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Abstract Advancements in precision medicine necessitate understanding drug clearance pathways, especially in organs like the liver and kidneys. Traditional techniques such as PET/CT pose radiation hazards, whereas optical imaging poses challenges in maintaining both depth penetration and high resolution. Moreover, very few longitudinal studies have been performed for drug candidates for different symptoms. Leveraging non-ionizing photoacoustic tomography for deep tissue imaging, we developed a spatiotemporally resolved clearance pathway tracking (SRCPT) method, providing unprecedented insights into drug clearance dynamics within vital organs. SRCPT addresses challenges like laser fluence attenuation, enabling dynamic visualization of drug clearance pathways and essential parameter extraction. We employed a novel frequency component selection based synthetic aperture focusing technique (FCS-SAFT) with respiratory-artifacts-free weighting factors to enhance three-dimensional imaging resolutions. Inspired by this, we investigated the clearance pathway of a clinical drug, mitoxantrone, revealing reduced liver clearance when hepatic function is impaired. Furthermore, immunoglobulin G clearance analysis revealed significant differences among mice with varying renal injury degrees. The accuracy of our method was validated using a double-labeled probe [68Ga]DFO-IRDye800CW, showing a strong positive correlation between SRCPT and PET. We believe that this powerful SRCPT promises precise mapping of drug clearance pathways and enhances diagnosis and treatment of liver and kidney-related diseases.

The treatment of oral squamous cell carcinoma (OSCC) remains a significant difficulty, as there has been no improvement in survival rates over the past fifty years. Hence, exploration and confirmation of new dependable treatment targets and biomarkers is imperative for OSCC therapy. TEAD transcription factors are crucial for integrating and coordinating multiple signaling pathways that are essential for embryonic development, organ formation, and tissue homeostasis. In addition, by attaching to coactivators, TEAD modifies the expression of genes such as Cyr61, Myc, and connective tissue growth factor, hence facilitating tumor progression. Therefore, TEAD is regarded as an effective predictive biomarker due to its significant connection with clinical parameters in several malignant tumors, including OSCC. The efficacy of existing drugs that specifically target TEAD has demonstrated encouraging outcomes, indicating its potential as an optimal target for OSCC treatment. This review provides an overview of current targeted therapy strategies for OSCC by highlighting the transcription mechanism and involvement of TEAD in oncogenic signaling pathways. Finally, the feasibility of utilizing TEAD as an innovative approach to address OSCC and its potential clinical applications were analyzed and discussed.

Abstract Background Aortic intramural hematoma (IMH) is one of the typical entities of acute aortic syndrome and probably accounts for 5–25% of all cases. The ulcer-like projections (ULP), which are described as a focal, blood-filled pouch protruding into the hematoma of the aortic wall, are regarded as one of the high-risk imaging features of IMH and may cause initial medical treatment failure and death. Case presentation We present a case report of an acute type B IMH patient with impaired renal function and newly developed ULP in the acute phase. The 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MR) was performed to evaluate the condition of aortic hematoma. The 18F-FDG focal uptake along the aortic wall of the hematoma was normal compared to the background (SUVmax 2.17; SUVSVC 1.6; TBR 1.35). We considered the IMH stable in such cases and opted for medical treatment and watchful observation. Six months after discharge, the patient’s recovery was satisfactory, and aortic remodeling was ideal. Conclusions The 18F-FDG PET/MR is a novel tool to evaluate the risk of IMH patients and thus provides information for therapy selection.

With the introduction of China’s “Carbon Peaking Action Plan Before 2030,” the transformation of the power industry has released huge opportunities and potential. The DC distribution network can well-coordinate the contradiction between distributed power and grid access, fully develop the benefits of distributed energy, and become a new direction for the development of the power industry. However, the current traditional DC–DC converters have problems such as single-topology structure and low power density, which can only complete one-way transmission of energy; hence, the distributed energy cannot be fully utilized. Addressing the problem of distributed energy transfer, this paper is based on a three-port DC–DC converter for a low-voltage DC distribution network to realize energy transfer between the DC distribution network, distributed energy, and low-voltage load. First, the energy transfer modes of the three-port DC–DC converter are introduced. Combined with the converter topology and energy transfer mode, a simplified equivalent model of the converter is established. The voltage gain characteristics and frequency characteristics of this converter are studied. Furthermore, the effects of the excitation inductance to primary resonance inductance ratio parameter k and quality factor Q on the voltage gain characteristics of the converter are discussed. On this basis, the resonant cavity design of the converter is based on the optimal selection of parameters k and Q so that the converter can meet the voltage gain requirements in both forward and reverse operations. The simulation results under different loads verify the reasonableness of the resonant cavity component selection.

Abstract Senescent cancer cells are endowed with high immunogenic potential that has been leveraged to elicit antitumor immunity and potentially complement anticancer therapies. However, the efficacy of live senescent cancer cell‐based vaccination is limited by interference from immunosuppressive senescence‐associated secretory phenotype and pro‐tumorigenic capacity of senescent cells. Here, a senescent cancer cell‐based nanovaccine with strong immunogenicity and favorable potential for immunotherapy is reported. The biomimetic nanovaccine integrating a senescent cancer cell membrane‐coated nanoadjuvant outperforms living senescent cancer cells in enhancing dendritic cells (DCs) internalization, improving lymph node targeting, and enhancing immune responses. In contrast to nanovaccines generated from immunogenic cell death‐induced tumor cells, senescent nanovaccines facilitate DC maturation, eliciting superior antitumor protection and improving therapeutic outcomes in melanoma‐challenged mice with fewer side effects when combined with αPD‐1. The study suggests a versatile biomanufacturing approach to maximize immunogenic potential and minimize adverse effects of senescent cancer cell‐based vaccination and advances the design of biomimetic nanovaccines for cancer immunotherapy.

Extracellular matrices (ECMs) play a key role in nerve repair and are recognized as the natural source of biomaterials. In parallel to extensively studied tissue-derived ECMs (ts-ECMs), cell-derived ECMs (cd-ECMs) also have the capability to partially recapitulate the complicated regenerative microenvironment of native nerve tissues. Notably, cd-ECMs can avoid the shortcomings of ts-ECMs. Cd-ECMs can be prepared by culturing various cells or even autologous cells in vitro under pathogen-free conditions. And mild decellularization can achieve efficient removal of immunogenic components in cd-ECMs. Moreover, cd-ECMs are more readily customizable to achieve the desired functional properties. These advantages have garnered significant attention for the potential of cd-ECMs in neuroregenerative medicine. As promising biomaterials, cd-ECMs bring new hope for the effective treatment of peripheral nerve injuries. Herein, this review comprehensively examines current knowledge about the functional characteristics of cd-ECMs and their mechanisms of interaction with cells in nerve regeneration, with a particular focus on the preparation, engineering optimization, and scalability of cd-ECMs. The applications of cd-ECMs from distinct cell sources reported in peripheral nerve tissue engineering are highlighted and summarized. Furthermore, current limitations that should be addressed and outlooks related to clinical translation are put forward as well.

The aim of the present study was to establish a simple and reliable ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method and apply it for the determination of pharmacokinetics of moxidectin-loaded microspheres (MOX-MS) in rats. Plasma samples were processed using a simplified liquid–liquid extraction method and were separated using an Agilent Zorbax Eclipse Plus C18 column (50 mm × 2.1 mm, 1.8 μm) with a mobile phase consisting of a 10 mM ammonium formate solution with 0.1% formic acid (A) and acetonitrile (B) at a flow rate of 0.4 mL/min for 5 min. Avermectin B1a was used as an internal standard (IS). The sample was injected at a volume of 10 μL with a column temperature of 35 °C and detected in a positive ion mode. A good linear response across the concentration range of 1.00–200 ng/mL (r2 > 0.99) and a lower limit of quantification (LLOQ) of 1.00 ng/mL were achieved. The extraction recovery of moxidectin exceeded 94.1%, the matrix effect was between 91.2% and 96.2%, the accuracy ranged from 100.1 to 103.6%, and the relative standard deviation (RSD) did not exceed 15% for the intra- and inter-day accuracy and precision. The pharmacokinetic results showed that MOX-MS significantly decreased Cmax, prolonged T1/2, and improved bioavailability. The developed method significantly reduced the assay volume, shortened detection time, simplified sample processing methods and saved assay costs, which may contribute to the development of the new antiparasitic drug.

Abstract The emerging stem cell‐derived hepatocyte‐like cells (HLCs) are the alternative cell sources of hepatocytes for treatment of highly lethal acute liver failure (ALF). However, the hostile local environment and the immature cell differentiation may compromise their therapeutic efficacy. To this end, human adipose‐derived mesenchymal stromal/stem cells (hASCs) are engineered into different‐sized multicellular spheroids and co‐cultured with 3D coaxially and hexagonally patterned human umbilical vein endothelial cells (HUVECs) in a liver lobule‐like manner to enhance their hepatic differentiation efficiency. It is found that small‐sized hASC spheroids, with a diameter of ≈50 µm, show superior pro‐angiogenic effects and hepatic differentiation compared to the other counterparts. The size‐dependent functional enhancements are mediated by the Wnt signaling pathway. Meanwhile, co‐culture of hASCs with HUVECs, at a HUVECs/hASCs seeding density ratio of 2:1, distinctly promotes hepatic differentiation and vascularization both in vitro and in vivo, especially when endothelial cells are patterned into hollow hexagons. After subcutaneous implantation, the mini‐liver, consisting of HLC spheroids and 3D‐printed interconnected vasculatures, can effectively improve liver regeneration in two ALF animal models through amelioration of local oxidative stress and inflammation, reduction of liver necrosis, as well as increase of cell proliferation, thereby showing great promise for clinical translation.

Abstract Exploration of medicines for efficient and safe management of metabolic‐associated fatty liver disease (MAFLD) remains a challenge. Obeticholic acid (OCA), a selective farnesoid X receptor agonist, has been reported to ameliorate injury and inflammation in various liver diseases. However, its clinical application is mainly limited by poor solubility, low bioavailability, and potential side effects. Herein a hepatic‐targeted nanodrugs composed of OCA and cholesterol‐lowering atorvastatin (AHT) with an ideal active pharmaceutical ingredient (API) content for orally combined treatment of MAFLD is created. Such carrier‐free nanocrystals (OCAHTs) are self‐assembled, not only improving the stability in gastroenteric environments but also achieving hepatic accumulation through the bile acid transporter‐mediated enterohepatic recycling process. Orally administrated OCAHT outperforms the simple combination of OCA and AHT in ameliorating of liver damage and inflammation in both acetaminophen‐challenged mice and high‐fat diet‐induced MAFLD mice with less systematic toxicity. Importantly, OCAHT exerts profoundly reverse effects on MAFLD‐associated molecular pathways, including impairing lipid metabolism, reducing inflammation, and enhancing the antioxidation response. This work not only provides a facile bile acid transporter‐based strategy for hepatic‐targeting drug delivery but also presents an efficient and safe full‐API nanocrystal with which to facilitate the practical translation of nanomedicines against MAFLD.

With the carbon emission ratio of buildings increasing, including buildings in the carbon market, an inevitable trend of social development is created. Buildings are characterized by their strong seasonality, high simultaneity rate, and large load, which is not only the main factor leading to the peak load of a power grid but also an important resource for load control. Under the guidance of dynamic carbon emission prices and real-time electricity prices, it is worth considering how best to balance the peak response ability of buildings and the cause of the secondary peak leading to load rebound. Therefore, this paper proposes a low-carbon demand response strategy for buildings considering load rebound. First, a building load is classified based on how schedulable the load remains, and a building demand response model which considers how the load schedulability is constructed. Second, according to the different rebounds of different building loads, a load rebound optimization model based on linear attenuation was built, and the rebound parameters of various loads were designed. Then, the real-time carbon emission factor, load fluctuation reward, punishment factor, and real-time electricity price are introduced. Thus, the lowest running cost of the building load is taken as the objective function needed to construct a building demand response optimization model while also considering load rebound. Finally, an example analysis is used to verify the effectiveness of the proposed model in reducing the comprehensive operation cost of buildings. The proposed model not only effectively reduces the comprehensive operation cost of buildings, but also reduces carbon emissions and load fluctuations under the premise of satisfying the actual building load, which provides a new idea for the research of a low-carbon demand response strategy of buildings with load rebound.

Abstract Body fluid biomarkers are very important, because they can be detected in a non-invasive or minimally invasive way. The discovery of secreted proteins in human body fluids is an essential step toward proteomic biomarker identification for human diseases. Recently, many computational methods have been proposed to predict secreted proteins and achieved some success. However, most of them are based on a manual negative dataset, which is usually biased and therefore limits the prediction performances. In this paper, we first propose a novel positive-unlabeled learning framework to predict secreted proteins in a single body fluid. The secreted protein discovery in a single body fluid is transformed into multiple binary classifications and solved via multi-task learning. Also, an effective convolutional neural network is employed to reduce the overfitting problem. After that, we then improve this framework to predict secreted proteins in multiple body fluids simultaneously. The improved framework adopts a globally shared network to further improve the prediction performances of all body fluids. The improved framework was trained and evaluated on datasets of 17 body fluids, and the average benchmarks of 17 body fluids achieved an accuracy of 89.48%, F1 score of 56.17%, and PRAUC of 58.93%. The comparative results demonstrate that the improved framework performs much better than other state-of-the-art methods in secreted protein discovery.

Despite mounting evidence for dietary protease benefits, the mechanisms beyond enhanced protein degradation are poorly understood. This study aims to thoroughly investigate the impact of protease addition on the growth performance, intestinal function, and microbial composition of weaned piglets. Ninety 28-day-old weaned pigs were randomly assigned to the following three experimental diets based on their initial body weight for a 28-day experiment: (1) control (CC), a basic diet with composite enzymes without protease; (2) negative control (NC), a diet with no enzymes; and (3) dietary protease (PR), a control diet with protease. The results show that dietary proteases significantly enhanced growth performance and boosted antioxidant capacity, increasing the total antioxidant capacity (T-AOC) levels (p < 0.05) while reducing malonaldehyde levels (p < 0.05). Additionally, protease addition reduced serum levels of inflammatory markers TNF-α, IL-1β, and IL-6 (p < 0.05), suppressed mRNA expression of pro-inflammatory factors in the jejunum (p < 0.01), and inhibited MAPK and NF-κB signaling pathways. Moreover, protease-supplemented diets improved intestinal morphology and barrier integrity, including zonula occludens protein 1(ZO-1), Occludin, and Claudin-1 (p < 0.05). Microbiota compositions were also significantly altered by protease addition with increased abundance of beneficial bacteria (Lachnospiraceae_AC2044_group and Prevotellaceae_UCG-001) (p < 0.05) and reduced harmful Terrisporobacter (p < 0.05). Further correlation analysis revealed a positive link between beneficial bacteria and growth performance and a negative association with inflammatory factors and intestinal permeability. In summary, dietary protease addition enhanced growth performance in weaned piglets, beneficial effects which were associated with improved intestinal barrier integrity, immunological response, and microbiota composition.

The proton exchange membrane electrolysis cell (PEMEC) has attracted considerable attention for large-scale and efficient hydrogen production because of its high current density, high hydrogen purity and fast dynamic response. Flow field distributions and water and thermal management characteristics of a PEMEC are vital for electrolytic cell structure and the determination of operating condition. A three-dimensional, non-isothermal, electrochemical model of a PEMEC was established in this manuscript. The flow field distribution and water and thermal management of the PEMEC are discussed. The corresponding results showed that the pressure of the flow channel decreased diagonally from the inlet to the outlet, and the pressure and velocity distribution exhibited a downward opening shape of a parabola. At the same inlet flow rate, when the voltage was 1.6 V, the oxygen generation rate was 15.74 mol/(cm2·s), and when the voltage was 2.2 V, the oxygen generation rate was 332.05 mol/(cm2·s); due to the change in the oxygen production rate, the pressure difference at 2.2 V was 2.5 times than that at 1.6 V. When the stoichiometric number was less than two, the average temperature of the catalyst layer (CL) decreased rapidly with the increase in the water flow rate. When the voltage decreased to 2.1 V, the current density came to the highest value when the stoichiometric number was 0.7, then the current density decreased with an increase in the stoichiometric number. When stoichiometric numbers were higher than five, the surface temperature and current density remained basically stable with the increase in the water flow rate, and the water and thermal management and electrolysis characteristics performed better. The research results could optimize the water supply of electrolysis cells. According to the velocity distribution law of the flow field, the water and thermal management performance of the PEMEC could be estimated, further promoting safety and reliability.

As the thickness of an ultra-thin flattened heat pipe (UTHP) decreases, the fabrication difficulty increases exponentially, and the thermal performance deteriorates rapidly. In this study, three types of composite wicks were developed for UTHPs with a 0.6 mm thickness: copper foam and mesh wick (CFMW), two layers of different mesh wick (TDMW), and three layers of the same mesh wick (TSMW). The startup and steady-state performances of the UTHPs with liquid filling ratios of 60% to 120% were investigated. The findings indicated that the CFMW UTHP with a filling ratio of 100% exhibited the best startup performance, with the highest equilibrium temperature of 58.37 °C. The maximum heat transport capacities of the CFMW, TDMW, and TSMW UTHP samples were 9, 8, and 8.5 W, respectively, at their corresponding optimum filling ratios of 110%, 90%, and 100%. The CFMW UTHP exhibited the lowest evaporation and condensation thermal resistances of 0.151 and 0.189 K/W, respectively, which were 24.67% and 41.85% lower than those of the TSMW UTHP. CFMW can be used to improve the thermal performance of UTHPs. This study provides important guidelines for the structural design, fabrication technology, and performance improvement of high-performance UTHPs used in portable electronic devices.

Abstract Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

Abstract Modifying the loess foundation effectively solved the deformation and settlement of the building foundation and improved its stability. However, burnt rock-solid waste was often used as filling material and light aggregate, while there were few studies on the engineering mechanical properties of modified soil. This paper proposed a method of burnt rock solid waste-modified loess. Therefore, we conducted compression-consolidation and direct shear tests on burnt rock solid waste-modified loess under different burnt rock contents to explore its improved loess’s deformation and strength characteristics. Then, we used an SEM to investigate the modified loess’s micro-structures under different burnt rock contents. The results showed that as the burnt rock-solid waste particle content continued to increase, the void ratio and compressibility coefficient of the samples with different ranges of burnt rock-solid waste particles gradually decreased with rising vertical pressure, while the compressive modulus increased first, then reduced and then increased with the increase of vertical pressure; the shear strength indexes all showed an increasing trend with the increased content of burnt rock-solid waste particles; when the content of burnt rock-solid waste particles was 50%, the compressibility of mixed soil was the lowest, the shear strength was the largest, and the compaction effect and shear resistance were the best. However, when the content of burnt rock particles was 10–20%, the shear strength of the soil improved significantly within the content range. The mechanism of burnt rock-solid waste to enhance the strength of the loess structure was mainly to reduce the porosity and average area of soil, significantly improve the strength and stability of mixed soil particles, and thus significantly improve the mechanical properties of soil. The results of this research will provide technical support for safe engineering construction and geological disaster prevention and control in loess areas.

Pyrroloquinoline quinone disodium (PQQ·Na2) has been considered a human food supplement for human health promotion with its antioxidant properties. To determine whether PQQ·Na2 had similar functions to improve the antioxidant ability of layers and eggs, 180 laying hens were fed with 0 or 0.4 mg/kg PQQ·Na2 diets. Supplementation with PQQ·Na2 increased the albumen height, Haugh unit of the eggs. PQQ·Na2 also led to a higher glutathione peroxidase (GSH-Px) concentration in plasma and a lower malondialdehyde (MDA) content in the liver and egg yolk. Similarly, liver gene and protein expression of nuclear factor erythroid 2-related 2 (Nrf2) and heme oxygenase 1 (HO-1) were up-regulated by PQQ·Na2. Moreover, PQQ·Na2 increased the abundance of Firmicutes, Microbacterium, Erysipelatoclostridium, Mailhella, Lachnospiraceae_UCG-010, and Herbaspirillum in gut. Overall, these results suggested PQQ·Na2 increased the antioxidant ability of layers and eggs which might be in connection with the activation of the Nrf2/HO-1 pathway and optimized gut microflora.

Abstract Background Mastitis not only deteriorates the composition or quality of milk, but also damages the health and productivity of dairy goats. Sulforaphane (SFN) is a phytochemical isothiocyanate compound with various pharmacological effects such as anti-oxidant and anti-inflammatory. However, the effect of SFN on mastitis has yet to be elucidated. This study aimed to explore the anti-oxidant and anti-inflammatory effects and potential molecular mechanisms of SFN in lipopolysaccharide (LPS)-induced primary goat mammary epithelial cells (GMECs) and a mouse model of mastitis. Results In vitro, SFN downregulated the mRNA expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6), inhibited the protein expression of inflammatory mediators (cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS)) while suppressing nuclear factor kappa-B (NF-κB) activation in LPS-induced GMECs. Additionally, SFN exhibited an antioxidant effect by increasing Nrf2 expression and nuclear translocation, up-regulating antioxidant enzymes expression, and decreasing LPS-induced reactive oxygen species (ROS) production in GMECs. Furthermore, SFN pretreatment promoted the autophagy pathway, which was dependent on the increased Nrf2 level, and contributed significantly to the improved LPS-induced oxidative stress and inflammatory response. In vivo, SFN effectively alleviated histopathological lesions, suppressed the expression of inflammatory factors, enhanced immunohistochemistry staining of Nrf2, and amplified of LC3 puncta LPS-induced mastitis in mice. Mechanically, the in vitro and in vivo study showed that the anti-inflammatory and anti-oxidative stress effects of SFN were mediated by the Nrf2-mediated autophagy pathway in GMECs and a mouse model of mastitis. Conclusions These results indicate that the natural compound SFN has a preventive effect on LPS-induced inflammation through by regulating the Nrf2-mediated autophagy pathway in primary goat mammary epithelial cells and a mouse model of mastitis, which may improve prevention strategies for mastitis in dairy goats.

Introduction: Investigating the genetic footprints of historical temperature selection can get insights to the local adaptation and feasible influences of climate change on long-term population dynamics. Object: Chicken is a significative species to study genetic adaptation on account of its similar domestication track related to human activity with the most diversified varieties. Yet, few studies have demonstrated the genetic signatures of its adaptation to naturally tropical and frigid environments. Method: Here, we generated whole genome resequencing of 119 domesticated chickens in China including the following breeds which are in order of breeding environmental temperature from more tropical to more frigid: Wenchang chicken (WCC), green-shell chicken (GSC), Tibetan chicken (TBC), and Lindian chicken (LDC). Results: Our results showed WCC branched off earlier than LDC with an evident genetic admixture between WCC and LDC, suggesting their closer genetic relationship. Further comparative genomic analyses solute carrier family 33 member 1 (SLC33A1) and thyroid stimulating hormone receptor (TSHR) genes exhibited stronger signatures for positive selection in the genome of the more tropical WCC. Furthermore, genotype data from about 3,000 African local ecotypes confirmed that allele frequencies of single nucleotide polymorphisms (SNPs) in these 2 genes appeared strongly associated with tropical environment adaptation. In addition, the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) gene exhibited a strong signature for positive selection in the LDC genome, and SNPs with marked allele frequency differences indicated a significant relationship with frigid environment adaptation. Conclusion: Our findings partially clarify how selection footprints from environmental temperature stress can lead to advantageous genomic adaptions to tropical and frigid environments in poultry and provide a valuable resource for selective breeding of chickens.

Abstract Background Observational studies reported an association between psoriasis and risk of lung cancer. However, whether psoriasis is causally associated with lung cancer is unclear. Methods Genetic summary data of psoriasis were retrieved from two independent genome-wide association studies (GWAS). Genetic information of lung cancer was retrieved from GWAS of International Lung Cancer Consortium. A set of quality control steps were conducted to select instrumental tools. We performed two independent two-sample Mendelian randomization (MR) analyses and a meta-analysis based on the two independent MR estimates to assess the causal relationship between psoriasis and lung cancer (LUCA) as well as its subtypes, squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD). Results Between-SNP heterogeneity was present for most MR analyses, whereas horizontal pleiotropy was not detected for all MR analyses. Multiplicative random-effect inverse variance weighted (IVW-MRE) method was therefore selected as the primary MR approach. Both IVW-MRE estimates from the two independent MR analyses suggested that there was no significant causal relationship between psoriasis and LUCA as well as its histological subtypes. Sensitivity analyses using other four MR methods gave similar results. Meta-analysis of the two IVW-MRE derived MR estimates yielded an odds ratio (OR) of 1.00 (95% CI 0.95–1.06) for LUCA, 1.01 (95% CI 0.93–1.08) for LUSC, and 0.97 (95% CI 0.90–1.06) for LUAD. Conclusion Our results do not support a genetic association between psoriasis and lung cancer and its subtypes. More population-based and experimental studies are warranted to further dissect the complex correlation between psoriasis and lung cancer.

Periodontitis is a common type of inflammatory bone loss, and cell-free DNA (cfDNA) can be a major source that enhances the periodontal tissue destruction. Here, the authors show that a cfDNA-scavenging approach is able to ameliorate periodontitis by using nanoparticulate cfDNA scavenger.

Abstract Increased levels of circulating cell‐free DNA (cfDNA) are associated with poor clinical outcomes in patients with acute kidney injury (AKI). Scavenging cfDNA by nanomaterials is regarded as a promising remedy for cfDNA‐associated diseases, but a nanomaterial‐based cfDNA scavenging strategy has not yet been reported for AKI treatment. Herein, polyglycerol‐amine (PGA)‐covered MoS2 nanosheets with suitable size are synthesized to bind negatively charged cfDNA in vitro, in vivo and ex vivo models. The nanosheets exhibit higher cfDNA binding capacity than polymer PGA and PGA‐based nanospheres owing to the flexibility and crimpability of their 2D backbone. Moreover, with low cytotoxicity and mild protein adsorption, the nanosheets effectively reduced serum cfDNA levels and predominantly accumulated in the kidneys to inhibit the formation of neutrophil extracellular traps and renal inflammation, thereby alleviating both lipopolysaccharide and ischemia‐reperfusion induced AKI in mice. Further, they decreased the serum cfDNA levels in samples from AKI patients. Thus, PGA‐covered MoS2 nanosheets can serve as a potent cfDNA scavenger for treating AKI and other cfDNA‐associated diseases. In addition, this work demonstrates the pivotal feature of a 2D sheet‐like structure in the development of the cfDNA scavenger, which can provide a new insight into the future design of nanoplatforms for modulating inflammation.

Abstract Acetaminophen (APAP) overdose is a leading cause of drug‐induced liver injury and acute liver failure, while the detection, prognosis prediction, and therapy for APAP‐induced liver injury (AILI) remain improved. Here, it is determined that the temporal pattern of circulating cell‐free DNA (cfDNA) is strongly associated with damage and inflammation parameters in AILI. CfDNA is comparable to alanine aminotransferase (ALT) in predicting mortality and outperformed ALT when combined with ALT in AILI. The depletion of cfDNA or neutrophils alleviates liver damage, while the addition of cfDNA or adoptive transfer of neutrophils exacerbates the damage. The combination of DNase I and N‐acetylcysteine attenuates AILI significantly. This study establishes that cfDNA is a mechanistic biomarker to predict mortality in AILI mice. The combination of scavenging cfDNA and reducing oxidative damage provides a promising treatment for AILI.

Electric vehicles (EVs) are experiencing explosive developments due to their advantages in energy conservation and environmental protection. As a pivotal component of EVs, the safety performance of lithium-ion batteries directly affects driving miles and even safety; hence, a battery thermal management system (BTMS) is especially important. To improve the thermal safety performance of power battery modules, first, a new leak-proof phase change material (PCM)-coupled liquid-cooled composite BTMS for large-scale battery modules is proposed in this research. Second, the numerical simulation analysis method was utilized to analyze the influences of the fluid flow channel shape, working fluid inlet temperature, inlet velocity, and reverse flow conditions on the BTMS. Eventually, the abovementioned performances were compared with the traditional PCM-coupled liquid-cooling strategy. The relative data indicated that the Tmax was reduced by 17.5% and the ΔTmax was decreased by 19.5% compared to the liquid-cooling approach. Further, compared with conventionally designed PCM composite liquid cooling, the ΔTmax was reduced by 34.9%. The corresponding data showed that, when using the e-type flow channel, reverse flow II, the inlet flow velocity was 0.001–0.005 m/s, and the inlet temperature was the ambient temperature of the working condition. The thermal performance of the anti-leakage system with a thermal conduction slot PCM-coupled liquid-cooling composite BTMS reached optimal thermal performance. The outcome proved the superiority of the proposed BTMS regarding temperature control and temperature equalization capabilities. It also further reduced the demand for liquid-cooling components, avoided the problem of the easy leakage of the PCM, and decreased energy consumption.

Abstract Background In China, 85.4% of adverse drug reactions (ADRs) are spontaneously reported by healthcare facilities. As a result, many ADRs are not reported due to lack of mandatory reporting requirements. As healthcare professionals, clinical pharmacists (CPhs) serve as a bridge between clinical work and medication and ensure rational drug use. In China, A team of CPhs implemented an intervention for ADRs reporting, with the goal of improving the number of ADRs reports, the number of unreported ADRs, and the standardized reporting rate. Methods On June 01, 2015, a team of CPhs implemented an intervention for ADRs reporting at a Grade A, Class 3 hospital in China. The drug review catalogue (DRC) was used to screen physician orders for having visible symptoms of ADRs across departments, pooled the ADRs, and submitted them to the Center for Advanced Drug Monitoring (CNCAM). We retrospectively analysed the effect of a CPhs ADRs reporting intervention on the number of clinical ADRs reports, the number of unreported ADRs, and the standardized reporting rate over a 9-year period by interrupted time series (ITS). The method was implemented at the hospital on June 1, 2015, and a segmented regression model was used to analyse the data from January 1, 2010, to December 31, 2019. Results After the CPhs ADRs reporting intervention, the number of inpatient ADRs reports submitted to the CNCAM immediately increased by approximately 63 (62.658, P 0.05); the standardized ADRs reporting rate per month immediately increased by 63.634% (P 0.05). Conclusion The CPhs ADRs reporting intervention had an immediate effect on improving ADRs reporting, which highlights the severity of ADRs underreporting in Chinese hospitals. The method is practical and should be used more widely in clinical practice. For example, the method can adjust and establish a DRC catalog that meets the actual situation of the implementing hospital based on the hospital's drug use habits and has the characteristics of good adaptability. However, it does have some limitations; for example, it may be difficult to detect early ADRs without visible symptoms.

Abstract Surgical resection to achieve tumor-free margins represents a difficult clinical scenario for patients with hepatocellular carcinoma. While post-surgical treatments such as chemotherapy and radiotherapy can decrease the risk of cancer recurrence and metastasis, growing concerns about the complications and side effects have promoted the development of implantable systems for locoregional treatment. Herein, 3D printed hydrogel scaffolds (designed as Gel-SA-CuO) were developed by incorporating one agent with multifunctional performance into implantable devices to simplify the fabrication process for efficiently inhibiting postoperative tumor recurrence. CuO nanoparticles can be effectively controlled and sustained released during the biodegradation of hydrogel scaffolds. Notably, the released CuO nanoparticles not only function as the reservoir for releasing Cu2+ to produce intracellular reactive oxygen species (ROS) but also serve as photothermal agent to generate heat. Remarkably, the heat generated by photothermal conversion of CuO nanoparticles further promotes the efficiency of Fenton-like reaction. Additionally, ferroptosis can be induced through Cu2+-mediated GSH depletion via the inactivation of GPX4. By implanting hydrogel scaffolds in the resection site, efficient inhibition of tumor recurrence after primary resection can be achieved in vivo. Therefore, this study may pave the way for the development of advanced multifunctional implantable platform for eliminating postoperative relapsable cancers. Graphical Abstract

ABSTRACT: The present study evaluated the effects of 3 supplemental levels of dietary genistein ingested during the late laying period (66–73 wk) of laying hens. A total of 384 Hy-Line brown hens (66 wk old) were randomly divided into 4 groups (6 replicates of 16 hens in each group), the basal diet group (CON), and groups for the basal diet supplemented with 80, 120, and 400 mg/kg of genistein, G1, G2, and G3, respectively. The results of the present study showed an increased laying rate in groups G2 and G3 (linear, P < 0.01), and decreased feed-egg ratios (linear, P < 0.05) and broken egg rate (P < 0.01) in all genistein-treated groups compared with the CON group. Moreover, the G2 group showed an increase in eggshell strength and ratio (linear, P < 0.05), whereas all genistein-treated groups saw a decrease in the L* value (linear, P < 0.01) and an increase in the a* value (linear, P < 0.05) compared with the CON group. Additionally, all genistein-treated groups had an increase in the total antioxidant capacity of plasma (linear, P < 0.05), along with reduced plasma, ovarian, and yolk malondialdehyde levels (linear, P < 0.05), compared with the CON group. The G2 group had an increase in both the superoxide dismutase activity of plasma (P < 0.01) and the total antioxidant capacity of the ovaries (linear, P < 0.05), compared with the CON group. The G3 group had an increase in both the glutathione peroxidase concentration of plasma (linear, P < 0.05) and the total antioxidant capacity of the ovaries (linear, P < 0.01), compared with the CON group. The transcript levels of nuclear factor erythroid 2-related factor 2, superoxide dismutase 1, and catalase were increased in all of the genistein-treated groups (P < 0.05) compared with the CON group, whereas heme oxygenase 1 and glutamate-cysteine ligase modifier subunit were increased only in the G2 group (P < 0.05). In conclusion, supplementation with 120 mg/kg dietary genistein had the best effect on improving the laying rate, eggshell quality, and antioxidant capacity in Hy-Line brown hens during the late laying period.

Inflammation is the host response of immune cells during infection and traumatic tissue injury. An uncontrolled inflammatory response leads to inflammatory cascade, which in turn triggers a variety of diseases threatening human and animal health. The use of existing inflammatory therapeutic drugs is constrained by their high cost and susceptibility to systemic side effects, and therefore new therapeutic candidates for inflammatory diseases need to be urgently developed. Natural products are characterized by wide sources and rich pharmacological activities, which are valuable resources for the development of new drugs. This study aimed to uncover the alleviating effect and potential mechanism of natural product Limonium aureum (LAH) on LPS-induced inflammatory responses in macrophages. The experimental results showed that the optimized conditions for LAH ultrasound-assisted extraction via response surface methodology were an ethanol concentration of 72%, a material-to-solvent ratio of 1:37 g/mL, an extraction temperature of 73 °C, and an extraction power of 70 W, and the average extraction rate of LAH total flavonoids was 0.3776%. Then, data of 1666 components in LAH ethanol extracts were obtained through quasi-targeted metabolomics analysis. The ELISA showed that LAH significantly inhibited the production of pro-inflammatory cytokines while promoting the secretion of anti-inflammatory cytokines. Finally, combined with the results of network pharmacology analysis and protein expression validation of hub genes, it was speculated that LAH may alleviate LPS-induced inflammatory responses of macrophages through the AKT1/RELA/PTGS2 signaling pathway and the MAPK3/JUN signaling pathway. This study preliminarily revealed the anti-inflammatory activity of LAH and the molecular mechanism of its anti-inflammatory action, and provided a theoretical basis for the development of LAH as a new natural anti-inflammatory drug.

This paper analyzed the factors that influence the seismic resilience of urban building groups and studied the laws that influence internal factors and external factors. Based on the data from the first national comprehensive risk survey of natural disasters, a refined classification study of urban building groups was carried out. Based on the existing evaluation methods of seismic resilience of individual buildings, the recovery time was selected as the resilience evaluation index to calculate the effect of internal factors on the seismic resilience of urban building groups. Then, we studied the quantitative relationship between external factors (i.e., disaster relief capacity, population density, and economic level) and the evaluation indicators of seismic resilience of urban building groups, and we proposed the kilometer grid coefficient. Based on that, we proposed a calculation method of the effect of external factors on the seismic resilience of urban building groups. Considering the influence of internal and external factors, the evaluation model for the seismic resilience of urban building groups was established. And the model was applied in a typical city. This paper proposes a method to evaluate the seismic resilience of urban building groups, which can master the functional recovery time of urban building groups after an earthquake. Based on the proposed model, we can optimize the functional recovery path and emergency rescue path of the disaster area, as well as improve the resilience of urban building systems and the construction of resilient cities.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a substrate protein of a Cullin 4B E3 ligase complex responsible for diverse cellular processes. In the lung, this receptor is responsible for the bioactivation of benzo[a]pyrene during tumorigenesis. Realizing that the AHR function is affected by its expression level, we are interested in the degradation mechanism of AHR in the lung. Here, we have investigated the mechanism responsible for AHR degradation using human lung epithelial A549 cells. We have observed that the AHR protein levels increase in the presence of chloroquine (CQ), an autophagy inhibitor, in a dose-dependent manner. Treatment with 6-aminonicotinamide (6-AN), a chaperone-mediated autophagy (CMA) activator, decreases AHR protein levels in a concentration-dependent and time-dependent manner. This decrease suppresses the ligand-dependent activation of the AHR target gene transcription, and can be reversed by CQ but not MG132. Knockdown of lysosome-associated membrane protein 2 (LAMP2), but not autophagy-related 5 (ATG5), suppresses the chloroquine-mediated increase in the AHR protein. AHR is resistant to CMA when its CMA motif is mutated. Suppression of the epithelial-to-mesenchymal transition in A549 cells is observed when the AHR gene is knocked out or the AHR protein level is reduced by 6-AN. Collectively, we have provided evidence supporting that AHR is continuously undergoing CMA and activation of CMA suppresses the AHR function in A549 cells.

Abstract Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.

Abstract Global increasing demand for high life quality and length facilitates the development of tissue engineering and regenerative medicine, which apply multidisciplinary theories and techniques to achieve the structural reconstruction and functional recovery of disordered or damaged tissues and organs. However, the clinical performances of adopted drugs, materials, and powerful cells in the laboratory are inescapably limited by the currently available technologies. To tackle the problems, versatile microneedles are developed as the new platform for local delivery of diverse cargos with minimal invasion. The efficient delivery, as well as painless and convenient procedure endow microneedles with good patient compliance in clinic. In this review, we first categorize different microneedle systems and delivery models, and then summarize their applications in tissue engineering and regenerative medicine mainly involving maintenance and rehabilitation of damaged tissues and organs. In the end, we discuss the advantages, challenges, and prospects of microneedles in depth for future clinical translations.

The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol–disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol–disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol–disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.

Distributed acoustic sensing (DAS) is regarded as a novel acquisition technology for seismic data. Compared with conventional electrical geophones, DAS has a series of obvious advantages including low-cost, high spatial resolution, good coverage, and strong resistance to the harsh environment. Noise attenuation is an essential step in seismic data processing. However, there are two main difficulties faced by the denoising task of DAS seismic data. On the one hand, some background noise in DAS seismic data, such as optical low-frequency noise, horizontal noise, and fading noise, is unique and not presented in the conventional seismic data; on the other hand, the signal-to-noise ratio (SNR) of DAS seismic data is relatively low. Recently, a convolutional neural network (CNN) has shown superior denoising performance compared to the traditional method. To follow this promising trend, we propose a multi-scale interactive convolutional neural network (MSI-Net) and apply it to denoise the challenging DAS seismic data. Different from most of the existing CNN architecture used in seismic data denoising, the MSI-Net considers both coarse-scale and fine-scale features by improving the inherent serial convolution to multi-scale parallel convolution, which is beneficial to recover detailed information. Moreover, we utilize some connections to achieve the information interaction between different scales, which promotes the flow of information and enables the network to extract more informative multi-scale features from the DAS seismic data. Moreover, both synthetic and real examples demonstrate that the proposed MSI-Net can effectively attenuate a variety of unique DAS background noise and also completely recover the weak signals. Compared with conventional CNN architecture, MSI-Net exhibits better performance in global SNR and local details.

Abstract The Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death.

Chemodynamic therapy (CDT) eradicates tumors by intratumoral catalytic chemical reaction and subsequently disrupts redox homeostasis, which shows tumor specific reactive oxygen species (ROS)-mediated therapy. However, insufficient ROS generation and high levels of glutathione (GSH) in cancer cells have limited the therapeutic efficacy of CDT. Herein, we constructed a multifunctional oxidative stress nanoamplifier with ROS amplification and GSH exhaustion for enhanced CDT. Such a sandwich-like nanoamplifier comprised layer-by-layer artesunate (AS) and calcium carbonate coatings on the surface of manganese dioxide (MnO2) nanoparticles. The nanoamplifier was disassembled under an acidic environment once accumulated into tumor sites, and subsequently released AS to replenish the intratumoral peroxide pool for ROS amplification. Besides being an AS carrier, MnO2 exhausted GSH to yield Mn2+ ions that catalyzed the overexpression of H2O2 in the tumor, further intensifying the oxidative stress and facilitating cancer cell death. Taken together, our findings not only provide a paradigm for fabricating intratumoral catalytic nanomaterials, but also present a new ROS enhancement strategy to improve anti-tumor efficacy. Our multifunctional oxidative stress nanoamplifier might broaden the future of CDT.

Heat stress, a widely occurred in subtropical climate regions, causes ecosystem destruction, and intestine injury in humans and animals. As an important compound in the metabolic pathway of choline, dimethylglycine (DMG) shows anti-inflammatory effects. This study examines the beneficial effects of dietary DMG against heat stress-induced intestine injury and further explores the underlying molecular mechanisms using a broiler model. Here, we showed that DMG supplements exhibited positive effects to growth performance, as evidenced by the significantly increased body weight and feed conversion rate. These therapeutic effects attributed to repaired gut barrier integrity, increased content of anti-inflammatory cytokines IL-10, decreased content of pro-inflammatory cytokines IL-6, and down-regulated gene expression of the NF-κB signaling pathway. DMG treatment led to the reshaping of the gut microbiota composition, mainly increasing the short-chain fatty acid (SCFAs) strains such as Faecalibacterium, and Marvinbryantia. DMG treatment also increased two main members of SCFAs, including acetate acid and isobutyrate. Particularly, distinct effects were found which mediated the tryptophan metabolism in intestines such as increased tryptophan and 5-HT, which further alleviate the occurrence of intestinal barrier damage caused by heat stress. Additionally, DMG treatment promoted neuroendocrine function and stimulated the hypothalamic neurotransmitter metabolism by activating tryptophan metabolism in the hypothalamus. Overall, DMG supplementation effectively reduced the occurrence of intestinal inflammation induced by heat stress through modulating cecal microbial communities and improving the metabolism function of microbiota gut brain axis. Our findings revealed a novel mechanism by which gut microbiota could improve host health.

Abstract Photothermal therapy (PTT) has been regarded as a promising strategy considering its advantages of high inherent specificity and a lower invasive burden. Since the photothermal killing of cells/bacteria showed different patterns of death depending on the varying temperature in PTT, the temperature change of PTT is vital to cell/tissue response in scientific research and clinical application. On one hand, mild PTT has received substantial attention in the treatment of cancer and soft/hard tissue repair. On the other hand, the high temperature induced by PTT is capable of antibacterial capacity, which is better than conventional antibiotic therapy with drug resistance. Herein, we summarize the recent developments in the application of temperature‐dependent photothermal biomaterials, mainly covering the temperature ranges of 40–42°C, 43–50°C, and over 50°C. We highlight the biological mechanism of PTT and the latest progress in the treatment of different diseases. Finally, we conclude by discussing the challenges and perspectives of biomaterials in addressing temperature‐orchestrated PTT. Given a deep understanding of the interaction between temperature and biology, rationally designed biomaterials with sophisticated photothermal responsiveness will benefit the outcomes of personalized PTT toward various diseases.

Udder traits, influencing udder health and function, are positively correlated with lactation performance. Among them, breast texture influences heritability and impacts on the milk yield of cattle; however, there is a lack of systematic research on its underlying mechanism in dairy goats in particular. Here, we showed the structure of firm udders with developed connective tissue and smaller acini per lobule during lactation and confirmed that there were lower serum levels of estradiol (E2) and progesterone (PROG), and higher mammary expression of estrogen nuclear receptor (ER) α and progesterone receptor (PR), in dairy goats with firm udders. The results of transcriptome sequencing of the mammary gland revealed that the downstream pathway of PR, the receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) signal, participated in the formation of firm mammary glands. During the culture of goat mammary epithelial cells (GMECs), high RANKL level additions promote the Inhibitor kappaB (IκB)/p65/Cyclin D1 expression related to cell proliferation and decrease the phosphorylated signal transduction and transcription activator 5 (Stat5) expression related to milk-protein synthesis of GMECs, which is consistent with electron microscope results showing that there are fewer lactoprotein particles in the acinar cavity of a firm mammary. Furthermore, co-culturing with adipocyte-like cells for 7 d is beneficial for the acinar structure formation of GMECs, while there is a slightly negative effect of high RANKL level on it. In conclusion, the results of this study revealed the structure of firm udders structure and confirmed the serum hormone levels and their receptor expression in the mammary glands of dairy goats with firm udders. The underlying mechanism leading to firm udders and a decrease in milk yield were explored preliminarily, which provided an important foundation for the prevention and amelioration of firm udders and improving udder health and milk yield.

Cerebrospinal fluid (CSF) proteins are very important because they can serve as biomarkers for central nervous system diseases. Although many CSF proteins have been identified with wet experiments, the identification of CSF proteins is still a challenge. In this paper, we propose a novel method to predict proteins in CSF based on protein features. A two-stage feature-selection method is employed to remove irrelevant features and redundant features. The deep neural network and bagging method are used to construct the model for the prediction of CSF proteins. The experiment results on the independent testing dataset demonstrate that our method performs better than other methods in the prediction of CSF proteins. Furthermore, our method is also applied to the identification of glioma biomarkers. A differentially expressed gene analysis is performed on the glioma data. After combining the analysis results with the prediction results of our model, the biomarkers of glioma are identified successfully.

Oxidative stress in high-yielding dairy goats adversely affects lactation length, milk quality, and the economics of dairy products. During the lactation period, goat mammary epithelial cells (GMECs) are often in a state of disordered metabolic homeostasis primarily caused by the overproduction of reactive oxygen species (ROS). Sulforaphane (SFN), an electrophilic compound that is enriched in broccoli, is a promising antioxidant agent for future potential clinical applications. The objective of the present study was to investigate the function of SFN on hydrogen peroxide (H2O2)-induced oxidative damage in primary GMECs and the underlying molecular mechanisms. Isolated GMECs in triplicate were pretreated with SFN (1.25, 2.5, and 5 μM) for 24 h in the absence or presence of H2O2 (400 μM) for 24 h. The results showed that SFN effectively enhanced superoxide dismutase (SOD) activity, elevated the ratio of glutathione (GSH)/glutathione oxidized (GSSG), and reduced H2O2-induced ROS and malondialdehyde (MDA) production and cell apoptosis. Mechanically, SFN-induced nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) translocation to the nucleus through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway coupled with inhibition of the caspase apoptotic pathway. In addition, GMECs were transfected with NFE2L2 small interfering RNA (NFE2L2 siRNA) for 48 h and/or treated with SFN (5 μM) for 24 h before being exposed to H2O2 (400 μM) for 24 h. We found that knockdown of NFE2L2 by siRNA abrogated the preventive effect of SFN on H2O2-induced ROS overproduction and apoptosis. Taken together, sulforaphane suppressed H2O2-induced oxidative stress and apoptosis via the activation of the AMPK/NFE2L2 signaling pathway in primary GMECs.

Magnetic activated carbon particles (Fe3O4/active carbon composites) as auxiliary electrodes (AEs) were fixed on the surface of Ti/Sb-SnO2 foil by a NdFeB magnet to form a new magnetically assembled electrode (MAE). Characterizations including cyclic voltammetry, Tafel analysis, and electrochemical impedance spectroscopy were carried out. The electrochemical oxidation performances of the new MAE towards different simulated wastewaters (azo dye acid red G, phenol, and lignosulfonate) were also studied. Series of the electrochemical properties of MAE were found to be varied with the loading amounts of AEs. The electrochemical area as well as the number of active sites increased significantly with the AEs loading, and the charge transfer was also facilitated by these AEs. Target pollutants’ removal of all simulated wastewaters were found to be enhanced when loading appropriate amounts of AEs. The accumulation of intermediate products was also determined by the AEs loading amount. This new MAE may provide a landscape of a more cost-effective and flexible electrochemical oxidation wastewater treatment (EOWT).

ObjectivesThis project aimed to construct an individualized PET/CT prognostic biomarker to accurately quantify the progression risk of patients with stage IIIC-IV epidermal growth factor receptor (EGFR)-mutated Non-small cell lung cancer (NSCLC) after first-line first and second generation EGFR- tyrosine kinase inhibitor (TKI) drug therapy and identify the first and second generation EGFR-TKI treatment-sensitive population.MethodsA total of 250 patients with stage IIIC-IV EGFR-mutated NSCLC underwent first-line first and second generation EGFR-TKI drug therapy were included from two institutions (140 patients in training cohort; 60 patients in internal validation cohort, and 50 patients in external validation cohort). 1037 3D radiomics features were extracted to quantify the phenotypic characteristics of the tumor region in PET and CT images, respectively. A four-step feature selection method was performed to enable derivation of stable and effective signature in the training cohort. According to the median value of radiomics signature score (Rad-score), patients were divided into low- and high-risk groups. The progression-free survival (PFS) behaviors of the two subgroups were compared by Kaplan–Meier survival analysis.ResultsOur results shown that higher Rad-scores were significantly associated with worse PFS in the training (p < 0.0001), internal validation (p = 0.0153), and external validation (p = 0.0006) cohorts. Rad-score can effectively identify patients with a high risk of rapid progression. The Kaplan–Meier survival curves of the three cohorts present significant differences in PFS between the stratified slow and rapid progression subgroups.ConclusionThe PET/CT-derived Rad-score can realize the precise quantitative stratification of progression risk after first-line first and second generation EGFR-TKI drug therapy for NSCLC and identify EGFR-mutated NSCLC populations sensitive to targeted therapy, which might help to provide precise treatment options for NSCLC.

Neutrophils are involved in the development of endometritis, but it remains unknown how neutrophils induce inflammation and tissue damage. Neutrophil extracellular traps (NETs) clear invading pathogens during infection but induce pyroptosis, leading to inflammation and tissue damage. Thus, our objective was to investigate whether NETs participate in bovine endometrial epithelial cell (BEEC) pyroptosis during endometritis. To confirm this, NETs and caspase-1/4; apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC); nod-like receptor protein-3 (NLRP3); and gasdermin D N-terminal (GSDMD-N), TNF-a, IL-1β, IL-6, and IL-18 in endometrial tissue were detected. Pathological section and vaginal discharge smears were performed to visually determine endometritis in the uterus. BEECs were stimulated with NETs to induce pyroptosis, which was treated with DNase I against pyroptosis. Caspase-1/4, ASC, NLRP3, GSDMD-N, TNF-a, IL-1β, IL-6, and IL-18 in BEECs were analyzed in endometrial tissue. The results showed that NET formation, as well as pyroptosis-related proteins and proinflammatory, cytokines were elevated in the endometrial tissue of cows with endometritis. Pathological sections and vaginal discharge smears showed increased neutrophils and plasma cells in the uterus, as well as tissue congestion. In BEECs, NETs increased the level of pyroptosis-related proteins and proinflammatory cytokines and were diminished by DNase I. In summary NETs participate BEEC pyroptosis during endometritis in dairy cows.

The cell membrane, as the protecting frontier of cells, is closely related to crucial biological behaviors including cell growth, death, and division. Lots of fluorescent probes have been fabricated to monitor cell membranes due to their simplicity and intuitiveness. However, the efficiency of those traditional probes has been limited by their susceptibility to photobleaching and poor water solubility. In this study, we have reported Ru(II)-coumarin complexes consisting of ruthenium, 1,10-phenanthroline, and coumarin 6 to further form self-assembled nanoprobes, for cell membrane targeting and imaging. The fluorescent property could be switchable from red to green through the dynamic disassembly of nanoprobes. Compared with commercial Dil, biocompatible nanoprobes exhibited superior stability for long-term cell imaging, along with remarkedly reduced background interference. Therefore, our self-assembled nanoprobe provides a powerful solution for investigating lipid trafficking with optical imaging.

Cerebrospinal fluid (CSF) exists in the surrounding spaces of mammalian central nervous systems (CNS); therefore, there are numerous potential protein biomarkers associated with CNS disease in CSF. Currently, approximately 4300 proteins have been identified in CSF by protein profiling. However, due to the diverse modifications, as well as the existing technical limits, large-scale protein identification in CSF is still considered a challenge. Inspired by computational methods, this paper proposes a deep learning framework, named DenSec, for secreted protein prediction in CSF. In the first phase of DenSec, all input proteins are encoded as a matrix with a fixed size of 1000 × 20 by calculating a position-specific score matrix (PSSM) of protein sequences. In the second phase, a dense convolutional network (DenseNet) is adopted to extract the feature from these PSSMs automatically. After that, Transformer with a fully connected dense layer acts as classifier to perform a binary classification in terms of secretion into CSF or not. According to the experiment results, DenSec achieves a mean accuracy of 86.00% in the test dataset and outperforms the state-of-the-art methods.