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Abstract Immunoproteasomes (IP) serve as an important modulator of immune responses to pathogens and other pathological factors. LMP7/β5i, one of the IP subunits, plays a critical role in autoimmune diseases by downregulating inflammation. Rhinovirus (RV) infection is a major risk factor in the exacerbations of respiratory inflammatory diseases, but whether LMP7 regulates RV-mediated inflammation in the lung particularly in the airway epithelium, the first line of defense against RV infection, remains unclear. In this study, we determined whether airway epithelial LMP7 promotes the resolution of RV-mediated lung inflammation. Inducible airway epithelial-specific LMP7-deficient (conditional knockout, CKO) mice were generated to reveal the in vivo anti-inflammatory and antiviral functions of LMP7. By using LMP7-deficient primary human airway epithelial cells generated by CRISPR-Cas9, we confirmed that airway epithelial LMP7 decreased pro-inflammatory cytokines and viral load during RV infection. Additionally, airway epithelial LMP7 enhanced the expression of a negative immune regulator A20/TNFAIP3 during viral infection that may contribute to the anti-inflammatory function of LMP7. We also discovered that induction of LMP7 by a low dose of polyinosinic:polycytidylic acid (PI:C) reduced RV-mediated inflammation in our CKO mice infected with RV. Our findings suggest that airway epithelial LMP7 has anti-inflammatory and antiviral functions that is critical to the resolution of RV-mediated lung inflammation. Induction of airway epithelial LMP7 may open a novel avenue for therapeutic intervention against RV infection.

Abstract The Aurignacian is one of the first cultural-technological traditions commonly associated with the expansion of Homo sapiens in Europe. Early Homo sapiens demographics across the continent are therefore typically inferred using the distribution of Aurignacian assemblages. Western Romania has been used as a tie-point to connect the well-researched lithic assemblages from the eastern Mediterranean and Western Europe through its early Homo sapiens fossils. However, Romania’s archeological record remains underexplored thereby hindering our ability to directly connect better understood regions through time and space. Here we report on excavations from the open-air Middle/Upper Paleolithic site of Româneș ti-Dumbrăvița I in southwestern Romania. Three stratified Paleolithic assemblages were extensively excavated within a 1-m-thick eolian-deposited sequence. Spatial, geochemical, raw material, techno-typological, and use-wear analysis of the site reveal patterns of artifact configuration, resource exploitation, fire history, knapping objectives, and functionality. Taken together, Românești-Dumbrăvița I is the first well-contextualized archeological site in close spatiotemporal proximity to many early, well-preserved human fossils and in East-Central Europe.

Respiratory influenza A virus (IAV) infection continues to pose significant challenges in healthcare of human diseases including asthma. IAV infection in mice was shown to increase IL-33, a key cytokine in driving airway inflammation in asthma, but how IL-33 is regulated during viral infection remains unclear. We previously found that a genetic mutation in Toll-interacting protein (Tollip) was linked to less airway epithelial Tollip expression, increased neutrophil chemokines, and lower lung function in asthma patients. As Tollip is involved in maintaining mitochondrial function, and mitochondrial stress may contribute to extracellular ATP release and IL-33 secretion, we hypothesized that Tollip downregulates IL-33 secretion via inhibiting ATP release during IAV infection. Wild-type and Tollip knockout (KO) mice were infected with IAV and treated with either an ATP converter apyrase or an IL-33 decoy receptor soluble ST2 (sST2). KO mice significantly lost more body weight and had increased extracellular ATP, IL-33 release, and neutrophilic inflammation. Apyrase treatment reduced extracellular ATP levels, IL-33 release, and neutrophilic inflammation in Tollip KO mice. Excessive lung neutrophilic inflammation in IAV-infected Tollip KO mice was reduced by sST2, which was coupled with less IL-33 release. Our data suggest that Tollip inhibits IAV infection, potentially by inhibiting extracellular ATP release and reducing IL-33 activation and lung inflammation. In addition, sST2 may serve as a potential therapeutic approach to mitigate respiratory viral infection in human subjects with Tollip deficiency.

The exercise of quantifying the energy consumption data assembled through household surveys, either by the recall-based approach or the meter-based approach, remains a challenging task, especially in rural areas of developing countries. In this article, we propose a device-based bottom-up accounting method for estimating household energy consumption. This method provides microlevel disaggregated estimates at the intensive margin and documents other difficult-to-measure energy consumption such as biomass at the extensive margin. Even though measurement errors of the household survey might still exist, the structured questionnaire of daily routine behavior questions should greatly alleviate the problem. The new method supplements the existing household energy statistical system, improves its flexibility, and is particularly applicable in developing countries and/or rural areas. We apply the method to a Chinese rural household survey and discuss its differences and similarities with the conventional methods.

Abstract Objectives To evaluate the effect at a one-year follow-up after an 18-month randomized controlled trial (RCT) of 90 gm/day low-carbohydrate diet (LCD) in type 2 diabetes. Research design and methods Eighty-five poorly controlled type 2 diabetic patients with an initial HbA1c ≥ 7.5% who have completed an 18-month randomized controlled trial (RCT) on 90 g/day low-carbohydrate diet (LCD) were recruited and followed for one year. A three-day weighted food record, relevant laboratory tests, and medication effect score (MES) were obtained at the end of the previous trial and one year after for a total of 30 months period on specific diet. Results 71 (83.5%) patients completed the study, 35 were in TDD group and 36 were in LCD group. Although the mean of percentage changes in daily carbohydrate intake was significantly lower for those in TDD group than those in LCD group (30.51 ± 11.06% vs. 55.16 ± 21.79%, p = 0.0455) in the period between 18 months and 30 months, patients in LCD group consumed significantly less amount of daily carbohydrate than patients in TDD group (131.8 ± 53.9 g vs. 195.1 ± 50.2 g, p 0.05). Conclusions The one-year follow-up for patients on 90 g/d LCD showed potential prolonged and better outcome on glycaemic control, liver function and MES than those on TDD for poorly controlled diabetic patients.

Abstracts: This work analyzed the electromagnetic field (EM) anomalies recorded by the electric field detector (EFD) and the search coil magnetometer (SCM) onboard the China Seismo-Electromagnetic Satellite (CSES) during the two earthquakes (EQ), which are the Yangbi Ms6.4 EQ on May 21 (China Standard Time, CST) and the Madoi Ms7.4 EQ on May 22 (CST), 2021. These two EQs successively occurred in West China. The prevailing frequency band excluding the interferences from the satellite platform was chosen to extract convincible seismic-related EM disturbances. Two criteria were put forward to obtain reliable precursors using the Kp and Dst index and the variation rate of Dst per hour to eliminate the tinier spatial perturbations. We found that the seismic-related EM disturbances mainly appeared 1–10 days before the two earthquakes within the spatial extension of 1000 ​km above the epicenters.

At present, research on the loading simulation test bench for overloaded vehicles is mostly limited to the realization of loading simulation under the condition of straight line driving of the vehicle. When simulating the whole vehicle load under straight line driving condition, only accurate road load and inertial load can be obtained to achieve accurate load simulation, and the inertial load required to be simulated by each side device is half of the whole vehicle inertial load. However, straight line driving is only the most ideal driving. The real driving conditions (including ground conditions) of the vehicle are usually composed of steering, longitudinal slope, lateral slope and different ground adhesion coefficients. Therefore, the loads borne by the two independent load simulation systems located on both sides of the vehicle may be different during the load simulation process. In addition, the frequency characteristics of the loads to be simulated by the same side load simulation device at different time sequences may also be different. This paper studies the dynamics modeling, load distribution and error compensation in the whole vehicle load simulation process in order to achieve accurate crawler vehicle load simulation from three aspects.

IntroductionMetabolic dysfunction such as elevated levels of saturated fatty acids (SFA) may play a role in obese asthma, but its contribution to airway inflammation remains unclear. We sought to determine the role of high-fat diet (HFD) and palmitic acid (PA), a major form of SFA, in regulating type 2 inflammation.MethodsAirway samples from asthma patients with or without obesity, mouse models and human airway epithelial cell culture were utilized to test if SFA amplify type 2 inflammation.ResultsAsthma patients with obesity had higher levels of airway PA than asthma patients without obesity. HFD increased the levels of PA in mice, and subsequently enhanced IL-13-induced airway eosinophilic inflammation. PA treatment amplified airway eosinophilic inflammation in mice that were previously exposed to IL-13 or house dust mite. IL-13 alone or in combination with PA increased dipeptidyl peptidase 4 (DPP4) release (soluble DPP4) and/or activity in mouse airways and human airway epithelial cells. Inhibition of DPP4 activity by linagliptin in mice pre-exposed to IL-13 or both IL-13 and PA increased airway eosinophilic and neutrophilic inflammation.DiscussionOur results demonstrated the exaggerating effect of obesity or PA on airway type 2 inflammation. Up-regulation of soluble DPP4 by IL-13 and/or PA may serve as a mechanism to prevent excessive type 2 inflammation. Soluble DPP4 may have the therapeutic potential in asthma patients with obesity who have an endotype with mixed airway eosinophilic and neutrophilic inflammation.

Based on steady-state experiments, a three-dimensional (3D) simulation study under pulsation conditions was carried out. This was performed to study the effect of pulsation of the supply system on the atomization characteristics of a gas-centered swirl coaxial injector. The results indicated that the spray shape resembled a pagoda when the Klystron effect occurred. When the low-frequency pulsation (200 Hz) was applied to the liquid inlet, the peak of the exit pressure was close to the trough of the inlet mass flow rate. Meanwhile, the exit mass flow rate and pressure were approximately sinusoidal. There was no significant lag effect in the response of the exit mass flow rate to the inlet mass flow rate but with a small sawtooth-like oscillation. Increasing the amplitude of the liquid inlet disturbance amplified the exit mass flow rate fluctuation, which was greater than the set amplitude of the inlet pulsation. The dominant frequency of the injector exit mass flow rate and pressure variation was significantly less than the inlet pulsation frequency when the frequency of the liquid inlet pulsation was increased to 1000 Hz. This was due to the low-pass filtering effect of the annular slit. There was no significant change in the overall spray morphology for the gas inlet pulsation. By applying the same amplitude and frequency of pulsation to the gas and liquid inlets of the injector, the pulsation of the liquid inlet had a stronger effect on the injector exit spray than that of the gas inlet.

The Ryukyu Trench is located in the northern Philippine Sea. The subduction of the Philippine Sea Plate to the Eurasia Plate along the Ryukyu Trench in the NNW direction leads to extremely complex tectonic processes such as subduction, collision, accretion, and back-arc expansion. It is of great significance to obtain the crustal structure of the Ryukyu Trench for understanding the crustal deformation characteristics, subduction direction and the scale of the Philippine Sea Plate. The ocean bottom seismometer (OBS) could provide important information on the deep structure of the oceanic area, and the wide coverage of gravity anomaly can provide more constraints for the regional crustal structure. In this study, we put the time-delay term of the sedimentary layer into the H-κ stacking formula, which eliminates the influence of the sedimentary layer in traditional H-κ stacking. Based on the accurate crustal thickness at OBS locations, a gravity inversion method is proposed to solve the problem of non-uniqueness in gravity data and limited distribution of OBSs. By using this method, we obtain a crustal structure with higher resolution than Crust1.0 model in Ryukyu Trench. The results show that the crustal thickness in the Ryukyu Trench region thickens along the NNW subduction direction, revealing that the Philippine Plate’s subduction direction towards the Eurasian Plate is in the NNW direction.

It has been a long-sought goal to explore the nature of amorphous formation. Investigate the role of interatomic potential can be a fascinating method to study this myth from bottom up. In this work, molecular dynamics is used to systematically study the glass forming processes of binary CuZr melts on both structural and dynamical evolutions. The strong repulsion between CuCu and the weak repulsion between ZrZr is found to determine the structural arrangement, and then affect the type, number and spatial correlation of clusters. The difference of melt dynamics is controlled by both the steep repulsion and the anharmonic attraction of potential. The increase of the anharmonic attraction in melts can also lead to a higher shear transformation zone density in the glass. Our findings provide deeper insights into the understanding of glass-forming processes and its connection to glassy performance controlled by interatomic potential.

Abstract Wearable electronic skins have aroused extensive interest in health detection, human–computer interaction, and robotics. However, it remains a great challenge to realize the multifunctional electronic skin with a wide detection range, high sensitivity, multi‐stimulus response, and wearable comfort on a single device. Here, a flexible porous thermoplastic polyurethane (TPU)/carbon black (CB) multimodal sensor that perceives multiple stimuli of pressure, strain, and humidity is prepared by the water vapor‐induced phase separation method. The as‐prepared device exhibits a wide pressure detection range (up to 49 kPa), excellent sensitivity (0.21 kPa−1), fast response (150 ms), and recovery time (120 ms). Furthermore, as a strain sensor, it is not only highly stretchable (730%), but also can operate over a strain range of 0–240% with a sensitivity of up to 1485.2 and excellent durability. Moreover, the designed sensor can detect humidity changes from 35% to 90% and has a fast response time (1.2 s), while enabling non‐contact sensing of a fingertip. Importantly, the porous TPU/CB film presents excellent breathability, enabling it to achieve a high level of comfort. Therefore, the perfect integration of these features ensures the potential applications of porous TPU/CB sensors in human activity detection, exhale monitoring, and breathable wearable devices.

Abstract Background Toll-interacting protein (Tollip) is one of the key negative regulators in host innate immunity. Genetic variation of Tollip has been associated with less Tollip expression and poor lung function in asthmatic patients, but little is known about the role of Tollip in human airway type 2 inflammatory response, a prominent feature in allergic asthma. Objective Our goal was to determine the role and underlying mechanisms of Tollip in human airway epithelial responses such as eotaxin to type 2 cytokine IL-13. Methods Tollip deficient primary human airway epithelial cells from 4 healthy donors were generated by the gene knockdown approach and stimulated with IL-13 to measure activation of transcription factor STAT3, and eotaxin-3, an eosinophilic chemokine. Results Following IL-13 treatment, Tollip deficient cells had significantly higher levels of STAT3 activation and eotaxin-3 than the scrambled control counterpart, which was reduced by a STAT3 inhibitor. Interaction between Tollip and STAT3 proteins was identified by co-immunoprecipitation. Conclusion Our results, for the first time, suggest that Tollip inhibits excessive eotaxin-3 induction by IL-13, in part through the interaction and inhibition of STAT3. These findings lend evidence to the potential of a STAT3 inhibitor as a therapeutic target, especially for type 2 inflammation-high asthmatics with Tollip deficiency.

Abstract Self‐healable elastomeric materials (PUAxPU10–x‐PDMS, x = 4, 6, or 8) have been synthesized and utilized as substrates or encapsulation films on the top of barrier films (deposited on polyethylene terephthalate (PET) substrates) to improve their gas barrier properties for packaging applications. Hexa‐layer (HL) assembly consisting of two inorganic 2D nanoplatelets, including Mg‐Al layered double hydroxide (LDH) and hexagonal boron nitride (hBN), and two oppositely charged polyelectrolytes, that is, polyethyleneimine (PEI) and poly(sodium styrene‐4‐sulfonate) (PSS), have been developed by alternative depositions of HL (i.e., PSS/LDH/PSS/PEI/hBN/PEI) sequentially. Then, a layer‐by‐layer technique is applied to produce multiple assemblies of hexa‐layer (HL)n and reduce water vapor transmission rate (WVTR) values of elastomeric PUA8PU2‐PDMS and PET substrates. The optimum WVTR values of 7.1 × 10−3 and 8.0 × 10−3 g m−2 day−1 are achieved using barrier PET/(HL)8/PUA8PU2‐PDMS (125/3/1 µm) and PUA8PU2‐PDMS/(HL)8 (125/3 µm) films, respectively. The self‐healable barrier PUA8PU2‐PDMS and PUA8PU2‐PDMS/(HL)8 films recover their initial WVTR values after self‐healing of mechanically damaged films. Organic light‐emitting diodes (OLEDs) encapsulated with PET/(HL)8/PUA8PU2‐PDMS and PUA8PU2‐PDMS/(HL)8 have 9–10 times longer half‐lifetime values than bare OLEDs. Accordingly, this report develops transparent, stretchable, and self‐healable gas barrier films for next‐generation flexible electronic device packaging applications.

Objective: Early diagnosis and intervention of diabetic nephropathy (DN) is necessary to optimize therapy in order to delay the progression of diabetes. This research aimed to reveal the change of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in patients with DN, and to assess possible correlations with glycated hemoglobin (HbAlc) values. Methods: The present study was a retrospective, single-center study conducted at a teaching hospital in the northeast China. A total of 120 patients were divided into proteinuria-positive group ( n = 40), the microalbuminuria group ( n = 40), and the high proteinuria group ( n = 40) according to the urinary albumin excretion rate (UAER), and 40 healthy volunteers were selected as the control group. The levels of VEGF, ET-1 and HbA1c were measured in all subjects and principal component analysis (PCA) was performed to classify and reveal correlations between VEGF, ET-1 and HbA1c. Results: Compared to the control group, a significant difference in the increase of HbA1c was detected in group I, II and III. A significant increase in the concentrations of serum VEGF and ET-1 was also observed. HbA1c in DN patients had proven to be positively correlated with VEGF (r = 0.7941; p < 0. 0001) and ET-1 (r = 0.8504; p < 0.0001) respectively. Conclusion: The elevated levels of VEGF and ET-1 in serum have been proposed as being able to supplement the additional information about the progression of DN. These data suggest that the decrease in endothelial function may be related to poor glycemic control.

This study investigates age-specific prostate-specific antigen (PSA) distributions in Taiwanese men and recommends reference ranges for this population after comparison with other studies. From January 1999 to December 2016, a total of 213,986 Taiwanese men aged above 19 years old without history of prostate cancer, urinary tract infection, or prostate infection were recruited from the Taiwan MJ cohort, an ongoing prospective cohort of health examinations conducted by the MJ Health Screening Center in Taiwan. Participants were divided into seven age groups. Simple descriptive statistical analyses were carried out and quartiles and 95th percentiles were calculated for each group as reference ranges for serum PSA in screening for prostate cancer in Taiwanese men. Serum PSA concentration correlated with age (r = 0.274, p

Background Neutrophilic asthma (NA) is associated with increased airway interleukin (IL)-17 and abnormal bacterial community such as dominance of nontypeable Haemophilus influenzae (NTHi), particularly during asthma exacerbations. Bacteria release various products including DNA, but whether they cooperate with IL-17 in exaggerating neutrophilic inflammation is unclear. We sought to investigate the role of bacteria-derived DNA in airway neutrophilic inflammation related to IL-17-high asthma and underlying mechanisms (e.g. Toll-like receptor 9 (TLR9)/IL-36γ signalling axis). Methods Bacterial DNA, IL-8 and IL-36γ were measured in bronchoalveolar lavage fluid (BALF) of people with asthma and healthy subjects. The role of co-exposure to IL-17 and bacterial DNA or live bacteria in neutrophilic inflammation, and the contribution of the TLR9/IL-36γ signalling axis, were determined in cultured primary human airway epithelial cells and alveolar macrophages, and mouse models. Results Bacterial DNA levels were increased in asthma BALF, which positively correlated with IL-8 and neutrophil levels. Moreover, IL-36γ increased in BALF of NA patients. Bacterial DNA or NTHi infection under an IL-17-high setting amplified IL-8 production and mouse lung neutrophilic inflammation. DNase I treatment in IL-17-exposed and NTHi-infected mouse lungs reduced neutrophilic inflammation. Mechanistically, bacterial DNA-mediated amplification of neutrophilic inflammation is in part dependent on the TLR9/IL-36γ signalling axis. Conclusions Bacterial DNA amplifies airway neutrophilic inflammation in an IL-17-high setting partly through the TLR9 and IL-36γ signalling axis. Our novel findings may offer several potential therapeutic targets including TLR9 antagonists, IL-36γ neutralising antibodies and DNase I to reduce asthma severity associated with exaggerated airway neutrophilic inflammation.