Biomechanical study of spinal cord and nerve root in idiopathic scoliosis: based on finite element analysis.

BACKGROUND: Current research lacks comprehensive investigation into the biomechanical changes in the spinal cord and nerve roots during scoliosis correction. This study employs finite element analysis to extensively explore these biomechanical variations across different Cobb angles, providing valuable insights for clinical treatment. METHODS: A personalized finite element model, incorporating vertebrae, ligaments, spinal cord, and nerve roots, was constructed using engineering software. Forces and displacements were applied to achieve Cobb angle improvements, designating T1/2-T4/5 as the upper segment, T5/6-T8/9 as the middle segment, and T9/10-L1/2 as the lower segment. Simulations under traction, pushing, and traction + torsion conditions were conducted, and biomechanical changes in each spinal cord segment and nerve roots were analyzed. RESULTS: Throughout the scoliosis correction process, the middle spinal cord segment consistently exhibited a risk of injury under various conditions and displacements. The lower spinal cord segment showed no significant injury changes under traction + torsion conditions. In the early correction phase, the upper spinal cord segment demonstrated a risk of injury under all conditions, and the lower spinal cord segment presented a risk of injury under pushing conditions. Traction conditions posed a risk of nerve injury on both sides in the middle and lower segments. Under pushing conditions, there was a risk of nerve injury on both sides in all segments. Traction + torsion conditions implicated a risk of injury to the right nerves in the upper segment, both sides in the middle segment, and the left side in the lower segment. In the later correction stage, there was a risk of injury to the upper spinal cord segment under traction + torsion conditions, the left nerves in the middle segment under traction conditions, and the right nerves in the upper segment under pushing conditions. CONCLUSION: When the correction rate reaches 61-68%, particular attention should be given to the upper-mid spinal cord. Pushing conditions also warrant attention to the lower spinal cord and the nerve roots on both sides of the main thoracic curve. Traction conditions require attention to nerve roots bilaterally in the middle and lower segments, while traction combined with torsion conditions necessitate focus on the right-side nerve roots in the upper segment, both sides in the middle segment, and the left-side nerve roots in the lower segment.

Mantis: High-throughput 4D imaging and analysis of the molecular and physical architecture of cells.

High-throughput dynamic imaging of cells and organelles is essential for understanding complex cellular responses. We report Mantis, a high-throughput 4D microscope that integrates two complementary, gentle, live-cell imaging technologies: remote-refocus label-free microscopy and oblique light-sheet fluorescence microscopy. Additionally, we report shrimPy (Smart High-throughput Robust Imaging and Measurement in Python), an open-source software for high-throughput imaging, deconvolution, and single-cell phenotyping of 4D data. Using Mantis and shrimPy, we achieved high-content correlative imaging of molecular dynamics and the physical architecture of 20 cell lines every 15 min over 7.5 h. This platform also facilitated detailed measurements of the impacts of viral infection on the architecture of host cells and host proteins. The Mantis platform can enable high-throughput profiling of intracellular dynamics, long-term imaging and analysis of cellular responses to perturbations, and live-cell optical screens to dissect gene regulatory networks.

Emerging mechanisms and promising approaches in pancreatic cancer metabolism.

Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.

Exploring serum N-glycome patterns as candidate non-invasive biomarkers in inguinal hernia.

Introduction: Although inguinal hernia (IH) is prevalent in elderly males, research on its specific diagnostic biomarkers is limited. Protein N-glycosylation is one of the most important and ubiquitous post-translational modifications and often results in a remarkable heterogeneity of protein glycoforms. Protein N-glycosylation often changes in a disease and holds great potential for discovering non-invasive biomarkers. This study aimed to gain insights into total serum protein N-glycosylation of IH to identify candidate non-invasive biomarkers for diagnosis and subtype classification of IH. Methods: Linkage-specific sialylation derivatization combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry detection was used to analyze serum protein N-glycosylation patterns in IH patients and healthy controls. Results: IH patients had abnormal glycan fucosylation and sialylation compared to healthy controls (HC), of which two glycan traits representing linkage-specific sialylation within monoantennary glycans showed high potential as diagnostic biomarkers for IH with an area under the curve (AUC) of 0.75. Additionally, serum N-glycans were different between indirect IH and direct IH in glycosylation features, namely complexity, fucosylation, galactosylation, sialylation, and α2,6-linked sialylation. Four distinctive glycans between the two subtypes showed good performance with AUC >0.8, suggesting that these glycan traits have potential as biomarkers for subtype classification. Conclusions: We first reported the serum N-glycomic features of IH patients. Furthermore, we identified several potential biomarkers for the diagnosis and subtype classification of IH. These findings can deepen the understanding of IH.

Recurrent spinal subdural hematoma following percutaneous kyphoplasty: A unique case report.

Spinal intradural (subdural and subarachnoid) hematoma following percutaneous kyphoplasty is an extremely rare complication. In this report, we described a case of 2 episodes of subarachnoid hemorrhage with delayed paralysis after kyphoplasty. A 73-year-old man underwent percutaneous kyphoplasty in our hospital an osteoporotic vertebral fracture at the T12 level. On the 55 h after kyphoplasty for T12 osteoporotic vertebral fracture, he developed paralysis of the lower limbs. An emergency posterior decompression from T8 to L2 was performed. And the subarachnoid hematomas were removed. Postoperatively, the neurological symptoms improved rapidly. However, 2 weeks after the operation, the patient experienced a setback with severe neurological decline (paraplegia with sensory and autonomic dysfunction). An emergency posterior decompression from T5 to L2 was performed. The subarachnoid hematomas were removed. This case reflects the cause and progression of spinal subdural hematoma. Previous literature has debated the best treatment approach for spinal subarachnoid hemorrhage, but the prognosis of patients is heavily dependent on precise symptom evaluation and localization.

Exosomes From Muscle-Derived Stem Cells Repair Peripheral Nerve Injury by Inhibiting Ferroptosis via the Keap1-Nrf2-Ho-1 Axis.

Currently, the clinical outcomes of peripheral nerve injuries are suboptimal, highlighting the urgent need to understand the mechanisms of nerve injury to enhance treatment strategies. Muscle-derived stem cells (MDSCs) are a diverse group of multipotent cells that hold promise for peripheral nerve regeneration due to their strong antioxidant and regenerative properties. Our research has revealed that severe ferroptosis occurs in the sciatic nerve and ipsilateral dorsal root ganglion following sciatic nerve injury. Interestingly, we have observed that MDSC-derived exosomes effectively suppress cell ferroptosis and enhance cell viability in Schwann cells and dorsal root ganglion cells. Treatment with exosomes led to increased expression of BDNF and P62 in Schwann cells, decreased expression of Keap1, Nrf2, and HO-1 in Schwann cells, and upregulated dorsal root ganglion cells. Rats treated with exosomes exhibited improvements in sciatic nerve function, sensitivity to stimuli, and reduced muscle atrophy, indicating a positive impact on post-injury recovery. In conclusion, our findings demonstrate the occurrence of ferroptosis in the sciatic nerve and dorsal root ganglion post-injury, with MDSC exosomes offering a potential therapeutic strategy by inhibiting ferroptosis, activating the Keap1-Nrf2-HO-1 pathway, and optimizing the post-injury repair environment.

Biomechanical Comparison of Different Surgical Strategies for Skip-level Cervical Degenerative Disc Disease: A Finite Element Study.

STUDY DESIGN: We constructed finite element (FE) models of the cervical spine consisting of C2-C7 and predicted the biomechanical effects of different surgical procedures and instruments on adjacent segments, internal fixation systems, and the overall cervical spine through FE analysis. OBJECTIVE: To compare the biomechanical effects between the zero-profile device and cage-plate device in skip-level multistage anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF is often considered the standard treatment for degenerative cervical spondylosis. However, the selection of surgical methods and instruments in cases of skip-level cervical degenerative disk disease is still controversial. MATERIALS AND METHODS: Three FE models were constructed, which used noncontiguous 2-level Zero-P (NCZP) devices for C3/4 and C5/6, a noncontiguous 2-level cage-plate (NCCP) for C3/4 and C5/6, and a contiguous 3-level cage-plate (CCP) for C3/6. Simulate daily activities in ABAQUS. The range of motion (ROM), von Mises stress distribution of the endplate and internal fixation system, and intervertebral disk pressure (IDP) of each model were recorded and compared. RESULTS: Similar to the stress of the cortical bone, the maximum stress of the Zero-P device was higher than that of the CP device for most activities. The ROM increments of the superior, inferior, and intermediate segments of the NCZP model were lower than those of the NCCP and CCP models in many actions. In terms of the IDP, the increment value of stress for the NCZP model was the smallest, whereas those of the NCCP and CCP models were larger. Similarly, the increment value of stress on the endplate also shows the minimum in the NCZP model. CONCLUSIONS: Noncontiguous ACDF with zero profile can reduce the stress on adjacent intervertebral disks and endplates, resulting in a reduced risk of adjacent segment disease development. However, the high cortical bone stress caused by the Zero-P device may influence the risk of fractures.

Effects of 28 h ahemeral light cycle on production performance, egg quality, blood parameters, and uterine characteristics of hens during the late laying period.

This study aimed to systematically determined the effect of 28 h ahemeral light cycle on production performance, egg quality, blood parameters, uterine morphological characteristics, and gene expression of hens during the late laying period. At 74 wk, 260 Hy-Line Brown layers were randomly divided into 2 groups of 130 birds each and in duplicates. Both a regular (16L:8D) and an ahemeral light cycle (16L:12D) were provided to the hens. The oviposition pattern in an ahemeral cycle shifted into darkness, with oviposition mostly occurring 3 to 5 h after light out. Production performance was unaffected by light cycle (P > 0.05). Nonetheless, compared to the normal group, the ahemeral group exhibited increased egg weight, eggshell weight, eggshell percentage, yolk percentage, eggshell thickness, and eggshell strength (P < 0.05). There were rhythmic changes in the uterine morphological structure in both cycles, however, the ahemeral group maintained a longer duration and had more uterine folds than the normal group. In the ahemeral cycle, the phases of the CLOCK and PER2 genes were phase-advanced for 3.96 h and 4.54 h compared to the normal cycle. The PHLPP1 gene, which controls clock resetting, exhibited a substantial oscillated rhythm in the ahemeral group (P < 0.05), while the expression of genes presenting biological rhythm, such as CRY2 and FBXL3, was rhythmically oscillated in normal cycle (P < 0.05). The ITPR2 gene, which regulates intracellular Ca2+ transport, displayed a significant oscillated rhythm in ahemeral alone (P < 0.05), while the CA2 gene, which presents biomineralization, rhythmically oscillated in both cycles (P < 0.05). The ahemeral cycle caused 2.5 h phase delays in the CA2 gene compared to the normal cycle. In conclusion, the 28 h ahemeral light cycle preserved the high condition of the uterine folds and changed the uterine rhythms of CLOCK, PER2, ITPR2, and CA2 gene expression to improve ion transport and uterine biomineralization.

BRAFV600E mutation does not predict lymph node metastases and recurrence in Chinese papillary thyroid microcarcinoma patients.

OBJECT: Previous studies suggest BRAFV600E mutation is a marker for poor prognosis in papillary thyroid cancer, however, its ability to further risk stratify papillary thyroid microcarcinoma (PTMC) remains controversial. We aimed to explore the association between BRAFV600E mutation and the clinicopathological features and recurrence in Chinese PTMC patients. METHODS: We retrospectively reviewed 2094 PTMC patients who underwent surgery and had a valid BRAFV600E mutation test result. Among them, 1292 patients had complete follow-up data. The mutation incidence was determined. Moreover, the clinicopathological characteristics, disease-free survival (DFS), and response to therapy distribution were compared between the mutation and non-mutation groups. RESULTS: BRAFV600E mutation was observed in 90.6 % of all patients and 89.2 % of patients with complete follow-up data. No significant difference was observed in lymph node metastases (LNM) number categories between the mutation and non-mutation groups among all patients (P = 0.329) and 1292 patients (P = 0.408). Neither the 3-year DFS (97.9 % vs. 98.0 %, P = 0.832) nor the response to therapy distribution (P > 0.05) indicated a significant difference between the mutation and non-mutation groups. The 3-year DFS differs among patients having different LNM number categories (99.8 % vs. 98.5 % vs. 77.3 %, P < 0.001). Multivariate analysis revealed that high-volume (over 5) LNM (Total thyroidectomy (TT): OR = 4.000, 95 % CI 2.390-6.694, P < 0.001; Unilateral thyroidectomy (UT): OR = 4.183, 95 % CI 1.565-11.190, P = 0.004), rather than BRAFV600E mutation (P > 0.05), was an independent risk factor of response to therapy. CONCLUSIONS: Our results suggested that BRAFV600E mutation could not accurately predict LNM or the recurrence of Chinese PTMC patients. Moreover, high-volume LNM is significantly associated with PTMC prognosis.

Utilizing mobile digital radiography for detection of thoracolumbar vertebrae traits in live donkeys.

It has been well-established that the number of vertebrae is associated with body size and meat productivity. In current study we utilized a digital radiography (DR) technology to detect the number of thoracolumbar vertebrae in live donkeys. For this purpose, we introduced for the first time a groundbreaking device designed by our team for assessing thoracolumbar vertebrae number traits in equids, employing a sample of 1,000 donkeys sourced from five distinct donkey farms. This assessment incorporates a range of crucial body metrics, including body height, length, and various other measurements. Subsequently, our study determined the number of thoracolumbar vertebrae in 112 donkeys, utilizing the DR system. These findings were further validated through post-mortem evaluations conducted by slaughtering the donkeys. Our findings demonstrated a remarkable resemblance between the thoracolumbar vertebrae numbers visualized through the DR system in live donkeys and those obtained via slaughter verification. In conclusion, this research underscores the accuracy and effectiveness of the DR system for the detection of thoracolumbar vertebrae in live donkeys, which might be helpful for assessing the body size and meat productivity. We also recommended the utilization of DR system for counting thoracolumbar vertebrae in other animals in live state and could be a useful addition to livestock business industry for the prediction of body size and meat productivity efficiency.

Deep-Learning-Guided Evaluation Method for the High-Volume Preparation of Flexible Sensors Based on Inkjet Printing.

Flexible sensors for application in various industries, including biomedicine and wearable electronics, are frequently made using silver nanoparticle (AgNP) inks and inkjet printing (IJP) technology. Inkjet-printed flexible electronic devices are made up of many printed lines that run parallel to each other, and the surface morphology of the printed lines and the interline state directly impact the electrical conductivity of the electronic devices. This paper describes the experimental setup for IJP, the definition of print line characteristics, and common unavoidable defects. Conductivity and physical defects are considered in defining the print line quality assessment. In addition, two prediction models of flexible sensors before batch printing and a model for detecting defects after printing are provided. The predictive models can guide actions, leading to a print success rate of over 80%. We build the defect detection model using a neural architecture search because manually fine-tuning neural networks for reference is challenging. Finally, a target detection model with a mAP@0.5 of 81.2% is built in just 0.77 graphics processing unit (GPU) days. The model takes only 4.6 ms to detect an image, satisfying the real-time monitoring needs. At the same time, an accuracy of 95.5% can be achieved in the test data set. This work provides a new idea for the high-volume preparation of flexible sensors.

Robot-assisted versus laparoscopic pheochromocytoma resection and construction of a nomogram to predict perioperative hemodynamic instability.

BACKGROUND: Despite recent improvements in perioperative outcomes after pheochromocytoma resection, hemodynamic instability (HI) remained of high concern. The emergence of robot-assisted surgery may bring different results to pheochromocytoma surgery. The purposes of this study were to investigate whether robot-assisted retroperitoneal pheochromocytoma resection promotes hemodynamic instability compared with laparoscopic retroperitoneal pheochromocytoma resection and construct a nomogram to predict perioperative hemodynamic instability. METHODS: The clinical data of 221 patients who underwent pheochromocytoma resection were analyzed retrospectively. The patients were divided into two groups according to the mode of operation. Stepwise logistic regression was used to determine the independent risk factors of perioperative hemodynamic instability and to construct a visual prediction model. The final model was visualized via a nomogram. RESULTS: 124 (56.1 %) out of 221 patients experienced HI. The variables that were eventually included in the model were tumor size (OR1.363(1.143-1.646), P < 0.001), abnormal blood glucose (OR3.381(1.534-7.903), P = 0.003), preoperative SBP(OR1.04(1.014-1.067),P = 0.002), robot-assisted surgery(OR0.241(0.108-0.513),P < 0.001), and catecholamines(OR4.567(2.424-8.834),P < 0.001). The receiver operating characteristic curve showed the area under curve was 0.816(95 %CI 0.761-0.871). CONCLUSION: We developed a nomogram for successful prediction of perioperative hemodynamics based on five independent risk factors. Clinicians can leverage this easy-to-use nomogram to perform personalized risk predictions for HI and develop preventive interventions to improve patient safety and surgical outcomes.

Clinical Efficacy, Analgesic Efficacy, and Effects of Cocktail Analgesic Regimens in Patients Undergoing Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

Objective: Multimodal cocktail analgesic injection (CAI) is widely used as an adjunct pain-reliever in the postoperative phase of patients undergoing total knee arthroplasty (TKA) due to intense postoperative pain accompanying the procedure leading to complications, thereby extending hospital stays. The aim of this study is to establish the clinical efficacy and effects of utilizing CAI regimens during the TKA procedure and the corresponding postoperative patient outcomes. Methods: A database search for pertinent articles literature search was performed in Embase, PubMed, Cochrane Library, Web of Science, and MEDLINE databases. RevMan version 5.4 was used to perform a meta-analysis on the included studies. Results: Data screening and selection produced 15 relevant articles that met the eligibility criteria of this study. The meta-analysis revealed insignificant difference between cocktail injected and control groups in VAS postoperative pain scores both at rest and during activity (OR 0.79, 95% CI 0.59 to 1.05; I2 = 0%; P = .93) and (OR 0.79, 95% CI 0.57 to 1.10; I2 = 0%; P = .75), respectively. Similarly, there was insignificant differences in postoperative knee flexion ROM, postoperative narcotic consumption, and length of stays between the two groups, (OR 1.20, 95% CI 1.03 to 1.40; P = .53), (OR 0.62, 95% CI 0.36 to 1.07; P = .09), and (OR 0.45, 95% CI 0.29 to 0.70; P = .21), respectively. However, the postoperative complications reveal statistical significance between the cocktail injected and the control group (OR 0.45, 95% CI 0.29 to 0.70; P = .004). Conclusion: It is concluded that CAI can play a crucial role in minimizing post-operative complications for patients undergoing TKA.

Mantis: high-throughput 4D imaging and analysis of the molecular and physical architecture of cells.

High-throughput dynamic imaging of cells and organelles is essential for understanding complex cellular responses. We report Mantis, a high-throughput 4D microscope that integrates two complementary, gentle, live-cell imaging technologies: remote-refocus label-free microscopy and oblique light-sheet fluorescence microscopy. Additionally, we report shrimPy, an open-source software for high-throughput imaging, deconvolution, and single-cell phenotyping of 4D data. Using Mantis and shrimPy, we achieved high-content correlative imaging of molecular dynamics and the physical architecture of 20 cell lines every 15 minutes over 7.5 hours. This platform also facilitated detailed measurements of the impacts of viral infection on the architecture of host cells and host proteins. The Mantis platform can enable high-throughput profiling of intracellular dynamics, long-term imaging and analysis of cellular responses to perturbations, and live-cell optical screens to dissect gene regulatory networks.

Multidimensional comprehensive and integrated analysis of the potential function of TMEM25 in renal clear cell carcinoma with low expression status.

BACKGROUND: Transmembrane 25(TMEM25) stands out as a potential prognostic biomarker and therapeutic target in the realm of cancer, yet its precise mechanism of action within clear cell renal cell carcinoma (ccRCC) remains unclear. MATERIALS AND METHODS: Gene expression data and clinically relevant information extracted from The Cancer Genome Atlas (TCGA) and Gene expression omnibus (GEO) databases unveil the expression patterns of TMEM25 within renal clear cell carcinoma, which reveals its prognostic and diagnostic significance. The protein expression data is available via the Human Protein Atlas (HPA) database. Further, qPCR experiments conducted on cells and tissues provide strong evidence of the gene's expression status. Additionally, they explore the correlations between TMEM25 expression and DNA methylation, gene mutations, immune cell infiltration, and drug sensitivity within this specific tumor context. RESULTS: At both the RNA and protein levels, TMEM25 displays a noteworthy downregulation in expression, which is consistently linked to an unfavorable prognosis. Receiver Operating Characteristic (ROC) curve analysis, univariate and multivariate Cox regression analyses confirmed the ability of TMEM25 to diagnose and determine prognosis in ccRCC. Its expression related closely with various immune cell types, immune checkpoints, immune inhibitors, and MHC molecules. Within ccRCC tissues, TMEM25 DNA methylation levels are observed to be elevated, and this upregulation is observed across various conditions. TMEM25 mutations also have an impact on the prognosis of ccRCC patients and the results of drug sensitivity analyses are useful for clinical decision-making. CONCLUSIONS: TMEM25 in ccRCC could potentially function as a tumor suppressor gene, holding substantial promise as a novel biomarker for diagnosing, treating, and prognosticating ccRCC patients.

Covalent organic frameworks with flexible side chains in hybrid PEMs enable highly efficient proton conductivity.

Electrochemical hydrogen compression (EHC) is an emerging energy conversion technology. Proton exchange membranes (PEMs) with high proton conductivity and high mechanical strength are highly required to meet the practical requirements of EHC. Herein, ionic covalent organic frameworks (iCOFs) with tunable side chains were synthesized and introduced into the sulfonated poly (ether ether ketone) (SPEEK) matrix to fabricate hybrid PEMs. In our membranes, the rigid iCOFs afford ordered proton conduction channels, whereas the flexible side chains on iCOFs afford abundant proton conduction sites, adaptive hydrogen bonding networks, and high local density short hydrogen bonds for highly efficient proton transport. Moreover, the hydrogen bond interactions between the side chains on iCOFs and the SPEEK matrix enhance the mechanical stability of membranes. As a result, the hybrid PEM acquires an enhanced proton conductivity of 540.4 mS cm-1 (80 °C, 100%RH), a high mechanical strength of 120.41 MPa, and a superior performance (2.3 MPa at 30 °C, 100%RH) in EHC applications.

TBC1 domain family member 25 protects against myocardial apoptosis and the proinflammatory response triggered by ischemia-reperfusion injury through suppression of the TAK1-JNK/p38 MAPK signaling cascade.

TBC1 domain family member 25 (TBC1D25) is a crucial mediator of signal transduction involved in the development of several diseases. Particularly, a cardioprotective role of TBC1D25 has been raised due to its antagonistic action on cardiac hypertrophy. However, whether TBC1D25 protects the myocardium from ischemia-reperfusion injury has not been reported. This work aimed to determine the role of TBC1D25 in myocardial ischemia-reperfusion (MIR) injury and to explore the potential mechanisms involved. Marked decreases in TBC1D25 levels occurred in cardiomyocytes suffering hypoxia/reoxygenation (H/R) injury in vitro and myocardium tissues of rats with MIR injury in vivo. Cardiomyocytes overexpressing TBC1D25 were protected from apoptosis and inflammation triggered by H/R, whereas TBC1D25-deficient cardiomyocytes were more sensitive to H/R injury. Intramyocardial injection of recombinant adenovirus expressing TBC1D25 into rats reduced infarct size and cardiac injury triggered by MIR injury accompanied by decreased myocardial apoptosis and inflammation. A subsequent mechanistic investigation revealed that the signaling cascade of transforming growth factor-ß-activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) activated under H/R or MIR conditions was markedly restrained by TBC1D25 overexpression. Moreover, TAK1 blockade remarkably reversed the TBC1D25 deficiency-induced aggravating effect on H/R injury. The work concludes that TBC1D25 protects against MIR injury through action on the TAK1-JNK/p38 MAPK signaling cascade. This work suggests TBC1D25 as a potential therapeutic target for MIR injury.

An investigation of genetic diversity in three Dezhou donkey original breeding farms.

Dezhou donkey is one of the excellent large donkey breeds in China. In our study, eight microsatellite markers were used to genotype from each of three populations of Chinese Dezhou donkeys: 67 individuals in Liaocheng (pop1), 103 individuals in Binzhou 1 (pop2), and 102 individuals in Binzhou 2 (pop3), in order to study the genetic diversity of these populations. A total of 213 alleles were detected, and the PIC results showed that eight loci were all highly polymorphic. The means of Ho and He of pop2 were the highest, which were 0.646 and 0.717, respectively. The PCoA analysis demonstrated that the samples from three conservation farms were mixed together. The phylogenetic tree showed that pop 2 and pop 3 were closely related. The phylogenetic tree results clustered that 272 donkeys were divided into six groups. AMOVA analysis showed that the genetic variation was mainly concentrated within the population and the genetic differentiation among the populations was low. Fst values between populations also indicated that genetic differentiation between populations was too small to be considered. This indicated a low probability of inbreeding within the population. And this also showed that the conservation and breeding of Dezhou donkeys in recent years have achieved excellent results. The investigation of genetic diversity in three Dezhou donkey original breeding farms can provide reference data for the selection and breeding of excellent breeds of Dezhou donkey.

Proteasome-dependent senescent tumor cells mediate immunosuppression through CCL20 secretion and M2 polarization in pancreatic ductal adenocarcinoma.

The outcome of pancreatic ductal adenocarcinoma (PDAC) remains poor due to few therapeutic options available and challenges with precision therapy to target each tumour's specific characteristics. In this study, a biologically meaningful patient stratification-prognostic model with therapeutic suggestion value based on tumor senescence was developed and validated in multiple independent cohorts. Further mechanistic investigation based on single-cell transcriptomic data and in vitro experiments revealed that complement derived from non-senescent tumor cells stimulates M1 differentiation and antigen presentation, while senescent tumor cells secrete CCL20 to favor immunosuppressive M2 polarization. Also, senescent phenotype depends on proteasome function, suggesting that high-risk, high-senescence patients may benefit from proteasome inhibitors, which reverse senescence-mediated resistance to conventional chemotherapy and improve outcome. In conclusion, the current study identified senescence as a tumor-specific, hazardous factor associated with immunosuppression in PDAC. Mechanistically, senescence abrogates complement-induced M1 activation and antigen presentation, and upregulates CCL20 to favor M2 polarization. The senescence-related risk model is prognostic and therapeutic-suggestive. In light of the reliance of senescent cells on proteasomal functions, proteasome inhibitors are promising agents for high-risk patients with senescent PDAC.