Tailoring surface stiffness to modulate senescent macrophage immunomodulation: Implications for osteo-/angio-genesis in aged bone regeneration.

The application of biomaterials in bone regeneration is a prevalent clinical practice. However, its efficacy in elderly patients remains suboptimal, necessitating further advancements. While biomaterial properties are known to orchestrate macrophage (MΦ) polarization and local immune responses, the role of biomaterial cues, specifically stiffness, in directing the senescent macrophage (S-MΦ) is still poorly understood. This study aimed to elucidate the role of substrate stiffness in modulating the immunomodulatory properties of S-MΦ and their role in osteo-immunomodulation. Our results demonstrated that employing collagen-coated polyacrylamide hydrogels with varying stiffness values (18, 76, and 295 kPa) as model materials, the high-stiffness hydrogel (295 kPa) steered S-MΦs towards a pro-inflammatory M1 phenotype, while hydrogels with lower stiffness (18 and 76 kPa) promoted an anti-inflammatory M2 phenotype. The immune microenvironment created by S-MΦs promoted the bioactivities of senescent endothelial cells (S-ECs) and senescent bone marrow mesenchymal stem cells BMSCs (S-BMSCs). Furthermore, the M2 S-MΦs, particularly incubated on the 76 kPa hydrogel matrices, significantly enhanced the ability of angiogenesis of S-ECs and osteogenic differentiation of S-BMSCs, which are crucial and interrelated processes in bone healing. This modulation aided in reducing the accumulation of reactive oxygen species in S-ECs and S-BMSCs, thereby significantly contributing to the repair and regeneration of aged bone tissue.

Effects of work-family conflict, social support and burnout on job satisfaction among primary care physicians in Huaihai economic zone.

Background: Primary care physicians (PCPs) are doctors in primary health care institutions, namely village clinics, township health centers and community health service centers (stations) who are the main providers of primary health care services in primary health care settings. Improving the overall health status of the population requires the support of a large number of primary care physicians; however, the job satisfaction of this group has not been sufficiently emphasized and recognized. Objective: The purpose of this study was to examine the effects of primary care physicians' work-family conflict on their job satisfaction, as well as the mediating role of burnout and the moderating role of social support. Methods: This cross-sectional study was conducted from February 2023 to March 2023. Participants were 749 primary care physicians from four cities of Xuzhou, Linyi, Huaibei, and Shangqiu in the Huaihai Economic Zone of China. SPSS statistical analysis was used to evaluate the relationship between work-family conflict, social support, burnout and job satisfaction among medical workers. Results: Work-family conflict had a significant negative effect on job satisfaction (ß = -0.36, p< 0.001), after adding burnout in the model, work-family conflict also negatively predicted job satisfaction (ß = -0.32, p< 0.001). Social support had a moderating effect on the direct effect of burnout on job satisfaction (ß = 0.00, t = 2.66, p< 0.01, 95%CI [0.001, 0.007]), the predictive effect of burnout on job satisfaction at high level of social support (ß = -0.45, p< 0.001) was higher than a low level of social support (ß = -0.33, p< 0.001). Conclusions: This study demonstrated the negative impact of work-family conflict on primary care physicians' job satisfaction, as well as the mediating role of burnout and the moderating role of social support on burnout and job satisfaction, which are important for improving primary care physicians' job satisfaction and enhancing the quality of primary care in the future.

Anterior or Posterior Tibial Tendon Transfer to the Peroneus Tertius for Equinovarus Deformity.

BACKGROUND: Equinovarus deformity correction was performed by soft tissue release and bone deformity correction, and tendon transfer to maintain deformity correction. Because of the high complication rate of tendon fixation methods, partial or total anterior tibial tendon or posterior tibial tendon transfer to the peroneus tertius tendon was reported. The purpose of this study was (i) to review the results of this tendon transfer technique after release and correction of talipes equinovarus, and (ii) to analyze the complication of this technique. METHODS: Between February 2017 and May 2022, 176 patients (210 feet) with equinus and/or varus foot and ankle deformities underwent anterior or posterior tibial tendon transfer to the peroneus tertius in our institute. Preoperative and postoperative foot and ankle range of motion (passive and active) were checked. The postoperative radiographic assessment included antero-posterior (AP), lateral, and hindfoot alignment radiographs. Preoperative and postoperative lateral tibio-talar, talo-calcaneal, talo-first metatarsal, tibial-sole angles, hindfoot alignment, and anterior subluxation of the talus were checked. The American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale, and visual analog scale (VAS) were used to assess pain. Paired Student's t-test was used to compare the clinical scores and radiographic angles before the operation and at the last follow-up. RESULTS: The mean age of the patients was 23.27 ± 13.44 years (range, 3-69 years). The mean follow-up time was 25.56 ± 16.37 months (range, 12-68 months). There were significant differences between the preoperative and postoperative measurements of the lateral tibio-talar angle, lateral talo-calcaneal angle, lateral talo-first metatarsal angle, lateral tibial-sole angle, and hindfoot alignment (p < 0.001). There was significant difference between the preoperative and postoperative AOFAS and VAS scores (p < 0.001). The early complications included infection in one patient, skin necrosis in two patients, and plantar numbness in three patients. The late complications included pin infection in three patients, tibio-talar joint compression in four patients, forefoot pain in two patients, toe flexion in two patients, and plantar numbness in one patient. There were three cases of complications (1.43%) related to the transferred tendons. CONCLUSION: Tibialis anterior or posterior tendon transfer to the peroneus tertius is a safe and effective method for equinovarus deformity correction. It yielded excellent outcomes that produced high patient satisfaction and few complications.

Bi-phase CT radiomics nomogram for the preoperative prediction of pylorus lymph node metastasis in non-pyloric gastric cancer patients.

BACKGROUND: The expansion of function-preserving surgery became possible due to a more profound understanding of gastric cancer (GC), and T1N + or T2N + gastric cancer patients might be potential beneficiaries. However, ways to evaluate the possibility of function-preserving pylorus surgery are still unknown. METHODS: A total of 288 patients at Renji Hospital and 58 patients at Huadong Hospital, pathologically diagnosed with gastric cancer staging at T1 and T2 with tumors located in the upper two-thirds of the stomach, were retrospectively enrolled from March 2015 to October 2022. Tumor regions of interest (ROIs) were manually delineated on bi-phase CT images, and a nomogram was built and evaluated. RESULTS: The radiomic features distributed differently between positive and negative pLNm groups. Two radiomic signatures (RS1 and RS2) and one clinical signature were constructed. The radiomic signatures exhibited good performance for discriminating pLNm status in the test set. The three signatures were then combined into an integrated nomogram (IN). The IN showed good discrimination of pLNm in the Renji cohort (AUC 0.918) and the Huadong cohort (AUC 0.649). The verification models showed high values. CONCLUSION: For GC patients with T1 and T2 tumors located in the upper two-thirds of the stomach, a nomogram was successfully built for predicting pylorus lymph node metastasis, which would guide the surgical indication extension of conservative gastrectomies.

Advanced glycation end products mediate biomineralization disorder in diabetic bone disease.

Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.

Deep learning for patient-specific quality assurance of volumetric modulated arc therapy: Prediction accuracy and cost-sensitive classification performance.

PURPOSE: To evaluate a deep learning model's performance in predicting and classifying patient-specific quality assurance (PSQA) results for volumetric modulated arc therapy (VMAT), aiming to streamline PSQA workflows and reduce the onsite measurement workload. METHODS: A total of 761 VMAT plans were analyzed using 3D-MResNet to process multileaf collimator images and monitor unit data, with the gamma passing rate (GPR) as the output. Thresholds for the predicted GPR (Th-p) and measured GPR (Th-m) were established to aid in PSQA decision-making, using cost curves and error rates to assess classification performance. RESULTS: The mean absolute errors of the model for the test set were 1.63 % and 2.38 % at 3 %/2 mm and 2 %/2 mm, respectively. For the classification of the PSQA results, Th-m was 88.3 % at 2 %/2 mm and 93.3 % at 3 %/2 mm. The lowest cost-sensitive error rates of 0.0127 and 0.0925 were obtained when Th-p was set as 91.2 % at 2 %/2 mm and 96.4 % at 3 %/2 mm, respectively. Additionally, the 2 %/2 mm classifier also achieved a lower total expected cost of 0.069 compared with 0.110 for the 3 %/2 mm classifier. The deep learning classifier under the 2 %/2 mm gamma criterion had a sensitivity and specificity of 100 % (10/10) and 83.5 % (167/200), respectively, for the test set. CONCLUSIONS: The developed 3D-MResNet model can accurately predict and classify PSQA results based on VMAT plans. The introduction of a deep learning model into the PSQA workflow has considerable potential for improving the VMAT PSQA process and reducing workloads.

Facial nerve regeneration via body-brain crosstalk: The role of stem cells and biomaterials.

The human body is a complex, integral whole, and disruptions in one organ can lead to dysfunctions in other parts of the organ network. The facial nerve, as the seventh cranial nerve, arises from the brainstem, controls facial expression muscles and plays a crucial role in brain-body communication. This vulnerable nerve can be damaged by trauma, inflammation, tumors, and congenital diseases, often impairing facial expression. Stem cells have gained significant attention for repairing peripheral nerve injuries due to their multidirectional differentiation potential. Additionally, various biomaterials have been used in tissue engineering for regeneration and repair. However, the therapeutic potential of stem cells and biomaterials in treating facial nerve injuries requires further exploration. In this review, we summarize the roles of stem cells and biomaterials in the regeneration and repair of damaged facial nerves, providing a theoretical basis for the recovery and reconstruction of body-brain crosstalk between the brain and facial expression muscles.

Association of blood cadmium, lead, and mercury with anxiety: a cross-sectional study from NHANES 2007-2012.

Objectives: The purpose of this paper is to explore the relationship between blood levels of cadmium, lead, and mercury and anxiety in American adults. Methods: Blood metals and self-reported anxiety days were extracted from laboratory data and questionnaire data, respectively, using NHANES data from 2007-2012. Weighted logistic regression was used to assess the relationship between cadmium, lead and mercury with anxiety. Restricted cubic spline was used to visualize the non-linear relationship between metal concentrations and anxiety. Weighted quantile sum (WQS) regression was used to investigate the effect of combined exposure to the three metals on anxiety. Results: The prevalence of anxiety in adults was 26.0%. After adjusting for potential confounding variables, cadmium levels in the highest quartile (Q4) were associated with a higher risk of anxiety compared to the lowest quartile (Q1) (OR = 1.279, 95% CI: 1.113-1.471, p < 0.01). Restricted cubic spline analysis indicated a positive association between blood cadmium levels and anxiety. Furthermore, co-exposure to multiple heavy metals was positively associated with anxiety risk (WQS positive: OR = 1.068, 95% CI: 1.016-1.160, p < 0.05), with cadmium contributing the most to the overall mixture effect. Compared to the Light RPA, the Vigorous/Moderate RPA group had a relatively low risk of anxiety after cadmium exposure. Conclusion: High levels of blood cadmium are positively associated with the development of anxiety disorders, which needs to be further verified in future studies.

Quantum dots for bone tissue engineering.

In confronting the global prevalence of bone-related disorders, bone tissue engineering (BTE) has developed into a critical discipline, seeking innovative materials to revolutionize treatment paradigms. Quantum dots (QDs), nanoscale semiconductor particles with tunable optical properties, are at the cutting edge of improving bone regeneration. This comprehensive review delves into the multifaceted roles that QDs play within the realm of BTE, emphasizing their potential to not only revolutionize imaging but also to osteogenesis, drug delivery, antimicrobial strategies and phototherapy. The customizable nature of QDs, attributed to their size-dependent optical and electronic properties, has been leveraged to develop precise imaging modalities, enabling the visualization of bone growth and scaffold integration at an unprecedented resolution. Their nanoscopic scale facilitates targeted drug delivery systems, ensuring the localized release of therapeutics. QDs also possess the potential to combat infections at bone defect sites, preventing and improving bacterial infections. Additionally, they can be used in phototherapy to stimulate important bone repair processes and work well with the immune system to improve the overall healing environment. In combination with current trendy artificial intelligence (AI) technology, the development of bone organoids can also be combined with QDs. While QDs demonstrate considerable promise in BTE, the transition from laboratory research to clinical application is fraught with challenges. Concerns regarding the biocompatibility, long-term stability of QDs within the biological environment, and the cost-effectiveness of their production pose significant hurdles to their clinical adoption. This review summarizes the potential of QDs in BTE and highlights the challenges that lie ahead. By overcoming these obstacles, more effective, efficient, and personalized bone regeneration strategies will emerge, offering new hope for patients suffering from debilitating bone diseases.

The risk of asthma in singletons conceived by ART: a retrospective cohort study.

STUDY QUESTION: Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons? SUMMARY ANSWER: The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART. WHAT IS KNOWN ALREADY: Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear. STUDY DESIGN SIZE DURATION: This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited. PARTICIPANTS/MATERIALS SETTING METHODS: Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling. MAIN RESULTS AND THE ROLE OF CHANCE: Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P = 0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P = 0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b = 0.025, P < 0.05) and a negative indirect effect of breastfeeding (b = -0.012, P < 0.05) on the association between ART and asthma in singleton offspring. LIMITATIONS REASONS FOR CAUTION: This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: ChiCTR2300069906.

Interfacial Membranization of Regenerated Cellulose Nanoparticles and a Protein Renders Stable Water-in-Water Emulsion.

Pickering water-in-water (W/W) emulsions stabilized by biobased colloids are pertinent to engineering biomaterials with hierarchical and confined architectures. In this study, stable W/W emulsions are developed through membranization utilizing biopolymer structures formed by the adsorption of cellulose II nanospheres and a globular protein, bovine serum albumin (BSA), at droplet surfaces. The produced cellulose II nanospheres (NPcat, 63 nm diameter) bearing a soft and highly accessible shell, endow rapid and significant binding (16 mg cm- 2) with BSA. NPcat and BSA formed complexes that spontaneously stabilized liquid droplets, resulting in stable W/W emulsions. It is proposed that such a system is a versatile all-aqueous platform for encapsulation, (bio)catalysis, delivery, and synthetic cell mimetics.

Biofabrication with microbial cellulose: from bioadaptive designs to living materials.

Nanocellulose is not only a renewable material but also brings functions that are opening new technological opportunities. Here we discuss a special subset of this material, in its fibrillated form, which is produced by aerobic microorganisms, namely, bacterial nanocellulose (BNC). BNC offers distinct advantages over plant-derived counterparts, including high purity and high degree of polymerization as well as crystallinity, strength, and water-holding capacity, among others. More remarkably, beyond classical fermentative protocols, it is possible to grow BNC on non-planar interfaces, opening new possibilities in the assembly of advanced bottom-up structures. In this review, we discuss the recent advances in the area of BNC-based biofabrication of three-dimensional (3D) designs by following solid- and soft-material templating. These methods are shown as suitable platforms to achieve bioadaptive constructs comprising highly interlocked biofilms that can be tailored with precise control over nanoscale morphological features. BNC-based biofabrication opens applications that are not possible by using traditional manufacturing routes, including direct ink writing of hydrogels. This review emphasizes the critical contributions of microbiology, colloid and surface science, as well as additive manufacturing in achieving bioadaptive designs from living matter. The future impact of BNC biofabrication is expected to take advantage of material and energy integration, residue utilization, circularity and social latitudes. Leveraging existing infrastructure, the scaleup of biofabrication routes will contribute to a new generation of advanced materials rooted in exciting synergies that combine biology, chemistry, engineering and material sciences.

Nitrogen-cycling microbial communities respond differently to nitrogen addition under two contrasting grassland soil types.

Introduction: The impact of nitrogen (N) deposition on the soil N-transforming process in grasslands necessitates further investigation into how N input influences the structural composition and diversity of soil N-cycling microbial communities across different grassland types. Methods: In this study, we selected two types of grassland soils in northwest Liaoning, temperate steppe and warm-temperate shrub, and conducted short-term N addition experiments using organic N, ammonium N, and nitrate N as sources with three concentration gradients to simulate N deposition. Illumina MiSeq sequencing technology was employed to sequence genes associated with N-cycling microbes including N-fixing, ammonia-oxidizing and denitrifying bacteria, and ammonia-oxidizing archaea. Results and discussion: The results revealed significant alterations in the structural composition and diversity of the N-cycling microbial community due to N addition, but the response of soil microorganisms varied inconsistent among different grassland types. Ammonium transformation rates had a greater impact on soils from temperate steppes while nitrification rates were more influential for soils from warm-temperate shrubs. Furthermore, the influence of the type of N source on soil N-cycling microorganisms outweighed that of its quantity applied. The ammonium type of nitrogen source is considered the most influential driving factor affecting changes in the structure of the microbial community involved in nitrogen transformation, while the amount of low nitrogen applied primarily determines the composition of soil bacterial communities engaged in nitrogen fixation and nitrification. Different groups of N-cycling microorganisms exhibited distinct responses to varying levels of nitrogen addition with a positive correlation observed between their composition, diversity, and environmental factors examined. Overall findings suggest that short-term nitrogen deposition may sustain dominant processes such as soil-N fixation within grasslands over an extended period without causing significant negative effects on northwestern Liaoning's grassland ecosystems within the next decade.

Bone-organ axes: bidirectional crosstalk.

In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.

Interleukin-1 increases SERPINE1 expression in human granulosa-lutein cell via P50/P52 signaling pathways.

It has been reported that immune factors are associated with the occurrence of polycystic ovary syndrome (PCOS). Interleukin-1 (IL-1) is a member of the interleukin family that widely participates in the regulation of the inflammatory response in the immune system. In addition, it has been reported that aberrant IL-1 accumulation in serum is associated with the occurrence of PCOS. However, little is known about how IL-1 participates in the pathogenesis of PCOS. In the present study, we demonstrated that the immune microenvironment was altered in follicular fluid from PCOS patients and that the expression levels of two IL-1 cytokines, IL-1α and IL-1ß were increased. Transcriptome analysis revealed that IL-1α and IL-1ß treatment induced primary human granulosa-lutein (hGL) cell inflammatory response and increased the expression of serpin family E member 1 (SERPINE1). Mechanistically, we demonstrated that IL-1α and IL-1ß upregulated SERPINE1 expression through IL-1R1-mediated activation of downstream P50 and P52 signaling pathways in human granulosa cells. Our study highlighted the role of immune state changes in the occurrence of PCOS and provided new insight into the treatment of patients with IL-1-induced ovarian function disorders.

The impact and inflammatory characteristics of SARS-CoV-2 infection during ovarian stimulation on the outcomes of assisted reproductive treatment.

Introduction: Despite the global prevalence of coronavirus disease 2019 (COVID-19), limited research has been conducted on the effects of SARS-CoV-2 infection on human reproduction. The aims of this study were to investigate the impact of SARS-CoV-2 infection during controlled ovarian stimulation (COS) on the outcomes of assisted reproductive treatment (ART) and the cytokine status of patients. Methods: This retrospective cohort study included 202 couples who received ART treatment, 101 couples infected with SARS-CoV-2 during COS and 101 matched uninfected couples. The parameters of ovarian stimulation and pregnancy outcomes were compared between the two groups. The All-Human Inflammation Array Q3 kit was utilized to measure cytokine levels in both blood and follicular fluid. Results: No difference was found in the number of good-quality embryos (3.3 ± 3.1 vs. 3.0 ± 2.2, P = 0.553) between the infected and uninfected groups. Among couples who received fresh embryo transfers, no difference was observed in clinical pregnancy rate (53.3% vs. 51.5%, P = 0.907). The rates of fertilization, implantation, miscarriage, ectopic pregnancy and live birth were also comparable between the two groups. After adjustments were made for confounders, regression models indicated that the quality of embryos (B = 0.16, P = 0.605) and clinical pregnancy rate (P = 0.206) remained unaffected by SARS-CoV-2 infection. The serum levels of MCP-1, TIMP-1, I-309, TNF-RI and TNF-RII were increased, while that of eotaxin-2 was decreased in COVID-19 patients. No significant difference was found in the levels of cytokines in follicular fluid between the two groups. Conclusion: Asymptomatic or mild COVID-19 during COS had no adverse effects on ART outcomes. Although mild inflammation was present in the serum, it was not detected in the follicular fluid of these patients. The subsequent immune response needs further investigation.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis.

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvß3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes.

In the meiotic prophase, programmed DNA double-strand breaks are repaired by meiotic recombination. Recombination-defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombination-defective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombination-defective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.

Organoid bioinks: construction and application.

Organoids have emerged as crucial platforms in tissue engineering and regenerative medicine but confront challenges in faithfully mimicking native tissue structures and functions. Bioprinting technologies offer a significant advancement, especially when combined with organoid bioinks-engineered formulations designed to encapsulate both the architectural and functional elements of specific tissues. This review provides a rigorous, focused examination of the evolution and impact of organoid bioprinting. It emphasizes the role of organoid bioinks that integrate key cellular components and microenvironmental cues to more accurately replicate native tissue complexity. Furthermore, this review anticipates a transformative landscape invigorated by the integration of artificial intelligence with bioprinting techniques. Such fusion promises to refine organoid bioink formulations and optimize bioprinting parameters, thus catalyzing unprecedented advancements in regenerative medicine. In summary, this review accentuates the pivotal role and transformative potential of organoid bioinks and bioprinting in advancing regenerative therapies, deepening our understanding of organ development, and clarifying disease mechanisms.