Interlamellar-Spacing Engineering of Stable and Toxicity-Reduced 2D Perovskite Single Crystal for High-Resolution X-ray Imaging.

Two-dimensional (2D) lead halide perovskites are excellent candidates for X-ray detection due to their high resistivity, high ion migration barrier, and large X-ray absorption coefficients. However, the high toxicity and long interlamellar distance of the 2D perovskites limit their wide application in high sensitivity X-ray detection. Herein, we demonstrate stable and toxicity-reduced 2D perovskite single crystals (SCs) realized by interlamellar-spacing engineering via a distortion self-balancing strategy. The engineered low-toxicity 2D SC detectors achieve high stability, large mobility-lifetime product, and therefore high-performance X-ray detection. Specifically, the detectors exhibit a record high sensitivity of 13488 µC Gy1- cm-2, a low detection limit of 8.23 nGy s-1, as well as a high spatial resolution of 8.56 lp mm-1 in X-ray imaging, all of which are far better than those of the high-toxicity 2D lead-based perovskite detectors. These advances provide a new technical solution for the low-cost fabrication of low-toxicity, scalable X-ray detectors.

Selection signatures and landscape genomics analysis to reveal climate adaptation of goat breeds.

Goats have achieved global prominence as essential livestock since their initial domestication, primarily owing to their remarkable adaptability to diverse environmental and production systems. Differential selection pressures influenced by climate have led to variations in their physical attributes, leaving genetic imprints within the genomes of goat breeds raised in diverse agroecological settings. In light of this, our study pursued a comprehensive analysis, merging environmental data with single nucleotide polymorphism (SNP) variations, to unearth indications of selection shaped by climate-mediated forces in goats. Through the examination of 43,300 SNPs from 51 indigenous goat breeds adapting to different climatic conditions using four analytical methods: latent factor mixed models (LFMM), F-statistics (Fst), Extended haplotype homozygosity across populations (XPEHH), and spatial analysis method (SAM), A total of 74 genes were revealed to display clear signs of selection, which are believed to be influenced by climatic conditions. Among these genes, 32 were consistently identified by at least two of the applied methods, and three genes (DENND1A, PLCB1, and ITPR2) were confirmed by all four approaches. Moreover, our investigation yielded 148 Gene Ontology (GO) terms based on these 74 genes, underlining pivotal biological pathways crucial for environmental adaptation. These pathways encompass functions like vascular smooth muscle contraction, cellular response to heat, GTPase regulator activity, rhythmic processes, and responses to temperature stimuli. Of significance, GO terms about endocrine regulation and energy metabolic responses, key for local adaptation were also uncovered, including biological processes, such as cell differentiation, regulation of peptide hormone secretion, and lipid metabolism. These findings contribute to our knowledge of the genetic structure of climate-triggered adaptation across the goat genome and have practical implications for marker-assisted breeding in goats.

A new integrative analysis of histopathology and single cell RNA-seq reveals the CCL5 mediated T and NK cell interaction with vascular cells in idiopathic pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. METHODS: Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. RESULTS: Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. CONCLUSIONS: Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

FHL3 promotes the formation of fast glycolytic muscle fibers by interacting with YY1 and muscle glycolytic metabolism.

The proportions of the various muscle fiber types are important in the regulation of skeletal muscle metabolism, as well as animal meat production. Four-and-a-half LIM domain protein 3 (FHL3) is highly expressed in fast glycolytic muscle fibers and differentially regulates the expression of myosin heavy chain (MyHC) isoforms at the cellular level. Whether FHL3 regulates the transformation of muscle fiber types in vivo and the regulatory mechanism is unclear. In this study, muscle-specific FHL3 transgenic mice were generated by random integration, and lentivirus-mediated gene knockdown or overexpression in muscles of mice or pigs was conducted. Functional analysis showed that overexpression of FHL3 in muscles significantly increased the proportion of fast-twitch myofibers and muscle mass but decreased muscle succinate dehydrogenase (SDH) activity and whole-body oxygen consumption. Lentivirus-mediated FHL3 knockdown in muscles significantly decreased muscle mass and the proportion of fast-twitch myofibers. Mechanistically, FHL3 directly interacted with the Yin yang 1 (YY1) DNA-binding domain, repressed the binding of YY1 to the fast glycolytic MyHC2b gene regulatory region, and thereby promoted MyHC2b expression. FHL3 also competed with EZH2 to bind the repression domain of YY1 and reduced H3K27me3 enrichment in the MyHC2b regulatory region. Moreover, FHL3 overexpression reduced glucose tolerance by affecting muscle glycolytic metabolism, and its mRNA expression in muscle was positively associated with hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Therefore, FHL3 is a novel potential target gene for the treatment of muscle metabolism-related diseases and improvement of animal meat production.

Clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism: a multicenter study report.

BACKGROUND: Clinical characteristics of patients with pulmonary thromboembolism have been described in previous studies. Although very old patients with pulmonary thromboembolism are a special group based on comorbidities and age, they do not receive special attention. OBJECTIVE: This study aims to explore the clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism in a relatively large population. DESIGN AND PARTICIPANTS: The study included a total of 7438 patients from a national, multicenter, registry study, the China pUlmonary thromboembolism REgistry Study (CURES). Consecutive patients with acute pulmonary thromboembolism were enrolled and were divided into three groups. Comparisons were performed between these three groups in terms of clinical characteristics, comorbidities and in-hospital prognosis. Mortality predictors were analyzed in very old patients with pulmonary embolism. KEY RESULTS: In 7,438 patients with acute pulmonary thromboembolism, 609 patients aged equal to or greater than 80 years (male 354 (58.1%)). There were 2743 patients aged between 65 and 79 years (male 1313 (48%)) and 4095 patients aged younger than 65 years (male 2272 (55.5%)). Patients with advanced age had significantly more comorbidities and worse condition, however, some predisposing factors were more obvious in younger patients with pulmonary thromboembolism. PaO2 < 60 mmHg, eGFR < 60 mL/min/1.73m2, malignancy, anticoagulation as first therapy were mortality predictors for all-cause death in very old patients with pulmonary thromboembolism. The analysis found that younger patients were more likely to have chest pain, hemoptysis (the difference was statistically significant) and dyspnea triad. CONCLUSION: In very old population diagnosed with pulmonary thromboembolism, worse laboratory results, atypical symptoms and physical signs were common. Mortality was very high and comorbid conditions were their features compared to younger patients. PaO2 < 60 mmHg, eGFR < 60 mL/min/1.73m2 and malignancy were positive mortality predictors for all-cause death in very old patients with pulmonary thromboembolism while anticoagulation as first therapy was negative mortality predictors.

The management pattern and outcomes of chronic thromboembolic pulmonary hypertension: rationale and design for a Chinese real-world study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. METHODS AND DESIGN: The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. CONCLUSIONS: As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT05311072.

Effect of Yangxin Huoxue Jiedu recipe on inflammatory factors and oxidative stress on viral myocarditis in children.

OBJECTIVE: This observation purposed to investigate the effect of the Yangxin Huoxue Jiedu formula on children with viral myocarditis and its effect on inflammatory factors and oxidative response. MATERIALS AND METHODS: A total of 121 children with viral myocarditis were randomly divided into two groups, namely the control group (N = 60) and the traditional Chinese medicine group (N = 61). The control group was mainly treated with routine therapy, while the traditional Chinese medicine group was treated with Yangxin Huoxue Jiedu recipes based on the control group. The creatine kinase, creatine kinase myocardial isoenzyme, aspartate aminotransferase, lactic dehydrogenase, hydroxybutyrate dehydrogenase, cardiac troponin I, brain natriuretic peptide, interleukin-6, interleukin-8, and tumour necrosis factor-alpha, superoxide dismutase and malondialdehyde in viral myocarditis patients were tested to estimate the myocardial function, inflammation, and oxidative situation. RESULTS: After Yangxin Huoxue Jiedu treatment, 15 cases were recovered, 20 were excellent, and 21 were effective, which had a significant difference from the control group. The concentration of creatine kinase, creatine kinase myocardial isoenzyme, aspartate aminotransferase, lactic dehydrogenase, hydroxybutyrate dehydrogenase, cardiac troponin I and brain natriuretic peptide was decreased in the traditional Chinese medicine group. The levels of interleukin-6, interleukin-8, and tumour necrosis factor-alpha in the traditional Chinese medicine group were significantly lower than those in the control group. Superoxide dismutase was higher and malondialdehyde was lower than those in the control group. CONCLUSION: The use of Yangxin Huoxue Jiedu in the treatment of viral myocarditis has a definite clinical effect, which could improve myocardial function, reduce body inflammation, and promote oxidative recovery.

Benzofuran Derivatives from Cortex Mori Radicis and Their Cholinesterase-Inhibitory Activity.

The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 µM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5-32.8 µM) than the positive control galantamine (IC50 35.3 µM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 µM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.

Elevated O3 concentrations alter the compartment-specific microbial communities inhabiting rust-infected poplars.

Elevated ozone (O3 ) can affect the susceptivity of plants to rust pathogens. However, the collective role of microbiomes involved in such interaction remains largely elusive. We exposed two cultivated poplar clones exhibiting differential O3 sensitivities, to non-filtered ambient air (NF), NF + 40 ppb or NF + 60 ppb O3 -enriched air in field open-top chambers and then inoculated Melampsora larici-populina urediniospores to study their response to rust infection and to investigate how microbiomes inhabiting four compartments (phyllosphere, rhizosphere, root endosphere, bulk soil) are involved in this response. We found that hosts with higher O3 sensitivity had significantly lower rust severity than hosts with lower sensitivity. Furthermore, the effect of increased O3 on the diversity and composition of microbial communities was highly dependent on poplar compartments, with the microbial network complexity patterns being completely opposite between the two clones. Notably, microbial source analysis estimated that phyllosphere fungal communities predominately derived from root endosphere and vice versa, suggesting a potential transmission mechanism between plant above- and below-ground systems. These promising results suggest that further investigations are needed to better understand the interactions of abiotic and biotic stresses on plant performance and the role of the microbiome in driving these changes.

Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population.

BACKGROUND: A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. METHODS: We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. RESULTS: After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 × 10-14), ABO rs582094 (p-value = 1.16 × 10-10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10-17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. CONCLUSIONS: We identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

Proteome-wide mendelian randomization identifies causal plasma proteins in venous thromboembolism development.

Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.

Cancer stem cells and their niche in cancer progression and therapy.

High recurrence and metastasis rates and poor prognoses are the major challenges of current cancer therapy. Mounting evidence suggests that cancer stem cells (CSCs) play an important role in cancer development, chemoradiotherapy resistance, recurrence, and metastasis. Therefore, targeted CSC therapy has become a new strategy for solving the problems of cancer metastasis and recurrence. Since the properties of CSCs are regulated by the specific tumour microenvironment, the so-called CSC niche, which targets crosstalk between CSCs and their niches, is vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. In this review, we aim to highlight the factors within the CSC niche that have important roles in regulating CSC properties, including the extracellular matrix (ECM), stromal cells (e.g., associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs)), and physiological changes (e.g., inflammation, hypoxia, and angiogenesis). We also discuss recent progress regarding therapies targeting CSCs and their niche to elucidate developments of more effective therapeutic strategies to eliminate cancer.

The prognostic value of systemic immune-inflammation index in patients with aneurysmal subarachnoid hemorrhage: a systematic review.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating and life-threatening stroke subtype, that has a high disability and fatality rate. By the use of the systemic immune-inflammation index (SII), it is possible to understand the pathophysiology that underlies immune and inflammatory responses and anticipate consequences including delayed cerebral ischemia (DCI), delayed cerebral vasospasm, and functional outcome. A systematic search of the English-language literature in PubMed and Embase was performed to locate articles addressing the usage of SII in aSAH patients. The cutoff value, sensitivity, specificity, and area-under-the curve (AUC) of the receiver operating characteristic (ROC) curve were collected. Four publications were reviewed after applying the exclusion criteria from the 53 included articles. All the studies indicated that higher SII on admission was significantly associated with poor prognosis. The research examined in this paper provides the earliest indications that higher SII predicts DCI, delayed cerebral vasospasm, and functional outcome, even though other medical subspecialties have used this ratio for a long time to make such predictions.

Identification of N1 methyladenosine-related biomarker predicting overall survival outcomes and experimental verification in ovarian cancer.

AIM: This study aimed to construct a N1-methyladenosine (m1A)-related biomarker model for predicting the prognosis of ovarian cancer (OVCA). METHODS: OVCA samples were clustered into two subtypes using the Non-Negative Matrix Factorization (NMF) algorithm, including TCGA (n = 374) as the training set and GSE26712 (n = 185) as the external validation set. Hub genes, which were screened to construct a risk model, and nomogram to predict the overall survival of OVCA were explored and validated through various bioinformatic analysis and quantitative real-time PCR. RESULTS: Following bootstrap correction, the C-index of nomogram was 0.62515, showing reliable performance. The functions of DEGs in the high- and low-risk groups were mainly enriched in immune response, immune regulation, and immune-related diseases. The immune cells relevant to the expression of hub genes were explored, for example, Natural Killer (NK) cells, T cells, activated dendritic cells (aDC). CONCLUSIONS: AADAC, CD38, CACNA1C, and ATP1A3 might be used as m1A-related biomarkers for OVCA, and the nomogram labeled with m1A for the first time had excellent performance for predicting overall survival in OVCA.

Spatial heterogeneity and source apportionment of soil metal(loid)s in an abandoned lead/zinc smelter.

Metal smelting have brought severe metal(loid)s contamination to the soil. Spatial distribution and pollution source analysis for soil metal(loid)s in an abandoned lead/zinc smelter were studied. The results showed that soil was contaminated heavily with metal(loid)s. The mean of lead (Pb), arsenic (As), cadmium (Cd), mercury (Hg) and antimony (Sb) content in topsoil is 9.7, 8.2, 5.0, 2.3, and 1.2 times higher than the risk screening value for soil contamination of development land of China (GB36600-2018), respectively. Cd is mainly enriched in the 0-6 m depth of site soil while As and Pb mainly deposited in the 0-4 m layer. The spatial distribution of soil metal(loid)s is significantly correlated with the pollution source in the different functional areas of smelter. As, Hg, Sb, Pb and copper (Cu) were mainly distributed in pyrometallurgical area, while Cd, thallium (Tl) and zinc (Zn) was mainly existed in both hydrometallurgical area and raw material storage area. Soil metal(loid)s pollution sources in the abandoned smelter are mainly contributed to the anthropogenic sources, accounting for 84.5%. Specifically, Pb, Tl, As, Hg, Sb and Cu mainly from atmospheric deposition (55.9%), Cd and Zn mainly from surface runoff (28.6%), While nickel (Ni) mainly comes from parent material (15.5%). The results clarified the spatial distribution and their sources in different functional areas of the smelter, providing a new thought for the risk prevention and control of metal(loid)s in polluted site soil.

Atomically Dispersed Iron Regulating Electronic Structure of Iron Atom Clusters for Electrocatalytic H2 O2 Production and Biomass Upgrading.

The integration of highly active single atoms (SAs) and atom clusters (ACs) into an electrocatalyst is critically important for high-efficiency two-electron oxygen reduction reaction (2e- ORR) to hydrogen peroxide (H2 O2 ). Here we report a tandem impregnation-pyrolysis-etching strategy to fabricate the oxygen-coordinated Fe SAs and ACs anchored on bacterial cellulose-derived carbon (BCC) (FeSAs/ACs-BCC). As the electrocatalyst, FeSAs/ACs-BCC exhibits superior electrocatalytic activity and selectivity toward 2e- ORR, affording an onset potential of 0.78 V (vs. RHE) and a high H2 O2 selectivity of 96.5 % in 0.1 M KOH. In a flow cell reactor, the FeSAs/ACs-BCC also achieves high-efficiency H2 O2 production with a yield rate of 12.51±0.18 mol gcat -1 h-1 and a faradaic efficiency of 89.4 %±1.3 % at 150 mA cm-2 . Additionally, the feasibility of coupling the produced H2 O2 and electro-Fenton process for the valorization of ethylene glycol was explored in detail. The theoretical calculations uncover that the oxygen-coordinated Fe SAs effectively regulate the electronic structure of Fe ACs which are the 2e- ORR active sites, resulting in the optimal binding strength of *OOH intermediate for high-efficiency H2 O2 production.

A Pacman-Like Titanium-Doped Cobalt Sulfide Hollow Superstructure for Electrocatalytic Oxygen Evolution.

Transition-metal sulfides (TMSs) are attractive oxygen evolution reaction (OER) electrocatalysts. Developing new strategies to improve their electrochemical performance of TMSs is of great significance. Herein, a unique pacman-like titanium-doped cobalt sulfide hollow superstructure (Ti-CoSx HSS) is fabricated as an OER electrocatalyst. Using a prearranged metal-organic framework (MOF)-on-MOF heterostructure as a precursor treated by one-pot sulfidation, a sequential structural conversion process leads to the formation of Ti-CoSx HSS, which is assembled by interconnected Ti-doped CoSx nanocages around a cake-like cavity. Benefiting from the architecture and compositional advantages, Ti-CoSx HSS exhibits excellent OER performance with an overpotential of 249 mV at 10 mA cm-2 and Tafel slope of 45.5 mV dec-1 due to increased active site exposure, enhanced electron and mass transfer. This strategy enabled by MOF-on-MOF paves the way toward innovative MOF derivatives for various applications.

LMWHs dosage and outcomes in acute pulmonary embolism with renal insufficiency, an analysis from a large real-world study.

BACKGROUND: Renal function is associated with prognoses for acute pulmonary embolism (PE). OBJECTIVE: To investigate the application of anticoagulants and dosage of LMWH among patients with renal insufficiency (RI), and the association between LWMH dosage and the patients' in-hospital outcomes. METHODS: Adult patients diagnosed with non-high risk acute PE from 2009 to 2015, with available data of creatinine clearance (CCr) were enrolled from a multicenter registry in China. Renal insufficiency (RI) was defined as CCr < 60 ml/min. LMWH dosage was converted into IU/kg daily dose and presented as adjusted dose (≤ 100 IU/kg/day) and conventional dose (> 100 IU/kg/day). All-cause death, PE-related death and bleeding events during hospitalization were analyzed as endpoints. RESULTS: Among the enrolled 5870 patients, RI occurred in 1311 (22.3%). 30 ≤ CCr < 60 ml/min was associated with higher rate of bleeding events and CCr < 30 ml/min was associated with all-cause death, PE-related death and major bleeding. Adjusted-dose LMWH was applied in 26.1% of patients with 30 ≤ CCr < 60 ml/min and in 26.2% of CCr < 30 ml/min patients. Among patients with RI, in-hospital bleeding occurred more frequently in those who were administered conventional dose of LMWH, compared with adjusted dose (9.2% vs 5.0%, p = 0.047). Adjusted dose of LMWH presented as protective factor for in-hospital bleeding (OR 0.62, 95%CI 0.27-1.00, p = 0.0496) and the risk of bleeding increased as length of hospital stay prolonged (OR 1.03, 95%CI 1.01-1.06, p = 0.0014). CONCLUSIONS: The proportion of adjusted usage of LMWH was low. The application of adjusted-dose LMWH was associated with lower risk of in-hospital bleeding for RI patients, in real-world setting of PE treatment. Anticoagulation strategy for RI patients should be paid more attention and requires evidence of high quality. TRIAL REGISTRATION: The CURES was registered in ClinicalTrias.gov, identifier number: NCT02943343 .

What Should Be Responsible for Eryptosis in Chronic Kidney Disease?

BACKGROUND: Renal anemia is an important complication of chronic kidney disease (CKD). In addition to insufficient secretion of erythropoietin (EPO) and erythropoiesis disorders, the impact of eryptosis on renal anemia demands attention. However, a systemic analysis concerning the pathophysiology of eryptosis has not been expounded. SUMMARY: The complicated conditions in CKD patients, including oxidative stress, osmotic stress, metabolic stress, accumulation of uremic toxins, and iron deficiency, affect the normal skeleton structure of red blood cells (RBCs) and disturbs ionic homeostasis, causing phosphatidylserine to translocate to the outer lobules of the RBC membrane that leads to early elimination and/or shortening of the RBC lifespan. Inadequate synthesis of RBCs cannot compensate for their accelerated destruction, thus exacerbating renal anemia. Meanwhile, EPO treatment alone will not reverse renal anemia. A variety of eryptosis inhibitors have so far been found, but evidence of their effectiveness in the treatment of CKD remains to be established. KEY MESSAGES: In this review, the pathophysiological processes and factors influencing eryptosis in CKD were elucidated. The aim of this review was to underline the importance of eryptosis in renal anemia and determine some promising research directions or possible therapeutic targets to correct anemia in CKD.

First report of leaf spot and stem blight on blueberry (Vaccinium corymbosum cv. Bluerain) caused by Calonectria pseudoreteaudii in China.

Blueberry has high nutritional value and is one of the five healthy fruits. In 2018, leaf spots and stem blights were observed on Vaccinium corymbosum cv. Bluerain in Guangzhou, Guangdong Province, China. Up to 80% of the plants were affected. Initial symptoms of affected leaves were red-brown, irregular, small spots, which gradually coalesced and formed larger irregular necrotic patches. The affected stems showed red-brown and irregular large lesions. Diseased tissues were surface sterilized with 75% alcohol for 15 s, followed by 2.5% NaClO for 30 s, and rinsing three times in sterile distilled water, placed on potato dextrose agar (PDA) and incubated at 25 C. Representative strains, ZHKUCC 21-0021 from diseased leaves and ZHKUCC 21-0073 from diseased stems, were selected for further studies. Colonies grew slowly at 25 C on malt extract agar (MEA) (average 5.68 mm/d), producing white aerial mycelium and red-brown color on the underside after 7 days. Macroconidiophores were hyaline, smooth, consisting of a stipe bearing fertile branches, and a stipe extension terminating in a vesicle. Each terminal branch produced 2-4 phialides, 8-13 × 3-6 µm, reniform or doliiform; Stipe extensions were septate, terminating in a narrowly clavate vesicle, 2-6 µm. Macroconidia were hyaline, straight cylindrical, round at both ends, 83-100 × 7-11 µm (average = 94 × 8 µm; n = 50), with 5 septa. These morphological characteristics were similar to the description of Calonectria pseudoreteaudii (Lombard et al., 2010). The partial calmodulin (cmdA), beta-tubulin (ß-tubulin), and translation elongation factor 1-alpha (tef1-α) genes of the two isolates were respectively amplified using primers CAL-228F/CAL-737R (Carbone et al., 1999), EF1-728F/EF2 and T1/CYLTUB1R (Lombard et al., 2015), and sequences were deposited in GenBank (cmdA: MZ516854 and MZ516855; ß-tubulin: MZ516858 and MZ516859; tef1-α: MZ516856 and MZ516857). BLAST analysis of three gene sequences showed 100% similarity to those of C. pseudoreteaudii. In the maximum likelihood (ML) tree of the concatenated sequences of the three genes, the two isolates from this study were clustered with C. pseudoreteaudii with 100% bootstrap support. Five-mm-diameter hyphal plugs of two representative isolates grown on PDA for five days were used in the pathogenicity test. Leaves were inoculated with ZHKUCC 21-0021, and stems were inoculated with ZHKUCC 21-0073 with five replicates. As controls, sterile PDA plugs were used. All inoculated plants were maintained at 25 C . After 7 days, inoculated leaves and stems developed symptoms similar to field samples, whereas the control plants remained asymptomatic. The pathogen was reisolated from inoculated plants and confirmed to be C. pseudoreteaudii by morphological characteristics. Five Calonectria species (C. canadensis, C. colhounii, C. ilicicola, C. kyotensis and C. pyrochroa), have been reported associated with blueberry (Farr and Rossman, 2022; Fei et al, 2017). Calonectria canadensis and C. ilicicola have been reported to cause stem blight and stem rot in Vaccinium spp. in China (Fei et al, 2017 and 2018). Calonectria colhounii has been reported to cause stem blight in V. angustifolium and V. corymbosum in the United States (Sadowsky et al, 2011). However, this is the first report of C. pseudoreteaudii causing leaf spot and stem blight on Vaccinium spp. worldwide. These results will provide a foundation for future research on prevention and control of this disease.