Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer.

Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore's independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.

The deterioration of calcified cartilage integrity reflects the severity of osteoarthritis-A structural, molecular, and biochemical analysis.

The calcified cartilage zone (CCZ) is a thin interlayer between the hyaline articular cartilage and the subchondral bone and plays an important role in maintaining the joint homeostasis by providing biological and mechanical support from unmineralized cartilage to the underlying mineralized subchondral bone. The hallmark of CCZ characteristics in osteoarthritis (OA) is less well known. The aim of our study is to evaluate the structural, molecular, and biochemical composition of CCZ in tissues affected by primary knee OA and its relationship with disease severity. We collected osteochondral tissue samples stratified according to disease severity, from 16 knee OA patients who underwent knee replacement surgery. We also used meniscectomy-induced rat samples to confirm the pathophysiologic changes of human samples. We defined the characteristics of the calcified cartilage layer using a combination of morphological, biochemical, proteomic analyses on laser micro-dissected tissue. Our results demonstrated that the Calcium/Phosphate ratio is unchanged during the OA progression, but the calcium-binding protein and cadherin binding protein, as well as carbohydrate metabolism-related proteins, undergo significant changes. These changes were further accompanied by thinning of the CCZ, loss of collagen and proteoglycan content, the occurrence of the endochondral ossification, neovasculature, loss of the elastic module, loss of the collagen direction, and increase of the tortuosity indicating an altered structural and mechanical properties of the CCZ in OA. In conclusion, our results suggest that the calcified cartilage changes can reflect the disease progression.

Rhodamine-Anchored Polyacrylamide Hydrogel for Fluorescent Naked-Eye Sensing of Fe3.

A fluorescent and colorimetric poly (acrylamide)-based copolymer probe P(AAm-co-RBNCH) has been designed via free radical polymerization of a commercial acrylamide monomer with a rhodamine-functionalized monomer RBNCH. Metal ion selectivity of RBNCH was investigated by fluorescence and colorimetric spectrophotometry. Upon addition of Fe3+, a visual color change from colorless to red and a large fluorescence enhancement were observed for the ring-opening of the rhodamine spirolactam mechanism. The monomer gives a sensitive method for quantitatively detecting Fe3+ in the linear range of 100-200 µM, with a limit of detection as low as 27 nM and exhibiting high selectivity for Fe3+ over 12 other metal ions. The hydrogel sensor was characterized by FTIR, and the effects of RBNCH amount on gel content and swelling properties were explored. According to the recipe of 1.0 mol% RBNCH to the total monomers, the fabricated hydrogel sensor displayed a good swelling property and reversibility performance and has potential for application in the imaging of Fe3+ level in industrial wastewater.

Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis.

The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the CL biosynthesis gene Crls1 to investigate the effects of CL loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by uncoordinated mitochondrial translation rates and impaired respiratory chain supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of CL resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that CL is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 (also known as OXA1L) during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

miR-136-3p targets PTEN to regulate vascularization and bone formation and ameliorates alcohol-induced osteopenia.

Alcohol consumption is regarded as one of the leading risk factors for secondary osteopenia. Coupled angiogenesis and osteogenesis via distinct type-H vessels orchestrates subtle biological processes of bone homeostasis. The dysfunction of angiogenesis and osteogenesis contributes to decreased bone mass during the development of osteopenia. Herein, we identified microRNA-136-3p was remarkedly downregulated in the mouse model of alcohol-induced osteopenia. Following the alcohol administration, downregulated microRNA-136-3p significantly suppressed vascularization and osteogenic differentiation in human umbilical vein endothelial cells (HUVECs) and bone mesenchymal stem cells (BMSCs), respectively. Furthermore, microRNA-136-3p could target phosphatase and tensin homolog deleted on chromosome ten (PTEN) in both HUVECs and BMSCs, thus substantially modulating the capacity of vessel formation and osteogenic differentiation. In the mouse model, microRNA-136-3p Agomir ameliorated alcohol-induced osteopenia, with the concomitant restoration of bone mass and type-H vessel formation. For the first time, this study demonstrated the pivotal role of microRNA-136-3p/PTEN axis in regulations of vascularization and bone formation, which might become the potential therapeutic target of alcohol-induced bone loss.

Horizontal fissuring at the osteochondral interface: a novel and unique pathological feature in patients with obesity-related osteoarthritis.

OBJECTIVES: Obesity is a well-recognised risk factor for osteoarthritis (OA). Our aim is to characterise body mass index (BMI)-associated pathological changes in the osteochondral unit and determine if obesity is the major causal antecedent of early joint replacement in patients with OA. METHODS: We analysed the correlation between BMI and the age at which patients undergo total knee replacement (TKR) in 41 023 patients from the Australian Orthopaedic Association National Joint Replacement Registry. We then investigated the effect of BMI on pathological changes of the tibia plateau of knee joint in a representative subset of the registry. RESULTS: 57.58% of patients in Australia who had TKR were obese. Patients with overweight, obese class I & II or obese class III received a TKR 1.89, 4.48 and 8.08 years earlier than patients with normal weight, respectively. Microscopic examination revealed that horizontal fissuring at the osteochondral interface was the major pathological feature of obesity-related OA. The frequency of horizontal fissure was strongly associated with increased BMI in the predominant compartment. An increase in one unit of BMI (1 kg/m2) increased the odds of horizontal fissures by 14.7%. 84.4% of the horizontal fissures were attributable to obesity. Reduced cartilage degradation and alteration of subchondral bone microstructure were also associated with increased BMI. CONCLUSIONS: The key pathological feature in OA patients with obesity is horizontal fissuring at the osteochondral unit interface. Obesity is strongly associated with a younger age of first TKR, which may be a result of horizontal fissures.

ASDB: a resource for probing protein functions with small molecules.

UNLABELLED: : Identifying chemical probes or seeking scaffolds for a specific biological target is important for protein function studies. Therefore, we create the Annotated Scaffold Database (ASDB), a computer-readable and systematic target-annotated scaffold database, to serve such needs. The scaffolds in ASDB were derived from public databases including ChEMBL, DrugBank and TCMSP, with a scaffold-based classification approach. Each scaffold was assigned with an InChIKey as its unique identifier, energy-minimized 3D conformations, and other calculated properties. A scaffold is also associated with drugs, natural products, drug targets and medical indications. The database can be retrieved through text or structure query tools. ASDB collects 333 601 scaffolds, which are associated with 4368 targets. The scaffolds consist of 3032 scaffolds derived from drugs and 5163 scaffolds derived from natural products. For given scaffolds, scaffold-target networks can be generated from the database to demonstrate the relations of scaffolds and targets. AVAILABILITY AND IMPLEMENTATION: ASDB is freely available at http://www.rcdd.org.cn/asdb/with the major web browsers. CONTACT: junxu@biochemomes.com or xujun9@mail.sysu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

High-resolution study of the 3D collagen fibrillary matrix of Achilles tendons without tissue labelling and dehydrating.

Knowledge of the collagen structure of an Achilles tendon is critical to comprehend the physiology, biomechanics, homeostasis and remodelling of the tissue. Despite intensive studies, there are still uncertainties regarding the microstructure. The majority of studies have examined the longitudinally arranged collagen fibrils as they are primarily attributed to the principal tensile strength of the tendon. Few studies have considered the structural integrity of the entire three-dimensional (3D) collagen meshwork, and how the longitudinal collagen fibrils are integrated as a strong unit in a 3D domain to provide the tendons with the essential tensile properties. Using second harmonic generation imaging, a 3D imaging technique was developed and used to study the 3D collagen matrix in the midportion of Achilles tendons without tissue labelling and dehydration. Therefore, the 3D collagen structure is presented in a condition closely representative of the in vivo status. Atomic force microscopy studies have confirmed that second harmonic generation reveals the internal collagen matrix of tendons in 3D at a fibril level. Achilles tendons primarily contain longitudinal collagen fibrils that braid spatially into a dense rope-like collagen meshwork and are encapsulated or wound tightly by the oblique collagen fibrils emanating from the epitenon region. The arrangement of the collagen fibrils provides the longitudinal fibrils with essential structural integrity and endows the tendon with the unique mechanical function for withstanding tensile stresses. A novel 3D microscopic method has been developed to examine the 3D collagen microstructure of tendons without tissue dehydrating and labelling. The study also provides new knowledge about the collagen microstructure in an Achilles tendon, which enables understanding of the function of the tissue. The knowledge may be important for applying surgical and tissue engineering techniques to tendon reconstruction.

The incidence of deep venous thrombosis before arthroscopy among patients suffering from high-energy knee trauma.

PURPOSE: The purpose of the present study was to analyse the incidence of deep venous thrombosis (DVT) before knee arthroscopy in patients who had sustained high-energy knee injuries. METHOD: This study included 64 patients who underwent arthroscopic knee surgery as a result of injury from a traffic accident or a high fall. Venography was performed on the injured leg of each patient before arthroscopy. The patients were divided into two groups based on whether they had DVT. Correlation analysis was performed to determine the factors associated with DVT. RESULTS: A total of 32 (50 %) of the 64 patients had venographic evidence of DVT. Of these DVTs, seven were proximal (10.9 %). The D-dimer (DD) level was significantly higher in the DVT group, especially among the patients whose symptoms had persisted for more than 10 days. DVT is difficult to diagnose solely based on clinical symptoms, as some patients are symptomatic while others exhibit symptoms that could be attributed to trauma. CONCLUSIONS: The incidence of DVT before knee arthroscopy in patients with high-energy knee injuries was 50 %, and the prevalence of proximal DVT was 10.9 %. DD is a sensitive marker for DVT. No patient developed DVT with a DD level lower than 0.8 mg/L, but those with DD level higher than 1.5 mg/L had a much higher incidence of DVT developing in patients who had been injured for more than 10 days. A routine examination to exclude DVT in these patients should be performed before arthroscopy. LEVEL OF EVIDENCE: IV.

Metabolic Syndrome and Deep Vein Thrombosis After Total Knee and Hip Arthroplasty.

BACKGROUND: Metabolic syndrome (MS), defined as obesity, hypertension, hyperglycemia, and dyslipidemia, is prevalent among patients undergoing total joint arthroplasty (TJA). MS has proven to promote a proinflammatory and prothrombotic state in patients. Venous thromboembolism is one of the major complications of TJA. The purpose of this retrospective study is to identify whether MS and its components increase the risk of deep vein thrombosis (DVT) after TJA. METHODS: We retrospectively reviewed 1553 patients undergoing primary unilateral TJA from 2007 to 2014. MS was diagnosed based on the World Health Organization criteria. All subjects received venography after operation to screen for DVT. Symptomatic DVT events after TJA were also recorded. Univariate analysis and multivariate logistic regression analysis were used to identify the association of MS and its components with postoperative DVT. RESULTS: The prevalence of MS in patients undergoing TJA was 5.1% (n = 79). A total of 335 patients (21.6%) were diagnosed with DVT by venography. Seventy-eight patients (5.0%) developed symptomatic DVT. In the total knee arthroplasty group, MS and obesity were related to postoperative DVT. MS alone was found to be associated with symptomatic DVT. In the total hip arthroplasty group, MS increased the risk of symptomatic DVT. However, obesity, rather than MS, was associated with total DVT after total hip arthroplasty. CONCLUSIONS: MS was a significant risk factor for DVT after TJA. Strategies to minimize the adverse effect of MS should be considered for these patients.

The preoperative incidence of deep vein thrombosis (DVT) and its correlation with postoperative DVT in patients undergoing elective surgery for femoral neck fractures.

INTRODUCTION: Data on the incidence of preoperative deep vein thrombosis (DVT) in patients, who are waiting for elective hip replacement for femoral neck fractures, are limited. Our primary goal was to determine the prevalence and risk factors of preoperative DVT in acute hip fracture patients awaiting hemi- or total hip arthroplasty using venography. The secondary objective was to find a possible relationship between preoperative and postoperative DVT. METHODS: We enrolled 119 consecutive patients with subcapital femoral neck fracture, who were awaiting hip replacement at our institution. All of them received venography before and after surgery. We used univariate analysis and multivariate logistic regression analysis to identify the risk factors for preoperative DVT. RESULTS: Of the patients, 35 patients (29.4 %) developed DVT in affected limbs before surgery. Both long duration of immobilization and increased level of D-dimer were associated with preoperative DVT independently. Intriguingly, 66.7 % of patients who were diagnosed with DVT after surgery had thrombus in the same location, as they did before surgery. CONCLUSIONS: We identified the high incidence and risk factors of preoperative DVT in patients awaiting elective surgery for femoral neck fractures. The majority of patients diagnosed with DVT postoperatively had already had thrombus before surgery.

ChemStable: a web server for rule-embedded naïve Bayesian learning approach to predict compound stability.

Predicting compound chemical stability is important because unstable compounds can lead to either false positive or to false negative conclusions in bioassays. Experimental data (COMDECOM) measured from DMSO/H2O solutions stored at 50 °C for 105 days were used to predicted stability by applying rule-embedded naïve Bayesian learning, based upon atom center fragment (ACF) features. To build the naïve Bayesian classifier, we derived ACF features from 9,746 compounds in the COMDECOM dataset. By recursively applying naïve Bayesian learning from the data set, each ACF is assigned with an expected stable probability (p(s)) and an unstable probability (p(uns)). 13,340 ACFs, together with their p(s) and p(uns) data, were stored in a knowledge base for use by the Bayesian classifier. For a given compound, its ACFs were derived from its structure connection table with the same protocol used to drive ACFs from the training data. Then, the Bayesian classifier assigned p(s) and p(uns) values to the compound ACFs by a structural pattern recognition algorithm, which was implemented in-house. Compound instability is calculated, with Bayes' theorem, based upon the p(s) and p(uns) values of the compound ACFs. We were able to achieve performance with an AUC value of 84% and a tenfold cross validation accuracy of 76.5%. To reduce false negatives, a rule-based approach has been embedded in the classifier. The rule-based module allows the program to improve its predictivity by expanding its compound instability knowledge base, thus further reducing the possibility of false negatives. To our knowledge, this is the first in silico prediction service for the prediction of the stabilities of organic compounds.

LBVS: an online platform for ligand-based virtual screening using publicly accessible databases.

Abundant data on compound bioactivity and publicly accessible chemical databases increase opportunities for ligand-based drug discovery. In order to make full use of the data, an online platform for ligand-based virtual screening (LBVS) using publicly accessible databases has been developed. LBVS adopts Bayesian learning approach to create virtual screening models because of its noise tolerance, speed, and efficiency in extracting knowledge from data. LBVS currently includes data derived from BindingDB and ChEMBL. Three validation approaches have been employed to evaluate the virtual screening models created from LBVS. The tenfold cross validation results of twenty different LBVS models demonstrate that LBVS achieves an average AUC value of 0.86. Our internal and external testing results indicate that LBVS is predictive for lead identifications. LBVS can be publicly accessed at http://rcdd.sysu.edu.cn/lbvs.

10-Year Prospective Clinical and Radiological Evaluation After Matrix-Induced Autologous Chondrocyte Implantation and Comparison of Tibiofemoral and Patellofemoral Graft Outcomes.

BACKGROUND: Long-term outcomes in larger cohorts after matrix-induced autologous chondrocyte implantation (MACI) are required. Furthermore, little is known about the longer-term clinical and radiological outcomes of MACI performed in the tibiofemoral versus patellofemoral knee joint. PURPOSE: To present the 10-year clinical and radiological outcomes in patients after MACI and compare outcomes in patients undergoing tibiofemoral versus patellofemoral MACI. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between September 2002 and December 2012, 204 patients who underwent MACI were prospectively registered into a research program and assessed preoperatively and at 2, 5, and 10 years postoperatively. Of these patients, 168 were available for clinical review at 10 years, with 151 (of a total of 182) grafts also assessed via magnetic resonance imaging (MRI). Patients were evaluated using the Knee injury and Osteoarthritis Outcome Score, a visual analog scale for pain frequency and severity, satisfaction, and peak isokinetic knee extensor and flexor strength. Limb symmetry indices (LSIs) were calculated for strength measures. Grafts were scored on MRI scans via the MOCART (magnetic resonance observation of cartilage repair tissue) system, with a focus on tissue infill and an overall MRI graft composite score. RESULTS: All patient-reported outcome measures improved (P < .0001) up to 2 years after surgery. Apart from the significant increase (P = .004) in the peak isokinetic knee extensor LSI, no other patient-reported outcome measure or clinical score had changed significantly from 2 to 10 years. At the final follow-up, 92% of patients were satisfied with MACI to provide knee pain relief, with 76% satisfied with their ability to participate in sports. From 2 to 10 years, no significant change was seen for any MRI-based MOCART variable nor the overall MRI composite score. Of the 151 grafts reviewed via MRI at 10 years, 14 (9.3%) had failed, defined by graft delamination or no graft tissue on MRI scan. Furthermore, of the 36 patients (of the prospectively recruited 204) who were not available for longer-term review, 7 had already proceeded to total knee arthroplasty, and 1 patient had undergone secondary MACI at the same medial femoral condylar site because of an earlier graft failure. Therefore, 22 patients (10.8%) essentially had graft failure over the period. At the final follow-up, patients who underwent MACI in the tibiofemoral (vs patellofemoral) joint reported significantly better Knee injury and Osteoarthritis Outcome Score subscale scores for Quality of Life (P = .010) and Sport and Recreation (P < .001), as well as a greater knee extensor strength LSI (P = .002). Even though the tibiofemoral group demonstrated better 10-year MOCART scores for tissue infill (P = .027), there were no other MRI-based differences (P > .05). CONCLUSION: This study reports the long-term review of a prospective series of patients undergoing MACI, demonstrating good clinical scores, high levels of patient satisfaction, and acceptable graft survivorship at 10 years. Patients undergoing tibiofemoral (vs patellofemoral) MACI reported better long-term clinical outcomes, despite largely similar MRI-based outcomes.

Mitochondrial dysfunction: mechanisms and advances in therapy.

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

Mitochondria from osteolineage cells regulate myeloid cell-mediated bone resorption.

Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer mitochondria to myeloid cells. Impairment of the transfer of mitochondria by deleting MIRO1 in osteolineage cells leads to increased myeloid cell commitment toward osteoclastic lineage cells and promotes bone resorption. In detail, impaired mitochondrial transfer from osteolineage cells alters glutathione metabolism and protects osteoclastic lineage cells from ferroptosis, thus promoting osteoclast activities. Furthermore, mitochondrial transfer from osteolineage cells to myeloid cells is involved in the regulation of glucocorticoid-induced osteoporosis, and glutathione depletion alleviates the progression of glucocorticoid-induced osteoporosis. These findings reveal an unappreciated mechanism underlying the interaction between osteolineage cells and myeloid cells to regulate skeletal metabolic homeostasis and provide insights into glucocorticoid-induced osteoporosis progression.

Emerging materials and technologies for advancing bioresorbable surgical meshes.

Surgical meshes play a significant role in the treatment of various medical conditions, such as hernias, pelvic floor issues, guided bone regeneration, and wound healing. To date, commercial surgical meshes are typically made of non-absorbable synthetic polymers, notably polypropylene and polytetrafluoroethylene, which are associated with postoperative complications, such as infections. Biological meshes, based on native tissues, have been employed to overcome such complications, though mechanical strength has been a main disadvantage. The right balance in mechanical and biological performances has been achieved by the advent of bioresorbable meshes. Despite improvements, recurrence of clinical complications associated with surgical meshes raises significant concerns regarding the technical adequacy of current materials and designs, pointing to a crucial need for further development. To this end, current research focuses on the design of meshes capable of biomimicking native tissue and facilitating the healing process without post-operative complications. Researchers are actively investigating advanced bioresorbable materials, both synthetic polymers and natural biopolymers, while also exploring the performance of therapeutic agents, surface modification methods and advanced manufacturing technologies such as 4D printing. This review seeks to evaluate emerging biomaterials and technologies for enhancing the performance and clinical applicability of the next-generation surgical meshes. STATEMENT OF SIGNIFICANCE: In the ever-transforming landscape of regenerative medicine, the embracing of engineered bioabsorbable surgical meshes stands as a key milestone in addressing persistent challenges and complications associated with existing treatments. The urgency to move beyond conventional non-absorbable meshes, fraught with post-surgery complications, emphasises the necessity of using advanced biomaterials for engineered tissue regeneration. This review critically examines the growing field of absorbable surgical meshes, considering their potential to transform clinical practice. By strategically combining mechanical strength with bioresorbable characteristics, these innovative meshes hold the promise of mitigating complications and improving patient outcomes across diverse medical applications. As we navigate the complexities of modern medicine, this exploration of engineered absorbable meshes emerges as a promising approach, offering an overall perspective on biomaterials, technologies, and strategies adopted to redefine the future of surgical meshes.

Rapid, sensitive, and convenient detection of Plasmodium falciparum infection based on CRISPR and its application in detection of asymptomatic infection.

Rapid and convenient detection of the Plasmodium in clinically diagnosed individuals and asymptomatically infected populations is essential for global malaria eradication, especially in malaria-endemic African countries where medical equipment and professionals are relatively deficient. Here, we described a CRISPR-based diagnostic for the detection of Plasmodium falciparum, the deadliest and most prevalent species of malaria parasite in Africa, via lateral flow strip readout without the need of nucleic acid extraction. The assay exhibited 100% sensitivity on clinical samples (5 P falciparum) and significant consistency with qPCR test on asymptomatic infection samples (49 P falciparum and 51 non-P. falciparum, Kappa=0.839). An artemisinin-resistant P. falciparum strain and 4 other laboratory-cultured strains can also be detected through this assay, whereas no cross-reactivity with Plasmodium vivax was observed. A 0.001% parasitaemia (corresponding to ∼60 parasites/µL) below the "low parasite density" test threshold (200 parasites/µL) is detectable. Our study demonstrated that direct malaria detection using whole blood on the spot and the detection of both clinical and asymptomatic infections of P. falciparum are feasible. This method is expected to be employed for clinical testing and large-scale community screening in Africa and possibly other places, contributing to the accurate diagnosis and control of malaria.

Regulation of blood-brain barrier integrity by Dmp1-expressing astrocytes through mitochondrial transfer.

The blood-brain barrier (BBB) acts as the crucial physical filtration structure in the central nervous system. Here, we investigate the role of a specific subset of astrocytes in the regulation of BBB integrity. We showed that Dmp1-expressing astrocytes transfer mitochondria to endothelial cells via their endfeet for maintaining BBB integrity. Deletion of the Mitofusin 2 (Mfn2) gene in Dmp1-expressing astrocytes inhibited the mitochondrial transfer and caused BBB leakage. In addition, the decrease of MFN2 in astrocytes contributes to the age-associated reduction of mitochondrial transfer efficiency and thus compromises the integrity of BBB. Together, we describe a mechanism in which astrocytes regulate BBB integrity through mitochondrial transfer. Our findings provide innnovative insights into the cellular framework that underpins the progressive breakdown of BBB associated with aging and disease.