Targeted Therapy of Osteoarthritis via Intra-Articular Delivery of Lipid-Nanoparticle-Encapsulated Recombinant Human FGF18 mRNA.

Fibroblast growth factor 18 (FGF18) emerges as a promising therapeutic target for osteoarthritis (OA). In this study, a novel articular cavity-localized lipid nanoparticle (LNP) named WG-PL14 is developed. This optimized formulation has a nearly 30-fold increase in mRNA expression as well as better articular cavity enrichment compared to commercial lipids MC3 when performing intra-articular injection. Then, a mRNA sequence encoding recombinant human FGF18 (rhFGF18) for potential mRNA therapy in OA is optimized. In vitro assays confirm the translation of rhFGF18 mRNA into functional proteins within rat and human chondrocytes, promoting cell proliferation and extracellular matrix (ECM) synthesis. Subsequently, the therapeutic efficacy of the LNP-rhFGF18 mRNA complex is systematically assessed in a mouse OA model. The administration exhibits several positive outcomes, including an improved pain response, upregulation of ECM-related genes (e.g., AGRN and HAS2), and remodeling of subchondral bone homeostasis compared to a control group. Taken together, these findings underscore the potential of localized LNP-rhFGF18 mRNA therapy in promoting the regeneration of cartilage tissue and mitigating the progression of OA.

Diagnostic and evaluative efficiency of 68Ga-FAPI-04 in skeletal muscle injury.

BACKGROUND: Skeletal muscles are vital for daily function, yet assessing their injuries remain challenging. We aimed to elucidate the effectiveness of 68Ga-FAPI-04 in evaluating skeletal muscle remodeling. RESULTS: C2C12 cells were subjected to graded H2O2 stimulation in vitro, revealing an initial rise and subsequent decline in fibroblast activation protein (FAP) expression as H2O2 concentration increased. In vivo, a murine triceps surae injury model was created using various solutions to simulate normal repair, mild repair failure, and severe repair failure. Assessments were conducted on days 1, 3, 7, and 14 using PET, MRI, and ultrasound. With 68Ga-FAPI-04, the normal and mild repair failure groups showed significantly higher SUVmax and T/B ratios on day 1 compared to the severe repair failure group. These values gradually decreased in the normal repair group, becoming negligible after day 7. MRI results for the normal repair group showed low to moderate signal intensity by day 7. A clinical study retrospectively evaluated post-hip arthroplasty patient images at intervals of 1 month, 2-3 months, 5-6 months, and over 7 months. In these patients, 18F-FDG SUVmax and volume remained relatively stable over time, while 68Ga-FAPI-04 SUVmax initially increased, then decreased, with a consistent reduction in volume. CONCLUSION: In skeletal muscle injuries, FAP demonstrates a distinctive mechanism of action, and 68Ga-FAPI-04, in comparison to other tests, more precisely captures alterations in lesion site uptake intensity and volume. TRIAL REGISTRATION: Trial registration: ChiCTR2000041204. Registered 22 December 2020, https://www.chictr.org.cn/showproj.html?proj=66211.

Wastewater treatment plant effluents increase the global warming potential in a subtropical urbanized river.

Rivers play a pivotal role in global carbon (C) and nitrogen (N) biogeochemical cycles. Urbanized rivers are significant hotspots of greenhouse gases (GHGs, N2O, CO2 and CH4) emissions. This study examined the GHGs distributions in the Guanxun River, an effluents-receiving subtropical urbanized river, as well as the key environmental factors and processes affecting the pattern and emission characteristics of GHGs. Dissolved N2O, CO2, and CH4 concentrations reached 228.0 nmol L-1, 0.44 mmol L-1, and 5.2 µmol L-1 during the wet period, and 929.8 nmol L-1, 0.7 mmol L-1, and 4.6 µmol L-1 during the dry period, respectively. Effluents inputs increased C and N loadings, reduced C/N ratios, and promoted further methanogenesis and N2O production dominated by incomplete denitrification after the outfall. Increased urbanization in the far downstream, high hydraulic residence time, low DO and high organic C environment promoted methanogenesis. The strong CH4 oxidation and methanogenic reactions inhibited by the effluents combined to suppress CH4 emissions in downstream near the outfall, and the process also contributed to CO2 production. The carbon fixation downstream from the outfall were inhibited by effluents. Ultimately, it promoted CO2 emissions downstream from the outfall. The continuous C, N, and chlorine inputs maintained the high saturation and production potential of GHGs, and altered microbial community structure and functional genes abundance. Ultimately, the global warming potential downstream increased by 186 % and 84 % during wet and dry periods on the 20-year scale, and increased by 91 % and 49 % during wet and dry periods on the 100-year scale, respectively, compared with upstream from the outfall. In urbanized rivers with sufficient C and N source supply from WWTP effluents, the large effluent equivalently transformed the natural water within the channel into a subsequent "reactor". Furthermore, the IPCC recommended EF5r values appear to underestimate the N2O emission potential of urbanized rivers with high pollution loading that receiving WWTP effluents. The findings of this study might aid the development of effective strategies for mitigating global climate change.

Land use/cover drive functional patterns of bacterial communities in sediments of a subtropical river, China.

The bacterial community in sediment serves as an important indicator for assessing the environmental health of river ecosystems. However, the response of bacterial community structure and function in river basin sediment to different land use/cover changes has not been widely studied. To characterize changes in the structure, composition, and function of bacterial communities under different types of land use/cover, we studied the bacterial communities and physicochemical properties of the surface sediments of rivers. Surface sediment in cropland and built-up areas was moderately polluted with cadmium and had high nitrogen and phosphorus levels, which disrupted the stability of bacterial communities. Significant differences in the α-diversity of bacterial communities were observed among different types of land use/cover. Bacterial α-diversity and energy sources were greater in woodlands than in cropland and built-up areas. The functional patterns of bacterial communities were shown that phosphorus levels and abundances of pathogenic bacteria and parasites were higher in cropland than in the other land use/cover types; Urban activities have resulted in the loss of the denitrification function and the accumulation of nitrogen in built-up areas, and bacteria in forested and agricultural areas play an important role in nitrogen degradation. Differences in heavy metal and nutrient inputs driven by land use/cover result in variation in the composition, structure, and function of bacterial communities.

Investigation of the differential susceptibility of extraocular muscles in patients diagnosed with ocular myasthenia gravis based on the computerized diplopia test and the Ocular Motor Nerve Palsy Scale.

Introduction: The pattern of extraocular muscle involvement in ocular myasthenia gravis varies across different reports, diverging from our own observations. Thus, we employed two novel tools to discern this pattern. Methods: A retrospective analysis was conducted to collect and organize clinical data from 43 patients diagnosed with ocular myasthenia gravis. Each patient underwent both the computerized diplopia test and the Ocular Motor Nerve Palsy Scale assessment to evaluate the involvement of extraocular muscles. Results: Among the patients, there were 30 male and 13 female individuals, with a total of 113 affected extraocular muscles identified. Among all the affected extraocular muscles, the involvement of the levator palpebrae superioris muscle accounted for 35.40%, medial rectus muscle 7.7%, lateral rectus muscle 16.81%, superior rectus muscle 13.27%, inferior rectus muscle 12.39%, superior oblique muscle 1.77%, and inferior oblique muscle 2.65% of the total affected extraocular muscles. The positivity rates of the Neostigmine test were 89.19%, AChR antibody detection was 59.38%, and repetitive nerve stimulation was 34.38%. The AChR antibody positive rate among patients with only diplopia was 100%; among those with only ptosis, it was 80%; and among those with both diplopia and ptosis, it was 86.67%. Conclusion: The involvement of the extraocular muscles is not uniform. The levator palpebrae superioris exhibits the highest incidence rate, followed by the four rectus muscles and two oblique muscles. The inferior oblique involvement typically occurs when four or more EOMs are affected. Moreover, the levator palpebrae superioris and medial rectus show a higher tendency for bilateral involvement compared with other extraocular muscles.

A Voltage-Assist 16-Channel Electrochemical Biosensor with Linearity Compensation.

Large capacitive loading of electrodes induces massive error current and imperfect settling in the electrochemical signal acquisition process, leading to inaccurate acquisition results. To efficiently mitigate this inaccuracy, this paper presents a current-and-voltage dual-mode acquisition technique in which a voltage front-end (VFE) is employed to acquire the electrode voltage error and compensate the nonlinearity induced by the electrode capacitive loading. Therefore, the gain and bandwidth requirements of the current front end (CFE) can be relaxed to reduce the complexity and power consumption. With a relieved gain requirement, an inverter-based capacitive trans-impedance amplifier (IB-CTIA) is adopted to boost the input transconductance for low-noise design. By reusing the supply current, the IB-CTIA effectively achieves a low input-referred current noise of 3.9 pArms and a dynamic range (DR) of 126 dB with only 18-µW static power. The prototype chip is fabricated in a 180-nm CMOS process. Interleukin-6 immunoassays (IL-6) are implemented to verify the chip's performance. With the proposed nonlinear error compensation, the correlation coefficient of the detection result is improved from 0.951 to 0.980 and the limit of detection (LoD) is reduced from 8.31 pg/mL to 6.90 pg/mL.

Mohawk protects against tendon damage via suppressing Wnt/ß-catenin pathway.

Degenerative tendon injuries are common clinical problems associated with overuse or aging, and understanding the mechanisms of tendon injury and regeneration can contribute to the study of tendon healing and repair. As a transcription factor, Mohawk (Mkx) is responsible for tendons development, yet, the roles of which in tendon damage remain mostly elusive. In this study, using Mkx overexpressed mice on long treadmill as an in vivo model and MkxOE Achilles tenocytes stimulated by equiaxial stretch as an in vitro model, we anaylsed the effects of Mkx overexpression on the tendon. Mkx and tendon tension strength were decreased after the expose to excessive mechanical forces, and Mkx overexpression protected the tendon from damage. Moreover, we revealed that the Wnt/ß-catenin activation, inflammation, and Runx2 expression were increased at the injured Achilles tendon, upregulated Mkx significantly reversed the increased Wnt/ß-catenin pathway, Tnf-α, Il-1ß, and Il-6 levels, and reduced tendon cell damage. However, Wnt3a, IWR and BIO had not significantly affected the Mkx expression in achilles tenocytes. In conclusion, Mkx is involved in tendon healing and protects the tendon from damage through suppressing Wnt/ß-catenin pathway, suggesting Mkx/Wnt/ß-catenin pathway may be potential therapeutic targets for tendon damage.

Meniscal fibrocartilage regeneration inspired by meniscal maturational and regenerative process.

Meniscus is a complex and crucial fibrocartilaginous tissue within the knee joint. Meniscal regeneration remains to be a scientific and translational challenge. We clarified that mesenchymal stem cells (MSCs) participated in meniscal maturation and regeneration using MSC-tracing transgenic mice model. Here, inspired by meniscal natural maturational and regenerative process, we developed an effective and translational strategy to facilitate meniscal regeneration by three-dimensionally printing biomimetic meniscal scaffold combining autologous synovium transplant, which contained abundant intrinsic MSCs. We verified that this facilitated anisotropic meniscus-like tissue regeneration and protected cartilage from degeneration in large animal model. Mechanistically, the biomechanics and matrix stiffness up-regulated Piezo1 expression, facilitating concerted activation of calcineurin and NFATc1, further activated YAP-pSmad2/3-SOX9 axis, and consequently facilitated fibrochondrogenesis of MSCs during meniscal regeneration. In addition, Piezo1 induced by biomechanics and matrix stiffness up-regulated collagen cross-link enzyme expression, which catalyzed collagen cross-link and thereby enhanced mechanical properties of regenerated tissue.

3D Printing of Microenvironment-Specific Bioinspired and Exosome-Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration.

In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment-specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double-network hydrogel scaffold produced via 3D printing with tissue-specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D-printed microenvironment-specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM-based microenvironment-specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell-free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.

Synthesis of zeolite A from fly ash and its application in the slow release of urea.

The study focused on the transformation of coal fly ash to zeolite A (ZA) as a potential carrier for the slow release of urea. After being treated with HCl aqueous solution and NaOH successively, SiO2 and Al2O3 were converted into sodium silicoaluminate. The obtained silicoaluminate was then heated with NaAlO2 in an aqueous NaOH solution at 70-110 °C for 3-18 h and zeolite A was successfully prepared according to the X-ray diffraction measurements. By changing the hydrothermal temperature and time, ZA could reach 237.3 mmol/100 g in maximum cation exchange capacity. ZA impregnated with urea (ZA-U) at a mass ratio of more than 5:1 exhibited slow release of urea and the kinetics release mechanism of ZA-U was proposed. The plant growth test proved that the slow release of urea from ZA-U can promote the growth of maize seedling.

Earlier and More Severe Cartilage Degeneration Occurs After Meniscal Tears in Juvenile Rabbits Compared with Adults.

OBJECTIVE: To compare the severity of cartilage degeneration after meniscal tears between juvenile and adult rabbits. DESIGN: This study included 20 juvenile rabbits (2 weeks after birth) and 20 adult rabbits (6 months after birth). Meniscal tears were prepared in the anterior horn of medial menisci of right knees. Rabbits were sacrificed at 1, 3, 6, and 12 weeks postoperatively. Cartilage degenerations in the medial femoral condyle and medial tibial plateau were evaluated macroscopically and histologically. The semiquantitative assessment of cartilage degeneration was graded by macroscopic Outerbridge scoring system and histological Osteoarthritis Research Society International (OARSI) scoring system. RESULTS: In juvenile rabbits, the morphologically intact cartilage and normal extracellular matrix architecture were observed at the first week postoperatively. Mild uneven cartilage surface and toluidine blue depletion in the medial femoral condyle were observed on histological assessment at 3 weeks postoperatively. The worsened cartilage deterioration demonstrating chondral fibrillation, prominent cell death, and glycosaminoglycan (GAG) release was observed at 6 and 12 weeks postoperatively. In adult rabbits, only mild cartilage degeneration was observed in the medial femoral condyle at 12 weeks postoperatively. The outcomes of Outerbridge and OARSI scores were consistent with the aforementioned findings in juvenile and adult rabbits. CONCLUSIONS: Our study validated that earlier and more severe cartilage degenerations were observed in juvenile rabbits after meniscal tears compared with adult rabbits. Moreover, the post-tear cartilage degeneration demonstrated regional specificity corresponded to the tear position. However, caution is warranted when extrapolating results of animal models to humans.

A prediction model for acute respiratory distress syndrome among patients with severe acute pancreatitis: a retrospective analysis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication among patients with severe acute pancreatitis (SAP), which may be associated with increased mortality in hospitalized patients. Thus, an effective model to predict ARDS in patients with SAP is urgently required. METHODS: We retrospectively analyzed the data from the patients with SAP who recruited in Xiangya Hospital between April 2017 and May 2021. Patients meeting the Berlin definition of ARDS were categorized into the ARDS group. Logistic regression models and a nomogram were utilized in the study. Descriptive statistics, logistic regression models, and a nomogram were used in the current study. RESULTS: Comorbidity of ARDS occurred in 109 (46.58%) of 234 patients with SAP. The SAP patients with ARDS group had a higher 60-day mortality rate, an increased demand for invasive mechanical ventilation, and a longer intensive care unit (ICU) stay than those without ARDS (p < .001 for all). Partial pressure of oxygen (PaO2): fraction of inspired oxygen (FiO2) < 200, platelets <125 × 109/L, lactate dehydrogenase >250 U/L, creatinine >111 mg/dL, and procalcitonin >0.5 ng/mL were independent risk variables for development of ARDS in SAP patients. The area under the curve for the model was 0.814, and the model fit was acceptable [p = .355 (Hosmer-Lemeshow)]. Incorporating these 5 factors, a nomogram was established with sufficient discriminatory power (C-index 0.814). Calibration curve indicated the proper discrimination and good calibration in the predicting nomogram model. CONCLUSION: The prediction nomogram for ARDS in patients with SAP can be applied using clinical common variables after the diagnosis of SAP. Future studies would be warranted to verify the potential clinical benefits of this model.

Blood Urea Nitrogen as a Prognostic Marker in Severe Acute Pancreatitis.

Objectives: To explore independent risk factors with good and early predictive power for SAP severity and prognosis. Methods: Patients with SAP were enrolled at Central South University Xiangya Hospital between April 2017 and May 2021 and used as the training cohort. From June 2021 to February 2022, all patients with SAP were defined as external patients for validation. Patients were grouped by survival status at a 30-day posthospital admission and then compared in terms of basic information and laboratory tests to screen the independent risk factors. Results: A total of 249 patients with SAP were enrolled in the training cohort. The all-cause mortality rate at a 30-day postadmission was 25.8% (51/198). Blood urea nitrogen (BUN) levels were significantly higher in the mortality group (20.45 [interquartile range (IQR), 19.7] mmol/L) than in the survival group (6.685 [IQR, 6.3] mmol/L; P < 0.001). After propensity score matching (PSM), the BUN level was still higher in the mortality group than in the survival group (18.415 [IQR, 19.555] mmol/L vs. 10.63 [IQR, 6.03] mmol/L; P = 0.005). The area under the curve (AUC) of the receiver operating characteristic curve (ROC) of BUN was 0.820 (95% confidence interval, 0.721-0.870; P < 0.001). The optimal BUN level cut-off for predicting a 30-day all-cause mortality was 10.745 mmol/L. Moreover, patients with SAP were grouped according to BUN levels and stratified according to optimal cut-off value. Patients with high BNU levels were associated with significantly higher rates of invasive mechanical ventilation (before PSM: 61.8% vs. 20.6%, P < 0.001; after PSM: 71.1% vs. 32%, P = 0.048) and a 30-day all-cause mortality (before PSM: 44.9% vs. 6.9%, P < 0.001; after PSM: 60% vs. 34.5%, P = 0.032) than those with low BNU levels before or after PSM. The effectiveness of BUN as a prognostic marker was further validated using ROC curves for the external validation set (n = 49). The AUC of BUN was 0.803 (95% CI, 0.655-0.950; P = 0.011). It showed a good ability to predict a 30-day all-cause mortality in patients with SAP. We also observed similar results regarding disease severity, including the Acute Physiology and Chronic Health Evaluation II score (before PSM: 16 [IQR, 8] vs. 8 [IQR, 6], P < 0.001; after PSM: 18 [IQR, 10] vs. 12 [IQR, 7], P < 0.001), SOFA score (before PSM: 7 [IQR, 5] vs. 3 [IQR, 3], P < 0.001; after PSM: 8 [IQR, 5] vs. 5 [IQR, 3.5], P < 0.001), and mMarshall score (before PSM: 4 [IQR, 3] vs. 3 [IQR, 1], P < 0.001; after PSM: 5 [IQR, 2.5] vs. 3 [IQR, 1], P < 0.001). There was significant increase in intensive care unit occupancy in the high BUN level group before PSM (93.3% vs. 73.1%, P < 0.001), but not after PSM (97.8% vs. 86.2%, P = 0.074). Conclusions: Our results showed that BUN levels within 24 h after hospital admission were independent risk factors for a 30-day all-cause death in patients with SAP.

The transplantation of particulated juvenile allograft cartilage and synovium for the repair of meniscal defect in a lapine model.

Background: Synovium has been confirmed to be the primary contributor to meniscal repair. Particulated Juvenile Allograft Cartilage (PJAC) has demonstrated promising clinical effect on repairing cartilage. The synergistic effect of synovium and PJAC transplant on meniscal fibrocartilaginous repair is unclear. We hypothesize that the transplantation of synovium and PJAC synergistically facilitates meniscal regeneration and the donor cells within graft tissues still survive in the regenerated tissue at the last follow up (16 weeks postoperatively). Methods: The study included 24 mature female rabbits, which were randomly divided into experimental and control groups. A cylindrical full-thickness defect measuring 2.0 â€‹mm was prepared in the avascular portion of the anterior horn of medial meniscus in both knees. The synovium and PJAC transplant were harvested from juvenile male rabbits (2 months after birth). The experimental group received synovium and PJAC transplant encapsulated with fibrin gel. The control groups received synovium transplant encapsulated with fibrin gel, pure fibrin gel and nothing. The macroscopic, imageological and histological evaluations of repaired tissue were performed at 8 weeks and 16 weeks postoperatively. The in situ hybridization (ISH) of male-specific sex-determining region Y-linked (SRY) gene was performed to detect the transplanted cells. Results: The regenerated tissue in experimental group showed superior structural integrity, superficial smoothness, and marginal integration compared to control groups at 8 weeks or 16 weeks postoperatively. More meniscus-like fibrochondrocytes filled the repaired tissue in the experimental group, and the matrix surrounding these cell clusters demonstrated strongly positive safranin O and type 2 collagen immunohistochemistry staining. By SRY gene ISH, the positive SRY signal of experimental group could be detected at 8 weeks (75.72%, median) and 16 weeks (48.69%, median). The expression of SOX9 in experimental group was the most robust, with median positive rates of 65.52% at 8 weeks and 67.55% at 16 weeks. Conclusion: The transplantation of synovium and PJAC synergistically facilitates meniscal regeneration. The donor cells survive for at least 16 weeks in the recipient. The translational potential of this article: This study highlighted the positive effect of PJAC and synovium transplant on meniscal repair. We also clarified the potential repair mechanisms reflected by the survival of donor cells and upregulated expression of meniscal fibrochondrocytes related genes. Thus, based on our study, further clinical experiments are needed to investigate synovium and PJAC transplant as a possible treatment to meniscal defects.

Pollution characteristics and source analysis of heavy metals in surface sediments of Luoyuan Bay, Fujian.

The concentrations of eight heavy metals, V, Cr, Co, Ni, Cu, Zn, Cd, and Pb, were analyzed to explore the environmental pollution characteristics, ecological risk levels, and sources of heavy metals in the surface sediments of Luoyuan Bay in Fujian Province. The results indicated that the mean concentrations of V, Cr, Co, Ni, Cu, Zn, Cd, and Pb were 110.44, 97.76, 17.35, 41.99, 36.78, 137.26, 0.09, and 35.81 mg⋅kg-1, respectively. The mean concentrations of Cr, Cu, and Zn exceeded the first category of the marine sediment quality standards, indicating a moderate regional comprehensive potential ecological hazard level. Due to variable hydrodynamic conditions, high concentrations of heavy metals were observed in the north and low concentrations were observed in the south, with high values generally recorded near steel plants and shipyard docks. Correlation and principal component analyses revealed that the V, Al, Co, Ni, and Pb originated from the weathering and erosion of rocks, and industrial wastewater discharge. Contrastingly, Cu, Zn, Cr, and Cd were mainly associated with the transportation and repair of ships, and marine aquaculture activities.

Histologically Confirmed Recellularization is a Key Factor that Affects Meniscal Healing in Immature and Mature Meniscal Tears.

Healing outcomes of meniscal repair are better in younger than in older. However, exact mechanisms underlying superior healing potential in younger remain unclear from a histological perspective. This study included 24 immature rabbits and 24 mature rabbits. Tears were created in the anterior horn of medial meniscus of right knee in each rabbit. Animals were sacrificed at 1, 3, 6, and 12 weeks postoperatively. We performed macroscopic and histological evaluations of post-meniscal repair specimens. Cells were counted within a region of interest to confirm cellularization at tear site in immature menisci. The width of cell death zone was measured to determine the region of cell death in mature menisci. Apoptosis was evaluated by TUNEL assay. Vascularization was assessed by CD31 immunofluorescence. The glycosaminoglycans and the types 1 and 2 collagen content was evaluated by calculating average optical density of corresponding histological specimens. Cartilage degeneration was also evaluated. Healing outcomes following untreated meniscal tears were superior in immature group. Recellularization with meniscus-like cell morphology was observed at tear edge in immature menisci. Superior recellularization was observed at meniscal sites close to joint capsule than at sites distant from the capsule. Recellularization did not occur at tear site in mature group; however, we observed gradual enlargement of cell death zone. Apoptosis was presented at 1, 3, 6, 12 weeks in immature and mature menisci after untreated meniscal tears. Vascularization was investigated along the tear edges in immature menisci. Glycosaminoglycans and type 2 collagen deposition were negatively affected in immature menisci. We observed glycosaminoglycan degradation in mature menisci and cartilage degeneration, specifically in immature cartilage of the femoral condyle. In conclusion, compared with mature rabbits, immature rabbits showed more robust healing response after untreated meniscal tears. Vascularization contributed to the recellularization after meniscal tears in immature menisci. Meniscal injury fundamentally alters extracellular matrix deposition.

Advances in the Mechanisms Affecting Meniscal Avascular Zone Repair and Therapies.

Injuries to menisci are the most common disease among knee joint-related morbidities and cover a widespread population ranging from children and the general population to the old and athletes. Repair of the injuries in the meniscal avascular zone remains a significant challenge due to the limited intrinsic healing capacity compared to the peripheral vascularized zone. The current surgical strategies for avascular zone injuries remain insufficient to prevent the development of cartilage degeneration and the ultimate emergence of osteoarthritis (OA). Due to the drawbacks of current surgical methods, the research interest has been transferred toward facilitating meniscal avascular zone repair, where it is expected to maintain meniscal tissue integrity, prevent secondary cartilage degeneration and improve knee joint function, which is consistent with the current prevailing management idea to maintain the integrity of meniscal tissue whenever possible. Biological augmentations have emerged as an alternative to current surgical methods for meniscal avascular zone repair. However, understanding the specific biological mechanisms that affect meniscal avascular zone repair is critical for the development of novel and comprehensive biological augmentations. For this reason, this review firstly summarized the current surgical techniques, including meniscectomies and meniscal substitution. We then discuss the state-of-the-art biological mechanisms, including vascularization, inflammation, extracellular matrix degradation and cellular component that were associated with meniscal avascular zone healing and the advances in therapeutic strategies. Finally, perspectives for the future biological augmentations for meniscal avascular zone injuries will be given.

Cereal Vinegar Sediment Alleviates Spontaneous Ulcerative Colitis in Il-10 Deficient Mice.

SCOPE: Cereal vinegar sediment (CVS) is precipitation generated during the preservation of vinegar. It has various functions such as anti-inflammatory, anti-tumor, hypoglycemic, and hypolipidemic. This study evaluates the effects of CVS on spontaneous colitis in Il-10-/- mice. METHODS AND RESULTS: CVS (1 g kg-1 body weight) is administered to mice for 42 days. CVS alleviated epithelium damage, inhibited myeloperoxidase (MPO) activity and malondialdehyde (MDA) level, decreased gene expression of tumor necrosis factor (Tnf )-a, inducible nitric oxide synthase (Inos), Interleukin(Il-23) in colon tissues is found. CVS also inhibited secretion of IL-2, IL-6, IL-13, Granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GMCSF), Interferon (IFN)-γ, and Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) in serum. While CVS enhanced Regenerating Family Member 3 Gamma (Reg3γ), Mucin (Muc2, Muc3, and Muc4 gene expression, promoted intestinal epithelial cells to secrete Muc-2, and increased the content of acetic acid in intestinal tract of Il-10-/- mice. Additionally, CVS altered the composition of the gut microbiota by promoting the abundance of Akkermansia, Alistipes, and Lactobacillus, while inhibiting Desulfovibrio and Clostridium sensu stricto 1. These changes may be related to the regulation of steroid, fatty acids, and bile acid biosynthesis. CONCLUSION: This study demonstrated that CVS ameliorates spontaneous ulcerative colitis in Il-10-/- mice, which suggests CVS supplementation may serve as a protective dietary nutrient against colitis.

Directionally Paired Principal Component Analysis for Bivariate Estimation Problems.

We propose Directionally Paired Principal Component Analysis (DP-PCA), a novel linear dimension-reduction model for estimating coupled yet partially observable variable sets. Unlike partial least squares methods (e.g., partial least squares regression and canonical correlation analysis) that maximize correlation/covariance between the two datasets, our DP-PCA directly minimizes, either conditionally or unconditionally, the reconstruction and prediction errors for the observable and unobservable part, respectively. We demonstrate the optimality of the proposed DP-PCA approach, we compare and evaluate relevant linear cross-decomposition methods with data reconstruction and prediction experiments on synthetic Gaussian data, multi-target regression datasets, and a single-channel image dataset. Results show that when only a single pair of bases is allowed, the conditional DP-PCA achieves the lowest reconstruction error on the observable part and the total variable sets as a whole; meanwhile, the unconditional DP-PCA reaches the lowest prediction errors on the unobservable part. When an extra budget is allowed for the observable part's PCA basis, one can reach an optimal solution using a combined method: standard PCA for the observable part and unconditional DP-PCA for the unobservable part.