Search

Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia.

Developing new pharmaceuticals is a costly and time-consuming endeavor fraught with significant safety risks. A critical aspect of drug research and disease therapy is discerning the existence of interactions between drugs and proteins. The evolution of deep learning (DL) in computer science has been remarkably aided in this regard in recent years. Yet, two challenges remain: (i) balancing the extraction of profound, local cohesive characteristics while warding off gradient disappearance and (ii) globally representing and understanding the interactions between the drug and target local attributes, which is vital for delivering molecular level insights indispensable to drug development. In response to these challenges, we propose a DL network structure, MolLoG, primarily comprising two modules: local feature encoders (LFE) and global interactive learning (GIL). Within the LFE module, graph convolution networks and leap blocks capture the local features of drug and protein molecules, respectively. The GIL module enables the efficient amalgamation of feature information, facilitating the global learning of feature structural semantics and procuring multihead attention weights for abstract features stemming from two modalities, providing biologically pertinent explanations for black-box results. Finally, predictive outcomes are achieved by decoding the unified representation via a multilayer perceptron. Our experimental analysis reveals that MolLoG outperforms several cutting-edge baselines across four data sets, delivering superior overall performance and providing satisfactory results when elucidating various facets of drug–target interaction predictions.

This work was designed to evaluate the effect of four enzyme-assisted extraction (EAE) combined hydrodistillation (HD) methods on the yield, microstructure and chemical composition of essential oil (EO) from leaves of Cinnamomum longepaniculatum(Gamble) N. Chao ex H. W. Li. The chemical composition of EO was analyzed using gas chromatography-mass spectrometry. Changes in the microstructure of leaf residues were observed by scanning electron microscopy. Response surface methodology was used to predict the best conditions for the EO extraction with the most effective enzyme pretreatment. Further, the anxiolytic effect and mechanism of the optimized EO were investigated by the open-field test (OFT), elevated plus-maze test (EPMT), hole-board test (HBT) and the assay of neurotransmitter concentrations (5-hydroxytryptamine, 5-HT; γ-aminobutyric acid, GABA; norepinephrine, NE). The results showed that different enzyme pretreatments increased the yield and quality of EO and disrupted the cell wall. The circumscribed-β-glucan/hemicellulose enzyme (1:1) pretreatment (4.33%) was the most effective compared to the enzyme-free group (2.82%). The optimum extraction process conditions were: pH:5, enzymolysis time: 67 min and digestion temperature: 48.5 °C. Under these conditions, the maximum yield of EO was 4.37%. After inhalation of EO, mice showed significant anxiolytic effects in EPMT, HBT, and OFT. In addition, EO significantly down-regulated 5-hydroxytryptamine and NE levels and up-regulated GABA levels. Cinnamomum longepaniculatumEO may be related to 5-HTergic, GABAergic and NEergic neurotransmitter systems for better anxiolytic effect.

•Outcomes in patients who developed septic shock after allo-HSCT were poor.•Gram-negative bacilli accounted for 61.5% of the positive isolates.•Escherichia coliwas the dominant isolated pathogen.•Patients with late-onset septic shock had a significantly worse outcome.•Of patients with sepsis-induced coagulopathy, the 28-day mortality rate was 88.1%.

Key message: Unreduced megagametophytes via second-division restitution were confirmed through heterozygosity analysis, and four candidate physical centromeres of rubber were located for the first time. Abstract: The evaluation of maternal heterozygosity restitution (MHR) is vital in identifying the mechanism of 2ngametogenesis and assessing the utilization value of 2ngametes. In this study, three full-sib triploid populations were employed to evaluate the MHR of 2nfemale gametes of rubber tree clone GT1 and to confirm their genetic derivation. The 2nfemale gametes of GT1 were derived from second-division restitution (SDR) and transmitted more than half of the parental heterozygosity. In addition, low recombination frequency markers were developed, and four candidate physical centromeres of rubber tree were located for the first time. The confirmation that 2nfemale gametes of rubber tree clone GT1 are derived from SDR provides insights into the molecular mechanisms of 2ngametogenesis. In addition, the identified centromere location will aid in the development of centromeric markers for the rapid identification of the 2ngametogenesis mechanism.

The utilization of global positioning system (GPS) for 3-D ionospheric electron density reconstruction, i.e., computerized ionospheric tomography (CIT), provides significant importance in investigating the internal structure, variations, and disturbances within the ionosphere. However, the ill-posed problem caused by insufficient observational data or uneven distribution will rely heavily on the selection of initial values, which are typically derived from empirical models with low precision. Aiming at this issue, this article uses the total electron content (TEC) obtained by the spaceborne full-polarization synthetic aperture radar (PolSAR) to correct the Empirical Canadian High Arctic Ionospheric Model (E-CHAIM), thus improving the authenticity of the initial value. This study makes full use of the advantages of low-frequency full-PolSAR in ionospheric sounding, including high precision and resolution, as well as all-day and all-weather operation without a ground receiver. Therefore, the precision of GPS-based tomography can be enhanced, particularly for small-scale anomalies, and it is also simple and easy to achieve. Numerical and measured experiments using GPS, incoherent scatter radar (ISR), PolSAR, and E-CHAIM data in Alaska demonstrate that the reconstruction accuracy of the proposed CIT is significantly improved than that of the tomography results using only empirical model. In addition, the effects of PolSAR system errors and voxel size on CIT are analyzed to demonstrate the robustness of the method proposed in this article.

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33–215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8–24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9–140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p< 0.001) and platelet engraftment (75.8% versus 32.3%, p< 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p= 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+subset polarization in a paracrine mode, in which TGFβ and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.govas #NCT03764228.

Aplastic anemia (AA) is a life-threatening disease characterized by bone marrow (BM) failure and pancytopenia. As an important component of the BM microenvironment, endothelial cells (ECs) play a crucial role in supporting hematopoiesis and regulating immunity. However, whether impaired BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve hematopoiesis and immune status in AA remain unknown. In this study, a classical AA mouse model and VE-cadherin blocking antibody that could antagonize the function of ECs were used to validate the role of BM ECs in the occurrence of AA. N-acetyl-L-cysteine (NAC, a reactive oxygen species scavenger) or exogenous EC infusion was administered to AA mice. Furthermore, the frequency and functions of BM ECs from AA patients and healthy donors were evaluated. BM ECs from AA patients were treated with NAC in vitro, and then the functions of BM ECs were evaluated. We found that BM ECs were significantly decreased and damaged in AA mice. Hematopoietic failure and immune imbalance became more severe when the function of BM ECs was antagonized, whereas NAC or EC infusion improved hematopoietic and immunological status by repairing BM ECs in AA mice. Consistently, BM ECs in AA patients were decreased and dysfunctional. Furthermore, dysfunctional BM ECs in AA patients led to their impaired ability to support hematopoiesis and dysregulate T cell differentiation toward proinflammatory phenotypes, which could be repaired by NAC in vitro. The reactive oxygen species pathway was activated, and hematopoiesis- and immune-related signaling pathways were enriched in BM ECs of AA patients. In conclusion, our data indicate that dysfunctional BM ECs with impaired hematopoiesis-supporting and immunomodulatory abilities are involved in the occurrence of AA, suggesting that repairing dysfunctional BM ECs may be a potential therapeutic approach for AA patients.

In patients with t(8;21) acute myeloid leukemia (AML) with recurrent measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), pre-emptive interferon-α therapy and donor lymphocyte infusion are noneffective in 30%–50% of patients. Avapritinib is a novel tyrosine kinase inhibitor targeting KIT mutations. We retrospectively report about 20 patients with t(8;21) AML and KIT mutations treated with avapritinib after allo-HSCT with MRD and most failing to respond to immunotherapy. Reduction of RUNX1-RUNX1T1after 1 month of treatment was ≥1 log in 12 patients (60%), which became negative in 4 patients (20%). In 13 patients who received avapritinib for ≥3 months, the reduction was ≥1 log in all patients, which became negative in 7 patients (53.8%). The median follow-up time was 5.5 (2.0–10.0) months from avapritinib initiation to the last follow-up. Three patients underwent hematologic relapse and survived. Among all 20 patients, RUNX1-RUNX1T1transcripts turned negative in 9 patients (45%). The efficacy did not differ significantly between D816 and non-D816 KIT mutation groups. The main adverse effect was hematological toxicity, which could generally be tolerated. In summary, avapritinib was effective for MRD treatment in patients with t(8;21) AML with KIT mutations failing to respond to immunotherapy after allo-HSCT.

•Our model is the first to predict heart failure mortality following allogeneic hematopoietic stem cell transplantation.•The BLIPS score demonstrated high discrimination and calibration power.•The model can provide early identification of patients with heart failure, with a higher 2-month mortality rate.

Vincristine is a natural vinca alkaloid drug, which is widely used in pediatric cancer treatment with dose-dependent neurotoxicity. Thus far, little is known about the association between neurotoxicity and plasma vincristine concentration, which markedly varies among individuals. Routine therapeutic drug monitoring (TDM) can be seen as a reliable strategy to improve efficacy and reduce side effects. Therefore, a rapid, sensitive, and reproducible method is critical for the clinical implementation of TDM. In this study, micro-volume (50 μL) human plasma samples were prepared by a simple one-step protein precipitation method with acetonitrile. Chromatographic separation of vincristine and its internal standard vincristine-d3from background noise was achieved on a Kinetex C18 column (2.1 mm × 50 mm, 1.7 μm) with a gradient elution program at a flow rate of 0.3 mL min−1in 4 min. The mass spectrometric detection was performed in electrospray ionization multiple reaction monitoring mode using the ion transitions of 825.4 → 765.1 for vincristine, and 828.2 → 768.2 for vincristine-d3, respectively. As a result, no matrix effect was observed. The lower limit of quantification was 0.5 ng mL−1with a precision of 14.6% and an accuracy of 97.4%. The calibration curve was linear from 0.5 to 100 ng mL−1(r2> 0.99, n= 8). The intra- and inter-batch precision and accuracy, recovery, and stability of the new method were all within the acceptable criteria. The method was successfully applied to monitor the vincristine concentration for six pediatric cancer patients. Arguably, such proactive TDM of vincristine may be helpful to manage the treatment for these cancer patients.

Bronchiolitis obliterans syndrome (BOS) is a common and potentially devastating noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, predictive tools for BOS are not available. We aimed to identify the clinical risk factors and establish a prognostic model for BOS in patients who undergo allo-HSCT. We retrospectively identified a cohort comprising 195 BOS patients from 6100 consecutive patients who were allografted between 2008 and 2022. The entire cohort was divided into a derivation cohort and a validation cohort based on the time of transplantation. Via multivariable Cox regression methods, declining forced expiratory volume at 1 s (FEV1) to <40%, pneumonia, cGVHD except lung, and respiratory failure were found to be independent risk factors for the 3-year mortality of BOS. A risk score called FACT was constructed based on the regression coefficients. The FACT model had an AUC of 0.863 (95% CI: 0.797–0.928) in internal validation and 0.749 (95% CI: 0.621–0.876) in external validation. The calibration curves showed good agreement between the FACT-predicted probabilities and actual observations. The FACT risk score will help to identify patients at high risk and facilitate future research on developing novel, effective interventions to personalize treatment.

[Display omitted]

Vigabatrin is one of the second-generation anti-seizure medications (ASMs) designated orphan drugs by the FDA for monotherapy for pediatric patients with infantile spasms from 1 month to 2 years of age. Vigabatrin is also indicated as the adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures. Ideally, the vigabatrin treatment entails achieving complete seizure freedom without significant adverse effects, and the therapeutic drug monitoring (TDM) will make a significant contribution to this aim, which provides a pragmatic approach to such epilepsy care in that the dose tailoring can be undertaken for uncontrollable seizures and in cases of clinical toxicity guided by the drug concentrations. Thus, reliable assays are mandatory for TDM to be valuable, and blood, plasma, or serum are the matrixes of choice. In this study, a simple, rapid, and sensitive LC-ESI-MS/MS method for the measurement of plasma vigabatrin was developed and validated. The sample clean-up was performed by an easy-to-use method, i.e., protein precipitation using acetonitrile (ACN). Chromatographic separation of vigabatrin and vigabatrin-13C,d2(internal standard) was achieved on the Waters symmetry C18 column (4.6 mm × 50 mm, 3.5 μm) with isocratic elution at a flow rate of 0.35 mL min−1. The target analyte was completely separated by elution with a highly aqueous mobile phase for 5 min, without any endogenous interference. The method showed good linearity over the 0.010–50.0 μg mL−1concentration range with a correlation coefficient r2= 0.9982. The intra-batch and inter-batch precision and accuracy, recovery, and stability of the method were all within the acceptable parameters. Moreover, the method was successfully used in pediatric patients treated with vigabatrin and also provided valuable information for clinicians by monitoring plasma vigabatrin levels in our hospital.

Emerging and re-emerging spotted fever group (SFG) rickettsioses are increasingly recognised worldwide as threats to public health, yet their global distribution and associated risk burden remain poorly understood.

The influence of MgO content in slag on wetting and corrosion behavior between slag and MgO–C refractory was investigated. It can be known from the high-temperature wetting experiment that as the MgO content in the slag increases, the final contact angle between the slag and the MgO–C refractory gradually increases and the penetration depth of the slag into the refractory gradually decreases from 60.54 μm (when the MgO content is 8%) to 28.11 μm (when the MgO content is 12%). The CaO and SiO2in the slag penetrate into the MgO–C refractory along the pores or surface cracks formed by carbon oxidation and react with MgO to generate a large amount of low-melting compound CaO–MgO–SiO2, which accelerates the corrosion of the refractory. As the MgO content in slag increases, the viscosity of the slag increases and the fluidity becomes worse, so that the mass transfer and diffusion of molecules or ions in the slag are weakened. In addition, the increase in MgO reduces the activity of FeO in the slag, which inhibits the interfacial chemical reaction, thereby weakening the wetting effect caused by the reaction.

ABSTRACTLiver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/β-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl4-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.

Osteoporosis, a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture, has led to a high risk of fatal osteoporotic fractures worldwide. Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis, with sex-specific differences in epidemiology and pathogenesis. Specifically, females are more susceptible than males to osteoporosis, while males are more prone to disability or death from the disease. To date, sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells. Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men. This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis, mainly in a population of aging patients, chronic glucocorticoid administration, and diabetes. Moreover, we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men. Additionally, the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancer cell glucose metabolism and plays a crucial role in the activation of various types of immune cells. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzes the conversion of D-glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate in the 6th critical step in glycolysis. GAPDH exerts metabolic flux control during aerobic glycolysis and therefore is an attractive therapeutic target for cancer and autoimmune diseases. Recently, GAPDH inhibitors were reported to function through common suicide inactivation by covalent binding to the cysteine catalytic residue of GAPDH. Herein, by developing a high-throughput enzymatic screening assay, we discovered that the natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG) is an inhibitor of GAPDH with Ki= 0.5 μM. PGG blocks GAPDH activity by a reversible and NAD+and Pi competitive mechanism, suggesting that it represents a novel class of GAPDH inhibitors. In-depth hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PGG binds to a region that disrupts NAD+and inorganic phosphate binding, resulting in a distal conformational change at the GAPDH tetramer interface. In addition, structural modeling analysis indicated that PGG probably reversibly binds to the center pocket of GAPDH. Moreover, PGG inhibits LPS-stimulated macrophage activation by specific downregulation of GAPDH-dependent glucose consumption and lactate production. In summary, PGG represents a novel class of GAPDH inhibitors that probably reversibly binds to the center pocket of GAPDH. Our study sheds new light on factors for designing a more potent and specific inhibitor of GAPDH for future therapeutic applications.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.

Flavoalkaloids are a unique class of compounds in tea, most of which have an N-ethyl-2-pyrrolidinone moiety substituted at the A ring of a catechin skeleton. 1-Ethyl-5-hydroxy-pyrrolidone, a decomposed product of theanine, was supposed to be the key intermediate to form tea flavoalkaloids. However, we have also detected another possible theanine intermediate, 1-ethyl-5-oxopyrrolidine-2-carboxylic acid, and speculated if there are related conjugated catechins. Herein, four novel spiro-flavoalkaloids with a spiro-γ-lactone structural moiety were isolated from Yingde green tea (Camellia sinensisvar. assamica) in our continuing exploration of new chemical constituents from tea. The structures of the new compounds, spiro-flavoalkaloids A-D (1–4), were further elucidated by extensive nuclear magnetic resonance (NMR) spectroscopy together with the calculated 13C NMR, IR, UV–vis, high-resolution mass, optical rotation, experimental, and calculated circular dichroism spectra. We also provided an alternative pathway to produce these novel spiro-flavoalkaloids. Additionally, their α-glucosidase inhibitory activities were determined with IC50values of 3.34 (1), 5.47 (2), 22.50 (3), and 15.38 (4) μM. Docking results revealed that compounds 1and 2mainly interacted with residues ASP-215, ARG-442, ASP-352, GLU-411, HIS-280, ARG-315, and ASN-415 of α-glucosidase through hydrogen bonds. The fluorescence intensity of α-glucosidase could be quenched by compounds 1and 2in a static style.

Non-healing diabetic wounds (DW) are a serious clinical problem that remained poorly understood. We recently found that topical application of growth differentiation factor 11 (GDF11) accelerated skin wound healing in both Type 1 DM (T1DM) and genetically engineered Type 2 diabetic db/db(T2DM) mice. In the present study, we elucidated the cellular and molecular mechanisms underlying the action of GDF11 on healing of small skin wound. Single round-shape full-thickness wound of 5-mm diameter with muscle and bone exposed was made on mouse dorsum using a sterile punch biopsy 7 days following the onset of DM. Recombinant human GDF11 (rGDF11, 50 ng/mL, 10 μL) was topically applied onto the wound area twice a day until epidermal closure (maximum 14 days). Digital images of wound were obtained once a day from D0 to D14 post-wounding. We showed that topical application of GDF11 accelerated the healing of full-thickness skin wounds in both type 1 and type 2 diabetic mice, even after GDF8 (a muscle growth factor) had been silenced. At the cellular level, GDF11 significantly facilitated neovascularization to enhance regeneration of skin tissues by stimulating mobilization, migration and homing of endothelial progenitor cells (EPCs) to the wounded area. At the molecular level, GDF11 greatly increased HIF-1ɑ expression to enhance the activities of VEGF and SDF-1ɑ, thereby neovascularization. We found that endogenous GDF11 level was robustly decreased in skin tissue of diabetic wounds. The specific antibody against GDF11 or silence of GDF11 by siRNA in healthy mice mimicked the non-healing property of diabetic wound. Thus, we demonstrate that GDF11 promotes diabetic wound healing via stimulating endothelial progenitor cells mobilization and neovascularization mediated by HIF-1ɑ-VEGF/SDF-1ɑ pathway. Our results support the potential of GDF11 as a therapeutic agent for non-healing DW.

Background: Pain is a contributing factor to the low compliance rate for performing a colonoscopy on screening for colorectal cancer. Purpose: This meta-analysis aimed to evaluate the effect of visual distraction on adults undergoing colonoscopy. Methods: We searched PubMed, EMBASE, Web of Science, and Cochrane Library Database from their inception to February 2022. Randomized controlled trials comparing visual distraction with non-visual distraction were considered for inclusion. The fixed-effects and random-effects models were used to pool the data from individual studies and the Cochrane risk of bias assessment tool was used to determine the methodology quality. Results: This meta-analysis included four studies (N= 301) for pain level and total procedure time, three studies (N= 181) for satisfaction score, three studies (N= 196) for anxiety level, and four studie (N= 402) for willingness to repeat the procedure. The pooled analysis shown that significantly lower pain levels (SMD, − 0.25; 95% CI − 0.47 to − 0.02; P= 0.03), higher satisfaction score with the procedure (SMD, 0.63; 95% CI, 0.33 to 0.93; P&lt; 0.0001), and higher willingness to repeat the procedure (OR, 2.66; 95% CI 1.70 to 4.17; P&lt; 0.0001) in the visual distraction group than those in the non-visual distraction group, with no significant differences in total procedure time (SMD,− 0.07; 95% CI − 0.30 to 0.15; P= 0.53) or anxiety level (SMD,− 0.27; 95% CI − 0.55 to 0.01; P= 0.06). Conclusions: Visual distraction improved the patient’s pain, satisfaction, and willingness to repeat the procedure. Thus, visual stimulation is an effective way to reduce pain during colonoscopy and should be recommended.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempted to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort, according to the time of transplantation, to perform external temporal validation. Patient age (odds ratio [OR], 2.371; 95% confidence interval [CI], 1.264-4.445), anemia (OR, 2.836; 95% CI, 1.566-5.138), severe thrombocytopenia (OR, 3.871; 95% CI, 2.156-6.950), elevated total bilirubin (OR, 2.716; 95% CI, 1.489-4.955), and proteinuria (OR, 2.289; 95% CI, 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was constructed according to the regression coefficients. The validated c-statistic was 0.816 (95%, CI, 0.766-0.867) and 0.756 (95% CI, 0.696-0.817) for the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempted to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort, according to the time of transplantation, to perform external temporal validation. Patient age (odds ratio [OR], 2.371; 95% confidence interval [CI], 1.264-4.445), anemia (OR, 2.836; 95% CI, 1.566-5.138), severe thrombocytopenia (OR, 3.871; 95% CI, 2.156-6.950), elevated total bilirubin (OR, 2.716; 95% CI, 1.489-4.955), and proteinuria (OR, 2.289; 95% CI, 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was constructed according to the regression coefficients. The validated c-statistic was 0.816 (95%, CI, 0.766-0.867) and 0.756 (95% CI, 0.696-0.817) for the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by toxic aggregates of mutant huntingtin protein (mHTT) in the brain. Decreasing mHTT is a potential strategy for therapeutic purpose of HD. Valosin-containing protein (VCP/p97) is a crucial regulator of proteostasis, which regulates the degradation of damaged protein through proteasome and autophagy pathway. Since VCP has been implicated in pathogenesis of HD as well as other neurodegenerative diseases, small molecules that specifically regulate the activity of VCP may be of therapeutic benefits for HD patients. In this study we established a high-throughput screening biochemical assay for VCP ATPase activity measurement and identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate dose-dependently inhibited the enzymatic activity of VCP in vitro with IC50of 6.53±0.6 μM. We further demonstrated that gossypol directly bound to the interface between the N and D1 domains of VCP. Gossypol acetate treatment not only lowered mHTT levels and rescued HD-relevant phenotypes in HD patient iPS-derived Q47 striatal neurons and HD knock-in mouse striatal cells, but also improved motor function deficits in both Drosophilaand mouse HD models. Taken together, gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. This study reveals a new strategy for treatment of HD and raises the possibility that an existing drug can be repurposed as a new treatment of neurodegenerative diseases.

Single-atom catalysis efficiently exposes the catalytic sites to reactant molecules while rendering opportunity to investigate the catalysis mechanisms at atomic levels for scientific insights. Here, for the first time, atomically dispersed Co atoms are synthesized as biomimetic “enzymes” to monitor superoxide anions (O2•–), delivering ultraordinary high sensitivity (710.03 μA·μM–1·cm–2), low detection limit (1.5 nM), and rapid response time (1.2 s), ranking the best among all the reported either bioenzymatic or biomimetic O2•–biosensors. The sensor is further successfully employed to real-time monitor O2•–released from living cells. Moreover, theoretical calculation and analysis associated with experimental results discover that a mode of end adsorption of the negatively charged O2•–on the Co3+atom rather than a bridge or/and side adsorption of the two atoms of O2•–on two Co3+atoms, respectively, plays an important role in the single-atomic catalysis toward O2•–oxidation, which not only facilitates faster electron transfer but also offers better selectivity. This work holds great promise for an inexpensive and sensitive atomic biomimetic O2•–sensor for bioresearch and clinic diagnosis, while revealing that the adsorption mode plays a critical role in single-atom catalysis for a fundamental insight.

Fenoxaprop-p-ethyl (FE), a type of acetyl-CoA carboxylase (ACCase) inhibitor, has been extensively applied to a variety of crop plants. It can cause damage to wheat (Triticum aestivum) even resulting in the death of the crop. On the prerequisite of not reducing herbicidal efficiency on target weed species, herbicide safeners selectively protect crops from herbicide injury. Based on fragment splicing, a series of novel substituted pyrazole derivatives was designed to ultimately address the phytotoxicity to wheat caused by FE. The title compounds were synthesized in a one-pot way and characterized viainfrared spectroscopy, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. The bioactivity assay proved that the FE phytotoxicity to wheat could be reduced by most of the title compounds. The molecular docking model indicated that compound IV-21prevented fenoxaprop acid (FA) from reaching or acting with ACCase. The absorption, distribution, metabolism, excretion, and toxicity predictions demonstrated that compound IV-21exhibited superior pharmacokinetic properties to the commercialized safener mefenpyr-diethyl. The current work revealed that a series of newly substituted pyrazole derivatives presented strong herbicide safener activity in wheat. This may serve as a potential candidate structure to contribute to the further protection of wheat from herbicide injury.

Epithelial-mesenchymal transition (EMT) enables dissemination of neoplastic cells and onset of distal metastasis of primary tumors. However, the regulatory mechanisms of EMT by microenvironmental factors such as transforming growth factor-β (TGF-β) remain largely unresolved. Protein tyrosine phosphatase L1 (PTPL1) is a non-receptor protein tyrosine phosphatase that plays a suppressive role in tumorigenesis of diverse tissues. In this study we investigated the role of PTPL1/PTPN13 in metastasis of lung cancer and the signaling pathways regulated by PTPL1 in terms of EMT of non-small cell lung cancer (NSCLC) cells. We showed that the expression of PTPL1 was significantly downregulated in cancerous tissues of 23 patients with NSCLC compared with adjacent normal tissues. PTPL1 expression was positively correlated with overall survival of NSCLC patients. Then we treated A549 cells in vitro with TGF-β1 (10 ng/mL) and assessed EMT. We found that knockdown of PTPL1 enhanced the migration and invasion capabilities of A549 cells, through enhancing TGF-β1-induced EMT. In nude mice bearing A549 cell xenografts, knockdown of PTPL1 significantly promoted homing of cells and formation of tumor loci in the lungs. We further revealed that PTPL1 suppressed TGF-β-induced EMT by counteracting the activation of canonical Smad2/3 and non-canonical p38 MAPK signaling pathways. Using immunoprecipitation assay we demonstrated that PTPL1 could bind to p38 MAPK, suggesting that p38 MAPK might be a direct substrate of PTPL1. In conclusion, these results unravel novel mechanisms underlying the regulation of TGF-β signaling pathway, and have implications for prognostic assessment and targeted therapy of metastatic lung cancer.

The inhalation of particulate matter (PM) is closely related to respiratory damage, including acute lung injury (ALI), characterized by inflammatory fluid edema and disturbed alveolar-capillary permeability. Ruscogenin (RUS), the main active ingredient in the traditional Chinese medicine Ophiopogonis japonicus, has been found to exhibit anti-inflammatory activity and rescue LPS-induced ALI. In this study, we investigated whether and how RUS exerted therapeutic effects on PM-induced ALI. RUS (0.1, 0.3, 1 mg·kg−1·d−1) was orally administered to mice prior to or after intratracheal instillation of PM suspension (50 mg/kg). We showed that RUS administration either prior to or after PM challenge significantly attenuated PM-induced pathological injury, lung edema, vascular leakage and VE-cadherin expression in lung tissue. RUS administration significantly decreased the levels of cytokines IL-6 and IL-1β, as well as the levels of NO and MPO in both bronchoalveolar lavage fluid (BALF) and serum. RUS administration dose-dependently suppressed the phosphorylation of NF-κB p65 and the expression of TLR4 and MyD88 in lung tissue. Furthermore, TLR4 knockout partly diminished PM-induced lung injury, and abolished the protective effects of RUS in PM-instilled mice. In conclusion, RUS effectively alleviates PM-induced ALI probably by inhibition of vascular leakage and TLR4/MyD88 signaling. TLR4 might be crucial for PM to initiate pulmonary lesion and for RUS to exert efficacy against PM-induced lung injury.

This study aimed to investigate immune cell infiltration (ICI) in breast cancer tissues and its impact on the prognosis of patients. The whole transcriptome sequencing data sets of breast tissue (GSE126125, GSE190275 and GSE45498) were downloaded from Gene Expression Omnibus database. Data sets, including 281 breast cancer tissue samples and 59 normal breast tissue samples. In this study, the CIBERSORT algorithm was used to calculate the infiltration content of 22 immune cells subtypes in breast cancer tissues and normal breast tissues. The ICI between normal and breast cancer tissue samples was examined through the Rank-sum test. Furthermore, Kaplan–Meier and the log-rank test were used for survival analysis. Univariate and multivariate COX analysis was used to screen the prognostic risk factors of breast cancer based on ICI. The correlation between 22 kinds of immune cells was analyzed by the Pearson test. The results of univariate COX analysis indicated that resting dendritic cells, eosinophils, resting mast cells, monocytes, and memory CD4 T cells resting were protective factors for the prognosis of breast cancer patients (hazard ratio [HR] < 1, P< .05). The activation of macrophage M0 and mast cells were also prognostic risk factors for breast cancer patients (HR > 1, P< .05). Besides, multivariate COX analysis showed that resting mast cells were independent protective factors for the prognosis of breast cancer patients (HR < 1, P< .05). Macrophage M0 and mast cell activation were independent risk factors for the prognosis of breast cancer patients (HR > 1, P< .05). High infiltration of macrophage M0 and activated mast cells is associated with poor prognosis. Meanwhile, macrophage M0 and activated mast cells promote breast cancer progression. Low infiltration of resting mast cells is associated with poor prognosis, which inhibits breast cancer progression.

In this work, different thermal aggregation behaviors of soy β-conglycinin and glycinin at pH 7.0 were characterized with size exclusion chromatography and low-angle light scattering. Limited aggregation that grew via the consumption of “monomers” was detected in β-conglycinin, forming soluble aggregates. For glycinin, the association between the aggregates that led to the appearance of insoluble materials was observed. Heated with β-conglycinin, the assembly between the glycinin aggregates was terminated and its solubility was recovered. The structure of the soluble and insoluble aggregates was analyzed by small-angle X-ray scattering and dynamic light scattering. Unlike the β-conglycinin soluble aggregates that possessed limited size and less compact conformation, particles with a denser core and a less dense outer shell were found in the glycinin insoluble aggregates. Evidence is presented to reveal the transition between the soluble and insoluble aggregates and the role of β-conglycinin in the solubilization of the soy protein aggregates during heating.

A highly efficient Cu-catalyzed 1,4-difunctionalization of isoquinolinium salts was developed with ether and X–(X = Br, Cl) as the halogen source under mild conditions. This transformation involves the combination of oxidative coupling and copper-catalyzed halogen atom-transfer radical processes. This method not only provides an efficient way to prepare various substituted azaarenes but also achieves the selective construction of C(sp2)–X (X = Br, Cl) bonds from a halogen anion and nucleophilic carbon atom via a free-radical process.

Acute cholecystitis (AC) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, only limited information is available on its clinical features, outcomes, and risk management strategies. This retrospective, nested, case–control study included 6701 patients undergoing allo-HSCT at our center from January 2004 to June 2019. In total, 72 patients (1.1%) were diagnosed with AC; among these, acute acalculous cholecystitis had a slightly higher prevalence (42 patients, 58.3%). Patients with moderate and severe AC exhibited remarkably worse overall survival (P = .001) and non-relapse mortality (P = .011) than others. Survival of haploidentical HSCT recipients with AC was comparable to that for patients with human leukocyte antigen (HLA)-identical donors. Age ≥ 18 years, antecedent stage II to IV acute graft-versus-host disease, and total parenteral nutrition were identified as potential risk factors for AC following allo-HSCT, while haploidentical transplantations were not more susceptible to AC than HLA-identical HSCT. Based on these criteria, a risk score model was developed and validated to estimate the probability of AC following allo-HSCT. The model separates all patients into low-, intermediate-, and high-risk groups and thereby provides a basis for early detection of this complication in the management of allo-HSCT.

Objective: We aim to investigate the anticancer effects and mechanisms of icaritin against breast cancer. Materials and Methods: Both estrogen receptor (ER) positive breast cancer cells MCF- 7 and ER-negative MDA-MB-231 cells were employed. We examined the effects of icaritin on the proliferation and migration by wound healing assay and transwell assay. Cell apoptosis and cell cycle of MCF-7 and MDA-MB-231 cells were analyzed using Flow cytometry. Cell autophagy of MCF-7 and MDA-MB-231 cells was assessed by western blotting, acridine orange staining and confocal microscopy. We also detected the expression of apoptosis-related genes by western blotting. In addition, an autophagy inhibitor was used to investigate whether cytoprotective autophagy was induced. Meanwhile, an ER inhibitor was utilized to explore whether ER was involved in autophagy. Results: Icaritin inhibited the proliferation and migration, and induced cell cycle arrest of both MDA-MB-231 and MCF-7 cells. Icaritin significantly induced apoptosis of MDA-MB- 231 cells by activating caspase-3. And icaritin stimulated autophagy in MCF-7 cells, as evidenced by increased LC3II/LC3I, enhanced p62 degradation, the accumulation of endogenous LC3 puncta formation, and the increased autophagy flux. Icaritin induced autophagy through upregulating the phosphorylation of AMPK and ULK1. Chloroquine, an autophagy inhibitor, increased icaritin-induced apoptosis and proliferation inhibition of MCF-7 cells. Meanwhile, tamoxifen, an ER inhibitor, reversed icaritin-induced autophagy and proliferation inhibition of MCF-7 cells. Conclusion: Our study demonstrated that the antitumor effects of icaritin against breast cancer are related to ER, which suggested that the status of ER should be considered in the clinical application of icaritin.