Enterovirus 71 Activates Plasmacytoid Dendritic Cell-Dependent PSGL-1 Binding Independent of Productive Infection.

Enterovirus 71 (EV71) is a significant causative agent of hand, foot, and mouth disease, with potential serious neurologic complications or fatal outcomes. The lack of effective treatments for EV71 infection is attributed to its elusive pathogenicity. Our study reveals that human plasmacytoid dendritic cells (pDCs), the main type I IFN-producing cells, selectively express scavenger receptor class B, member 2 (SCARB2) and P-selectin glycoprotein ligand 1 (PSGL-1), crucial cellular receptors for EV71. Some strains of EV71 can replicate within pDCs and stimulate IFN-α production. The activation of pDCs by EV71 is hindered by Abs to PSGL-1 and soluble PSGL-1, whereas Abs to SCARB2 and soluble SCARB2 have a less pronounced effect. Our data suggest that only strains binding to PSGL-1, more commonly found in severe cases, can replicate in pDCs and induce IFN-α secretion, highlighting the importance of PSGL-1 in these processes. Furthermore, IFN-α secretion by pDCs can be triggered by EV71 or UV-inactivated EV71 virions, indicating that productive infection is not necessary for pDC activation. These findings provide new insights into the interaction between EV71 and pDCs, suggesting that pDC activation could potentially mitigate the severity of EV71-related diseases.

Efficient Acidic Photoelectrochemical Water Splitting Enabled by Ru Single Atoms Anchored on Hematite Photoanodes.

Photoelectrochemical (PEC) water splitting in acidic media holds promise as an efficient approach to renewable hydrogen production. However, the development of highly active and stable photoanodes under acidic conditions remains a significant challenge. Herein, we demonstrate the remarkable water oxidation performance of Ru single atom decorated hematite (Fe2O3) photoanodes, resulting in a high photocurrent of 1.42 mA cm-2 at 1.23 VRHE under acidic conditions. Comprehensive experimental and theoretical investigations shed light on the mechanisms underlying the superior activity of the Ru-decorated photoanode. The presence of single Ru atoms enhances the separation and transfer of photogenerated carriers, facilitating efficient water oxidation kinetics on the Fe2O3 surface. This is achieved by creating additional energy levels within the Fe2O3 bandgap and optimizing the free adsorption energy of intermediates. These modifications effectively lower the energy barrier of the rate-determining step for water splitting, thereby promoting efficient PEC hydrogen production.

Unlocking Lattice Oxygen on Selenide-Derived NiCoOOH for Amine Electrooxidation and Efficient Hydrogen Production.

In pursuit of advancing the electrooxidation of amines, which is typically encumbered by the inertness of C(sp3)-H/N(sp3)-H bonds, our study introduces a high-performance electrocatalyst that significantly enhances the production efficiency of vital chemicals and fuels. We propose a novel electrocatalytic strategy employing a uniquely designed (NixCo1-x)Se2-R electrocatalyst, which is activated through Se-O exchange and electron orbital spin manipulation. This catalyst efficiently generates M4+ species, thus enabling the activation of lattice oxygen and streamlining the electrooxidation of amines. Empirical evidence from isotope labeling, molecular probes, and computational analyses indicates that the electrocatalyst fosters the formation of energetically favorable peroxy radical intermediates, which substantially expedite the reaction kinetics. The refined electrocatalyst achieves an exceptional current density of 20 mA cm-2 at a potential of 1.315 V, with selectivity surpassing 99% for propionitrile, while demonstrating remarkable stability over 560 h. This work emphasizes the criticality of deciphering the fundamental mechanisms of amine electrooxidation and charts a more sustainable pathway for the nitrile and hydrogen production, marking a substantial advancement in the field of electrocatalysis.

Ir Single Atoms Boost Metal-Oxygen Covalency on Selenide-Derived NiOOH for Direct Intramolecular Oxygen Coupling.

This investigation probes the intricate interplay of catalyst dynamics and reaction pathways during the oxygen evolution reaction (OER), highlighting the significance of atomic-level and local ligand structure insights in crafting highly active electrocatalysts. Leveraging a tailored ion exchange reaction followed by electrochemical dynamic reconstruction, we engineered a novel catalytic structure featuring single Ir atoms anchored to NiOOH (Ir1@NiOOH). This novel approach involved the strategic replacement of Fe with Ir, facilitating the transition of selenide precatalysts into active (oxy)hydroxides. This elemental substitution promoted an upward shift in the O 2p band and intensified the metal-oxygen covalency, thereby altering the OER mechanism toward enhanced activity. The shift from a single-metal site mechanism (SMSM) in NiOOH to a dual-metal-site mechanism (DMSM) in Ir1@NiOOH was substantiated by in situ differential electrochemical mass spectrometry (DEMS) and supported by theoretical insights. Remarkably, the Ir1@NiOOH electrode exhibited exceptional electrocatalytic performance, achieving overpotentials as low as 142 and 308 mV at current densities of 10 and 1000 mA cm-2, respectively, setting a new benchmark for the electrocatalysis of OER.

miR171-targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 regulate somatic embryogenesis in citrus.

Somatic embryogenesis (SE) is a key regeneration pathway in various biotechnology approaches to crop improvement, especially for economically important perennial woody crops like citrus. However, maintenance of SE capability has long been a challenge and becomes a bottleneck in biotechnology-facilitated plant improvement. In the embryogenic callus (EC) of citrus, we identified 2 csi-miR171c-targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 (CsSCL2/3), which exert positive feedback regulation on csi-miR171c expression. Suppression of CsSCL2 expression by RNA interference (RNAi) enhanced SE in citrus callus. A thioredoxin superfamily protein CsClot was identified as an interactive protein of CsSCL2/3. Overexpression of CsClot disturbed reactive oxygen species (ROS) homeostasis in EC and enhanced SE. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA-Seq identified 660 genes directly suppressed by CsSCL2 that were enriched in biological processes including development-related processes, auxin signaling pathway, and cell wall organization. CsSCL2/3 bound to the promoters of regeneration-related genes, such as WUSCHEL-RELATED HOMEOBOX 2 (CsWOX2), CsWOX13, and Lateral Organ Boundaries Domain 40 (LBD40), and repressed their expression. Overall, CsSCL2/3 modulate ROS homeostasis through the interactive protein CsClot and directly suppress the expression of regeneration-related genes, thus regulating SE in citrus. We uncovered a regulatory pathway of miR171c-targeted CsSCL2/3 in SE, which shed light on the mechanism of SE and regeneration capability maintenance in citrus.

Theory and application of temporal coupling mode for a SiC/CaF2/Ag cell-based grating.

Tailoring spectral thermal radiation properties via multiple resonances excited by micro/nanoscale-patterned structures plays a vital role in designing functional emitters and devices. However, predicting thermal radiation properties of a structure with multiple resonances-via a fast and accurate algorithm-is still challenging because of the complex mode coupling effects of different resonances. Herein, we establish a temporal coupling mode (TCM) model for a SiC/CaF2/Ag cell-based grating by extracting the intrinsic parameters and coupling constants of the resonances. The accuracy and efficiency of the established TCM model for predicting absorption spectra of SiC/CaF2/Ag gratings with multiple resonances in each unit cell is verified. Results indicate that the narrowband absorption of the SiC/CaF2/Ag cell-based grating can be enhanced via the multiple-resonance coupling effects. This work provides an alternative tool for predicting absorption characteristics of complex structures with multiple-resonance coupling effects.

Hypoxic Preconditioning Enhances Cellular Viability and Migratory Ability: Role of DANCR/miR-656-3p/HIF-1α Axis in Placental Mesenchymal Stem Cells.

Preeclampsia (PE) is a common complication of pregnancy characterized by new-onset hypertension, albuminuria, or end-stage organ dysfunction, which is seriously harmful to maternal and infant health. Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from extraembryonic mesoderm. They have the potential for self-renewal, multidirectional differentiation, immunomodulation, and tissue regeneration. Several in vivo and in vitro experiments have confirmed that MSCs can delay the pathological progression of PE and improve maternal and fetal outcomes. However, the major limitations in the application of MSCs are their low-survival rates in ischemic and hypoxic disease areas after transplantation and their low rate of successful migration to the diseased regions. Therefore, enhancing cell viability and migration ability of MSCs in both ischemic and anoxic environments is important. This study aimed to investigate the effects of hypoxic preconditioning on the viability and migration ability of placental mesenchymal stem cells (PMSCs) and their underlying mechanisms. In this study, we found that hypoxic preconditioning enhanced the viability and migration ability of PMSCs, increased the expression of DANCR and hypoxia-inducible factor-1α (HIF-1α), and decreased the expression of miR-656-3p in PMSCs. Inhibiting the expression of HIF-1α and DACNR in PMSCs under hypoxia can inhibit the promotive effect of hypoxic preconditioning on viability and migration ability. In addition, RNA pull down and double luciferase assays confirmed that miR-656-3p could directly bind to DANCR and HIF-1α. In conclusion, our study showed that hypoxia could promote the viability and migration ability of PMSCs through the DANCR/miR-656-3p/HIF-1α axis.

"Access to pharmacy services is difficult in China": a qualitative study from the perspective of transplant recipients to explore their expectations.

PURPOSE: To gain an in-depth and comprehensive understanding of Chinese organ transplant recipients' perceptions, expectations, and suggestions of pharmacy services to hospital pharmacists. METHODS: This qualitative study was conducted in central China, from February to December 2020. Participants were collected with a purposive and snowball sampling method. Focus group discussions were conducted with organ transplant recipients and content analysis was applied to identify themes and subthemes. RESULTS: 21 recipients participated in the qualitative study. Four themes and thirteen subthemes were identified: (1) perceptions of clinical pharmacists and pharmacy services; (2) expectations for pharmacy service content; (3) expectations for pharmacy service form; and (4) difficulties as a special group. CONCLUSION: The pharmacy services provided by Chinese healthcare institutions are inadequate to meet the needs of organ transplant recipients. However, the acceptance and expectation of pharmacy services by transplant recipients are high. Therefore, China should learn from the experience of developed countries and focus on the actual needs of patients to establish a better pharmacy service system for organ transplantation.

Association between PM10 pollution and the hospitalization of chronic obstructive pulmonary disease with comorbidity: evidence in 17 cities of Henan, Central China.

Particulate matter (PM10) changes have been confirmed as one of the contributory factors affecting human health, the association between PM10 pollution and the hospitalization of chronic obstructive pulmonary disease (COPD) with comorbidity diseases was rarely reported. The same inpatient more than twice times admissions with COPD illness from January 1, 2016 to December 31, 2021 were identified from hospitals in the 17 cities of Henan, Central China. City-specific associations were firstly estimated using the case time series (CTS) model and then combined to obtain the regional average association. The multivariate meta-analytic model produces pooled estimates of the set of coefficients representing the PM10-COPD hospitalizations association across the 17 cities. Cause-specific hospitalization analyses were performed by COPD patients with different comorbidity combinations. A total of 34,348 elderly (age ≥ 65) subjects were analyzed and with a total of 35,122.35 person-years. These coefficients can be used to compute the linear exposure-response curve expressed as relative risk (RR) in per 10 µg/m3 increase in PM10 at lag03, which was 1.0091 (95% CI 1.0070-1.0112) for COPD with comorbidity, 1.0089 (95% CI 1.0067-1.0110) for COPD with circulatory system diseases, 1.0079 (95% CI 1.0052-1.0105) for COPD with respiratory system diseases, 1.0076 (95% CI 1.0032-1.0121) for COPD with endocrine system diseases, and 1.0087 (95% CI 1.0013-1.0162) for COPD with genitourinary system diseases, respectively. Some heterogeneity was found across cities, with estimates ranging from 1.0227 in the Puyang and Jiaozuo to 1.0053 in Henan Provance, China. The effect of higher PM10, on average, was higher in studies for northern cities, with a steeper raise in risk: per 10 µg/m3 increase in PM10, the RR from 1.0062 (95% CI 1.0030-1.0093) for the 10th percentile of latitude to 1.0124 (95% CI 1.0089-1.0160) for the 90th percentile. Our findings indicated that PM10 exposure may increase the risk of hospitalizations for COPD with comorbidity. Moreover, there might be a higher morbidity risk associated with PM10 in northern latitudes, indicating that stricter air quality standards could potentially reduce PM10-related morbidity among individuals with COPD. These findings have implications for the implementation of effective clean air interventions aligned with national climate policies.

Screening and Resistance Locus Identification of the Mutant fcrZ22 Resistant to Crown Rot Caused by Fusarium pseudograminearum.

Crown rot caused by Fusarium pseudograminearum is a devastating wheat disease worldwide. In addition to yield losses, the fungi causing Fusarium crown rot (FCR) also deteriorate the quality and safety of food because of the production of mycotoxins. Planting resistant cultivars is an effective way to control FCR. However, most wheat cultivars are susceptible to FCR. Therefore, development of new sources and detection of loci for FCR resistance are necessary. In the present study, a resistant mutant, fcrZ22, was identified from an ethyl methane sulfonate (EMS)-mutagenized population of the cultivar Zhoumai 22, and then fcrZ22 was crossed with the wild type to produce an F2 population. Genetic analysis of the F2 population was carried out by the mixed inheritance model of major genes plus polygenes, and 20 resistant and 20 susceptible plants were selected to assemble mixed pools. Combining 660K SNP arrays, the resistance loci were detected by bulked segregant analysis. The resistance to FCR caused by F. pseudograminearum in the F2 population was in accordance with the "mixed model with two major genes of additive-epistasis effect + additive-dominant polygenes," and the heritability of the major gene was 0.92. Twenty-one loci were detected, which were located on 10 chromosomes, namely, 1B (1), 1D (1), 2A (3), 1B (1), 3A (3), 3B (3), 4A (2), 5A (2), 7A (3), and 7B (2). Among the 21 loci, eight were new loci for FCR resistance. This is the first report of detecting loci for FCR resistance from a mutant. The results of the present study provided excellent germplasm resources for breeding wheat cultivars with FCR resistance and laid the foundation for fine mapping of FCR resistance loci.

Mutagenesis-Derived Resistance to Black Point in Wheat.

Black point, a severe global wheat disease, necessitates deploying resistant cultivars for effective control. However, susceptibility remains prevalent among most wheat cultivars. Identifying new sources of resistance and understanding their mechanisms are crucial for breeding resistant cultivars. This study pinpointed black point resistance in an ethyl methane sulfonate (EMS)-mutagenized wheat population of Wanyuanbai 1 (WYB) and analyzed resistant mutants using RNA-Seq. The findings revealed the following: (i) wyb-18, among 10,008 EMS-mutagenized lines, exhibited robust resistance with significantly lower black point incidence under artificial Bipolaris sorokiniana inoculation in 2020 and 2021 (average incidence of 5.2% over 2 years), markedly reduced compared with WYB (50.9%). (ii) wyb-18 kernels displayed black point symptoms at 12 days after inoculation (dai), 3 days later than WYB. At 15 dai, wyb-18 kernels had isolated black spots, unlike WYB kernels, where the entire embryo turned black. (iii) wyb-18 showed heightened antioxidant enzyme activity, including peroxidase, catalase, and superoxide dismutase. (iv) Analysis of 543 differentially expressed genes between wyb-18 and WYB at 9 dai identified enrichment in the MAPK signaling pathway through KEGG analysis. Ten genes in this pathway exhibited upregulated expression, while one was downregulated in wyb-18. Among these genes, PR1, WRKY11, SAPK5, and TraesCS1A02G326800 (chitin recognition protein) consistently showed upregulation in wyb-18, making them potential candidates for black point resistance. These results offer valuable germplasm resources for breeding and novel insights into the mechanisms of black point resistance.

Development of a self-assessment tool to evaluate the readiness of pharmacy departments for internship training in China: a two-phase study.

OBJECTIVES: Internships in the pharmacy departments of training hospitals represent a crucial stage in the professional development of pharmacy students. However, the quality of internship training varies significantly across training hospitals in China, and there is a lack of standardized readiness evaluation tools. Therefore, the purpose of this study was to develop a self-assessment tool to evaluate the preparedness of training hospitals for providing internship training. METHODS: This study employed an exploratory mixed-methods approach and was conducted in two phases. In the first phase, during 2021, focus groups were conducted with 16 interns from three tertiary hospitals in Henan Province. In 2022, 14 preceptors from tertiary hospitals in various provinces were interviewed either one-on-one or in focus groups. The interview data were analyzed using thematic analysis to compile a set of self-assessment indicators for internship training readiness. Subsequently, the initial draft of the self-assessment tool for internship training readiness was developed by integrating the indicators derived from the interviews and literature review. In the second phase, the Delphi method was utilized. In 2023, the experts participated in two rounds of correspondence (21 experts in the first round and 19 in the second round), and consensus was reached on the indicators of the self-assessment tool after the two rounds. Meanwhile, these experts assessed the current status of internship training in training hospitals across China. RESULTS: The qualitative findings of the first phase included five themes and 22 sub-themes, which were integrated with the indicators derived from the literature review to develop an initial indicator framework for the second phase. This initial framework comprised five domains and 37 items. The second phase involved two rounds of expert surveys, with effective response rates of 90.48% and 89.47%, respectively. Ultimately, the self-assessment tool for evaluating the readiness of pharmacy departments in training hospitals for internships included five dimensions and 35 secondary indicators: (1) organizational structure, (2) training content, (3) training mode, (4) effectiveness evaluation, and (5) emergency management. Additionally, experts assessed the readiness of pharmacy departments in Chinese training hospitals for internships, yielding varied results. Emergency management preparedness scored the highest, followed by organizational structure and training content preparation. However, the modes of internship training and the evaluation of training effectiveness received lower scores. CONCLUSION: The developed tool provides a comprehensive self-assessment checklist for the pharmacy departments of training hospitals and possesses the potential to enhance the development of more effective internship training programs.

Exploring the problems and coping strategies of pharmacy internship in large general hospitals in China: from the perspective of preceptors.

OBJECTIVE: The role of the Hospital Pharmacy Preceptor (HPP) is pivotal in upholding the excellence of experiential training and fostering the professional growth of pharmacy interns. However, there is a lack of studies that provide an overview of pharmacy internships from the perspective of HPP. This study explores the experience and expectations of HPPs regarding existing problems and possible coping strategies in intern teaching. METHODS: This is a qualitative study that was conducted through individual interviews and focus group discussions. HPPs were invited as participants from large-scale tertiary hospitals in representative provinces of mainland China. Interview and focus group discussion data were analyzed using thematic analysis to see emerging themes from the data. Nvivo 12 was utilized for data management and processing. RESULTS: Eight individual interviews and two focus group discussions were conducted, involving 14 HPPs as participants. Upon the examination of the interviews and focus group data, four themes were summarized regarding HPPs' perceptions: 1) current presenting problems; 2) possible coping strategies; 3) something HPPs should do; 4) something interns should do. CONCLUSION: This study found that from the HPPs' perspective, the hospital-based pharmacy internship still has some problems from policy to practice, which need to be addressed by the joint efforts of the state, schools, internship bases, pharmacy preceptors, and students.

Transcriptome- and metabolome-based candidate mechanism of BCR-ABL-independent resistance to olverembatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib represents the third-generation breakpoint cluster region protein-Abelson-murine leukemia 1 (BCR-ABL1) tyrosine kinase inhibitor with oral bioavailability, which can be used to overcome the T315I mutation in Philadelphia chromosome-positive (Ph +) leukemia. BCR-ABL-independent resistance to olverembatinib has been reported among patients in various clinical cases. However, the mechanism of olverembatinib resistance has rarely been reported. This study has illustrated bone marrow cell transcriptome and metabolome profiles among Ph + acute lymphoblastic leukemias (ALL) cases pre- and post-olverembatinib resistance. The transcriptome studies demonstrated that PI3K/AKT, purine metabolism, and other signaling pathways could play a vital role in olverembatinib resistance. As suggested by metabolomics, olverembatinib resistance in Ph + ALL was associated with purine metabolism alterations. Subsequently, high-performance liquid chromatography along with real-time quantitative PCR was utilized to measure purine metabolism-related mRNA levels and metabolism expression levels between olverembatinib resistance and sensitive cell lines. Our results elucidate the mechanism of olverembatinib resistance in Ph + ALL at transcriptome and metabolome levels, which facilitate a better understanding of olverembatinib resistance and hence may prove crucial in identifying novel drugs to tackle this conundrum.

Association of social isolation and cognitive performance: a longitudinal study using a four-wave nationwide survey.

BACKGROUND: This study aimed to examine the bidirectional relationship between social isolation and cognitive performance among Chinese middle-aged and older adults. METHODS: We used four waves of data from the China Health and Retirement Longitudinal Study. A latent growth model (LGM) was applied to examine the association between social isolation and cognitive performance across different characteristics. RESULTS: In the analysis, we ultimately included 9,367 participants after excluding respondents with missing key variables. Social isolation and cognitive performance showed significant differences across time. After adjusting for the confounders, there was a significant association between higher social isolation and poor cognitive performance (ß = -1.38, p < 0.001), and higher levels of social isolation resulted in a more pronounced decline in cognition over time (ß = 0.17, p < 0.001). Additionally, the path coefficient between the initial level of cognition at baseline and the slope of social isolation was - 0.07 (p < 0.001) and 0.01 (p = 0.021), respectively. For the correlation between slopes, our study found that females' cognition scores were more susceptible to social isolation (ß = - 2.78, p < 0.001). Similarly, regarding cognition scores, the influence of social isolation was greater among people with education below the primary level (ß = - 2.89, p = 0.002) or a greater number of chronic diseases (ß = - 2.56, p = 0.001). CONCLUSION: Our findings support the bidirectional association between social isolation and cognition. Specifically, higher baseline social isolation and its rate of increase over time contribute to an intensification of cognitive decline at follow-up. Besides, poorer cognitive performance predicted higher social isolation.

Glochodpurnoid B from Glochidion puberum Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Colorectal Cancer Cells.

Glochidpurnoids A and B (1 and 2), two new coumaroyl or feruloyl oleananes, along with 17 known triterpenoids (3-19) were obtained from the stems and twigs of Glochidion puberum. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, and single crystal X-ray diffraction. All compounds were screened for cytotoxicity against the colorectal cancer cell line HCT-116, and 2, 3, 5, 6, 11, and 17 showed remarkable inhibitory activities (IC50: 0.80-2.99 µM), being more active than the positive control 5-fluorouracil (5-FU). The mechanistic study of 2, the most potent compound, showed that it could induce endoplasmic reticulum (ER) stress-mediated apoptosis and improve the sensitivity of HCT-116 cells to 5-FU.

Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma.

Recent studies have suggested the potency of berberine (BBR) for multiple cancer treatments, including multiple myeloma (MM). However, the direct target and underlying mechanism of BBR remain largely understood in MM. Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells. BBR treatment induced MM cell cycle arrest by downregulating several cell cycle-related proteins. Murine double minute 2 (MDM2) as a BBR-binding protein was identified by surface plasmon resonance image (SPRi) analysis and molecular docking. Overexpression of MDM2 is associated with MM progression and a poor prognosis. Knockdown MDM2 by siRNA transfection can repress MM malignant progression and attenuate the BBR sensitivity to MM.1S cells. BBR treatment induced the degradation of MDM2 through the ubiquitin-proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.

Efficacy and safety of novel oral anticoagulants in patients with atrial nonvalvular atrial fibrillation and diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVE: This study incorporates the results of subgroup analyses of currently published randomized controlled trials (RCTs) and real-world cohort studies to compare the effectiveness and safety of new direct oral anticoagulants (NOACs) and warfarin among nonvalvular atrial fibrillation patients with diabetes. METHODS: The PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov databases were searched. Five retrospective cohort studies and four subgroup analyses of RCTs were included in this meta-analysis. RESULTS: A meta-analysis of the data of 26,7272 patients showed that for patients with nonvalvular atrial fibrillation and diabetes, NOACs can significantly reduce the incidence of stroke/systemic embolism (SSE), ischaemic stroke, and haemorrhagic stroke compared with warfarin, with no significant difference in major bleeding and all-cause mortality. Additionally, NOACs were superior to warfarin in the incidence of intracranial bleeding, gastrointestinal bleeding, myocardial infarction, and vascular death. CONCLUSIONS: Among nonvalvular atrial fibrillation patients with diabetes, NOACs were associated with a lower risk of SSE versus warfarin, with no significant difference in major bleeding. Therefore, NOACs may be a better clinical choice.

Autophagy activation mediates resistance to FLT3 inhibitors in acute myeloid leukemia with FLT3-ITD mutation.

BACKGROUND: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. METHODS: We detected the expression of autophagy markers in FLT3-ITD-positive leukemic cells after vs. before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. RESULTS: Sorafenib-resistant cells markedly overpresented autophagy markers in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to mediate FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame resistance to FLT3 inhibitors. CONCLUSIONS: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance.

miR156 regulates somatic embryogenesis by modulating starch accumulation in citrus.

Somatic embryogenesis (SE) is a major regeneration approach for in vitro cultured tissues of plants, including citrus. However, SE capability is difficult to maintain, and recalcitrance to SE has become a major obstacle to plant biotechnology. We previously reported that miR156-SPL modules regulate SE in citrus callus. However, the downstream regulatory pathway of the miR156-SPL module in SE remains unclear. In this study, we found that transcription factors CsAGL15 and CsFUS3 bind to the CsMIR156A promoter and activate its expression. Suppression of csi-miR156a function leads to up-regulation of four target genes, SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (CsSPL) genes, and reduction of SE efficiency. In the short tandem target mimic (STTM)-miR156a overexpression callus (MIM156), the number of amyloplasts and starch content were significantly reduced, and genes involved in starch synthesis and transport were down-regulated. csi-miR172d was down-regulated, whereas the target genes, CsTOE1.1 and CsTOE1.2, which inhibit the expression of starch biosynthesis genes, were up-regulated. In our working model, CsAGL15 and CsFUS3 activate csi-miR156a, which represses CsSPLs and further regulates csi-miR172d and CsTOEs, thus altering starch accumulation in callus cells and regulating SE in citrus. This study elucidates the pathway of miR156-SPLs and miR172-TOEs-mediated regulation of SE, and provides new insights into enhancing SE capability in citrus.