Differential Etching of Rays at Wood Surfaces Exposed to an Oxygen Glow Discharge Plasma.

Basswood samples were exposed to oxygen glow-discharge plasmas for 30 min, and etching of radial and tangential longitudinal surfaces was measured. It was hypothesized that there would be a positive correlation between etching and plasma energy, and differential etching of wood surfaces because of variation in the microstructure and chemical composition of different woody tissues. Etching at the surface of basswood samples was examined using profilometry. Light and scanning electron microscopy were used to examine the microstructure of samples exposed to plasma. There was a large effect of plasma energy on etching of basswood surfaces, and radial surfaces were etched to a greater extent than tangential surfaces. However, rays at radial surfaces were more resistant to etching than fibers, resulting in greater variation in the etching of radial versus tangential surfaces. The same phenomenon occurred at radial surfaces of balsa wood, jelutong and New Zealand white pine subjected to plasma etching. The possible reasons for the greater resistance of rays to plasma etching are explored, and it is suggested that such differential etching of wood surfaces may impose a limitation on the use of plasma to precisely etch functional patterns at wood surfaces (raised pillars, grooves), as has been done with other materials.

An End-to-End Dynamic Posture Perception Method for Soft Actuators Based on Distributed Thin Flexible Porous Piezoresistive Sensors.

This paper proposes a method for accurate 3D posture sensing of the soft actuators, which could be applied to the closed-loop control of soft robots. To achieve this, the method employs an array of miniaturized sponge resistive materials along the soft actuator, which uses long short-term memory (LSTM) neural networks to solve the end-to-end 3D posture for the soft actuators. The method takes into account the hysteresis of the soft robot and non-linear sensing signals from the flexible bending sensors. The proposed approach uses a flexible bending sensor made from a thin layer of conductive sponge material designed for posture sensing. The LSTM network is used to model the posture of the soft actuator. The effectiveness of the method has been demonstrated on a finger-size 3 degree of freedom (DOF) pneumatic bellow-shaped actuator, with nine flexible sponge resistive sensors placed on the soft actuator's outer surface. The sensor-characterizing results show that the maximum bending torque of the sensor installed on the actuator is 4.7 Nm, which has an insignificant impact on the actuator motion based on the working space test of the actuator. Moreover, the sensors exhibit a relatively low error rate in predicting the actuator tip position, with error percentages of 0.37%, 2.38%, and 1.58% along the x-, y-, and z-axes, respectively. This work is expected to contribute to the advancement of soft robot dynamic posture perception by using thin sponge sensors and LSTM or other machine learning methods for control.

Fibroblastic reticular cells in lymph node potentiate white adipose tissue beiging through neuro-immune crosstalk in male mice.

Lymph nodes (LNs) are always embedded in the metabolically-active white adipose tissue (WAT), whereas their functional relationship remains obscure. Here, we identify fibroblastic reticular cells (FRCs) in inguinal LNs (iLNs) as a major source of IL-33 in mediating cold-induced beiging and thermogenesis of subcutaneous WAT (scWAT). Depletion of iLNs in male mice results in defective cold-induced beiging of scWAT. Mechanistically, cold-enhanced sympathetic outflow to iLNs activates ß1- and ß2-adrenergic receptor (AR) signaling in FRCs to facilitate IL-33 release into iLN-surrounding scWAT, where IL-33 activates type 2 immune response to potentiate biogenesis of beige adipocytes. Cold-induced beiging of scWAT is abrogated by selective ablation of IL-33 or ß1- and ß2-AR in FRCs, or sympathetic denervation of iLNs, whereas replenishment of IL-33 reverses the impaired cold-induced beiging in iLN-deficient mice. Taken together, our study uncovers an unexpected role of FRCs in iLNs in mediating neuro-immune interaction to maintain energy homeostasis.

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma.

BACKGROUND: This study aimed to validate whether infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells is safe and whether CAR-T cells exert anti-glioblastoma (GBM) activity. METHODS: A total of eight patients with GD2-positive GBM were enrolled and infused with autologous GD2-specific 4SCAR-T cells, either through intravenous administration alone or intravenous combined with intracavitary administration. RESULTS: 4SCAR-T cells expanded for 1-3 weeks and persisted at a low frequency in peripheral blood. Of the eight evaluable patients, four showed a partial response for 3 to 24 months, three had progressive disease for 6 to 23 months, and one had stable disease for 4 months after infusion. For the entire cohort, the median overall survival was 10 months from the infusion. GD2 antigen loss and infiltrated T cells were observed in the tumor resected after infusion. CONCLUSION: Both single and combined infusions of GD2-specific 4SCAR-T cells in targeting GBM were safe and well tolerated, with no severe adverse events. In addition, GD2-specific 4SCAR-T cells partially mediate antigen loss and activate immune responses in the tumor microenvironment. Validation of our findings in a larger prospective trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03170141 . Registered 30 May 2017.

Src homology 3 domain binding kinase 1 protects against hepatic steatosis and insulin resistance through the Nur77-FGF21 pathway.

BACKGROUND AND AIMS: Metabolism in the liver is dysregulated in obesity, contributing to various health problems including steatosis and insulin resistance. While the pathogenesis of lipid accumulation has been extensively studied, the protective mechanism against lipid challenge in the liver remains unclear. Here, we report that Src homology 3 domain binding kinase 1 (SBK1) is a regulator of hepatic lipid metabolism and systemic insulin sensitivity in response to obesity. APPROACH AND RESULTS: Enhanced Sbk1 expression was found in the liver of high-fat diet (HFD)-induced obese mice and fatty acid (FA)-challenged hepatocytes. SBK1 knockdown in mouse liver cells augmented FA uptake and lipid accumulation. Similarly, liver-specific SBK1 knockout ( Lsko ) mice displayed more severe hepatosteatosis and higher expression of genes in FA uptake and lipogenesis than the Flox/Flox ( Fl/Fl ) control mice when fed the HFD. The HFD-fed Lsko mice also showed symptoms of hyperglycemia, poor systemic glucose tolerance, and lower insulin sensitivity than the Fl/Fl mice. On the other hand, hepatic Sbk1 overexpression alleviated the high-fructose diet-induced hepatosteatosis, hyperlipidemia, and hyperglycemia in mice. White adipose tissue browning was also observed in hepatic SBK1 -overexpressed mice. Moreover, we found that SBK1 was a positive regulator of FGF21 in the liver during energy surplus conditions. Mechanistically, SBK1 phosphorylates the orphan nuclear receptor 4A1 (Nur77) on serine 344 to promote hepatic FGF21 expression and inhibit the transcription of genes involved in lipid anabolism. CONCLUSIONS: Collectively, our data suggest that SBK1 is a regulator of the metabolic adaption against obesity through the Nur77-FGF21 pathway.

Dietary exposure to polystyrene nanoplastics impairs fasting-induced lipolysis in adipose tissue from high-fat diet fed mice.

The health concerns of microplastics (MPs) and nanoplastics (NPs) surge, but the key indicators to evaluate the adverse risks of MPs/NPs are elusive. Recently, MPs/Ps were found to disturb glucose and lipid metabolism in rodents, suggesting that MPs/NPs may play a role in obesity progression. In this study, we firstly demonstrated that the distribution of fluorescent polystyrene nanoplastics (nPS, 60 nm) white adipose tissue (WAT) of mice. Furthermore, nPS could traffic across adipocytes in vitro and reduced lipolysis under ß-adrenergic stimulation in adipocytes in vitro and ex vivo. Consistently, chronic oral exposure to nPS at the dietary exposure relevant concentrations (3 and 223 µg/kg body weight) impaired fasting-induced lipid mobilization in obese mice and subsequently contributed to larger adipocyte size in the subcutaneous WAT. In addition, the chronic exposure of nPS induced macrophage infiltration in the small intestine and increased lipid accumulation in the liver, accelerating the disruption of systemic metabolism. Collectively, our findings highlight the potential obesogenic role of nPS via diminishing lipid mobilization in WAT of obese mice and suggest that lipolysis relevant parameters may be used for evaluating the adverse effect of MPs/NPs in clinics.

Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride-VLDL Secretion via ApoB Degradation.

Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.

YY1 Regulates Glucose Homeostasis Through Controlling Insulin Transcription in Pancreatic ß-Cells.

To date, identification of nonislet-specific transcriptional factors in the regulation of insulin gene expression has been little studied. Here, we report that the expression level of the transcription factor YY1 is increased dramatically in both human and mouse pancreatic ß-cells after birth. Nevertheless, the physiological role of YY1 during ß-cell development and its regulatory mechanism in ß-cell function remain largely unknown. After ß-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced ß-cell mass in neonatal and adult mice. These mice also had hypoinsulinemia with normal insulin sensitivity compared with their wild-type littermates, manifesting as a type 1 diabetic phenotype. Mechanistically, genome-wide RNA sequencing has defined dysregulated insulin signaling and defective glucose responsiveness in ß-cells devoid of YY1. Integrative analyses coupled with chromatin immunoprecipitation assays targeting YY1, and histone modifications, including H3K4me1, H3K27ac, and H3K27me3, have further identified Ins1 and Ins2 as direct gene targets of YY1. Luciferase reporter assays and loss- and gain-of-function experiments also demonstrated that YY1 binds to the enhancer regions in exon 2 of Ins1 and Ins2, activating insulin transcription and, therefore, proinsulin and insulin production in pancreatic ß-cells. YY1 also directly interacts with RNA polymerase II, potentially stabilizing the enhancer-promoter interaction in the multiprotein-DNA complex during transcription initiation. Taken together, our findings suggest a role for YY1 as a transcriptional activator of insulin gene expression, assisting ß-cell maturation and function after birth. These analyses may advance our understanding of ß-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes.

A new role of the early endosome in restricting NLRP3 inflammasome via mitophagy.

NLRP3 (NLR family pyrin domain containing 3) inflammasome is a potent mediator of inflammation due to its ability to produce the pro-inflammatory cytokines IL1B (interleukin 1 beta) and IL18 in response to numerous danger signals and pathogens. Mitophagy, a selective form of autophagy, restricts NLRP3 inflammasome activation by limiting the mitochondrial-derived danger signals. Here, we demonstrated that the adaptor protein APPL1 together with its interaction partner RAB5 in early endosomes negatively regulate NLRP3 inflammasome activation via induction of mitophagy in macrophages. Hematopoietic-deletion of Appl1 exacerbates systemic NLRP3 inflammasome activation in rodent models under obese or septic conditions. Our study identified a new regulatory network between early endosomes and mitochondria in control of NLRP3 inflammasome activation.

Surfaces Decorated with Enantiomorphically Pure Polymer Nanohelices via Hierarchical Chirality Transfer across Multiple Length Scales.

Mesoscale chiral materials are prepared by lithographic methods, assembly of chiral building blocks, and through syntheses in the presence of polarized light. Typically, these processes result in micrometer-sized structures, require complex top-down manipulation, or rely on tedious asymmetric separation. Chemical vapor deposition (CVD) polymerization of chiral precursors into supported films of liquid crystals (LCs) are discovered to result in superhierarchical arrangements of enantiomorphically pure nanofibers. Depending on the molecular chirality of the 1-hydroxyethyl [2.2]paracyclophane precursor, extended arrays of enantiomorphic nanohelices are formed from achiral nematic templates. Arrays of chiral nanohelices extend over hundreds of micrometers and consistently display enantiomorphic micropatterns. The pitch of individual nanohelices depends on the enantiomeric excess and the purity of the chiral precursor, consistent with the theoretical model of a doubly twisted LC director configuration. During CVD of chiral precursors into cholesteric LC films, aspects of molecular and mesoscale asymmetry combine constructively to form regularly twisted nanohelices. Enantiomorphic surfaces permit the tailoring of a wide range of functional properties, such as the asymmetric induction of weak chiral systems.

PM20D1 is a circulating biomarker closely associated with obesity, insulin resistance and metabolic syndrome.

OBJECTIVE: Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans. DESIGN AND METHODS: Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography-mass spectrometry, respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes. RESULTS: Serum PM20D1 level was significantly elevated in overweight/obese individuals and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2 h postprandial glucose, HbA1c, fasting insulin and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes. CONCLUSIONS: Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.

Adipose MDM2 regulates systemic insulin sensitivity.

The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.

The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages.

Although mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs mitophagy, leading to accumulation of damaged mitochondria producing reactive oxygen species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1ß, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting mitophagy in macrophages.

Kinect-based rapid movement training to improve balance recovery for stroke fall prevention: a randomized controlled trial.

BACKGROUND: Falls are more prevalent in stroke survivors than age-matched healthy older adults because of their functional impairment. Rapid balance recovery reaction with adequate range-of-motion and fast response and movement time are crucial to minimize fall risk and prevent serious injurious falls when postural disturbances occur. A Kinect-based Rapid Movement Training (RMT) program was developed to provide real-time feedback to promote faster and larger arm reaching and leg stepping distances toward targets in 22 different directions. OBJECTIVE: To evaluate the effectiveness of the interactive RMT and Conventional Balance Training (CBT) on chronic stroke survivors' overall balance and balance recovery reaction. METHODS: In this assessor-blinded randomized controlled trial, chronic stroke survivors were randomized to receive twenty training sessions (60-min each) of either RMT or CBT. Pre- and post-training assessments included clinical tests, as well as kinematic measurements and electromyography during simulated forward fall through a "lean-and-release" perturbation system. RESULTS: Thirty participants were recruited (RMT = 16, CBT = 14). RMT led to significant improvement in balance control (Berg Balance Scale: pre = 49.13, post = 52.75; P = .001), gait control (Timed-Up-and-Go Test: pre = 14.66 s, post = 12.62 s; P = .011), and motor functions (Fugl-Meyer Assessment of Motor Recovery: pre = 60.63, post = 65.19; P = .015), which matched the effectiveness of CBT. Both groups preferred to use their non-paretic leg to take the initial step to restore stability, and their stepping leg's rectus femoris reacted significantly faster post-training (P = .036). CONCLUSION: The RMT was as effective as conventional balance training to provide beneficial effects on chronic stroke survivors' overall balance, motor function and improving balance recovery with faster muscle response. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03183635 , NCT03183635) on 12 June 2017.

Septic arthritis of the acromioclavicular joint secondary to methicillin-resistant Staphylococcus aureus infection.

Septic arthritis of the acromioclavicular joint (ACJ) is a rare pathology with very few documented case reports available in the literature. In addition, ACJ septic arthritis secondary to methicillin-resistant Staphylococcus aureus (MRSA) is a rarer pathology with only two previously documented case reports in the medical literature to our knowledge. We present the case of a 46-year-old man who was diagnosed with a confirmed ACJ septic arthritis secondary to MRSA following admission to the local trauma and orthopaedic service at a district general hospital. We aim to give an insight into this pathology and highlight the importance of the relationship between orthopaedics and microbiology in optimising patient care, particularly in a period of rising rates of antimicrobial resistance.

Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes.

Early changes in astrocyte energy metabolism are associated with late-onset Alzheimer's disease (LOAD), but the underlying mechanism remains elusive. A previous study suggested an association between a synonymous SNP (rs1012672, C→T) in LRP6 gene and LOAD; and that is indeed correlated with diminished LRP6 gene expression in the frontal cortex region. The authors show that LRP6 is a unique Wnt coreceptor on astrocytes, serving as a bimodal switch that modulates their metabolic landscapes. The Wnt-LRP6 mediated mTOR-AKT axis is essential for sustaining glucose metabolism. In its absence, Wnt switches to activate the LRP6-independent Ca2+ -PKC-NFAT axis, resulting in a transcription network that favors glutamine and branched chain amino acids (BCAAs) catabolism over glucose metabolism. Exhaustion of these raw materials essential for neurotransmitter biosynthesis and recycling results in compromised synaptic, cognitive, and memory functions; priming for early changes that are frequently found in LOAD. The authors also highlight that intranasal supplementation of glutamine and BCAAs is effective in preserving neuronal integrity and brain functions, proposing a nutrient-based method for delaying cognitive and memory decline when LRP6 cell surface levels and functions are suboptimal.

Sarcopenia and mortality in different clinical conditions: A meta-analysis.

OBJECTIVES: Sarcopenia is recognized to be a health problem which is as serious as obesity, but its relevance to mortality is unclear. We conducted a meta-analysis of cohort studies on lean mass and mortality in populations with different health conditions. METHODS: In this study, a systematic search of PubMed, Cochrane Library and Embase was performed for cohort studies published before Dec 20, 2017 which examined the relationship between lean mass and mortality. We included studies reporting lean mass measurement by dual-energy X-ray absorptiometry, bioimpedance analysis or computed tomography, as continuous (per standard deviation [SD] decrease) or binary variables (using sarcopenia cutoffs). We excluded studies which used muscle mass surrogates, anthropometric measurement of muscle, rate of change in muscle mass, and sarcopenia defined by composite criteria. The primary study outcome was all-cause mortality. Pooled hazard ratio estimates were calculated using a random effects model. RESULTS: A total of 9602 articles were identified from the systematic search, and 188 studies with 98 468 participants from 34 countries were included in the meta-analysis. Of the 68 studies included in the present meta-analysis, the pooled HR was 1.36 and 1.74 for every SD decrease in lean mass and in people with low lean mass (cutoffs), respectively. Significant associations were also observed in elderly and all disease subgroups, irrespective of the measurement modalities. CONCLUSIONS: Lower lean mass is robustly associated with increased mortality, regardless of health conditions and lean mass measurement modalities. This meta-analysis highlighted low lean mass as a key public health issue.

The effect of different measurement modalities in the association of lean mass with mortality: A systematic review and meta-analysis.

OBJECTIVES: Lean mass is commonly measured by 3 modalities, dual energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and computerized tomography (CT). CT is considered the most accurate, while lean mass measured by DXA and BIA often consists of non-muscle compartment, and hence considered less accurate when compared with CT. It remains unclear if the association of lean mass with mortality would differ using different measurement modalities. METHODS: A systematic review and meta-analysis of lean mass and mortality was conducted. The analysis was stratified by different measurement modalities and health conditions. Pooled hazard ratios were estimated using a random effects model. RESULTS: This meta-analysis included 188 studies with 98 468 participants. Reduced lean mass measured by BIA, DXA, and CT, was associated with increased risk of mortality with a hazard ratio (HR) of 1.35 (95% CI, 1.21-1.49), 1.18 (95% CI, 1.06-1.30), and 1.44 (95% CI, 1.32-1.57), respectively. Similarly, low lean mass defined by BIA-, DXA-, and CT-measurement was associated with increased risk of mortality, with an HR of 1.81 (95% CI, 1.56-2.10), 1.44 (95% CI, 1.29-1.60), and 1.78 (95% CI, 1.64-1.93). CONCLUSIONS: Reduced and low lean mass were robustly associated with increased mortality in studies using different measurement modalities.