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Sepsis is an infection‐triggered, rapidly progressive systemic inflammatory syndrome with a high mortality rate. Currently, there are no promising therapeutic strategies for managing this disease in the clinic. Heparanase plays a crucial role in the pathology of sepsis, and its inhibition can significantly relieve related symptoms. Here, a novel heparanase inhibitor CV122 is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)‐induced sepsis mouse models are evaluated. It is found that CV122 potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, CV122 significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis‐induced death. Mechanistically, CV122 inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that CV122 provides effective protection from organ damage and death caused by Crimean‐Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that CV122 is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm. [ABSTRACT FROM AUTHOR]

The electrocatalytic oxidation of urea combined with wastewater splitting is considered a promising approach for sustainable hydrogen production, characterized by minimal energy consumption. However, its evolution is greatly hindered by the shortage of efficient and easily accessible electrocatalytic materials. Here, a facile electrochemical activation strategy was conceived and proposed to construct a Cu-doped NiOOH nanolayer encapsulated on Cu2O nanodendrites on Cu mesh substrate (Cu-NiOOH/Cu2O/CM) from the electrodeposited Ni/Cu2O/CM heterostructured precatalyst. It was verified that the incorporation of Cu not only facilitates the rapid formation of Ni(III) species but also contributes to the formation of Cu-Ni(III) bifunctional electrocatalytic active sites. Benefiting from the accessible Cu-Ni(III) dual active sites, high active surface area, good hydrophilic and aerophobic surface properties and superior electrical conductivity of the Cu mesh substrate, the as-prepared Cu-NiOOH/Cu2O/CM exhibits enhanced bifunctional electrocatalytic abilities for electrocatalytic urea oxidation reaction (UOR) and hydrogen evolution reaction (HER). Particularly, for the Cu-NiOOH/Cu2O/CM||Cu-NiOOH/Cu2O/CM configuration toward the UOR||HER coupled system, a significantly reduced cell voltage of 1.43 V vs. RHE @ 10 mA·cm−2 was obtained. The observed cell voltage for the conventional overall water splitting is approximately 190 mV higher than that observed for overall urea splitting. This study proposes a viable approach to achieve and optimize the bifunctional UOR/HER performance of NiOOH active species, which holds significant importance for efficient and stable hydrogen generation from urea-contaminated substandard water. [ABSTRACT FROM AUTHOR]

Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10–150 μm well. In comparison to γ-CD and β-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125–200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils. [ABSTRACT FROM AUTHOR]

The electrochemiluminescence (ECL) efficiency of porphyrins is limited by the quenching of π–π stacking due to their poor water solubility and inherent instability. Therefore, there is an urgent need to design and explore novel porphyrin luminophores with high ECL efficiency, which presents a significant challenge. In this work, a facile one-pot strategy was developed to synthesize a self-promoter-doped porphyrin-based ECL luminophore with high ECL efficiency for the first time. The silver nanoparticle (AgNPs)-doped meso-tetra(4-carboxyphenyl) porphyrin (TCPP) (AgNPs@TCPP) nanoassembly was prepared by inducing TCPP assembly using Ag nanoseeds produced by the reduction of silver nitrate with N,N-dimethylformamide. In this process, AgNPs could coordinate with the carboxyphenyl groups at the terminus of TCPP and the pyrrole nitrogen of TCPP. The resulting AgNPs@TCPP nanoassembly demonstrated superior ECL performance using K2S2O8 as a co-reactant, with an ECL efficiency of 217%, significantly higher than that of previously reported sodium dodecyl sulfate-assisted TCPP aggregate (92.3%) and cetyltrimethylammonium bromide-assisted TCPP aggregate (57.5%). The self-promoted and highly efficient ECL of the AgNPs@TCPP nanoassembly was attributed to overcoming the ECL quenching due to bad TCPP aggregation by virtue of Ag nanoseeds induced TCPP assembly and the self-promoted ECL amplification by doping AgNPs with excellent conductivity. These findings offer a new approach for exploring highly efficient porphyrin-based ECL luminophores, thereby expanding the applications of porphyrins in ECL. [ABSTRACT FROM AUTHOR]

Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc‐HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc‐HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc‐HZ10 transcription. Meanwhile, lnc‐HZ10 also increases AhR levels by suppressing its CUL4B‐mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc‐HZ10 (mainly 1‐447 nt) interacts with γ‐H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc‐HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

Background: With rapid increase in the global use of various plastics, microplastics (MPs) and nanoplastics (NPs) pollution and their adverse health effects have attracted global attention. MPs have been detected out in human body and both MPs and NPs showed female reproductive toxicological effects in animal models. Miscarriage (abnormal early embryo loss), accounting for 15-25% pregnant women worldwide, greatly harms human reproduction. However, the adverse effects of NPs on miscarriage have never been explored. Results: In this study, we identified that polystyrene (PS) plastics particles were present in women villous tissues. Their levels were higher in villous tissues of unexplained recurrent miscarriage (RM) patients vs. healthy control (HC) group. Furthermore, mouse assays further confirmed that exposure to polystyrene nanoplastics (PS-NPs, 50 nm in diameter, 50 or 100 mg/kg) indeed induced miscarriage. In mechanism, PS-NPs exposure (50, 100, 150, or 200 µg/mL) increased oxidative stress, decreased mitochondrial membrane potential, and increased apoptosis in human trophoblast cells by activating Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3 signaling through mitochondrial pathway. The alteration in this signaling was consistent in placental tissues of PS-NPs-exposed mouse model and in villous tissues of unexplained RM patients. Supplement with Bcl-2 could efficiently suppress apoptosis in PS-NPs-exposed trophoblast cells and reduce apoptosis and alleviate miscarriage in PS-NPs-exposed pregnant mouse model. Conclusions: Exposure to PS-NPs activated Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3, leading to excessive apoptosis in human trophoblast cells and in mice placental tissues, further inducing miscarriage. [ABSTRACT FROM AUTHOR]

Mimetic enzymes are devised as alternates or supplements of natural enzymes in broad fields but regulating their activities in a switchable manner remains challenging. Herein, we proposed an enzymatic self-assembly/disassembly strategy to address this issue. A peptide molecule NapFFEYIH (YH) was rationally designed which, after self-assembling into nanofibers, lined up the histidine moieties to form active hydrolysis centers for mimicking hydrolase activity. Enzymatic dephosphorylation of NapF-FEYpIH (YpH) by alkaline phosphatase to yield YH also turned "ON" the hydrolase activity. In turn, phosphorylation of YH by phosphokinase epidermal growth factor receptor to yield YpH disassembled the nanofibers and thus turned the activity "OFF". As such, the "ON"/"OFF" of the mimetic hydrolase activities could be regulated under physiological conditions through ALP/EGFR-mediated self-assembly/disassembly of histidine nanofibers. This work provides a feasible strategy for the on-demand fabrication of artificial enzymes with controllable and superior activities. [ABSTRACT FROM AUTHOR]

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins. Author summary: Crimean-Congo hemorrhagic fever (CCHF) is a priority disease by the World Health Organization (WHO). It is a deadly viral infectious disease with case fatalities up to 40%, and no approved vaccine or treatment. Neutralizing antibodies are a promising approach toward treating viral infections, as exemplified in other hemorrhagic fevers such as Ebola. Currently, there are few reports of efficient neutralizing antibodies against CCHF virus (CCHFV). This study successfully screened mouse-derived monoclonal antibodies with high in vitro neutralizing activity and in vivo protective efficacy against CCHFV infection. Among those, mAb Gc13 was the most efficient because it strongly bound to the highly conserved fusion loop regions of the CCHFV Gc subunit, thus blocking the crucial virus membrane fusion process. This study highlights the potential of neutralizing antibody-based strategies for CCHF treatment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is an autoimmune disease characterized by synovium hyperplasia and bone destruction. Macrophage extracellular traps are released from macrophages under various stimuli and may generate stable autoantigen–DNA complexes, as well as aggravate autoantibody generation and autoimmune responses. We aimed to investigate the role of macrophage extracellular traps on the biologic behaviors of rheumatoid arthritis fibroblast-like synoviocytes. Synovial tissues and fibroblast-like synoviocytes were obtained from patients with rheumatoid arthritis. Extracellular traps in synovium and synovial fluids were detected by immunofluorescence, immunohistochemistry, and SYTOX Green staining. Cell viability, migration, invasion, and cytokine expression of rheumatoid arthritis fibroblast-like synoviocytes were assessed by CCK-8, wound-healing assay, Transwell assays, and quantitative real-time polymerase chain reaction, respectively. RNA sequencing analysis was performed to explore the underlying mechanism, and Western blot was used to validate the active signaling pathways. We found that extracellular trap formation was abundant in rheumatoid arthritis and positively correlated to anti-CCP. Rheumatoid arthritis fibroblast-like synoviocytes stimulated with purified macrophage extracellular traps demonstrated the obvious promotion in tumor-like biologic behaviors. The DNA sensor cGAS in rheumatoid arthritis fibroblast-like synoviocytes was activated after macrophage extracellular trap stimuli. RNA sequencing revealed that differential genes were significantly enriched in the PI3K/Akt signaling pathway, and cGAS inhibitor RU.521 effectively reversed the promotion of tumor-like biologic behaviors in macrophage extracellular trap–treated rheumatoid arthritis fibroblast-like synoviocytes and downregulated the PI3K/Akt activation. In summary, our study demonstrates that macrophage extracellular traps promote the pathogenically biological behaviors of rheumatoid arthritis fibroblast-like synoviocytes through cGAS-mediated activation of the PI3K/Akt signaling pathway. These findings provide a novel insight into the pathogenesis of rheumatoid arthritis and the mechanisms of macrophages in modulating rheumatoid arthritis fibroblast-like synoviocyte tumor-like behaviors. [ABSTRACT FROM AUTHOR]

Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on our societies. Moreover, the disease's extensive and sustained symptoms are now becoming a nonnegligible medical challenge. In this respect, data indicate that heart failure is one of the most common readmission diagnoses among COVID-19 patients. Methods: In this study, we used human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes to develop an in vitro model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and studied the dynamic changes occurring in cardiomyocytes after SARS-CoV-2 infection. Results: To this end, we have created an effective time series SARS-CoV-2 infection model exhibiting different functional patterns of up- and downregulated proteins, and demonstrating that SARS-CoV-2 mainly affects (i) the lipid and the energy metabolism of hiPSC-derived cardiomyocytes during the early infection stage, and (ii) the DNA repair ability of cardiomyocytes during the late infection stage. By analyzing the proteome changes occurring at different infection timepoints, we were able to observe that the simulated disease (COVID-19) course developed rapidly, and that each of the studied timepoints was characterized by a distinct protein expression pattern. Conclusions: Our findings highlight the importance of early detection and personalized treatment based on the disease stage. Finally, by combing the proteomics data with virus-host interaction network analysis, we were able to identify several potential drug targets for the disease. [ABSTRACT FROM AUTHOR]

Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 pathogen requiring urgent research and development efforts. The glycoproteins of CCHFV, Gn and Gc, are considered to play multiple roles in the viral life cycle by interactions with host cells; however, these interactions remain largely unclear to date. Here, we analyzed the cellular interactomes of CCHFV glycoproteins and identified 45 host proteins as high-confidence Gn/Gc interactors. These host molecules are involved in multiple cellular biological processes potentially associated with the physiological actions of the viral glycoproteins. Then, we elucidated the role of a representative cellular protein, HAX1. HAX1 interacts with Gn by its C-terminus, while its N-terminal region leads to mitochondrial localization. By the strong interaction, HAX1 sequestrates Gn to mitochondria, thus depriving Gn of its normal Golgi localization that is required for functional glycoprotein-mediated progeny virion packaging. Consistently, the inhibitory activity of HAX1 against viral packaging and hence propagation was further elucidated in the contexts of pseudotyped and authentic CCHFV infections in cellular and animal models. Together, the findings provide a systematic CCHFV Gn/Gc-cell protein-protein interaction map, but also unravel a HAX1/mitochondrion-associated host antiviral mechanism, which may facilitate further studies on CCHFV biology and therapeutic approaches. Here, Ning et al report the cellular interactomes of Crimean-Congo haemorrhagic fever virus glycoproteins and uncover a host restriction factor HAX1 that hijacks the viral glycoproteins to mitochondria, disabling progeny virion packaging. [ABSTRACT FROM AUTHOR]

Ulungur Lake is the largest lake in northern Xinjiang and undertakes important aquatic tasks. It is the No. 1 fishing ground in northern Xinjiang, and the problem of persistent organic pollution in the water has received much attention. However, there are few studies on phthalate esters (PAEs) in the water of Ulungur Lake. Understanding the pollution levels, distribution characteristics and sources of PAEs is of great significance for the protection and prevention of water. Fifteen sampling sites are established in Ulungur Lake to collect water samples during flood and dry periods, then seventeen PAEs are extracted from the water samples and purified by liquid–liquid extraction—solid-phase purification. Gas chromatography–mass spectrometry is used to detect the pollution levels and distribution characteristics of the 17 PAEs and analyse their sources. Results show that the concentrations of PAEs in the dry and flood periods are 0.451–9.97 µg/L and 0.0490–6.38 µg/L, respectively. The concentration of ∑PAEs with time is characterised by the dry period > the flood period. The change in flow is the main reason for the diverse concentration distributions of PAEs in different periods. The concentration of ΣPAEs in the dry period is much lower on the side near the lake entrance of the Ulungur River and Irtysh River. In the dry period, PAEs mainly come from chemical production and the use of cosmetics and personal care products; in the flood period, they mainly come from chemical production. River input and atmospheric sedimentation are the main sources of PAEs in the lake. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing‐based strategy to generate primary, orthotopic, and driver‐defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid‐initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high‐throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy. [ABSTRACT FROM AUTHOR]

KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX‐5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition. [ABSTRACT FROM AUTHOR]

Azide-alkyne cycloaddition reaction is a very common organic reaction to synthesize nitrogen-containing heterocycles. Once catalyzed by Cu(I) or Ru(II), it turns out to be a click reaction and thus is widely applied in chemical biology for labeling. However, besides their poor regioselectivity towards this reaction, these metal ions are not biologically friendly. Hence, it is an urgent need to develop a metal-free azide–alkyne cycloaddition reaction for biomedical applications. In this work, we found that, in the absence of metal ions, supramolecular self-assembly in an aqueous solution could realize this reaction with excellent regioselectivity. Nap-Phe-Phe-Lys(azido)-OH firstly self-assembled into nanofibers. Then, Nap-Phe-Phe-Gly(alkynyl)-OH at equivalent concentration approached to react with the assembly to yield the cycloaddition product Nap-Phe-Phe-Lys(triazole)-Gly-Phe-Phe-Nap to form nanoribbons. Due to space confinement effect, the product was obtained with excellent regioselectivity. Employing the excellent properties of supramolecular self-assembly, we are applying this strategy to realize more reactions without metal ion catalysis. Metal-free versions of azide–alkyne cycloadditions could find widespread applications in biomedical contexts. Here, the authors report an assembly-driven, regioselective azide–alkyne cycloaddition. [ABSTRACT FROM AUTHOR]

Aim: The molecular mechanism underlying Alzheimer's disease (AD) pathologies remains unclear. The brain is extremely sensitive to oxygen deprivation, and brief interruptions in oxygen supply may lead to permanent brain damage. The objective here was to access the red blood cell (RBC) physiological alterations and the changes in blood oxygen saturation of an AD model as well as to explore the possible mechanism underlying these pathologies. Methods: We used female APPswe/PS1ΔE9 mice as AD models. Data were collected at the age of 3, 6, and 9 months. In addition to examining classic features of AD, namely cognitive deficiency and Aβ depositions, 24 h blood oxygen saturation was monitored by Plus oximeters in real time. In addition, RBC physiological parameters were measured by blood cell counter using peripheral blood from the epicanthal veins. Furthermore, in the mechanism investigations, the expression of phosphorylated band 3 protein was examined by a series of Western blot analyses, and the levels of soluble Aβ40 and Aβ42 on the membrane of RBCs were determined by ELISA. Results: Our results showed that the blood oxygen saturation in the AD mice was significantly reduced as early as at 3 months of age, preceding the neuropathological changes and cognitive impairments. Meanwhile, the expression of phosphorylated band 3 protein and levels of soluble Aβ40 and Aβ42 were all elevated in the erythrocytes of the AD mice. Conclusion: APPswe/PS1ΔE9 mice exhibited decreased oxygen saturation together with reduced RBC counts and hemoglobin concentrations at the early stage, which may aid in the development of predictive markers for AD diagnosis. The increased expression of band 3 protein and elevated Aβ40 and Aβ42 levels may contribute to the deformation of RBCs and, in turn, cause the subsequent AD development. [ABSTRACT FROM AUTHOR]

Bosten Lake is the main fishing and grazing area in Xinjiang. The pollution of phthalate esters (PAEs) in water has attracted much attention, but limited research has been conducted on PAEs in Bosten Lake. The distribution of PAEs in fifteen sampling sites of surface water in the dry and flood seasons were investigated to explore the content level of PAEs in Bosten Lake, and the risk was evaluated. Seventeen PAEs were detected by GC–MS after liquid–liquid and solid-phase purification. Results showed that the content of ∑PAEs in the water during dry and flood seasons is ND-26.226 μg/L and ND-7.179 μg/L. The content of PAEs in the water of Bosten Lake is at a medium level. DBP and DIBP are the main PAEs. The content of PAEs is related to the physicochemical properties of water, and the physicochemical properties of water in dry season have a more serious impact on PAEs. PAEs in water mainly come from domestic pollution and chemical production. The results of health risk assessment indicate that PAEs in water do not pose a carcinogenic risk or a non carcinogenic risk to human, which can meet the conditions of Bosten Lake as a fishing ground and livestock base, but the pollution of PAEs cannot be ignored. [ABSTRACT FROM AUTHOR]

Osteoporosis is a systemic osteopathy characterized by bone metabolism disorders that become more serious with age increases in postmenopausal women. Recent studies have found that antler protein is the main bioactive component of cervus pantotrichum, and it has a positive regulatory effect on bone metabolism and can improve estrogen level. This study aimed to investigate the effect of velvet antler extract (VAE) on the prevention of osteoporosis and the modulation of gut microbiota in ovariectomized (OVX) mice. OVX mice treated with 12 weeks of VAE exhibited higher levels of serum BGP, Ca2+, CT, and HyP (p <.05). Micro‐CT scans showed that VAE significantly elevated bone volume fraction (BV/TV), trabecular bone number (Tb.N), trabecular bone thickness (Tb.Th), trabecular bone connection density (Conn.D), decreased trabecular separation (Tb.Sp), and structural modality index (SMI) than untreated OVX mice. The right tibial retinaculum in the VAE group was clearer, with a clearer reticular structure, smaller gaps, a tighter distribution, and a more orderly arrangement. The gut microbiota of the cecal contents was analyzed by 16 s rDNA amplicon sequencing. The data indicated that VAE modulated the species, numbers, and diversity of the gut microbiota in OVX mice. Ovariectomy caused dysbiosis of the intestinal microbiota by increasing the ratio of Firmicutes to Bacteroidetes in mice, but the ratio decreased after treatment with VAE. These results suggest that VAE has a therapeutic effect on OVX mice via modulate bone‐related biochemical markers in serum and structure of gut microbiota. In this paper, I show that velvet antler extract has a positive effect on osteoporosis model mice. I found that velvet antler extract can improve the serum biochemical indexes, bone microstructure, and intestinal flora of osteoporosis model mice. In addition, I noticed that the antler extract significantly increased the content of Akkermansia bacteria in the intestinal tract of mice, indicating that Akkermansia bacteria may be a new biomarker of osteoporosis. [ABSTRACT FROM AUTHOR]

Cyclodextrin metal-organic frameworks (CD-MOFs) exhibit a high structural diversity, which contributes to their functional properties. In this study, we have successfully synthesized a novel type of β-cyclodextrin metal-organic framework (β-CD-POF(I)) that exhibits excellent drug adsorption capacity and enhances stability. Single-crystal X-ray diffraction analysis revealed that β-CD-POF(I) possessed the dicyclodextrin channel moieties and long-parallel tubular cavities. Compared with the reported β-CD-MOFs, the β-CD-POF(I) has a more promising drug encapsulation capability. Here, the stability of vitamin A palmitate (VAP) was effectively improved by the solvent-free method. Molecular modeling and other characterization techniques like synchrotron radiation Fourier transform infrared spectroscopy (SR-FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and nitrogen adsorption isotherm were applied to confirm that the VAP was successfully encapsulated into the channel formed by the dicyclodextrin pairs. Furthermore, the mechanism of stability enhancement for VAP was determined to be due to the constraint and separation effects of β-CD pairs on VAP. Therefore, β-CD-POF(I) is capable of trapping and stabilizing certain unstable drug molecules, offering benefits and application possibilities. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) caused by a novel bunyavirus (SFTSV) is an emerging infectious disease with up to 30% case fatality. Currently, there are no specific antiviral drugs or vaccines for SFTS. Here, we constructed a reporter SFTSV in which the virulent factor nonstructural protein (NSs) was replaced by eGFP for drug screening. First, we developed a reverse genetics system based on the SFTSV HBMC5 strain. Then, the reporter virus SFTSV-delNSs-eGFP was constructed, rescued, and characterized in vitro. SFTSV-delNSs-eGFP showed similar growth kinetics with the wild-type virus in Vero cells. We further detected the antiviral efficacy of favipiravir and chloroquine against wild-type and recombinant SFTSV by the quantification of viral RNA, and compared the results with that of fluorescent assay using high-content screening. The results showed that SFTSV-delNSs-eGFP could be used as a reporter virus for antiviral drug screening in vitro. In addition, we analyzed the pathogenesis of SFTSV-delNSs-eGFP in interferon receptor-deficient (IFNAR−/−) C57BL/6J mice and found that unlike the fatal infection of the wild-type virus, no obvious pathological change or viral replication were observed in SFTSV-delNSs-eGFP-infected mice. Taken together, the green fluorescence and attenuated pathogenicity make SFTSV-delNSs-eGFP a potent tool for the future high-throughput screening of antiviral drugs. [ABSTRACT FROM AUTHOR]

The effect of magnesium (Mg) content on the microstructure, mechanical properties, and cytocompatibility of degradable Zn-0.5Mn-xMg (x = 0.05 wt%, 0.2 wt%, 0.5 wt%) alloys was investigated. The microstructure, corrosion products, mechanical properties, and corrosion properties of the three alloys were then thoroughly characterized by scanning electron microscopy (SEM), electron back-scattered diffraction (EBSD), and other methods. According to the findings, the grain size of matrix was refined by the addition of Mg, while the size and quantity of Mg2Zn11 phase was increased. The Mg content could significantly improve the ultimate tensile strength (UTS) of the alloy. Compared with the Zn-0.5Mn alloy, the UTS of Zn-0.5Mn-xMg alloy was increased significantly. Zn-0.5Mn-0.5Mg exhibited the highest UTS (369.6 MPa). The strength of the alloy was influenced by the average grain size, the solid solubility of Mg, and the quantity of Mg2Zn11 phase. The increase in the quantity and size of Mg2Zn11 phase was the main reason for the transition from ductile fracture to cleavage fracture. Moreover, Zn-0.5Mn-0.2Mg alloy showed the best cytocompatibility to L-929 cells. [ABSTRACT FROM AUTHOR]

Exploring effective and robust strategies for enhancing electrochemiluminescence (ECL) emissions of porphyrin-based metal–organic frameworks (MOFs) is of great importance for expanding their applications in bioassays. Herein, a simple, convenient, and effective endogenous strategy of post-synthesis-modified Zn2+ was proposed to enhance ECL of nonmetal porphyrin-based MOFs. The ECL emissions of porphyrin-cobuilt UiO-66-NH2 (TCPP/UiO-66-NH2), PCN-224, PCN-222, and Ce–TCPP–LMOF could be enhanced 31.9, 47.1, 49.9, and 19.2 times, respectively. By studying TCPP/UiO-66-NH2 nanoluminophores as a model, Zn2+ was incorporated into TCPP/UiO-66-NH2 through the coordination of Zn and pyrrolic N of TCPP. The ECL enhancement was attributed to the conversion of TCPP to ZnTCPP with high emission efficiency and MOFs could enrich co-reactants, shorten the ion/electron-transfer distance, and render electrochemical activation of porphyrin luminophores. On this basis, a simple ECL biosensor for detecting nanoscale exosomes was developed based on the boosted ECL signal of Zn–TCPP/UiO-66-NH2 nanoluminophores without additional recognition and amplification elements. The ECL biosensor exhibited good sensitivity with a detection range from 1.00 × 104 to 3.16 × 106 particles/μL and a detection limit of 9.08 × 103 particles/μL (S/N = 3). The linear range and detection limit of the proposed label-free ECL biosensor are better than most of the existing label-free methods for detecting exosomes, indicating its good performance as a powerful tool for accurate and sensitive detection of HepG2-derived exosomes. As a result, this work provides inspiration for exploring strategies to enhance ECL efficiencies of porphyrin-based MOFs, which has important application prospects in sensitive bioassays. [ABSTRACT FROM AUTHOR]

Zn-Li alloys have been demonstrated to be potential biodegradable materials because of their favorable biocompatibility and exceptional strength. The corrosion behaviors of Zn–0.4Li in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were investigated. Compared with samples in SIF, those in SGF were severely corroded locally. Pepsin and pancreatin participated in the formation of degradation products. After immersion in SGF and SIF, the corrosion process presented two interfaces. Lithium (Li) preferentially reacted in the near-surface region to form a Li-rich region. Simultaneously, there were two Li-poor regions around the Li-rich region. Then Zn-rich products gradually became dominant with time. Li+ releasement dominated over Zn2+ releasement throughout the immersion process in SGF and SIF. These results can guide the development of biodegradable gastrointestinal anastomotic nails in the future. [ABSTRACT FROM AUTHOR]

The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro. In this study, we discussed the syntheses of two novel heterocylic compounds: tert-butyl rel-4-(((3R,4S)-3-(1H-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (trans-1) and rel-(3R,4S)-3-(1H-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (trans-2), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans-1 showed higher anti-SARS-CoV-2 activity than trans-2, with a half maximal effective concentration (EC50) of 3.15 μM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans-1 efficiently inhibited viral replication (EC50 = 2.78 μM; SI: > 71.94) and performed better than CQ (EC50 = 44.90 μM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans-1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed. [ABSTRACT FROM AUTHOR]

Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS‐CoV‐2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS‐CoV‐2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu‐3) cell lines. TET functioned during the early‐entry stage of SARS‐CoV‐2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5‐human angiotensin‐converting enzyme 2 (hACE2)‐transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS‐CoV‐2‐infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route‐dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off‐target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route‐dependent pulmonary biodistribution of TET associated with its efficacy. [ABSTRACT FROM AUTHOR]

Wulungu Lake is the second largest lake and the second largest fishery base in Xinjiang, but there are few studies on heavy metal pollution in water environment. In order to explore the characteristics and sources of heavy metal pollution in the water environment of Wulungu Lake, the distribution characteristics, ecological risks and pollution sources of 8 heavy metals (Cr, Cu, Cd, Zn, Ni, Pb, Hg and As) in water and sediments of 13 sampling points of Wulungu Lake were analyzed. Geological accumulation index method and potential ecological hazard index method show that Hg has a strong potential ecological risk, which leads to a high potential ecological risk in Wulungu Lake. The water quality of Wulungu Lake is good, but we need to pay attention to the health risk of as. Multivariate statistical analysis shows that Cu, Cd, Zn, Ni and Pb in the water body of Wulungu Lake are affected by the discharge of mining or enterprise wastewater. Hg and Cr may come from the use of fertilizer in farmland. Cr, Cu, Zn, Ni and As in surface sediments are mainly affected by regional geochemical characteristics, while Cd, Pb and Hg are also affected by human activities. The distribution of heavy metals in sediments is different from that in water, which should also be affected by the hydrological conditions of lakes. [ABSTRACT FROM AUTHOR]

Baculoviruses have been widely used as expression vectors. However, numerous genes in the baculoviral genome are non-essential for cellular infection and protein expression, making the optimisation of baculovirus expression vectors possible. We used a synthetic biological method to reduce the number of genes in a partial region of the autograph californica multiple nucleopolyhedrovirus (AcMNPV), the most widely used baculovirus expression vector. The C1 region of the AcMNPV is 46.4 kb and is subdivided into B1, B2, and B3 fragments. We first designed modified B1, B2, and B3 fragments by deleting the non-essential genes, and then synthesised complete viral genomes containing either individual modified B fragments or joint modified B fragments through transformation-related recombination in yeast. The synthetic genomes were then transfected into Sf9 cells to rescue the progeny viruses and test their infectivity. The design-build-test cycle was repeated until the ultimately rescued virus could produce progeny viruses efficiently. Finally, AcMNPV-Syn-mC1-1.1 by deleting approximately 17.2 kb, including 20 ORFs, in the C1 region, was obtained. This is essential to the synthesis of a minimal AcMNPV genome that can generate infectious progeny viruses and can be further used to optimise the foundation of baculovirus expression vectors. [ABSTRACT FROM AUTHOR]

P26, a homolog of the viral-encoded nuclease poxin that neutralizes the cGAS-STING innate immunity, is widely distributed in various invertebrate viruses, lepidopteran insects, and parasitoid wasps. P26/poxin from certain insect viruses also retains protease activity, though its biological role remains unknown. Given that many P26s contain a signal peptide, it is surmised that P26 may possess certain extracellular functions. Here, we report that a secretory baculoviral P26 suppresses melanization, a prominent insect innate immunity against pathogen invasion. P26 targets the cofactor of a prophenoloxidase-activating protease, and its inhibitory function is independent of nuclease activity. The analysis of P26/poxin homologs from different origins suggests that the ability to inhibit the extracellular melanization pathway is limited to P26s with a signal peptide and not shared by the homologs without it. These findings highlight the independent evolution of a single viral suppressor to perform dual roles in modulating immunity during virus-host adaptation. Poxins or P26 have been identified as inhibitors of cGAS-STING mediated innate immunity. Here, the authors describe an independently evolved antiviral function of P26 in suppressing melanization, an insect immune response. [ABSTRACT FROM AUTHOR]

Background: The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious disease by World Health Organization due to the high fatality rate of 5-30% and the lack of effective antiviral drugs and vaccines and therefore raised the urgent need to develop effective anti-SFTSV drugs to improve disease treatment.Methods: The antiviral drugs to inhibit SFTSV infection were identified by screening the library containing 1340 FDA-approved drugs using the SFTSV infection assays in vitro. The inhibitory effect on virus entry and the process of clathrin-mediated endocytosis under different drug doses was evaluated based on infection assays by qRT-PCR to determine intracellular viral copies, by Western blot to characterize viral protein expression in cells, and by immunofluorescence assays (IFAs) to determine virus infection efficiencies. The therapeutic effect was investigated in type I interferon receptor defective A129 mice in vivo with SFTSV infection, from which lesions and infection in tissues caused by SFTSV infection were assessed by H&E staining and immunohistochemical analysis.Results: Six drugs were identified as exerting inhibitory effects against SFTSV infection, of which anidulafungin, an antifungal drug of the echinocandin family, has a strong inhibitory effect on SFTSV entry. It suppresses SFTSV internalization by impairing the late endosome maturation and decreasing virus fusion with the membrane. SFTSV-infected A129 mice had relieving symptoms, reduced tissue lesions, and improved disease outcomes following anidulafungin treatment. Moreover, anidulafungin exerts an antiviral effect in inhibiting the entry of other viruses including SARS-CoV-2, SFTSV-related Guertu virus and Heartland virus, Crimean-Congo hemorrhagic fever virus, Zika virus, and Herpes simplex virus 1.Conclusions: The results demonstrated that the antifungal drug, anidulafungin, could effectively inhibit virus infection by interfering with virus entry, suggesting it may be utilized for the clinical treatment of infectious viral diseases, in addition to its FDA-approved use as an antifungal. The findings also suggested to further evaluate the anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases. [ABSTRACT FROM AUTHOR]

A recent article in Advanced Science discusses a novel drug candidate for sepsis, a condition that currently lacks specific clinical treatment. The drug targets Heparanase, which is responsible for increased vascular permeability and endothelial damage in sepsis. In mouse models, the drug protected the vascular endothelial glycocalyx and significantly improved survival rates from 0 to 80%. This research shows promise for the development of a treatment for sepsis. [Extracted from the article]

Background: Altered phenotype of Fibroblast-like synoviocyte(FLS) is an important cause of the pathogenesis and progression of rheumatoid arthritis(RA), but the specific mechanism causing this change has not yet been fully explained. The exact mechanism by which the biological properties of FLS change in RA is still unclear. microRNAs (miRNAs) have been shown to affect changes in the biological properties of RA-FLS, but the critical miRNAs remain to be discovered. Thus, we first used miRNA microarray and WGCNA to confirm the RA-FLS miRNA landscape and establish their biological functions via network analyses at the system level, as well as to provide a platform for modulating the overall phenotypic effects of RA-FLS. Methods: We enrolled a total of 3 patients with RA and 3 healthy participants, constructed a network analysis of via miRNA microarray and RNA-sequencing. Furthermore, the coexpression analyses of miR-7 and ciRS-7 were verified by siRNA transfection, overexpression and qPCR analyses. Finally, we evaluated the effects of adjusting the expression levels of miR-7 and ciRS-7 on RA-FLS, respectively. Results: We identified distinct miRNA features in RA-FLS, including miR-7, which was significantly lower expressed. Furthermore, we discovered the negative regulatory relationship between ciRS-7 and miR-7 in RA-FLS. Finally, we overexpressed miR-7 in RA-FLS and discovered that miR-7 inhibited RA-FLS hyperproliferation, migration, invasion, and apoptosis, whereas ciRS-7 overexpression reversed these effects. Conclusions: The results indicate that the dysregulation of miR-7 in FLS may be involved in the pathological processes of RA and that ciRS-7 induced the suppression of tumor-like biological characters of RA-FLS via modulation of miR-7. These findings help us understand the essential roles of a regulatory interaction between ciRS-7 and miR-7 mediating disease activity of RA, and will facilitate to develop potential intervention target for RA. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms. [ABSTRACT FROM AUTHOR]

Summary: The gas diffusion layer (GDL) is a vital constituent of proton exchange membrane fuel cells (PEMFCs), which directly affects the performance and cost of PEMFCs. Also, the GDL integration can simplify the structure of PEMFC. Herein, a novel substrate‐free microporous layer (sfMPL) has been successfully prepared by a dry‐press method, which broadens the usable humidity range of PEMFCs and improves the performance under different humidity conditions. Precisely, the maximum power density of a single‐cell assembled by sfMPL (with optimised 10 wt.% binder content and 1.0 g pore‐forming agent) is 754 mW cm−2 at 40% relative humidity, which is 36.6% higher than that with conventional GDL (552 mW cm−2). Furthermore, the sfMPL shows outstanding stability after high potential oxidation (1.6 V vs RHE). Our results highlight a promising new class of low‐cost, substrate‐free MPL for PEMFCs and provide a basis for future research on substrate‐free MPL. [ABSTRACT FROM AUTHOR]

Mutation rates are of key importance for understanding evolutionary processes and predicting their outcomes. Empirical mutation rate estimates are available for a number of RNA viruses, but few are available for DNA viruses, which tend to have larger genomes. Whilst some viruses have very high mutation rates, lower mutation rates are expected for viruses with large genomes to ensure genome integrity. Alphabaculoviruses are insect viruses with large genomes and often have high levels of polymorphism, suggesting high mutation rates despite evidence of proofreading activity by the replication machinery. Here, we report an empirical estimate of the mutation rate per base per strand copying (s/n/r) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). To avoid biases due to selection, we analyzed mutations that occurred in a stable, non-functional genomic insert after five serial passages in Spodoptera exigua larvae. Our results highlight that viral demography and the stringency of mutation calling affect mutation rate estimates, and that using a population genetic simulation model to make inferences can mitigate the impact of these processes on estimates of mutation rate. We estimated a mutation rate of μ = 1×10−7 s/n/r when applying the most stringent criteria for mutation calling, and estimates of up to μ = 5×10−7 s/n/r when relaxing these criteria. The rates at which different classes of mutations accumulate provide good evidence for neutrality of mutations occurring within the inserted region. We therefore present a robust approach for mutation rate estimation for viruses with stable genomes, and strong evidence of a much lower alphabaculovirus mutation rate than supposed based on the high levels of polymorphism observed. Author summary: Virus populations can evolve rapidly, driven by the large number of mutations that occur during virus replication. It is challenging to measure mutation rates because selection will affect which mutations are observed: beneficial mutations are overrepresented in virus populations, while deleterious mutations are selected against and therefore underrepresented. Few mutation rates have been estimated for viruses with large DNA genomes, and there are no estimates for any insect virus. Here, we estimate the mutation rate for an alphabaculovirus, a virus that infects caterpillars and has a large, 134 kilobase pair DNA genome. To ensure that selection did not bias our estimate of mutation rate, we studied which mutations occurred in a large artificial region inserted into the virus genome, where mutations did not affect viral fitness. We deep sequenced evolved virus populations, and compared the distribution of observed mutants to predictions from a simulation model to estimate mutation rate. We found evidence for a relatively low mutation rate, of one mutation in every 10 million bases replicated. This estimate is in line with expectations for a DNA virus with self-correcting replication machinery and a large genome. [ABSTRACT FROM AUTHOR]

Bombyx mori nucleopolyhedrovirus (BmNPV) is a pathogen that causes severe disease in silkworms. In a previous study, we demonstrated that by using the CRISPR/Cas9 system to disrupt the BmNPV ie-1 and me53 genes, transgenic silkworms showed resistance to BmNPV infection. Here, we used the same strategy to simultaneously target lef8 and lef9, which are essential for BmNPV replication. A PCR assay confirmed that double-stranded breaks were induced in viral DNA at targeted sequences in BmNPV-infected transgenic silkworms that expressed small guide RNAs (sgRNAs) and Cas9. Bioassays and qPCR showed that replication of BmNPV and mortality were significantly reduced in the transgenic silkworms in comparison with the control groups. Microscopy showed degradation of midgut cells in the BmNPV-infected wild type silkworms, but not in the transgenic silkworms. These results demonstrated that transgenic silkworms using the CRISPR/Cas9 system to disrupt BmNPV lef8 and lef9 genes could successfully prevent BmNPV infection. Our research not only provides more alternative targets for the CRISPR antiviral system, but also aims to provide new ideas for the application of virus infection research and the control of insect pests. [ABSTRACT FROM AUTHOR]

Background: Convulsive status epilepticus (CSE) is a common neurologic emergency with high morbidity and mortality. This single center study is aimed to assess changes of serum biochemical biomarkers after seizure, and their associations with the development of CSE.Methods: From January 2015 to October 2016, a total of 57 CSE patients, and 30 healthy controls without central nervous system diseases were enrolled in Children's Hospital of Soochow University. CSE patients were further divided into viral encephalitis (VEN, 13 cases), primary generalized epilepsy (PGE, 30 cases), and complex febrile seizures (CFS, 14 cases). The levels of serum biochemical biomarkers were measured using the corresponding commercial ELISA kits. Logistic regression analysis was performed to identify the associations between these biomarkers and diseases.Results: At the 1st and 4th day of CSE, neuron-specific enolase (NSE; 1st day: 20.553 ± 5.360, 4th day: 10.094 ± 3.426) and vascular endothelial growth factor (VEGF; 1st day: 153.504 ± 31.246, 4th day: 138.536 ± 25.221) in the CSE group were increased compared to the control (NSE: 6.138 ± 1.941; VEGF: 119.210 ± 31.681). Both the levels of S-100 calcium binding protein B (S-100B; 1st day: 0.738 ± 0.391) and C-reactive protein (CRP; 1st day: 11.128 ± 12.066) were elevated at 1st day of CSE (S-100B: 0.387 ± 0.040; CRP: 3.915 ± 2.064). For glial fibrillary acidic protein (GFAP), it was remarkably upregulated at 4th day of CSE (3.998 ± 1.211). NSE (P = 0.000), S-100B (P = 0.000), CRP (P = 0.011), and VEGF (P = 0.000) at 1st day of CSE, and NSE (P = 0.000), VEGF (P = 0.005), and GFAP (P = 0.000) at 4th day of CSE were significantly associated with the occurrence of CSE. Besides, NSE (P = 0.002), S-100B (P = 0.001), and VEGF (P = 0.002) at 4th day of CSE were significantly associated with VEN.Conclusions: The levels of serum NSE, S-100B, CRP, VEGF, and GFAP are associated with CSE. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory in joints. Invasive pannus is a characteristic pathological feature of RA. RA fibroblast-like synoviocytes (FLSs) are showed tumor-like biological characters that facilitate pannus generation. Importantly, it has been documented that extracellular vesicle (EVs) derived microRNAs have a vital role of angiogenesis in various immune inflammatory diseases. However, whether RA FLSs derived EVs can facilitate angiogenesis and the underlying mechanism is undefined. Herein, we aim to investigate the key role of RA FLSs derived EVs on angiogenesis in endothelial cells (ECs). We indicate that RA FLSs derived EVs promote ECs angiogenesis by enhancing migration and tube formation of ECs in vitro. Also, we confirm that RA FLSs derived EVs can significantly facilitate ECs angiogenesis with a matrigel angiogenesis mice model. In terms of the mechanisms, both RNAs and proteins in EVs play roles in promoting ECs angiogenesis, but the RNA parts are more fundamental in this process. By combining microRNA sequencing and qPCR results, miR-1972 is identified to facilitate ECs angiogenesis. The blockage of miR-1972 significantly abrogated the angiogenesis stimulative ability of RA FLSs derived EVs in ECs, while the overexpression of miR-1972 reversed the effect in ECs. Specifically, the p53 level is decreased, and the phosphorylated mTOR is upregulated in miR-1972 overexpressed ECs, indicating that miR-1972 expedites angiogenesis through p53/mTOR pathway. Collectively, RA FLSs derived EVs can promote ECs angiogenesis via miR-1972 targeted p53/mTOR signaling, targeting on RA FLSs derived EVs or miR-1972 provides a promising strategy for the treatment of patients with RA. [ABSTRACT FROM AUTHOR]

Objectives. To discover a more powerful diagnostic tool for the detection of hepatocellular carcinoma (HCC). Methods. 16 extracellularly located candidates were selected by analyzing the expression array datasets in GEO. 10 of them were validated in clinical samples by ELISA. Differences of each variable were compared by one-way ANOVA or Kruskal-Wallis test. CCL20 and LCN2 were determined in all samples (HCC, 167; liver cirrhosis, 106; and healthy control, 106) and finally chosen for the construction of the combination model by binary logistic regression. The models were first built using a comprehensive control, including both liver cirrhosis (LC) and healthy donors. Then, the models were rebuilt by using the LC group alone as a control. ROC analysis was performed to compare the diagnostic efficiency of each indicator. Results. Levels of CCL20 and LCN2 in HCC sera were significantly higher than those in all controls. Using the comprehensive control, ROC curves showed that the optimum diagnostic cutoff of the CCL20 and LCN2 combination was 0.443 (area under curve (AUC) of 0.927 (95% CI 0.896-0.951), sensitivity of 0.808, specificity of 0.892, and accuracy of 0.859). For detection of HCC from LC control, the optimum diagnostic cutoff was 0.590 (AUC of 0.919 (95% CI 0.880-0.948), sensitivity of 0.814, specificity of 0.868, and accuracy of 0.834). Furthermore, the model maintained diagnostic accuracy for patients with HCC in the early stage, with the sensitivity and specificity of 0.75 and 0.77 from LC control, yet the AFP only reached 0.5 and 0.67, respectively. Conclusion. A combination model composed of CCL20 and LCN2 may serve as a more efficient tool for distinguishing HCC from nonmalignant liver diseases. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS‐CoV‐2 at a molecular level are limited. Especially, the ability of SARS‐CoV‐2 to infect skin cells and impact their function is not well understood. A proteome map of COVID‐19 skin is established here and the susceptibility of human‐induced pluripotent stem cell (hiPSC)‐derived skin organoids with hair follicles and nervous system is investigated, to SARS‐CoV‐2 infection. It is shown that KRT17+ hair follicles can be infected by SARS‐CoV‐2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID‐19 and hair loss. hiPSC‐derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS‐CoV‐2 infection and can help identify various pathological mechanisms and drug screening strategies. [ABSTRACT FROM AUTHOR]

Fibroblast‐like synoviocytes (FLSs) are the predominant effector cells in the pathological progression of rheumatoid arthritis (RA). Therefore, elucidating the underlying molecular mechanism of the biologic behaviors in RA‐FLSs will be helpful in developing the potent targets for the treatment of RA. We have previously documented that the tumor‐like biologic behaviors of RA‐FLSs are exacerbated by urokinase‐type plasminogen activator receptor (uPAR), a specifically up‐regulated receptor in RA‐FLSs. Here, we investigate the further mechanism of uPAR and clarify its function in RA‐FLSs. We demonstrate that miR‐221‐3p positively correlates to uPAR and regulates uPAR level in RA‐FLSs. Simultaneously, one long noncoding RNA, nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) is identified, which can predictively target miR‐221‐3p at three sites, indicating a strong possibility of being a competing endogenous RNA in RA‐FLSs. Interestingly, NEAT1_1 and miR‐221‐3p can colocate in the nucleus and cytoplasm in RA‐FLSs. Importantly, NEAT1_1 can act as a rheostat for the miR‐221‐3p/uPAR axis and the downstream JAK signaling. In line with the biologic function, NEAT1_1 negatively regulates the tumor‐like characters, and cytokine secretions of RA‐FLSs. Collectively, our data provide new insight into the mechanisms of NEAT1_1 in modulating RA‐FLSs tumor‐like behaviors. The targeting of NEAT1_1 and miR‐221‐3p/uPAR axis may have a promising therapeutic role in patients with RA. [ABSTRACT FROM AUTHOR]

Baculoviruses are natural enemies of agricultural and forest insect pests and play an important role in biological pest control. Oral infection by baculovirus in the insect midgut is necessary for establishing systemic infection and eventually killing the insect. Since the insect midgut continuously encounters microbiota, the gut microbiota could affect baculovirus infection. Here, we demonstrated that gut microbiota modulates immune responses and promotes baculovirus infection in the cotton bollworm, Helicoverpa armigera. After oral infection, numerous host immunity‐related genes including genes encoding Toll and immune deficiency (IMD) pathway components were upregulated in the midgut. Elimination of the gut microbiota significantly increased the resistance to viral infection in H. armigera. Quantitative real‐time reverse transcription polymerase chain reaction and proteomic analysis showed that downregulation of the antiviral factor prophenoloxidase (PPO) could be mediated by microbiota during infection. It implied that midgut microbiota diminishes the expression of PPO to facilitate viral infection in H. armigera. Our findings revealed that the microbiota plays an important role in modulating the resistance of H. armigera to baculovirus infection, providing new insights in applying biopesticide. [ABSTRACT FROM AUTHOR]

In recent years, antibiotics have become widely used in animal breeding. The application of antibiotics in livestock may lead to the presence of antibiotic residues in animal‐derived foods, especially meat, that may pose a threat to human health. In this study, 26 common antibiotics (eight sulfonamides, nine fluoroquinolones, four tetracyclines, and five macrolides) were screened in 88 meat samples (cattle muscles and sheep muscles, kidneys, and livers) obtained from southern Xinjiang. The antibiotics were screened via the clean‐up step based on solid‐phase extraction and determined through ultraperformance liquid chromatography–tandem mass spectrometry. Moreover, their risk to human health was analyzed. Overall, 16 antibiotics were detected with a total detection rate of 95.46%. The percentage of noncompliant samples was 28.41% with an exceedance maximum residue limit of 1.14%. The illegal use rate of the antibiotic norfloxacin was 27.27%. The estimated daily exposure doses of all compounds in adults were <102.218 ng/kg bw/day even after applying the worst‐case scenario approach. This result demonstrated that the antibiotic residues in the tested samples imposed negligible harm to people's health and had an acceptable level of food safety risk. However, the high detection frequencies found in this work indicated that the risk of antibiotic residues could not be ignored given the cumulative risk of antibiotics, particularly the emergence of bacterial resistance, to the human body. The need for effective strategies and publicity for the judicious use of antibiotics to safeguard residents' health is immediate. [ABSTRACT FROM AUTHOR]

Background: Many clinicians are facing the dilemma about whether they should apply the active surveillance (AS) strategy for managing Clinically Node-negative (cN0) PTMC patients in daily clinical practice. This research plans to construct a dynamic nomogram based on network, connected with ultrasound characteristics and clinical data, to predict the risk of central lymph node metastasis (CLNM) in cN0 PTMC patients before surgery. Methods: A retrospective analysis of 659 patients with cN0 PTMC who had underwent thyroid surgery and central compartment neck dissection. Patients were randomly (2:1) divided into the development cohort (439 patients) and validation cohort (220 patients). The group least absolute shrinkage and selection operator (Group Lasso) regression method was used to select the ultrasonic features for CLNM prediction in the development cohort. These features and clinical data were screened by the multivariable regression analysis, and the CLNM prediction model and web-based calculator were established. Receiver operating characteristic, calibration curve, Clinical impact curve and decision curve analysis (DCA) were used to weigh the performance of the prediction model in the validation set. Results: Multivariable regression analysis showed that age, tumor size, multifocality, the number of contact surface, and real-time elastography were risk factors that could predict CLNM. The area under the curve of the prediction model in the development and validation sets were 0.78 and 0.77, respectively, with good discrimination and calibration. A web-based dynamic calculator was built. DCA proved that the prediction model had excellent net benefits and clinical practicability. Conclusions: The web-based dynamic nomogram incorporating US and clinical features was able to forecast the risk of preoperative CLNM in cN0 PTMC patients, and has good predictive performance. As a new observational indicator, NCS can provide additional predictive information. [ABSTRACT FROM AUTHOR]

Objective: The COVID-19 epidemic has generated great stress throughout healthcare workers (HCWs). The situation of HCWs should be fully and timely understood. The aim of this meta-analysis is to determine the psychological impact of COVID-19 pandemic on health care workers. Method: We searched the original literatures published from 1 Nov 2019 to 20 Sep 2020 in electronic databases of PUBMED, EMBASE and WEB OF SCIENCE. Forty-seven studies were included in the meta-analysis with a combined total of 81,277 participants. Results: The pooled prevalence of anxiety is 37% (95% CI 0.31–0.42, I2 = 99.9%) from 44 studies. Depression is estimated in 39 studies, and the pooled prevalence of depression is 36% (95% CI 0.31–0.41, I2 = 99.6%). There are 10 studies reported the prevalence of insomnia, and the overall prevalence of insomnia is 32% (95% CI 0.23–0.42, I2 = 99.5%). The subgroup analysis showed a higher incidence of anxiety and depression among women and the frontline HCWs compared to men and non-frontline HCWs respectively. Conclusions: The COVID-19 pandemic has caused heavy psychological impact among healthcare professionals especially women and frontline workers. Timely psychological counseling and intervention ought to be implemented for HCWs in order to alleviate their anxiety and improve their general mental health. [ABSTRACT FROM AUTHOR]