Powerful Rare-Variant Association Analysis of Secondary Phenotypes.

Most genome-wide association studies are based on case-control designs, which provide abundant resources for secondary phenotype analyses. However, such studies suffer from biased sampling of primary phenotypes, and the traditional statistical methods can lead to seriously distorted analysis results when they are applied to secondary phenotypes without accounting for the biased sampling mechanism. To our knowledge, there are no statistical methods specifically tailored for rare variant association analysis with secondary phenotypes. In this article, we proposed two novel joint test statistics for identifying secondary-phenotype-associated rare variants based on prospective likelihood and retrospective likelihood, respectively. We also exploit the assumption of gene-environment independence in retrospective likelihood to improve the statistical power and adopt a two-step strategy to balance statistical power and robustness. Simulations and a real-data application are conducted to demonstrate the superior performance of our proposed methods.

Wrinkle Clamp Down on Structure Crack Strain Sensor Based on High Poisson's Ratio Material for Home Health Monitoring and Human-Machine Interaction.

Flexible wearable crack strain sensors are currently receiving significant attention because they can be used in a wide range of physiological signal monitoring and human-machine interaction applications. However, sensors with high sensitivity, great repeatability, and wide sensing range remain challenging. Herein, a tunable wrinkle clamp down structure (WCDS) crack strain sensor based on high Poisson's ratio material with high sensitivity, high stability, and wide strain range is proposed. Based on the high Poisson's ratio of the acrylic acid film, the WCDS was prepared by a prestretching process. The wrinkle structures can clamp down the crack to improve the cyclic stability of the crack strain sensor while maintaining its high sensitivity. Moreover, the tensile properties of the crack strain sensor are improved by introducing wrinkles in the bridge-like gold stripes connecting each separated gold flake. Owing to this structure, the sensitivity of the sensor can reach 3627, stable operation over 10 000 cycles is achieved, and the strain range can reach about 9%. In addition, the sensor exhibits low dynamic response and good frequency characteristics. Because of its demonstrated excellent performance, the strain sensor can be used in pulse wave and heart rate monitoring, as well as posture recognition and game control.

Miniaturized Flexible Non-Contact Interface Based on Heat Shrinkage Technology.

High-performance miniaturized flexible sensors are becoming increasingly important in wearable electronics. However, miniaturization of devices often requires high-precision manufacturing processes and equipment, which limits the commercialization of flexible sensors. Therefore, revolutionary technologies for manufacturing miniaturized flexible sensors are highly desired. In this work, a new method for manufacturing miniaturized flexible humidity sensor by utilizing heat shrinkage technology is presented. This method successfully achieves much smaller sensor and denser interdigital electrode. Utilizing this method, a miniaturized flexible humidity sensor and array are presented, fabricated by anchoring nano-Al2 O3 into carbon nano-tube as the humidity sensitive film. This heat shrinkage technology, forming wrinkle structure on the humidity sensitive film, endows the sensor with a high sensitivity over 200% (ΔR/R0 ) at humidity levels ranging from 0 to 90%RH and a fast recovery time (0.5 s). The sensor allows non-contact monitoring human respiration and alerting in case of an asthma attack and the sensor array can be adaptively attached to the wrist as a non-contact human-machine interface to control the mechanical hand or computer. This work provides a general and effective heat shrinkage technology for the development of smaller and more efficient flexible circuits and sensor devices.

A highly adaptive real-time water wave sensing array for marine applications.

The ocean accounts for about 70% of the Earth's surface area. In recent years, there has been increasing research into large-scale power generation device networks for ocean energy and the number of mobile sensing nodes in the ocean is expected to increase with the operation of the Internet of Things (IoT). Since water waves are low-frequency intermittent energy, they are suitable for harvesting and sensing by a triboelectric nanogenerator (TENG) with high conversion efficiency, flexible structural design, and environmental friendliness. Furthermore, TENG-units are suitable for large-scale water waves. We proposed a 6 × 4 cross-vertical double-layer electrode array device to sense and restore the water wave state. The design of this structure can refine the waveform display while reducing the electrode interfaces and achieving efficient and accurate sensing of the water wave. Then we developed a complete display system combined with the device and demonstrated the superior performance of each unit and the whole array both on a curved surface and underwater. It can be expected that the device and the system will have great potential in maritime applications.

Flexible Triboelectric Tactile Sensor Based on a Robust MXene/Leather Film for Human-Machine Interaction.

With the rapid development of Internet of Things (IoT) technology in recent years, self-actuated sensor systems without an external power supply such as flexible triboelectric nanogenerator (TENG)-based strain sensors have received wide attention due to their simple structure and self-powered active sensing properties. However, to satisfy the practical applications of human wearable biointegration, flexible TENGs impose higher requirements for establishing a balance between material flexibility and good electrical properties. In this work, the strength of the MXene/substrate interface was greatly improved by utilizing leather with a unique surface structure as the substrate material, resulting in a mechanically strong and electrically conductive MXene film. Due to the natural fiber structure of the leather surface, the surface of the MXene film with a rough structure was obtained, which improved the electrical output performance of the TENG. The electrode output voltage of MXene film on leather based on single-electrode TENG can reach 199.56 V and the maximum output power density can reach 0.469 mW/cm2. Combined with laser-assisted technology, the efficient array preparation of MXene and graphene was achieved and applied to various human-machine interface (HMI) applications.

Adipose-derived mesenchymal stem cell-secreted extracellular vesicles alleviate non-alcoholic fatty liver disease via delivering miR-223-3p.

Increasing studies have identified the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in non-alcoholic fatty liver disease (NAFLD) treatment. Hence, we further focused on the potential of adipose-derived MSC (ADSC)-EVs in NAFLD by delivering miR-223-3p. The uptake of isolated ADSC-EVs by hepatocytes was assessed, and the expression of miR-223-3p in ADSC-EVs and hepatocytes was characterized. It was established that miR-223-3p, enriched in ADSC-EVs, could be delivered by ADSC-EVs into hepatocytes. Using co-culture system and gain-of-function approach, we evaluated the effect of ADSC-EVs carrying miR-223-3p on lipid accumulation and liver fibrosis in pyrrolizidine alkaloids (PA)-induced hepatocytes and a high-fat diet-induced NAFLD mouse model. Bioinformatics websites and dual-luciferase reporter gene assay were performed to determine the interactions between miR-223-3p and E2F1, which was further validated by rescue experiments. ADSC-EVs containing miR-223-3p displayed suppressive effects on lipid accumulation and liver fibrosis through E2F1 inhibition, since E2F1 was demonstrated as a target gene of miR-223-3p. The protective role of ADSC-EVs by delivering miR-223-3p was then confirmed in the mouse model. Collectively, this study elucidated that ADSC-EVs delayed the progression NAFLD through the delivery of anti-fibrotic miR-223-3p and subsequent E2F1 suppression, which may suggest miR-223-3p-loaded ADSC-EVs to be a potential therapeutic approach for NAFLD.

Flexible alternating current electroluminescent devices integrated with high voltage triboelectric nanogenerators.

Flexible alternating current electroluminescent (ACEL) devices have attracted growing interest as promising wearable displays for their uniformity of light emission, low power consumption, and excellent reliability. However, the requirement of high-voltage power sources for driving ACEL devices greatly impedes their portability and commercialization. Here, we developed flexible ACEL devices integrated with high output-voltage triboelectric nanogenerators (TENG) using easy and low-cost crumpled Al electrodes. The output voltage and current could reach as high as 490 V and 71.74 µA, corresponding to the maximum instantaneous output power density of 1.503 mW cm-2, which was demonstrated to power an integrated flexible ACEL patterned display. In addition, through signal acquisition and transmission, ACEL can display the compression frequency of TENG in real time. Such self-powered ACEL devices are very promising as flexible displays in wearable electronics.

Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages.

M1-polarized macrophages are involved in chronic inflammatory diseases, including nonalcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the activation of macrophages in NAFLD have not been fully elucidated. This study aimed at investigating the physiological mechanisms by which extracellular vesicles (EVs)-encapsulated microRNA-9-5p (miR-9-5p) derived from lipotoxic hepatocytes might activate macrophages in NALFD. After blood sample and cell collection, EVs were isolated and identified followed by co-culture with macrophages. Next, the palmitic acid-induced cell and high fat diet-induced mouse NALFD models were established to explore the in vitro and in vivo effects of EVs-loaded miR-9-5p on NAFLD as evidenced by inflammatory cell infiltration and inflammatory reactions in macrophages. Additionally, the targeting relationship between miR-9-5p and transglutaminase 2 (TGM2) was identified using dual-luciferase reporter gene assay. miR-9-5p was upregulated in the NAFLD-EVs, which promoted M1 polarization of THP-1 macrophages. Furthermore, miR-9-5p could target TGM2 to inhibit its expression. Downregulated miR-9-5p in NAFLD-EVs alleviated macrophage inflammation and M1 polarization as evidenced by reduced levels of macrophage inflammatory factors, positive rates of CD86+ CD11b+, and levels of macrophage surface markers in vitro. Moreover, the effect of silencing of miR-9-5p was replicated in vivo, supported by reductions in TG, TC, AST and ALT levels and attenuated pathological changes. Collectively, lipotoxic hepatocytes-derived EVs-loaded miR-9-5p downregulated the expression of TGM2 and facilitated M1 polarization of macrophages, thereby promoting the progression of NAFLD. This highlights a potential therapeutic target for treating NAFLD.

Splenic infarction associated with obstructive sleep apnoea/hypopnoea syndrome: a case report.

Splenic infarction is rare, resulting from occlusion of the splenic artery or its branches. Its aetiology is complex and multifactorial involving various vascular and thrombotic diseases, thus, misdiagnosis or missed diagnosis is common. Here, the case of a 45-year old male patient diagnosed with splenic infarction caused by secondary erythrocytosis associated with obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is reported. The patient presented with 10 days of abdominal distension and pain that worsened after eating, and had developed to include nausea, vomiting and fever. The patient had a history of night snoring for over 10 years without treatment, a diagnosis of chronic pulmonary heart disease and secondary polycythaemia 5 years previously, and diagnosis of OSAHS 1 year previously. He had not received previous non-invasive ventilation or oxygen therapy. Enhanced upper abdomen computed tomography (CT) showed splenic infarction, bone marrow cytology suggested secondary polycythaemia, and sleep polysomnography revealed severe OSAHS. Low molecular-weight heparin, ceftriaxone, fluid and oxygen treatment gradually relieved abdominal distension and pain. Enhanced CT showed splenic infarction improvement. The present case highlights that splenic embolism should not be ignored as a potential complication of OSAHS.

Photocatalytically renewable peptide-based electrochemical impedance method for sensing lipopolysaccharide.

A peptide (Li5-025)-modified gold nanoparticle (AuNP)/(titania (TiO2) + 5,10,15,20-tetrakis(4-aminophenyl)-21H,23H-porphine (TAPP))/glassy carbon electrode (GCE) was developed for lipopolysaccharide (LPS) determination. This electrode not only performs well in the electrochemical impedance determination of LPS in serum but can also be easily regenerated under light irradiation. Using Fe(CN)63-/4- as a redox probe, LPS recognition can be indicated by the significantly increased electron-transfer resistance (Ret) as a result of the coaction of the increased steric hindrance from the peptide-LPS complex and the electrostatic repulsion between LPS and Fe(CN)63-/4-. The impedimetric signal was acquired in the frequency range 0.1 Hz ~ 100 kHz with an initial voltage of 174 mV and an amplitude of 10 mV. The resistance changes (ΔRet) are linearly related to the LPS concentrations in a broad range (0.1 pg mL-1 ~ 100 ng mL-1) with a low detection limit (0.08 pg mL-1). Importantly, the electrode shows high selectivity to LPS from Escherichia coli O55:B5 compared to other bacterial sources and considerable anti-interference to 0.1% fetal calf serum, demonstrating its potential application in clinically relevant samples. Another highlight is that the AuNP/(TiO2 + TAPP)/GCE surface can be photocatalytically regenerated under light irradiation (50 mW cm-2, 300-2500 nm) without any obvious damage to the electrode microstructure. After simple peptide re-immobilization, the regenerated electrode demonstrates LPS response similar to the peptide less one, and the deviation is only 2.89% after 5-cycle reuse. Graphical abstract A peptide (Li5-025)-modified AuNP/(TiO2 + TAPP porphine)/GCE was proposed, which not only has excellent electrochemical analytical performances for LPS assay in serum but also can be reused after light irradiation and subsequent peptide re-immobilization.

Role of gingival mesenchymal stem cell exosomes in macrophage polarization under inflammatory conditions.

OBJECTIVE: Exosomes have been shown to play a strong role in intercellular communication. While GMSCs have been extensively studied, less research exists on exosomes derived from GMSCs, especially on how exosomes affect macrophages. This study aimed to investigate the impact of GMSC-derived exosomes on macrophage polarization and phenotype under inflammatory conditions. METHODS: Exosomes were isolated from GMSCs-conditioned media by ultracentrifugation (UC) and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot (WB). In vitro, GMSC-derived exosomes were co-incubated with macrophages for 24 h in the absence or presence of M1 polarizing conditions in the six-well plate. The protein and mRNA expression levels of M1 and M2 macrophage markers were detected and the supernatants were collected for an enzyme-linked immunosorbent assay (ELISA). RESULTS: Exosomes were successfully isolated from GMSCs. Macrophages co-cultured with exosomes showed significantly decreased levels of the M1 markers Tumor Necrosis Factor-α (TNF-α), Interleukin-12 (IL-12), CD86 and Interleukin-1ß (IL-1ß). By contrast, M2 marker Interleukin-10 (IL-10) levels moderately increased. Meanwhile, similar results were acquired in the cell culture supernatants. CONCLUSION: GMSC-derived exosomes may promote M1 macrophage transformation into M2 macrophages, reducing the pro-inflammatory factors produced by M1 macrophages.

Molecular weight impact on the mechanical forces between hyaluronan and its receptor.

Hyaluronan (HA) possesses manifold mechanical and signaling properties in the body. Most of these activities are largely regulated by its molecular weight, which often triggers opposing functions. However the molecular basis for such function distinction between HA size categories remains unclear. Using a combination of biophysical techniques, we measured the physical forces between HA ligand and its specific receptor CD44 in both normal and lateral directions, at different HA molecular weights and bound states. It was found that the impact of HA multivalency is more than just the sum of separate monovalent bindings. The HA-CD44 specific interaction enhances with HA molecular weight and the maximum binding occurs at ∼1000 kD, possibly due to the balance between multivalent HA zipping effect and conformational entropy. High friction patches, probably from CD44 protein clustering, was observed in friction force microscopy (FFM) upon HA shearing, which is also dependent on HA molecular weight. These results could help to understand the biophysical mechanism of HA in regulating CD44-induced physiological activities and thus facilitate the new design of HA-based material in fine tuning the receptor responses.

Hydromethanolic extract of Rehum emodi exhibits significant antimicrobial activity against acute gastroenteriti bacterial strains.

Rehum emodi is an important medicinal herbal and has been reported to exhibit tremendous pharmacological potential. The present study was designed to evaluate the antibacterial activity of hydromethanolic extract of rhizome of Rehum emodi against the acute gastroenteriti bacterial strains. The antimicrobial activity was determined by micro-dilution method. Antioxidant activity was determined by DPPH assay and cytotoxicity by MTT assay. Phytochemical analysis was carried out by LC/MS analysis. The results of the present study showed that hydromethanolic extract of rhizome of Rehum emodi (REE) exhibited significant antimicrobial activity against the gastroenteriti bacterial strains. The MIC values ranged from 25 µg/ml to 125 µg/ml. Moreover, the cytotoxicity of the REE was evaluated against the human breast cell line FR-2 and it was observed that REE exerted minimal cytotoxic effects on these cells with an IC50 of 250 µg/ml indicating that this extract is non-toxic to human cells. The phytochemical analysis revealed the presence of several secondery metabolites such as anthroquinones (anthrone, emodin, aloe emodin and rhein) flavonoids (quercetin, and naringenin) and phenolics (sinapinic acid and gallic acid) which could potentially be responsible for the activity of the extract. In conclusion REE could potentially prove to be useful in the treatment of acute gastroenteritis.

A Cluster of Symptomatic and Asymptomatic Infections of Severe Fever with Thrombocytopenia Syndrome Caused by Person-to-Person Transmission.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus that was identified to be the etiological pathogen of the emerging infectious disease, severe fever with thrombocytopenia syndrome (SFTS). SFTSV could be transmitted through tick bite. Transmission of SFTSV among humans has also been reported mainly through direct blood contact. In July 2014, a cluster of six suspected SFTS cases occurred in Shandong Province, China. In this cluster, both symptomatic and asymptomatic persons were included. By analyzing the clinical data and results of laboratory tests, and conducting the epidemiological interviews with the cases and their families, risk factors responsible for the transmission were evaluated. The findings suggested that SFTSV transmission among humans may cause asymptomatic infection via personal contact without blood exposure.