Coherent feedback enhanced quantum-dense metrology in a lossy environment.

Quantum dense metrology (QDM) performs high-precision measurements by a two-mode entangled state created by an optical parametric amplifier (PA), where one mode is a meter beam and the other is a reference beam. In practical applications, the photon losses of meter beam are unavoidable, resulting in a degradation of the sensitivity. Here, we employ coherent feedback that feeds the reference beam back into the PA by a beam splitter to enhance the sensitivity in a lossy environment. The results show that the sensitivity is enhanced significantly by adjusting the splitting ratio of the beam splitter. This method may find its potential applications in QDM. Furthermore, such a strategy that two non-commuting observables are simultaneous measurements could provide a new way to individually control the noise-induced random drift in phase or amplitude of the light field, which would be significant for stabilizing the system and long-term precision measurement.

Protection of Noise Squeezing in a Quantum Interferometer with Optimal Resource Allocation.

Interferometers are crucial for precision measurements, including gravitational waves, laser ranging, radar, and imaging. The phase sensitivity, the core parameter, can be quantum-enhanced to break the standard quantum limit (SQL) using quantum states. However, quantum states are highly fragile and quickly degrade with losses. We design and demonstrate a quantum interferometer utilizing a beam splitter with a variable splitting ratio to protect the quantum resource against environmental impacts. The optimal phase sensitivity can reach the quantum Cramér-Rao bound of the system. This quantum interferometer can greatly reduce the quantum source requirements in quantum measurements. In theory, with a 66.6% loss rate, the sensitivity can break the SQL using only a 6.0 dB squeezed quantum resource with the current interferometer rather than a 24 dB squeezed quantum resource with a conventional squeezing-vacuum-injected Mach-Zehnder interferometer. In experiments, when using a 2.0 dB squeezed vacuum state, the sensitivity enhancement remains at ∼1.6 dB via optimizing the first splitting ratio when the loss rate changes from 0% to 90%, indicating that the quantum resource is excellently protected with the existence of losses in practical applications. This strategy could open a way to retain quantum advantages for quantum information processing and quantum precision measurement in lossy environments.

Prevalence and Risk Factors of Primary Dysmenorrhea in Students: A Meta-Analysis.

OBJECTIVES: Primary dysmenorrhea (PD), as the most common complaint among students, is also one of the public problems worldwide. Prevalence and risk factors of PD were variant between studies; as the main population, no meta-analysis for PD has hitherto been conducted in students. METHODS: We searched the published literature in PubMed, Embase, the Cochrane Library, Web of Science, National Knowledge Infrastructure, WANFANG, and VIP database. After screening and assessing the quality of studies, data from eligible studies were extracted for meta-analysis via the R language. RESULTS: A total of 96 studies published from 1991 to 2021 with 78 068 students were included, the mean age of participants was 19.4, and 79.9% were university students. The pooled overall prevalence of PD was 66.1% (95% confidence interval [CI] 63.4-68.9), and 31.1% (CI 28.1-34.3), 25.7% (CI 23.4-28.0), and 8.3% of students (CI 7.4-9.3) reported mild, moderate, and severe PD, respectively. Besides, the prevalence of PD was estimated at 58.8% (CI 54.3-63.7) before 2010, but ascended to 68.5% (CI 65.5-71.6) after 2010 and rose to 71.5% (CI 65.8-76.6) in 2015 to 2021. About risk factors for PD, underweight, skipping breakfast, poor sleep quality, staying up late, lack of physical exercise, exposure to cold and eating cold or spicy foods during menstruation, dietary bias, prefer snacks, family history of dysmenorrhea, irregular menstrual cycle, heavy stress, negative emotion during menstruation, and anxiety were significantly related to PD. CONCLUSIONS: The overall prevalence of PD among students was 66.1% and had a rising tendency in the last 10 years. Our findings helped understand the current prevalence and improve the administration of PD among students.

Carnosol suppresses microglia cell inflammation and apoptosis through PI3K/AKT/mTOR signaling pathway.

Context: Ischemic stroke is the most common type of acute cerebrovascular disease. Carnosol is a polyphenol compound extracted from rosemary.Objective: This study aimed to explore the effects of carnosol on the oxygen-glucose deprivation (OGD) treated BV2 microglia cells.Materials and methods: MTT and EdU assays were used to detect the cell viability and proliferation. Flow cytometry was conducted to measure the apoptosis rates. Additionally, the protein expression was determined by western blot. The inflammatory factors and antioxidant indexes were detected by corresponding kits.Results and discussion: Carnosol promoted the proliferation and inhibited the apoptosis of the OGD treated BV2 cells. What's more, the protein expressions of PCNA and Bcl-2 were up-regulated, the Bax expression was down-regulated after carnosol treatment. In addition, carnosol decreased the levels of MDA, LPO, TNF-α, IL-1ß and IL-6, and increased the levels of GSH, SOD, IL-4 and IL-10 in the OGD treated BV2 cells. Furthermore, the PI3K/AKT/mTOR signaling pathway was activated after carnosol treatment and inhibition of the PI3K/AKT/mTOR signaling pathway reversed the carnosol effects.Conclusions: Carnosol promotes the proliferation, inhibits the apoptosis, relieves the oxidative damage and inflammation of OGD treated cells through regulating the PI3K/AKT/mTOR signaling pathway.

Comparison of the efficiency, safety, and survival outcomes in two stem cell mobilization regimens with cyclophosphamide plus G-CSF or G-CSF alone in multiple myeloma: a meta-analysis.

Autologous stem cell transplantation as a frontline treatment for patients with multiple myeloma (MM) requires an adequate peripheral blood stem cell (PBSC) collection before processing. Granulocyte-colony stimulating factor (G-CSF) with or without cyclophosphamide (CTX) is a common regimen for PBSC mobilization; their benefits and risks are controversial. To compare the efficiency, safety, and survival outcomes between the two regimens, we conducted a meta-analysis including 18 studies with 4 prospective and 14 retrospective studies; a total of 2770 patients with MM were analyzed. The CTX plus G-CSF regimen had higher yields of total CD34+ cells (SMD = 0.39, 95% CI (0.30, 0.49)), and higher mobilization rates of the target ⩾ 2 × 106/kg (OR = 3.34, 95% CI (1.82, 6.11)) and 4 × 106/kg (OR = 2.16, 95% CI (1.69, 2.76)) cells. A favorable event-free survival (EFS) (HR = 0.73, 95% CI (0.58, 0.93), p = 0.01) and better 3-year EFS rate (OR = 1.65, 95% CI (1.1, 2.47), p = 0.02) were also reached in the patients with CTX plus G-CSF mobilization, although the risks of admission (OR = 26.49, 95% CI (7.31, 95.97)) and fever (OR = 13.66, 95% CI (6.21, 30.03)) during mobilization were increased, the treatment-related mortality was consistent (p = 0.26). The CTX plus G-CSF regimen was superior to the G-CSF-alone regimen for PBSC mobilization in patients with MM.

Path Planning of Pattern Transfer Based on Dual-Operator and a Dual-Population Ant Colony Algorithm for Digital Mask Projection Lithography.

In the process of digital micromirror device (DMD) digital mask projection lithography, the lithography efficiency will be enhanced greatly by path planning of pattern transfer. This paper proposes a new dual operator and dual population ant colony (DODPACO) algorithm. Firstly, load operators and feedback operators are used to update the local and global pheromones in the white ant colony, and the feedback operator is used in the yellow ant colony. The concept of information entropy is used to regulate the number of yellow and white ant colonies adaptively. Secondly, take eight groups of large-scale data in TSPLIB as examples to compare with two classical ACO and six improved ACO algorithms; the results show that the DODPACO algorithm is superior in solving large-scale events in terms of solution quality and convergence speed. Thirdly, take PCB production as an example to verify the time saved after path planning; the DODPACO algorithm is used for path planning, which saves 34.3% of time compared with no path planning, and is about 1% shorter than the suboptimal algorithm. The DODPACO algorithm is applicable to the path planning of pattern transfer in DMD digital mask projection lithography and other digital mask lithography.

AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells.

Multiple myeloma (MM) is an incurable malignancy of plasma cells that is sensitive to T-5224, an AP-1 inhibitor. Previous study indicated that T-5224 inhibits proliferation and induces apoptosis in MM cells. However, the high mortality cannot be fully explained. To date, no studies have investigated ferroptosis induced by T-5224 in MM. Therefore, we further investigated the mechanism by which T-5224 kills MM cells. We observed that T-5224 exhibits antimyeloma properties both in vitro and in vivo. T-5224-induced MM cell death was reversed by the ferroptosis-specific inhibitor ferropstatin-1 (Fer-1). The protein levels of the key ferroptosis regulators GPX4 and SLC7A11 were decreased by T-5224 in MM cells. Furthermore, T-5224 reduced the phosphorylation of PI3K and AKT signaling pathway components, ultimately causing MM cell death. Using 740 Y-P, a PI3K activator, and Fer-1, a ferroptosis inhibitor, we discovered that T-5224 induces ferroptosis through the PI3K/AKT pathway. Bortezomib (BTZ), an FDA-approved drug for MM treatment, can be administered in combination with other agents. We evaluated the synergistic effect of BTZ combined with AP-1 inhibitors on MM in vivo. Our findings provide a better theoretical basis for the potential mechanism of T-5224 and a new perspective on MM treatment.

Multiple myeloma exosomal miRNAs suppress cGAS-STING antiviral immunity.

DNA virus infection is a significant cause of morbidity and mortality in patients with multiple myeloma (MM). Monocyte dysfunction in MM patients plays a central role in infectious complications, but the precise molecular mechanism underlying the reduced resistance of monocytes to viruses in MM patients remains to be elucidated. Here, we found that MM cells were able to transfer microRNAs (miRNAs) to host monocytes/macrophages via MM cell-derived exosomes, resulting in the inhibition of innate antiviral immune responses. The screening of miRNAs enriched in exosomes derived from the bone marrow (BM) of MM patients revealed five miRNAs that negatively regulate the cGAS-STING antiviral immune response. Notably, silencing these miRNAs with antagomiRs in MM-bearing C57BL/KaLwRijHsd mice markedly reduced viral replication. These findings identify a novel mechanism whereby MM cells possess the capacity to inhibit the innate immune response of the host, thereby rendering patients susceptible to viral infection. Consequently, targeting the aberrant expression patterns of characteristic miRNAs in MM patients is a promising avenue for therapeutic intervention. Considering the miRNA score and relevant clinical factors, we formulated a practical and efficient model for the optimal assessment of susceptibility to DNA viral infection in patients with MM.

Exploring the immunogenicity of Rv2201-519: A T-cell epitope-based antigen derived from Mycobacterium tuberculosis AsnB with implications for tuberculosis infection detection and vaccine development.

Research dedicated to diagnostic reagents and vaccine development for tuberculosis (TB) is challenging due to the paucity of immunodominant antigens that can predict disease risk and exhibit protective potential. Therefore, it is crucial to identify T-cell epitope-based Mycobacterium tuberculosis (MTB) antigens characterized by specific and prominent recognition by the immune system. In this study, we constructed a T-cell epitope-rich tripeptide-splicing fragment (nucleotide positions 131-194, 334-377, and 579-643) of Rv2201 (also known as the 72 kDa AsnB)from the MTB genome, ultimately yielding the recombinant protein Rv2201-519 in Escherichia coli BL21 (DE3). Subsequently, we gauged the recombinant protein's ability to detect tuberculosis infection through ELISpot and assessed its immunostimulatory effect on mouse models using flow cytometry and ELISA. Our results indicated that Rv2201-519 possessed promising sensitivity; however, the sensitivity was lower than that of a commercial diagnostic kit containing ESAT-6, CFP-10, and Rv3615c (80.56 % vs. 94.44 %). The Rv2201-519 group exhibited a propensity for a CD4+ Th1 cell immune response in inoculated BALB/c mice that manifested as higher levels of antigen-specific IgG production (IgG2a/IgG1 > 1). In comparison to Ag85B, Rv2201-519 induced a more robust Th1-type cellular immune response as evidenced by a notable rise in the ratio of IFN-γ/IL-4 and IL-12 cytokine production and increased CD4+ T cell activation with a higher percentage of CD4+IFN-γ+ T cells. Rv2201-519 also induced a higher level of IL-6 compared with Ag85B, a higher percentage of CD8+ T cells specific for Rv2201-519, and a lower percentage of CD8+IL-4+ T cells. Collectively, the current evidence suggests that Rv2201-519 could potentially serve as an immunodominant protein for tuberculosis infection screening, laying the groundwork for further evaluation in recombinant Bacillus Calmette-Guérin (BCG) and subunit vaccines against MTB challenges in future studies.

Enhanced risk of record-breaking regional temperatures during the 2023-24 El Niño.

In 2023, the development of El Niño is poised to drive a global upsurge in surface air temperatures (SAT), potentially resulting in unprecedented warming worldwide. Nevertheless, the regional patterns of SAT anomalies remain diverse, obscuring where historical warming records may be surpassed in the forthcoming year. Our study underscores the significant influence of El Niño and the persistence of climate signals on the inter-annual variability of regional SAT, both in amplitude and spatial distribution. The likelihood of global mean SAT exceeding historical records, calculated from July 2023 to June 2024, is estimated at 90%, contingent upon annual-mean sea surface temperature anomalies in the eastern equatorial Pacific exceeding 0.6 °C. Regions particularly susceptible to recording record-high SAT include coastal and adjacent areas in Asia such as the Bay of Bengal and the South China Sea, as well as Alaska, the Caribbean Sea, and the Amazon. This impending warmth heightens the risk of year-round marine heatwaves and escalates the threat of wildfires and other negative consequences in Alaska and the Amazon basin, necessitating strategic mitigation measures to minimize potential worst-case impacts.

Depressive symptoms, alone or together with physical comorbidity, are predictive of healthcare use and spending in older adults.

OBJECTIVE: Depressive symptoms and physical comorbidity are common health problems in older adults and are both posing increasingly considerable challenges to global healthcare systems. This study investigated the relationships of depressive symptoms, alone or together with physical comorbidity, with healthcare utilization and spending among older adults, as well as examined sex differences. METHODS: We used data of the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018 and enrolled 6519 participants. Depressive symptoms was operationalized following the Center for Epidemiological Studies Depression Scale and physical comorbidity was assessed according to the presence of 11 physical non-communicable diseases. The relationships of depressive symptoms and comorbidity with healthcare outcomes were examined using mixed-effects regression models. RESULTS: Compared with the neither depressive symptoms nor physical comorbidity category, older adults classified as depressive symptoms-only, physical comorbidity-only or both conditions were all associated with elevated risks for healthcare use and spending (all OR/IRR > 1; all p < 0.001). Depressive symptoms and physical comorbidity in combination consistently led to higher risks for studied endpoints than either condition alone (outpatient visit: OR = 3.50, outpatient visit number: IRR = 3.39, inpatient visit: OR = 3.35, hospitalization days: IRR = 2.82, catastrophic health expenditure: OR = 1.70; all p-trend < 0.001). Stratification analyses revealed similar relationships irrespective of sex. CONCLUSION: Depressive symptoms and physical comorbidity are separately and jointly associated with increased healthcare utilization and spending among Chinese older adults. These two conditions in combination lead to highest risks than either condition alone. Early screen for depressive symptoms, alone or together with physical comorbidity, may offer implications for appropriate policy interventions.

Health-related quality of life associated with sensory impairment in Chinese middle-aged and older adults: a cohort study.

BACKGROUND: The impact of sensory impairment (SI) on individual multidimensional health has not been adequately explored in developing countries. This study examined the association of hearing or/and visual impairment with health-related quality of life (HRQoL) in the Chinese middle-aged and older population, and further explored potential discrepancies in associations by gender and rural-urban residence. METHODS: This cohort study used four-wave data during 2011-2018 from the China Health and Retirement Longitudinal Study, and enrolled 13 342 community-dwelling adults aged 45 years or older. We employed linear mixed effects models to estimate the longitudinal associations between SI and HRQoL, and conducted interaction tests to assess gender or rural-urban differences in above associations. RESULTS: Hearing impairment (HI) and visual impairment (VI) were separately and jointly associated with deteriorated overall HRQoL and decreased physical/mental component of HRQoL (all ß<0, all p<0.05), and in particular, dual sensory impairment (DSI) exhibited greater impacts on HRQoL than either HI or VI alone. The impacts of SI on HRQoL were more evident among women or rural population than their counterparts (all p for interaction<0.05). CONCLUSION: This study observed decreased HRQoL in association with SI. The greater impact of DSI underlines the need for integrated care for comorbid sensory conditions. Our findings also indicate the necessity to reduce the burden of SI among more vulnerable populations such as females and rural adults.

Establishment of the multi-component bone-on-a-chip: to explore therapeutic potential of DNA aptamers on endothelial cells.

Background: Despite great efforts to develop microvascular bone chips in previous studies, current bone chips still lacked multi-component of human-derived cells close to human bone tissue. Bone microvascular endothelial cells (BMECs) were demonstrated to be closely related to the glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Tumor necrosis factor-alpha (TNF-α) aptamer has been proved to bind to its receptor and block cascade activities. Objective: There are two main objectives in this study: 1) to establish a multi-component bone-on-a-chip within the microfluidic system in vitro, 2) to explore the therapeutic potential of TNF-α aptamer on BMECs in the GC-induced ONFH model. Methods: Histological features of clinical samples were analyzed before BMECs isolation. The functional bone-on-a-chip consists of the vascular channel, stromal channel and structure channel. GC-induced ONFH model was established based on the multi-component of human-derived cells. Truncation and dimerization were performed on a previously reported DNA aptamer (VR11). BMECs apoptosis, cytoskeleton and angiogenesis status in the ONFH model were observed by the TUNEL staining and confocal microscope. Results: The multi-component of BMECs, human embryonic lung fibroblasts and hydroxyapatite were cultured within the microfluidic bone-on-a-chip. TNF-α was found up-regulated in the necrotic regions of femoral heads in clinical samples and similar results were re-confirmed in the ONFH model established in the microfluidic platform by detecting cell metabolites. Molecular docking simulations indicated that the truncated TNF-α aptamer could improve the aptamer-protein interactions. Further results from the TUNEL staining and confocal microscopy showed that the truncated aptamer could protect BMECs from apoptosis and alleviate GC-induced damages to cytoskeleton and vascularization. Conclusion: In summary, a microfluidic multi-component bone-on-a-chip was established with 'off-chip' analysis of cell metabolism. GC-induced ONFH model was achieved based on the platform. Our findings provided initial evidence on the possible potentials of TNF-α aptamer as a new type of TNF-α inhibitor for patients with ONFH.

GmABCG5, an ATP-binding cassette G transporter gene, is involved in the iron deficiency response in soybean.

Iron deficiency is a major nutritional problem causing iron deficiency chlorosis (IDC) and yield reduction in soybean, one of the most important crops. The ATP-binding cassette G subfamily plays a crucial role in substance transportation in plants. In this study, we cloned the GmABCG5 gene from soybean and verified its role in Fe homeostasis. Analysis showed that GmABCG5 belongs to the ABCG subfamily and is subcellularly localized at the cell membrane. From high to low, GmABCG5 expression was found in the stem, root, and leaf of young soybean seedlings, and the order of expression was flower, pod, seed stem, root, and leaf in mature soybean plants. The GUS assay and qRT-PCR results showed that the GmABCG5 expression was significantly induced by iron deficiency in the leaf. We obtained the GmABCG5 overexpressed and inhibitory expressed soybean hairy root complexes. Overexpression of GmABCG5 promoted, and inhibition of GmABCG5 retarded the growth of soybean hairy roots, independent of nutrient iron conditions, confirming the growth-promotion function of GmABCG5. Iron deficiency has a negative effect on the growth of soybean complexes, which was more obvious in the GmABCG5 inhibition complexes. The chlorophyll content was increased in the GmABCG5 overexpression complexes and decreased in the GmABCG5 inhibition complexes. Iron deficiency treatment widened the gap in the chlorophyll contents. FCR activity was induced by iron deficiency and showed an extraordinary increase in the GmABCG5 overexpression complexes, accompanied by the greatest Fe accumulation. Antioxidant capacity was enhanced when GmABCG5 was overexpressed and reduced when GmABCG5 was inhibited under iron deficiency. These results showed that the response mechanism to iron deficiency is more actively mobilized in GmABCG5 overexpression seedlings. Our results indicated that GmABCG5 could improve the plant's tolerance to iron deficiency, suggesting that GmABCG5 might have the function of Fe mobilization, redistribution, and/or secretion of Fe substances in plants. The findings provide new insights into the ABCG subfamily genes in the regulation of iron homeostasis in plants.

Generating Neural Retina from Human Pluripotent Stem Cells.

Retinopathy is one of the main causes of blindness worldwide. Investigating its pathogenesis is essential for the early diagnosis and timely treatment of retinopathy. Unfortunately, ethical barriers hinder the collection of evidence from humans. Recently, numerous studies have shown that human pluripotent stem cells (PSCs) can be differentiated into retinal organoids (ROs) using different induction protocols, which have enormous potential in retinopathy for disease modeling, drug screening, and stem cell-based therapies. This study describes an optimized induction protocol to generate neural retina (NR) that significantly reduces the probability of vesiculation and fusion, increasing the success rate of production until day 60. Based on the ability of PSCs to self-reorganize after dissociation, combined with certain complementary factors, this new method can specifically drive NR differentiation. Furthermore, the approach is uncomplicated, cost-effective, exhibits notable repeatability and efficiency, presents encouraging prospects for personalized models of retinal diseases, and supplies a plentiful cell reservoir for applications such as cell therapy, drug screening, and gene therapy testing.

Unravelling chilling-stress resistance mechanisms in endangered Mangrove plant Lumnitzera littorea (Jack) Voigt.

Lumnitzera littorea (Jack) Voigt is one of the most endangered mangrove species in China. Previous studies have showed the impact of chilling stress on L. littorea and the repsonses at physiological and biochemical levels, but few attentions have been paid at molecular level. In this study, we conducted genome-wide investigation of transcriptional and post-transcriptional dynamics in L. littorea in response to chilling stress (8 °C day/5 °C night). In the seedlings of L. littorea, chilling sensing and signal transducing, photosystem II regeneration and peroxidase-mediated reactive oxygen species (ROS) scavenging were substantially enhanced to combat the adverse impact induced by chilling exposure. We further revealed that alternative polyadenylation (APA) events participated in chilling stress-responsive processes, including energy metabolism and steroid biosynthesis. Furthermore, APA-mediated miRNA regulations downregulated the expression of the genes involved in fatty acid biosynthesis and elongation, and protein phosphorylation, reflecting the important role of post-transcriptional regulation in modulating chilling tolerance in L. littorea. Our findings present a molecular view to the adaptive characteristics of L. littorea and shed light on the conservation genomic approaches of endangered mangrove species.

Development and Validation of a Nomogram for Predicting Risk of Emergency Department Revisits in Chinese Older Patients.

Objective: The identification of older patients at risk of repeated emergency department (ED) visits is crucial for managing preventable adverse outcomes. This study aims to identify risk factors associated with ED revisits and to develop and validate a nomogram for predicting risk of geriatric ED revisits. Methods: This was a cohort study comprising 553 older patients, who attended the two tertiary hospitals EDs in China from August 2018 to February 2019 and were prospectively followed for any unplanned revisit within 1 year after discharge. Patients were randomly assigned to a training or validation set at a ratio of 2:1. Stepwise selection procedure was applied to select factors associated with ED revisits for inclusion in a multivariable logistic model from which a nomogram was elaborated. Discrimination, calibration and clinical utility of the nomogram were assessed using C-statistic, calibration plot, Hosmer-Lemeshow test, and decision curve analysis (DCA). Results: The final nomogram included four predictors for ED revisits: age, BMI, frailty and polypharmacy. Older patients having revisits were more likely to be frail (OR = 1.17, p = 0.031), have polypharmacy (OR = 1.69, p = 0.049) or BMI <18.5 kg/m2 (OR = 2.45, p = 0.025), and were less likely to be older than 90 years (OR = 0.21, p = 0.002). The nomogram demonstrated acceptable discrimination ability in the training (C-index = 0.661) and validation sets (C-index = 0.651), satisfactory calibration (p > 0.05), and good clinical applicability. Conclusion: A nomogram incorporating four obtainable variables was constructed to individualize ED readmission risk in older patients. These patients may benefit from early triage and better-targeted care if considering the nomogram as a clinical decision aid.

Extracellular arginine is required but the arginine transporter CAT3 (Slc7a3) is dispensable for mouse normal and malignant hematopoiesis.

Amino acid-mediated metabolism is one of the key catabolic and anabolic processes involved in diverse cellular functions. However, the role of the semi-essential amino acid arginine in normal and malignant hematopoietic cell development is poorly understood. Here we report that a continuous supply of exogenous arginine is required for the maintenance/function of normal hematopoietic stem cells (HSCs). Surprisingly, knockout of Slc7a3 (CAT3), a major L-arginine transporter, does not affect HSCs in steady-state or under stress. Although Slc7a3 is highly expressed in naïve and activated CD8 T cells, neither T cell development nor activation/proliferation is impacted by Slc7a3 depletion. Furthermore, the Slc7a3 deletion does not attenuate leukemia development driven by Pten loss or the oncogenic Ptpn11E76K mutation. Arginine uptake assays reveal that L-arginine uptake is not disrupted in Slc7a3 knockout cells. These data suggest that extracellular arginine is critically important for HSCs, but CAT3 is dispensable for normal hematopoiesis and leukemogenesis.

JMML tumor cells disrupt normal hematopoietic stem cells by imposing inflammatory stress through overproduction of IL-1ß.

Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11E76K) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11E76K/+ BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11E76K/+ MPN cells produced excessive IL-1ß, but not IL-6, T NF-α, IFN-γ, IL-1α, or other inflammatory cytokines. Depletion of the IL-1ß receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/+/IL-1R-/- double mutant mice. These findings suggest IL-1ß signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.