CDK9 phosphorylates RUNX1 to promote megakaryocytic fate in megakaryocytic-erythroid progenitors.

The specification of megakaryocytic (Mk) or erythroid (E) lineages from primary human megakaryocytic-erythroid progenitors (MEP) is crucial for hematopoietic homeostasis, yet the underlying mechanisms regulating fate specification remain elusive. In this study, we identify RUNX1 as a key modulator of gene expression during MEP fate specification. Overexpression of RUNX1 in primary human MEP promotes Mk specification, while pan-RUNX inhibition favors E specification. Although total RUNX1 levels do not differ between Mk progenitors (MkP) and E progenitors (ErP), there are higher levels of serine-phosphorylated RUNX1 in MkP than ErP, and mutant RUNX1 with phospho-serine/threonine mimetic mutations (RUNX1-4D) significantly enhances the functional efficacy of RUNX1. To model the effects of RUNX1 variants, we employ human erythroleukemia (HEL) cell lines expressing wild-type (WT), phosphomimetic (RUNX1-4D), and non-phosphorylatable (RUNX1-4A) mutants showing that the three forms of RUNX1 differentially regulate expression of 2,625 genes. Both WT and RUNX1-4D variants increase expression in 40%, and decrease expression in another 40%, with lesser effects of RUNX1-4A. We find a significant overlap between the upregulated genes in WT and RUNX1-4D-expressing HEL cells and those upregulated in primary human MkP versus MEP. While inhibition of known RUNX1 serine/threonine kinases does not affect phosphoserine RUNX1 levels in primary MEP, specific inhibition of CDK9 in MEP leads to both decreased RUNX1 phosphorylation and increased erythroid commitment. Collectively, our findings show that serine/threonine phosphorylation of RUNX1 promotes Mk fate specification and introduce a novel kinase for RUNX1 linking the fundamental transcriptional machinery with activation of a cell-type specific transcription factor.

Root-derived long-distance signals trigger ABA synthesis and enhance drought resistance in Arabidopsis.

Vascular plants have evolved intricate long-distance signaling mechanisms to cope with environmental stress, with reactive oxygen species (ROS) emerging as pivotal systemic signals in plant stress responses. However, the exact role of ROS as root-to-shoot signals in the drought response has not been determined. In this study, we reveal that compared with wild-type plants, ferric reductase defective 3 (frd3) mutants exhibit enhanced drought resistance concomitant with elevated NINE-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (NCED3) transcript levels and abscisic acid (ABA) contents in leaves as well as increased hydrogen peroxide (H2O2) levels in roots and leaves. Grafting experiments distinctly illustrate that drought resistance can be conferred by the frd3 rootstock regardless of the scion genotype, indicating that long-distance signals originating from frd3 roots promote an increase in ABA levels in leaves. Intriguingly, the drought resistance conferred by the frd3 mutant rootstock is weakened by the CAT2-overexpressing scion, suggesting that H2O2 may be involved in long-distance signaling. Moreover, the results of comparative transcriptome and proteome analyses support the drought resistance phenotype of the frd3 mutant. Taken together, our findings substantiate the notion that frd3 root-derived long-distance signals trigger ABA synthesis in leaves and enhance drought resistance, providing new evidence for root-to-shoot long-distance signaling in the drought response of plants.

Knockout of OsSPL10 confers enhanced glufosinate resistance in rice.

This study shows that OsSPL10 is a novel genetic locus of glufosinate resistance in rice. OsSPL10 negatively regulates the expression of OsGS genes and thereby decreases GS activity. Knockout of OsSLP10 thus enhances glufosinate resistance, making it a candidate gene for improvement of crop glufosinate and stress resistance.

Meroterpenoids from Ganoderma petchii inhibiting migration of triple negative breast cancer cells.

Ganoderpetchoids A-E and (-)-dayaolingzhiol H, six undescribed meroterpenoids, were isolated from Ganoderma petchii. Their structures including the relative configurations were identified by means of spectroscopic methods and 13C NMR calculations. Chiral separation of the new racemics was performed to afford their respective enantiomers. The absolute configurations of the new isolates were clarified by computational approaches, CD comparisons and X-ray diffraction analysis. Biological studies toward triple negative breast cancer indicated that (+)-6 and (-)-6 significantly inhibit the migration of MDA-MB-231 cell line.

Nitrate-responsive OsMADS27 promotes salt tolerance in rice.

Salt stress is a major constraint on plant growth and yield. Nitrogen (N) fertilizers are known to alleviate salt stress. However, the underlying molecular mechanisms remain unclear. Here, we show that nitrate-dependent salt tolerance is mediated by OsMADS27 in rice. The expression of OsMADS27 is specifically induced by nitrate. The salt-inducible expression of OsMADS27 is also nitrate dependent. OsMADS27 knockout mutants are more sensitive to salt stress than the wild type, whereas OsMADS27 overexpression lines are more tolerant. Transcriptomic analyses revealed that OsMADS27 upregulates the expression of a number of known stress-responsive genes as well as those involved in ion homeostasis and antioxidation. We demonstrate that OsMADS27 directly binds to the promoters of OsHKT1.1 and OsSPL7 to regulate their expression. Notably, OsMADS27-mediated salt tolerance is nitrate dependent and positively correlated with nitrate concentration. Our results reveal the role of nitrate-responsive OsMADS27 and its downstream target genes in salt tolerance, providing a molecular mechanism for the enhancement of salt tolerance by nitrogen fertilizers in rice. OsMADS27 overexpression increased grain yield under salt stress in the presence of sufficient nitrate, suggesting that OsMADS27 is a promising candidate for the improvement of salt tolerance in rice.

SUE4, a novel PIN1-interacting membrane protein, regulates acropetal auxin transport in response to sulfur deficiency.

Sulfur (S) is an essential macronutrient for plants and a signaling molecule in abiotic stress responses. It is known that S availability modulates root system architecture; however, the underlying molecular mechanisms are largely unknown. We previously reported an Arabidopsis gain-of-function mutant sulfate utilization efficiency4 (sue4) that could tolerate S deficiency during germination and early seedling growth with faster primary root elongation. Here, we report that SUE4, a novel plasma membrane-localized protein, interacts with the polar auxin transporter PIN1, resulting in reduced PIN1 protein levels and thus decreasing auxin transport to the root tips, which promotes primary root elongation. Moreover, SUE4 is induced by sulfate deficiency, consistent with its role in root elongation. Further analyses showed that the SUE4-PIN1 interaction decreased PIN1 levels, possibly through 26 S proteasome-mediated degradation. Taken together, our finding of SUE4-mediated root elongation is consistent with root adaptation to highly mobile sulfate in soil, thus revealing a novel component in the adaptive response of roots to S deficiency.

Guideline for the diagnosis and treatment of chronic refractory wounds in orthopedic trauma patients (version 2023) / 中华创伤杂志

Chronic refractory wound (CRW) is one of the most challengeable issues in clinic due to complex pathogenesis, long course of disease and poor prognosis. Experts need to conduct systematic summary for the diagnosis and treatment of CRW due to complex pathogenesis and poor prognosis, and standard guidelines for the diagnosis and treatment of CRW should be created. The Guideline forthe diagnosis and treatment of chronic refractory wounds in orthopedic trauma patients ( version 2023) was created by the expert group organized by the Chinese Association of Orthopedic Surgeons, Chinese Orthopedic Association, Chinese Society of Traumatology, and Trauma Orthopedics and Multiple Traumatology Group of Emergency Resuscitation Committee of Chinese Medical Doctor Association after the clinical problems were chosen based on demand-driven principles and principles of evidence-based medicine. The guideline systematically elaborated CRW from aspects of the epidemiology, diagnosis, treatment, postoperative management, complication prevention and comorbidity management, and rehabilitation and health education, and 9 recommendations were finally proposed to provide a reliable clinical reference for the diagnosis and treatment of CRW.

Practice and reflection on homogeneous management of medical services in multi-campus hospitals / 中华医院管理杂志

Homogeneous management of multi-campus medical care is an effective way to promote the expansion of high-quality medical resources, improve medical quality, and ensure medical safety. The Second Affiliated Hospital Zhejiang University School of Medicine actively explored an integrated and high-quality management mode to effectively improve medical service capacity, ensure medical technology and quality, and enhance hospital influence and social benefits from three dimensions: unified establishment, implementation of core elements, and unified quality and safety evaluation and monitoring. These practices had achieved good results and could provide reference for the multi-campus construction of other large public hospitals.

Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis.

Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)+ monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. Here we show that CCR2+ monocytes in murine CF lungs drive pathogenic transforming growth factor ß (TGF-ß) signaling and sustain a pro-inflammatory environment by facilitating neutrophil recruitment. Targeting CCR2 to lower the numbers of monocytes in CF lungs ameliorates neutrophil inflammation and pathogenic TGF-ß signaling and prevents lung tissue damage. This study identifies CCR2+ monocytes as a neglected contributor to the pathogenesis of CF lung disease and as a therapeutic target for patients with CF, for whom lung hyperinflammation and tissue damage remain an issue despite recent advances in CF transmembrane conductance regulator (CFTR)-specific therapeutic agents.

Dosimetric impact of tumor position displacements between photon and proton stereotactic body radiation therapy for lung cancer.

Purpose: To investigate the impact of tumor position displacements (TPDs) on tumor dose coverage in photon and proton stereotactic body radiation therapy (SBRT) treatments for lung cancer patients. Methods: From our institutional database of 2877 fractions from 770 lung cancer patients treated with photon SBRT in 2017-2021, 163 fractions from 88 patients with recorded iso-center shifts of >1.5 cm in any direction under kV-cone-beam CT guidance were identified. By double registrations with bony and tumor alignments, the difference between the iso-center shifts of these two alignments was categorized as TPDs. One fraction from each of 15 patients who had TPD magnitudes >3 mm were selected for this study. For each patient, one proton plan using intensity modulated proton therapy (IMPT) with robust optimization was generated retrospectively. All photon plans had V100%RX>99% of GTVs and V100%RX>98% of ITVs. Proton plans were evaluated with two worse-case scenario (voxelwise worst and worst scenario) using 5mm and 3.5% uncertainty to achieve the same planning goals as the corresponding photon plans. These two evaluation proton plans were named proton-1st and proton-2nd plans. The dosimetric effect of TPD was simulated by shifting tumor contours with the corresponding shift on patient specific planning CT and by recalculating the dose of the original plan. Results: The range of magnitude of TPDs was 3.58-28.71 mm. In photon plans, TPDs did not impact tumor dose coverage, still achieving V100%RX of the GTV≥99% and V100%RX of the ITV≥98%. In proton plans for patients with TPDs>10 mm, inadequate target dose coverage was observed. More specifically, 8 fractions of proton-1st plans and 4 fractions of proton-2nd had V100%RX of the GTV<99% and V100%RX of the ITV<98%. Conclusions: Adequate tumor dose coverage was achieved in photon SBRT for magnitude of TPDs up to 20 mm. TPDs had greater impact in proton SBRT and adaptive planning was needed when the magnitude of TPDs>10 mm to provide adequate tumor dose coverage.

Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis.

Overwhelming neutrophilic inflammation is a leading cause of lung damage in many pulmonary diseases, including cystic fibrosis (CF). The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway mediates the resolution of inflammation and is defective in CF-affected macrophages (MΦs). Here, we provide evidence that systemic administration of PP-007, a CO releasing/O2 transfer agent, induces the expression of HO-1 in a myeloid differentiation factor 88 (MyD88) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-dependent manner. It also rescues the reduced HO-1 levels in CF-affected cells induced in response to lipopolysaccharides (LPS) or Pseudomonas aeruginosa (PA). Treatment of CF and muco-obstructive lung disease mouse models with a single clinically relevant dose of PP-007 leads to effective resolution of lung neutrophilia and to decreased levels of proinflammatory cytokines in response to LPS. Using HO-1 conditional knockout mice, we show that the beneficial effect of PP-007 is due to the priming of circulating monocytes trafficking to the lungs in response to infection to express high levels of HO-1. Finally, we show that PP-007 does not compromise the clearance of PA in the setting of chronic airway infection. Overall, we reveal the mechanism of action of PP-007 responsible for the immunomodulatory function observed in clinical trials for a wide range of diseases and demonstrate the potential use of PP-007 in controlling neutrophilic pulmonary inflammation by promoting the expression of HO-1 in monocytes/macrophages.

First-principles calculations of 0D/2D GQDs-MoS2 mixed van der Waals heterojunctions for photocatalysis: a transition from type I to type II.

The fabrication of type II heterojunctions is an efficient strategy to facilitate charge separation in photocatalysis. Here, mixed dimensional 0D/2D van der Waals (vdW) heterostructures (graphene quantum dots (GQDs)-MoS2) for generating hydrogen from water splitting are investigated based on density functional theory (DFT). The electronic and photocatalytic properties of three heterostructures, namely, C6H6-MoS2, C24H12-MoS2 and C32H14-MoS2 are estimated by analyzing the density of states, charge density difference, work function, Bader charge, absorption spectra and band alignment. The results indicated that the built-in electric fields from GQDs to MoS2 boost charge separation. Meanwhile, all the GQDs-MoS2 exhibit strong absorption in the visible light region. Surprisingly, the transition of heterojunctions from type I to type II is realized by tuning the size of GQDs. In particular, C32H14-MoS2 with enhanced visible-light absorption and an appropriate band edge position, as a type II heterostructure, may be a promising photocatalyst for generating hydrogen from water splitting. Thus, in this work a novel type II 0D/2D nanocomposite as a photocatalyst is constructed that provides a strategy to regulate the type of heterostructure from the perspective of theoretical calculation.

Diagnostic efficacy of CCTA and CT-FFR based on risk factors for myocardial ischemia.

BACKGROUND: Coronary artery coronary computed tomography angiography (CCTA) can observe the degree of coronary artery stenosis and fractional flow reserve (FFR) can diagnose hemodynamic abnormalities caused by coronary artery stenosis. However, noninvasive imaging examination that can both observe the above two methods at the same time has not yet been elucidated. OBJECTIVE: To investigate the diagnostic efficacy of CCTA and computed tomography-derived fractional flow reserve (CT-FFR) based on different risk factors for myocardial ischemia. METHODS: Patients undergoing CCTA in our hospital from August 18, 2020 to April 28, 2021 were randomly selected, and the data were subjected to CT-FFR analysis. Vascular characteristics were measured, including total plaque volume, calcified plaque volume, non-calcified plaque volume, plaque length, and lumen stenosis, and the patients were categorized into a non-ischemia group (FFR > 0.8) and an ischemia group (FFR ≤ 0.8). Plaque characteristics were compared between the two groups, and logistic regression analysis was employed to explore the correlations between plaque characteristics and ischemic lesions. RESULTS: From a total of 122 patients enrolled in the study, there were 218 vascular branches with FFR > 0.8 and 174 vascular branches with FFR ≤ 0.8. There were significant group differences in total plaque volume, calcified plaque volume, plaque length, and lumen stenosis > 50% (n). The obtained data were as follows: non-ischemic group 10.57 (4.80, 259.65), ischemic group 14.87 (3.39, 424.45), Z = 9.772, p = 0.002, non-ischemic group 10.57 (0, 168.77), ischemic group 14.87 (0, 191.00), Z = 2.503, p ≤ 0.001), non-ischemic group 8.17 (37.05, 40.53), ischemic group 8.38 (56.66, 86.47), Z = 5.923, p = 0.016, and lumen stenosis > 50%, non-ischemic group 46, ischemic group 90, x2 = 14.77, p ≤ 0.001. The regression analysis results indicated that total plaque volume, calcified plaque volume, plaque length and lumen stenosis > 50% were risk factors for myocardial ischemia, with ORs and p values of (2.311, p = 0.002), (1.021, p = 0.004), (2.159, p < 0.001), and (0.181, p < 0.001), respectively. CONCLUSION: Total plaque volume, calcified plaque volume, plaque length and lumen stenosis > 50% are predictors for myocardial ischemia. Coronary artery CCTA combined with CT-FFR could simultaneously observe the anatomical stenosis and evaluate myocardial blood supply at the functional level. Thus, myocardial ischemia could be better diagnosed.

Expert consensus on diagnosis, prevention and treatment of perioperative lower extremity vein thrombosis in orthopedic trauma patients (2022 edition) / 中华创伤杂志

Lower extremity deep vein thrombosis (DVT) is one of the main complications in patients with traumatic fractures, and for severe patients, the DVT can even affect arterial blood supply, resulting in insufficient limb blood supply. If the thrombus breaks off, pulmonary embolism may occur, with a high mortality. The treatment and rehabilitation strategies of thrombosis in patients with lower extremity fractures have its particularity. DVT in traumatic fractures patients has attracted extensive attention and been largely studied, and the measures for prevention and treatment of DVT are constantly developing. In recent years, a series of thrombosis prevention and treatment guidelines have been updated at home and abroad, but there are still many doubts about the prevention and treatment of DVT in patients with different traumatic fractures. Accordingly, on the basis of summarizing the latest evidence-based medical evidence at home and abroad and the clinical experience of the majority of experts, the authors summarize the clinical treatment and prevention protocols for DVT in patients with traumatic fractures, and make this consensus on the examination and assessment, treatment, prevention and preventive measures for DVT in patients with different fractures so as to provide a practicable approach suitable for China ′s national conditions and improve the prognosis and the life quality of patients.

Effect of Duhuo Jisheng Decoction on early cartilage destruction markers in patients with rheumatoid arthritis with liver-kidney yin deficiency syndrome / 国际中医中药杂志

Objective:To investigate the effect of Duhuo Jisheng Decoction on early cartilage destruction markers in patients with rheumatoid arthritis with kidney-qi deficiency and cold syndrome.Methods:A total of 64 patients with rheumatoid arthritis in our hospital from March 2019 to March 2020 who met the inclusion criteria were divided into 2 groups, according to the random number table method, with 32 in each group. The control group was given conventional western medicine therapy, and the observation group was given Duhuo Jisheng decoction on the basis of the control group. Both groups were treated for 8 weeks. TCM syndrome scores were performed before and after treatment, serum CRP, IL-6, cartilage oligosaccharide protein (COMP) and β-catenin were detected by ELISA method, and adverse eventns during treatment were observed and compared. The clinical efficacy was evaluated.Results:The total effective rate was 87.5% (28/32) in the observation group and 65.6% (21/32) in the control group, and the difference between the two groups was statistically significant ( χ2=4.27, P=0.039). After treatment, the main symptoms, secondary symptoms and tongue and pulse scores of the observation group were significantly lower than those in the control group ( t=7.11, 3.11, 2.41, P<0.01 or P<0.05); serum CRP and IL-6 levels were significantly lower than those in the control group ( t=3.04, 4.56, P<0.01); serum COMP [(12.37±1.68) μg/L vs. (14.24±1.88) μg/L, t=4.20], β-catenin [(1.35±0.24) μg/L vs. (1.68±0.31) μg/L, t=4.76] levels were significantly lower than those in the control group ( P<0.01). During the treatment, the incidence of adverse events was 25.0% (8/32) in the observation group and 18.8% (6/32) in the control group, and there was no significant difference between the two groups ( χ2=0.37, P=0.546). Conclusion:The Duhuo Jisheng Decoction can help to reduce the levels of inflammatory cytokines and early cartilage destruction markers in patients with rheumatoid arthritis, and improve the clinical efficacy safely.