Exploring the causal relationship between antihypertensive drugs and glioblastoma by combining drug target Mendelian randomization study, eQTL colocalization, and single-cell RNA sequencing.

Recent reports indicate a potential oncogenic role of antihypertensive drugs in common cancers. However, it remains uncertain whether this phenomenon influences the risk of glioblastoma multiforme (GBM). This study aimed to assess the potential causal effects of blood pressure (BP) and antihypertensive drugs on GBM. Genome-wide association study (GWAS) summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), and GBM in Europeans were downloaded. To represent the effects of antihypertensive drugs, we utilized single nucleotide polymorphisms (SNPs) associated with SBP/DBP adjacent to the coding regions of different antihypertensive drugs as instrumental variables to model five antihypertensive drugs, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, ß-receptor blockers (BBs), and thiazide diuretics. Positive control studies were performed using GWAS data in chronic heart failure. The primary method for causality estimation was the inverse-variance-weighted method. Mendelian randomization analysis showed that BBs with the ß1-adrenergic receptor (ADRB1) as a therapeutic target could significantly reduce the risk of GBM by mediating DBP (OR = 0.431, 95% CI: 0.267-0.697, p < .001) and that they could also significantly reduce the risk of GBM by mediating SBP (OR = 0.595, 95% CI: 0.422-0.837, p = .003). Sensitivity analysis and colocalization analysis reinforced the robustness of these findings. Finally, the low expression of the ADRB1 gene in malignant gliomas was found by GBM data from TCGA and single-cell RNA sequencing, which most likely contributed to the poor prognosis of GBM patients. In summary, our study provides preliminary evidence of some causal relationship between ADRB1-targeted BBs and glioblastoma development. However, more studies are needed to validate these findings and further reveal the complex relationship between BP and GBM.

RARRES2 is involved in the "lock-and-key" interactions between osteosarcoma stem cells and tumor-associated macrophages.

Osteosarcoma (OS) is a type of tumor. Osteosarcoma stem cells (OSCs) are responsible for drug resistance, recurrence, and immunosuppression in OS. We aimed to determine the heterogeneity of OSCs and the immunosuppression mechanisms underlying the interactions between OSCs and tumor-associated macrophages (TAMs). The cell components, trajectory changes, and cell communication profiles of OS cells were analyzed by transcriptomics at the single-cell level. The intercellular communication patterns of OSCs were verified, and the role of the cell hub genes was revealed. Hub geneS are genes that play important roles in regulating certain biological processes; they are often defined as the genes with the strongest regulatory effect on differentially expressed gene sets. Moreover, various cellular components of the OS microenvironment were identified. Malignant cells were grouped, and OSCs were identified. Further regrouping and communication analysis revealed that the genes in the stemness maintenance and differentiation subgroups were involved in communication with macrophages. Key receptor-ligand pairs and target gene sets for cell communication were obtained. Transcriptome data analysis revealed the key gene RARRES2, which is involved in intercellular communication between OSCs and TAMs. In vitro studies confirmed that macrophages promote RARRES2-mediated stemness maintenance in OSCs via the TAM-secreted cytokine insulin-like growth factor 1. Patient studies confirmed that RARRES2 could be a biomarker of OS. OSCs are highly heterogeneous, and different subgroups are responsible for proliferation and communication with other cells. The IGF-RARRES2 axis plays a key role in maintaining OSC stemness through communication with TAMs.

Lateral trochlear inclination measured by the transepicondylar axis holds potential for evaluating trochlear dysplasia in patients with lateral patellar dislocation.

PURPOSE: To verify that lateral trochlear inclination (LTI) measured by the transepicondylar axis can reliably be used to evaluate trochlear dysplasia (TD) on MRI and can serve as an objective indication of trochleoplasty for patients with lateral patellar dislocation (LPD). METHODS: Eighty patients with recurrent LPD and eighty healthy subjects were included. TD, posterior condylar angle (PCA), and LTI measured by the posterior condylar reference line (LTIp), surgical transepicondylar axis (LTIs), and anatomical transepicondylar axis (LTIa) were assessed on MRI. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed, the correlations and differences amongst the parameters were identified, and a binary logistic regression model was established. RESULTS: Each measurement had excellent inter- and intra-observer agreement. The LTIp, LTIs and LTIa were smaller in the study group than in the control group, with mean differences of 9.0°, 7.2° and 7.0°, respectively (P < 0.001). The PCA was larger in patients with LPD than in the control group (P < 0.001). LTIp was associated with PCA in the study group (r = - 0.41, P < 0.001). The pathological values of LTIp, LTIs and LTIa were 11.7°, 15.3° and 17.4°, respectively. LTIs and LTIa were independent risk factors for LPD, with ORs of 7.33 (95% CI [1.06-52.90], P = 0.048) and 10.29 (95% CI [1.38-76.96], P = 0.023), respectively. CONCLUSION: The LTI can be reliably measured by MRI, but LTIp could potentially decrease the recorded value from the actual inclination angle. LTIs and LTIa are more appropriate to serve as trochleoplasty indications for patients with LPD, which could help orthopedists with surgical decision-making. LEVEL OF EVIDENCE: Level III.

AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.

AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD+. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.

Tenofovir disoproxil fumarate mediates neuronal injury by inducing neurotoxicity.

PURPOSE: Highly active antiretroviral therapy (HAART) is an accepted treatment option for patients with virus infection. Mounting evidence indicated that persistent HAART treatment is implicated with increased morbidity of HIV-associated neurocognitive disorders (HAND) in patients. Tenofovir disoproxil fumarate (TDF), a novel nucleotide reverse transcriptase inhibitor (NRTI), was used in patients with HIV co-infected with HBV. And it is still a vital first-line antiretroviral compounds in HAART. However, whether persistent treatment with TDF is involved in HAND development remains to be further elucidated. In this study, we aimed to discuss the neurotoxicity of TDF. METHODS: We used SH-SY5Y cells and primary neuronal cells to evaluate the neurotoxicity of TDF in vitro. The cytotoxicity of TDF on SH-SY5Y cells and primary neuronal cells was evaluated by the cell viability and LDH levels by MTT assay and LDH kit, respectively. Hoechst 33342 staining, TUNEL assay and flow cytometry were performed to evaluate the cells apoptosis. The intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) production were measured by commercial kits. In addition, the activation level of caspase-3 was evaluated using spectrophotometry and western blotting. RESULTS: Our results showed that TDF treatment significantly induced cell viability and induced apoptosis of SH-SY5Y cells and primary neuronal cells. Furthermore, the ROS levels and MDA productions were significantly up-regulated in nerve cells treated with TDF.  CONCLUSION: Our findings indicated that TDF may induce neuronal cell apoptosis through increasing the intracellular ROS and the expression level of caspase-3, which may be related to the increasing prevalence of HAND.

Immunology and immunotherapy in gastric cancer.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. As the diagnosis of early gastric cancer is difficult, most patients are at a late stage of cancer progression when diagnosed. The current therapeutic approaches based on surgical or endoscopic resection and chemotherapy indeed improve patients' outcomes. Immunotherapy based on immune checkpoint inhibitors has opened a new era for cancer treatment, and the immune system of the host is reshaped to combat tumor cells and the strategy differs according to the patient's immune system. Thus, an in-depth understanding of the roles of various immune cells in the progression of gastric cancer is beneficial to application for immunotherapy and the discovery of new therapeutic targets. This review describes the functions of different immune cells in gastric cancer development, mainly focusing on T cells, B cells, macrophages, natural killer cells, dendritic cells, neutrophils as well as chemokines or cytokines secreted by tumor cells. And this review also discusses the latest advances in immune-related therapeutic approaches such as immune checkpoint inhibitors, CAR-T or vaccine, to reveal potential and promising strategies for gastric cancer treatment.

Integrating machine learning and bioinformatics analysis to m6A regulator-mediated methylation modification models for predicting glioblastoma patients' prognosis and immunotherapy response.

BACKGROUND: Epigenetic regulations of immune responses are essential for cancer development and growth. As a critical step, comprehensive and rigorous explorations of m6A methylation are important to determine its prognostic significance, tumor microenvironment (TME) infiltration characteristics and underlying relationship with glioblastoma (GBM). METHODS: To evaluate m6A modification patterns in GBM, we conducted unsupervised clustering to determine the expression levels of GBM-related m6A regulatory factors and performed differential analysis to obtain m6A-related genes. Consistent clustering was used to generate m6A regulators cluster A and B. Machine learning algorithms were implemented for identifying TME features and predicting the response of GBM patients receiving immunotherapy. RESULTS: It is found that the m6A regulatory factor significantly regulates the mutation of GBM and TME. Based on Europe, America, and China data, we established m6Ascore through the m6A model. The model accurately predicted the results of 1206 GBM patients from the discovery cohort. Additionally, a high m6A score was associated with poor prognoses. Significant TME features were found among the different m6A score groups, which demonstrated positive correlations with biological functions (i.e., EMT2) and immune checkpoints. CONCLUSIONS: m6A modification was important to characterize the tumorigenesis and TME infiltration in GBM. The m6Ascore provided GBM patients with valuable and accurate prognosis and prediction of clinical response to various treatment modalities, which could be useful to guide patient treatments.

Femoral Anteversion Measured by the Surgical Transepicondylar Axis Is Correlated with the Tibial Tubercle-Roman Arch Distance in Patients with Lateral Patellar Dislocation.

Background and Objectives: Various predisposing factors for lateral patellar dislocation (LPD) have been identified, but the relation between femoral rotational deformity and the tibial tubercle-Roman arch (TT-RA) distance remains elusive. Materials and Methods: We conducted this study including 72 consecutive patients with unilateral LPD. Femoral anteversion was measured by the surgical transepicondylar axis (S-tAV), and the posterior condylar reference line (P-tAV), TT-RA distance, trochlear dysplasia, knee joint rotation, patellar height, and hip-knee-ankle angle were measured by CT images or by radiographs. The correlations among these parameters were analyzed, and the parameters were compared between patients with and without a pathological TT-RA distance. Binary regression analysis was performed, and receiver operating characteristic curves were obtained. Results: The TT-RA distance was correlated with S-tAV (r = 0.360, p = 0.002), but the correlation between P-tAV and the TT-RA distance was not significant. S-tAV had an AUC of 0.711 for predicting a pathological TT-RA, with a value of >18.6° indicating 54.8% sensitivity and 82.9% specificity. S-tAV revealed an OR of 1.13 (95% CI [1.04, 1.22], p = 0.003) with regard to the pathological TT-RA distance by an adjusted regression model. Conclusions: S-tAV was significantly correlated with the TT-RA distance, with a correlation coefficient of 0.360, and was identified as an independent risk factor for a pathological TT-RA distance. However, the TT-RA distance was found to be independent of P-tAV.

Anterior Screw Insertion Results in Greater Tibial Tunnel Enlargement Rates after Single-Bundle Anterior Cruciate Ligament Reconstruction than Posterior Insertion: A Retrospective Study.

Background and Objectives: Tunnel enlargement (TE) is a widely reported phenomenon after anterior cruciate ligament reconstruction (ACLR). Given the paucity of knowledge in the literature, it remains unclear whether screw position in the tunnel affects TE. This retrospective cohort study evaluated differences in postoperative tunnel enlargement rates (TER) and clinical results between anterior and posterior tibial interference screw insertion during single-bundle ACLR using autologous hamstring grafts. Materials and Methods: A group of consecutive patients that underwent primary arthroscopic single-bundle ACLR in our hospital were screened and divided into two groups based on the position of the tibial interference screw (determined by Computer Tomography within 3 days after surgery): anterior screw position group (A) and posterior screw position group (B). The bone tunnel size was measured using magnetic resonance imaging (MRI) performed 1 year after surgery. International Knee Documentation Committee (IKDC) score and the Knee Injury and Osteoarthritis Outcome Score (KOOS) were used for clinical results 1 year postoperatively. Results: 87 patients were included. The TER of Group A is higher than that of Group B (43.17% vs. 33.80%, p = 0.024). Group A showed a significant increase (12.1%) in enlargement rates at the joint line level than group B (43.77% vs. 31.67%, p = 0.004). Moreover, KOOS and IKDC scores improved in both groups. There were no significant differences in clinical outcomes between the two groups. Conclusions: One year after ACLR, patients with posterior screw showed significantly lower TE than patients with anterior screw. However, the position of screw did not lead to differences in clinical results over our follow-up period. Posterior screw position in the tibial tunnel maybe a better choice in terms of reducing TE. Whether the different screw positions affect the long-term TE and long-term clinical outcomes needs to be confirmed by further studies.

Femoral anteversion measured by the surgical transepicondylar axis is a reliable parameter for evaluating femoral rotational deformities in patients with patellar dislocation.

PURPOSE: To verify whether femoral anteversion measured by the surgical transepicondylar axis (S-FA) is a reliable parameter for evaluating femoral rotational deformities and to provide an indication for derotational distal femoral osteotomy (DDFO) in patients with patellar dislocation. METHODS: Ninety patients with recurrent patellar dislocation and 90 healthy individuals were enrolled. The S-FA, the femoral anteversion measured by posterior condylar reference line (P-FA), the length of posterior femoral condyles, and the posterior condylar angle (PCA) were assessed by CT images. The unpaired t test and Pearson correlation analysis were conducted. Receiver operating characteristic curves and the area under the curve (AUC) were used to evaluate the diagnostic capacity of the parameters. The pathological value of the measurements was determined, and a binary regression model was established. RESULTS: The S-FA and P-FA were greater in the study group (14.2 ± 7.7° and 19.7 ± 7.3°, respectively) than in the control group (7.2 ± 8.0° and 12.2 ± 8.2°, respectively) (P < 0.001). The lateral/posterior condyle was shorter in patients with patellar dislocation (21.2 ± 2.5 mm) than in healthy individuals (23.5 ± 2.7 mm) (P = 0.001). The P-FA was correlated with PCA in the study group (P < 0.001). The S-FA and P-FA had AUCs of 0.734 and 0.767 for patellar dislocation, respectively. The pathological values of the S-FA and P-FA were 20.4° and 25.8°, respectively. The S-FA revealed a significant OR of 10.47 (P = 0.014) for patellar dislocation. CONCLUSION: The S-FA is a reliable parameter for identifying femoral rotational deformities in patients with patellar dislocation. DDFO is recommended when a pathological S-FA (> 20.4°) is presented. LEVEL OF EVIDENCE: Retrospective cohort study (diagnostic), level II.

Tibial Tubercle to Trochlear Groove Distance Measured by Posterior Condylar Reference Line on MRI Can Over-Evaluate Lateralization Deformity of Tibial Tubercle in Patients with Recurrent Patellar Dislocation.

Background: The tibial tubercle to trochlear groove (TT-TG) distance is currently considered as an indication for tibial tubercle osteotomy. While the influence of femoral condylar morphology on such measurement remains unclear. Methods: A total of 86 patients with patellar dislocation (PD) and 86 healthy individuals were enrolled. Femoral condylar morphology and the TT-TG distance measured by anatomical transepicondylar axis (TT-TGa), by surgical transepicondylar axis (TT-TGs), and by posterior condylar reference line (TT-TGp) were assessed by MRI. Unpaired t-test, Spearman, and Pearson correlation analysis were conducted. We determined the pathological value of the parameters and established a binary regression model. Results: The interclass correlation coefficients of all the TT-TG distances were greater than 0.75 in all types of trochlear dysplasia. The lateral/posterior femoral condyle was shorter and the medial/posterior condyle was longer in the study group (28.5 ± 3.3 and 35.2 ± 2.8, respectively) than in the control group (30.9 ± 2.7 and 33.5 ± 2.3, respectively). In the study group, the TT-TGp distance was greater than TT-TGs and TT-TGa distance (p < 0.001). The pathological value of the TT-TG distance was 13.0 mm. Each TT-TG distance revealed a significant OR with regard to PD. Conclusion: The TT-TGa, TT-TGs, and TT-TGp distance can be reliably measured by MRI even in patients with trochlear dysplasia. While the TT-TGp distance may overestimate the lateralization deformity of the tibial tubercle. Posterior femoral condylar dysplasia may be a reason for such overestimating. These findings have not been correlated to clinical outcomes and further studies are required.

Establishment of an endoplasmic reticulum stress-related signature predicting outcomes of gastric adenocarcinoma patients.

Background: Gastric adenocarcinoma (GAC) is a common clinical malignancy with a poor prognosis. Endoplasmic reticulum (ER) stress plays important roles in the progression, immune filtration, and chemoresistance of cancers. However, whether ER stress-related gene signatures can predict the prognosis of GAC patients remains unknown. Methods: GAC patient RNA-seq data downloaded from The Cancer Genome Atlas and gastric cancer patient microarray data from Gene Expression Omnibus datasets were analyzed using LASSO regression to construct an ER stress-related signature. Survival analysis, time-dependent receiver operating characteristic (ROC) curves, and Cox regression analysis were used to verify the efficacy of the signature. Immune infiltration, somatic mutation, immune checkpoint, and copy number variation analyses were utilized to explore the potential biological significance of the signature. Results: In the present study, eight ER stress-related gene signatures were constructed. Survival analysis showed that patients in the high-risk group had a significantly worse prognosis. The area under the time-dependent ROC curves was 0.65, 0.70, and 0.63 at 1, 3, and 5 years, respectively, in the training cohort. Cox regression analysis showed that the signature is an independent prognostic factor. To predict GAC patients' prognosis meeting individual needs, a nomogram was constructed with good accuracy. In addition, gene set enrichment and immune infiltration analyses showed that the ER stress-related signature is associated with cancer-related pathway activation and an immunosuppressive tumor microenvironment in GAC. Conclusion: In the current study, we established an ER stress-related signature. This prognostic signature has good predictive power and could facilitate the development of novel strategies for the clinical treatment of GAC.

Clinical effect of micturition interruption exercise on urinary incontinence after radical prostatectomy.

PURPOSE: To explore the effectiveness of micturition interruption exercise in improving the incidence of urinary incontinence after radical prostatectomy. MATERIALS AND METHODS: With a retrospective case-control study, 96 patients admitted in the Second Affiliated Hospital of Zhejiang Chinese Medical University from August 2014 to August 2020 and underwent radical prostatectomy were collected as the subjects. Those patients who used micturition interruption exercise (n = 48) were set as the therapy group, and the control group was collected according to the ratio of 1:1; the patients used Kegel exercise (n = 48) to compare the rehabilitation of urinary incontinence in patients and the effect of training compliance on rehabilitation. RESULTS: The recovery time of urinary incontinence in the therapy group was significantly shorter than that of the control group. In the therapy group, 83.3% of patients with training compliance reached an average or above, while the control group only accounted for 58.3%. International Consultation on Incontinence Questionnaire Short-Form score of the therapy group was lower than that of the control group after surgery. Spearman analysis suggests that there is a negative correlation between the postoperative urinary incontinence recovery time and compliance with the micturition interruption exercise. CONCLUSIONS: Micturition interruption exercise could not only improve the compliance of patients with exercise, but also significantly shorten the recovery time of urinary incontinence after radical prostatectomy.

Ipsilateral patellofemoral morphological abnormalities are more severe than those of contralateral joints in patients with unilateral patellar dislocation.

PURPOSE: To determine the differences in anatomic parameters between ipsilateral dislocated knees and contralateral non-dislocated knees in patients with unilateral patellar dislocation and to identify any variations in ipsilateral knees contributing to contralateral anatomic abnormalities. METHODS: A total of 82 patients with unilateral patellar dislocation from 2016 to 2019 were retrospectively evaluated. Bilateral anatomic factors, including the tibial tubercle to trochlear groove (TT-TG) distance, lower limb rotational deformities, trochlear dysplasia, patella tilt, and patellar height, were assessed by CT. RESULTS: The study included 46 patients (32 females and 14 males, mean age ± SD 20.5 ± 6.8). The interobserver reliability of each parameter showed excellent agreement. The ipsilateral TT-TG distance (P = 0.004), patella tilt (P = 0.001), and patellar height (P = 0.01) were greater in the ipsilateral knees than in the contralateral knees. The lateral trochlea inclination (LTI) in the contralateral knees was larger than that in the ipsilateral knees (P = 0.022). There was a significant difference in the distribution of trochlear dysplasia of Dejour between the ipsilateral knees (dislocated side) and the contralateral knees (P = 0.036). However, bilateral femoral and/or tibial torsion, and bilateral knee joint rotation did not differ significantly. Binary logistic regression showed that only ipsilateral LTI revealed significant ORs of 8.83 (P = 0.016) and 7.64 (P = 0.018) with regard to contralateral abnormal tibial torsion and LTI, respectively. CONCLUSION: In patients with unilateral patellar dislocation, the ipsilateral TT-TG distance, patella tilt, and patellar height values were larger in the ipsilateral knees than in the contralateral knees, and trochlear dysplasia was more severe in the ipsilateral joints. The risks of contralateral pathological tibial torsion and LTI were 8.8- and 7.6-fold higher, respectively, in patients with abnormal ipsilateral LTI. LEVEL OF EVIDENCE: Level IV.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aß, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.

Type F scavenger receptor expressed by endothelial cells (SREC)-II from Epinephelus coioides is a potential pathogen recognition receptor in the immune response to Vibrio parahaemolyticus infection.

Scavenger receptors play a central role in defending against infectious diseases in mammals. However, the function of SRECII remains unknown in teleost fish. In this study, type F scavenger receptor expressed by endothelial cells-II (SRECII) cDNA sequence was first identified from Epinephelus coioides, named EcSRECII, which contained an N-terminal signal peptide, eight EGF/EGF-like cysteine-rich motifs and a C-terminal low-complexity region. The gene location maps revealed that EcSRECII has the conservation of synteny among selected species. Subcellular localization showed that EcSRECII was mainly located in the cytoplasm in HEK293T cells and GS cells. In healthy E. coioides, EcSRECII mRNA was highly expressed in spleen, skin, gill, thymus and head kidney. The relative EcSRECII mRNA expression after Vibrio parahaemolyticus infection was significantly up-regulated at 12 h in spleen, head kidney and thymus, but downregulated at 1 d in skin and reduced at 3 d and 1 w in spleen. Furthermore, overexpression of EcSRECII activated NF-κB and IFN-ß signaling pathway in vitro. Taken together, these results indicated that EcSRECII could be as the potential pathogen recognition receptor for involving in bacterial infection by regulating innate immunity responses in E. coioides.

Femoral Anteversion Is Related to Tibial Tubercle-Trochlear Groove Distance in Patients with Patellar Dislocation.

PURPOSE: To evaluate the potential relationship between the tibial tubercle-trochlear groove (TT-TG) distance and the femoral anteversion of different segments of the femur in patients with patellar dislocation. METHODS: A total of 60 patients with a diagnosis of patellar dislocation were included in our study. Patients with previous knee surgeries, previous fractures, or lack of necessary radiologic examinations were excluded from our study. The data of computed tomography scanning within a week before the surgery was used to measure the TT-TG distance, total anteversion, proximal anteversion, diaphyseal anteversion, distal anteversion, and tibial torsion. All the data were obtained from the picture archiving and communication system (PACS) workstation. The Pearson correlation analysis was performed to confirm the potential relationship between TT-TG distance and femoral anteversion of different segments. The intraclass correlation coefficient was used to assess the interobserver reliability of measurements. RESULTS: The TT-TG distance was significantly correlated with the diaphyseal anteversion (r = -0.305, P = 0.008) and distal anteversion (r = 0.365, P = 0.004). The total anteversion was associated with proximal anteversion (r = 0.392, P = 0.02) and diaphyseal anteversion (r = 0.631, P < 0.001). The intraclass correlation coefficient showed the measurements of included parameters were presented with excellent agreement. CONCLUSION: Our study showed that patients with high diaphyseal anteversion and distal anteversion tend to had a higher TT-TG distance but the value of total and proximal femoral anteversion were independent of the value of TT-TG distance. LEVEL OF EVIDENCE: Level IV therapeutic case series.

Transcriptomic Analysis Revealed the Regulatory Mechanisms of Oocyte Maturation and Hydration in Orange-Spotted Grouper (Epinephelus coioides).

Oocyte maturation and hydration are regulated by a complex interplay of various hormones and local factors. We have investigated the morphological changes of follicles and serum steroid levels during the HCG (human choionic gonadotophin)-induced oocyte maturation in the orange-spotted grouper. For the first time, a large-scale transcriptomic analysis of follicles during the maturation has been conducted in a fish species which produce pelagic oocytes. Eight cDNA libraries of follicle samples, from full-grown immature follicles to mature follicles, were constructed. A total of 402,530,284 high-quality clean reads were obtained after filtering, 79.66% of which perfectly mapped to the orange-spotted grouper genome. Real-time PCR results of 12 representative genes related to oocyte maturation and hydration verified the reliability of the RNA-seq data. A large number of genes related to oocyte maturation and hydration were identified in the transcriptome dataset. And the transcriptomic analysis revealed the dynamic changes of the steroid synthesis pathway and the pathway of hydration during oocyte maturation. The present study will facilitate future study on the oocyte maturation and hydration in the orange-spotted grouper and other marine pelagic egg spawner.

Deciphering the three-domain architecture in schlafens and the structures and roles of human schlafen12 and serpinB12 in transcriptional regulation.

Schlafen proteins are important in cell differentiation and defense against viruses, and yet this family of vertebrate proteins is just beginning to be understood at the molecular level. Here, the three-dimensional architecture and molecular interfaces of human schlafen12 (hSLFN12), which promotes intestinal stem cell differentiation, are analyzed by sequence conservation and structural modeling in light of the functions of its homologs and binding partners. Our analysis shows that the schlafen or divergent AAA ATPase domain described in the N-terminal region of schlafens in databases and the literature is a misannotation. This N-terminal region is conclusively an AlbA_2 DNA/RNA binding domain, forming the conserved core of schlafens and their sequence homologs from bacteria through mammals. Group III schlafens additionally contain a AAA NTPase domain in their C-terminal helicase region. In hSLFN12, we have uncovered a domain matching rho GTPases, which directly follows the AlbA_2 domain in all group II-III schlafens. Potential roles for the GTPase-like domain include antiviral activity and cytoskeletal interactions that contribute to nucleocytoplasmic shuttling and cell polarization during differentiation. Based on features conserved with rSlfn13, the AlbA_2 region in hSLFN12 is likely to bind RNA, possibly as a ribonuclease. We hypothesize that RNA binding by hSLFN12 contributes to an RNA-induced transcriptional silencing/E3 ligase complex, given the functions of hSLFN12's partners, SUV39H1, JMJD6, and PDLIM7. hSLFN12's partner hSerpinB12 may contribute to heterochromatin formation, based on its homology to MENT, or directly regulate transcription via its binding to RNA polymerase II. The analysis presented here provides clear architectural and transcriptional regulation hypotheses to guide experimental design for hSLFN12 and the thousands of schlafens that share its motifs.

Cytosolic lipid droplets as engineered organelles for production and accumulation of terpenoid biomaterials in leaves.

Cytosolic lipid droplets are endoplasmic reticulum-derived organelles typically found in seeds as reservoirs for physiological energy and carbon to fuel germination. Here, we report synthetic biology approaches to co-produce high-value sesqui- or diterpenoids together with lipid droplets in plant leaves. The formation of cytosolic lipid droplets is enhanced in the transient Nicotiana benthamiana system through ectopic production of WRINKLED1, a key regulator of plastid fatty acid biosynthesis, and a microalgal lipid droplet surface protein. Engineering of the pathways providing the universal C5-building blocks for terpenoids and installation of terpenoid biosynthetic pathways through direction of the enzymes to native and non-native compartments boost the production of target terpenoids. We show that anchoring of distinct biosynthetic steps onto the surface of lipid droplets leads to efficient production of terpenoid scaffolds and functionalized terpenoids. The co-produced lipid droplets "trap" the terpenoids in the cells.