RESULTS: There was no significant difference between density of osteocyte lacuna and bone volume fraction (BV/TV) between groups. A total of 230,076 and 78,758 osteocyte lacunae from facet joints of apical vertebra of scoliotic curve and iliac bone were included in the analysis, respectively. In facet joint bone biopsies, lacunar stretch (Lc.St) was higher, and lacunar equancy (Lc.Eq), lacunar oblateness (Lc.Ob), and lacunar sphericity (Lc.Sr) were lower in AIS and CS groups when compared with NS group. CA side was associated with higher Lc.St when compared with CX side. In iliac bone biopsies, Lc.Ob was higher and lacunar surface area (Lc.S) was lower in AIS group than NS group. Median values of Lc.St, Lc.Eq and Lc.Sr were significantly associated with radiological Cobb angle with adjustment for age and BMI (R-squared: 0.576, 0.558 and 0.543, respectively). CONCLUSIONS: This large-scale assessment of osteocyte lacunae confirms that AIS osteocyte lacunae are more oblate in iliac bone that is less influenced by asymmetric loading of the deformed spine than the vertebrae. Shape of osteocyte lacunae in iliac bone is associated with radiological Cobb angle of the major curve in AIS patients, suggesting the likelihood of systemic abnormal osteocyte morphology in AIS. Osteocyte lacunae from concave side of scoliotic curves were more stretched in both AIS and CS groups, which is likely secondary to asymmetric mechanical loading.

Alterations of RNA-binding protein found in neurons in Drosophila neurons and glia influence synaptic transmission and lifespan.

The found in neurons (fne), a paralog of the RNA-binding protein ELAV gene family in Drosophila, is required for post-transcriptional regulation of neuronal development and differentiation. Previous explorations into the functions of the FNE protein have been limited to neurons. The function of fne in Drosophila glia remains unclear. We induced the knockdown or overexpression of fne in Drosophila neurons and glia to determine how fne affects different types of behaviors, neuronal transmission and the lifespan. Our data indicate that changes in fne expression impair associative learning, thermal nociception, and phototransduction. Examination of synaptic transmission at presynaptic and postsynaptic terminals of the larval neuromuscular junction (NMJ) revealed that loss of fne in motor neurons and glia significantly decreased excitatory junction currents (EJCs) and quantal content, while flies with glial fne knockdown facilitated short-term synaptic plasticity. In muscle cells, overexpression of fne reduced both EJC and quantal content and increased short-term synaptic facilitation. In both genders, the lifespan could be extended by the knockdown of fne in neurons and glia; the overexpression of fne shortened the lifespan. Our results demonstrate that disturbances of fne in neurons and glia influence the function of the Drosophila nervous system. Further explorations into the physiological and molecular mechanisms underlying neuronal and glial fne and elucidation of how fne affects neuronal activity may clarify certain brain functions.