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Compromised autophagy and mitochondrial dysfunction downregulate chondrocytic activity, accelerating the development of osteoarthritis (OA). Irisin, a cleaved form of fibronectin type III domain containing 5 (FNDC5), regulates bone turnover and muscle homeostasis. Little is known about the effect of Irisin on chondrocytes and the development of osteoarthritis. This study revealed that human osteoarthritic articular chondrocytes express decreased level of FNDC5 and autophagosome marker LC3-II but upregulated levels of oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) and apoptosis. Intra-articular administration of Irisin further alleviated symptoms of medial meniscus destabilization, like cartilage erosion and synovitis, while improved the gait profiles of the injured legs. Irisin treatment upregulated autophagy, 8-OHdG and apoptosis in chondrocytes of the injured cartilage. In vitro, Irisin improved IL-1β-mediated growth inhibition, loss of specific cartilage markers and glycosaminoglycan production by chondrocytes. Irisin also reversed Sirt3 and UCP-1 pathways, thereby improving mitochondrial membrane potential, ATP production, and catalase to attenuated IL-1β-mediated reactive oxygen radical production, mitochondrial fusion, mitophagy, and autophagosome formation. Taken together, FNDC5 loss in chondrocytes is correlated with human knee OA. Irisin repressed inflammation-mediated oxidative stress and extracellular matrix underproduction through retaining mitochondrial biogenesis, dynamics and autophagic program. Our analyses shed new light on the chondroprotective actions of this myokine, and highlight the remedial effects of Irisin on OA development.

Assimilation of the Moderate Resolution Imaging Spectroradiometer (MODIS) total aerosol optical depth (AOD) retrieval products (at 550 nm wavelength) from both Terra and Aqua satellites have been developed within the National Centers for Environmental Prediction (NCEP) Gridpoint Statistical Interpolation (GSI) three‐dimensional variational (3DVAR) data assimilation system. This newly developed algorithm allows, in a one‐step procedure, the analysis of 3‐D mass concentration of 14 aerosol variables from the Goddard Chemistry Aerosol Radiation and Transport (GOCART) module. The Community Radiative Transfer Model (CRTM) was extended to calculate AOD using GOCART aerosol variables as input. Both the AOD forward model and corresponding Jacobian model were developed within the CRTM and used in the 3DVAR minimization algorithm to compute the AOD cost function and its gradient with respect to 3‐D aerosol mass concentration. The impact of MODIS AOD data assimilation was demonstrated by application to a dust storm from 17 to 24 March 2010 over East Asia. The aerosol analyses initialized Weather Research and Forecasting/Chemistry (WRF/Chem) model forecasts. Results indicate that assimilating MODIS AOD substantially improves aerosol analyses and subsequent forecasts when compared to MODIS AOD, independent AOD observations from the Aerosol Robotic Network (AERONET) and Cloud‐Aerosol Lidar with Orthogonal Polarization (CALIOP) instrument, and surface PM10 (particulate matter with diameters less than 10 μm) observations. The newly developed AOD data assimilation system can serve as a tool to improve simulations of dust storms and general air quality analyses and forecasts. Key Points Assimilating MODIS AOD with a 3DVAR method coupled with WRF/Chem model Using individual aerosol species as analysis variables in 3DVAR AOD data assimilation substantially improved aerosol analysis and forecast

Directed energy deposition (DED), also known as laser cladding, is a metal additive manufacturing process in which a high-power laser combined with a coaxial powder delivery system is used to additively manufacture a three-dimensional metal component layer-by-layer. Due to its convenience and superior quality, DED has gained popularity in recent years. However, despite many advantages, it has low deposition efficiency and produces parts with poor surface evenness, high porosity, and poor mechanical properties. This study performs one-factor-at-a-time experiments to valuate five DED processing parameters, namely the laser and powder focus point positions, laser head raising height (Z-offset), laser power, powder feed rate, and laser scanning speed. The laser and powder focus point positions and the Z-offset are first adjusted to maximize the surface evenness and deposition efficiency. Several experiments are then performed to investigate the effects of laser power, powder feed rate, and laser cladding speed on the porosity and dilution of DED-built parts. Finally, a mathematical model is proposed to predict the quality (i.e., dilution) of DED-built parts as a function of DED processing parameters. Based on the results, the optimal focus point positions and Z-offset are found. The variations of porosity and dilution with three processing parameters are shown. The proposed model can be used to set up DED processing parameters to produce higher quality parts on the first attempt.

Background Prior research has highlighted the synergistic impact of protein supplementation on muscle function post‐exercise in adults; however, evidence supporting the combined effects were less robust and inconsistent on those with protein insufficiency. This investigation aims to explore efficacy of protein‐enriched soup coupled with exercise on muscle health and metabolism in middle‐aged and older adults with suboptimal protein intake. Methods An open‐label, 12‐week, randomized controlled trial involving participants with insufficient protein intake (<1.0 g/kg/day) was done. The intervention group consumed protein‐enriched soup (24–30 g protein daily) and 1‐h weekly exercise, while controls received health education. Assessments included laboratory tests, functional assessments, and body composition. Results In this trial, 97 out of 100 randomized participants (mean age: 64.65 ± 4.84 years, 81.8% female) completed the study (47 in intervention group and 50 in control group). Compared results of baselines, at 1 and 3 months of intervention, significant improvements in waist circumference (83.48 ± 10.22 vs. 82.5 ± 9.88 vs. 82.37 ± 9.42 cm, P for trend = 0.046), 6‐min walking distance (525.65 ± 58.46 vs. 534.47 ± 51.87 vs. 552.02 ± 57.66 m, P for trend = 0.001), five‐time sit‐to‐stand time (7.63 ± 1.63 vs. 6.81 ± 1.8 vs. 6.4 ± 1.42 s, P for trend <0.001), grip strength (26.74 ± 6.54 vs. 27.53 ± 6.99 vs. 28.52 ± 7.09 kg, P for trend <0.001), and MNA score (26.8 ± 2.14 vs. 27.73 ± 1.74 vs. 27.55 ± 1.72, P for trend <0.001) were discerned within the intervention group. The intervention demonstrated a significant reduction in serum triglyceride (105.32 ± 49.84 vs. 101.36 ± 42.58 vs. 93.43 ± 41.49 mg/dL, P for trend = 0.023), increased HDL‐C (60.04 ± 16.21 vs. 60 ± 17.37 vs. 62.55 ± 18.27 mg/dL, P for trend = 0.02), and DHEA‐S levels (97.11 ± 54.39 vs. 103.39 ± 56.75 vs. 106.83 ± 60.56 μg/dL, P for trend = 0.002). Serum myostatin did not differ in both groups, but serum leptin levels significantly increased (9118.88 ± 5811.68 vs. 11508.97 ± 7151.08 vs. 11220.80 ± 7190.71 pg/mL, P for trend = 0.016) in controls. The intervention group showed greater improvements in 6 min walking distance (β = 0.71, 95% CI: 6.88 to 40.79, P = 0.006), five‐time sit‐to‐stand test (β = −0.87, 95% CI: −1.59 to −0.15, P = 0.017), MNA score (β = 0.96, 95% CI: 0.20 to 1.71, P = 0.013), serum triglycerides (β = −15.01, 95% CI: −27.83 to −2.20, P = 0.022), LDL‐C (β = −9.23, 95% CI: −16.98 to −1.47, P = 0.020), and DHEA‐S levels (β = 9.98, 95% CI: 0.45 to 19.51, P = 0.04) than controls. Conclusions Protein‐enriched soup with weekly exercise over 12 weeks significantly improved physical performance, lipid profile, and DHEA‐S levels among middle‐aged and older adults with inadequate protein intake, while studies assessing long‐term benefits of the intervention are needed.

Blood culture is viewed as the golden standard for the diagnosis of sepsis but suffers from low sensitivity and long turnaround time. LightCycler SeptiFast (LC-SF) is a real-time multiplex polymerase chain reaction test able to detect 25 common pathogens responsible for bloodstream infections within hours. We aim to assess the accuracy of LC-SF by systematically reviewing the published studies. Related literature on Medline, Embase, and Cochrane databases was searched up to October 2012 for studies utilizing LC-SF to diagnose suspected sepsis and that provided sufficient data to construct two-by-two tables. A total of 34 studies enrolling 6012 patients of suspected sepsis were included. The overall sensitivity and specificity for LC-SF to detect bacteremia or fungemia was 0·75 (95% CI: 0·65-0·83) and 0·92 (95%CI:0·90-0·95), respectively. LC-SF had a high positive likelihood ratio (10·10) and a moderate negative likelihood ratio (0·27). Specifically, LC-SF had a sensitivity of 0·80 (95%CI: 0·70-0·88) and a specificity of 0·95(95%CI: 0·93-0·97) for the bacteremia outcome, and a sensitivity of 0·61 (95%CI: 0·48-0·72) and a specificity of 0·99 (95%CI: 0·99-0·99) for the fungemia outcome. High heterogeneity was found in the bacteremia outcome subgroup but not in the fungemia outcome subgroup. LC-SF is of high rule-in value for early detection of septic patients. In a population with low pretest probability, LC-SF test can still provide valuable information for ruling out bacteremia or fungemia.

Engineering approaches were adopted for liver microsystems to recapitulate cell arrangements and culture microenvironments in vivo for sensitive, high-throughput and biomimetic drug screening. This review introduces liver microsystems in vitro for drug hepatotoxicity, drug-drug interactions, metabolic function and enzyme induction, based on cell micropatterning, hydrogel biofabrication and microfluidic perfusion. The engineered microsystems provide varied microenvironments for cell culture that feature cell coculture with non-parenchymal cells, in a heterogeneous extracellular matrix and under controllable perfusion. The engineering methods described include cell micropatterning with soft lithography and dielectrophoresis, hydrogel biofabrication with photolithography, micromolding and 3D bioprinting, and microfluidic perfusion with endothelial-like structures and gradient generators. We discuss the major challenges and trends of liver microsystems to study drug response in vitro.

Non-alcoholic fatty liver disease (NAFLD) has been on a global rise. While animal models have rendered valuable insights to the pathogenesis of NAFLD, discrepancy with patient data still exists. Since non-alcoholic steatohepatitis (NASH) involves chronic inflammation, and CD4 T cell infiltration of the liver is characteristic of NASH patients, we established and characterized a humanized mouse model to identify human-specific immune response(s) associated with NAFLD progression. Immunodeficient mice engrafted with human immune cells (HIL mice) were fed with high fat and high calorie (HFHC) or chow diet for 20 weeks. Liver histology and immune profile of HIL mice were analyzed and compared with patient data. HIL mice on HFHC diet developed steatosis, inflammation and fibrosis of the liver. Human CD4 central and effector memory T cells increased within the liver and in the peripheral blood of our HIL mice, accompanied by marked up-regulation of pro-inflammatory cytokines (IL-17A and IFNγ). depletion of human CD4 T cells in HIL mice reduced liver inflammation and fibrosis, but not steatosis. Our results highlight CD4 memory T cell subsets as important drivers of NAFLD progression from steatosis to fibrosis and provides a humanized mouse model for pre-clinical evaluation of potential therapeutics.

Parkinson’s disease (PD) is a neurodegenerative disorder and always results in balance loss. Although studies in lower-extremity exoskeleton robots are ample, applications with a lower-extremity exoskeleton robot for PD patients are still challenging. This paper aims to develop an effective assistive control for PD patients with a lower-extremity exoskeleton robot to maintain standing balance while being subjected to external disturbances. When an external force is applied to participants to force them to lose balance, the hip strategy for balance recovery based on the zero moment point (ZMP) metrics is used to generate a reference trajectory of the hip joint, and then, a model-free linear extended state observer (LESO)-based fuzzy sliding mode control (FSMC) is synthesized to regulate the human body to recover balance. Balance recovery trials for healthy individuals and PD patients with and without exoskeleton assistance were conducted to evaluate the performance of the proposed exoskeleton robot and balance recovery strategy. Our experiments demonstrated the potential effectiveness of the proposed exoskeleton robot and controller for standing balance recovery control in PD patients.

We evaluated the IOP-lowering efficacy and safety of latanoprostene bunod (LBN) ophthalmic solution 0.024% (Vyzulta®), the first topical nitric oxide-donating prostaglandin analog (PGA), in clinical practice. A retrospective medical chart review from July 2021 to July 2023 of patients with open-angle glaucoma receiving LBN with at least 1 year follow-up was conducted. All included patients received LBN 0.024% as a replacement for a PGA, with examinations at 1-, 3-, 6-and 12-months follow-up. Main outcome measures were IOP, retinal nerve fiber layer thickness, visual fields before/after LBN use and adverse effects. Subgroup analysis with glaucoma types and PGA use were performed for additional IOP reduction after LBN use. Among 78 included patients, 47 patients (81 eyes), 60% with open-angle glaucoma (OAG) remained on LBN throughout 12-month follow-up. Baseline IOP was 18.2±4.2 mm Hg, and Prostaglandin analog (PGA)-IOP was 14.4 ± 3.0 mm Hg (21% mean IOP reduction). After switched to LBN, mean additional IOP reduction was 1.0 mm Hg at month 1, and the greatest reduction was 1.6 mm Hg (8.8% additional mean IOP reduction) at month 12 (P<0.0001). Subgroup analysis (NTG, 73%) showed that mean additional IOP reduction at month 12 was 1.3±2.0 mm Hg in NTG group and 2.1±3.2 mm Hg in POAG group (7.7% vs. 8.7% additional IOP reduction rates, P = 0.23). Subgroup analysis of PGA use at month 12 was 1.8±2.3 mm Hg in tafluoprost group and 0.5±1.7 mm Hg in travoprost group (9.5% vs.2.6% additional IOP reduction rates, P = 0.02). Tolerable ocular adverse effects included irritation (n = 16, 19.8%), mild conjunctival hyperemia (n = 11, 13.6%), dark circles (n = 4, 4.9%) and blurred vision (n = 2, 2.5%). There were no significant visual field and retinal nerve fiber layer thickness changes after 12 months of treatment with LBN 0.024%. Although high intolerable adverse effects including conjunctival hyperemia and eye irritation happened in the first month, remaining sixty percent of patients exhibited statistically significant additional IOP reductions in the replacement of other PGAs during 12 months of clinical use of LBN 0.024%.

Bioassay-guided fractionation of extracts derived from solid cultures of a Herbidospora daliensis originating from Taiwan led to the isolation of five new compounds, for which we propose the name herbidosporadalins A–E (1–5), one isolated for the first time, herbidosporadalin F (6), together with two known compounds (7 & 8). Their structures were elucidated by spectroscopic analyses, including 1D- and 2D-NMR experiments with those of known analogues, and on the basis of HR-EI-MS mass spectrometry, their anti-inflammatory activities were also evaluated. Of these isolates, herbidosporadalin A (1), B (2), F (6) and G (8) showed NO inhibitory activity, with IC50 values of 11.8 ± 0.9, 7.1 ± 2.9, 17.8 ± 1.7, and 13.3 ± 6.5 μM, stronger than the positive control quercetin (IC50 = 36.8 ± 1.3 μM). To the best of our knowledge, this is the first report on 3,4-seco-friedelane metabolites (5, 6 & 8) from the genus Herbidospora.