Robust, fast and accurate mapping of diffusional mean kurtosis.

Diffusional kurtosis imaging (DKI) is a methodology for measuring the extent of non-Gaussian diffusion in biological tissue, which has shown great promise in clinical diagnosis, treatment planning, and monitoring of many neurological diseases and disorders. However, robust, fast, and accurate estimation of kurtosis from clinically feasible data acquisitions remains a challenge. In this study, we first outline a new accurate approach of estimating mean kurtosis via the sub-diffusion mathematical framework. Crucially, this extension of the conventional DKI overcomes the limitation on the maximum b-value of the latter. Kurtosis and diffusivity can now be simply computed as functions of the sub-diffusion model parameters. Second, we propose a new fast and robust fitting procedure to estimate the sub-diffusion model parameters using two diffusion times without increasing acquisition time as for the conventional DKI. Third, our sub-diffusion-based kurtosis mapping method is evaluated using both simulations and the Connectome 1.0 human brain data. Exquisite tissue contrast is achieved even when the diffusion encoded data is collected in only minutes. In summary, our findings suggest robust, fast, and accurate estimation of mean kurtosis can be realised within a clinically feasible diffusion-weighted magnetic resonance imaging data acquisition time.

Outcomes of COVID-19 in patients with obinutuzumab compared with patients with rituximab: a retrospective cohort study.

BACKGROUND: Patients treated with anti-CD20 monoclonal antibodies could have a higher risk of adverse outcomes of coronavirus disease 2019 (COVID-19). The novel anti-CD20 monoclonal antibody obinutuzumab has shown greater B-cell depletion and superior in vitro efficacy than rituximab. We aimed to assess whether obinutuzumab would result in worse COVID-19 outcomes than rituximab. METHODS: We retrospectively reviewed 124 patients with B-cell lymphoma, 106 of whom received rituximab treatment and 18 of whom received obinutuzumab treatment. The adverse outcomes of COVID-19 were compared between patients in the two cohorts. RESULTS: The proportions of patients who were hospitalized (55.6% vs. 20.8%, p = 0.005), experienced prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (38.9% vs. 2.9%, p < 0.001), and developed severe COVID-19 (33.3% vs. 4.7%, p < 0.001) were higher in patients with obinutuzumab than in those with rituximab. Multivariate analyses showed that obinuzumab treatment was associated with higher incidences of prolonged SARS-CoV-2 infection (OR 27.05, 95% CI 3.75-195.22, p = 0.001) and severe COVID-19(OR 15.07, 95% CI 2.58-91.72, p = 0.003). CONCLUSIONS: Our study suggested that patients treated with obinutuzumab had a higher risk of prolonged SARS-CoV-2 infection and severe COVID-19 than those treated with rituximab.

Kaempferol attenuates cyclosporine-induced renal tubular injury via inhibiting the ROS-ASK1-MAPK pathway.

Cyclosporine (CSA) is a widely used immunosuppressive medication. CSA nephrotoxicity severely limits its application. Kaempferol (KPF), a naturally occurring phenolic compound, has a promising protective effect in reducing CSA-induced renal tubular injury, but the mechanism remains unknown. Our study aimed to determine the protective role of KPF against CSA-induced renal tubular injury. C57/B6 mice and the NRK-52E cell line were employed. CSA worsened renal function in mice, causing detachment and necrosis of tubular cells, leading to tubular vacuolation and renal interstitial fibrosis. CSA caused the detachment, rupture, and death of tubular cells in vitro, resulting in cell viability loss. KPF mitigated all these injurious alterations. KPF hindered CSA-induced ROS generation and protected renal tubular epithelial cells, similar to the antioxidant NAC. CSA lowered SOD activity and GSH levels while increasing MDA levels, and KPF ameliorated these changes. CSA caused phosphorylation of ASK1, JNK, and p38, similar to H2O2, whereas KPF significantly inhibited these changes. In conclusion, KPF reduces CSA-induced tubular epithelial cell injury via its antioxidant properties, inhibits the phosphorylation of ASK1, and inhibits the phosphorylation of p38 and JNK, implying that the synergistic use of KPF in CSA immunotherapy may be a promising option to reduce CSA-evoked renal injury.

Association of electronic screen exposure with depression among women in early pregnancy: a cross-sectional study.

BACKGROUND: Previous studies indicated that excessive engagement in digital devices could lead to negative psychological impacts in general population. We aimed to determine the association of electronic screen exposure with depression among women in early pregnancy. METHODS: A cross-sectional study was conducted from June 2021 to June 2022. A total of 665 women in early pregnancy were recruited and the information included socio-demographic characteristics, screen exposure and Patient Health Questionnaire - 9 depression scale. RESULTS: Among the women in early pregnancy, the total daily smartphone viewing time was the longest (median [P25-P75], 5 [3-6] hours/day) in the three types of electronic screen exposure. The total daily smartphone viewing time (P = 0.015, OR[95%CI] = 1.09[1.11-1.18]), smartphone (P = 0.016, OR[95%CI] = 1.24[1.04-1.47]) and television viewing time (P = 0.006, OR[95%CI] = 1.35[1.09-1.67]) before nocturnal sleep were significantly associated with depression among women in early pregnancy. The thresholds calculated by receiver operator characteristic curves were 7.5 h/day, 1.5 h/day and 1.5 h/day, respectively. In addition, women with higher scores of smartphone addiction were more susceptible to depression (P<0.001, OR[95%CI] = 1.11[1.07-1.16]). The top three smartphone usages in women with depression were watching videos (22.0%), listening to music (20.9%) and playing games (16.7%). CONCLUSIONS: In conclusion, electronic screen exposure, including screen viewing time, smartphone addiction and problematic smartphone use was associated with depression among women in early pregnancy. Further studies are warranted to verify the conclusions.

Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies.

Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.

Producing Freestanding Single-Crystal BaTiO3 Films through Full-Solution Deposition.

Strontium aluminate, with suitable lattice parameters and environmentally friendly water solubility, has been strongly sought for use as a sacrificial layer in the preparation of freestanding perovskite oxide thin films in recent years. However, due to this material's inherent water solubility, the methods used for the preparation of epitaxial films have mainly been limited to high-vacuum techniques, which greatly limits these films' development. In this study, we prepared freestanding single-crystal perovskite oxide thin films on strontium aluminate using a simple, easy-to-develop, and low-cost chemical full-solution deposition technique. We demonstrate that a reasonable choice of solvent molecules can effectively reduce the damage to the strontium aluminate layer, allowing successful epitaxy of perovskite oxide thin films, such as 2-methoxyethanol and acetic acid. Molecular dynamics simulations further demonstrated that this is because of their stronger adsorption capacity on the strontium aluminate surface, which enables them to form an effective protective layer to inhibit the hydration reaction of strontium aluminate. Moreover, the freestanding film can still maintain stable ferroelectricity after release from the substrate, which provides an idea for the development of single-crystal perovskite oxide films and creates an opportunity for their development in the field of flexible electronic devices.

Sex difference and socioeconomic inequity in hypertension: a national survey study of 98,658 adults from 162 study sites.

BACKGROUND: Sex differences in blood pressure (BP) levels and hypertension are important and the role of socioeconomic status (SES) in sex differences of hypertension remains unclear. OBJECTIVE: We aimed to evaluate the impact of SES on sex differences of hypertension in a nationally representative survey study. METHODS: A total of 98,658 participants aged ≥18 years who have lived in their current residence for ≥6 months were recruited from 162 study sites across mainland China. Sex was self-reported. Individual-level SES included the highest level of education and annual household income. Area-level SES included economic development status, urban/rural residency, and north/south location. Outcomes included levels of systolic and diastolic BP, and hypertension. Linear and Cox regression models were used to examine the associations between sex (women vs. men) and BP characteristics stratified by individual or combined SES indicators. RESULTS: Systolic and diastolic BP levels and prevalence of hypertension were higher in men than women. This sex difference was found across categories of SES with widened sex disparities in participants having more favorable SES. Significant multiplicative interaction effects of SES on the association of sex with BP characteristics were found. Women with improving SES were associated with lower BP and hypertension prevalence compared with men. For combined SES, a 9% (prevalence ratio (PR)=0.91, 95% confidence interval (CI)=0.83, 0.98) and a 30% lower probability (PR=0.70, 95% CI=0.63, 0.78) of having hypertension were found in women with an overall intermediate SES and high SES, respectively compare with low SES while no significant reduction was found in men. CONCLUSIONS: There are significant sex differences in BP characteristics and SES has a potent impact on the disparities. Sex-specific public health policies to alleviate socioeconomic inequalities, especially in women are important for the prevention of hypertension.

Cross-species single-cell spatial transcriptomic atlases of the cerebellar cortex.

The molecular and cellular organization of the primate cerebellum remains poorly characterized. We obtained single-cell spatial transcriptomic atlases of macaque, marmoset, and mouse cerebella and identified primate-specific cell subtypes, including Purkinje cells and molecular-layer interneurons, that show different expression of the glutamate ionotropic receptor Delta type subunit 2 (GRID2) gene. Distinct gene expression profiles were found in anterior, posterior, and vestibular regions in all species, whereas region-selective gene expression was predominantly observed in the granular layer of primates and in the Purkinje layer of mice. Gene expression gradients in the cerebellar cortex matched well with functional connectivity gradients revealed with awake functional magnetic resonance imaging, with more lobule-specific differences between primates and mice than between two primate species. These comprehensive atlases and comparative analyses provide the basis for understanding cerebellar evolution and function.

Target-Navigated CBT-Cys "Stapling" Coupled with CRISPR/Cas12a Amplification for the Photoelectrochemical Nucleic Acid Assay.

Generally, rolling circle amplification (RCA) is based on an enzyme-linked padlock extension reaction. Herein, rapid linking that utilizes click chemistry for joining sticky ends of DNA molecules was developed. The ends of nucleic acid were modified with 2-cyano-6-aminobenzothiazole (CBT) and cystine (Cys-Cys), while glutathione was introduced to break the disulfide bond under target navigation and promote the linkage between CBT and Cys at the terminus of the nucleic acid at pH 7.4. Subsequently, RCA was performed using phi29 polymerase. CRISPR/Cas12a cleavage was triggered by the product of RCA amplification. Assisted by alkaline phosphatase, the electron exchange process between the photoelectroactive Sb@Co(OH)F nanorod and p-aminophenol (p-AP) was collected in the form of photoelectrochemical (PEC) signals. Mass spectrometry, gel electrophoresis, and PEC signals were employed to verify the linking process and the RCA coupled with CRISPR/Cas12a cleavage amplification. CBT-Cys connection exhibited a high reaction rate (23.79 M-1·s-1). This enzyme-free linking process was superior to traditional enzyme catalysis in terms of the reaction environment and linking rate. This efficient nonenzymatic joining system holds great potential for constructing nonhomologous end joining, modifying DNA with molecules, and facilitating nucleic acid-protein modification processes.

Free-Standing Poly(vinyl benzoquinone)/Reduced Graphene Oxide Composite Films as a Cathode for Lithium-Ion Batteries.

Quinones with a rapid reduction-oxidation rate are promising high-capacity cathodes for lithium-ion batteries. However, the high solubility of quinone molecules in polar organic electrolytes results in low cycle stability, while their low electric conductivity causes low utilization of electrode materials. In this article, a new p-benzoquinone derivative, poly(vinyl benzoquinone) (PVBQ), is designed and synthesized, and a solution-based method of preparing free-standing PVBQ/reduced graphene oxide (RGO) composite films is developed. PVBQ has a high theoretical specific capacity (400 mA h g-1) because of its low dead moiety mass. In the produced composite films, PVBQ nanoparticles are uniformly dispersed on RGO sheets, which endows the composite films with high electric conductivity and inhibits the dissolution of PVBQ through strong adsorption. As a result, the composite films show a high active material utilization, high practical specific capacity, and excellent cycling stability. PVBQ in the composite membrane containing 60.2 wt % RGO deliver 244 mA h g-1 capacity after 200 charge-discharge cycles at a current density of 300 mA g-1. At a current density of 1500 mA g-1, the reversible specific capacity is still 170 mA h g-1. This work provides a high-performance cathode material for lithium-ion batteries, and the molecular structure and electrode structure design ideas are also instructive for developing other organic electrode materials.

The effect of SGLT2 inhibition on brain-related phenotypes and aging: a drug target Mendelian randomization study.

INTRODUCTION: Observational study suggested SGLT2 inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological, biological age and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs). METHODS: We selected genetic variants associated with both expression levels of SLC5A2 (GTEx and eQTLGen data; N=129 to 31,684) and HbA1c levels (UK Biobank; N=344,182) and used them to proxy the effect of SGLT2 inhibition. Aging related outcomes, including parental longevity (N=389,166) and epigenetic clocks (N=34,710), and cognitive phenotypes, including cognitive function (N=300,486) and intelligence (N= 269,867) were derived from genome-wide association studies. Two-step MR were conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes, cognition. RESULTS: SGLT2 inhibition was associated with longer father's attained age (years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95%CI 1.95 to 11.15), better cognitive function (beta = 0.17, 95%CI 0.03 to 0.31) and higher intelligence (beta = 0.47, 95%CI 0.19 to 0.75). Two-step MR identified two IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where four and five IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence respectively (total proportion of mediation = 61.6% and 68.6% respectively). CONCLUSIONS: Our study supported that SGLT2 inhibition increases father's attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether similar effect could be observed for users of SGLT2 inhibitors.

FolIws1-driven nuclear translocation of deacetylated FolTFIIS ensures conidiation of Fusarium oxysporum.

Plant diseases caused by fungal pathogens pose a great threat to crop production. Conidiation of fungi is critical for disease epidemics and serves as a promising drug target. Here, we show that deacetylation of the FolTFIIS transcription elongation factor is indispensable for Fusarium oxysporum f. sp. lycopersici (Fol) conidiation. Upon microconidiation, Fol decreases K76 acetylation of FolTFIIS by altering the level of controlling enzymes, allowing for its nuclear translocation by FolIws1. Increased nuclear FolTFIIS enhances the transcription of sporulation-related genes and, consequently, enables microconidia production. Deacetylation of FolTFIIS is also critical for the production of macroconidia and chlamydospores, and its homolog has similar functions in Botrytis cinerea. We identify two FolIws1-targeting chemicals that block the conidiation of Fol and have effective activity against a wide range of pathogenic fungi without harm to the hosts. These findings reveal a conserved mechanism of conidiation regulation and provide candidate agrochemicals for disease management.

Majorbio Cloud 2024: Update single-cell and multiomics workflows.

Majorbio Cloud (https://cloud.majorbio.com/) is a one-stop online analytic platform aiming at promoting the development of bioinformatics services, narrowing the gap between wet and dry experiments, and accelerating the discoveries for the life sciences community. In 2024, three single-omics workflows, two multiomics workflows, and extensions were newly released to facilitate omics data mining and interpretation.

Exploring Protein Bioconjugation: A Redox-Based Strategy for Tryptophan Targeting.

Amino acid bioconjugation technology has emerged as a pivotal tool for linking small-molecule fragments with proteins, antibodies, and even cells. The study in Nature by Chang and Toste introduces a redox-based strategy for tryptophan bioconjugation, employing N-sulfonyloxaziridines as oxidative cyclization reagents, demonstrating high efficiency comparable to traditional click reactions. Meanwhile, this tool provides feasible methods for investigating the mechanisms underlying functional tryptophan-related biochemical processes, paving the way for protein function exploration, activity-based proteomics for functional amino acid identification and characterization, and even the design of covalent inhibitors.

Efficient Expression and Application of a Modified Rhizomucor miehei Lipase for Simultaneous Production of Biodiesel and Eicosapentaenoic Acid Ethyl Ester from Nannochloropsis Oil.

Few reports exist on one-step enzymatic methods for the simultaneous production of biodiesel and eicosapentaenoic acid ethyl ester (EPA-EE), a high-value pharmaceutical compound. This study aimed to efficiently express Rhizomucor miehei lipase (pRML) in Pichia pastoris X-33 via propeptide mutation and high-copy strain screening. The mutated enzyme was then used to simultaneously catalyze the production of both biodiesel and EPA-EE. The P46N mutation in the propeptide (P46N-pRML) significantly boosted its production, with the four-copy strain increasing enzyme yield by 3.7-fold, reaching 3425 U/mL. Meanwhile, its optimal temperature increased to 45-50 °C, pH expanded to 7.0-8.0, specific activity doubled, Km reduced to one-third, and kcat/Km increased 7-fold. Notably, P46N-pRML efficiently converts Nannochloropsis gaditana oil's eicosapentaenoic acid (EPA). Under optimal conditions, it achieves up to 93% biodiesel and 92% EPA-EE yields in 9 h. Our study introduces a novel, efficient one-step green method to produce both biodiesel and EPA-EE using this advanced enzyme.

Impact of monocytic differentiation on acute myeloid leukemia patients treated with venetoclax and hypomethylating agents.

INTRODUCTION: Although the combination of venetoclax (VEN) and hypomethylating agents (HMAs) results in impressive efficacy in acute myeloid leukemia (AML), there is still a subset of patients who are refractory. We investigated the outcomes of AML patients with monocytic differentiation who were treated with frontline VEN/HMA. METHODS: A total of 155 patients with newly diagnosed AML treated with frontline VEN/HMA were enrolled in the study. Monocyte-like AML was identified by flow cytometry with typical expression of monocytic markers, and M5 was identified according to French, American, and British category. We compared the outcomes of patients with different characteristics. RESULTS: The rate of complete remission (CR) and CR with incomplete recovery of blood counts (CRi), progression-free survival (PFS), and overall survival (OS) in monocyte-like AML were inferior to those in nonmonocyte-like AML (CR/CRi rates, 26.7% vs. 80.0%, p < 0.001; median PFS, 2.1 vs. 8.8 months, p < 0.001; median OS, 9.2 vs. 19 months, p = 0.013). CR/CRi rate in M5 was lower than that in non-M5 (60.7% vs. 75.5%, p = 0.049). Multivariate analyses showed that monocyte-like AML was associated with lower odds of CR/CRi and higher risk of progression. CONCLUSION: Our study suggested that newly diagnosed AML with a monocytic immunophenotype had a poor prognosis with VEN/HMA treatment.

Case report: Successful combination therapy with isavuconazole and amphotericin B in treatment of disseminated Candida tropicalis infection.

Disseminated candidiasis is a severe complication in patients with hematological malignancies who have undergone chemotherapy or hematopoietic stem cell transplantation. It has a high mortality rate. When disseminated candidiasis caused by Candida tropicalis involves either the brain or heart, the prognosis is extremely poor. Traditional methods such as cultures are limited in diagnosing disseminated candidiasis. We describe a case report of a 55-year-old man with acute myeloid leukemia who developed candidemia caused by Candida tropicalis after chemotherapy, which disseminated extensively to the heart, brain, skin, liver, spleen and kidneys. In this instance, the patient was rapidly diagnosed with candida infection by metagenomic next generation sequencing, and successfully treated with combination therapy of isavuconazole and amphotericin B. The patient continued with treatment of leukemia while simultaneously receiving antifungal therapy, and both leukemia and disseminated candidiasis were effectively controlled. This case report provides real-world experience for treatment of patients with leukemia complicated by disseminated candidiasis.

Clinicopathological significance of cancer stem cell marker CD44/SOX2 in esophageal squamous cell carcinoma (ESCC) patients and construction of a nomogram to predict overall survival.

Background: Esophageal squamous cell carcinoma (ESCC), a prevalent malignancy within the upper gastrointestinal system, is characterized by its unfavorable prognosis and the absence of specific indicators for outcome prediction and high-risk case identification. In our research, we examined the expression levels of cancer stem cells (CSCs), markers CD44/SOX2 in ESCC, scrutinized their association with clinicopathological parameters, and developed a predictive nomogram model. This model, which incorporates CD44/SOX2, aims to forecast the overall survival (OS) of patients afflicted with ESCC. Methods: Immunohistochemistry was utilized to detect the expression levels of CD44 and SOX2 in both cancerous and paracancerous tissues of 68 patients with ESCC. The correlation between CD44/SOX2 expression and clinicopathological parameters was subsequently analyzed. Factors impacting the prognosis of ESCC patients were assessed through univariate and multivariate Cox regression analyses. Leveraging the results of these multivariate regression analyses, a nomogram prognostic model was established to provide individualized predictions of ESCC patient survival outcomes. The predictive accuracy of the nomogram prognostic model was evaluated using the consistency index (C-index) and calibration curves. Results: The expression levels of CD44 were markedly elevated in the tumor tissues of ESCC patients. Similarly, SOX2 was significantly overexpressed in the tumor tissues of ESCC patients. The positive expression of SOX2 in ESCC demonstrated a strong correlation with both the pathological T-stage and the presence of carcinoembryonic antigen. CD44 and SOX2 co-positive expression was significantly associated with the pathological T-stage and tumor node metastasis (TNM) stage. Furthermore, ESCC patients exhibiting CD44-positive expression in their tumor tissue generally had a more adverse prognosis. The co-expression of CD44 and SOX2 resulted in a grimmer prognosis compared to patients with other combinations. Multivariate Cox regression analysis identified the co-expression of CD44 and SOX2, the pathological T-stage, and lymph node metastasis as independent prognostic indicators for ESCC patients. The three identified variables were subsequently incorporated into a nomogram for predicting OS. The C-index of the measurement model and the area under the curve of the subjects' work characteristics showed good individual prediction. This prognostic model stratified patients into low- and high-risk categories. Analysis revealed that the 5-year OS rate was significantly higher in the low-risk group compared to the high-risk group. Conclusions: Elevated CD44 levels, indicative of CSC presence, are intimately linked with the oncogenesis of ESCC and are strongly predictive of unfavorable patient outcomes. Concurrently, the SOX2 gene exhibits a heightened expression in ESCC, markedly accelerating tumor progression and fostering more extensive disease infiltration. The co-expression of CD44 and SOX2 correlates significantly with ESCC patient prognosis, serving as a reliable, independent prognostic marker. Our constructed nomogram, incorporating CD44/SOX2 expression, enhances the prediction of OS and facilitates risk stratification in ESCC patients.

DNMT1 regulates human erythropoiesis by modulating cell cycle and endoplasmic reticulum stress in a stage-specific manner.

The dynamic balance of DNA methylation and demethylation is required for erythropoiesis. Our previous transcriptomic analyses revealed that DNA methyltransferase 1 (DNMT1) is abundantly expressed in erythroid cells at all developmental stages. However, the role and molecular mechanisms of DNMT1 in human erythropoiesis remain unknown. Here we found that DNMT1 deficiency led to cell cycle arrest of erythroid progenitors which was partially rescued by treatment with a p21 inhibitor UC2288. Mechanically, this is due to decreased DNA methylation of p21 promoter, leading to upregulation of p21 expression. In contrast, DNMT1 deficiency led to increased apoptosis during terminal stage by inducing endoplasmic reticulum (ER) stress in a p21 independent manner. ER stress was attributed to the upregulation of RPL15 expression due to the decreased DNA methylation at RPL15 promoter. The upregulated RPL15 expression subsequently caused a significant upregulation of core ribosomal proteins (RPs) and thus ultimately activated all branches of unfolded protein response (UPR) leading to the excessive ER stress, suggesting a role of DNMT1 in maintaining protein homeostasis during terminal erythroid differentiation. Furthermore, the increased apoptosis was significantly rescued by the treatment of ER stress inhibitor TUDCA. Our findings demonstrate the stage-specific role of DNMT1 in regulating human erythropoiesis and provide new insights into regulation of human erythropoiesis.