Decoding Endothelial MPL and JAK2V617F Mutation: Insight Into Cardiovascular Dysfunction in Myeloproliferative Neoplasms.

BACKGROUND: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN. METHODS: We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. RESULTS: Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function. CONCLUSIONS: JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients.

A dose-dependent effect of UV-328 on photosynthesis: Exploring light harvesting and UV-B sensing mechanisms.

Benzotriazole ultraviolet (UV) stabilizers (BUVs) have emerged as significant environmental contaminants, frequently detected in various ecosystems. While the toxicity of BUVs to aquatic organisms is well-documented, studies on their impact on plant life are scarce. Plants are crucial as they provide the primary source of energy and organic matter in ecosystems through photosynthesis. This study investigated the effects of UV-328 (2-(2-hydroxy-4',6'-di-tert-amylphenyl) benzotriazole) on plant growth indices and photosynthesis processes, employing conventional physiological experiments, RNA sequencing (RNA-seq) analysis, and computational methods. Results demonstrated a biphasic response in plant biomass and the maximum quantum yield of PS II (Fv/Fm), showing improvement at a 50 µM UV-328 treatment but reduction under 150 µM UV-328 exposure. Additionally, disruption in thylakoid morphology was observed at the higher concentration. RNA-seq and qRT-PCR analysis identified key differentially expressed genes (light-harvesting chlorophyll-protein complex Ⅰ subunit A4, light-harvesting chlorophyll b-binding protein 3, UVR8, and curvature thylakoid 1 A) related to photosynthetic light harvesting, UV-B sensing, and chloroplast structure pathways, suggesting they may contribute to the observed alterations in photosynthesis activity induced by UV-328 exposure. Molecular docking analyses further supported the binding affinity between these proteins and UV-328. Overall, this study provided comprehensive physiological and molecular insights, contributing valuable information to the evaluation of the potential risks posed by UV-328 to critical plant physiological processes.

Histone Lactylation Is Involved in Mouse Oocyte Maturation and Embryo Development.

Numerous post-translational modifications are involved in oocyte maturation and embryo development. Recently, lactylation has emerged as a novel epigenetic modification implicated in the regulation of diverse cellular processes. However, it remains unclear whether lactylation occurs during oocyte maturation and embryo development processes. Herein, the lysine lactylation (Kla) modifications were determined during mouse oocyte maturation and early embryo development by immunofluorescence staining. Exogenous lactate was supplemented to explore the consequences of modulating histone lactylation levels on oocyte maturation and embryo development processes by transcriptomics. Results demonstrated that lactylated proteins are widely present in mice with tissue- and cell-specific distribution. During mouse oocyte maturation, immunofluorescence for H3K9la, H3K14la, H4K8la, and H4K12la was most intense at the germinal vesicle (GV) stage and subsequently weakened or disappeared. Further, supplementing the culture medium with 10 mM sodium lactate elevated both the oocyte maturation rate and the histone Kla levels in GV oocytes, and there were substantial increases in Kla levels in metaphase II (MII) oocytes. It altered the transcription of molecules involved in oxidative phosphorylation. Moreover, histone lactylation levels changed dynamically during mouse early embryogenesis. Sodium lactate at 10 mM enhanced early embryo development and significantly increased lactylation, while impacting glycolytic gene transcription. This study reveals the roles of lactylation during oocyte maturation and embryo development, providing new insights to improving oocyte maturation and embryo quality.

Trastuzumab-Induced Cardiotoxicity: When and How Much Should We Worry?

This review critically analyzes the incidence of trastuzumab-induced left ventricular systolic dysfunction and congestive heart failure (CHF), distinguishing between cases with and without prior anthracycline exposure. It highlights the fact that the elevated risk of trastuzumab-induced cardiotoxicity is closely associated with prior anthracycline exposure. In the absence of prior anthracycline exposure, the incidence rates of trastuzumab-induced cardiotoxicity, particularly CHF (ranging from 0% to 0.5%), are largely comparable with those reported in the general population, especially when reversibility is taken into account. Current cardiac surveillance recommendations during trastuzumab treatment have not yet adapted to the increasing adoption of nonanthracycline treatment strategies and the associated low risk of cardiotoxicity. We propose a refined monitoring protocol to reduce the frequency of cardiac evaluations for low-risk to moderate-risk patients, especially those receiving nonanthracycline treatments. By focusing on patients at high risk or those with prior anthracycline exposure, this strategy seeks to optimize the cost-effectiveness of cardiac care in oncology.

Limiting Temperature Rise in Cochlear Implantation Bone Drilling: A Novel Approach.

OBJECTIVE: In the process of cochlear implantation surgery, it is crucial to develop a method to control the temperature during the drilling of the implant channel since high temperatures can result in damage to bone and nerve tissue. METHODS: This paper simplified the traditional point heat source temperature rise model and proposed a novel extreme peck drilling model to quantitatively calculate the maximum temperature rise value. It is also innovatively introduced a new method for calculating the best peck drilling duty cycle to strictly control the maximum temperature rise value. Besides, the neural network is trained with virtual data to identify two important thermal parameters in the temperature rise model. RESULTS: In the experiment of epoxy resin and temporal bone, the difference between predicted maximum temperature and actual maximum temperature was less than 1.5 °C, and the error rate was less than 10%. And the error source was analyzed by variational mode decomposition, along with discussion of potential solutions. In the temperature control experiment, the model successfully controlled the maximum temperature rise within 10 °C.For cochlear implantation surgery, we also divide the implantation channel into different stages based on the bone density in CT images to identify thermal parameters and calculate drilling strategies. CONCLUSION: This method provides a new strategy for accurate and effective control of borehole heat generation. SIGNIFICANCE: These achievements provide new ideas and directions for research in cochlear implantation surgery and related fields, and are expected to have extensive application in medical practice.

Unlocking the Role of Endothelial MPL Receptor and JAK2V617F Mutation: Insights into Cardiovascular Dysfunction in MPNs and CHIP.

Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) are at a significantly higher risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in many MPN patients. Here, we investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and human induced pluripotent stem cell lines. Our findings revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we found that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. These findings propose that targeting the endothelial MPL receptor could be a promising therapeutic approach to manage CVD complications in patients with JAK2V617F-positive MPNs and CHIP. Further investigations into the impact of other CHIP-associated mutations on endothelial dysfunction are needed to improve risk stratification for individuals with CHIP.

N fertilizers promote abscisic acid-catabolizing bacteria to enhance heavy metal phytoremediation from metalliferous soils.

Bacterial-assisted phytoextraction is an attractive strategy to enhance the phytoremediation efficiency of heavy metal (HM)-contaminated soils. In the present study, we investigated the synergistic effects of N fertilizers and abscisic acid (ABA)-catabolizing bacteria on the HM (Cd, Zn, and Pb) phytoremediation efficiency of Brassica juncea L. (B. juncea). Compared with Rhodococcus qingshengii (R. qingshengii) alone, urea, ammonium­nitrogen (NH4+-N), and nitrate­nitrogen (NO3--N) fertilizers combined with R. qingshengii increased HM concentrations in B. juncea by 13.8 %-48.2 %, 44.2 %-54.4 %, and 59.4 %-113.6 %, respectively, and enhanced the biomass of B. juncea by 7.7 %-38.8 %, 10.9 %-29.5 %, and 19.9 %-46.8 %, respectively. Consequently, the bioconcentration factor increased by 3.4 %-30.9 % and the phytoextraction rate increased by 18.5 %-98.7 %. Treatment with NO3--N showed the most significant effect. In structural equation modeling, R. qingshengii inoculation showed greater path coefficients with soil pH and ABA and indoleacetic acid concentrations of B. juncea than N fertilization, indicating that R. qingshengii contributed more to HM extraction efficiency than N fertilizers. Additionally, differences in the extraction rates of Cd, Zn, and Pb from B. juncea were reduced following N fertilization. In summary, synergistic R. qingshengii inoculation and N fertilization have substantial potential to enhance phytoremediation efficiency. Combined application of R. qingshengii and NO3--N fertilizers is recommended.

Synergistic interplay between ABA-generating bacteria and biochar in the reduction of heavy metal accumulation in radish, pakchoi, and tomato.

Heavy metal (HM) contamination is an environmental concern that threatens the agricultural product safety and human health. To address this concern, we developed a novel strategy involving the synergistic application of Azospirillum brasilense, a growth-promoting rhizobacterium which produces abscisic acid (ABA), and biochar to minimize HM accumulation in the edible parts of vegetable crops. Compared to A. brasilense or biochar alone, the concentrations of Cd, Ni, Pb, and Zn in radish (Raphanus sativus L.), pakchoi (Brassica chinensis L.), and tomato (Lycopersicon esculentum L.) decreased by 18-63% and 14-56%, respectively. Additionally, the synergistic treatment led to a 14-63% decrease in the bioconcentration factor. The biomass of the edible parts of the three crops increased by 65-278% after synergistic treatment, surpassing the effects of single treatments. Furthermore, the synergistic application enhanced the SPAD values by 1-45% compared to single treatments. The MDA concentrations in stressed plants decreased by 16-39% with the bacteria-biochar co-treatment compared to single treatments. Co-treatment also resulted in increased soluble protein and sugar concentrations by 8-174%, and improvements in flavonoids, total phenols, ascorbic acid, and DPPH levels by 2-50%. Pearson correlation analysis and structural equation modeling revealed that the synergistic effect was attributed to the enhanced growth of A. brasilense facilitated by biochar and the improved availability of HMs in soils. Notably, although ABA concentrations were not as high as those achieved with A. brasilense alone, they were maintained at relatively high levels. Overall, the synergistic application of A. brasilense-biochar might have remarkable potential for reducing the accumulation of HMs while promoting growth and improving nutritional and antioxidant qualities in tuberous, leafy, and fruit crops.

Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1).

Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential anticancer lead. Nitrovin showed significant cytotoxicity to a panel of cancer cell lines. Nitrovin induced cytoplasmic vacuolation, reactive oxygen species (ROS) generation, MAPK activation, and Alix inhibition but had no effect on caspase-3 cleavage and activity, suggesting paraptosis activation. Nitrovin-induced cell death of GBM cells was significantly reversed by cycloheximide (CHX), N-acetyl-l-cysteine (NAC), glutathione (GSH), and thioredoxin reductase 1 (TrxR1) overexpression. Vitamins C and E, inhibitors of pan-caspase, MAPKs, and endoplasmic reticulum (ER) stress failed to do so. Nitrovin-triggered cytoplasmic vacuolation was reversed by CHX, NAC, GSH, and TrxR1 overexpression but not by Alix overexpression. Furthermore, nitrovin interacted with TrxR1 and significantly inhibited its activity. In addition, nitrovin showed a significant anticancer effect in a zebrafish xenograft model, which was reversed by NAC. In conclusion, our results showed that nitrovin induced non-apoptotic and paraptosis-like cell death mediated by ROS through targeting TrxR1. Nitrovin might be a promising anticancer lead for further development.

Knockdown of Csnk1a1 results in preimplantation developmental arrest in mice.

Casein kinase 1, alpha 1 (CSNK1A1), is a member of the highly conserved serine/threonine protein kinase family. This study was established to analyze the expression and localization of CSNK1A1 and its function in early embryonic development in mice. Csnk1a1 mRNA and protein are expressed in multiple mouse tissues including the ovary. After ovulation and fertilization, Csnk1a1 mRNA and protein were detected in preimplantation embryos and their expression was highest in two-cell-stage embryos. CSNK1A1 protein was also mainly localized in the cytoplasm of preimplantation embryos. Moreover, knockdown of Csnk1a1 in zygotes led to a significant decrease in the rate of blastocyst formation. Furthermore, treatment of zygotes with the CSNK1A1-specific inhibitor D4476 also resulted in embryonic developmental arrest. These results provide the first evidence for a novel function of CSNK1A1 in early embryonic development in mice.

Neferine Suppresses Experimental Colitis-Associated Colorectal Cancer by Inhibition of NF-[Formula: see text]B p65 and STAT3.

Colitis is an important risk factor for the development of colorectal cancer (CRC). The inhibitory effect and the underlying mechanism of neferine on colitis-associated colorectal cancer (CA-CRC) were investigated using an azoxymethane (AOM)/dextran sulfate sodium (DSS) triggered mice model. Compared with the CA-CRC model, oral treatment of neferine (2.5 and 5.0 mg/kg) significantly inhibited the DAI scores, decreased the tumor number, and reduced the tumor size. Neferine decreased inflammatory cell infiltration and epithelial hyperplasia in colon tissues. The levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text], interleukin-1beta (IL-1[Formula: see text], and interleukin 6 (IL-6) in colon tissues were decreased by neferine. Furthermore, neferine significantly decreased protein expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), p-p65, and p-STAT3 in both tumor and non-tumor tissues. In addition, neferine inhibited LPS and IL-6-induced phosphorylation of both NF-[Formula: see text]B p65 and STAT3. Molecular docking demonstrated the interactions of neferine with both NF-[Formula: see text]B p65 and STAT3. In conclusion, these results suggested that neferine inhibited CA-CRC carcinogenesis possibly by regulating NF-[Formula: see text]B and STAT3. Neferine might be a lead compound for the chemoprevention of CA-CRC.

Reduced cardiac function is associated with cardiac injury and mortality risk in hospitalized COVID-19 Patients.

BACKGROUND: Cardiac injury is common in COVID-19 patients and is associated with increased mortality. However, it remains unclear if reduced cardiac function is associated with cardiac injury, and additionally if mortality risk is increased among those with reduced cardiac function in COVID-19 patients. HYPOTHESIS: The aim of this study was to assess cardiac function among COVID-19 patients with and without biomarkers of cardiac injury and to determine the mortality risk associated with reduced cardiac function. METHODS/RESULTS: This retrospective cohort study analyzed 143 consecutive COVID-19 patients who had an echocardiogram during hospitalization between March 1, 2020 and May 5, 2020. The mean age was 67 ± 16 years. Cardiac troponin-I was available in 131 patients and an increased value (>0.03 ng/dL) was found in 59 patients (45%). Reduced cardiac function, which included reduced left or right ventricular systolic function, was found in 40 patients (28%). Reduced cardiac function was found in 18% of patients without troponin-I elevation, 42% with mild troponin increase (0.04-5.00 ng/dL) and 67% with significant troponin increase (>5 ng/dL). Reduced cardiac function was also present in more than half of the patients on mechanical ventilation or those deceased. The in-hospital mortality of this cohort was 28% (N = 40). Using logistic regression analysis, we found that reduced cardiac function was associated with increased mortality with adjusted odds ratio (95% confidence interval) of 2.65 (1.18 to 5.96). CONCLUSIONS: Reduced cardiac function is highly prevalent among hospitalized COVID-19 patients with biomarkers of myocardial injury and is independently associated with mortality.

COVID-19 Presenting as Major Thromboembolic Events: Virchow's Triad Revisited and Clinical Considerations of Therapeutic Anticoagulation.

This case series describes clinical course of three COVID-19 patients who presented with major thromboembolic events. Patient 1 is a 57-year-old male with asymptomatic COVID-19 who presented with a large left ventricular thrombus. His hospital course was complicated with a stroke. Patient 2 is a 71-year-old male with mild COVID-19 who presented with an acute stroke. Patient 3 is a 47-year-old male with severe COVID-19 who presented with a large pulmonary embolism. He died of a recurrent massive pulmonary embolism. This case series demonstrates that thromboembolic event can be the presenting feature of COVID-19 and can occur in the patients with asymptomatic or mild COVID-19. Diffuse endothelial injury and hypercoagulability play a pivotal role in recurrent thromboembolic events despite the anticoagulation. Therapeutic anticoagulation may be considered for severe COVID-19 patients and patients with important comorbidities or pre-existing endothelial dysfunction.