Efficacy of venetoclax and rituximab in the treatment of concurrent acute myeloid leukemia and untreated chronic lymphocytic leukemia: A case report and literature review.

To date, few cases of concurrent acute myeloid leukemia (AML) and untreated chronic lymphocytic leukemia (CLL) have been reported. Due to the complexity of the pathogenesis and the absence of a uniform treatment regimen, the associated prognosis remains poor. The present study reports the case of a 58-year-old male with asymptomatic leukocytosis, who was previously healthy with no malignancies. Flow cytometry analysis revealed protocytosis, monocytosis and monoclonal B lymphocytosis in a bone marrow specimen. Results of a gene rearrangement assay demonstrated positive immunoglobulin heavy-chain variable region gene status in monoclonal B lymphocytes. Thus, the patient was diagnosed with AML with maturation (AML-M2) that co-existed with untreated CLL. The normative daunorubicin (40 mg/m2 on days 1-3) and cytarabine (80 mg/m2 on days 1-7) regimen combined with venetoclax (400 mg on days 1-7) and rituximab (375 mg/m2 on day 0) was used as induction chemotherapy. The patient achieved morphological complete remission in both AML and CLL following the first course of chemotherapy. In addition, the present study retrospectively analyzed the data of 22 patients with concurrent AML and untreated CLL, and the results demonstrated that the median age at the time of AML diagnosis was 69 years (range, 52-86 years). Moreover, the male:female ratio was 6.33:1 and AML-M2 was the most frequent subtype at diagnosis. The presence of a complex karyotype was associated with the poorest prognosis, and patients who received venetoclax often exhibited an improved prognosis. In conclusion, the combination of venetoclax and rituximab improves the prognosis of patients with concurrent AML and untreated CLL.

Balloon atrial septostomy: a weapon to challenge right heart failure after cardiac surgery.

Right heart failure is a common complication after cardiac surgery, and its mortality remains high. The medical management and veno-arterial extracorporeal membrane oxygenation has shown significant improvement in the majority of cases. However, a minority of patients may still require long-term mechanical circulatory support or heart transplantation. Balloon atrial septostomy is a new method for the prevention and treatment of right heart failure, which may avoid the patient's dependence on mechanical circulatory support. We used this method to try to treat patients with right heart failure after cardiac surgery, and all received good benefits. Therefore, we selected several representative cases to report, in order to guide other qualified cardiac surgeons to carry out relevant clinical practice.

Dilute Electrolytes with Fluorine-free Ether Solvents for 4.5 V Lithium Metal Batteries.

The limited oxidation stability of ether solvents has posed significant challenges for their applications in high-voltage lithium metal batteries (LMBs). To tackle this issue, the prevailing strategy either adopts a high concentration of fluorinated salts or relies on highly fluorinated solvents, which will significantly increase the manufacturing cost and create severe environmental hazards. Herein, an alternative and sustainable salt engineering approach is proposed to enable the utilization of dilute electrolytes consisting of fluorine (F)-free ethers in high-voltage LMBs. The proposed 0.8 M electrolyte supports stable lithium plating-stripping with a high Coulombic efficiency of 99.47% and effectively mitigates the metal dissolution, phase transition, and gas release issues of the LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode upon charging to high voltages. Consequently, the 4.5 V high-loading Li||NCM 811 cell shows a capacity retention of 75.2% after 300 cycles. Multimodal experimental characterizations coupled with theoretical investigations demonstrate that the boron-containing salt plays a pivotal role in forming the passivation layers on both anode and cathode. The present simple and cost-effective electrolyte design strategy offers a promising and alternative avenue for using commercially mature, environmentally benign, and low-cost F-free ethers in high-voltage LMBs.

Echocardiographic features and pathological ultrastructural characteristics of fetal interruption of aortic arch. / èƒŽå„¿ä¸»åŠ¨è„‰å¼“ç¦»æ–­çš„è¶ å£°å¿ƒåŠ¨å›¾å’Œç— ç†å­¦è¶ å¾®ç»“æž„ç‰¹å¾.

OBJECTIVES: Interruption of aortic arch (IAA) is a rare congenital heart disease. This study aims to investigate echocardiographic features and pathological ultrastructural characteristics of fetal IAA and to further analyze its pathological evolution. METHODS: A retrospective analysis was conducted on prenatal echocardiographic, post-surgical, or autopsy findings of fetuses prenatally diagnosed with IAA. Prenatal echocardiographic tracking was used to observe the internal diameters and Z-scores of different segments of the aortic arch and the changes in the narrowed section. These observations were combined with autopsy and pathological findings to explore the potential intrauterine evolution of IAA and its cytological basis. RESULTS: The study included 34 fetuses with IAA, with 3, 3, and 28 fetuses prenatally diagnosed with aortic arch dysplasia (AAD), coarctation of aorta (CoA), and IAA, respectively. The 3 AAD and 3 CoA fetuses chose termination of pregnancy 1 to 2 weeks after prenatal ultrasound diagnosis, and autopsy confirmed IAA. Among the 28 fetuses prenatally diagnosed with IAA, 6 cases of CoA progressively worsened, eventually evolving into type A IAA as observed through echocardiographic follow-up. The remaining 22 cases were diagnosed as IAA on the first prenatal ultrasound. Postnatal surgery corrected 3 cases, while 27 cases opted for pregnancy termination, and 4 cases resulted in intrauterine death. Echocardiographic features of the fetal IAA included a significantly smaller left ventricle compared with the right or negligible difference on the four-chamber view, a significantly smaller aorta than the pulmonary artery on the three-vessel view, and a lack of connection between the aorta and the descending aorta on the three-vessel-trachea and aortic arch views. The aortic arch appears less curved and more rigid, losing the normal "V" shape between the aorta, ductus arteriosus, and descending aorta. Color Doppler ultrasound showed no continuous blood flow signal at the interruption site, with reversed blood flow visible in the ductus arteriosus. Transmission electron microscopy of 7 IAA fetuses revealed numerous disorganized smooth muscle cells between the elastic membranes near the aortic arch interruption site, significantly increased in number compared with the proximal ascending aorta. The elastic membranes were thicker and more twisted near the interruption site. The interruption area lacked normal endothelial cells and lumen, with only remnants of necrotic endothelial cells, disorganized short and thick elastic membranes, and randomly arranged smooth muscle cells. CONCLUSIONS: Prenatal echocardiography is the primary diagnostic tool for fetal IAA. Post-surgical follow-up and autopsy help identify complications and disease characteristics, enhancing diagnostic accuracy. Some fetal IAA may evolve from AAD or CoA, with potential pathogenesis related to ischemia, hypoxia, and migration of ductal constrictive components.

BNT12, a novel hybrid peptide of opioid and neurotensin pharmacophores, produces potent central antinociception with limited side effects.

The development of multitarget opioid drugs has emerged as an attractive approach for innovative pain management with reduced side effects. In the present study, a novel hybrid peptide BNT12 containing the opioid and neurotensin (NT)-like fragments was synthesized and pharmacologically characterized. In acute radiant heat paw withdrawal test, intracerebroventricular (i.c.v.) administration of BNT12 produced potent antinociception in mice. The central antinociceptive activity of BNT12 was mainly mediated by µ-, δ-opioid receptor, neurotensin receptor type 1 (NTSR1) and 2 (NTSR2), supporting a multifunctional agonism of BNT12 in the functional assays. BNT12 also exhibited significant antinociceptive effects in spared nerve injury (SNI)-neuropathic pain, complete Freund's adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain after i.c.v. administration. Furthermore, BNT12 exhibited substantial reduction of acute antinociceptive tolerance, shifted the dose-response curve to the right by only 1.3-fold. It is noteworthy that BNT12 showed insignificant chronic antinociceptive tolerance at the supraspinal level. In addition, BNT12 exhibited reduced or no opioid-like side effects on conditioned place preference (CPP) response, naloxone-precipitated withdrawal response, acute hyperlocomotion, motor coordination, gastrointestinal transit, and cardiovascular responses. The present investigation demonstrated that the novel hybrid peptide BNT12 might serve as a promising analgesic candidate with limited opioid-like side effects.

Atomic Level-Macroscopic Structure-Activity of Inhomogeneous Localized Aggregates Enabled Ultra-Low Temperature Hybrid Aqueous Batteries.

The utilization of hybrid aqueous electrolytes has significantly broadened the electrochemical and temperature ranges of aqueous batteries, such as aqueous zinc and lithium-ion batteries, but the design principles for extreme operating conditions remain poorly understood. Here, we systematically unveil the ternary interaction involving salt-water-organic co-solvents and its intricate impacts on both the atomic-level and macroscopic structural features of the hybrid electrolytes. This highlights a distinct category of micelle-like structure electrolytes featuring organic-enriched phases and nanosized aqueous electrolyte aggregates, enabled by appropriate low donor number co-solvents and amphiphilic anions. Remarkably, the electrolyte enables exceptional high solubility, accommodating up to 29.8 m zinc triflate within aqueous micelles. This configuration maintains an intra-micellar salt-in-water setup, allowing for a broad electrochemical window (up to 3.86 V), low viscosity, and state-of-the-art ultralow-temperature zinc ion conductivity (1.58 mS cm-1 at -80°C). Building upon the unique nature of the inhomogeneous localized aggregates, this micelle-like electrolyte facilitates dendrite-free Zn plating/stripping, even at -80°C. The assembled Zn||PANI battery showcases an impressive capacity of 71.8 mAh g-1 and an extended lifespan of over 3000 cycles at -80°C. This study opens up a promising approach in electrolyte design that transcends conventional local atomic solvation structures, broadening the water-in-salt electrolyte concept.

Analysis of research hotspots and trends in pediatric ophthalmopathy based on 10 years of WoSCC literature.

Background: Ophthalmopathy occurring in childhood can easily lead to irreversible visual impairment, and therefore a great deal of clinical and fundamental researches have been conducted in pediatric ophthalmopathy. However, a few studies have been performed to analyze such large amounts of research using bibliometric methods. This study intended to apply bibliometric methods to analyze the research hotspots and trends in pediatric ophthalmopathy, providing a basis for clinical practice and scientific research to improve children's eye health. Methods: Publications related to pediatric ophthalmopathy were searched and identified in the Web of Science Core Collection (WoSCC) database. Bibliometric and visualized analysis was performed using the WoSCC analysis system and CiteSpace.6.2.6 software, and high-impact publications were analyzed. Results: This study included a total of 7,177 publications from 162 countries and regions. Of these, 2,269 from the United States and 1,298 from China. The centrality and H-index were highest in the United States at 0.27 and 66, respectively. The University of London and Harvard University had the highest H-index at 37. Freedman,Sharon F published 55 publications, with the highest H-index at 19. The emerging burst keyword in 2020-2023 was "eye tracking," and the burst keywords in 2021-2023 were "choroidal thickness," "pediatric ophthalmology," "impact" and "childhood glaucoma." Retinopathy of prematurity, myopia, retinoblastoma and uveitis in juvenile idiopathic arthritis were the main topics in the high-impact publications, with clinical studies in the majority, especially in retinopathy of prematurity. Conclusion: Eye health in children is a research hotspot, with the United States publishing the largest number of papers and having the greatest influence in research on pediatric ophthalmopathy, and China coming in second. The University of London and Stanford University had the greatest influence. Freedman, Sharon F was the most influential author. Furthermore, "choroidal thickness," "pediatric ophthalmology," "impact," "childhood glaucoma" and "eye tracking"are the latest hotspots in the field of pediatric ophthalmopathy. These hotspots represent hot diseases, hot technologies and holistic concepts, which are exactly the research trends in the field of pediatric ophthalmopathy, providing guidance and grounds for clinical practice and scientific research on children's eye health.

Application of modified Yamane technique in intrascleral intraocular lens fixation combined with or without iris reconstruction.

AIMS: To explore the application and long-term clinical effects of modified Yamane technique in intrascleral intraocular lens (IOL) fixation combined with or without iris reconstruction. SETTINGS AND DESIGN: The data of patients receiving IOL fixation with modified Yamane technique in an ophthalmology department between December 2021 and August 2023 were analyzed retrospectively. The longest follow-up duration was > 12 months. METHODS AND MATERIAL: The trailing haptic was fixed with the needle before the leading haptic. The silicone haptic stoppers were used to stabilize the IOL when iris reconstruction was combined. Preoperative and postoperative best-corrected visual acuity (BCVA), corneal endothelial cells (CECs), postoperative intraocular pressure (IOP), surgical indications and methods, and postoperative complications were recorded. Anterior segment optical coherence tomography (OCT) was used to evaluate IOL decentration and tilt. The paired sample t-test or Wilcoxon rank sum test were used to compare the results of the same index before and after the operation. RESULTS: Twelve patients (12 eyes) were included in this cohort. There were 1 case of IOL dislocation, eight cases of lens dislocation or subluxation, and three cases of aphakia. Traumatic lens dislocation was the main cause of aphakia. Primary lens extraction was performed in previous surgeries, and all three were combined with pars plana vitrectomy (PPV). Four of 12 patients underwent IOL fixation and iris reconstruction. The mean age of participants was 63 ± 10.61 years. The mean BCVA increased from 0.89 ± 0.72 logMAR to 0.39 ± 0.56 logMAR at the last visit (p < 0.05). The postoperative relative refractive error was - 0.13 ± 0.42 D (-0.60 D to + 0.57 D). The OCT showed that the IOLs were well centered, with a mean decentration of 0.20 ± 0.13 mm and a mean tilt of 2.31°±0.93°. Ten patients did not experience any complications. CONCLUSIONS: The modified Yamane technique in IOL fixation surgery, especially combined with iris reconstruction, reduces operation difficulty, increases operational stability and safety, and improves postoperative visual acuity without serious intra- or postoperative complications. The long-term improvement effect was remarkable.

[Effects of iris xanthin on airway inflammation, airway remodeling, and the HMGB1/TLR4/NF-κB pathway in asthmatic young mice]. / é¸¢å°¾é»„ç´ å¯¹å“®å–˜å¹¼é¼ æ°”é“ç‚Žç—‡ã€æ°”é“é‡å¡‘åŠHMGB1/TLR4/NF-κB通路的影响.

OBJECTIVES: To explore the effects of iris xanthin on airway inflammation, airway remodeling, and the high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in asthmatic young mice. METHODS: Sixty male BALB/c young mice were randomly assigned into six groups: a blank group, a model group, a dexamethasone group, and low, medium, and high dose groups of iris xanthin, with ten mice per group. Asthma models were induced through intraperitoneal injections of a sensitizing agent [ovalbumin (OVA) 20 µg + aluminum hydroxide gel 2 mg], followed by 4% OVA aerosol inhalation. Lung function was measured using a pulmonary function tester to determine lung volume (LV), resting ventilation per minute (VE), and airway reactivity (Penh value). Hematoxylin-eosin (HE) staining was employed to examine and analyze airway remodeling. The contents of interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid were quantified using ELISA. Real-time fluorescence quantitative polymerase chain reaction and Western blot analysis were used to assess the expression of HMGB1/TLR4/NF-κB pathway-related mRNA and proteins in lung tissues. RESULTS: Compared to the model group, the dexamethasone and iris xanthin-treated groups (low, medium, and high doses) exhibited significant increases in LV and VE (P<0.05), with incremental dose-dependent increases observed in the iris xanthin groups. Additionally, Penh values, IL-1ß, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, and NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were all reduced (P<0.05) in a dose-dependent manner. When compared to the dexamethasone group, the low and medium dose iris xanthin groups showed decreases in LV and VE (P<0.05), whereas Penh values, IL-1ß, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were increased (P<0.05). No significant differences were noted in these indices between the high dose iris xanthin group and the dexamethasone group (P>0.05). CONCLUSIONS: Iris xanthin can effectively alleviates airway inflammation and inhibits airway remodeling in asthmatic young mice, possibly through the suppression of the HMGB1/TLR4/NF-κB pathway.

Genome-Wide Identification and Characterization of Lignin Synthesis Genes in Maize.

Lignin is a crucial substance in the formation of the secondary cell wall in plants. It is widely distributed in various plant tissues and plays a significant role in various biological processes. However, the number of copies, characteristics, and expression patterns of genes involved in lignin biosynthesis in maize are not fully understood. In this study, bioinformatic analysis and gene expression analysis were used to discover the lignin synthetic genes, and two representative maize inbred lines were used for stem strength phenotypic analysis and gene identification. Finally, 10 gene families harboring 117 related genes involved in the lignin synthesis pathway were retrieved in the maize genome. These genes have a high number of copies and are typically clustered on chromosomes. By examining the lignin content of stems and the expression patterns of stem-specific genes in two representative maize inbred lines, we identified three potential stem lodging resistance genes and their interactions with transcription factors. This study provides a foundation for further research on the regulation of lignin biosynthesis and maize lodging resistance genes.

Raddeanin A Protects the BRB Through Inhibiting Inflammation and Apoptosis in the Retina of Alzheimer's Disease.

Neuroinflammation and endothelial cell apoptosis are prominent features of blood-brain barrier (BBB) disruption, which have been described in Alzheimer's disease (AD) and can predict cognitive decline. Recent reports revealed vascular ß-amyloid (Aß) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer's disease by targeting ß-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aß-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/ß-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.

Effect of Ward Noise Management Combined with Meditation Training on Stroke Rehabilitation Patients.

OBJECTIVE: To study the value of ward noise management combined with meditation training in stroke rehabilitation patients. METHODS: According to the retrospective analysis method, 150 stroke patients hospitalized in the rehabilitation center of a Tangshan Workers' Hospital from July 2020 to December 2023 were selected as study objects. They were divided into three groups, namely the control group (routine rehabilitation care, n = 50), observation group A (meditation training, n = 50), and observation group B (meditation training and ward noise management, n = 50) according to whether they received ward noise management and meditation training. The general demographic data, Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), and the Short Form 36 (SF-36) were collected. Chi-square test and analysis of variance were used to analyse the data. RESULTS: The baseline data of the patients in each group were not statistically significant (P > 0.05). Before treatment, no difference in the FSS, PSQI, SF-36 scores and environmental noise level between the groups (P > 0.05) was observed. After management, the scores of SF-36 in observation group B were higher than those in the control group and observation group A (P < 0.05) except for somatic pain. Other indicators in observation group B were lower than those in the control and observation group A (P < 0.001). CONCLUSIONS: Ward noise management and meditation training can effectively reduce patients' fatigue, significantly reducing ambient noise levels, promoting the improvement of life quality, and improving sleep quality.

Berberine improves cognitive impairment by alleviating brain atrophy and promoting white matter reorganization in diabetic db/db mice: a magnetic resonance imaging-based study.

Diabetic cognitive impairment is a common complication in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid that has been shown to have neuroprotective effects against diabetes. This study aimed to investigate the effect of BBR on the gray and white matter of the brain by using magnetic resonance imaging (MRI) and to explore the underlying mechanisms. The study used diabetic db/db mice and administered BBR (50 and 100 mg/kg) intragastrically for twelve weeks. Morris water maze was applied to examine cognitive function. T2-weighted imaging (T2WI) was performed to assess brain atrophy, and diffusion tensor imaging (DTI) combined with fiber tracking was conducted to monitor the structural integrity of the white matter, followed by histological immunostaining. Furthermore, the protein expressions of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3ß (GSK-3ß) were detected. The results revealed that BBR significantly improved the spatial learning and memory of the db/db mice. T2WI exhibited ameliorated brain atrophy in the BBR-treated db/db mice, as evidenced by reduced ventricular volume accompanied by increased hippocampal volumes. DTI combined with fiber tracking revealed that BBR increased FA, fiber density and length in the corpus callosum/external capsule of the db/db mice. These imaging findings were confirmed by histological immunostaining. Notably, BBR significantly enhanced the protein levels of phosphorylated AKT at Ser473 and GSK-3ß at Ser9. Collectively, this study demonstrated that BBR significantly improved the cognitive function of the diabetic db/db mice through ameliorating brain atrophy and promoting white matter reorganization via AKT/GSK-3ß pathway.

Matrine induces autophagic cell death by triggering ROS/AMPK/mTOR axis and apoptosis in multiple myeloma.

Despite significant advancements in multiple myeloma (MM) treatment in recent years, most patients will eventually develop resistance or experience relapse. Matrine, a primary active compound of traditional Chinese medicinal herb Sophora flavescens Ait, has been found to have anti-tumor properties in various types of malignant tumors. Whether autophagy plays a crucial role in the anti-MM effect of matrine remain unknown. Herein, we found that matrine could trigger apoptosis and cell cycle arrest, and meanwhile induce autophagy in MM cells in vitro. We further ascertained the role of autophagy by using ATG5 siRNA or the autophagy inhibitor spautin-1, which partially reversed matrine's inhibitory effect on MM cells. Conversely, the combination of matrine with the autophagy inducer rapamycin enhanced their anti-tumor activity. These findings suggest that autophagy induced by matrine can lead to cell death in MM cells. Further mechanism investigation revealed that matrine treatment increased the levels of reactive oxygen species (ROS) and AMPKα1 phosphorylation and decreased the phosphorylation of mTOR in MM cells. Additionally, co-treatment with AMPKα1 siRNA or the ROS scavenger N-acetyl-1-cysteine weakened the increase in autophagy that was induced by matrine. Finally, we demonstrated a synergistic inhibitory effect of matrine and rapamycin against MM in a xenograft mouse model. Collectively, our findings provided novel insights into the anti-MM efficacy of matrine and suggest that matrine induces autophagy by triggering ROS/AMPK/mTOR axis in MM cells, and combinatorial treatment of matrine and rapamycin may be a promising therapeutic strategy against MM.

Phages enhance both phytopathogen density control and rhizosphere microbiome suppressiveness.

Bacteriophages, viruses that specifically target plant pathogenic bacteria, have emerged as a promising alternative to traditional agrochemicals. However, it remains unclear how phages should be applied to achieve efficient pathogen biocontrol and to what extent their efficacy is shaped by indirect interactions with the resident microbiota. Here, we tested if the phage biocontrol efficacy of Ralstonia solanacearum phytopathogenic bacterium can be improved by increasing the phage cocktail application frequency and if the phage efficacy is affected by pathogen-suppressing bacteria already present in the rhizosphere. We find that increasing phage application frequency improves R. solanacearum density control, leading to a clear reduction in bacterial wilt disease in both greenhouse and field experiments with tomato. The high phage application frequency also increased the diversity of resident rhizosphere microbiota and enriched several bacterial taxa that were associated with the reduction in pathogen densities. Interestingly, these taxa often belonged to Actinobacteria known for antibiotics production and soil suppressiveness. To test if they could have had secondary effects on R. solanacearum biocontrol, we isolated Actinobacteria from Nocardia and Streptomyces genera and tested their suppressiveness to the pathogen in vitro and in planta. We found that these taxa could clearly inhibit R. solanacearum growth and constrain bacterial wilt disease, especially when combined with the phage cocktail. Together, our findings unravel an undiscovered benefit of phage therapy, where phages trigger a second line of defense by the pathogen-suppressing bacteria that already exist in resident microbial communities. IMPORTANCE: Ralstonia solanacearum is a highly destructive plant-pathogenic bacterium with the ability to cause bacterial wilt in several crucial crop plants. Given the limitations of conventional chemical control methods, the use of bacterial viruses (phages) has been explored as an alternative biological control strategy. In this study, we show that increasing the phage application frequency can improve the density control of R. solanacearum, leading to a significant reduction in bacterial wilt disease. Furthermore, we found that repeated phage application increased the diversity of rhizosphere microbiota and specifically enriched Actinobacterial taxa that showed synergistic pathogen suppression when combined with phages due to resource and interference competition. Together, our study unravels an undiscovered benefit of phages, where phages trigger a second line of defense by the pathogen-suppressing bacteria present in resident microbial communities. Phage therapies could, hence, potentially be tailored according to host microbiota composition to unlock the pre-existing benefits provided by resident microbiota.

Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.

Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.

Activation of Piezo1 Inhibits Kidney Cystogenesis.

The disruption of calcium signaling associated with polycystin deficiency has been proposed as the primary event underlying the increased abnormally patterned epithelial cell growth characteristic of Polycystic Kidney Disease. Calcium can be regulated through mechanotransduction, and the mechanosensitive cation channel Piezo1 has been implicated in sensing of intrarenal pressure and in urinary osmoregulation. However, a possible role for PIEZO1 in kidney cystogenesis remains undefined. We hypothesized that cystogenesis in ADPKD reflects altered mechanotransduction, suggesting activation of mechanosensitive cation channels as a therapeutic strategy for ADPKD. Here, we show that Yoda-1 activation of PIEZO1 increases intracellular Ca 2+ and reduces forskolin-induced cAMP levels in mIMCD3 cells. Yoda-1 reduced forskolin-induced IMCD cyst surface area in vitro and in mouse metanephros ex vivo in a dose-dependent manner. Knockout of polycystin-2 dampened the efficacy of PIEZO1 activation in reducing both cAMP levels and cyst surface area in IMCD3 cells. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor affected cystogenesis in the Pkd1 RC/RC model of ADPKD. Our study suggests that polycystin-2 and PIEZO1 play a role in mechanotransduction during cystogenesis in vitro , and ex vivo , but that in vivo cyst expansion may require inactivation or repression of additional suppressors of cystogenesis and/or growth. Our study provides a preliminary proof of concept for PIEZO1 activation as a possible component of combination chemotherapy to retard or halt cystogenesis and/or cyst growth.

Early megakaryocyte lineage-committed progenitors in adult mouse bone marrow.

Hematopoietic stem cells (HSCs) have been considered to progressively lose their self-renewal and differentiation potentials prior to the commitment to each blood lineage. However, recent studies have suggested that megakaryocyte progenitors (MkPs) are generated at the level of HSCs. In this study, we newly identified early megakaryocyte lineage-committed progenitors (MgPs) mainly in CD201-CD48- cells and CD48+ cells separated from the CD150+CD34-Kit+Sca-1+Lin- HSC population of the bone marrow in adult mice. Single-cell colony assay and single-cell transplantation showed that MgPs, unlike platelet-biased HSCs, had little repopulating potential in vivo, but formed larger megakaryocyte colonies in vitro (on average 8 megakaryocytes per colony) than did previously reported MkPs. Single-cell RNA sequencing supported that HSCs give rise to MkPs through MgPs along a Mk differentiation pathway. Single-cell reverse transcription polymerase chain reaction (RT-PCR) analysis showed that MgPs expressed Mk-related genes, but were transcriptionally heterogenous. Clonal culture of HSCs suggested that MgPs are not direct progeny of HSCs. We propose a differentiation model in which HSCs give rise to MgPs which then give rise to MkPs, supporting a classic model in which Mk-lineage commitment takes place at a late stage of differentiation.

Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.