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N-Hydroxyurea has been known since the 1960s as an antiproliferative drug and is used both in oncology and for treatment of hematological disorders such as sickle cell anemia where very high daily doses are administered. It is assumed that the cellular effect of N-hydroxyurea is caused by inhibition of ribonucleotide reductase, while alternative mechanisms, e.g., generation of nitric oxide, have also been proposed. Despite its many therapeutic applications, the metabolism of hydroxyurea is largely unexplored. The major elimination pathway of N-hydroxyurea is the reduction to urea. Since the mitochondrial amidoxime reducing component (mARC) is known for its N-reductive activity, we investigated the reduction of NHU by this enzyme system. This study presents in vitroand in vivoevidence that this reductive biotransformation is specifically mediated by the mARC1. Inactivation by mARC1 is a possible explanation for the high doses of NHU required for treatment.

This study aimed to investigate whether changes in presepsin, procalcitonin, high-sensitivity C-reactive protein, and interleukin 6 levels predict mortality in septic patients in the intensive care unit. This study enrolled septic patients between November 2020 and December 2021. Levels of presepsin, procalcitonin, high-sensitivity C-reactive protein, and interleukin 6 were measured on the first (PSEP_0, PCT_0, hsCRP_0, IL-6_0) and third days (PSEP_3, PCT_3, hsCRP_3, IL-6_3). Follow-up was performed on days 3, 7, 14, 21, and 28 after enrollment. The outcome was all-cause death. The study included 119 participants, and the mortality was 18.5%. In univariable Cox proportional hazards regression analysis, ΔPSEP (= PSEP_3 – PSEP_0) > 211.49 pg/mL (hazard ratio, 2.70; 95% confidence interval, 1.17–6.22), ΔPCT (= PCT_3 – PCT_0) > –0.13 ng/mL (hazard ratio, 7.31; 95% confidence interval, 2.68–19.80), ΔhsCRP (= hsCRP_3 – hsCRP_0) > −19.29 mg/L (hazard ratio, 6.89; 95% confidence interval, 1.61–29.40), and ΔIL-6 (= IL-6_3 – IL-6_0) > 1.00 pg/mL (hazard ratio, 3.13; 95% confidence interval, 1.35–7.24) indicated an increased risk of mortality. The composite concordance index for alterations in all 4 distinct biomarkers was highest (concordance index, 0.83; 95% confidence interval, 0.76–0.91), suggesting the optimal performance of this panel in mortality prediction. In decision curve analysis, compared with the Acute Physiology and Chronic Health Evaluation II and Sequential (sepsis-related) Organ Failure Assessment scores, the combination of the 4 biomarkers had a larger net benefit. Interestingly, interleukin 6 was predominantly produced by monocytes upon lipopolysaccharide stimulation in peripheral blood mononuclear cells. ΔPSEP, ΔPCT, ΔhsCRP, and ΔIL-6 are reliable biomarkers for predicting mortality in septic patients in the intensive care unit, and their combination has the best performance.Changes in PSEP, PCT, hsCRP, and IL-6 levels in septic patients on the third and first days of intensive care unit admission are reliable biomarkers for predicting mortality, and their combination has the best performance.

Nutrients in human milk, including minerals, relate growth and development of breast-fed infants. Tibetan mother-infant dyads possess unique characteristics on early nutrition due to their featured long-lasting life-style. This study longitudinally investigated the relationship between the mineral composition in human milk and the Z-scores of infants among Tibetan mother-infant dyads during their first 6 months postpartum through a prospective cohort study. The results show that the minerals of Na, Mg, K, Ca, Cu, Zn, and Se were of higher levels in colostrum than other lactation stages. Several minerals were below the recommended values for infants according to Chinese dietary guidelines. Besides, a large proportion of infant Z-scores were below −2 as lactation period continued. Multivariate statistical analysis revealed that classifications and correlations in varying degrees were observed between minerals in human milk and infant Z-scores. These findings will be advantageous for research upon Chinese early nutrition and progress of tailor-made infant formula.

Crustacean shellfish are major allergens in East Asia. In the present study, a major allergic protein in crustaceans, tropomyosin, was detected accurately using multiple reaction monitoring mode-based mass spectrometry, with shared signature peptides identified through proteomic analysis. The peptides were deliberately screened through thermal stability and enzymatic digestion efficiency to improve the suitability and accuracy of the developed method. Finally, the proposed method demonstrated a linear range of 0.15 to 30 mgTM/kgfood(R2> 0.99), with a limit of detection of 0.15 mgTM/kg foodand a limit of quantification of 0.5mgTM/kgfoodand successfully applied to commercially processed foods, such as potato chips, biscuits, surimi, and hot pot seasonings, which evidenced the applicability of proteomics-based methodology for food allergen analysis.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of different variants of concerns with immune evasion that have been prevalent over the past three years. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, have garnered interest in developing neutralizing antibodies due to their smaller size, structural stability, ease of production, high affinity, and low immunogenicity, among other characteristics. In this work, we describe an integrated proteomics platform for the high-throughput screening of nanobodies against different SARS-CoV-2 spike variants. To demonstrate this platform, we immunized a camel with subunit 1 (S1) of the wild-type spike protein and constructed a nanobody phage library. The binding and neutralizing activities of the nanobodies against 72 spike variants were then measured, resulting in the identification of two nanobodies (C-282 and C-39) with broad neutralizing activity against six non-Omicron variants (D614G, Alpha, Beta, Gamma, Delta, Kappa) and five Omicron variants (BA.1–5). Their neutralizing capability was validated using in vitro pseudovirus-based neutralization assays. All these results demonstrate the utility of our proteomics platform to identify new nanobodies with broad neutralizing capability and to develop a treatment for patients with SARS-CoV-2 variant infection in the future.

Objectives: To demonstrate the equivalence and substitutability of two blood collection methods: the push-pull method from a CVC and direct venous puncture (DVP).Methods: A comparative, within-subject study was conducted between September 2021 and December 2021 at a hospital in NanTong city. The sample comprised critically ill patients aged 18 and older in critical care units such as general, emergent, cardiac, respiratory, and neurological units. A total of 154 paired blood samples were collected via a CVC and direct venous puncture. This study focused on the laboratory results of the coagulation and hematologic tests. The reproducibility and reliability of the results were calculated by the mean of the coefficient of variation (CV) and the intraclass correlation coefficient (ICC). Bland–Altman statistics were used to analyze the substitutability of the two blood collection methods.Results: The difference in the means between the two methods ranged from −1.61 to 0.09, and the coefficients of variation for both methods were similar. The ICCs of the two methods were all above 0.90, which indicated excellent reliability. In the Bland–Altman plots, all of the blood samples that obtained by the push-pull method were within clinically acceptable ranges compared to the samples obtained by direct venous puncture.Conclusion: The push-pull method of collecting blood specimens from a CVC should be acceptable for coagulation and hematologic laboratory tests.

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Cells are the fundamental units of life. The cell membrane primarily composed of two layers of phospholipids (a bilayer) structurally defines the boundary of a cell, which can protect its interior from external disturbances and also selectively exchange substances and conduct signals from the extracellular environment. The complexity and particularity of transmembrane proteins provide the foundation for versatile cellular functions. Nanomedicine as an emerging therapeutic strategy holds tremendous potential in the healthcare field. However, it is susceptible to recognition and clearance by the immune system. To overcome this bottleneck, the technology of cell membrane coating has been extensively used in nanomedicines for their enhanced therapeutic efficacy, attributed to the favorable fluidity and biocompatibility of cell membranes with various membrane-anchored proteins. Meanwhile, some engineering strategies of cell membranes through various chemical, physical and biological ways have been progressively developed to enable their versatile therapeutic functions against complex diseases. In this review, we summarized the potential clinical applications of four typical cell membranes, elucidated their underlying therapeutic mechanisms, and outlined their current engineering approaches. In addition, we further discussed the limitation of this technology of cell membrane coating in clinical applications, and possible solutions to address these challenges.

Recent developments in intelligence technologies have led to an explosion in the use of connected and automated vehicles (CAVs). Unfortunately, these autonomous vehicles face an increasing risk of vulnerability due to various attacks. Vehicle intrusion detection mechanisms are widely employed to mitigate the threats. Although some works have addressed this issue, few works consider situations that the attack detection may be fooled via simultaneous attacking multiple sensors. In this article, we propose a novel intrusion detection system integrated Space Dimension Model and Time Dimension Model based on sensor data fusion for countering both independent attack and confederate attack in automated vehicles. In Space Dimension Model, the correlations of multivariate in-vehicle sensor data among multiple sensors are utilized as the input of our optimized convolutional neural network (CNN) model. Especially, we construct vehicle state matrices to characterize the underlying correlation of data between each sensor and other sensors, and then input them into our network for classification. To describe the abrupt deviation caused by anomalous multivariate sensor data itself, we design Time Dimension Model to capture the sensor behaviors of vehicle state vectors at adjacent time by utilizing the Mahalanobis distance (MD) metric. Extensive empirical studies based on a real-world vehicular dataset demonstrate the effectiveness of our integrated anomaly detection mechanisms by a comparative analysis with two detection models that consider only Space Dimension and Time Dimension respectively. The method can outperform the related work under different scenarios 1) with the gain of up to 3.01% in accuracy and 3.04% in F1 score; 2) with ability of defending against confederate attack effectively.

ObjectiveWhether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC.DesignMetabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77Sand AKT1C224Sknock-in cells, Zdhhc17and Zdhhc24knockout mice and Akt1C224Sknock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies.ResultsBy screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis.ConclusionsOur findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.

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An elaborate design of multimodal antibacterial agents has been revealed to be a promising strategy to address bacterial resistance, originating from the abuse of antibiotics. In this work, we have developed a positively charged and porous material, FePPOPHydantoin, as a disinfectant viaintroducing 1,3-dibromo-5,5-dimethylhydantoin (Hydantoin) and porphyrin iron units into a polymer framework. The extended π conjugated networks of FePPOPHydantoinendowed the material with strong near-infrared (NIR) absorption, high density of surface catalytic active centers, superior stability, and reproducibility. FePPOPHydantoinexhibits high peroxidase mimetic and photo-Fenton activity, which can catalyze the biologically allowable maximum concentrations of hydrogen peroxide (100 μM) to produce a vast amount of hydroxyl radicals. Simultaneously, the effective electrostatic interaction between the positively charged FePPOPHydantoinand the negatively charged bacteria facilitates the binding of FePPOPHydantoinon the bacterial membrane, restricting bacteria within the destruction range of hydroxyl radicals and thus making the bacteria more vulnerable. Finally, further close contact between bacteria and Hydantoin units in FePPOPHydantoingave the material an antibacterial efficiency of over 99.999%. Compared with chemical therapy, photo-Fenton therapy, or peroxidase catalytic therapy alone, FePPOPHydantoinhad a noteworthy multi-amplified antibacterial efficiency. Furthermore, FePPOPHydantoinexhibited good biocompatibility and negligible cytotoxicity. The in vivoantibacterial therapy on the Staphylococcus aureus(S. aureus) infected mouse wound model clearly proved the effectiveness of FePPOPHydantoinfor fighting bacterial infections. This work highlights opportunities for the design of nanozymes with enhanced bacteriostatic activity, providing a new avenue for the construction of novel antibiotics.

This study assessed the efficacy, safety, pharmacokinetics (PK), and immunogenicity profiles of a denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women with a high risk of fracture.

Low-intensity light beams carrying orbital angular momentum (OAM), commonly known as vortex beams, have garnered significant attention due to promising applications in areas ranging from optical trapping to communication. In recent years, there has been a surge in global research exploring the potential of high-intensity vortex laser beams and specifically their interactions with plasmas. This paper provides a comprehensive review of recent advances in this area. Compared with conventional laser beams, intense vortex beams exhibit unique properties such as twisted phase fronts, OAM delivery, hollow intensity distribution, and spatially isolated longitudinal fields. These distinct characteristics give rise to a multitude of rich phenomena, profoundly influencing laser-plasma interactions and offering diverse applications. The paper also discusses future prospects and identifies promising general research areas involving vortex beams. These areas include low-divergence particle acceleration, instability suppression, high-energy photon delivery with OAM, and the generation of strong magnetic fields. With growing scientific interest and application potential, the study of intense vortex lasers is poised for rapid development in the coming years.

The ribosome-binding site (RBS) in the 5′ untranslated region is recognized by 16S rRNA to start translation and is an essential element of the gene expression system. RBSs have been widely applied in regulating gene expression in various scenarios, including Gram-negative or Gram-positive bacteria. Here, we first rationally designed and constructed an RBS mutant library containing 66 RBSs. The strength of these RBSs in E. coliand C. glutamicumwas characterized individually. The RBS strength spanned about 200 and 15 times in the two species, respectively. The strength of RBSs in C. glutamicumwas generally lower than that of in E. coli. A total of 18 RBSs showed similar strength (within twofold differences) between the species in our study, and the correlation analysis of the strength of RBSs between E. coliand C. glutamicum(R2= 0.7483) revealed that these RBSs can be used across species. The sequence analysis revealed that the RBS region with two Ts stated was beneficial for RBS to function cross-species. The RBS characterized here can be used to precisely regulate gene expression in both hosts, and the characteristics of cross-species RBSs provide basic information for RBS rational design.

Background Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD[44.sup.+]/CD[24.sup.-/low]) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD[44.sup.+] and CD[24.sup.-/low] cell population. Methods Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. Results Chemotherapy treatment increased the percentage of CD[44.sup.+]/CD[24.sup.-/low]cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non-statistically significant decrease in the percentage of CD[44.sup.+]/CD[24.sup.-/low] cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a non--statistically significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). Conclusion These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.

Two different skeletons have been constructed by cyclization of α‐(3‐isoindolinonyl) propargylic alcohols with 5‐aminoisoxazoles bearing different N‐substituents under the relay catalysis of Brønsted acid and Lewis acid. This method provided spiro‐isoindolinone‐dihydropyridines with moderate to high yields (up to 99 %) as well as isoxazolo[4,5‐b]pyridines in moderate to good yields (up to 86 %). The structures of two products were determined by X‐ray crystal structural analyses. Moreover, fluorescence testing proved that one of the isoxazolo[4,5‐b]pyridines exhibited aggregation induced emission (AIE) effect. Finally, the control experiments revealed the possible reaction mechanism. Relay catalytic [3+3] cyclization of α‐(3‐isoindolinonyl) propargylic alcohols with 5‐aminoisoxazoles bearing different N‐substituents provide novel spiro‐isoindolinone‐dihydropyridines as well as isoxazolo[4,5‐b]pyridines in moderate to good yields. The structures of two products are determined by X‐ray crystal structural analyses.

With the continuous increase of electronic products, there is an urgent need to effectively recover gold from e-waste and other secondary resources other than the original mine. Here, hypercross-linking and polyamine-functionalized porous organic polymers (Pc–POSS–POP) were designed and facially synthesized based on multiple azo-coupling polymerizations between 2,9,16,23-tetraaminophthalocyanine (H2Pc(NH2)4) and octa(aminophenyl)-t8-silsesquioxane (OAPS) for the first time. The reaction requires no metal as a catalyst, thereby benefiting the purification of the product and the industrial scalability. Pc–POSS–POPs possess a hypercross-linking structure, highly conjugated frameworks, nitrogen-rich active sites, and extensively visible and near-infrared light absorption, which was utilized as an absorbent to retrieve Au (III). The results demonstrated that Pc–POSS–POPs have a high adsorption capacity (862.07 mg g–1) and a rapid adsorption rate toward gold recycling. The maximum adsorption capacity could reach up to 1026.87 mg g–1as in the case of light irradiation. Due to the strong N coordination sites and the electronic interaction between the −NH4+groups of Pc–POSS–POPs and AuCl4–, Pc–POSS–POPs also exhibited excellent selectivity toward gold over several coordinated metals [Cr (VI), Co (II), Cd (II), Ni (II), and Hg (II)]. These properties together with the good regenerative ability and superior recyclability demonstrated that Pc–POSS–POPs possess promising potential as hypercross-linking polymers for capturing and recycling of Au (III).

ABSTRACTAging has become an irreversible trend in the world, the health problems caused by aging cannot be ignored. The physiological functions of human body begin to decline with aging, the decline of gastrointestinal function caused by aging is an important problem that needs to be resolved. In this work, we evaluated the anti-aging effect of uridine in the senescent gastric epithelial cell model, and found that the aging level of gastric epithelial cell was significantly down-regulated by uridine treatment, uridine could obviously down-regulate the ratio of the SA-β-gal-positive senescent cells. Furthermore, aging-related marker molecules (such as p16 and p21) were also significantly down-regulated under uridine treatment. Additionally, the levels of inflammation and oxidative stress were also significantly reduced by uridine treatment. Next, our further studies the effect of aging on FGF activity on gastric epithelial cell, and found that FGF/FGFR-mediated signaling pathways were significantly down-regulated. However, uridine treatment can not only alleviate the senescence of gastric epithelial cell, but also can partially restore the sensitivity of FGF signaling. Taken together, the current work indicates that uridine shows a good anti-aging effect, which lays a solid foundation for the related research in this filed.

Aim: The purpose of this study was to evaluate the effect of education and mobile health management on improvement of blood glucose levels in patients with type 2 diabetes mellitus. Subjects and methods: A total of 209 patients (91 women, 118 men) with type 2 diabetes mellitus using both basal insulin and oral hypoglycemic agents participated in the study from August to December 2015. They were followed up at week 1, 2, 4, 8, 12, and 16, respectively. During follow-up, patients received education from professional diabetes educator nurses. Meanwhile, patients needed to upload their fasting plasma glucose levels three times or more and their postprandial plasma glucose level on a panel computer. The program duration was 16 weeks. Results: Compared with baseline, fasting plasma glucose (9.7 mmol/l vs. 6.8 mmol/l, P&lt; 0.001) and postprandial plasma glucose (10.4 mmol/l vs. 9.5 mmol/l, P&lt; 0.001) levels had decreased significantly at week 16. The number of patients with hemoglobin A1c &lt; 7% increased significantly from 33 at baseline to 115 at week 16 (P&lt; 0.001). Conclusion: Our study indicated that education and the mobile health management can effectively improve blood glucose levels of patients with postprandial plasma glucose.

Background: Bibliometric analysis can analyze development trends and predict researchhotspots. We used these analyses to better understand the pregnancy-related implications of thyroiddiseases. Methods: Publications on thyroid diseases during pregnancy from 1926 to hitherto were retrievedbased on the Web of Science database. The publications and references, the institutions and countries,the journals, the keywords and citations were analyzed by utilizing VOSviewer, CiteSpace and Cit-NetExplorer. Results: A total of 3310 publications were retrieved and were cited 87913 times. The United Statestook the dominant position in outputs and collaborations. Harvard University had the most articles 86,which also had the highest h-index 30. Thyroid ranked first with 201 publications and Journal of ClinicalEndocrinology Metabolism had the highest h-index 67. Among the 49 burst keywords, "antibody"had the longest burst period from 1991 to 2012, "thyroxine" had the strongest burst strength 16.7026,"hypothyroxinemia" appeared most recently in 2018. The most frequent keyword was "pregnancy"which occurred 1324 times. All the top 98 frequent keywords were clustered into 4 clusters. The citationnetwork visualization was grouped into 8 groups. Conclusion: The research focus of thyroid diseases in pregnancy ranged from clinical thyroid dysfunctionto milder thyroid dysfunction. Guidelines published by the American Thyroid Association enacteda crucial purpose in the treatment and development of thyroid diseases during pregnancy. Some randomizedcontrolled studies of unresolved problems and long-term follow-up of offspring may be thedirection of future research. In the meantime, bibliometric methods can help scholars choose journals,track research hotspots, and identify the direction or focus of future research.

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n= 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was −1.02% (−1.11, −0.93) in the dorzagliatin group and −0.36% (−0.45, −0.26) in the placebo group (estimated treatment difference, −0.66%; 95% CI: −0.79, −0.53; P< 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile (NCT03141073).

IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function and underlying mechanism of IKBKE contributing to breast cancer metastasis remain largely elusive. Here, we report that depletion of Ikbkemarkedly decreases polyoma virus middle T antigen (PyVMT)-induced mouse mammary tumorigenesis and subsequent lung metastasis. Biologically, ectopic expression of IKBKE accelerates, whereas depletion of IKBKEattenuates breast cancer invasiveness and migration in vitro and tumor metastasis in vivo. Mechanistically, IKBKE tightly controls the stability of transcriptional factor Snail in different layers, in particular by directly phosphorylating Snail, which markedly blocks the E3 ligase β-TRCP1-mediated Snail degradation, resulting in breast cancer epithelial-mesenchymal transition (EMT) and metastasis. These findings together reveal a novel oncogenic function of IKBKE in promoting breast cancer metastasis by governing Snail abundance, and highlight the potential of targeting IKBKE for metastatic breast cancer therapies.

ABSTRACTBovine respiratory syncytial virus (BRSV) is a clinically important causative agent of acute respiratory diseases in postweaning calves and feedlot cattle and causes numerous economic losses to the cattle industry. In June 2018, an outbreak of an acute respiratory disease occurred among 4- to 10-month-old calves on three intensive beef cattle farms in Heilongjiang Province, Northeast China, with a 27.42% morbidity rate (329/1200) and a > 25% mortality rate (85/329). Using next-generation sequencing, we comprehensively analyzed microbial diversity in the lung samples of the diseased cattle and found that the causative agent of this epidemic outbreak is mainly a bovine orthopneumovirus named BRSV strain DQ. We then isolated and confirmed the virus by RT-PCR and an indirect immunofluorescence assay. Phylogenetic analysis of genes G, F, N, NS1, NS2, and SHof BRSV strain DQ showed that this strain shares the highest genetic similarity with strains USII/S1, 15489, V41, and NY487834 belonging to subgroup III of BRSV. This is the first report of subgroup III strain of BRSV presence in China. Heilongjiang Province is a major cattle-breeding province in China; therefore, it is necessary to test for BRSV in the cattle trade and to conduct region-extended epidemiological surveillance for BRSV in China.

In this study, the chemical structure characteristics and reactivity features of three thermally altered coals with different ranks were analyzed by combining molecular modeling and molecular simulation methods to reveal and predict their chemical behaviors and properties. First, 2D molecular models of the three thermally altered coals were constructed based on X-ray photoelectron spectroscopy (XPS), solid-state 13C nuclear magnetic resonance spectroscopy (13C NMR), high-resolution transmission electron microscopy (HRTEM), and ultimate analysis data. 2D molecular models of the three thermally altered coals show different structural characteristics. 3D molecular models of the three thermally altered coals and their potential energy distributions were obtained by geometry optimization and anneal dynamics simulations. For exploring the reactivity of the three thermally altered coals with different ranks, the frontier molecular orbitals and Mulliken bond orders of the three molecular models were calculated based on quantum chemistry calculations. The frontier orbital (HOMO and LUMO) analysis results indicated that compared with the other two thermally altered coals, the thermally altered coal with Roof 8.32% had higher reactivity in electrophilic or nucleophilic reactions. The bond order results provided detailed information on the active sites of the three thermally altered coal molecules, thereby predicting the thermal behaviors of the three thermally altered coals. These works can provide a theoretical basis for the industrial utilization of thermally altered coal. Meanwhile, these three models will be used in the future to study the combustion, pyrolysis, and graphitization mechanisms of thermally altered coals by reactive molecular dynamics methods.

The purpose of this study was to investigate lipase-catalysis bioprocess in the application of sensory enhancement upon modified skim milk products. Through the comparison of various experimental elements, an optimal lipase-catalysis protocol for flavor rich milk was set, which was to catalyze pasteurized whole milk under the experimental parameters of reaction temperature 55 °C, reaction time 3 h, Lipozyme TLIM 3.0 U/mL, alcohol 135.00 μL/100 mL by a molar ratio of mpropanediol:methanol= 3:2. Then, the acquired flavor rich milk was partially utilized into the preparation of modified skim milk products. The results from volatile compositional analysis showed that high amounts of volatiles could be yielded in modified skim milk products, which can be amounted to 394.39 μg/L, mainly including short-chain fatty acids, fatty acid esters, methyl ketones, alkanes and aldehydes. Descriptive sensory results showed that the advantageous volatile characters of modified skim milk products were intensified and favorable in the sensory traits of milk flavor and mouthfeel, yet with some defects.

This paper addresses the problem of consensus-based state estimation for interval type-2 Takagi–Sugeno (T–S) fuzzy time-delay systems over a wireless sensor network under deception attacks, partial information exchange and switching sensor-network topologies. The switching-topology-dependent estimators are constructed using interval type-2 fuzzy models considering the cases where the premise variables are available and unavailable. By means of the mode-dependent dwell time approach, sufficient conditions are established such that the estimation error system is exponentially and ultimately bounded. In addition, a fuzzy Lyapunov functional is utilized to derive the existence conditions of estimators for the case that the premise variable are unavailable. Two illustrative examples are provided to verify the effectiveness of the proposed method.

Herein, we synthesize the thiophene tetraphenylethene-based conjugated microporous polymer (ThT-CMP) using the tetraphenylethylene derivative [i.e., 1,1,2,2-tetrakis(4-bromophenyl)ethane (TPBE)] and 2,5-thiophenediboronic acid as the precursors. The aggregation of TPBE in the ThT-CMP can induce a strong dual-band bipolar electrochemiluminescence (AIECL) emission at 554 nm (anodic) and 559 nm (cathodic) with tri-n-propylamine (TPrA) and S2O82–as the coreactants, respectively. The anodic and cathodic ECL efficiencies are measured to be 11.49 and 3.82% with respect to the standard of the Ru(bpy)32+/TPrA system, respectively. We further develop a dipolar ECL sensor to sensitively detect rhodamine B (RhB) based on resonance energy transfer. This ECL sensor possesses a large dynamic range and high sensitivity. This research provides a new avenue of designing organic structures with the characteristic of bipolar AIECL for the development of luminescent devices.

Bovine casein, particularly α-casein, is a common source of allergenic epitopes that trigger adverse immune responses in susceptible individuals. In this study, we developed a method to significantly reduce the antigenicity of α-casein by combining hydrolysis with yeast and alkaline proteases. enzyme-linked immunosorbent assay, liquid chromatography coupled with tandem mass spectrometry, Tricine-SDS-PAGE, and electronic tongue were employed to assess the products of two-step hydrolysis. Infant and child allergy serum was used to evaluate IgE binding capacity. The serum IgE inhibition rate of the hydrolysate was 23.55% and the antigenicity of α-casein decreased by 81.40%. The bitterness and astringency produced during hydrolysis are also reduced. These results indicate that the combined hydrolysis of Clavispora lusitaniaeDPU-MWFCl-D2 with an alkaline protease enhances the breakdown of allergenic epitopes, striking a balance between diminished antigenicity and good taste. This study provides a potential solution for developing hypoallergenic dairy products.

Na-ion batteries are considered as promising battery systems for large-scale energy storage. Although Na-ion batteries exhibit enhanced low-temperature cycling performance compared with lithium-ion batteries, there is still a great challenge to overcome for practical low-temperature applications. In this work, we propose a low-performance Na-ion battery composed of FeNi co-doped Mn-based Prussian cathode (FeNi-MnHCF) and a low-concentration electrolyte (0.5 mol L−1) containing a small amount of 2,2,2-trifluoroethyl acetate (ETFA, 1 wt%). The introduction of ETFA could decrease the viscosity, increase ionic conductivity and change the solvation structure of the electrolyte at low temperature. ETFA could also participate in constructing a uniform, stable, and Na-ion conductive CEI layer, enabling rapid Na-ion transport and effective protection of FeNi-MnHCF. The cells with the ETFA-contained electrolyte and FeNi-MnHCF cathode exhibit excellent rate capability and long cycle life at low temperature. When being cycled at −20 °C, the cell with ETFA could retain 92.1 % of the capacity after 1120 cycles at 1 C. The cell could also show stable cycling after overcharge to 4.8 Vor overdischarge to 1.2 V at −20 °C. This work sheds light on the design of long-life and robust Na-ion batteries for sustainable energy storage at low temperature.

Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here we show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, we found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptors tyrosine kinases can trigger Rpt2–Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2–Y439 in vitro and negatively regulates 26S proteasome activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase nonreceptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2–Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anticancer therapies.

To estimate the sex differences in the prevalence of overweight and obesity aged 20–89 in Chinese patients with type 2 diabetes (T2D).811,264 patients with T2D from six hospital-based, cross-sectional studies, and 46,053 subjects from the general population were included in our analysis. Prevalence of underweight, overweight, obesity were calculated in each sex.In patients with T2D, the standardized prevalence of underweight (BMI <18.5 kg/m2), overweight (24 kg/m2≤ BMI < 28 kg/m2), and general obesity (BMI ≥28 kg/m2) were 2.2%, 43.2%, and 11.6%, respectively. Similar trend patterns of the prevalence of underweight and overweight were observed in general and T2D population, in males and females with T2D (all Pfor trend <0.01). In patients with T2D, patients at a younger age and older age were more likely to be underweight. The prevalence of overweight increased first, then stabilized or decreased with age. However, different trend patterns of the prevalence of obesity in males and females were found. In males, the prevalence of obesity decreased first, and then stabilized after 60 years of age. In females, the prevalence of obesity decreased first, then increased after 50 years of age. In the general population, the prevalence of obesity increased with age in females, while, the trend of prevalence of obesity with age in males was not obvious.Different trends in the prevalence of obesity with age in different sex were found in Chinese patients with T2D.

Comprehensive profiling of humoral antibody response to severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) proteins is essential in understanding the host immunity and in developing diagnostic tests and vaccines. To address this concern, we developed a SARS-CoV-2 proteome peptide microarray to analyze antibody interactions at the amino acid resolution. With the array, we demonstrate the feasibility of employing SARS-CoV-1 antibodies to detect the SARS-CoV-2 nucleocapsid phosphoprotein. The first landscape of B-cell epitopes for SARS-CoV-2 IgM and IgG antibodies in the serum of 10 coronavirus disease of 2019 (COVID-19) patients with early infection is also constructed. With array data and structural analysis, a peptide epitope for neutralizing antibodies within the SARS-CoV-2 spike receptor-binding domain’s interaction interface with the angiotensin-converting enzyme 2 receptor was predicted. All the results demonstrate the utility of our microarray as a platform to determine the changes of antibody responses in COVID-19 patients and animal models as well as to identify potential targets for diagnosis and treatment.

We performed an in-depth proteomics analysis of serum of early COVID-19 patients using a high-density antibody microarray. We identified a large set of differentially expressed proteins (n= 132) that constitute a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways were observed. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Developing new photoactive materials and electrode preparation technology with high stability, repeatability, easy fabrication, and a low electron–hole recombination rate is promising for ideal photoelectrochemical (PEC) biosensors, but it remains a great challenge. Here, a porous and crystalline oriented two-dimensional (2D) ultrathin covalent organic framework film (D-TA COF film) was formed in situon indium-doped tin oxide (ITO) substrates under very mild conditions. The structure and morphology of D-TA COF film were characterized by means of Raman spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, and powder X-ray diffraction. Compared with the randomly oriented D-TA COF powder drop-coated on ITO, the photocurrent of the D-TA COF film grown on the ITO surface in situachieved as high as ∼333-fold increase. This photocurrent can be further amplified by O2(acting as electron acceptors). Benefiting from the fabrication in situ, D-TA COF film also exhibited tough adhesion, assuring the film was difficult to separate from the electrode. Accordingly, D-TA COF film was applied as the photoactive material to build a PEC biosensor for H2O2detection based on coupling with large amounts of catalase (CAT) through simple adsorption. The introduced CAT catalyzed the decomposition of H2O2to O2, leading to an enhancement of the photocurrent response. As a result, a “signal-on” PEC biosensor was fabricated with good sensitivity, rapid response, and high stability, and it can also detect H2O2released from living cells. Taking into account these advantages, the D-TA COF film is expected to be an ideal photoactive material to construct various PEC biosensors, which as far as we know have not been reported.

ABSTRACTBackgroundA novel nanoemulsion (CU/FU-LN) was developed as an oral 5-fluorouracil and curcumin co-delivery system for synergistic efficacy against liver cancer.MethodsMTT assay, confocal laser scanning microscope, and H&E staining were utilized to establish the efficacy and safety of CU/FU-LN.ResultsThe AUC(0-t)of CU/FU-LN was 8.85-fold and 8.59-fold greater than those of CU and FU, respectively. The IC50of CU/FU-LN was 4.6-fold and 4.9-fold lower than those of FU and CU in HepG2 cells, respectively. In vivo anti-tumor trials, the tumor inhibition rate was significantly elevated by CU/FU-LN (49.29%), compared 24.84% and 4.72% for FU and CU, respectively. Ki-67 immunohistochemical analysis revealed that CU/FU-LN had an obvious anti-proliferation effect. The IC50of CU/FU-LN in L02 cells was 1.51-fold and 2.60-fold higher than those of CU and FU, respectively. Certain vital organs in the mice of the CU/FU-LN group showed markedly fewer lesions than those of the CU, FU, and CU+FU groups. The CU/FU-LN treatment caused no significant change in mouse body weight relative to the control group (P> 0.05). ConclusionsWe successfully prepared a promising co-delivery platform for the synergistic treatment of liver cancer and it has a comparatively enhanced efficacy and mitigated toxicity.

Recently, several types of lead halide perovskites have been demonstrated as active layers in resistive switching memory or artificial synaptic devices for neuromorphic computing applications. However, the thermal instability and toxicity of lead halide perovskites severely restricted their further practical applications. Herein, the environmentally friendly and uniform Cs3Cu2I5perovskite films are introduced to act as the active layer in the Ag/Cs3Cu2I5/ITO memristor. Generally, the Ag ions could react with iodide ions and form AgIxcompounds easily, so the Ag/PMMA/Cs3Cu2I5/ITO memristor was designed by employing the ultrathin polymethylmethacrylate (PMMA) layer to avoid the direct contact between the top Ag electrode and Cs3Cu2I5perovskite films. After optimization, the obtained memristor demonstrated bipolar resistive switching with low operating voltage (< ±1 V), large on/off ratio (102), stable endurance (100 cycles), and long retention (>104s). Additionally, biological synaptic behaviors including long-term potentiation and long-term depression have been investigated. By using the MNIST handwritten recognition data set, the handwritten recognition rate based on experimental data could reach 94%. In conclusion, our work provides the opportunity of exploring the novel application for the development of next-generation neuromorphic computing based on lead-free halide perovskites.

Salmonellais a common cause of foodborne disease worldwide, including Australia. More than 85% of outbreaks of human salmonellosis in Australia were caused by five Salmonellaserovars. Rapid, accurate, and sensitive identification of Salmonellaserovars is vital for diagnosis and public health surveillance. Recently, an isothermal amplification technique, termed multiple cross-displacement amplification (MCDA), has been employed to detect Salmonellaat the species level. Herein, seven MCDA assays were developed and evaluated for rapid detection and differentiation of the five most common Salmonellaserovars in Australia: Typhimurium, Enteritidis, Virchow, Saintpaul, and Infantis. MCDA primer sets were designed by targeting seven serovar/lineage-specific gene markers identified through genomic comparisons. The sensitivity and specificity of the seven MCDA assays were evaluated using 79 target strains and 32 nontarget strains. The assays were all highly sensitive and specific to target serovars, with the sensitivity ranging from 92.9% to 100% and the specificity from 93.3% to 100%. The limit of detection of the seven MCDA assays was 50 fg per reaction (10 copies) from pure DNA, and positive results were detected in as little as 8 minutes. These seven MCDA assays offer a rapid, accurate, and sensitive serotyping method. With further validation in clinically relevant conditions, these assays could be used for culture-independent serotyping of common Salmonellaserovars directly from clinical samples.

Objective:To summarize the clinical experience of Professor Liangduo Jiang in the prevention and control of the new coronavirus disease COVID-19.Methods:Between January 2020 and February 2020, 87 subjects who have had contact with patients tested positive for COVID-19 in an isolated observation site in Tianjin were given the Chinese medicine prescription for prevention prescribed by Professor Liangduo Jiang continuously for three days. Their basic information, clinical manifestations and medication adherence were statistically analyzed, and the clinical manifestations, temperature changes and infection status after medication were summarized.Results:After the 14-day isolation observation period, only one patient who had close contact with confirmed patients developed a positive test for COVID-19 after taking the preventive Chinese medicine prescription, with the infection rate of 1.149%.Conclusion:The preventive treatment by Professor Liangduo Jiang is effective in the prevention and control of the epidemic.

The efficient fabrication of multifunctional nanoplatforms for bacterial detection and elimination is of great importance in nanobiotechnology. A new porphyrin-based porous organic polymer, FePPOPBFPB, was synthesized via the reaction between pyrrole and 4-{2,2-bis[(4-formylphenoxy)methyl]-3-(4-formylphenoxy) propoxy} benzaldehyde (BFPB). The C-centric tetrahedral structure of BFPB promoted the formation of FePPOPBFPBwith a 3D interconnected porous structure, high specific surface area, and plentiful surface catalytic active sites. The adjustable structural alkyl chain also enhanced the absorption capability of FePPOPBFPBin the long-wavelength visible and near-infrared regions (NIR). FePPOPBFPBexhibited excellent peroxidase-like activity toward a representative peroxidase substrate, 3,3′,5,5′-tetramethylbenzidine (TMB) with H2O2. Utilizing these features, a rapid and visual detection of Staphylococcus aureus(S. aureus) based on FePPOPBFPBwas established and exhibited high sensitivity and stability. Combining the catalysis with near-infrared-light (NIR) absorption, FePPOPBFPBcan effectively catalyze the decomposition of biologically relevant concentrations of H2O2to produce vast amounts of •OH radicals via the photo-Fenton reaction, which avoids the utilization of high toxic concentrations of H2O2. On the basis of these satisfactory features, FePPOPBFPBhad a conspicuous bactericidal performance against S. aureusunder NIR irradiation. To our knowledge, this is the first example of a porphyrin-based porous organic polymer antibacterial agent. The main reactive oxygen species (ROS) produced in this system and the possible antibacterial mechanism of FePPOPBFPBwas also proposed through a series of experiments.