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In this study, a novel low-silver Ag-xCu-5Ga (x = 28, 34, 39, 49 and 55) solder with high strength was designed and prepared. The effect of element composition on microstructure evolution, thermal behavior, and the mechanical performance of Ag–Cu-Ga solders were investigated in detail. The results indicated that the melting temperature of Ag–Cu alloy could be reduced effectively with Ga addition, and the typical joint consisted of the block-shaped Cu-rich phase in the welded seam and the ribbon-shaped Cu-rich phase adjacent to the interface. The shear strength of joints brazed with Ag-xCu-5Ga (x = 28, 34, 39 and 49) filler metals can be improved significantly compared to that of commercial Ag–28Cu solder, with a maximum value of approximately 445 MPa in Ag–39Cu–5Ga solder. The best mechanical properties are obtained as the second-phase strengthening and interfacial strengthening reach a balanced coexistence state, determined by the block-shaped Cu-rich phase in the welded seam and the ribbon-shaped Cu-rich phase adjacent to the interface, respectively. This study can provide insights to investigate strengthening mechanisms and develop high-strength solders for vacuum brazing.

Diabetes mellitus (DM) aggravates periodontitis, resulting in accelerated periodontal bone resorption. Disordered glucose metabolism in DM causes reactive oxygen species (ROS) overproduction resulting in compromised bone healing, which makes diabetic periodontal bone regeneration a major challenge. Inspired by the natural bone healing cascade, a mesoporous silica nanoparticle (MSN)-incorporated PDLLA (poly(dl-lactide))-PEG-PDLLA (PPP) thermosensitive hydrogel with stepwise cargo release is designed to emulate the mesenchymal stem cell “recruitment-osteogenesis” cascade for diabetic periodontal bone regeneration. During therapy, SDF-1 quickly escapes from the hydrogel due to diffusion for early rat bone marrow stem cell (rBMSC) recruitment. Simultaneously, slow degradation of the hydrogel starts to gradually expose the MSNs for sustained release of metformin, which can scavenge the overproduced ROS under high glucose conditions to reverse the inhibited osteogenesis of rBMSCs by reactivating the AMPK/β-catenin pathway, resulting in regulation of the diabetic microenvironment and facilitation of osteogenesis. In vitro experiments indicate that the hydrogel markedly restores the inhibited migration and osteogenic capacities of rBMSCs under high glucose conditions. In vivo results suggest that it can effectively recruit rBMSCs to the periodontal defect and significantly promote periodontal bone regeneration under type 2 DM. In conclusion, our work provides a novel therapeutic strategy of a bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration.

Abnormal melanogenesis can lead to hyperpigmentation. Tyrosinase (TYR), a key rate-limiting enzyme in melanin production, is an important therapeutic target for these disorders. We investigated the TYR inhibitory activity of hydrolysates extracted from the muscle tissue of Takifugu flavidus (TFMH). We used computer-aided virtual screening to identify a novel peptide that potently inhibited melanin synthesis, simulated its binding mode to TYR, and evaluated functional efficacy in vitro and in vivo. TFMH inhibited the diphenolase activities of mTYR, reducing TYR substrate binding activity and effectively inhibiting melanin synthesis. TFMH indirectly reduced cAMP response element-binding protein phosphorylation in vitro by downregulating melanocortin 1 receptor expression, thereby inhibiting expression of the microphthalmia-associated transcription factor, further decreasing TYR, tyrosinase related protein 1, and dopachrome tautomerase expression and ultimately impeding melanin synthesis. In zebrafish, TFMH significantly reduced black spot formation. TFMH (200 μg/mL) decreased zebrafish TYR activity by 43% and melanin content by 52%. Molecular dynamics simulations over 100 ns revealed that the FGFRSP (T-6) peptide stably binds mushroom TYR via hydrogen bonds and ionic interactions. T-6 (400 μmol/L) reduced melanin content in B16F10 melanoma cells by 71% and TYR activity by 79%. In zebrafish, T-6 (200 μmol/L) inhibited melanin production by 64%. TFMH and T-6 exhibit good potential for the development of natural skin-whitening cosmetic products.

CO2 monitoring is important for carbon emission evaluation. Low-cost and medium-precision sensors (LCSs) have become an exploratory direction for CO2 observation under complex emission conditions in cities. Here, we used a calibration method that improved the accuracy of SenseAir K30 CO2 sensors from ±30 ppm to 0.7–4.0 ppm for a CO2-monitoring instrument named the SENSE-IAP, which has been used in several cities, such as in Beijing, Jinan, Fuzhou, Hangzhou, and Wuhan, in China since 2017. We conducted monthly to yearly synchronous observations using the SENSE-IAP along with reference instruments (Picarro) and standard gas to evaluate the performance of the LCSs for indoor use with relatively stable environments. The results show that the precision and accuracy of the SENSE-IAP compared to the standard gases were rather good in relatively stable indoor environments, with the short-term (daily scale) biases ranging from −0.9 to 0.2 ppm, the root mean square errors (RMSE) ranging from 0.7 to 1.6 ppm, the long-term (monthly scale) bias ranging from −1.6 to 0.5 ppm, and the RMSE ranging from 1.3 to 3.2 ppm. The accuracy of the synchronous observations with Picarro was in the same magnitude, with an RMSE of 2.0–3.0 ppm. According to our evaluation, standard instruments or reliable standard gases can be used as a reference to improve the accuracy of the SENSE-IAP. If calibrated daily using standard gases, the bias of the SENSE-IAP can be maintained within 1.0 ppm. If the standard gases are hard to access frequently, we recommend a calibration frequency of at least three months to maintain an accuracy within 3 ppm.

Analyzing land subsidence using Multi-temporal Interferometric Synthetic Aperture Radar (MT-InSAR) technology holds significant importance for the secure development of urban areas. Shenzhen, being a crucial component of the Pearl River Delta, faces the threat of land subsidence, similar to most deltaic cities. Numerous studies have already indicated the presence of severe land subsidence in certain localities of Shenzhen. However, due to limitations in data scope and research methodologies, the comprehensive spatial-temporal distribution of land subsidence across the entire city of Shenzhen remains unclear. This study initially employed MT-InSAR technology to process a total of 534 Sentinel-1A SAR images from three different frames (P11F71, P113F71, P11F65), covering the entire city of Shenzhen. This processing resulted in the generation of subsidence rate maps and subsidence time series. Subsequently, the temporal evolution patterns of the subsidence were analyzed while significant subsidence regions were identified. By integrating information from optical images reflecting human activities on the Earth’s surface, the study deduced the subsidence mechanisms in various significant subsidence areas. Research findings indicate that land subsidence in Shenzhen is primarily caused by construction activities, with a concentration in the western coastal areas of Shenzhen, reaching a maximum rate of 80 mm/yr, located at the estuary of Dongbao River (113.770385, 22.745305). The cumulative subsidence from March 2017 to June 2023 amounts to 500 mm. The expansion of the Qinglinjing Reservoir has led to an increased demand for water, resulting in a significant rise in formation pressure and subsequent land subsidence. InSAR land subsidence monitoring and analysis in urban areas can address the spatial and temporal resolution limitations of traditional subsidence monitoring methods, providing effective recommendations for widespread subsidence prevention and control.

Understanding the capillary imbibition laws of brackish water in rocks is necessary to reveal the mechanism of fluid, salt, and ion transport. In this study, we investigated the capillary imbibition laws of a Na2SO4 solution of different concentrations in sandstone by measuring the parameters of water absorption mass, water migration front height, nuclear magnetic resonance (NMR) T2 spectra, and stratified moisture distribution. The results indicate the following: (1) With an increase in the salt solution concentration, the water absorption rate of samples increases, specifically manifested in an increase in the rate of absorption mass and a rising rate of the absorption front. (2) With an increase in the salt solution concentration, the total NMR signals in samples measured at the end of water absorption decreases; that is, the total amount of water absorption decreases. (3) When the solution concentration exceeds 0.50 g/L, variations in the NMR signal of samples and the absorbed water mass over time are not synchronic and are even opposite at some stages. Based on the capillary dynamic theories of liquid, the influence of salts on solution properties and the modification of the pore structure by crystallization are considered when discussing the underlying mechanism of capillary imbibition in sandstone. By calculating the physical properties such as the density, viscosity, surface tension, and contact angle of solutions with different concentrations, the imbibition process does not exhibit any significant variation with the difference in the properties of the liquid. The equivalent capillary radii of the samples at varying salt concentrations are obtained by fitting the capillary dynamics curves with the theoretically calculated values. The equivalent capillary radii of samples in higher salt concentrations are larger, i.e., the difference in capillary imbibition laws introduced by the salt concentration should be attributed to modifications to the pore structure caused by salt crystallization.

Surface waterlogging disasters due to underground mining and geological status have caused the abandonment of fertile land, seriously damaged the ecological environment, and have influenced the sustainable development of coal resource-based cities, which has become a problem that some mining areas need to face. However, the traditional underwater terrain measurement method using sonar encompasses a time-consuming and labor-intensive process. Thus, an inversion method for obtaining the underwater spatial information of subsidence waterlogging in coal mining subsidence waterlogging areas is proposed, based on differential interferometric synthetic aperture radar (D-InSAR) and the probability integral prediction method. First, subsidence values are obtained in the marginal area of the subsidence basin using D-InSAR technology. Then, the subsidence prediction parameters of the probability integral method (PIM) are inverted by a genetic algorithm (GA) based on the subsidence values. Finally, the underwater spatial information of subsidence waterlogging is calculated on the basis of the prediction parameters. The subsidence waterlogging area in the Wugou coal mine was adopted as the study area, and the underwater spatial information of subsidence waterlogging was inverted by the proposed method. The results show that this method can effectively provide the underwater spatial information of subsidence waterlogging, including the maximum subsidence value, waterlogging volume, subsidence waterlogging area, and underwater terrain in the subsidence waterlogging area. Compared with field-measured data from the same period, the RMSE of water depth is 99 mm, and the relative error is 9.9%, which proves that this inversion method is accurate and can meet engineering precision requirements.

The Gram-negative marine bacterium GXY010T, which has been isolated from the surface seawater of the western Pacific Ocean, is aerobic, non-motile and non-flagellated. Strain GXY010T exhibits growth across a temperature range of 10–42 °C (optimal at 37 °C), pH tolerance from 7.0 to 11.0 (optimal at 7.5) and a NaCl concentration ranging from 1.0 to 15.0% (w/v, optimal at 5.0%). Ubiquinone-8 (Q-8) was the predominant isoprenoid quinone in strain GXY010T. The dominant fatty acids (>10%) of strain GXY010T were iso-C15:0 (14.65%), summed feature 9 (iso-C17:1 ω9c and/or 10-methyl C16:0) (12.41%), iso-C17:0 (10.85%) and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c) (10.41%). Phosphatidylethanolamine (PE), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), unidentifiable glycolipid (GL) and four non-identifiable aminolipids (AL1-AL4) were the predominant polar lipids of strain GXY010T. The genomic DNA G+C content was identified as a result of 48.0% for strain GXY010T. The strain GXY010T genome consisted of 2,766,857 bp, with 2664 Open Reading Frames (ORFs), including 2586 Coding sequences (CDSs) and 78 RNAs. Strain GXY010T showed Average Nucleotide Identity (ANI) values of 73.4% and 70.6% and DNA–DNA hybridization (DDH) values of 19.2% and 14.5% with reference species Pseudidiomarina tainanensis MCCC 1A02633T (=PIN1T) and Pseudidiomarina taiwanensis MCCC 1A00163T (=PIT1T). From the results of the polyphasic analysis, a newly named species, Pseudidiomarina fusca sp. nov. within the genus Pseudidiomarina, was proposed. The type strain of Pseudidiomarina fusca is GXY010T (=JCM 35760T = MCCC M28199T = KCTC 92693T).

Cotton is one of the most important natural fibers used in the textile industry worldwide. It is important to identify the key factors involved in cotton fiber development. In this study, zinc finger protein8 (GhZFP8) encoding a C2H2 transcription factor (TF) was cloned from cotton. qPCR showed that the transcripts of GhZFP8 in cotton were detected in the leaves and fibers at 3, 6, and 30 days post-anthesis (DPA), but not in the roots, stems, or flowers. The overexpression of GhZFP8 increased the trichome number on the siliques, leaves, and inflorescence, but inhibited the growth. The expression of trichome development and cell-elongation-related genes decreased obviously in GhZFP8 overexpressor Arabidopsis. Indole-3-acetic acid (IAA) and 1-Aminocyclopropanecarboxylic acid (ACC) contents were much higher in GhZFP8 overexpressors than that found in the wild type, but the gibberellin (GA) content was lower. The interference of GhZFP8 in cotton caused smaller bolls and shorter fibers than that of the control. The results of DNA affinity purification (DAP)-seq showed that GhZFP8 could bind to the promoter, exon, intron, and intergenic region of the target genes, which are involved in photosynthesis, signal transduction, synthesis of biomass, etc. Our findings implied that GhZFP8 processed multiple biological functions and regulated the development of cotton fiber.

Abstract The spike protein of SARS‐CoV‐2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS‐CoV‐2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion potential through mutations in their spike proteins, leading to sharply reduced efficacy of current spike‐focused vaccines and therapeutics. Compared with the fast‐evolving spike protein, targeting host ACE2 offers an alternative antiviral strategy that is more resistant to viral evolution and can even provide broad prevention against SARS‐CoV and HCoV‐NL63. Here, we use prime editor (PE) to precisely edit ACE2 at structurally selected sites. We demonstrated that residue changes at Q24/D30/K31 and/or K353 of ACE2 could completely ablate the binding of tested viruses while maintaining its physiological role in host angiotensin II conversion. PE‐mediated ACE2 editing at these sites suppressed the entry of pseudotyped SARS‐CoV‐2 major variants of concern and even SARS‐CoV or HCoV‐NL63. Moreover, it significantly inhibited the replication of the Delta variant live virus. Our work investigated the unexplored application potential of prime editing in high‐risk infectious disease control and demonstrated that such gene editing‐based host factor reshaping strategy can provide broad‐spectrum antiviral activity and a high barrier to viral escape or resistance.

BackgroundMost coronary artery disease (CAD) patients with a normal left ventricular ejection fraction (LVEF) experience a poor prognosis. Single-photon emission computerized tomography (SPECT)–myocardial perfusion imaging (MPI), a routine examination, is useful in assessing risk and predicting major adverse cardiovascular events (MACEs) in populations with suspected or known CAD. SPECT/CT is a “one-stop shop” examination, which, through non-contrast CT, can produce attenuation correction for MPI and obtain information on coronary artery calcium (CAC) and epicardial fat volume (EFV) simultaneously. This study aims to investigate the predictive and incremental value of EFV to MPI for MACE in Chinese populations with suspected or known CAD with a normal LVEF.Methods and resultsWe retrospectively studied 290 suspected or known CAD inpatients with a normal LVEF who underwent SPECT/CT between February 2014 and December 2017. Abnormal MPI was defined as a summed stress score ≥4 or summed difference score ≥2. EFV and CAC were calculated using non-contrast CT. The end date of follow-ups was in February 2022. The follow-up information was obtained from the clinical case notes of the patients or reviews of telephone calls. MACE was defined as cardiac death, late coronary revascularization ≥3 months after MPI, non-fatal myocardial infarction, angina-related rehospitalization, heart failure, and stroke. During the 76-month follow-up, the event rate was 32.0% (93/290). Univariate and multivariate Cox regression analyses concluded that high EFV (>108.3 cm3) [hazard ratio (HR): 3.3, 95% CI: 2.1–5.2, P

Abstract Simultaneously optimizing elementary steps, such as water dissociation, hydroxyl transferring, and hydrogen combination, is crucial yet challenging for achieving efficient hydrogen evolution reaction (HER) in alkaline media. Herein, Ru single atom‐doped WO2 nanoparticles with atomically dispersed Ru–W pair sites (Ru–W/WO2‐800) are developed using a crystalline lattice‐confined strategy, aiming to gain efficient alkaline HER. It is found that Ru–W/WO2‐800 exhibits remarkable HER activity, characterized by a low overpotential (11 mV at 10 mA cm−2), notable mass activity (5863 mA mg−1 Ru at 50 mV), and robust stability (500 h at 250 mA cm−2). The highly efficient activity of Ru–W/WO2‐800 is attributed to the synergistic effect of Ru–W sites through ensemble catalysis. Specifically, the W sites expedite rapid hydroxyl transferring and water dissociation, while the Ru sites accelerate the hydrogen combination process, synergistically facilitating the HER activity. This study opens a promising pathway for tailoring the coordination environment of atomic‐scale catalysts to achieve efficient electro‐catalysis.

BackgroundDegenerative cervical myelopathy (DCM) is estimated to affect 2% of the adult population. DCM occurs when degenerative processes cause compression and injure the spinal cord. Surgery to remove the stress caused by the compression of the spinal cord is the mainstay of treatment, with a range of techniques in use. Although various factors are described to inform the selection of these techniques, there needs to be more consensus and limited comparative evidence. ObjectiveThe main objective of this survey was to explore the variation of practice and decision-making, with a focus on laminectomy versus laminectomy and fusion in posterior surgery of the cervical spine. We present the results of a survey conducted among the principal investigators (PIs) of the National Institute for Health and Care Research (NIHR) randomized controlled trial on posterior laminectomy with fixation for degenerative cervical myelopathy (POLYFIX-DCM). MethodsA series of 7 cases were shared with 24 PIs using SurveyMonkey. Each case consisted of a midsagittal T2-weighted magnetic resonance imaging and lateral cervical x-rays in flexion and extension. Surgeons were asked if their preferred approach was anterior or posterior. If posterior, they were asked whether they preferred to instrument and whether they had the equipoise to randomize in the NIHR POLYFIX-DCM trial. Variability in decision-making was then explored using factors reported to inform decision-making, such as alignment, location of compression, number of levels operated, presence of mobile spondylolisthesis, and patient age. ResultsThe majority of PIs (16/30, 53%) completed the survey. Overall, PIs favored a posterior approach (12/16, 75%) with instrumentation (75/112, average 66%) and would randomize (67/112, average 62%) most cases. Factors reported to inform decision-making poorly explained variability in responses in both univariate testing and with a multivariate model (R2=0.1). Only surgeon experience of more than 5 years and orthopedic specialty training background were significant predictors, both associated with an anterior approach (odds ratio [OR] 1.255; P=.02 and OR 1.344; P=.007, respectively) and fusion for posterior procedures (OR 0.628; P

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent modulator of cholesterol metabolism and plays a crucial role in the normal functioning of pancreatic islets and the progression of diabetes. Islet autocrine PCSK9 deficiency can lead to the enrichment of low-density lipoprotein (LDL) receptor (LDLR) and excessive LDL cholesterol (LDL-C) uptake, subsequently impairing the insulin secretion in β-cells. Circulatory PCSK9 levels are primarily attributed to hepatocyte secretion. Notably, anti-PCSK9 strategies proposed for individuals with hypercholesterolemia chiefly target liver-derived PCSK9; however, these anti-PCSK9 strategies have been associated with the risk of new-onset diabetes mellitus (NODM). In the current review, we highlight a new direction in PCSK9 inhibition therapy strategies: screening candidates for anti-PCSK9 from the drugs used in type 2 diabetes mellitus (T2DM) treatment. We explored the association between circulating, local pancreatic PCSK9 and T2DM, as well as the relationship between PCSK9 monoclonal antibodies and NODM. We discussed the emergence of artificial and natural drugs in recent years, exhibiting dual benefits of antidiabetic activity and PCSK9 reduction, confirming that the diverse effects of these drugs may potentially impact the progression of diabetes and associated disorders, thereby introducing novel avenues and methodologies to enhance disease prognosis.

Summary: Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit “non-classic” characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis.

Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC is not been fully understood. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. In the current study, we show that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and high Lnc-PLA2G4A-4 expression was remarkably associated with tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitated lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitate miR-23b-3p's target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reverse Lnc-PLA2G4A-4 induced cell phenotypes in HCC and suppress versican expression of by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes HCC progression by targeting the miR-23b-3p/versican axis, which may be a potential biomarker and therapeutic target for HCC.

Abstract Background Organ failure (OF) and death are considered the most significant adverse outcomes in necrotizing pancreatitis (NP). However, there are few NP-related studies describing the clinical traits of OF and aggravated outcomes. Purpose An improved insight into the details of OF and death will be helpful to the management of NP. Thus, in our research, we addressed the risk factors of OF and death in NP patients. Methods We performed a study of 432 NP patients from May 2017 to December 2021. All patients with NP were followed up for 36 months. The primary end-points were risk factors of OF and death in NP patients. The risk factors were evaluated by logistic regression analysis. Results NP patients with OF or death patients were generally older, had a higher APACHE II score, longer hospital stay, longer ICU stay, as well as a higher incidence of severe acute pancreatitis (SAP), shock and pancreatic necrosis. Independent risk factors related to OF included BMI, APACHE II score and SAP (P

In recent years, with the large-scale and high-intensity mining of coal resources, the problem of water accumulation in mining areas with high groundwater levels has become particularly prominent, which has had a serious impact on the surrounding ecological environment. In order to provide scientific basis for the restoration of the ecological environment, the study on the temporal and spatial evolution characteristics and influencing factors of the coal mining subsidence area with high groundwater level were carried out. Taking the whole mining area of Anhui Province as the research subject, based on Landsat TM/OLI remote sensing data, the NDWI and visual interpretation method were used to conduct surveys on the water accumulation area in the subsidence area from 1995 to 2020 (22 periods ) and 12 months in 2020 (12 periods) and the spatial information of waterlogging in the coal mining subsidence area in Anhui Province in recent 25 years was obtained. Combined with hydrological and rainfall data, the factors affecting the spatio-temporal evolution of waterlogging in the subsidence area were analyzed and discussed. The results show that: ① In the past 25 years, the area of accumulated water in the coal mining subsidence area in Anhui Province has been growing in three stages: slow, fast and stable. During the study period, the average stagnant area increased by about 6 times, from 18.95 km2 to 118.09 km2, with an average annual increase of 3.97 km2. ② From the time scale, the evolution of accumulation area in the subsidence area can be divided into three stages: the first stage (1995—2005), due to the fact that most of the accumulation water has not yet stabilized initially, the growth rate is relatively slow, with an average annual growth rate of 4.65%; In the second stage (2005—2013), based on the rapid growth of coal mining, the area of accumulation water has also entered a period of rapid growth, with an average annual growth rate of 6.64%; In the third stage (2013—2020), the growth rate has begun to decrease, and the accumulation water has gradually stabilized, with an average annual growth rate of 3.42%. From the spatial scale, the accumulation water is mainly concentrated in Huainan and Huaibei cities, accounting for about 70% of the total accumulated water area. ③The long-term factor for the change of the water accumulation is coal mining volume, while the main influencing factor in short time scale is atmospheric rainfall. ④The logistic regression curve was used to establish a prediction model for the water accumulation area of coal mining subsidence in Anhui Province. It is predicted that the coal mining subsidence water area in Anhui Province will still be in a low-speed growth stage in the future. By 2030, the accumulation area in the dry season will reach about 130 km2. The high-precision water accumulation information in the subsidence area was obtained, and its temporal and spatial evolution laws and influencing factors were analyzed, which can provide a scientific basis for the treatment of water accumulation in the coal mining subsidence area with high groundwater level and the ecological restoration of the subsidence area.

The North China Craton (NCC) is one of the oldest cratons on earth. Several important tectonic transformations of Mesozoic-Cenozoic tectonic regime led to the destruction of the North China craton. The knowledge of crustal structure can provide important constraints for the formation and evolution of cratons. New maps of sediment thickness, crustal thickness (H) and vP/vS (κ) in the central and western NCC were obtained using sequential H-κ stacking. P-wave receiver functions are calculated using teleseismic waveform data recorded by 405 stations from ChinArray project. Benefiting from the densely distribution of temporary seismic stations, our results reveal details of the crustal structure in the study area. The thickness of sedimentary layer in North China ranges from 0–6.4 km, and the thickest sedimentary layer is in Ordos block and its surroundings (about 2.8–6 km); The thickness of sedimentary layer in the Mongolia fold belt and Yinshan orogenic belt is relatively thin (less than 1 km). The crustal thickness of the study area varies between 27–48 km, of which the crust of the North China Plain is about 30–33 km, the central NCC is about 33–40 km, and the Ordos block is 40–48 km thick. The average vP/vS ratios in the study area is mostly between 1.66 and 1.90, and that in the Yanshan-Taihang mountain fold belt is between 1.70 and 1.85, and that in the Ordos block is between 1.65 and 1.90, with an average value of 1.77, indicating the absence of a thick basaltic lower crust. The obvious negative correlation between crustal thickness and average vP/vS ratio within Ordos and Central Asia orogenic belt may be related to magmatic underplating during the crustal formation. There is no significant correlation between the crustal thickness and the vP/vS ratio in the Lüliang-Taihang mountain fold belt, which may be related to the multiple geological processes such as underplating and crustal extension and thinning in this area. The lack of correlation between crust thickness and topography in the central orogenic belt and the North China Basin indicates the topography of these areas are controlled not only by crustal isostatic adjustment but also by the lithospheric mantle processes.

Abstract Main goal of the JUNO experiment is to determine the neutrino mass ordering using a 20 kt liquid-scintillator detector. Its key feature is an excellent energy resolution of at least 3% at 1 MeV, for which its instruments need to meet a certain quality and thus have to be fully characterized. More than 20,000 20-inch PMTs have been received and assessed by JUNO after a detailed testing program which began in 2017 and elapsed for about four years. Based on this mass characterization and a set of specific requirements, a good quality of all accepted PMTs could be ascertained. This paper presents the performed testing procedure with the designed testing systems as well as the statistical characteristics of all 20-inch PMTs intended to be used in the JUNO experiment, covering more than fifteen performance parameters including the photocathode uniformity. This constitutes the largest sample of 20-inch PMTs ever produced and studied in detail to date, i.e. 15,000 of the newly developed 20-inch MCP-PMTs from Northern Night Vision Technology Co. (NNVT) and 5000 of dynode PMTs from Hamamatsu Photonics K. K.(HPK).

Considering that the mechanical mechanism and energy release law of gradual failure of columnar jointed basalt (CJB) are affected by lateral pressure, rock heterogeneity and column irregularity, etc., the numerical CJB models with various column dip angles, irregularity degrees of column and lateral pressures were established through the digital image correlation. The progressive failure process and released energy of CJBs were simulated under the loading rate of 0.05 mm/step based the continuum mechanics and statistical damage theory. The influences of rock inhomogeneity, column irregularity degree, and model boundary on the nonlinear deformation and failure of CJB were comprehensively investigated. The results demonstrate that the effect of the inhomogeneity index depends on column dip angle, and the equivalent deformation modulus of CJBs is more sensitive to the inhomogeneity index than the lateral pressure. Moreover, the compressive strength along the direction perpendicular to the column axis basically decreases with column irregularity degree increasing when the meso strength of rock is 120 MPa. Besides, the mechanical properties and elastic energy of irregular CJBs are greatly affected by the model boundaries. These achievements will contribute to understanding the inner failure mechanism and energy evolution of CJBs.

Objective To explore the association of hub genes and immune infiltration with acne pathogenesis by integrating and analyzing multi-chip data. Methods Gene microarray datasets were obtained from the GEO database, and differentially expressed genes (DEGs) in the acne phenotype-related gene module were screened using the "limma" R package and weighted gene co-expression network analysis (WGCNA). Moreover, GO functional enrichment and KEGG pathway analysis were performed. STRING online database and Cytoscape software were used to construct protein interaction network and to screen hub genes. Analysis of immune cell infiltration and correlation of hub genes with immune cell infiltration were based on the CIBERSORT algorithm. Results A total of 154 DEGs were screened. The DEGs associated with signaling receptor binding, cytokine activity and chemokine receptor binding were mainly enriched in pathways such as viral protein interaction with cytokine and cytokine receptors, cytokine-cytokine receptor interactions, chemokine signaling, NF-κB signaling and IL-17 signaling. The PPI network was constructed with 139 nodes and 1 597 edges, identifying two hub genes (CCR5, CXCL8). Among the 22 infiltrating immune cells, lesional site exhibited more neutrophils, activated mast cells, activated dendritic cells and activated CD4 memory T cells, but fewer regulatory T cells, resting dendritic cells and resting mast cells, in comparison to normal controls. Conclusion Changes in hub genes and immune cell infiltration, as identified by bioinformatics methods, may play an important role in the pathogenesis of acne.

Abstract. Background:. MicroRNA-20a (miR-20a) is dysregulated in many types of malignancies, including human hepatocellular carcinoma (HCC), but its expression level and functional significance in HCC are still disputed. We aimed to study the role of miR-20a-5p in HCC and its downstream molecular mechanisms. Methods:. We used real-time polymerase chain reaction to detect the expression of miR-20a-5p and runt-related transcription factor 3 (RUNX3) in HCC and paraneoplastic tissue, transfected Huh7 and highly metastatic human hepatocellular carcinoma (MHCC97H) cells. A live cell workstation was used to observe the proliferation and migration of transfected cells. The invasiveness of transfected cells was verified by Transwell assay. Cell apoptosis was detected by flow cytometry. The expression levels of proteins after transfection were measured using simple western immunoblot measurements. Gene expression profiles between HCC and normal samples were obtained from The Cancer Genome Atlas. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment results were processed by the database for annotation, visualization and integrated discovery. Potential target genes of miR-20a-5p were predicted to further investigate how miR-20a-5p regulates epithelial-mesenchymal transition (EMT) in HCC. Results:. MiR-20a-5p was significantly highly expressed in HCC tissues, and overexpression of miR-20a-5p significantly promoted HCC cell proliferation, migration, and invasion and inhibited apoptosis in vitro. The protein expression of E-cadherin was decreased and that of vimentin was increased after overexpression of miR-20a-5p in HCC cells. We discovered the intersection of genes from miRDB, miR TarBase, and TargetScan, obtained 397 target genes and finally focused on RUNX3. RUNX3 was not only reduced in HCC specimens but also drastically reduced in HCC cells overexpressing miR-20a-5p. RUNX3 expression decreased with elevated miR-20a-5p, which activated downstream EMT signaling and promoted cell proliferation, migration, and invasion. Conclusions:. Since RUNX3 is involved in EMT in HCC, as proven by previous research, our findings provide further evidence for a novel regulatory pathway comprising the miR-20a/RUNX3/EMT axis that upregulates EMT signaling and enhances the migration of HCC cells.

ABSTRACT Porcine circovirus type 3 (PCV3) is a newly discovered pathogen that causes porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, multisystemic inflammation, and reproductive failure. Heme oxygenase-1 (HO-1), a stress-inducible enzyme, exerts protective functions by converting heme into carbon monoxide (CO), biliverdin (BV), and iron. However, the effects of HO-1 and its metabolites on PCV3 replication remain unknown. In this study, experiments involving specific inhibitors, lentivirus transduction, and small interfering RNA (siRNA) transfection revealed that active PCV3 infection reduced HO-1 expression and that the expression of HO-1 negatively regulated virus replication in cultured cells, depending on its enzymatic activity. Subsequently, the effects of the HO-1 metabolites (CO, BV, and iron) on PCV3 infection were investigated. The CO inducers (cobalt protoporphyrin IX [CoPP] or tricarbonyl dichloro ruthenium [II] dimer [CORM-2]) mediate PCV3 inhibition by generating CO, and this inhibition is reversed by hemoglobin (Hb; a CO scavenger). The inhibition of PCV3 replication by BV depended on BV-mediated reactive oxygen species (ROS) reduction, as N-acetyl-l-cysteine affected PCV3 replication while reducing ROS production. The reduction product of BV, bilirubin (BR), specifically promoted nitric oxide (NO) generation and further activated the cyclic GMP/protein kinase G (cGMP/PKG) pathway to attenuate PCV3 infection. Both the iron provided by FeCl3 and the iron chelated by deferoxamine (DFO) with CoPP treatment failed to affect PCV3 replication. Our data demonstrate that the HO-1-CO-cGMP/PKG, HO-1-BV-ROS, and HO-1-BV-BR-NO-cGMP/PKG pathways contribute crucially to the inhibition of PCV3 replication. These results provide important insights regarding preventing and controlling PCV3 infection. IMPORTANCE The regulation of host protein expression by virus infection is the key to facilitating self-replication. As an important emerging pathogen of swine, clarification of the interaction between PCV3 infection and the host enables us to understand the viral life cycle and pathogenesis better. Heme oxygenase-1 (HO-1) and its metabolites carbon monoxide (CO), biliverdin (BV), and iron have been demonstrated to involve a wealth of viral replications. Here, we, for the first time, demonstrated that HO-1 expression decreases in PCV3-infected cells and negatively regulates PCV3 replication and that the HO-1 metabolic products CO and BV inhibit PCV3 replication by the CO- or BV/BR/NO-dependent cGMP/PKG pathway or BV-mediated ROS reduction, but the iron (the third metabolic product) does not. Specifically, PCV3 infection maintains normal proliferation by downregulating HO-1 expression. These findings clarify the mechanism by which HO-1 modulates PCV3 replication in cells and provide important targets for preventing and controlling PCV3 infection.

BackgroundBased on previous research, both dapagliflozin (DAPA) and sacubitril-valsartan (S/V) improve the prognosis of patients with heart failure (HF). Our study aims to investigate whether the early initiation of DAPA or the combination of DAPA with S/V in different orders would exert a greater protective effect on heart function than that of S/V alone in post-myocardial infarction HF (post-MI HF).MethodsRats were randomized into six groups: (A) Sham; (B) MI; (C) MI + S/V (1st d); (D) MI + DAPA (1st d); (E) MI + S/V (1st d) + DAPA (14th d); (F) MI + DAPA (1st d) + S/V (14th d). The MI model was established in rats via surgical ligation of the left anterior descending coronary artery. Histology, Western blotting, RNA-seq, and other approaches were used to explore the optimal treatment to preserve the heart function in post-MI HF. A daily dose of 1 mg/kg DAPA and 68 mg/kg S/V was administered.ResultsThe results of our study revealed that DAPA or S/V substantially improved the cardiac structure and function. DAPA and S/V monotherapy resulted in comparable reduction in infarct size, fibrosis, myocardium hypertrophy, and apoptosis. The administration of DAPA followed by S/V results in a superior improvement in heart function in rats with post-MI HF than those in other treatment groups. The administration of DAPA following S/V did not result in any additional improvement in heart function as compared to S/V monotherapy in rats with post-MI HF. Our findings further suggest that the combination of DAPA and S/V should not be administered within 3 days after acute myocardial infarction (AMI), as it resulted in a considerable increase in mortality. Our RNA-Seq data revealed that DAPA treatment after AMI altered the expression of genes related to myocardial mitochondrial biogenesis and oxidative phosphorylation.ConclusionsOur study revealed no notable difference in the cardioprotective effects of singular DAPA or S/V in rats with post-MI HF. Based on our preclinical investigation, the most effective treatment strategy for post-MI HF is the administration of DAPA during the 2 weeks, followed by the addition of S/V to DAPA later. Conversely, adopting a therapeutic scheme whereby S/V was administered first, followed by later addition of DAPA, failed to further improve the cardiac function compared to S/V monotherapy.

Prime Editor (PE) is a precise genome manipulation technology based on the CRISPR-Cas9 system, while its application in human induced pluripotent stem cells (iPSCs) remains limited. Here, we established a repaired hiPS cell line (SKLRMi001-A-1) from hiPSCs with androgen receptor (AR) mutation (c.2710G > A; p.V904M). The repaired iPSC line expressed pluripotency markers, retained normal karyotype, showed the capability of differentiating into three germ layers and was absence of mycoplasma infection. The repaired iPSC line will help to elucidate the mechanism of androgen insensitivity syndrome (AIS) and benefit treatment for AIS in the future.

Receptor tyrosine kinases (RTKs) are major signaling hubs in metazoans, playing crucial roles in cell proliferation, migration, and differentiation. However, few tools are available to measure the activity of a specific RTK in individual living cells. Here, we present pYtags, a modular approach for monitoring the activity of a user-defined RTK by live-cell microscopy. pYtags consist of an RTK modified with a tyrosine activation motif that, when phosphorylated, recruits a fluorescently labeled tandem SH2 domain with high specificity. We show that pYtags enable the monitoring of a specific RTK on seconds-to-minutes time scales and across subcellular and multicellular length scales. Using a pYtag biosensor for epidermal growth factor receptor (EGFR), we quantitatively characterize how signaling dynamics vary with the identity and dose of activating ligand. We show that orthogonal pYtags can be used to monitor the dynamics of EGFR and ErbB2 activity in the same cell, revealing distinct phases of activation for each RTK. The specificity and modularity of pYtags open the door to robust biosensors of multiple tyrosine kinases and may enable engineering of synthetic receptors with orthogonal response programs.

Abstract A smart textile that could harvest mechanical‐energy for photo‐thermal energy utilization facilitates the development of a flexible self‐heating wearable device. This study presents novel triboelectric materials with a dynamic‐bond‐cross‐linking azobenzene‐based polymer (PAzo‐M) with diverse metal ions. The flexible nylon fabric coated with PAzo‐M (NF@PAzo‐M) serves as a friction layer of the photothermal triboelectric nanogenerator (PT‐TENG) to harvest human mechanical energy. The prepared PT‐TENG could exhibit a maximum open‐circuit voltage of up to 188.8 V with excellent electron loss capability because of its minimum vertical electron affinity of internal ion. And it can harvest mechanical energy from human motion (0.5–1 Hz) to drive the self‐powering irradiation of ultraviolet light or visible light, leading to the reversible isomerization of NF@PAzo‐M. The NF@PAzo‐M textile cyclically utilizes photo‐thermal energy for self‐heating. These results suggest new opportunities to harvest human mechanical energy for self‐powering multifunctional wearable devices for functions.

The physics potential of detecting ^8 B solar neutrinos will be exploited at the Jiangmen Underground Neutrino Observatory (JUNO), in a model-independent manner by using three distinct channels of the charged current (CC), neutral current (NC), and elastic scattering (ES) interactions. Due to the largest-ever mass of ^13 C nuclei in the liquid scintillator detectors and the expected low background level, ^8 B solar neutrinos are observable in the CC and NC interactions on ^13 C for the first time. By virtue of optimized event selections and muon veto strategies, backgrounds from the accidental coincidence, muon-induced isotopes, and external backgrounds can be greatly suppressed. Excellent signal-to-background ratios can be achieved in the CC, NC, and ES channels to guarantee the observation of the ^8 B solar neutrinos. From the sensitivity studies performed in this work, we show that JUNO, with 10 yr of data, can reach the 1 σ precision levels of 5%, 8%, and 20% for the ^8 B neutrino flux, ${\sin }^{2}{\theta }_{12}$ , and ${\rm{\Delta }}{m}_{21}^{2}$ , respectively. Probing the details of both solar physics and neutrino physics would be unique and helpful. In addition, when combined with the Sudbury Neutrino Observatory measurement, the world's best precision of 3% is expected for the measurement of the ^8 B neutrino flux.

Mg3Bi2−vSbv (0 ≤ v ≤ 2) is a class of promising thermoelectric materials that have a high thermoelectric performance around room temperatures, whereas their thermoelectric properties under pressures and temperatures are still illusive. In this study, we examined the influence of pressure, temperature, and carrier concentration on the thermoelectric properties of Mg3Bi2−vSbv using first-principle calculations accompanied with Boltzmann transport equations method. There is a decrease in the lattice thermal conductivity of Mg3Sb2 (i.e., v = 2) with increasing pressure. For a general Mg3Bi2−vSbv system, power factors are more effectively improved by n-type doping where electrons are the primary carriers over holes in n-type doping, and can be further enhanced by applied pressure. The figure of merit (zT) exhibits a positive correlation with temperature. A high zT value of 1.53 can be achieved by synergistically tuning the temperature, pressure, and carrier concentration in Mg3Sb2. This study offers valuable insights into the tailoring and optimization of the thermoelectric properties of Mg3Bi2−vSbv.

In recent years, underwater acoustic applications have attracted much attention, for example, for underwater environmental monitoring, underwater exploration, etc. Hydrophones play a particularly important role. Although hydrophone design has been in multifarious application forms, it still needs to consider increasing demand for low-cost, low-consumption, and multiple-function devices, as well as issues around miniaturization, lossless data collection, etc. In this paper, we design a compact underwater acoustic device that has the capability of underwater acoustic signal storage, underwater acoustic signal transmission via the Internet, and decoding based on the direct sequences spread spectrum (DSSS). The key problem is how to implement multiple functions in only one micro-controller unit (MCU). The hardware and software of the proposed multi-function hydrophone are described in detail. In particular, the MCU, the pre-amplifier with gain control, and the analog-to-digital integrated chip are introduced. Moreover, underwater acoustic data storage, underwater acoustic transmission, and the DSSS receiver are depicted in terms of software. The different functions of the hydrophone are verified in sea trial experiments. The results show that the proposed multi-function hydrophone is able to sample underwater acoustic data at high quality. In addition, to demonstrate configurable parameters, the DSSS receiver with different carrier frequencies is provided. The proposed multi-function hydrophone realizes zero bit error rate (BER) when carrier frequency fc=9 kHz, and the BER with 10−3 order of magnitude when carrier frequency fc=15.5 kHz. The results show that the proposed multi-function hydrophone has great potential to explore the ocean.

Abstract Road geometry perception indicates road direction and drivable area for Lane Keeping System and Lane Departure Warning System in Advanced Driver Assistance Systems or routing and decision‐making in Autonomous Driving. High‐definition map with accurate positioning or lane information is generally required. However, these two types of information are not always available because of positioning failure or lane mark degradation. In this paper, a road geometry estimation method is proposed without requirement of accurate positioning and lane information. Due to the fact the lane guides the front vehicle, the potential correlation between the relative azimuth of front vehicle and the direction of road is explored. The stable and observable information of front vehicles are exploited, such as the license plate location. A radar‐camera fusion system using image processing, and a nonlinear system is then built with Unscented Kalman Filter to estimate the road curvature. Simulation results with Carla demonstrate that the method enhances the road geometry perception by 77.1%, compared with the baseline method. The proposed method can provide reliable road geometry information for autonomous driving when accurate positioning and lane information are unavailable, so that it renders more robust and safer perception for future autonomous driving.

The multidrug and toxic compound extrusion (MATE) family plays pivotal roles in the detoxification process in plants, while no information has been provided for this gene family in melon (Cucumis melo L.) thus far, limiting our understanding of its functions in melon acclimation to stressful environments. In this study, a total of 39 MATEs (CmMATE1–CmMATE39) were observed in the melon genome; these were unevenly distributed in all chromosomes, with the most on Chromosome 1. Based on their orthologous relationship with those from Arabidopsis, rice, and sorghum, melon MATEs were clustered into three subfamilies of Clades I, II, and III, wherein 23, 9, and 7 members were included, respectively. Variable exon number was observed in CmMATEs, and the most were harbored by CmMATE8. Gene ontology (GO) term and cis-regulatory element (CRE) analyses pointed to the potential roles of CmMATEs in both the regulation of melon development and acclimation to various abiotic and biotic stressors. The RNA-seq and qRT-PCR (quantitative real-time PCR) results demonstrated that under normal growth conditions, CmMATEs were expressed in a tissue- and development-specific manner, while their abundance apparently varied in a stress-dependent manner when melon plants were exposed to unfavorable environmental conditions. Altogether, these observations could expand our knowledge about the plant MATE family and benefit functional genomics analysis for CmMATEs in the future.

Abstract Background Lung resident mesenchymal stem cells (LR-MSCs) play an important role in idiopathic pulmonary fibrosis (IPF) by transforming into myofibroblasts, thereby losing their repair ability. Evidence suggests that key proteins of multiple signaling pathways are involved in myofibroblast differentiation of LR-MSCs, such as β-Catenin and GLI family zinc finger 1 (GLI1). These proteins are regulated by SUMO (small ubiquitin-like modifier) modification, which is a post-translational modification that promotes protein degradation, while Sumo specific protein 1 (SENP1)-mediated deSUMOylation produces the opposite biological effects. Therefore, we speculated that SENP1 might be a potential target for treating pulmonary fibrosis by preventing the myofibroblast differentiation of LR-MSCs. Methods LR-MSCs were isolated from mice by using immunomagnetic beads. The extracted LR-MSCs were identified by flow cytometric analysis and multilineage differentiation assays. Lentivirus packaged shRNA silenced the expression of SENP1 in vitro and vivo. The silencing efficacy of SENP1 was verified by real-time quantitative PCR. The effect of down-regulated SENP1 on the myofibroblast differentiation of LR-MSCs was assessed by Immunofluorescence and Western blot. Immunoprecipitation was used to clarify that SENP1 was a key target for regulating the activity of multiple signaling pathways in the direction of LR-MSCs differentiation. LR-MSCs resident in the lung was analyzed with in vivo imaging system. HE and Masson staining was used to evaluate the therapeutic effect of LR-MSCs with SENP1 down-regulation on the lung of BLM mice. Results In this study, we found that the myofibroblast differentiation of LR-MSCs in IPF lung tissue was accompanied by enhanced SENP1-mediated deSUMOylation. The expression of SENP1 increased in LR-MSCs transition of bleomycin (BLM)-induced lung fibrosis. Interfering with expression of SENP1 inhibited the transformation of LR-MSCs into myofibroblasts in vitro and in vivo and restored their therapeutic effect in BLM lung fibrosis. In addition, activation of the WNT/β-Catenin and Hedgehog/GLI signaling pathways depends on SENP1-mediated deSUMOylation. Conclusions SENP1 might be a potential target to restore the repair function of LR-MSCs and treat pulmonary fibrosis. Video Abstract

Abstract Background As a fatal interstitial lung disease, idiopathic pulmonary fibrosis (IPF) was characterized by the insidious proliferation of extracellular matrix (ECM)-producing mesenchymal cells. Recent studies have demonstrated that lung resident mesenchymal/stromal cells (LR-MSC) are the source of myofibroblasts. Endoplasmic reticulum (ER) stress is prominent in IPF lung. This study sought to investigate the effects of ER stress on the behavior of LR-MSC during pulmonary fibrosis. Methods ER stress and myofibroblast differentiation of LR-MSC in patients with IPF were evaluated. Primary mouse LR-MSC was harvested and used in vitro for testing the effects of ER stress and C/EBP homologous protein (CHOP) on LR-MSC. Adoptive transplantation of LR-MSC to bleomycin-induced pulmonary fibrosis was done to test the in vivo behavior of LR-MSC and its influence on pulmonary fibrosis. Results We found that myofibroblast differentiation of LR-MSC is associated with ER stress in IPF and bleomycin-induced mouse fibrotic lung. Tunicamycin-induced ER stress impairs the paracrine, migration, and reparative function of mouse LR-MSC to injured type 2 alveolar epithelial cells MLE-12. Overexpression of the ER stress responder C/EBP homologous protein (CHOP) facilitates the TGFβ1-induced myofibroblast transformation of LR-MSC via boosting the TGFβ/SMAD signaling pathway. CHOP knockdown facilitates engraftment and inhibits the myofibroblast transformation of LR-MSC during bleomycin-induced pulmonary fibrosis, thus promoting the efficacy of adopted LR-MSC in alleviating pulmonary fibrosis. Conclusion Our work revealed a novel role that ER stress involved in pulmonary fibrosis by influencing the fate of LR-MSC and transformed to “crime factor” myofibroblast, during which CHOP acts as the key modulator. These results indicate that pharmacies targeting CHOP or therapies based on CHOP knockdown LR-MSC may be promising ways to treat pulmonary fibrosis.

Abstract We study damping signatures at the Jiangmen Underground Neutrino Observatory (JUNO), a medium-baseline reactor neutrino oscillation experiment. These damping signatures are motivated by various new physics models, including quantum decoherence, ν 3 decay, neutrino absorption, and wave packet decoherence. The phenomenological effects of these models can be characterized by exponential damping factors at the probability level. We assess how well JUNO can constrain these damping parameters and how to disentangle these different damping signatures at JUNO. Compared to current experimental limits, JUNO can significantly improve the limits on τ 3/m 3 in the ν 3 decay model, the width of the neutrino wave packet σ x , and the intrinsic relative dispersion of neutrino momentum σ rel.

The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration. However, cartilage defects are considerably more complicated in clinical conditions, especially when injuries occur at specific sites (e.g., osteochondral tissue, growth plate, and weight-bearing area) or under inflammatory microenvironments (e.g., osteoarthritis and rheumatoid arthritis). Therapeutic implantations, including advanced scaffolds, developed growth factors, and various cells alone or in combination currently used to treat cartilage lesions, address cartilage regeneration under abnormal conditions. This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.

The mechanical characteristics of columnar jointed basalts (CJBs) are generally considered to be subject to size effects. They display complex mechanical behaviors under lateral pressure, which may be related to the variation in the rock's mesoproperties. In this study, many nonuniform CJB models with various rock meso-constitutive relations and model sizes were established, and their influences on the strength and deformation properties, multistage mechanical damage behavior, and acoustic emission characteristics of CJBs were investigated. The results show that, as the residual strength coefficient increases, the compressive strength of CJBs rises, and the equivalent deformation modulus of CJBs decreases or increases slightly; with an increase in the model size, the compressive strength slightly decreases at first and then varies moderately, and the equivalent deformation modulus shows a fluctuating trend. Furthermore, the macro stress–strain relationships can be divided into different stages according to the corresponding damage behaviors. The strains and energy accumulations before peak stress was reached were further analyzed. The results greatly improve our understanding of the collapse process of CJBs and the instability precursors of related structures.

The shade avoidance syndrome (SAS) is a collective adaptive response of plants under shade highlighted by characteristic phenotypes such as hypocotyl elongation, which is largely mediated by concerted actions of auxin and GA. We identified ATHB2, a homeodomain-leucine zipper (HD-Zip) domain transcription factor known to be rapidly induced under shade condition, as a positive regulator of GA biosynthesis necessary for the SAS by transactivating the expression of GA20ox2, a key gene in the GA biosynthesis pathway. Based on promoter deletion analysis, EMSA and ChIP assay, ATHB2 appears to regulate the GA20ox2 expression as a direct binding target. We also found that the GA20ox2 expression is under negative control by TCP13, the effect of which can be suppressed by presence of ATHB2. Considering a rapid induction kinetics of ATHB2, this relationship between ATHB2 and TCP13 may allow ATHB2 to play a shade-specific activator for GA20ox by derepressing a pre-existing activity of TCP13.

GATA binding protein 6 (GATA6) is an important transcription factor of cardiovascular endothelial cells, has the potential to regulate the process of cardiac development. Consequently, its abnormal expression is related to congenital heart disease.Human GATA6 gene clones were on chromosome 18 q11.1- q 11.2, consists of 7 exons and 6 intron.Now, a human embryonic stem cell line with GATA6 c.620_647del (p.S208Afs*77) mutation was generated. Interestingly, the ESC line displayed a normal karyotype, pluripotency and morphology of stem cells.This cell line has the ability to undergo differentiation into three germ layers in vivo.

Researches have demonstrated that microorganisms are indispensable for the nutrition transportation, growth and development of human bodies, and disorder and imbalance of microbiota may lead to the occurrence of diseases. Therefore, it is crucial to study relationships between microbes and diseases. In this manuscript, we proposed a novel prediction model named MADGAN to infer potential microbe-disease associations by combining biological information of microbes and diseases with the generative adversarial networks. To our knowledge, it is the first attempt to use the generative adversarial network to complete this important task. In MADGAN, we firstly constructed different features for microbes and diseases based on multiple similarity metrics. And then, we further adopted graph convolution neural network (GCN) to derive different features for microbes and diseases automatically. Finally, we trained MADGAN to identify latent microbe-disease associations by games between the generation network and the decision network. Especially, in order to prevent over-smoothing during the model training process, we introduced the cross-level weight distribution structure to enhance the depth of the network based on the idea of residual network. Moreover, in order to validate the performance of MADGAN, we conducted comprehensive experiments and case studies based on databases of HMDAD and Disbiome respectively, and experimental results demonstrated that MADGAN not only achieved satisfactory prediction performances, but also outperformed existing state-of-the-art prediction models.

LAB fermentation could reduce the beany flavor, the sensitization of soymilk and improve the digestibility of soymilk, easy to be accepted by consumers. This study evaluated the characterization, stability, in vitro digestion and antioxidant capacity of soymilk fermented by different Lactic acid bacteria (LAB). The results showed that fat content of L.plantarum-S (0.77 g/100 mL) was the lowest, which proved that L.plantarum had a significant effect on lipid degradation, the protein content of L.delbrueckii-S (23.01 mg/mL) was higher. L.delbrueckii-S and L.paracasei-S were more acceptable to people, as well as high overall ratings. L.paracasei fermented soymilk has better suspension stability and smaller particle size. The fermented soymilk showed higher free amino acids (FAA) content, peptide content and stronger antioxidant activity than soymilk after digestion. The soymilk fermented by L. plantarum contained higher FAA content and L.delbrueckii contained the highest peptide content compared with other strains. L.acidophilus-S and L.rhamnosus-S showed stronger DPPH scavenging rate and FARP, which were 57.03 % and 52.78 % stronger than unfermented soymilk, respectively. These results may be provided a theoretical basis for the strain screening of fermented soymilk.

ABSTRACT Avian metapneumovirus subgroup C (aMPV/C) is an important pathogen that causes upper respiratory symptoms and egg production decline in turkeys and chickens. aMPV/C infection leads to inhibition of the host antiviral immune response. However, our understanding of the molecular mechanisms underlying host immune response antagonized by aMPV/C infection is limited. In this study, we demonstrated that the aMPV/C phosphoprotein (P) inhibits the IFN antiviral signaling pathway triggered by melanoma differentiation gene 5 (MDA5) and reduces interferon β (IFN-β) production and IFN-stimulated genes (ISGs) by targeting IFN regulatory factor 7 (IRF7) but not nuclear factor κB (NF-κB) in DF-1 cells. Moreover, we found that aMPV/C P protein only blocks the nuclear translocation of IRF3 by interacting with IRF3 in HEK-293T cells, instead of affecting IRF3 phosphorylation and inducing IRF3 degradation, which suppresses IRF3 signaling activation and results in a decrease in IFN-β production. Collectively, these results reveal a novel mechanism by which aMPV/C infection disrupts IFN-β production in the host. IMPORTANCE The innate immune response is the first defense line of host cells and organisms against viral infections. When RNA viruses infect cells, viral RNA induces activation of retinoic acid-induced gene I and melanoma differentiation gene 5, which initiates downstream molecules and finally produces type I interferon (IFN-I) to regulate antiviral immune responses. The mechanism for avian metapneumovirus (aMPV) modulating IFN-I production to benefit its replication remains unknown. Here, we demonstrate that phosphoprotein of aMPV subgroup C (aMPV/C) selectively inhibits the nuclear translocation of interferon regulatory 3 (IRF3), instead of affecting the expression and phosphorylation of IRF3, which finally downregulates IFN-I production. This study showed a novel mechanism for aMPV/C infection antagonizing the host IFN response.

Tryptophan and its derived metabolites have been assumed to play important roles in the development and survival of organisms. However, the links of tryptophan and its derived metabolites to temperature change remained largely cryptic. Here we presented that a class of prenyl indole alkaloids biosynthesized from tryptophan dramatically accumulated in thermophilic fungus Thermomyces dupontii under cold stress, in which lipid droplets were also highly accumulated and whose conidiophores were highly build-up. Concurrently, disruption of the key NRPS gene involved in the biosynthesis of prenyl indole alkaloids, resulted in decreased lipid and shrunken mitochondria but enlarged vacuoles. Moreover, the Fe3+ and superoxide levels in ΔNRPS were significantly increased but the reactive oxygen species lipid peroxidation and autophagy levels decreased. Metabolomics study revealed that most enriched metabolites in ΔNRPS were mainly composed of tryptophan degraded metabolites including well known ROS scavenger kynurenamines, and lipid-inhibitors, anthranilic acid and indoleacetic acid, and free radical reaction suppressor free fatty acids. Transcriptomic analysis suggested that the key gene involved in tryptophan metabolism, coinciding with the lipid metabolic processes and ion transports were most up-regulated in ΔNRPS under stress. Our results confirmed a lipid-mediated fungal response to cold stress and unveiled a link of tryptophan-based metabolic reprogramming to the fungal cold adaption.

Objective To explore molecular mechanisms of polygonum multiflorum in the treatment of androgenic alopecia and to provide underlying drug targets. Methods Bioinformatics analysis tool for molecular mechanism of Traditional Chinese Medicine and five disease gene databases were used to establish effective ingredients-targets of polygonum multiflorum network and protein-protein interaction network. The core sub-network was extracted through network topology, and then GO and KEGG analyses were performed. Finally, these top 10 molecules with highest connectivity were performed to molecular docking. Results A total of 1 357 common target genes were generated based on the intersection of effective ingredients-targets of polygonum multiflorum and underlying disease targets. The core sub-network including 67 genes was extracted by topological analysis. The KEGG enrichment results showed that polygonum multiflorum produce biological functions mainly through regulating inflammatory response, apoptosis, oxidative stress and autophagy pathways. The molecular docking results demonstrated the binding energy of PIK3CA-emodin, PIK3CA-chrysophanol, PIK3CA-guaijaverin and PIK3CB-emodin were less -9 kcal/mol. Conclusions The mechanism of polygonum multiflorum to treat androgenic alopecia is that PI3K/Akt pathway was mediated to regulate the expression of PIK3CA and PIK3CB to cell apoptosis through emodin. In addition, it is involved in the process of the inhibition of inflammatory response and oxidative stress, and induction of melanin production.

Abstract Background Endoplasmic reticulum (ER) stress is involved in the pathological process of pulmonary fibrosis, including IPF. It affects a broad scope of cellular types during pulmonary fibrosis but the role in epithelial-mesenchymal crosstalk has not been fully defined. The present study aimed to investigate the effects of Shh secretion by ER stress-challenged type II alveolar epithelial cells (AECII) on fibroblast and pulmonary fibrosis. Methods Conditioned medium (CM) from tunicamycin (TM)-treated AECII was collected and incubated with fibroblast. Short hairpin RNA (shRNA) was used for RNA interference of C/EBP homologous protein (CHOP). The effects of CHOP and HH signaling were evaluated by TM administration under the background of bleomycin-induced pulmonary fibrosis in mice. Results Both expression of CHOP and Shh in AECII, and HH signaling in mesenchyme were upregulated in IPF lung. TM-induced Shh secretion from AECII activates HH signaling and promotes pro-fibrotic effects of fibroblast. Interfering CHOP expression reduced ER stress-induced Shh secretion and alleviated pulmonary fibrosis in mice. Conclusions Our work identified a novel mechanism by which ER stress is involved in pulmonary fibrosis. Inhibition of ER stress or CHOP in epithelial cells alleviated pulmonary fibrosis by suppressing Shh/HH signaling pathway of fibroblasts.

Osteonecrosis is a common orthopedic disease in clinic, resulting in joint collapse if no appropriate treatment is performed in time. Core decompression is a general treatment modality for early osteonecrosis. However, effective bone regeneration in the necrotic area is still a significant challenge. This study developed a biofunctionalized composite scaffold (PLGA/nHA30VEGF) for osteonecrosis therapy through potentiation of osteoconduction, angiogenesis, and a favorable metabolic microenvironment. The composite scaffold had a porosity of 87.7% and compressive strength of 8.9 MPa. PLGA/nHA30VEGF had an average pore size of 227.6 μm and a water contact angle of 56.5° with a sustained release profile of vascular endothelial growth factor (VEGF). After the implantation of PLGA/nHA30VEGF, various osteogenic and angiogenic biomarkers were upregulated by 2–9 fold compared with no treatment. Additionally, the metabolomic and lipidomic profiling studies demonstrated that PLGA/nHA30VEGF effectively regulated the multiple metabolites and more than 20 inordinate metabolic pathways in osteonecrosis. The excellent performances reveal that the biofunctionalized composite scaffold provides an advanced adjuvant therapy modality for osteonecrosis.

To improve the corrosion resistance of 6061 Al in electric vehicle battery packs, a composite coating of nano-SiO2/Micro-Arc oxidation (MAO) ceramic structure was prepared on its surface. Electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization curves (PDP) were used to evaluate the corrosion resistance of the specimens after 7 days immersion in a 3.5% NaCl solution. The corrosion resistance of the prefabricated coatings was measured via local electrochemical impedance spectroscopy (LEIS). Confocal microscopy, scanning electron microscopy (SEM), and X-ray diffraction (XRD) were used to characterize the microstructure and phase composition of the specimens. An energy dispersive spectrometer (EDS) was used to detect the elemental composition of the surface of the specimen. The results showed that the specimen with nano-SiO2/MAO composite coating had the least amount of micropores and superior corrosion resistance. The global electrochemical impedance of nano-SiO2/MAO composite coating was 1.1 times higher than that of the MAO coating and 8.4 times higher than that of the 6061 Al. When the coating was defective, the local electrochemical impedance of the nano-SiO2/MAO composite coating was still two times higher than that of the MAO coating. In the presence of scratches, the nano-SiO2/MAO composite coating still showed high corrosion resistance. The collapse corrosion mechanism of the nano-SiO2/MAO composite coating was proposed.

GaN devices are nowadays attracting global attention due to their outstanding performance in high voltage, high frequency, and anti-radiation ability. Research on total ionizing dose and annealing effects on E-mode GaN Cascode devices has been carried out. The Cascode device consists of a low-voltage MOSFET and a high-voltage depletion-mode GaN MISHEMT. Cascode devices of both conventional processed MOSFET and radiation-hardened MOSFET devices are fabricated to observe the TID effects. Experiment results indicate that, for the Cascode device with conventional processed MOSFET, the VTH shifts to negative values at 100 krad(Si). For the Cascode device with radiation-hardened MOSFET, the VTH shifts by −0.5 V at 100 krad(Si), while shifts to negative values are 500 krad(Si). The annealing process, after the TID experiment, shows that it can release trapped charges and help VTH recover. On one hand, the VTH shift and recover trends are similar to those of a single MOSFET device, suggesting that the MOSFET is the vulnerable part in the Cascode which determines the anti-TID ability of the device. On the other hand, the VTH shift amount of the Cascode device is much larger than that of a previously reported p-GaN HEMT device, indicating that GaN material shows a better anti-TID ability than Si.