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Background and Objective: Exenatide promotes insulin secretion and inhibits postprandial glucagon secretion. Polyethylene glycolated exenatide injection (PB-119), a derivative obtained by modification of exenatide, is more stable in metabolic behavior than exenatide in vivo. Our study aimed to evaluate the safety, tolerability and pharmacokinetic characteristics of polyethylene glycolated exenatide as a single subcutaneous injection in healthy volunteers. Methods: Seventy subjects were randomly assigned to 8 incremental dosage groups (2, 5, 10, 25, 50, 100, 200 and 400 µg). The 2- to 50-µg groups had 8 subjects in each group (the ratio of test preparation to placebo was 3:1), and the 100- to 400-µg groups had 10 subjects in each group (the ratio of test preparation to placebo was 4:1). All the subjects received a single subcutaneous injection of polyethylene glycolated exenatide and placebo according to the dosage groups. The tolerability test was conducted in the 2- to 10-µg groups. The pharmacokinetic test was carried out in the 25- to 400-µg groups, and plasma samples were collected to determine the pharmacokinetics of polyethylene glycolated exenatide. After medication, the vital signs of the subjects were monitored, and laboratory tests and electrocardiogram tests were carried out regularly in all the subjects. Results: All 70 subjects completed the experiment. Except for the 5-µg and 10-µg groups, the safety and tolerability tests showed no adverse reactions in the 2-µg to 50-µg groups. Several subjects in the 100-µg and 200-µg groups had tolerable gastrointestinal tract reactions, and all subjects in the 400-µg group experienced adverse reactions, mainly gastrointestinal tract reactions and liver dysfunction. The pharmacokinetics of polyethylene glycolated exenatide was studied in 36 subjects, which showed slow absorption, a mean peak time of 20–40 h, and a mean elimination half-life of 51–64 h. Conclusion: The administration of polyethylene glycolated exenatide injection at a single dose of 2–200 µg is safe and tolerable for healthy volunteers. Once-weekly polyethylene glycolated exenatide injection can be recommended. Clinical Trials Registration: The study was registered at clinicaltrials.gov (No. NCT02084251).

Nonapoptotic ferroptosis is a promising cancer treatment which offers a solution to the multidrug resistance of conventional apoptosis-induced programmed cancer cell death therapies. Reducing intracellular glutathione (GSH) is essential for inducing excess ROS and has been considered a crucial process to trigger ferroptosis. However, treatments reducing GSH alone have not produced satisfactory effects due to their restricted target. In this regard, FeCDs (Fe3+-modified l-histidine -sourced carbon dots) with dual GSH-consumption capabilities were constructed to engineer ferroptosis by self-amplifying intratumoral oxidative stress. Carbon dots have the ability to consume GSH, and the introduction of Fe3+can amplify the GSH-consuming ability of CDs, reacting with excess H2O2in the tumor microenvironment to generate highly oxidized •OH. This is a novel strategy through synergistic self-amplification therapy combining Fe3+and CDs with GSH-consuming activity. The acid-triggered degradation material (FeCDs@PAE–PEG) was prepared by encapsulating FeCDs in an oil-in-water manner. Compared with other ferroptosis-triggering nanoparticles, the established FeCDs@PAE–PEG is targeted and significantly enhances the consumption efficiency of GSH and accumulation of excess iron without the involvement of infrared light and ultrasound. This synergistic strategy exhibits excellent ferroptosis-inducing ability and antitumor efficacy both in vitro and in vivo and offers great potential for clinical translation of ferroptosis.

A novel three-component Pd/norbornene cooperative catalysis cascade decarboxylative [2+2+2]/[2+2+3]cyclization of 4-iodoisoquinolin-1(2H)-ones and o-bromobenzoic acids or 8-bromo-1-naphthoic acid has been developed. The method affords a range of fused phenanthridinones and hepta[1,2-c]isoquinolinones and displays unique regioselectivity and broad substrate scope. Palladium/norbornene (Pd/NBE)-catalyzed C–H activation and subsequent decarboxylative coupling reactions were involved, and NBE acts as a building block for the construction of rigid nonplanar molecular architectures.

Photochemical methods are effective for controllable synthesis of silver nanoparticles with specific sizes and shapes. Whether they are capable of fabricating Ag nanoclusters (NCs) with atomic precision is yet to be proved. In this work, we synthesize an atomically precise Ag NC, [Ag25(4-MePhC≡C)20(Dpppe)3](SbF6)3(Ag25), viaa process mediated by visible light. Its total structure is determined by X-ray crystallography. The investigation of the mechanism reveals that the formation of Ag25is triggered by a photoinduced electron-transfer (PET) process. An electron of certain amines is excited by light with wavelength shorter than 455 nm and transferred to Ag+. The amine is oxidized to the corresponding amine N-oxide. Such a PET process is supported by experimental and density functional theory studies. To expand the application scope of the photochemical method, another three NCs, [Ag19(4-tBuPhC≡C)14(Dpppe)3](SbF6)3(Ag19), [Ag32(4-tBuPhC≡C)22(Dppp)4](SbF6)3(Ag32), and bimetallic [Ag22Au3(4-tBuPhC≡C)20(Dpppe)3](SbF6)3(Ag22Au3), are produced by replacing certain ingredients. Furthermore, since the formation of Ag19can be regarded as a photochromatic process, a facile amine visual detection method is also presented based on this mechanism.

The development and the synthetic applications of a novel class of diphosphine ligands (SPSiPs) based on chiral spirosilabiindane diol (SPSiOL) are presented. Starting from SPSiOL, the diphosphine ligands could be readily prepared in three steps with high efficiency. This novel class of diphosphine ligands features rigid configuration, a large dihedral angle, a large P–M–P angle, and a long P–P distance. The potentials of SPSiPs in asymmetric catalysis have also been preliminarily disclosed.

SHR4640, also named as ruzinurad, is a selective human urate transporter 1 (URAT1) inhibitor developed for the treatment of hyperuricemia and gout. This study evaluated the high‐fat, high‐calorie food effect on the pharmacokinetics and pharmacodynamics of SHR4640 in healthy Chinese male volunteers. In this open‐label, randomized, 2‐period crossover phase 1 trial, 14 healthy male subjects were randomized to receive a single 10‐mg dose of SHR4640 under both fasted and fed conditions. The washout period was 7 days. Blood samples were collected for pharmacokinetic and pharmacodynamic analysis. Pharmacokinetic parameters were analyzed by a noncompartmental method. The safety of the drug was also evaluated in the trial. A total of 14 healthy male volunteers were enrolled in the study, and finally 13 healthy volunteers completed the study. A single 10‐mg dose of SHR4640 was safe and well tolerated in healthy Chinese male volunteers. After single‐dose administration of SHR4640, the 90%CIs of the geometric mean ratios of the area under the plasma concentration–time curve from time 0 to the last quantifiable concentration and the area under the plasma concentration–time curve from time 0 to infinity were within the equivalence criteria of 0.80‐1.25. The 90%CIs of maximum plasma concentration was slightly outside the lower limit of bioequivalent criteria, with about 13.40% decrease in the fed versus fasted condition. The time to maximum concentration was slightly delayed under the fasted condition. A single 10‐mg dose of SHR4640 was safe and well tolerated in this trial. The main pharmacokinetic parameters and serum uric acid lowering of SHR4640 were not affected by food effect; thus, SHR4640 can be recommended to be administered with or without food

Photo composition is one of the most important factors in the aesthetics of photographs. As a popular application, composition recommendation for a photo focusing on a specific subject has been ignored by recent deep-learning-based composition recommendation approaches. In this paper, we propose a subject-aware image composition recommendation method, SAC-Net, which takes an RGB image and a binary subject window mask as input, and returns good compositions as crops containing the subject. Our model first determines candidate scores for all possible coarse cropping windows. The crops with high candidate scores are selected and further refined by regressing their corner points to generate the output recommended cropping windows. The final scores of the refined crops are predicted by a final score regression module. Unlike existing methods that need to preset several cropping windows, our network is able to automatically regress cropping windows with arbitrary aspect ratios and sizes. We propose novel stability losses for maximizing smoothness when changing cropping windows along with view changes. Experimental results show that our method outperforms state-of-the-art methods not only on the subject-aware image composition recommendation task, but also for general purpose composition recommendation. We also have designed a multistage labeling scheme so that a large amount of ranked pairs can be produced economically. We use this scheme to propose the first subject-aware composition dataset SACD, which contains 2777 images, and more than 5 million composition ranked pairs. The SACD dataset is publicly available at https://cg.cs.tsinghua.edu.cn/SACD/.

Chemoresistance and relapse are the leading cause of AML-related deaths. Utilizing single-cell RNA sequencing (scRNA-seq), we dissected the cellular states of bone marrow samples from primary refractory or short-term relapsed AML patients and defined the transcriptional intratumoral heterogeneity. We found that compared to proliferating stem/progenitor-like cells (PSPs), a subpopulation of quiescent stem-like cells (QSCs) were involved in the chemoresistance and poor outcomes of AML. By performing longitudinal scRNA-seq analyses, we demonstrated that PSPs were reprogrammed to obtain a QSC-like expression pattern during chemotherapy in refractory AML patients, characterized by the upregulation of CD52 and LGALS1 expression. Flow cytometric analysis further confirmed that the preexisting CD99+CD49d+CD52+Galectin-1+(QSCs) cells at diagnosis were associated with chemoresistance, and these cells were further enriched in the residual AML cells of refractory patients. Interaction of CD52-SIGLEC10 between QSCs and monocytes may contribute to immune evading and poor outcomes. Furthermore, we identified that LGALS1 was a promising target for chemoresistant AML, and LGALS1 inhibitor could help eliminate QSCs and enhance the chemotherapy in patient-derived primary AML cells, cell lines, and AML xenograft models. Our results will facilitate a better understanding of the AML chemoresistance mechanism and the development of novel therapeutic strategies for relapsed/refractory AML patients.

To date, the extremely high polarity and poor signal intensity of macromolecular nucleic acids are greatly impeding the progress of mass spectrometry technology in the quality control of nucleic acid drugs and the characterization of DNA oxidation and RNA modifications. We recently described a general N-(tert-butyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) labeling method for oligonucleotide determination and applied it to the full-range profiling of tRNA in vitro and in vivo studies for the first time. The primary advantages of this method include strong retention, no observable byproducts, predictable and easily interpreted MS2data, and the circumvention of instrument harmful reagents that were necessary in previous methods. Selective labeling of N-(tert-butyldimethylsilyl)-N-methyl-trifluoroacetamide to the terminal phosphate groups of oligonucleotides endows it broadly applicable for DNA/RNA profiling. Moreover, the improvement of sequence coverage was achieved in yeast tRNAphe(GAA)analysis owing to this method’s good detection capability of 1–12 nucleotides in length. We also extended this strategy to determine the abundance of modified bases and discover new modifications via digesting RNA into single-nucleotide products, promoting the comprehensive mapping of RNA. The easy availability of derivatization reagent and the simple, rapid one-step reaction render it easy to operate for researchers. When applied in characterizing tRNAs in HepG2 cells and rats with nonalcoholic fatty liver disease, a fragment of U[m1G][m2G], specific for tRNAAsn(QUU)in cells, was significantly upregulated, indicating a possible clue to nonalcoholic fatty liver disease pathogenesis.

Continuous complete power range monitoring of the performance of permanent in-core neutron detectors is needed to lessen the monitoring burden placed on operations engineers, reduce operational risk, and improve reactor safety. Current monitoring systems only target a subset of anomaly types and often require costly expert knowledge to develop and maintain due to the challenges involving complexity and unpredictability. A high prediction accuracy of the virtual redundancy model based on the XGBoost algorithm is proposed to detect in-core neutron detector abnormalities. The model is trained on healthy samples only, and it uses the complex relationships between the output currents of the in-core neutron instruments to improve prediction accuracy and reduce complexity. Different types of multiple in-core neutron detector abnormalities are presented, and the appropriate fault threshold is set to improve the robustness of the model when detecting multiple faults. Additionally, the relationship between the virtual redundancy model and the number of faulty in-core neutron detectors has been elaborated.

As a new generation of photovoltaic devices, organic polymer solar cell (Organic Solar Cell, OSC) have attracted wide attention of researchers in recent years because of their unique advantages such as simple process, low energy consumption, low cost and large area preparation. However, the development of OSC has encountered bottlenecks: the low carrier mobility of photovoltaic materials forces the thickness of the active layer of OSC to be reduced as much as possible to meet the requirements of effective collection of photogenerated carriers, while the thinner absorption layer will lead to serious optical absorption loss and device performance degradation. Therefore, how to enhance the optical absorptivity of OSC on the premise of effective carrier collection has become a research hot-spot. Based on this characteristic, with the help of finite element method, the structure model of OSC with multi-tip metal nanoparticles is established, and the effects of metal nanospheres and star particles on OSC light absorption factors are studied systematically. Firstly, the effects of introducing metal nanoparticles into different functional layers of OSC (active layer and buffer layer) are compared and analyzed to determine the introduction location of metal nanoparticles in OSC. Secondly, the localized resonance enhancement rules of spherical and cubic metal nanoparticles in the functional layer are discussed. Combined with the theoretical model, the optimal design method of metal nanoparticles structure parameters (size and period) is established. The results show that the absorption enhancement of metal nanoparticles in the active layer of OSC is higher than that in the buffer layer. On the one hand, it can stimulate more electron hole pair separation, improve the separation rate of electron hole pair, on the other hand, it can also make the separated electron hole to obtain more energy, recombination becomes relatively difficult, and the arrival rate of the battery electrode is improved.

The study aimed to examine the indirect factors underlying the association between work–family conflict and posttraumatic stress symptoms (PTSS) in college teachers during the COVID‐19 pandemic. Three potential indirect factors were examined: perceived stress, basic psychological needs, and rumination. A total of 274 college teachers were recruited. All participants completed an electronic questionnaire that assessed their exposure to the pandemic, work–family conflict, perceived stress, basic psychological needs, rumination, and PTSS. The results showed that after controlling for pandemic exposure, gender, and age, work–family conflict was associated with PTSS via perceived stress alone, rumination alone, a path from perceived stress to basic psychological needs, and a path from perceived stress to rumination. These results indicate that work–family conflict is positively associated with PTSS indirectly via perceived stress, rumination, and basic psychological needs during the COVID‐19 pandemic. These three mediators may completely explain the relation of work–family conflict to PTSS.

Youkenafil hydrochloride is a novel selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Its safety, tolerability, and pharmacokinetics were evaluated in healthy Chinese male volunteers. In addition, this study explored the effect of food on the pharmacokinetic parameters of youkenafil hydrochloride. The study was divided into 3 trials: a single ascending dose (25, 50, 100, 150, or 200 mg youkenafil), multiple dose (50, 100, or 150 mg youkenafil once daily for 7 consecutive days), and food effect (50 mg youkenafil single dose). The overall tolerability of youkenafil was good. Youkenafil was rapidly absorbed after a single oral dose. Food intake impeded absorption efficiency but had no significant effect on area under the plasma concentration–time curve values. The mean accumulation ratio in area under the plasma concentration–time curve and maximum plasma concentration ranged from 1.3 to 1.6 and from 1.2 to 1.4 after once‐daily dosing. There was no apparent accumulation following consecutive administration for 7 days. Less than 1% of the dose was found in urine as the intact drug for all dose groups. Single‐dose youkenafil up to 200 mg and multiple doses up to 150 mg were generally safe and well tolerated.

Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitroand in vivo.Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

On the basis of the structure of nicotlactone A (L1), a series of novel α-methylene-γ-butyrolactone derivatives B1–B43were designed and synthesized by structure simplification and active fragment replacement strategies, and their antiviral and antifungal activities were evaluated. The bioassay studies indicated that many target compounds possessed good to excellent antiviral activity against tobacco mosaic virus (TMV) and some of these compounds exhibited specific antifungal activities against Valsa maliand Fusarium graminearum. Compound B32exhibited the best anti-TMV activity (inactivation effect, 88.9%; protection effect, 65.8%; curative effect, 52.8%) in vivoat 500 mg/L, which is significantly higher than that of commercial virucides ribavirin and ningnanmycin. The inhibition effect of compound B32was also visualized by the inoculation test using green fluorescent protein (GFP)-labeled TMV. The preliminary antiviral mechanism of compound B32was investigated. Transmission electron microscopy (TEM) showed that compound B32could destroy the integrity of virus particles. Then, molecular docking and isothermal titration calorimetry (ITC) analysis further demonstrated that compound B32exhibited a strong binding affinity to the TMV coat protein with a dissociation constant (Kd) of 3.06 μM, superior to ribavirin. Thus, we deduced that compound B32may interfere with the self-assembly of TMV particles by binding TMV coat protein (CP). In addition, compound B28showed good in vitroactivity against F. graminearumwith an inhibition rate of 90.9% at 50 mg/L, which was greater than that of fluxapyroxad (59.1%) but lower than that of the commercial fungicide carbendazim (96.8%). The present study provides support for the application of these α-methylene-γ-butyrolactone derivatives as novel antiviral and antifungal agents in crop protection.

Drought stress is one of the main limiting factors in apple (Malus domesticaBorkh.) cultivation. Rootstock plays an important role in the drought tolerance of apple plants. ‘M.9-T337’ is a novel apple rootstock that was recently introduced and widely cultivated in China. In this study, we selected the new, widely promoted Chinese apple variety ‘Huashuo’ as the scion and grafted it onto ‘M.9-T337’ (HM9). Another combination, ‘Huashuo’/‘M.26’/Malus robustaRehd. (HM26), served as the experimental control to analyse drought resistance in the two hybrids. We believe that this empirical approach is more representative than merely studying rootstock seedlings. After sustained drought stress for over 1 month, the leaf relative water content had decreased in both types of plants, but to a lesser extent in HM26 than in HM9. The SPAD values increased in both plants, but without significant difference. Drought stress reduced photosynthetic activity in both plants, and the net photosynthetic rate was higher in HM26 than in HM9. The observed changes in the chlorophyll fluorescence parameters indicated that drought had damaged the PSII activity centres of both plants, photosynthetic electron transfer was inhibited, and excessive excitation energy accumulated. However, compared to HM26, HM9 displayed lower maximal PSII quantum photochemical efficiency and potential PSII activity. Moreover, HM9 showed lower antioxidant enzyme activity than HM26 under drought stress. A membership function analysis confirmed that ‘M.9-T337’ was less drought resistant than ‘M.26’. Nevertheless, ‘M.9-T337’ could still recover after prolonged drought stress, indicating it also had good drought resistance.

The need for palliative care (PC) has gained increased attention during the COVID-19 pandemic. Palliative care adds an extra layer of support and care for patients with advanced chronic illnesses and their families. Because of pandemic restrictions, access and provision of PC services were challenging and resulted in huge suffering and caregiving burden among patients with advanced chronic illnesses and their families, especially those living in smaller towns and rural communities. The study aimed to describe the impact of COVID-19 on PC services and examine various ethical, moral, and practice issues and challenges experienced by rural providers. Using a community-based participatory research approach, a purposive sample of health care providers (n = 15) was obtained from smaller towns and rural communities in Indiana, United States. Online individual interviews were used for data collection. Thematic analysis showed several concerns including restricted visitation, communication challenges, “hard to say goodbye over iPad”, moral distress among providers, and preference for home hospice services. Findings call for strategies to implement best PC practices and programs to support providers and families in smaller towns and rural communities.

The innate cytokine IL-33 is increasingly recognised to possess biological effects on various immune cells. We have previously demonstrated elevated serum level of soluble ST2 in patients with active systemic lupus erythematosus suggesting involvement of IL-33 and its receptor in the lupus pathogenesis. This study sought to examine the effect of exogenous IL-33 on disease activity of pre-disease lupus-prone mice and the underlying cellular mechanisms. Recombinant IL-33 was administered to MRL/lpr mice for 6 weeks, whereas control group received phosphate-buffered saline. IL-33-treated mice displayed less proteinuria, renal histological inflammatory changes, and had lower serum levels of pro-inflammatory cytokines including IL-6 and TNF-α. Renal tissue and splenic CD11b+ extracts showed features of M2 polarisation with elevated mRNA expression of Arg1, FIZZI, and reduced iNOS. These mice also had increased IL-13, ST2, Gata3, and Foxp3 mRNA expression in renal and splenic tissues. Kidneys of these mice displayed less CD11b+ infiltration, had downregulated MCP-1, and increased infiltration of Foxp3-expressing cells. Splenic CD4+ T cells showed increased ST2-expressing CD4+Foxp3+ population and reduced IFN-γ+ population. There were no differences in serum anti-dsDNA antibodies and renal C3 and IgG2a deposit in these mice. Exogenous IL-33 was found to ameliorate disease activity in lupus-prone mice with induction of M2 polarisation, Th2 response, and expansion of regulatory T cells. IL-33 likely orchestrated autoregulation of these cells through upregulation of ST2 expression.

Study Design: Meta-analysis.Objective: To systematically compare the effectiveness and safety of vertebral augmentation procedure (VAP) with non-surgical management (NSM) for the treatment of osteoporotic vertebrate compression fractures (OVCFs).Methods: Systematic reviews and meta-analyses with the comparison between VAP and NSM were identified to extract randomized controlled trials from electronic database. Additionally, recently published RCTs were identified. Two researchers independently extracted the data. The primary outcome of this meta-analysis was pain relief evaluated by visual analogue scale (VAS).Results: Twenty RCTs involving 2566 patients with painful OVCFs were included. Significant differences were found between percutaneous vertebroplasty (PVP) and conservative treatment (CT) in VAS at each time point during follow-up period. The differences of VAS were not significant between PVP and sham procedure at most time points during follow-up period. In subgroup analysis based on fracture type and fracture location, significant differences of VAS were found between PVP and CT and were not found between PVP and sham procedure. In subgroup analysis of duration of back pain, significant differences were found between PVP and CT in VAS at 1 week, 3 month and 1 year. And the differences of VAS were not significant between PVP and CT at 1 month and 6 month.Conclusion: BKP is considered sufficient to achieve good clinical outcomes. PVP is associated with on beneficial effect on treatment of painful OVCFs compared with sham procedure. The indication and timing of VAP need further research. More independently high-quality RCTs with sufficiently large sample sizes reporting cost-effectiveness are needed.

We proposed and compared three methods (filter burnup, single energy burnup, and burnup extremum analysis) to build a high-resolution neutronics model for 238Pu production in high-flux reactors. The filter burnup and single energy burnup methods have no theoretical approximation and can achieve a spectrum resolution of up to ~ 1 eV, thereby constructing the importance curve and yield curve of the full energy range. The burnup extreme analysis method combines the importance and yield curves to consider the influence of irradiation time on production efficiency, thereby constructing extreme curves. The three curves, which quantify the transmutation rate of the nuclei in each energy region, are of physical significance because they have similar distributions. A high-resolution neutronics model for 238Pu production was established based on these three curves, and its universality and feasibility were proven. The neutronics model can guide the neutron spectrum optimization and improve the yield of 238Pu by up to 18.81%. The neutronics model revealed the law of nuclei transmutation in all energy regions with high spectrum resolution, thus providing theoretical support for high-flux reactor design and irradiation production of 238Pu.

ABSTRACTCystic fibrosis (CF) is one of the most common hereditary lung diseases. Pseudomonas aeruginosa(PA), Aspergillus fumigatus(AF) and Candida albicans(CA) are the principal bacterial and fungal pathogens in the airways of CF patients. The interactions of coexisting bacterial-fungal pathogens are of great interest. In the present work, we reviewed the literature of available in vitroand in vivostudies, whereas most of the reports have shown that PA inhibits the growth of fungi through restriction of iron uptake and secretion of toxic substances. Fungi may also affect the growth or virulence of PA through their secreted molecules. To clarify the bacterial-fungal interaction, more in-depth and detailed studies are still needed, which will provide a better understanding of species, microbial population dynamics, and related mechanisms in CF patients.

AbstractIn a high dominance ratio system, the problem of slow fission source convergence is faced during the Monte Carlo criticality calculation. The Wielandt method and the Superhistory method have been proven to reduce the dominance ratio. Still, the Wielandt method and the Superhistory method have also proven to be unable to accelerate the convergence of the fission source. With the estimation of errors in the cumulative fission source and the batch size optimization methodology, the optimal batch size growth for the Wielandt method and the Superhistory method is proposed. Compared with the direct simulation with the optimal batch size growth, the Wielandt simulation and the Superhistory simulation better use the optimal batch size growth. A single fuel rod model was tested, and the results show that the new method is helpful for the acceleration of fission source convergence.

The high incidence of lymphatic metastasis is closely related to poor prognosis and mortality in cancers. Potent inhibitors to prevent pathological lymphangiogenesis and lymphatic spread are urgently needed. The VEGF-C-VEGFR3 pathway plays a vital role in driving lymphangiogenesis and lymph node metastasis. In addition, COX2 in tumor cells and tumor-associated macrophages (TAMs) facilitates lymphangiogenesis. We recently reported that aiphanol, a natural stilbenolignan, attenuates tumor angiogenesis by repressing VEGFR2 and COX2. In this study, we evaluated the antilymphangiogenic and antimetastatic potency of aiphanol using in vitro, ex vivo and in vivo systems. We first demonstrated that aiphanol directly bound to VEGFR3 and blocked its kinase activity with an half-maximal inhibitory concentration (IC50) value of 0.29 μM in an in vitro ADP-GloTMkinase assay. Furthermore, we showed that aiphanol (7.5−30 μM) dose-dependently counteracted VEGF-C-induced proliferation, migration and tubular formation of lymphatic endothelial cells (LECs), which was further verified in vivo. VEGFR3 knockdown markedly mitigated the inhibitory potency of aiphanol on lymphangiogenesis. In 4T1-luc breast tumor-bearing mice, oral administration of aiphanol (5 and 30 mg· kg−1·d−1) dose-dependently decreased lymphatic metastasis and prolonged survival time, which was associated with impaired lymphangiogenesis, angiogenesis and, interestingly, macrophage infiltration. In addition, we found that aiphanol decreased the COX2-dependent secretion of PGE2 and VEGF-C from tumor cells and macrophages. These results demonstrate that aiphanol is an appealing agent for preventing lymphangiogenesis and lymphatic dissemination by synergistically targeting VEGFR3 and inhibiting the COX2-PGE2-VEGF-C signaling axis.

•Genkwanin suppressed MPP+-induced neuroinflammation and neurotoxicity in SH-SY5Y cells.•Genkwanin inactivated MPP+-induced TLR4/MyD88/NLRP3 inflammasome pathway in SH-SY5Y cells.•Genkwanin attenuated neuroinflammation and neurotoxicity by inhibiting TLR4/MyD88/NLRP3 inflammasome pathway.

Polynitrogen heterocycles are readily available and have recently arisen as versatile synthons for the formation of various C–C and C–X bonds, and medicinally active nitrogen-containing heterocycles. Several cascade reactions, including annulation, radical cascade, and borylation reactions, have been reported in which polynitrogen heterocycles are applied as arylation reagents. The success of these exceptional reactions illustrates the great synthetic potential of polynitrogen heterocycles, which provides a direct and useful approach to arylation reactions and the synthesis of nitrogen-containing heterocycles. The use of photocatalysts to effectively transfer energy from visible light to non-absorbing compounds has gained increasing attention as this method allows for the mild and efficient generation of radicals in a controlled manner. This approach has thus led to new methods that involve unique bond formation reactions. In addition, the use of free radical intermediates stabilized by transition metal catalysts is a powerful way to construct new chemical bonds. The aim of this review is to highlight the rapidly expanding area of radical-initiated denitrogenative cascade reactions of polynitrogen heterocycles and elaborate on their mechanisms from a new perspective by using photocatalysis and metal-based catalysis.

Cardiotoxicity has been one of the most common causes of withdrawal of drugs from the market, and prolongation of the QT interval is one of the manifestations of drug cardiotoxicity. Iptakalim hydrochloride (ITKL) is a selective ATP‐sensitive potassium channel opener used to treat hypertension. It is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. A randomized, double‐blind, placebo‐controlled single‐ and multidose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5, 10, 15, and 20 mg with single oral administration and 10 and 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. A ΔΔQTcF effect above 10 milliseconds was excluded at all observed plasma levels. Among them, the highest dose was 20 mg, which is twice the therapeutic dose. We concluded that ITKL did not prolong the QT interval in healthy subjects within the therapeutic dose. Retrospectively registered: The study was registered at Chinese Clinical Trial Registry with registration number ChiCTR1800014466.

Byline: Yun-Lin. Cai, Yun-Chun. Zou, Jia-Hong. Lei, Guan-Peng. Zeng, Ying. Wang Purpose: The aim of this study is to preliminarily investigate the expression of mitochondrial fusion protein 1 (MFN1) in [...]

Byline: Yang. Shen, Xiao-Yu. Zhang, Xi. Chen, Mu-Lan. Ren, Yun-Lang. Cai Objective: To study the anti-tumor effects of octreotide on A2780/Taxol ovarian cancer cells in vitro, and further explore its [...]

S100 calcium binding protein P (S100P) and miR‐495 are aberrantly expressed and exert essential roles in cancers. However, the mechanisms of miR‐495‐S100P in pancreatic cancer are yet to be illustrated. Thus, we explored the regulatory functions of miR‐495‐S100P axis in pancreatic adenocarcinoma cells growth and invasion. In this study, we identified that S100P was upregulated in pancreatic adenocarcinoma by bioinformatics analysis of the GEO (Gene Expression Omnibus database) microarray dataset (GSE16515). Western blotting and luciferase reporter gene analysis exhibited that miR‐495 negatively determined the level of S100P via binging to its 3′‐untranslated regions (3′‐UTRs). A series of functional experiments indicated that upregulation of miR‐495 or S100P knockdown suppressed pancreatic adenocarcinoma cells proliferation, invasion, and promoted apoptosis. Furthermore, the expression of S100P was negatively associated with the level of miR‐495 in The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma case‐cohort. Besides, reintroduction of S100P debilitated the anti‐cancer action of miR‐495 in pancreatic adenocarcinoma cells. Our data indicated that miR‐495 performed suppressive roles in pancreatic adenocarcinoma through targeting S100P.

Graphene coating is a new type of coating made by using the unique structural properties of graphene. It has broad application prospects of anticorrosive coatings, conductive coatings and heat-dissipating coatings. In order to study the development of graphene coating technology research, we use CiteSpace information visualization software, based on the literature of 8 813 articles in the research and application of graphene coatings in Web of Science database from 2010 to 2018. From the perspective of literature measurement, we apply the knowledge map to research the national, discipline and related hotspot analysis of graphene coating research, cited literatures and research frontier status. By comparing and analyzing the literature information on the field of graphene coating research and application at home and abroad, the research progresses and development trend of graphene coatings can be evaluated from the disciplinary distribution and research fronts. It is pointed out that the wear resistance of graphene coatings is the focus of the future research.

•Acute bacterial skin and skin-structure infections (ABSSSIs) are a significant healthcare burden.•Oritavancin (ORI) is the only single-dose antibiotic approved by the FDA for treatment of ABSSSIs.•This study evaluated the efficacy and safety of single-dose ORI for patients with ABSSSIs.•ORI was non-inferior, if not improved, to its comparators, indicating a better optimal antibiotic selection.

The direct double dehydrogenation from primary amines to nitriles without an oxidant or hydrogen acceptor is both intriguing and challenging. In this paper, we describe a non-noble metal catalyst capable of realizing such a transformation with high efficiency. A cobalt-centered N,N-bidentate complex was designed and employed as a metal–ligand cooperative dehydrogenation catalyst. Detailed kinetic studies, control experiments, and DFT calculations revealed the crucial hydride transfer, proton transfer, and hydrogen evolution processes. Finally, a tandem outer-sphere/inner-sphere mechanism was proposed for the dehydrogenation of amines to nitriles through an imine intermediate.

Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin’s structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3gdemonstrating the most potent in vivoanti-TMV activity. At 500 μg/mL, compound 3gachieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycinand ribavirin. Notably, the syn-diastereomer (syn-3g) exhibited superior antiviral activity compared to the anti-diastereomer (anti-3g). Mechanistic studies revealed that syn-3gcould bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g, with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.

LMNAgene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that Lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase ZDHHC5 and depalmitoylase α/β hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of Lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of Lamin A promotes, whereas high-level palmitoylation of Lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of Lamin A controls myoblast differentiation.

A fungal C4-alkylated dihydroisocoumarin pathway was discovered and elucidated. This pathway includes the following (1) a nonreducing polyketide synthase and a P450 collaboratively synthesize hydroxylated C3-methylated isocoumarin 3; (2) a methyltransferase methylates 3to 8; and (3) importantly, an esterase specifically catalyzes a ring reconstruction process of 8to C4-alkylated dihydroisocoumarin 10. Our discovery fills the gap in the enzymatic transformation process of natural C4-alkylated isocoumarin derivates.

•Dalbavancin (DAL) maintains good activity to Gram-positive bacteria, including MRSA and VRE.•DAL exhibited similar clinical and microbiological responses to comparator antibiotics.•DAL has a good effect on osteomyelitis and catheter-related bloodstream infection.•The safety profile of DAL was comparable with other antibiotics.

Background: A liquid chromatography-tandem mass spectrometry (LC-MS/MS). Method: For the quantification of voriconazole in human cerebrospinal fluid (CSF) was developed and validated, to guide the clinical use of voriconazole in the treatment of central nervous system infections. CSF samples were treated by protein precipitation with methanol containing fluconazole as the internal standard (IS). The supernatant was analyzed by LC-MS/MS using an Agilent EclipsePlus C18 column eluted with a methanol and water mobile phase at a flow rate of 0.4 mL min−1. Quantification was performed by multiple-reaction monitoring using the precursor and product ion pair 350/280.9 for voriconazole and 307/219.9 for fluconazole. Results: The calibration curve was linear over the range of 0.1–10.0 μg mL−1(R2= 0.9991). The inter-day and intra-day precisions were <4.20% and <9.97%, respectively. The recoveries for the three concentrations (0.2, 1.0, and 8.0 μg mL−1) were 99.96%, 107.00%, and 99.85%, and the matrix effects were 99.35%, 103.41%, and 99.64%, respectively. The stability under various conditions was also acceptable. The study also demonstrated that the CSF matrix could be replaced by plasma and artificial CSF. Conclusion: A simple and accurate method for the determination of voriconazole concentrations in human CSF was developed and validated, which can be used for drug monitoring in the treatment of central nervous system infections.

Purpose: The different mechanisms that trigger the autoimmune attack to the thyroid between Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are still unclear. The aim of this study was to recognize thyroid antigens specific CD8+ T-cell epitopes and explore the relationship between these epitopes and thyroid autoantibodies, duration and classification in these two diseases. Methods: Free thiiodothyronine, free tetraiodothyronine, thyroid-stimulating hormone, TgAb, and TPOAb were all measured by immunochemiluminometric assays, while TRAb was tested by radioimmunoassay. HLA class I peptide affinity algorithms were applied to predict candidate thyroid autoantigen peptides that blind to HLA-A*0201. The ELISpot assay was used to detect Tg-, TPO-, and TSHR-specific CD8+ T cells. Results: We demonstrated that TG-6 was a novel HLA-A*0201-restricted CTL epitope in GD. TG-6, TG-7, TG-10, TG-11, and TPO-6 were immunodominant in GD patients compared with HT patients (TG-6: 38.5 vs. 8%, P= 0.034; TG-7, TG-10, TG-11, and TPO-6: 23.1 vs. 0%, P= 0.034). The immunodominance of TG-6 in GD patients was more evident than healthy controls (HC) (TG-6: 35.8 vs. 0%, P= 0.011), but there was no statistically significant difference between HT patients and HC. Subgroup analyses revealed the T-cell responsiveness to TG-6 was stronger in TgAb-negative HT patients (0 vs. 40%, P= 0.033). However, there was no correlation showed for TPOAb, TRAb, medication and duration in both HT and GD patients. Conclusions: We report for the first time that both diseases, HT and GD, recognize different antigen-specific CD8-positive T cells. Tg maybe the dominant thyroid autoantigen contributing to breaking tolerance in GD. It could improve our knowledge of autoimmune thyroid diseases pathogenesis as well as offer new therapeutical tools in terms of peptide vaccine therapy.

•CAZ-AVI maintains good activity against Gram-negative bacteria, especially Enterobacteriaceae.•The higher resistance rate of CAZ-AVI is associated with carbapenem resistance.•β-Lactamase-related mutations are represent the main mechanism leading to CAZ-AVI resistance.•For CAZ-AVI-resistant strains, other effective antibacterial agents or CAZ-AVI in combination with other antibacterial agents should be considered.

Wound bleeding and infection are two of the major threats to patients’ lives, but developing safe materials with high hemostasis efficiency and antibacterial activity remains a major challenge. Silver nanoparticles (AgNPs) are suitable as antibacterial agents in the hemostatic process, but the application is hampered because of easy accumulation of toxicity. Herein, thiol-modified chitosan (TMC) was prepared by modifying with mercaptosuccinic acid and then was used to immobilize AgNPs to obtain composite sponges (TMC/AgNPs) for stemming the bleeding and preventing infection. TMC/AgNPs sponges had complex interlaced tubular porous structure with high porosity (99.42%), indicating high absorption. TMC had high immobilization efficiency for AgNPs—the release rate of AgNPs was 14.35% after 14 days—but the TMC/AgNPs sponge still had excellent antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. In vitroand in vivoexperiments confirm that the TMC/AgNPs sponge had fast and efficient hemostatic performance in comparison with the PVF sponge, and its possible mechanism was the synergistic effect of high blood absorption capacity and the interaction between amino, sulfydryl, and blood cells. Furthermore, the TMC/AgNPs sponge can promote wound healing by preventing wound infection, while the PVF sponge cannot. More importantly, the sponges had good safety due to the immobilization of TMC for AgNPs.

This experiment was conducted to investigate the effects of heat stress (HS) on the feed intake, milk production and composition and metabolic alterations in the mammary gland of dairy cows. Twenty Holstein cows were randomly assigned to one of two treatments according to a completely randomized design. Half of the cows were allocated to the HS group in August (summer season), and the other half were assigned to the HS-free group in November (autumn season). HS reduced (P<0.01) dry matter intake (DMI), milk yield, milk protein and milk urea nitrogen (MUN) of cows compared with HS-free control, but increased (P<0.01) milk somatic cell counts (SCC). We determined the HS-induced metabolic alterations and the relevant mechanisms in dairy cows using liquid chromatography mass spectrometry combined with multivariate analyses. Thirty-four metabolites were identified as potential biomarkers for the diagnosis of HS in dairy cows. Ten of these metabolites, glucose, lactate, pyruvate, lactose, β-hydroxybutyrate, citric acid, α-ketoglutarate, urea, creatine, and orotic acid, had high sensitivity and specificity for HS diagnoses, and seven metabolites were also identified as potential biomarkers of HS in plasma, milk, and liver. These substances are involved in glycolysis, lactose, ketone, tricarboxylic acid (TCA), amino acid and nucleotide metabolism, indicating that HS mainly affects lactose, energy and nucleotide metabolism in the mammary gland of lactating dairy cows. This study suggested that HS might affect milk production and composition by affecting the feed intake and substance metabolisms in the mammary gland tissue of lactating dairy cows.

Substantial previous studies have almost reached an agreement on the gender effect on maternal serum human chorionic gonadotropin (MsHCG) in and after the late first trimester of pregnancy. However, there is little knowledge of the sex-related difference in MsHCG level at the preliminary stage of pregnancy. The purpose of this study is to reveal this difference in women after fresh or frozen single blastocyst transfer (SBT).

BackgroundAlthough the initial overall response rate is high (70%-90%) in adult acute lymphoblastic leukemia (ALL) patients (pts), a large percentage of them frequently relapse. Prognosis of relapsed/refractory (R/R) ALL remains poor and there are no clear guidelines on the best treatment approach. Currently, an anthracycline-based multidrug chemotherapy regimen remains the treatment cornerstone in ALL. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics and significantly prolong the survival time of animals compared with the same dose of mitoxantrone. However, there is still a lack of systematic reports about the real-world application of PLM60 in ALL.

Background:Therapies for relapsed or refractory (R/R) AML remain limited, with low response rates and short duration of response, especially in patients ineligible for intensive cytotoxic chemotherapy. Combinations of venetoclax (VEN), chidamide (CHI) plus azacytidine (AZA) have shown to be synergistic with low intensity and intensive chemotherapy in preclinical data and in relapsed or refractory (R/R) setting (Phase II, 2022 ASH). Here we present updated results of this Phase II trial.

Decreased follicular regulatory T (Tfr) cells are associated with lower levels of islet function and higher levels of autoantibodies in type 1 diabetes. Adoptive transfer of Tfr cells prevents diabetes in the mice model.