Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception.

Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, CD3254-RXRα axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-γ and TNF-α pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254-RXRα-RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.

Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Protein Profiles and Novel Molecular Biomarkers of Schizophrenia Based on 4D-DIA Proteomics.

Schizophrenia is a severe psychological disorder. The current diagnosis mainly relies on clinical symptoms and lacks laboratory evidence, which makes it very difficult to make an accurate diagnosis especially at an early stage. Plasma protein profiles of schizophrenia patients were obtained and compared with healthy controls using 4D-DIA proteomics technology. Furthermore, 79 DEPs were identified between schizophrenia and healthy controls. GO functional analysis indicated that DEPs were predominantly associated with responses to toxic substances and platelet aggregation, suggesting the presence of metabolic and immune dysregulation in patients with schizophrenia. KEGG pathway enrichment analysis revealed that DEPs were primarily enriched in the chemokine signaling pathway and cytokine receptor interactions. A diagnostic model was ultimately established, comprising three proteins, namely, PFN1, GAPDH and ACTBL2. This model demonstrated an AUC value of 0.972, indicating its effectiveness in accurately identifying schizophrenia. PFN1, GAPDH and ACTBL2 exhibit potential as biomarkers for the early detection of schizophrenia. The findings of our studies provide novel insights into the laboratory-based diagnosis of schizophrenia.

Effect of the Water Content on the Adsorption of CO2 and CH4 in Calcite Slit Nanopores: Insights from GCMC, MD, and DFT.

It is significant to understand the adsorption mechanisms of shale gas (CH4) and CO2 in shale formations to enhance CH4 recovery rates and enable geological CO2 storage. This study provides a comprehensive investigation into the adsorption behaviors of CO2 and CH4 within dry and hydrous calcite nanopores, utilizing a combination of grand canonical Monte Carlo simulations, molecular dynamics simulations, and density functional theory calculations. In dry calcite slits, the calculated results for the adsorption capacity, density profile, and isosteric heat of CO2 and CH4 reveal that CO2 possesses a stronger adsorption affinity, making it preferentially adsorb on the pore surface compared to CH4. In hydrous calcite slits, calculating the adsorption capacity and density profile of CO2 and CH4, the results show that the gas adsorption sites become progressively occupied by H2O molecules, leading to a substantial decrease in the adsorption capacity of CO2 and CH4. Furthermore, by analysis of the adsorption energy and electronic structure, the reason for the reduction of gas adsorption capacity caused by H2O is further revealed. This work has a deep understanding of the adsorption mechanisms of shale gas and CO2 in calcite and can offer valuable theoretical insights for the development of a CO2-enhanced shale gas recovery technology.

Cadmium exposure promotes inflammation through the PPAR signaling pathway in the small intestine and colon of Hu sheep.

With the increase of cadmium content in the environment, the losses caused by cadmium-induced intestinal diseases to animal husbandry are increasing year by year. However, most of the on-going research activities focus on zoonotic diseases rather than exploring the mechanisms of animal disease occurrence from an anthropogenic environmental perspective. In this study, stressed Hu sheep under cadmium environmental exposure were selected to explore the mechanism of inflammatory bowel disease development. 16 s, untargeted metabolomics and transcriptomic multiomics were used to analyze the changes of their intestinal tract and intestinal contents. The results showed that the beneficial microorganisms (s_Ruminococcus_sp) in the Cd group were significantly decreased and the potentially harmful microorganisms were significantly enriched, and the changes of these microorganisms affected the changes of metabolites (caprylic acid) to a certain extent, resulting in a decrease in fatty acids in the intestine. Due to the combined effect of cadmium ion and fatty acid reduction, the PPAR signaling pathway was inhibited, and the fatty acid transport and binding were further reduced, causing very serious damage to the intestine. We revealed for the first time the mechanism of intestinal injury in Hu sheeps under cadmium environmental exposure and provided new prevention and treatment methods of intestinal diseases under the environmental exposure to trace metals.

Development of a MEMS Piezoresistive High-g Accelerometer with a Cross-Center Block Structure and Reliable Electrode.

A MEMS piezoresistive sensor for measuring accelerations greater than 100,000 g (about 106 m/s2) is described in this work. To enhance the performance of the sensor, specifically widening its measurement range and natural frequency, a cross-beam construction with a center block was devised, and a Wheatstone bridge was formed by placing four piezoresistors at the ends of the fixed beams to convert acceleration into electricity. The location of the varistor was determined using the finite element approach, which yielded the optimal sensitivity. Additionally, a reliable Pt-Ti-Pt-Au electrode was designed to solve the issue of the electrode failing under high impact and enhancing the stability of the ohmic contact. The accelerometer was fabricated using MEMS technology, and the experiment with a Hopkinson pressure bar and hammering was conducted, and the bias stability was measured. It had a sensitivity of 1.06 µV/g with good linearity. The simulated natural frequency was 633 kHz The test result revealed that the accelerometer can successfully measure an acceleration of 100,000 g.

Unveiling geospatial heterogeneity in climate's impacts on wheat production to advance spatially-matched climate-adaptive agricultural management in the North China plain.

Influence of climate change on the geospatial heterogeneity in agricultural production remains poorly understood. In this study, heterogeneity in climate's impacts on wheat production across the North China Plain (NCP) was explored by integrating APSIM model, process-based factor-control quantitative approach, and geostatistical analyses. The results indicated that increased precipitation and minimum temperature boosted yields, while elevated maximum temperature and reduced radiation exerted adverse effects. The most pronounced negative impact arose from the coupling variation between maximum temperature and radiation, contributing to yields' variations of -5.84% from 2000 to 2010 and -5.22% from 2010 to 2020. In last two decades, climate change has augmented the overall geospatial heterogeneity degree in wheat yields. The chief factor contributing to yields' heterogeneity was the maximum temperature during anthesis-maturation stage, explaining an average of 37.6% of yields' heterogeneity, followed by precipitation throughout the whole growth period and the anthesis-maturation stage, explaining 36.1% and 34.5% respectively. A reciprocal enhancement mechanism exists between factors in driving yields' heterogeneity. Wheat yields in the southwestern NCP benefited more from increased precipitation and minimum temperature. Between 2000 and 2010, yields in the central NCP (junctions of Henan, Hebei, and Shandong) experienced the most pronounced adverse impact from increased maximum temperature. However, by 2010-2020, significant adverse impact shifted to western NCP, expanding spatially. During 2010-2020, the geospatial scope of radiation's significant negative impact expanded compared to the preceding decade, particularly affecting the yields in central and eastern NCP. The identified geospatial heterogeneity pattern of climate's impacts can guide spatially-matched climate-adaptive management adjustments. For instance, intensifying the defense against high-temperature's impacts in northwestern Henan, southern Hebei, and western Shandong, while improving the adaptation to radiation reduction in the central and eastern NCP. The findings are expected to advance regional-scale climate-smart agricultural development.

The triglyceride glucose index trajectory is associated with hypertension: a retrospective longitudinal cohort study.

BACKGROUND: Previous studies have found that the triglyceride glucose index (TyG index) trajectories are associated with cardiovascular diseases. However, the association between the patterns of TyG index trajectories and risk for hypertension has not been investigated. In a longitudinal general population, we aimed to identify distinct TyG index trajectories over 12 years and describe their association with incidence of hypertension. METHOD: Of the 15,056 adults retrospectively recruited from the Physical Examination Center of the Second Affiliated Hospital of Dalian Medical University in northeast of China from 2011 to 2022. TyG index was calculated as ln (fasting TG [mg/dL] × FPG [mg/dL]/2) and the TyG index trajectories were developed using group-based trajectory modelling. Cox regression analysis was accomplished to assess the association between TyG index and incidence of hypertension. RESULTS: The median age of the population was 38 years, and 7352 (48.83%) of the participants were men. Three distinct TyG index trajectories were identified: "low increasing" (N = 7241), "moderate increasing" (N = 6448), and "high stable" (N = 1367). Using "low increasing" trajectory as a reference, "moderate increasing" and "high stable" trajectory were associated with increased risk of hypertension (HR = 2.45; 95% CI 2.25-2.67 and HR = 3.88; 95% CI 3.48-4.33). After adjusting for baseline sex, age, diabetes, smoking, systolic blood pressure, diastolic blood pressure, BMI, cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, blood glucose, triglyceride, urea, uric acid, and glomerular filtration rate, the HR were slightly attenuate in "moderate increasing" and "high stable" trajectories to 1.38 (95% CI 1.23-1.54) and 1.69 (95% CI 1.40-2.02) respectively. Meanwhile, similar results were observed in multiple sensitivity analyses. The HR of the "moderate increasing" and "high stable" trajectory groups were 2.63 (95% CI 2.30-3.00) and 4.66 (95% CI 3.66-5.93) in female, and 1.66 (95% CI 1.48-1.86) and 2.33 (95% CI 2.04-2.66) in male. CONCLUSIONS: Elevated TyG index at baseline and long-term TyG index trajectories were associated with the risk of hypertension. Early identification of increasing TyG index could provide insights for preventing hypertension later in life.

Research of a Cross-Interference Suppression Method for Piezoresistive Three-Dimensional Force Sensor.

Cross-interference is not only an important factor that affects the measuring accuracy of three-dimensional force sensors, but also a technical difficulty in three-dimensional force sensor design. In this paper, a cross-interference suppression method is proposed, based on the octagonal ring's structural symmetry as well as Wheatstone bridge's balance principle. Then, three-dimensional force sensors are developed and tested to verify the feasibility of the proposed method. Experimental results show that the proposed method is effective in cross-interference suppression, and the optimal cross-interference error of the developed sensors is 1.03%. By optimizing the positioning error, angle deviation, and bonding process of strain gauges, the cross-interference error of the sensor can be further reduced to -0.36%.

Spinal 5-HT2A receptor is involved in electroacupuncture inhibition of chronic pain.

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, and it is a typical disease which can develop chronic pain. Our previous study has proved that endocannabinoid (2-AG)-CB1R-GABA-5-HT pathway is involved in electroacupuncture (EA) mediated inhibition of chronic pain. However, it is still unclear which among the 5-HT receptor subtype is involved in EA evoked 5-HT mediated inhibition of chronic pain in the dorsal spinal cord. 5-HT2A is a G protein-coupled receptor and it is involved in 5-HT descending pain modulation system. We found that EA treatment at frequency of 2 Hz +1 mA significantly increased the expression of 5-HT2A receptor in the dorsal spinal cord and intrathecal injection of 5-HT2A receptor antagonist or agonist reversed or mimicked the analgesic effect of EA in each case respectively. Intrathecal injection of a selective GABAA receptor antagonist Bicuculline also reversed the EA effect on pain hypersensitivity. Additionally, EA treatment reversed the reduced expression of GABAA receptor and KCC2 in the dorsal spinal cord of KOA mice. Furthermore, we demonstrated that intrathecal 5-HT2A receptor antagonist/agonist reversed or mimicked the effect of EA up-regulate of KCC2 expression, respectively. Similarly, intrathecal injection of PLC and PKC inhibitors prevented both anti-allodynic effect and up-regulation of KCC2 expression by EA treatment. Our data suggest that EA treatment up-regulated KCC2 expression through activating 5-HT2A-Gq-PLC-PKC pathway and enhanced the inhibitory function of GABAA receptor, thereby inhibiting chronic pain in a mouse model of KOA.

Simulation of Water Flow in a Nanochannel with a Sudden Contraction or Expansion.

Water flow in a nanoscale channel is known to be affected by strong water-wall interactions; as a result, the flow considerably deviates from the conventional continuum flow. Nanochannel with a sudden contraction or expansion is the most fundamental morphological nanostructure in many nanoporous systems such as shale matrix, mudrock, membrane, etc. However, the nanoconfinement effects of water flow in nanoporous systems and its effect on macroscopic flow behavior are still evolving research topics. In this work, our recently developed pore-scale lattice Boltzmann method (LBM) considering the nanoscale effects is extended to directly simulate water flow in nanoporous systems. The results show that the flow rate is dramatically decreased in hydrophobic nanopores because of additional flow resistances at the contraction and expansion junctions. This indicates that the bundle of capillary models or the permeability averaging method overestimates the water flow rate in nanoporous media if the contraction/expansion effects between different nanopores are ignored. This work highlights the importance of wettability of the nanochannel in the determination of dynamic water flow behaviors in the contraction/expansion nanosystem. Other important aspects, including velocity distribution, flow patterns, and vortex characteristics as well as pressure variation along the flow direction, are for the first time revealed and quantified. Large differences can be found comparing gas or larger-scale water flows through the same system. A new type of pressure variation curve along the axis of flow direction is found in the hydrophobic nanochannel with a sudden contraction/expansion. This work provides the fundamental understanding of water transport through the nanoscale system with contraction and expansion effects, giving implications to a wide range of industry applications.

Visible Light-Induced Coupling Cyclization Reaction of α-Diazosulfonium Triflates with α-Oxocarboxylic Acids or Alkynes.

A photocatalyst-free radical cleavage of α-diazo sulfonium salts has been developed for the first time. The reaction provides an efficient method for the generation of diazomethyl radicals from α-diazosulfonium triflates under photochemical conditions. Utilizing the in situ generated diazomethyl radicals as key intermediate, the coupling cyclization reaction of α-diazosulfonium triflates with α-oxocarboxylic acids or alkynes has been achieved. The method affords a diverse set of important 2,5-disubstituted 1,3,4-oxadiazoles and 3,5-disubstituted-1H-pyrazoles with excellent regioselectivity in a single step. A reaction mechanism involving a radical pathway was further supported by control experiments and DFT calculations.

NaN(SiMe3)2/CsTFA Copromoted Aminobenzylation/Cyclization of 2-Isocyanobenzaldehydes with Toluene Derivatives or Benzyl Compounds: One-Pot Access to Dihydroquinazolines and Quinazolines.

A NaN(SiMe3)2/CsTFA copromoted aminobenzylation/cyclization reaction of 2-isocyanobenzaldehydes with toluene derivatives or benzyl compounds has been developed. The reaction works with a broad range of toluene derivatives and benzyl compounds, and provides a simple and efficient strategy for the synthesis of 4-benzyl-substitued dihydroquinazoline and quinazoline derivatives from easily available acyclic starting materials in a single step. Further applications, including synthesis of quinazoline, dihydroindolo[1,2-c]quinazoline, and dihydro-8H-isoquinolino[2,3-c]quinazoline, demonstrated the tremendous potential of the tandem reaction.

Collective Total Syntheses of Five Lycopodium Alkaloids.

It is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold-catalyzed enamide-alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting-group-free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten-membered lactam system in phlegmariurine B; 3) a Fukuyama one-pot protocol for the construction of the 2-pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

A new adenylyl cyclase, putative disease-resistance RPP13-like protein 3, participates in abscisic acid-mediated resistance to heat stress in maize.

In plants, 3´,5´-cyclic adenosine monophosphate (cAMP) is an important second messenger with varied functions; however, only a few adenylyl cyclases (ACs) that synthesize cAMP have been identified. Moreover, the biological roles of ACs/cAMP in response to stress remain largely unclear. In this study, we used quantitative proteomics techniques to identify a maize heat-induced putative disease-resistance RPP13-like protein 3 (ZmRPP13-LK3), which has three conserved catalytic AC centres. The AC activity of ZmRPP13-LK3 was confirmed by in vitro enzyme activity analysis, in vivo RNAi experiments, and functional complementation in the E. coli cyaA mutant. ZmRPP13-LK3 is located in the mitochondria. The results of in vitro and in vivo experiments indicated that ZmRPP13-LK3 interacts with ZmABC2, a possible cAMP exporter. Under heat stress, the concentrations of ZmRPP13-LK3 and cAMP in the ABA-deficient mutant vp5 were significantly less than those in the wild-type, and treatment with ABA and an ABA inhibitor affected ZmRPP13-LK3 expression in the wild-type. Application of 8-Br-cAMP, a cAMP analogue, increased heat-induced expression of heat-shock proteins in wild-type plants and alleviated heat-activated oxidative stress. Taken together, our results indicate that ZmRPP13-LK3, a new AC, can catalyse ATP for the production of cAMP and may be involved in ABA-regulated heat resistance.

A Flexible Pressure Sensor Based on Magnetron Sputtered MoS2.

Although two-dimensional (2D) layered molybdenum disulfide (MoS2) has widespread electrical applications in catalysis, energy storage, and photodetection, there are few reports available regarding sputtered MoS2 for piezoresistive sensors. In this research, we found that the resistance of magnetron sputtered MoS2 on a flexible substrate changed significantly and regularly when pressure was applied. Scanning electron microscope (SEM) and atomic force microscope (AFM) images revealed an MoS2 micro-grain-like structure comprising nano-scale particles with grooves between the particles. Chemical characterization data confirmed the successful growth of amorphous MoS2 on a polydimethylsiloxane (PDMS) substrate. A micro-thickness film flexible sensor was designed and fabricated. In particular, the sensor with a 1.5 µm thick polydimethylsiloxane (PDMS) substrate exhibited the best resistance performance, displaying a maximum ΔR/R of 70.39 with a piezoresistive coefficient as high as 866.89 MPa-1 while the pressure was 0.46 MPa. A proposed flexible pressure sensor based on an MoS2 film was also successfully used as a wearable pressure sensor to measure plantar pressure and demonstrated good repeatability. The results showed that the thin film pressure sensor had good piezoresistive performance and high sensitivity.

The calcium-dependent protein kinase ZmCDPK7 functions in heat-stress tolerance in maize.

Global warming poses a serious threat to crops. Calcium-dependent protein kinases (CDPKs)/CPKs play vital roles in plant stress responses, but their exact roles in plant thermotolerance remains elusive. Here, we explored the roles of heat-induced ZmCDPK7 in thermotolerance in maize. ZmCDPK7-overexpressing maize plants displayed higher thermotolerance, photosynthetic rates, and antioxidant enzyme activity but lower H2 O2 and malondialdehyde (MDA) contents than wild-type plants under heat stress. ZmCDPK7-knockdown plants displayed the opposite patterns. ZmCDPK7 is attached to the plasma membrane but can translocate to the cytosol under heat stress. ZmCDPK7 interacts with the small heat shock protein sHSP17.4, phosphorylates sHSP17.4 at Ser-44 and the respiratory burst oxidase homolog RBOHB at Ser-99, and upregulates their expression. Site-directed mutagenesis of sHSP17.4 to generate a Ser-44-Ala substitution reduced ZmCDPK7's enhancement of catalase activity but enhanced ZmCDPK7's suppression of MDA accumulation in heat-stressed maize protoplasts. sHSP17.4, ZmCDPK7, and RBOHB were less strongly upregulated in response to heat stress in the abscisic acid-deficient mutant vp5 versus the wild type. Pretreatment with an RBOH inhibitor suppressed sHSP17.4 and ZmCDPK7 expression. Therefore, abscisic acid-induced ZmCDPK7 functions both upstream and downstream of RBOH and participates in thermotolerance in maize by mediating the phosphorylation of sHSP17.4, which might be essential for its chaperone function.

A Capacitive MEMS Inclinometer Sensor with Wide Dynamic Range and Improved Sensitivity.

This paper proposes a novel capacitive liquid metal microelectromechanical system (MEMS) inclinometer sensor and introduces its design, fabrication, and signal measurement. The sensor was constructed using three-layer substrates. A conductive liquid droplet was rolled along an annular groove of the intermediate substrate to reflect angular displacement, and capacitors were used to detect the position of the droplet. The numerical simulation work provides the working principle and structural design of the sensor, and the fabrication process of the sensor was proposed. Furthermore, the static capacitance test and the dynamic signal test were designed. The sensor had a wide measurement range from ±2.12° to ±360°, and the resolution of the sensor was 0.4°. This sensor further expands the measurement range of the previous liquid droplet MEMS inclinometer sensors.

Design and Development of a Fully Printed Accelerometer with a Carbon Paste-Based Strain Gauge.

In this paper, we present a fully printed accelerometer with a piezoresistive carbon paste-based strain gauge printed on its surface, which can be manufactured at low cost and with high efficiency. This accelerometer is composed of two parts: a sensor substrate made from high-temperature resin, which is printed by a 3D printer based on stereolithography apparatus (SLA), and a carbon paste-based strain gauge fabricated by screen-printing technology and by direct ink writing (DIW) technology for the purposes of comparison and optimization. First, the structural design, theoretical analysis, simulation analysis of the accelerometer, and analyses of the conductive mechanism and the piezoresistive mechanism of the carbon paste-based strain gauge were carried out. Then the proposed accelerometer was fabricated by a combination of different printing technologies and the curing conditions of the carbon paste were investigated. After that, the accelerometers with the screen-printed strain gauge and DIW strain gauge were characterized. The results show that the printing precision of the screen-printing process on the sensor substrate is higher than the DIW process, and both accelerometers can perform acceleration measurement. Also, this kind of accelerometer can be used in the field of measuring body motion. All these findings prove that 3D printing technology is a significant method for sensor fabrication and verification.

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML.

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.