A new, effective method for diagnosing GLAD lesions: the chicken-wing muscle up test.

PURPOSE: We aimed to develop and evaluate a new diagnostic method, the 'chicken-wing muscle up test', to improve the accuracy of diagnosis of glenolabral articular disruption (GLAD) lesions compared to currently used clinical tests for injuries to the labrum. METHODS: Preoperative evaluations were conducted on 85 patients undergoing arthroscopic surgery at a single center between July 2021 to July 2022. The diagnostic performance of the preoperative clinical examinations (chicken-wing muscle up test, O'Brien test, crank test, and O'Driscoll test) were validated against the findings of arthroscopic examinations. RESULTS: 12 of the 85 patients in this study had arthroscopically confirmed GLAD lesions. The chicken-wing muscle up test demonstrated significantly higher sensitivity (83.33%) for GLAD lesions than the O'Brien test (33.33%), but not the crank test (50.00%) or O'Driscoll test (25.00%), and significantly higher specificity (95.89%) than the O'Brien test (75.34%), crank test (82.19%), and O'Driscoll test (71.23%). The chicken-wing muscle up test had the largest area under the receiver operating characteristic curve (AUC = 0.896, P < 0.001; O'Driscoll test AUC = 0.543, P > 0.05; crank test AUC = 0.661, P > 0.05; O'Brien test AUC = 0.481, P > 0.05), indicating significantly better diagnostic efficacy for GLAD lesions than the other three tests. CONCLUSIONS: The chicken-wing muscle up test is a reliable diagnostic method that improves the accuracy of diagnosis of GLAD lesions.

Comparative effectiveness of three treatment options for slade and dodds grade III-IV scaphoid nonunion: a retrospective study.

OBJECTIVE: To compare the clinical efficacy of open debridement screw fixation combined with bone grafting, percutaneous screw fixation, and percutaneous screw fixation combined with injection of platelet-rich plasma (PRP) for the treatment of Slade and Dodds Grade III to IV scaphoid nonunion (SNU). METHODS: This retrospective study included patients with Grade III (25 patients) and Grade IV (28 patients) SNU. They were treated with open surgery bone grafting and internal fixation (group A), percutaneous screw fixation (group B) or percutaneous screw fixation and PRP injection (group C) from January 2015 to May 2020. The fracture consolidation rate, VAS score, and Mayo wrist function score were compared across the three groups. RESULTS: The consolidation rate was not significantly different among the three groups for both Grade III and IV SNU. However, patients in group C reported significantly less pain and better wrist function 7 days after surgery compared to group A and B, for both nonunion grades. At 3 months after surgery, group C had significantly better VAS and Mayo wrist scores compared to group A for both nonunion grades, and compared to group B for Grade IV SNU. At 6 and 12 months after surgery, patients with Grade IV SNU in groups A and C had significantly better VAS and Mayo wrist scores compared to group B. CONCLUSION: This study suggests that percutaneous screw fixation with PRP injection could be a more effective method for treating Grade IV SNU. This approach may reduce postoperative wrist pain and improve wrist function in the early stages after surgery for patients with both Grade III and IV SNU. TYPE OF STUDY/LEVEL OF EVIDENCE: IV.

Circ_0001721 enhances doxorubicin resistance and promotes tumorigenesis in osteosarcoma through miR-758/TCF4 axis.

BACKGROUND: Osteosarcoma (OS) is a common type of bone malignancy that often occurs in children and adolescents. Chemoresistance is a huge barrier to cancer therapy. This study aimed to investigate the role and potential mechanism of circ_0001721 in doxorubicin (DXR) resistance and OS development. METHODS: The levels of circ_0001721, miR-758 and transcription factor 4 (TCF4) were detected by quantitative real-time polymerase chain reaction or western blot assay. Cell Counting Kit-8 (CCK-8) assay was used to calculate the half inhibition concentration (IC50) of DXR and assess cell viability. Cell migration and invasion were evaluated by transwell assay. Cell apoptosis was monitored by flow cytometry. The levels of multidrug resistance-related and Wnt/ß-catenin pathway-related proteins were measured by western blot assay. The interaction among circ_0001721, miR-758 and TCF4 were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation assay or RNA pull-down assay. The xenograft model was established to analyze tumor growth in vivo. RESULTS: Circ_0001721 and TCF4 were upregulated, whereas miR-758 was down-regulated in DXR-resistant OS tissues and cells. Circ_0001721 silence reduced DXR resistance of KHOS/DXR and MG63/DXR cells. Circ_0001721 regulated DXR resistance via sponging miR-758. Moreover, miR-758 modulated DXR resistance by targeting TCF4. Besides, circ_0001721 knockdown inhibited tumor growth in vivo. CONCLUSION: Circ_0001721 potentiated DXR resistance and facilitated the progression of OS by regulating miR-758/TCF4 axis, which provides promising therapeutic targets for OS treatment.

Unsupervised Learning with Generative Adversarial Network for Automatic Tire Defect Detection from X-ray Images.

Automatic defect detection of tire has become an essential issue in the tire industry. However, it is challenging to inspect the inner structure of tire by surface detection. Therefore, an X-ray image sensor is used for tire defect inspection. At present, detection of defective tires is inefficient because tire factories commonly conduct detection by manually checking X-ray images. With the development of deep learning, supervised learning has been introduced to replace human resources. However, in actual industrial scenes, defective samples are rare in comparison to defect-free samples. The quantity of defective samples is insufficient for supervised models to extract features and identify nonconforming products from qualified ones. To address these problems, we propose an unsupervised approach, using no labeled defect samples for training. Moreover, we introduce an augmented reconstruction method and a self-supervised training strategy. The approach is based on the idea of reconstruction. In the training phase, only defect-free samples are used for training the model and updating memory items in the memory module, so the reproduced images in the test phase are bound to resemble defect-free images. The reconstruction residual is utilized to detect defects. The introduction of self-supervised training strategy further strengthens the reconstruction residual to improve detection performance. The proposed method is experimentally proved to be effective. The Area Under Curve (AUC) on a tire X-ray dataset reaches 0.873, so the proposed method is promising for application.

Identification of hub genes and construction of transcriptional regulatory network for the progression of colon adenocarcinoma hub genes and TF regulatory network of colon adenocarcinoma.

The aim of this study was to identify key genes related to the progression of colon adenocarcinoma (COAD), and to investigate the regulatory network of hub genes and transcription factors (TFs). Dataset GSE20916 including 44 normal colon, 55 adenoma, and 36 adenocarcinoma tissue samples was used to construct co-expression networks via weighted gene co-expression network. Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis for the objective module were performed using the online Database for Annotation, Visualization and Integrated Discovery. Hub genes were identified by taking the intersection of differentially expressed genes between dataset GSE20916 and GSE39582 and validated using The Cancer Genome Atlas (TCGA) database. The correlations between microRNA (miRNA) and hub genes were analyzed using the online website StarBase. Cytoscape was used to establish a regulatory network of TF-miRNA-target gene. We found that the orange module was a key module related to the tumor progression in COAD. In datasets GSE20916 and GSE39582, a total of eight genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) were selected, which were closely related with patients' survivals in TCGA database and dataset GSE20916. COAD patients with higher expressions of each hub gene had a worse prognosis than those with lower expressions. A regulatory network of TF-miRNA-target gene with 144 TFs, 26 miRNAs, and 7 hub genes was established, including model KLF11-miR149-BGN, TCEAL6-miR29B2-COL1A1, and TCEAL6-miR29B2-COL1A2. In conclusion, during the progression of COAD, eight core genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) play vital roles. Regulatory networks of TF-miRNA-target gene can help to understand the disease progression and optimize treatment strategy.

Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40⁻CD154 Costimulatory Protein-Protein Interaction.

We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40⁻CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory interaction that is an important therapeutic target since it plays crucial roles in the activation of T cell responses, and there is resurgent interest in its modulation with several biologics in development. However, this interaction, just as all other PPIs, is difficult to target by small molecules. Following up on our previous work, we have now identified novel compounds such as DRI-C21091 or DRI-C21095 that show activity (IC50) in the high nanomolar to low micromolar range in the binding inhibition assay and more than thirty-fold selectivity versus other TNFSF PPIs including OX40⁻OX40L, BAFFR-BAFF, and TNF-R1-TNFα. Protein thermal shift (differential scanning fluorimetry) assays indicate CD154 and not CD40 as the binding partner. Activity has also been confirmed in cell assays and in a mouse model (alloantigen-induced T cell expansion in a draining lymph node). Our results expand the chemical space of identified small-molecule CD40⁻CD154 costimulatory inhibitors and provide lead structures that have the potential to be developed as orally bioavailable immunomodulatory therapeutics that are safer and less immunogenic than corresponding biologics.

Chinese Medicine Supplementing Qi and Activating Blood Circulation Relieves the Progression of Diabetic Cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is the leading cause of diabetic death as the final occurrence of heart failure and arrhythmia. Traditional Chinese medicine is usually used to treat various diseases including diabetes. OBJECTIVE: This study sought to investigate the effects of Traditional Chinese medicine supplementing Qi and activating blood circulation (SAC) in DCM. METHODS: After the construction of the DCM model by streptozotocin (STZ) injection and high glucose/fat diet feeding, rats were administered intragastrically with SAC. Then, cardiac systolic/diastolic function was evaluated by detecting left ventricular systolic pressure (LVSP), maximal rate of left ventricular pressure rise (+LVdp/dtmax), and fall (-LVdp/dtmax), heart rate (HR), left ventricular ejection fraction (EF), LV fractional shortening (FS) and left ventricular end-diastolic pressure (LVEDP). Masson's and TUNEL staining were used to assess fibrosis and cardiomyocyte apoptosis. RESULTS: DCM rats exhibited impaired cardiac systolic/diastolic function manifested by decreasing LVSP, + LVdp/dtmax, -LVdp/dtmax, HR, EF and FS, and increasing LVEDP. Intriguingly, traditional Chinese medicine SAC alleviated the above-mentioned symptoms, indicating a potential role in improving cardiac function. Masson's staining substantiated that SAC antagonized the increased collagen deposition and interstitial fibrosis area and the elevations in protein expression of fibrosisrelated collagen I and fibronectin in heart tissues of DCM rats. Furthermore, TUNEL staining confirmed that traditional Chinese medicine SAC also attenuated cardiomyocyte apoptosis in DCM rats. Mechanically, DCM rats showed the aberrant activation of the TGF-ß/Smad signaling, which was inhibited after SAC. CONCLUSION: SAC may exert cardiac protective efficacy in DCM rats via the TGF-ß/Smad signaling, indicating a new promising therapeutic approach for DCM.

Can intermuscular cleavage planes provide proper transverse screw angle? Comparison of two paraspinal approaches.

PURPOSE: The goal of this study was to determine which paraspinal approach provided a better transverse screw angle (TSA) for each vertebral level in lower lumbar surgery. METHODS: Axial computed tomography (CT) images of 100 patients, from L3 to S1, were used to measure the angulation parameters, including transverse pedicle angle (TPA) and transverse cleavage plane angle (TCPA) of entry from the two approaches. The difference value between TCPA and TPA, defined as difference angle (DA), was calculated. Statistical differences of DA obtained by the two approaches and the angulation parameters between sexes, and the correlation between each angulation parameter and age or body mass index (BMI) were analyzed. RESULTS: TPA ranged from about 16° at L3 to 30° at S1. TCPA through the Wiltse's and Weaver's approach ranged from about -10° and 25° at L3 to 12° and 32° at S1, respectively. The absolute values of DA through the Weaver's approach were significantly lower than those through the Wiltse's approach at each level. The angulation parameters showed no significant difference with sex and no significant correlation with age or BMI. CONCLUSIONS: In the lower lumbar vertebrae (L3-L5) and S1, pedicle screw placement through the Weaver's approach may more easily yield the preferred TSA consistent with TPA than that through the Wiltse's approach. The reference values obtained in this paper may be applied regardless of sex, age or BMI and the descriptive statistical results may be used as references for applying the two paraspinal approaches.

Clinical and radiological outcomes of spinal cord injury without radiologic evidence of trauma with cervical disc herniation.

PURPOSE: To verify the relationship between neurologic deficit after spinal cord injury without radiologic evidence of trauma (SCIWORET) and coexisting cervical disc herniation (CDH). METHODS: A retrospective review was made to compare the neurologic and radiological outcomes in SCIWORET patients with and without CDH. The neurologic deficit was evaluated by the American Spinal Injury Association (ASIA) scale at admission and last follow-up. The radiological evaluation was performed with magnetic resonance imaging to determine the maximum canal compromise (MCC) and maximum spinal cord compression (MSCC). RESULTS: Prevalence of CDH was 37.1 % among all 70 SCIWORET cases. There was no significant difference between the CDH and non-CDH group in the ASIA grade at admission and last follow-up and the improvement. Patients with CDH had more substantial MSCC (P < 0.05) but not MCC than those without CDH. No significant correlation was noted between the extent of MSCC or MCC and the initial and final neurologic functions. 12 of 26 patients with CDH underwent anterior cervical discectomy fusion, while the remaining 14 received anterior cervical corpectomy fusion. No significant difference was noted in the neurologic outcomes between the two techniques. CONCLUSIONS: CDH in most patients with SCIWORET likely occurred before rather than after trauma. CDH caused more severe cord compression but did not aggravate the neurologic injury. The extent of MSCC had no association with the initial neurologic deficit or final recovery.

Fractional-order iterative learning control for fractional-order systems with initialization non-repeatability.

The effect of initialization non-repeatability on iterative learning control performance for fractional-order systems has not been sufficiently investigated. It is a hidden deficiency that leads directly to the breaking of perfect tracking conditions in both theoretical analysis and real-world applications. Therefore, under the framework of general fractional-order nonlinear systems, this paper proposes an open-close loop Dα-type iterative learning control scheme based on system preconditioning and strictly derives two convergence conditions. By applying the preconditioning optimization strategy based on the short-memory principle, the tracking error due to initialization nonrepetition can converge to any desired range. Compared with the existing results, the proposed iteration scheme fully considers the complexity of the initialization and initial conditions of fractional-order systems, and provides several practical preconditioning methods to improve the tracking efficiency. Two numerical examples are presented to validate the above conclusions.

Postoperative urinary leakage after bilateral totally extraperitoneal herniorrhaphy in a patient with a healed cystostomy and appendectomy: A case report.

We report a case of postoperative urinary leakage after bilateral laparoscopic totally extraperitoneal (TEP) herniorrhaphy. A man in his upper 80s with a healed cystostomy and appendectomy underwent bilateral TEP herniorrhaphy. Urinary leakage was noted by ultrasound examination 4 days after bilateral TEP. Cystography and computed tomography conclusively confirmed a 6-mm extraperitoneal fistula at the site of the previous cystostomy. The fistula involved the anterior bladder wall and was associated with an extended urinoma. The patient was treated by indwelling catheterization using a Foley catheter and repeated ultrasound-guided puncture and aspiration of the inguinal effusion at the bedside. The patient was completely healed 69 days after the operation with no mesh infection or bladder dysfunction. We believe that urinary leakage is possible after TEP herniorrhaphy in patients with a healed suprapubic cystostomy. Therefore, indwelling catheterization using a Foley catheter should be implemented before surgery, and the Foley catheter can be removed within 1 week after surgery if no postoperative urinary leakage is observed. A history of suprapubic cystotomy should not be regarded as a contraindication for TEP surgery. This is the first report of urinary leakage after bilateral TEP herniorrhaphy in a patient with a healed cystostomy and appendectomy.

Iodine-doped TiO2 nanotube coatings: a technique for enhancing the antimicrobial properties of titanium surfaces against Staphylococcus aureus.

BACKGROUND: Implant-related infections are a challenging complication of orthopedic surgery, primarily due to the formation of bacterial biofilms on the implant surface. An antibacterial coating for titanium implants was developed to provide novel insights into the prevention and treatment of implant-related infections. METHODS: Titanium plates were coated with TiO2 nanotubes by anodization, and iodine was doped onto the coating via electrophoretic deposition. The obtained plates were characterized using a range of analytical techniques. Subsequently, Staphylococcus aureus was inoculated onto the surfaces of untreated titanium plates (control group), TiO2-nanocoated titanium plates (TiO2 group), and iodine-doped TiO2-nanocoated titanium plates (I-TiO2 group) to compare their antibacterial properties. RESULTS: Twenty-four hour in vitro antimicrobial activity test of the I-TiO2 group against Staphylococcus aureus was superior to those of the other groups, and this difference was statistically significant (P < 0.05). CONCLUSIONS: This coating technology provides a new theoretical basis for the development of anti-infective implants against Staphylococcus aureus in orthopedics.

Bioinformatics analyses for the identification of tumor antigens and immune subtypes of gastric adenocarcinoma.

Background: Although mRNA vaccines have been effective against multiple cancers, their efficacy against stomach adenocarcinoma (STAD) remains undefined. Immunotyping can indicate the comprehensive immune status in tumors and their immune microenvironment, which is closely associated with therapeutic response and vaccination potential. The aim of this study was to identify potential antigens in STAD for mRNA vaccine development, and further distinguish immune subtypes of STAD to construct an immune landscape for selecting suitable patients for vaccination. Methods: The gene expression and clinicopathological features of patients with gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Program (GTEx). 729 samples from GSE66229 and GSE84437 were downloaded through GEO and were used as the validation cohorts. Differential gene expression, genetic alterations and prognosis were analyzed using the R package, cBioPortal program and Kaplan-Meier. The relationship between tumor antigens and immune cells was evaluated and plotted by TIMER. ConsensusClusterPlus was used for consistency matrix construction and data clustering, and graph learning-based dimensional reduction was used to depict immune landscape. WGCNA was used to estimate the relationship between the color modules and immune subtypes. Results: Two overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in STAD, including RAI14 and NREP. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to IS3, while IS3 tumors was immunologically cold. Immunogenic cell death modulators, immune checkpoints, and CA125, and CEA were also differentially expressed among the three immune subtypes. Finally, the immune landscape of STAD showed a high degree of heterogeneity between individual patients. Conclusion: RAI14 and NREP are potential antigens for developing anti-STAD mRNA vaccine, and patients with IS1 and IS3 tumors may be suitable for vaccination.

Effects of Ruanmailing in Blocking Early Stages of Atherosclerosis by TNF-α Regulation via Kir2.1.

Objective: Ruanmailing oral solution consists of 16 herbs, has anti-lipid peroxidation activity, protects vascular endothelial cells, and improves vascular elasticity. It is an effective drug for the treatment of atherosclerosis (AS). The objective of this study was to investigate the mechanism underlying the antiatherosclerotic effects of Ruanmailing oral solution. Methods: Macrophages were isolated, cultured, and divided into the macrophage control; macrophage foam cell; and low-, medium-, and high-concentration Ruanmailing groups. Cell proliferation was analyzed by cell counting kit-8 (CCK-8) assay, and the expression levels of inward-rectifier potassium ion channel 2.1 (Kir2.1) and tumor necrosis factor (TNF)-α were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. Results: CCK-8 assay results showed that the tested concentrations of Ruanmailing solution did not affect macrophage proliferation. RT-PCR and Western blot assays indicated that TNF-α expression increased significantly with the formation of macrophage foam cells (P < 0.05). In addition, significant decreases in Kir2.1 and TNF-α expression were observed following treatment with various concentrations of Ruanmailing (P < 0.05). Conclusion: Based on the results, Ruanmailing affects macrophage foam cell formation by regulating Kir2.1 expression, which in turn reduces TNF-α expression and exerts antiatherosclerotic effects. These findings provide a scientific basis for the use of traditional Chinese medicine for AS treatment.

Post atlantoaxial fusion for unilateral cleft of atlas posterior arch associated with os odontoideum: case report and technique note.

A case of a 34-year-old female with unilateral cleft of atlas posterior arch associated with os odontoideum is reported. The patient had experienced neck pain for 6 months. Five days earlier to admission the pain aggravated as a result of mild head trauma from behind. Imaging examinations revealed C1-2 subluxation as well as the deformity. After 3 days of skull traction, a sound C1-2 reduction was achieved. Post atlantoaxial fusion using bilateral transarticular screws combined with C1 laminar hook on the intact side and autogenous bone graft was performed. On the sixth month of postoperative follow-up, CT revealed solid fusion was achieved. No related complications were detected within 3 years of follow-up. The clinical manifestations and imaging findings were presented. The incidence and etiopathogenesis of hypoplastic posterior arch of the atlas were concisely introduced. Techniques of post atlantoaxial fusion under circumstances of unilateral C1 posterior elements defects were discussed. The authors believe bilateral transarticular screws combined with C1 laminar hook on the intact side and autogenous bone graft can be applicable to atlantoaxial fusion on the premise of preoperative C1-2 reduction and C1 posterior arch remaining >1/2 of its full length.

Outcomes of three anterior decompression and fusion techniques in the treatment of three-level cervical spondylosis.

The purpose of this article is to compare the outcomes of three different anterior approaches for three-level cervical spondylosis. The records of 120 patients who underwent anterior approaches because of three-level cervical spondylosis between 2006 and 2008 were reviewed. Based on the type of surgery, the patients were divided into three groups: Group 1 was three-level anterior cervical discectomy and fusion (ACDF); Group 2 anterior cervical hybrid decompression and fusion (ACHDF, combination of ACDF and ACCF); and Group 3 two-level anterior cervical corpectomy and fusion (ACCF). The clinical outcomes including blood loss, operation time, complications, Japanese Orthopedic Association (JOA) scores, C2-C7 angle, segmental angle, and fusion rate were compared. There were no significant differences in JOA improvement and fusion rate among three groups. However, in terms of segmental angle and C2-C7 angle improvement, Group 2 was superior to Group 3 and inferior to Group 1 (all P < 0.01). Group 2 was less in operation time than Group 3 (P < 0.01) and more than Group 1 (P < 0.01). Group 3 had more blood loss than Group 1 and Group 2 (all P < 0.01) and had higher complication rate than Group 1 (P < 0.05). No significant differences in blood loss and complication rate were observed between Group 1 and Group 2 (P > 0.05). ACDF was superior in most outcomes to ACCF and ACHDF. If the compressive pathology could be resolved by discectomy, ACDF should be the treatment of choice. ACHDF was an ideal alternative procedure to ACDF if retro-vertebral pathology existed. ACCF was the last choice considered.

Anterior hybrid decompression and segmental fixation for adjacent three-level cervical spondylosis.

OBJECTIVE: To evaluate the outcomes of anterior hybrid decompression and segmental fixation for adjacent three-level cervical spondylosis. METHODS: 53 patients with adjacent three-level cervical spondylosis underwent anterior hybrid decompression and segmental fixation. Titanium mesh and PEEK cage were used to span the defects due to decompression and anterior locking plate was placed over the entire construct. Japanese Orthopedic Association (JOA) scores, segmental and C2-C7 angles before and after operation were analyzed. RESULTS: The average follow up was 37.3 ± 7.0 months. Bone fusions were observed in all patients at follow-up intervals. JOA scores improved from preoperative 8.1 ± 2.2 (range 4-13) to 13.1 ± 2.3 (range 7-16) at final follow-up (P = 0.000). Meanwhile, surgical segmental angle was significantly improved from preoperative 6.9 ± 8.3° (range -10.4° to 27.6°) to postoperative 16.3 ± 7.2° (range -2.0° to 37.6°)(P = 0.000), and C2-C7 angle from 9.7 ± 8.6° (range -9.9° to 27.4°) to 17.8 ± 7.7° (range -1.2° to 34.3°) (P = 0.000). Postoperative complications included C5 palsy, cerebrospinal fluid leakage, hematoma, and titanium mesh subsidence. CONCLUSION: Anterior hybrid decompression and segmental fixation is a safe and effective procedure for adjacent three-level cervical spondylosis.

Small-Molecule Inhibitors of the Coronavirus Spike: ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2.

Inhibitors of the protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and human ACE2 (hACE2), which acts as a ligand-receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are of considerable interest as potential antiviral agents. While blockade of such PPIs with small molecules is more challenging than that with antibodies, small-molecule inhibitors (SMIs) might offer alternatives that are less strain- and mutation-sensitive, suitable for oral or inhaled administration, and more controllable/less immunogenic. Here, we report the identification of SMIs of this PPI by screening our compound library focused around the chemical space of organic dyes. Among promising candidates identified, several dyes (Congo red, direct violet 1, Evans blue) and novel druglike compounds (DRI-C23041, DRI-C91005) inhibited the interaction of hACE2 with the spike proteins of SARS-CoV-2 as well as SARS-CoV with low micromolar activity in our cell-free ELISA-type assays (IC50's of 0.2-3.0 µM), whereas control compounds, such as sunset yellow FCF, chloroquine, and suramin, showed no activity. Protein thermal shift assays indicated that the SMIs of interest identified here bind SARS-CoV-2-S and not hACE2. While dyes seemed to be promiscuous inhibitors, DRI-C23041 showed some selectivity and inhibited the entry of two different SARS-CoV-2-S expressing pseudoviruses into hACE2-expressing cells in a concentration-dependent manner with low micromolar IC50's (6-7 µM). This provides proof-of-principle evidence for the feasibility of small-molecule inhibition of PPIs critical for SARS-CoV-2 attachment/entry and serves as a first guide in the search for SMI-based alternative antiviral therapies for the prevention and treatment of diseases caused by coronaviruses in general and COVID-19 in particular.

Helical chiral 2-aminopyridinium ions: a new class of hydrogen bond donor catalysts.

Helical chiral 2-aminopyridinium ions were designed as a significantly more acidic (active) dual hydrogen-bonding catalyst than commonly used (thio)urea-based systems. The helicene framework was specifically utilized to position an inherently chiral barrier on the hydrogen-bonding side of the catalyst. The catalyst reactivity and enantioselectivity were successfully demonstrated in additions of 4,7-dihydroindoles to nitroalkenes (0.5-2 mol % catalyst loadings, up to 98:2 er).

The importance of preoperative T1 slope for determining proper postoperative C2-7 Cobb's angle in patients undergoing cervical reconstruction.

BACKGROUND: This study aimed to explore the relationship among different cervical sagittal parameters in asymptomatic volunteers and the correlation between surgical efficacy and difference of presumed and actual postoperative C2-7 Cobbs's angle (C2-7COBB), which was calculated based on preoperative T1 slope (T1S) in patients undergoing cervical reconstruction. METHODS: In total, 158 inpatients with cervical spondylosis and 274 asymptomatic volunteers were retrospectively reviewed. Cervical sagittal parameters, such as C2-7COBB, T1S, thoracic inlet angle (TIA), and neck tilt (NT), were compared. Then, the correlation among these parameters was analyzed in asymptomatic volunteers, and a regression equation between T1S and C2-7COBB was established and used to analyze the correlation among the Japanese Orthopaedic Association (JOA) score improvement, the sagittal parameters, and the difference between presumed and actual postoperative C2-7COBB in patients after cervical reconstruction. RESULTS: The mean T1S, C2-7COBB, and TIA were significantly decreased in patients (P < 0.01). T1S and NT had a strong correlation with TIA (P < 0.01). T1S demonstrated a moderate correlation with C2-7COBB in asymptomatic volunteers (r = 0.569, P < 0.01). A regression equation had been established as C2-7COBB = 0.742 × T1S - 0.866. The mean C2-7COBB and JOA score improved significantly (P < 0.05) postoperatively. Moreover, the JOA improvement rate showed a significant negative correlation with the difference in the presumed and actual postoperative C2-7COBB (r = - 0.696, P < 0.01). CONCLUSION: Our study successfully established a regression equation for calculating postsurgical C2-7COBB based on the correlation between T1S and C2-7COBB in asymptomatic volunteers. The regression equation could be used for guiding surgeons to accomplish an ideal postsurgical C2-7COBB for patients with cervical spondylosis.