Utilizing a structure-based virtual screening approach to discover potential LSD1 inhibitors.

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.

Cadmium-induced annulus fibrosus cell senescence contributes to intervertebral disc degeneration via the JNK/p53 signaling pathway.

Objectives: Investigating the impact of cadmium (Cd) on annulus fibrosus (AF) cells and its potential mechanism was the purpose of the current study. Materials and Methods: Cd was cultivated in different concentrations (0, 1, 5, 10, and 20 µM) on AF cells and the potential effects of the metal were assessed. Using the CCK-8 method, cell viability and proliferation were identified. Using transcriptome analysis, the annulus fibrosus cells were sequenced both with and without cadmium chloride. The EdU method was used to determine the rate of cell proliferation; senescence-associated ß-galactosidase (SA-ß-Gal) staining was used to determine the number of positive cells; and western blot, RT-PCR, and immunofluorescence were used to determine the protein and mRNA expression of senescence-associated proteins (p16, p21, and p53) and c-Jun N-terminal kinase (JNK). Results: According to the findings, Cd has the ability to increase the production of senescence-associated genes (p16 and p21) and senescence-associated secreted phenotype (SASP), which includes IL-1ß and IL-6. Through the JNK/p53 signal pathway, Cd exposure simultaneously accelerated AF cell senescence and promoted SASP. Following JNK inhibitor (SP600125) treatment, the expression of p53, JNK, and senescence-associated indices were all down-regulated. Conclusion: By activating the JNK/p53 signaling pathway, Cd can induce oxidative stress damage and AF cell senescence. These findings could provide a new approach for treating and preventing intervertebral disc degeneration (IVDD) caused by Cd exposure.

Suture Bridge Technique with 5-Ethibond: A Promising Approach for Infrapatellar Pole Fracture Treatment.

Purpose: Infrapatellar pole fractures are challenging injuries that require appropriate treatment to ensure optimal functional outcomes. This study aimed to introduce the application of the Suture Bridge technique using the 5-Ethibond for the treatment of infrapatellar patella fracture. Methods: Five cases of infrapatellar pole fracture that were treated at our institution between February 2020 and September 2021. The patients included one male and four females, with an average age of 66 years (range: 60-77 years). All patients were treated with the Suture Bridge technique using the 5-Ethibond to preserve the infrapatellar pole. Results: The average operative time was 64 min (range: 50-80 min). The average blood loss during surgery was 51 mL (range: 40-60 mL). All cases demonstrated fracture healing at an average of 10 weeks (range 8-12) after surgery. The patients were followed up for an average period of 14.8 months (8-22). No wound infection or second displacement of fracture fragment was found. Full range of motion was restored in all patients within 12-14 weeks after surgery. None of the patients complained of anterior knee pain. Conclusions: Based on the findings of the study, it appears that the Suture Bridge technique using 5-Ethibond is a promising and viable option for the treatment of infrapatellar pole fractures.

[Morphological and biochemical characterization during seed development of Notopterygium incisum].

This study aimed to examine the morphological, physiological, and biochemical alterations occurring in Notopterygium incisum seeds throughout their developmental stages, with the objective of establishing a theoretical foundation for the cultivation of superior quality seeds. The experimental materials utilized in this study were the seeds of N. incisum at various stages of development following anthesis. Through the employment of morphological observation and plant physiology techniques, the external morphology, nutrients, enzyme activity, and endogenous hormones of the seeds were assessed. The results revealed a transition in seed coat color from light green to brown during the growth and development of N. incisum seeds. Additionally, as the seeds matured, a decrease in water content was observed. Conversely, starch content exhibited a progressive increase, while sucrose content displayed fluctuations. At 7 days after anthesis, the soluble sugar content attained its highest level of 4.52 mg·g~(-1), whereas the soluble protein content reached its maximum of 6.00 mg·g~(-1) at 14 days after anthesis and its minimum of 4.94 mg·g~(-1) at 42 days after anthesis. The activity of superoxide dismutase(SOD) exhibited an initial increase, followed by a decrease, and eventually reached a stable state. Conversely, the activities of catalase(CAT) and peroxidase(POD) demonstrated a decrease initially, followed by an increase, and then another decrease. The levels of the four endogenous hormones, namely gibberellin(GA_3), zeatin riboside(ZR), auxin(IAA), and abscisic acid(ABA), in the seeds displayed significant variations, with IAA and ABA exhibiting considerably higher levels compared to the other hormones. The levels of plant growth-promoting hormones, represented by IAA, generally displayed a pattern of initial increase followed by a subsequent decrease during seed development, while the plant growth-inhibiting hormone ABA showed the opposite trend. The findings indicate that the alterations in nutrient composition, antioxidant enzyme activity, and endogenous hormone levels vary throughout the maturation process of N. incisum seeds. These observations hold relevance for the cultivation of N. incisum seeds.

Fenton-like Reaction Inspired "·OH Catalyzed" Osteogenic Process for the Treatment of Osteoporosis.

Inspired by the Fenton-like reaction, this work combines copper peroxide (CP) nanoparticles with black phosphorus (BP) nanosheets to form a hydroxyl radical (·OH)-centered "catalytic" osteogenic system. CP-produced ·OH interacts with BP to rapidly produce a large amount of phosphate ions, thus accelerating self-mineralization and promoting bone formation. In turn, BP not only exerts anti-inflammatory effects, thereby providing a favorable microenvironment for bone formation, but also offsets the potential toxicity of CP induced by reactive oxygen species (ROS). Together with copper ions (Cu2+ ), phosphate ions are also released as a byproduct of this process, which can contribute to the comprehensive promotion of osteogenesis.

Human umbilical cord mesenchymal stem cells overexpressing RUNX1 promote tendon-bone healing by inhibiting osteolysis, enhancing osteogenesis and promoting angiogenesis.

BACKGROUND: Rotator cuff injury (RCI) is a common shoulder injury, which is difficult to be completely repaired by surgery. Hence, new strategies are needed to promote the healing of tendon-bone. OBJECTIVE: We aimed to investigate the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) overexpressing RUNX1 on the tendon-bone healing after RCI, and to further explore its mechanism. METHODS: Lentiviral vector was used to mediate the overexpression of RUNX1. RUNX1-overexpressed UCB-MSCs (referred to as MSC-RUNX1) were co-cultured with osteoclasts, and TRAP staining was performed to observe the formation of osteoclasts. Then MSC-RUNX1 was cultured in osteogenic differentiation medium, Alizarin red staining was conducted to detect osteogenic differentiation. The expression of markers of osteogenesis and osteoclast was detected by RT-qPCR. EA. hy926 cells were co-cultured with MSC-RUNX1. Transwell assay was used to detect the migration, and the expression of angiogenesis related-genes VEGF and TGF-ß was detected by RT-qPCR. The rat rotator cuff reconstruction model was established and MSCs were injected at the tendon-bone junction. Biomechanical test and micro-CT scanning were performed, and HE, Masson and Alcian Blue staining were used for histological evaluation of tendon-bone healing. TUNEL and PCNA immunofluorescence (IF) staining were performed to evaluate apoptosis and proliferation at the tendon-bone healing site. The levels of TNF-α, IL-6 and IL-8 in serum were detected by ELISA. The expression of CD31 and Endomucin that related to angiogenesis was detected by IF. Safranin O-fast and TRAP/CD40L immunohistochemical staining were used to assess the levels of osteoclasts and osteoblasts at the tendon-bone healing site. RESULTS: hUC-MSCs overexpressing RUNX1 inhibited osteoclast formation and promoted osteogenic differentiation. MSC-RUNX1 could promote the migration and tube formation of EA. hy926 cells, and up-regulate the levels of VEGF and TGF-ß. Model mice treated with MSC-RUNX1 partially restored the biomechanical indexes. Treatment of MSC-RUNX1 obviously increased the bone density, accompanied by the formation of new bone. In vivo experiments showed that MSC-RUNX1 treatment could promote tendon-bone healing and inhibit inflammatory response in rats. MSC-RUNX1 treatment also promoted angiogenesis at the tendon-bone healing site, while inhibiting osteoclast formation and promoting osteogenic differentiation. CONCLUSION: hUC-MSCs overexpressing RUNX1 can inhibit the formation of osteoclasts and differentiation of osteoblasts, promote angiogenesis and inhibit inflammation, thereby promoting tendon-bone healing after RCI.

Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

A Multi-Scale Fusion and Transformer Based Registration Guided Speckle Noise Reduction for OCT Images.

Optical coherence tomography (OCT) images are inevitably affected by speckle noise because OCT is based on low-coherence interference. Multi-frame averaging is one of the effective methods to reduce speckle noise. Before averaging, the misalignment between images must be calibrated. In this paper, in order to reduce misalignment between images caused during the acquisition, a novel multi-scale fusion and Transformer based (MsFTMorph) method is proposed for deformable retinal OCT image registration. The proposed method captures global connectivity and locality with convolutional vision transformer and also incorporates a multi-resolution fusion strategy for learning the global affine transformation. Comparative experiments with other state-of-the-art registration methods demonstrate that the proposed method achieves higher registration accuracy. Guided by the registration, subsequent multi-frame averaging shows better results in speckle noise reduction. The noise is suppressed while the edges can be preserved. In addition, our proposed method has strong cross-domain generalization, which can be directly applied to images acquired by different scanners with different modes.

Inflammatory and nutritional markers predict the risk of post-operative delirium in elderly patients following total hip arthroplasty.

Objectives: This study intended to explore whether albumin-associated inflammatory and nutritional markers could predict post-operative delirium (POD) in older patients after total hip arthroplasty (THA). In addition, we established a nomogram model for POD prediction. Methods: Totally, 254 elderly cases who received THA were included. Clinical and laboratory data of these patients were retrospectively collected. Albumin-associated inflammatory and nutritional markers included neutrophil-to-albumin ratio (NAR), CRP-to-albumin ratio (CAR), prognostic nutritional index (PNI), and systemic inflammation score (SIS). The LASSO, univariate and multivariate logistic regression analyses were utilized to screen risk factors. A nomogram model was developed according to the results of multivariate regression analyses. Results: Among 254 patients, 49 cases had POD with an incidence of 19.3%. LASSO regression and multivariate logistic analyses suggested that preoperative NAR, preoperative PNI, preoperative SIS, and age >75 years were risk factors for POD. A nomogram model was developed according to the results of multivariate logistic analyses. The calibration curve suggested that the predicted probability of this nomogram model was in good line with the actual probability. The DCA showed that this nomogram model had net benefits for the prediction of POD for elderly patients following THA. Conclusion: Albumin-associated inflammatory and nutritional markers including NAR, PNI, and SIS could predict POD in elderly patients following THA.

Bibliometric and visualized analysis of arthroscopic treatment of acromioclavicular joint injury.

BACKGROUND: Since arthroscopy was discovered to treat acromioclavicular joint injury, people have had great interest and attention to this beautiful and minimally invasive operation, and related research has been increasing worldwide. At present, there is no bibliometric and visualized analysis in this field. The purpose of this study is to explore the research hotspots and trends of arthroscopic treatment of acromioclavicular joint injury through bibliometric and visualized analysis and look forward to the future development direction of clinical practice. METHODS: The publications on arthroscopic treatment of acromioclavicular joint injury diseases from its establishment to April 2023 were obtained from the Web of Science (WOS) Core Collection database. CiteSpace, VOSviewer, Scimago graphica and Origin were used for bibliometric and visualized analysis. RESULTS: This study included a total of 330 publications. The number of publications tends to increase every year. The USA has the most significant number of publications and citations. Imhoff AB is the most relevant scholar with the largest number of publications in this field, and the scholar with the highest citation and average citations is Mazzocca AD. Tech Univ Munich, Rush University and Charite are the three institutions with the greatest contribution. Tech Univ Munich, Rush University and Charite are the three institutions with the greatest contribution. In addition, "Arthroscopy-the Journal of Arthroscopic and Related Surgery" and "American Journal of Sports Medicine" are the institutions with the most significant number of publications and average citations, respectively. The most common keywords are "acromioclavicular joint dislocation," "arthroscopic resection," "arthroscopic reconstruction" and "coracoclavicular ligament." CONCLUSION: The number of publications shows a steady upward trend as a whole. However, there is still a lack of cooperation among countries, institutions and scholars around the world, so various countries, institutions and scholars need to strengthen academic exchanges and expand the field of cooperation, so as to promote further research and development in related fields. However, minimally invasive methods such as arthroscopy are still the hotspots and frontiers in the treatment of acromioclavicular joint injury in the future.

Analysis of risk factors for procedure-related hemorrhage in rotator cuff repair surgery under shoulder arthroscopy.

The present study aims to validate the methods of quantifying blood loss in arthroscopic rotator cuff repair and to investigate the correlation between blood loss and joint pain and joint function recovery. A total of 38 patients with unilateral rotator cuff injuries who underwent shoulder arthroscopy were analyzed in this study. Related information, including age, gender, blood pressure, body mass index (BMI), disease entity, comorbidity, joint release, and operating time, were collected into a spreadsheet. Serum hemoglobin and hematocrit (HCT) levels were obtained before the surgery and on the first and third days after the operation. The visual analog scale (VAS) score and the constant-Murley score of the shoulder joint were evaluated 1 year after the operation. Preoperative blood volume (PBV), red blood cell (RBC), hemoglobin (Hb), and HCT levels were significantly higher than those on postoperative day 1 and day 3. The average surgery-related blood loss was calculated to be 435.2 ±â€…53.6 mL during the surgery and the first postoperative day and 542.5 ±â€…63.0 mL during the surgery and the first 3 days after the surgery. The VAS score was significantly reduced 1 year after surgery. The multivariate linear regression analysis showed that joint release was a potential risk factor for predicting blood loss 1 or 3 days postoperatively. The actual blood loss from shoulder arthroscopy may be underestimated. The joint release was regarded as the leading risk factor for blood loss.

Robotic-assisted systems for the safe and reliable treatment of femoral neck fractures: retrospective cohort study.

BACKGROUND: Robots are being used in a wide range of surgical procedures. However, in clinical practice, the efficacy of orthopedic robotic-assisted treatment of femoral neck fractures is still poorly reported, particularly in terms of screw placement accuracy, femoral neck fracture healing rates and postoperative functional recovery. Moreover, there is a lack of comparative analysis between robot-assisted surgery and traditional surgical approaches. PURPOSE: The purpose of this study was to compare the clinical outcomes of patients with femoral neck fractures treated with TiRobot-assisted hollow screw fixation with those of patients with femoral neck fractures treated with traditional surgical approaches. METHODS: This study included 112 patients with femoral neck fracture who were treated from March 2017 to October 2021 with percutaneous hollow screw internal fixation. These included 56 cases in the TiRobot-assisted surgery group and 56 cases in the standard surgery group. After at least 1 year of follow-up, the treatment outcomes of the two groups were compared, including the amount of intraoperative bleeding, the duration of intraoperative fluoroscopy, the number of guide pin positioning adjustments, the length of hospital stay, the accuracy rate of screw placement, the final Harris Hip Score, the fracture healing rate, and the rate of femoral head necrosis. Statistical analysis software was used to process and analyze the result. RESULTS: The TiRobot-assisted group had a statistically significant improvement over the control group in terms of intraoperative bleeding, the duration of intraoperative fluoroscopy, the number of guide pin positioning adjustments, length of hospital stay, accuracy of screw placement and incidence of femoral head necrosis (P < 0.05). There was no statistically significant difference in time to surgery, final Harris hip score and fracture healing rate (P > 0.05). CONCLUSION: This study shows that TiRobot-assisted surgery has the advantages of short hospital stay, high safety, minimally invasive, high success rate of nail placement, and can reduce the amount of intraoperative radiation and the incidence of femoral head necrosis, thus achieving satisfactory clinical outcomes, and is worthy of clinical promotion.

The latest edition of WHO and ELN guidance and a new risk model for Chinese acute myeloid leukemia patients.

Objective: Diagnosis classification and risk stratification are crucial in the prognosis prediction and treatment selection of acute myeloid leukemia (AML). Here, we used a database of 536 AML patients to compare the 4th and 5th WHO classifications and the 2017 and 2022 versions of ELN guidance. Methods: AML patients were classified according to the 4th and 5th WHO classifications, as well as the 2017 and 2022 versions of the European LeukemiaNet (ELN) guidance. Kaplan-Meier curves with log-rank tests were used for survival analysis. Results: The biggest change was that 25 (5.2%), 8 (1.6%), and 1 (0.2%) patients in the AML, not otherwise specified (NOS) group according to the 4th WHO classification, were re-classified into the AML-MR (myelodysplasia-related), KMT2A rearrangement, and NUP98 rearrangement subgroups based on the 5th WHO classification. Referring to the ELN guidance, 16 patients in the favorable group, six patients in the adverse group, and 13 patients in the intermediate group based on the 2017 ELN guidance were re-classified to the intermediate and adverse groups based on the 2022 ELN guidance. Regrettably, the Kaplan-Meier curves showed that the survival of intermediate and adverse groups could not be distinguished well according to either the 2017 or 2022 ELN guidance. To this end, we constructed a risk model for Chinese AML patients, in which the clinical information (age and gender), gene mutations (NPM1, RUNX1, SH2B3, and TP53), and fusions (CBFB::MYH11 and RUNX1::RUNX1T1) were included, and our model could help divide the patients into favorable, intermediate, and adverse groups. Conclusion: These results affirmed the clinical value of both WHO and ELN, but a more suitable prognosis model should be established in Chinese cohorts, such as the models we proposed.

Analyzing the topology of N-linked glycans by PNGase F accessibility assay.

While N-glycans are synthesized in the lumens, some of them reach the cytosolic side of membranes through retro-translocation independent of endoplasmic-reticulum-associated degradation. Here, we present a protocol to measure the topology of N-glycans in a transmembrane protein, based on the principle that cytosolic but not luminal N-glycans are trimmed by PNGase F in the absence of detergent. We describe the procedures for this protocol consisting of microsome preparation from cells, PNGase F accessibility assay, and western blot analysis. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

Chemical screens in aging-relevant human motor neurons identify MAP4Ks as therapeutic targets for amyotrophic lateral sclerosis.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

Distributed control for a class of nonlinear systems based on distributed high-gain observer.

This paper concerns the problem of designing distributed control law for a class nonlinear system in which the measurement outputs of the system are distributed in different subsystems. It leads to a challenge that the states of the original systems cannot be completely reconstructed by any single subsystem. In order to solve this problem, distributed state observers and the distributed observer-based distributed control problem emerges as the times require. However, the distributed observers problem of the nonlinear systems is rarely studied, and the distributed control law formed by distributed nonlinear observers has hardly ever been studied up to now. To this end, this paper develops the distributed high-gain observers for a class of nonlinear systems. Unlike the previous several results, our study has the ability to deal with model uncertainty, and devotes itself to overcoming the problem that the separation principle is not tenable. In addition, based on the state estimate generated by the designed distributed observer, an output feedback control law formed by applying the state estimate is developed. Furthermore, a class of sufficient conditions is proved for guaranteeing the error dynamics of the distributed observer and the state trajectory of the closed-loop system to enter an arbitrary small invariant set around the origin. Finally, the simulation results verify the effectiveness of the proposed method.

IFN-α-2b Reduces Postoperative Arthrofibrosis in Rats by Inhibiting Fibroblast Proliferation and Migration through STAT1/p21 Signaling Pathway.

Objective: To investigate the effect of IFN-α-2b in preventing postoperative arthrofibrosis in rats, its antiproliferation effect on fibroblasts in vitro, and its molecular mechanism. Methods: The rat model of arthrofibrosis was established and treated with different concentrations of drugs. Knee specimens were collected for histological and immunohistochemical staining to observe the effect of IFN-α-2b on arthrofibrosis in rats. The biological information was further mined according to the database data, and the possible regulatory mechanism of IFN-α-2b on fibroblasts was analyzed. The inhibitory effect of IFN-α-2b on fibroblast proliferation and migration in vitro was detected by cell counting kit-8 (CCK-8), immunofluorescence analysis, cell cycle test, EdU assay, wound healing test, and Transwell method, and the analysis results were verified by Western blotting method. Results: The test results of rat knee joint specimens showed that IFN-α-2b significantly inhibited the degree of fibrosis after knee joint surgery, the number of fibroblasts in the operation area was less than that of the control group, and the expression of collagen and proliferation-related proteins decreased. In vitro experimental results show that IFN-α-2b can inhibit the proliferation and migration of fibroblasts. According to the results of database analysis, it is suggested that the STAT1/P21 pathway may be involved, and it has been verified and confirmed by Western blotting and other related methods. Conclusion: IFN-α-2b can reduce surgery-induced arthrofibrosis by inhibiting fibroblast proliferation and migration, which may be related to the regulation of STAT1/p21 signaling pathway.