Low-field-driven large strain in lead zirconate titanium-based piezoceramics incorporating relaxor lead magnesium niobate for actuation.

Studies on the piezoelectric materials capable of efficiently outputting high electrostrains at low electric fields are driven by the demand for precise actuation in a wide range of applications. Large electrostrains of piezoceramics in operation require high driving fields, which limits their practical application due to undesirable nonlinearities and high energy consumption. Herein, a strategy is developed to enhance the electrostrains of piezoceramics while maintaining low hysteresis by incorporating lead magnesium niobate relaxors into lead zirconate titanium at the morphotropic phase boundary. An ultrahigh inverse piezoelectric coefficient d 33 * of 1380 pm/V with a reduced hysteresis of 11.5% is achieved under a low electric field of 1 kV/mm, outperforming the major lead-based piezoelectric materials. In situ synchrotron X-ray diffraction and domain wall dynamics characterization with sub-microsecond temporal resolution reveal that the outstanding performances originate from facilitated domain wall movement, which in turn is due to reduced lattice distortion and miniaturized domain structures. These findings not only address the pending challenges of effective actuation under reduced driving conditions but also lay the foundation for a more systematic approach to exploring the origin of large electrostrains.

Sliding Mode Fault-Tolerant Control for Nonlinear High-Order Fully Actuated Systems.

The high-order fully actuated systems (HOFASs) approach can only completely eliminate known nonlinearities. However, the practical systems often encounter unknown nonlinearities, including disturbances and faults. Therefore, this article studies a class of nonlinear HOFAS with component faults and disturbances. By applying the HOFAS theory, a novel integrated sliding mode fault-tolerant control strategy is proposed to ensure the stability of the closed-loop system. The state feedback and output feedback controllers are designed, respectively. For output feedback control, an extended state observer is designed to estimate system states. Once the HOFAS model is established, the designed controller and extended state observer can be directly implemented, facilitating the analysis and design of the control system. And the stability analysis does not depend on the complexity of the nonlinear functions. Finally, a numerical simulation example shows the effectiveness of the proposed method.

Design, synthesis and biological evaluation of novel diphenylamine analogues as NLRP3 inflammasome inhibitors.

The aberrant activation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous inflammation-related diseases. Development of NLRP3 inflammasome inhibitors is expected to provide a new strategy for the treatment of these diseases. Herein, a novel series of diphenylamine derivatives were designed based on the lead compounds H20 and H28, and the preliminary structure-activity relationship was studied. The representative compound 19 displayed significantly higher inhibitory activity against NLRP3 inflammasome compared to lead compounds H20 and H28, with an IC50 of 0.34 µM. Mechanistic studies indicated that compound 19 directly targets the NLRP3 protein (KD: 0.45 µM), blocking the assembly and activation of the NLRP3 inflammasome, leading to anti-inflammatory effects and inhibition of cellular pyroptosis. Our findings indicated that compound 19 is a promising NLRP3 inhibitor and could potentially serve as a lead compound for further optimization.

Effects of Social Support Provided by Disabled Older Adults to Others on Their Own Depressive Symptoms: A Moderated Mediation Model.

Purpose: While previous studies have extensively examined the impact of receiving positive social support during social support interactions on depressive symptoms among older adults, adverse effects experienced, such as being rejected or ignored, are often overlooked. Moreover, there has been limited discussion on the effects of giving social support to others. Thus, this study investigates the impacts of social support given by disabled older adults to others on their own depressive symptoms, as well as the mediating role of receiving social support (both positive and negative aspects) and the moderating effect of the activity of daily living (ADL). Patients and Methods: This cross-sectional, community-based study was conducted in Wenzhou and Jiaxing City, China, from September 2021 to September 2022, with a total of 255 disabled older adults meeting the inclusion and exclusion criteria. The data were collected face-to-face using a structured questionnaire. The participants were asked to complete the Barthel Index Scale, the Chinese version of the Positive and Negative Social Exchange Scale, the Giving Social Support questionnaire, and the Short Form Chinese Geriatric Depression Scale to measure disability, receiving positive and negative social support, giving social support, and depressive symptoms, respectively. Descriptive statistical analysis, correlation analysis, mediation effect tests, and moderation effect tests were used to analyse the questionnaire data. Results: The social support provided by disabled older adults to others primarily involved companionship and care. The positive aspect of social support received was largely emotional support, while the negative aspect was mainly characterised by failure to obtain help and unsympathetic behaviour. Providing social support was found to be associated with a potential beneficial effect on depressive symptoms, linked to lower severity, with this effect fully mediated by receiving social support. Specifically, receiving emotional support accounted for 56.63% of the effect size, while failure to obtain help and unsympathetic behaviour contributed 21.55%, and rejection and neglect collectively accounted for 21.83%. Additionally, the effect was partially moderated by ADL, with older adults exhibiting lower ADL scores showing a greater benefit from both giving and receiving social support compared to those with higher ADL scores. Conclusion: It is imperative to recognise and encourage disabled older adults to provide social support to others, especially emotional support, while reducing negative feedback, such as neglect and unnecessary blame. This could alleviate their depressive symptoms and promote psycho-social well-being.

Design, synthesis, and biological activity evaluation of novel HDAC3 selective inhibitors for combination with Venetoclax against acute myeloid leukemia.

Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3. In this work, we improved the HDAC3 isotype selectivity of 13a, and obtained compound 9c through rational drug design. 9c shows a selectivity of 71 fold for HDAC3 over HDAC1 and can significantly inhibit the proliferation activity of MV4-11 cells in vitro. Furthermore, when combined with Venetoclax, 9c can effectively induce apoptosis in MV4-11 cells in vitro and reduce the expression of anti-apoptotic proteins, the development of HDAC3 selective inhibitors may serve as a potential lead compound to reverse Venetoclax resistance.

Biological function and small molecule inhibitors of histone deacetylase 11.

HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.

Case report: Sequential therapy with dupilumab and baricitinib for severe alopecia areata with atopic dermatitis in children.

An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the features of active stage alopecia areata, with a Severity of Alopecia Tool (SALT) score of 70%. The diagnosis was severe alopecia areata. The patient had a history of atopic dermatitis since infancy, with recurrent episodes of scattered papules and pruritus for 8 years. Initial treatment involved subcutaneous injections of dupilumab 300mg every 2 weeks for 6 months, resulting in a reduction of SALT score to 20% and improvement of atopic dermatitis symptoms. Discontinuation of Dupilumab and initiation of daily oral Baricitinib at a dose of 2mg for a duration of 5 months. According to the SALT score evaluation, the severity of hair loss was less than 10% and there was significant regrowth of hair. No significant adverse reactions were observed during the treatment period.

Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways.

Crosstalk-oriented chemical evolution of natural products (NPs) is an efficacious strategy for generating novel skeletons through coupling reactions between NP fragments. In this study, two NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors, sorbremnoids A and B (1 and 2), with unprecedented chemical architectures were identified from a fungus Penicillium citrinum. Compounds 1 and 2 exemplify rare instances of hybrid NPs formed via a major facilitator superfamily (MFS)-like enzyme by coupling reactive intermediates from two separate biosynthetic gene clusters (BGCs), pcisor and pci56. Both sorbremnoids A and B are NLRP3 inflammasome inhibitors. Sorbremnoid A demonstrated strong inhibition of IL-1ß by directly binding to the NLRP3 protein, inhibiting the assembly and activation of the NLRP3 inflammasome in vitro, with potential application in diabetic refractory wound healing through the suppression of excessive inflammatory responses. This research will inspire the development of anti-NLRP3 inflammasome agents as lead treatments and enhance knowledge pertaining to NPs derived from biosynthetic crosstalk.

Siamese-DETR for Generic Multi-Object Tracking.

The ability to detect and track the dynamic objects in different scenes is fundamental to real-world applications, e.g., autonomous driving and robot navigation. However, traditional Multi-Object Tracking (MOT) is limited to track objects belonging to the pre-defined closed-set categories. Recently, Generic MOT (GMOT) is proposed to track interested objects beyond pre-defined categories and it can be divided into Open-Vocabulary MOT (OVMOT) and Template-Image-based MOT (TIMOT). Taking the consideration that the expensive well pre-trained (vision-)language model and fine-grained category annotations are required to train OVMOT models, in this paper, we focus on TIMOT and propose a simple but effective method, Siamese-DETR. Only the commonly used detection datasets (e.g., COCO) are required for training. Different from existing TIMOT methods, which train a Single Object Tracking (SOT) based detector to detect interested objects and then apply a data association based MOT tracker to get the trajectories, we leverage the inherent object queries in DETR variants. Specifically: 1) The multi-scale object queries are designed based on the given template image, which are effective for detecting different scales of objects with the same category as the template image; 2) A dynamic matching training strategy is introduced to train Siamese-DETR on commonly used detection datasets, which takes full advantage of provided annotations; 3) The online tracking pipeline is simplified through a tracking-by-query manner by incorporating the tracked boxes in the previous frame as additional query boxes. The complex data association is replaced with the much simpler Non-Maximum Suppression (NMS). Extensive experimental results show that Siamese-DETR surpasses existing MOT methods on GMOT-40 dataset by a large margin.

Marine Cytotoxin Santacruzamate A Derivatives as Potent HDAC1-3 Inhibitors and Their Synergistic Anti-Leukemia Effects with Venetoclax.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.

Discovery, Total Synthesis, and Anti-Inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A-C (1-3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17-895, which represent the first naturally occurring naphthopyrone-macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro-inflammatory cytokine IL-1ß release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.

Transformer Based Pluralistic Image Completion With Reduced Information Loss.

Transformer based methods have achieved great success in image inpainting recently. However, we find that these solutions regard each pixel as a token, thus suffering from an information loss issue from two aspects: 1) They downsample the input image into much lower resolutions for efficiency consideration. 2) They quantize 2563 RGB values to a small number (such as 512) of quantized color values. The indices of quantized pixels are used as tokens for the inputs and prediction targets of the transformer. To mitigate these issues, we propose a new transformer based framework called "PUT". Specifically, to avoid input downsampling while maintaining computation efficiency, we design a patch-based auto-encoder P-VQVAE. The encoder converts the masked image into non-overlapped patch tokens and the decoder recovers the masked regions from the inpainted tokens while keeping the unmasked regions unchanged. To eliminate the information loss caused by input quantization, an Un-quantized Transformer is applied. It directly takes features from the P-VQVAE encoder as input without any quantization and only regards the quantized tokens as prediction targets. Furthermore, to make the inpainting process more controllable, we introduce semantic and structural conditions as extra guidance. Extensive experiments show that our method greatly outperforms existing transformer based methods on image fidelity and achieves much higher diversity and better fidelity than state-of-the-art pluralistic inpainting methods on complex large-scale datasets (e.g., ImageNet).

An overview of sphingosine-1-phosphate receptor 2: Structure, biological function, and small-molecule modulators.

Over the past decade, there has been a notable increase in research on sphingosine-1-phosphate receptor 2 (S1PR2), which is a type of G-protein-coupled receptor. Upon activation by S1P or other ligands, S1PR2 initiates downstream signaling pathways such as phosphoinositide 3-kinase (PI3K), Mitogen-activated protein kinase (MAPK), Rho/Rho-associated coiled-coil containing kinases (ROCK), and others, contributing to the diverse biological functions of S1PR2 and playing a pivotal role in various physiological processes and disease progressions, such as multiple sclerosis, fibrosis, inflammation, and tumors. Due to the extensive biological functions of S1PR2, many S1PR2 modulators, including agonists and antagonists, have been developed and discovered by pharmaceutical companies (e.g., Novartis and Galapagos NV) and academic medicinal chemists for disease diagnosis and treatment. However, few reviews have been published that comprehensively overview the functions and regulators of S1PR2. Herein, we provide an in-depth review of the advances in the function of S1PR2 and its modulators. We first summarize the structure and biological function of S1PR2 and its pathological role in human diseases. We then focus on the discovery approach, design strategy, development process, and biomedical application of S1PR2 modulators. Additionally, we outline the major challenges and future directions in this field. Our comprehensive review will aid in the discovery and development of more effective and clinically applicable S1PR2 modulators.

Multiscale Structural Engineering Boosts Piezoelectricity in Na0.5Bi2.5Nb2O9-Based High-Temperature Piezoceramics.

High-temperature piezoelectric materials, which enable the accurate and reliable sensing of physical parameters to guarantee the functional operation of various systems under harsh conditions, are highly demanded. To this end, both large piezoelectricity and high Curie temperature are pivotal figures of merit (FOMs) for high-temperature piezoceramics. Unfortunately, despite intensive pursuits, it remains a formidable challenge to unravel the inverse correlation between these FOMs. Herein, a conceptual material paradigm of multiscale structural engineering was proposed to address this dilemma. The synergistic effects of phase structure reminiscent of a polymorphic phase boundary and refined domain morphology simultaneously contribute to a large piezoelectric coefficient d33 of 30.3 pC/N and a high Curie temperature TC of 740 °C in (LiCeNd) codoped Na0.5Bi2.5Nb2O9 (NBN-LCN) ceramics. More encouragingly, the system has exceptional thermal stability and is nonsusceptible to mechanical loading. This study not only demonstrates that the high-performance and robust NBN-LCN high-temperature piezoceramics hold great potential for implements under harsh conditions but also opens an avenue for integrating antagonistic properties for the enhancement of the collective performance in functional materials.

Prevalence and risk factors of MAFLD and its metabolic comorbidities in community-based adults in China: A cross-sectional study.

AIMS: There is a growing interest in the co-management of metabolic dysfunction-associated fatty liver disease (MAFLD) and its metabolic comorbidities. However, there is insufficient epidemiological data regarding MAFLD and its metabolic comorbidities in China. This study aims to investigate the prevalence and risk factors of MAFLD and its metabolic comorbidities. METHODS: 9171 participants were recruited in this cross-sectional study, utilizing a multistage, stratified sampling method. All participants underwent a comprehensive assessment. The diagnosis of MAFLD was based on vibration-controlled transient elastography (VCTE). The prevalence of MAFLD and its metabolic comorbidities was calculated. Binary and ordinary logistic regressions were conducted. RESULTS: The overall weighted prevalence of MAFLD was 21.18%. Of the 2081 adults with MAFLD, 1866 (89.67%) had more than one metabolic comorbidity, and only 215 (10.33%) did not have comorbidity. Among the population with MAFLD, the prevalence of dyslipidemia, hypertension, hyperuricemia, and diabetes was 67.47%, 43.73%, 39.10%, and 33.88%, respectively. Advanced age, male gender, overweight/obesity, excessive alcohol consumption, and elevated HOMA-IR levels were positively correlated with the number of MAFLD-related metabolic comorbidities. CONCLUSIONS: A significant proportion of individuals diagnosed with MAFLD presented with metabolic comorbidities. Therefore, engaging in the co-management of MAFLD and its metabolic comorbidities is imperative.

Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors.

The aberrant activation of NLRP3 inflammasome has been observed in various human diseases. Targeting the NLRP3 protein with small molecule inhibitors shows immense potential as an effective strategy for disease intervention. Herein, a series of novel biphenyl-sulfonamide NLRP3 inflammasome inhibitors were designed and synthesized. The representative compound H28 was identified as potent and specific NLRP3 inflammasome inhibitor with IC50 values of 0.57 µM. Preliminary mechanistic studies have revealed that compound H28 exhibits direct binding to the NLRP3 protein (KD: 1.15 µM), effectively inhibiting the assembly and activation of the NLRP3 inflammasome. The results in a mouse acute peritonitis model revealed that H28 effectively inhibit the NLRP3 inflammasome pathway, demonstrating their anti-inflammatory properties. Our findings strongly support the further development of H28 as potential lead compound for treating NLRP3-related diseases.

Associations of thyroid feedback quantile-based index with diabetes in euthyroid adults in the United States and China.

BACKGROUND: We aimed to investigate the associations between thyroid hormone sensitivity indices and diabetes in euthyroid adults in the United States and China. METHODS: 2296 euthyroid adults from the NHANES in the United States and 8319 euthyroid adults from the SPEED-Shunde in China were involved. The thyroid sensitivity indices, namely TFQIFT4 and TFQIFT3, were calculated. Multivariable logistic regression, restricted cubic spline analysis, and general ordinal logit regression were utilized. RESULTS: In the NHANES, compared with participants in quartile 1st (Q1), those in Q4 of TFQIFT3 (OR 2.12, 95% CI (1.18, 3.81)) and those in Q3 of TFQIFT4 (OR 2.31, 95% CI (1.18, 4.53)) (both P for trend < 0.05) were associated with a greater prevalence of diabetes. In the SPEED-Shunde, compared with participants in Q1, those in Q4 of TFQIFT3 had a greater prevalence of diabetes (OR 1.36, 95% CI (1.11, 1.66) (P for trend < 0.05), while no significant associations between TFQIFT4 and diabetes were found. CONCLUSIONS: TFQIFT3 was associated with a higher prevalence of diabetes both in the United States and China. However, TFQIFT4 was only associated with a higher prevalence of diabetes in the United States, not in China. Further prospective cohort studies are necessary to validate these findings.

NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.

Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.

Association of sensitivity to thyroid hormones with all-cause mortality in euthyroid US adults: A nationwide cohort study.

Background This study aimed to examine the associations of thyroid hormone sensitivity indices, including free triiodothyronine to free thyroxine (FT3/FT4) ratio, thyroid feedback quantile-based index by FT4 (TFQIFT4), thyroid-stimulating hormone index (TSHI), and thyrotrophic thyroxine resistance index (TT4RI) with all-cause mortality in euthyroid adults. Methods The study included 6243 euthyroid adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2012. FT3/FT4 ratio, TFQIFT4, TSHI, and TT4RI were calculated. The multivariable Cox proportional hazard regression, restricted cubic spline (RCS), and subgroup analysis were conducted. Results Individuals in quartile 4th (Q4) had lower all-cause mortality than those in quartile 1st (Q1) of FT3/FT4 ratio (OR 0.70, 95% CI (0.51, 0.94)). Regarding TFQIFT4, individuals in Q4 of TFQIFT4 had a 43% higher all-cause mortality than those in Q1 (OR 1.43, 95% CI (1.05, 1.96)) (P <0.05, all). Compared with participants in Q1, no associations of TSHI and TT4RI with mortality were found. TFQIFT4 was linearly and positively associated with mortality. However, the FT3/FT4 ratio showed a U-shaped association with mortality. Conclusions Increased risk for all-cause mortality was positively associated with TFQIFT4, suggesting that increased risk for all-cause mortality was associated with decreased central sensitivity to thyroid hormones. Furthermore, the FT3/FT4 ratio showed a U-shaped association with mortality, with an inflection point at 0.5. However, more cohort studies are needed to validate the conclusions.

HDAC/NAMPT dual inhibitors overcome initial drug-resistance in p53-null leukemia cells.

The occurrence of cancer is closely related to metabolism and epigenetics. Histone deacetylases (HDACs) play a crucial role in the regulation of gene expression as epigenetic regulators, while nicotinamide phosphoribosyltransferase (NAMPT) is significantly involved in maintaining cellular metabolism. In this study, we rationally designed a series of novel HDAC/NAMPT dual inhibitors based on the structural similarity between HDAC and NAMPT inhibitors. The representative compounds 39a and 39h exhibit significant selective inhibitory activity on HDAC1-3 with IC50 values of 0.71-25.1 nM, while displaying modest activity against NAMPT. Compound 39h did not exhibit inhibitory activity against 370 kinases, demonstrating its target specificity. These two compounds exhibit potent anti-proliferative activity in multiple leukemia cell lines with low nanomolar IC50s. It is worth noticing that the dual inhibitors 39a and 39h overcome the primary resistance of HDAC or NAMPT single target inhibitor in p53-null AML cell lines, with the induction of apoptosis-related cell death. NMN recovers the cell death induced by HDAC/NAMPT dual inhibitors, which indicates the lethal effects are caused by the inhibition of NAD biosynthesis pathway as well as HDAC. This research provides an effective strategy to overcome the limitations of HDAC inhibitors in treating p53-null leukemia.