DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2.

Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney causes ciliary elongation and cystogenesis, and cell-based proximity labeling proteomics and fluorescence microscopy show alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20, and polycystin-2 (PC2) are reduced in the cilia of DLG1-deficient cells compared to control cells. This phenotype is recapitulated in vivo and rescuable by re-expression of wild-type DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggest that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

Air-Stable Na3.5C6O6 as a Sodium Compensation Additive in Cathode of Na-Ion Batteries.

Sodium-ion battery (SIB) is a candidate for the stationary energy storage systems because of the low cost and high abundance of sodium. However, the energy density and lifespan of SIBs suffer severely from the irreversible consumption of the Na-ions for the formation of the solid electrolyte interphase (SEI) layer and other side reactions on the electrodes. Here, Na3.5C6O6 is proposed as an air-stable high-efficiency sacrificial additive in the cathode to compensate for the lost sodium. It is characteristic of low desodiation (oxidation) potential (3.4-3.6 V vs. Na+/Na) and high irreversible desodiation capacity (theoretically 378 mAh g-1). The feasibility of using Na3.5C6O6 as a sodium compensation additive is verified with the improved electrochemical performances of a Na2/3Ni1/3Mn1/3Ti1/3O2ǀǀhard carbon cells and cells using other cathode materials. In addition, the structure of Na3.5C6O6 and its desodiation path are also clarified on the basis of comprehensive physical characterizations and the density functional theory (DFT) calculations. This additive decomposes completely to supply abundant Na ions during the initial charge without leaving any electrochemically inert species in the cathode. Its decomposition product C6O6 enters the carbonate electrolyte without bringing any detectable negative effects. These findings open a new avenue for elevating the energy density and/or prolonging the lifetime of the high-energy-density secondary batteries.

A Bibliometric Analysis of the Spatial Transcriptomics Literature from 2006 to 2023.

In recent years, spatial transcriptomics (ST) research has become a popular field of study and has shown great potential in medicine. However, there are few bibliometric analyses in this field. Thus, in this study, we aimed to find and analyze the frontiers and trends of this medical research field based on the available literature. A computerized search was applied to the WoSCC (Web of Science Core Collection) Database for literature published from 2006 to 2023. Complete records of all literature and cited references were extracted and screened. The bibliometric analysis and visualization were performed using CiteSpace, VOSviewer, Bibliometrix R Package software, and Scimago Graphica. A total of 1467 papers and reviews were included. The analysis revealed that the ST publication and citation results have shown a rapid upward trend over the last 3 years. Nature Communications and Nature were the most productive and most co-cited journals, respectively. In the comprehensive global collaborative network, the United States is the country with the most organizations and publications, followed closely by China and the United Kingdom. The author Joakim Lundeberg published the most cited paper, while Patrik L. Ståhl ranked first among co-cited authors. The hot topics in ST are tissue recognition, cancer, heterogeneity, immunotherapy, differentiation, and models. ST technologies have greatly contributed to in-depth research in medical fields such as oncology and neuroscience, opening up new possibilities for the diagnosis and treatment of diseases. Moreover, artificial intelligence and big data drive additional development in ST fields.

Application of Medical Statistical and Machine Learning Methods in the Age Estimation of Living Individuals.

In the study of age estimation in living individuals, a lot of data needs to be analyzed by mathematical statistics, and reasonable medical statistical methods play an important role in data design and analysis. The selection of accurate and appropriate statistical methods is one of the key factors affecting the quality of research results. This paper reviews the principles and applicable principles of the commonly used medical statistical methods such as descriptive statistics, difference analysis, consistency test and multivariate statistical analysis, as well as machine learning methods such as shallow learning and deep learning in the age estimation research of living individuals, and summarizes the relevance and application prospects between medical statistical methods and machine learning methods. This paper aims to provide technical guidance for the age estimation research of living individuals to obtain more scientific and accurate results.

Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalogue differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.

Spatio-temporal change of winter wheat yield and its quantitative responses to compound frost-dry events - An example of the Huang-Huai-Hai Plain of China from 2001 to 2020.

Extreme climate events such as frost and drought have great influence on wheat growth and yield. Understanding the effects of frost, drought and compound frost-dry events on wheat growth and yield is of great significance for ensuring national food security. In this study, wheat yield prediction model (SCYMvp) was developed by combining crop growth model (CGM), satellite images and meteorological variables. Wheat yield maps in the Huang-Huai-Hai Plain (HHHP) during 2001-2020 were generated using SCYMvp model. Meanwhile, accumulative frost days (AFD), accumulative dry days (ADD) and accumulative frost-dry days (AFDD) in different growth periods of wheat were calculated, and the effects of frost and drought on wheat yield were quantified by the first difference method and linear mixed model. The results showed that wheat yield increased significantly, while the rising trend was obvious at more than half of the regions. Extreme climate events (ECEs) showed a relatively stable change trend, although the change trend was significant only in a few areas. Compared with frost and drought in the early growth period, ECEs in the middle growth period (spring ECEs) had more negative effects on wheat growth and yield. Wheat yield was negatively correlated with spring ECEs, and yield loss was between 4.6 and 49.8 kg/ha for each 1 d increase of spring ECEs. The effects of spring ECEs on wheat yield were ranked as AFDD > AFD > ADD. The negative effect of ADD on wheat yield in the late growth period was higher than that in the other periods. The negative effects of spring ECEs on yield in southern regions were higher than those in northern regions. Overall, due to the adverse effects of frost and drought on wheat yield in the middle and late growth periods, the mean annual yield loss was 6.4 %, among which spring AFD caused the greatest loss to wheat yield (3.1 %). The results have important guiding significance for formulating climate adaptation management strategies.

Fast Interfacial Defluorination Kinetics Enables Stable Cycling of Low-Temperature Lithium Metal Batteries.

The development of low-temperature lithium metal batteries (LMBs) encounters significant challenges because of severe dendritic lithium growth during the charging/discharging processes. To date, the precise origin of lithium dendrite formation still remains elusive due to the intricate interplay between the highly reactive lithium metal anode and organic electrolytes. Herein, we unveil the critical role of interfacial defluorination kinetics of localized high-concentration electrolytes (LHCEs) in regulating lithium dendrite formation, thereby determining the performance of low-temperature LMBs. We investigate the impact of solvation structures of LHCEs on low-temperature LMBs by employing tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MeTHF) as comparative solvents. The combination of comprehensive characterizations and theoretical simulations reveals that the THF-based LHCE featured with a strong solvation strength exhibits fast interfacial defluorination reaction kinetics, thus leading to the formation of an amorphous and inorganic-rich solid-electrolyte interphase (SEI) that can effectively suppress the growth of lithium dendrites. As a result, the highly reversible Li metal anode achieves an exceptional Coulombic efficiency (CE) of up to ∼99.63% at a low temperature of -30 °C, thereby enabling stable cycling of low-temperature LMB full cells. These findings underscore the crucial role of electrolyte interfacial reaction kinetics in shaping SEI formation and provide valuable insights into the fundamental understanding of electrolyte chemistry in LMBs.

Mechanism of lncRNA SNHG16 on kidney clear cell carcinoma cells by targeting miR-506-3p/ETS1/RAS/ERK molecular axis.

Objective: This study aimed to investigate the mechanism of long noncoding ribonucleic acid (lncRNA) SNHG16 on kidney clear cell carcinoma (KIRC) cells by targeting miR-506-3p/ETS proto-oncogene 1, transcription factor (ETS1)/RAS/Extracellular regulated protein kinases (ERK) molecular axis, thus to provide reference for clinical diagnosis and treatment of KIRC in the future. Methods: Thirty-six patients with KIRC were enrolled in this study, and their carcinoma tissues and adjacent tissues were obtained for the detection of SNHG16/miR-506-3p/ETS1/RAS/ERK expression. Then, over-expressed SNHG16 plasmid and silenced plasmid were transfected into KIRC cells to observe the changes of their biological behavior. Results: SNHG16 and ETS1 were highly expressed while miR-506- 3p was low expressed in KIRC tissues; the RAS/ERK signaling pathway was significantly activated in KIRC tissues (P < 0.05). After SNHG16 silence, KIRC cells showed decreased proliferation, invasion and migration capabilities and increased apoptosis rate; correspondingly, increase in SNHG16 expression achieved opposite results (P < 0.05). Finally, in the rescue experiment, the effects of elevated SNHG16 on KIRC cells were reversed by simultaneous increase in miR-506-3p, and the effects of miR-506-3p were reversed by ETS1. Activation of the RAS/ERK pathway had the same effect as increase in ETS1, which further worsened the malignancy of KIRC. After miR-506-3p increase and ETS1 silence, the RAS/ERK signaling pathway was inhibited (P < 0.05). At last, the rescue experiment (co-transfection) confirmed that the effect of SNHG16 on KIRC cells is achieved via the miR-506-3p/ETS1/RAS/ERK molecular axis. Conclusion: SNHG16 regulates the biological behavior of KIRC cells by targeting the miR-506-3p/ETS1/RAS/ERK molecular axis.

Cannabis Use Disorder Associated With Increased Risk of Postoperative Complications After Hip or Knee Arthroplasties: A Meta-analysis of Observational Studies.

INTRODUCTION: With the legalization of marijuana in the United States, the number of patients with cannabis use disorder (CUD) in the joint arthroplasty population has increased markedly. The primary purpose of this meta-analysis was to determine whether there were differences in clinical and economic outcomes after total joint arthroplasty (TJA) between patients with and without perioperative CUD. METHODS: We searched PubMed, Embase, Scopus, and Web of Science databases up to July 2018 to identify all eligible studies investigating the association of CUD with postoperative outcomes in patients undergoing TJA. Postoperative outcomes assessed consisted of complications, readmission, length of stay (LOS), implant revision, and cost of care. For dichotomous outcomes, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random effects model. RESULTS: We identified 10 retrospective cohort studies with a total of 17,981,628 study participants. Patients with CUD had significantly higher odds of medical complications (OR 1.33 [95% CI 1.07 to 1.66], P = 0.01) and implant-related complications (OR 1.75 [95% CI: 1.64 to 1.88], P < 0.00001) than noncannabis users. Specifically, CUD was associated with significantly increased odds of cardiac complications (OR 1.95 [95% CI 1.50 to 2.54], P < 0.00001), cerebrovascular accidents (OR 2.06 [95% CI 1.66 to 2.57], P < 0.00001), postoperative infections (OR 1.68 [95% CI 1.34 to 2.10], P < 0.00001), periprosthetic fracture (OR 1.42 [95% CI 1.19 to 1.70], P < 0.0001), mechanical loosening (OR 1.54 [95% CI 1.42 to 1.66], P < 0.00001), and dislocation/instability (OR 1.88 [95% CI 1.32 to 2.68], P = 0.0005). Longer LOS and higher cost of care were also found in patients with CUD. CONCLUSION: This study strengthens the body of evidence that patients with CUD face higher risk of postoperative complications and greater financial burden after knee and hip arthroplasties. Physicians should inform patients about adverse outcomes and undertake appropriate risk adjustments before elective orthopaedic surgery. LEVEL OF EVIDENCE: Level III.

Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity.

Generation of chimeric antigen receptor macrophages (CAR-Ms) from human pluripotent stem cells (hPSCs) offers new prospects for cancer immunotherapy but is currently challenged by low differentiation efficiency and limited function. Here, we develop a highly efficient monolayer-based system that can produce around 6,000 macrophages from a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Ms with stable CAR expression and potent tumoricidal activity in vitro. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms in vivo, we use interferon-γ and monophosphoryl lipid A to activate an innate immune response that repolarizes the hPSC-CAR-Ms to tumoricidal macrophages. Moreover, through combined activation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborative innate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Ms in vivo. Collectively, our study provides feasible methodologies that significantly improve the production and function of hPSC-CAR-Ms to support their translation into clinical applications.

p21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells.

The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.

Targeting SRSF2 mutations in leukemia with RKI-1447: A strategy to impair cellular division and nuclear structure.

Spliceosome machinery mutations are common early mutations in myeloid malignancies; however, effective targeted therapies against them are still lacking. In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified RKI-1447, a Rho-associated protein kinase inhibitor, as selective cytotoxic effector of SRSF2 mutant cells. RKI-1447 targeted SRSF2 mutated primary human samples in xenografts models. RKI-1447 induced mitotic catastrophe and induced major reorganization of the microtubule system and severe nuclear deformation. Transmission electron microscopy and 3D light microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation that are apparently driven by microtubule-rich cytoplasmic intrusions, which are exacerbated by RKI-1447. The severe nuclear deformation in RKI-1447-treated SRSF2 mutant cells prevents cells from completing mitosis. These findings shed new light on the interplay between microtubules and the nucleus and offers new ways for targeting pre-leukemic SRSF2 mutant cells.

Circulating tumor cells help differentiate benign ovarian lesions from cancer before surgery: A literature review and proof of concept study using flow cytometry with fluorescence imaging.

Current tools are insufficient for distinguishing patients with ovarian cancer from those with benign ovarian lesions before extensive surgery. The present study utilized a readily accessible platform employing a negative selection strategy, followed by flow cytometry, to enumerate circulating tumor cells (CTCs) in patients with ovarian cancer. These counts were compared with those from patients with benign ovarian lesions. CTC counts at baseline, before and after anticancer therapy, and across various clinical scenarios involving ovarian lesions were assessed. A negative-selection protocol we proposed was applied to patients with suspected ovarian cancer and prospectively utilized in those subsequently confirmed to have malignancy. The protocol was implemented before anticancer therapy and at months 3, 6, 9 and 12 post-treatment. A cut-off value for CTC number at 4.75 cells/ml was established to distinguish ovarian malignancy from benign lesions, with an area under the curve of 0.900 (P<0.001). In patients with ovarian cancer, multivariate Cox regression analysis revealed that baseline CTC counts and the decline in CTCs within the first three months post-therapy were significant predictors of prolonged progression-free survival. Additionally, baseline CTC counts independently prognosticated overall survival. CTC counts obtained with the proposed platform, used in the present study, suggest that pre-operative CTC testing may be able to differentiate between malignant and benign tumors. Moreover, CTC counts may indicate oncologic outcomes in patients with ovarian cancer who have undergone cancer therapies.

Clinical use of macitentan in the treatment of connective tissue disease-associated pulmonary arterial hypertension.

Background: Connective tissue disease (CTD) is the second most common cause of the pulmonary arterial hypertension (PAH). Currently, clinical data concerning CTD-PAH is scarce. Our study aimed to assess the efficacy and safety of macitentan in the treatment of CTD-PAH. Methods: In this retrospective study, patients diagnosed with CTD-PAH at The First Affiliated Hospital of Soochow University from April 2020 to November 2021 were included. Of the patients, 9 were switched to macitentan monotherapy whereas 23 received initial combination therapy. The mean follow-up time was 24 weeks. Six-minute walking distance (6MWD), World Health Organization functional class (WHO-FC), serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiography parameters before and after medication were assessed. Adverse reactions were also recorded and compared. Results: After 24 weeks of treatment, 6MWD, NT-proBNP, systolic pulmonary artery pressure (sPAP) estimated by ultrasound, tricuspid regurgitation pressure gradient (TRPG) and tricuspid annular plane systolic excursion (TAPSE) in the macitentan monotherapy group revealed significant differences (Z=-2.67, Z=-2.67, t=6.20, t=5.60, t=-3.04, P<0.05). There were no statistically significant differences in right ventricular diameter (RVD), right atrial diameter (RAD), ascending aortic root inner diameter (AAO) and left ventricular end-diastolic diameter (LVEDd) (P>0.05). After 24 weeks of medication, the number of patients with WHO-FC grade III/IV symptoms decreased from 6 to 3, 1 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 2, 2 to 4 respectively(P<0.05). After 24 weeks of treatment, 6MWD, NT-proBNP, LVEDd, sPAP and TRPG in the macitentan combined with sildenafil treatment group revealed statistically significant differences (Z=-4.11, Z=-3.74, Z=-3.83, t=6.88, t=6.54, P<0.001). Significant differences in RVD, RAD, and TAPSE were found (t=3.46, t=3.69, t=-3.12, P<0.05). There were no statistically significant variances in AAO between the groups (P>0.05). The number of patients with WHO-FC grade III/IV symptoms decreased from 16 to 8, 5 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 1, 2 to 14 respectively (P<0.001). There were no statistically significant differences before and after treatment in 6MWD, NT-proBNP, RVD, RAD, AAO, LVEDd, sPAP, TRPG and TAPSE between the two groups (P>0.05). There were no statistically significant differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr) and hemoglobin (Hb) between 0 and 24 weeks (P>0.05). Conclusions: Exercise tolerance and cardiac function in patients with CTD-PAH were significantly improved after treatment with macitentan, which was well tolerated. Therefore, macitentan may be an effective and safe targeted drug for CTD-PAH.

Mitochondrial tRNA pseudouridylation governs erythropoiesis.

Pseudouridine is the most prevalent RNA modification, and its aberrant function is implicated in various human diseases. However, the specific impact of pseudouridylation on hematopoiesis remains poorly understood. In this study, we investigated the role of tRNA pseudouridylation in erythropoiesis and its association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia syndrome (MLASA) pathogenesis. By utilizing patient-specific induced pluripotent stem cells (iPSCs) carrying a genetic PUS1 mutation and a corresponding mutant mouse model, we demonstrated impaired erythropoiesis in MLASA iPSCs and anemia in the MLASA mouse model. Both MLASA iPSCs and mouse erythroblasts exhibited compromised mitochondrial function and impaired protein synthesis. Mechanistically, we revealed that PUS1 deficiency resulted in reduced mitochondrial tRNA levels due to pseudouridylation loss, leading to aberrant mitochondrial translation. Screening of mitochondrial supplements aimed at enhancing respiration or heme synthesis showed limited effect in promoting erythroid differentiation. Interestingly, the mTOR inhibitor rapamycin facilitated erythroid differentiation in MLASA-iPSCs by suppressing mTOR signaling and protein synthesis, and consistent results were observed in the MLASA mouse model. Importantly, rapamycin treatment effectively ameliorated anemia phenotypes in the MLASA patient. Our findings provide novel insights into the crucial role of mitochondrial tRNA pseudouridylation in governing erythropoiesis and present potential therapeutic strategies for anemia patients facing challenges related to protein translation.

Sulfur-Tuned Main-Group Sb-N-C Catalysts for Selective 2-Electron and 4-Electron Oxygen Reduction.

The selective oxygen reduction reaction (ORR) is important for various energy conversion processes such as the fuel cells and metal-air batteries for the 4e- pathway and hydrogen peroxide (H2O2) electrosynthesis for the 2e- pathway. However, it remains a challenge to tune the ORR selectivity of a catalyst in a controllable manner. Herein, an efficient strategy for introducing sulfur dopants to regulate the ORR selectivity of main-group Sb-N-C single-atom catalysts  is reported. Significantly, Sb-N-C with the highest sulfur content follows a 2e- pathway with high H2O2 selectivity (96.8%) and remarkable mass activity (96.1 A g-1 at 0.65 V), while the sister catalyst with the lowest sulfur content directs a 4e- pathway with a half-wave potential (E1/2 = 0.89 V) that is more positive than commercial Pt/C. In addition, practical applications for these two 2e-/4e- ORR catalysts are demonstrated by bulk H2O2 electrosynthesis for the degradation of organic pollutants and a high-power zinc-air battery, respectively. Combined experimental and theoretical studies reveal that the excellent selectivity for the sulfurized Sb-N-Cs is attributed to the optimal adsorption-desorption of the ORR intermediates realized through the electronic structure modulation by the sulfur dopants.

Tailoring Localized Electrolyte via a Dual-Functional Protein Membrane toward Stable Zn Anodes.

Considerable attention has been by far paid to stabilizing metallic Zn anodes, where side reactions and dendrite formation still remain detrimental to their practical advancement. Electrolyte modification or protected layer design is widely reported; nonetheless, an effective maneuver to synergize both tactics has been rarely explored. Herein, we propose a localized electrolyte optimization via the introduction of a dual-functional biomass modificator over the Zn anode. Instrumental characterization in conjunction with molecular dynamics simulation indicates local solvation structure transformation owing to the limitation of bound water with intermolecular hydrogen bonds, effectively suppressing hydrogen evolutions. Meanwhile, the optimized nucleation throughout the protein membrane allows uniform Zn deposition. Accordingly, the symmetric cell exhibits an elongated lifespan of 3280 h at 1.0 mA cm-2/1.0 mAh cm-2, while the capacity retention of the full cell sustains 91.1% after 2000 cycles at 5.0 A g-1. The localized electrolyte tailoring via protein membrane introduction might offer insights into operational metal anode protection.

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.

Despite the identification of driver mutations leading to the initiation of myeloproliferative neoplasms (MPNs), the molecular pathogenesis of MPNs remains incompletely understood. Here, we demonstrate that growth arrest and DNA damage inducible gamma (GADD45g) is expressed at significantly lower levels in patients with MPNs, and JAK2V617F mutation and histone deacetylation contribute to its reduced expression. Downregulation of GADD45g plays a tumor-promoting role in human MPN cells. Gadd45g insufficiency in the murine hematopoietic system alone leads to significantly enhanced growth and self-renewal capacity of myeloid-biased hematopoietic stem cells, and the development of phenotypes resembling MPNs. Mechanistically, the pathogenic role of GADD45g insufficiency is mediated through a cascade of activations of RAC2, PAK1 and PI3K-AKT signaling pathways. These data characterize GADD45g deficiency as a novel pathogenic factor in MPNs.