Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Derivation of persistent time for anisotropic migration of cells

Cell migration plays an essential role in a wide variety of physiological and pathological processes. In this paper we numerically discuss the properties of an anisotropic persistent random walk （APRW） model, in which two different and independent persistent times are assumed for cell migrations in the x-and y-axis directions. An intrinsic orthogonal coordinates with the primary and non-primary directions can be defined for each migration trajectory based on the singular vector decomposition method. Our simulation results show that the decay time of single exponential distribution of velocity auto-correlation function （VACF） in the primary direction is actually the large persistent time of the APRW model, and the small decay time of double exponential VACF in the non-primary direction equals the small persistent time of the APRW model. Thus, we propose that the two persistent times of anisotropic migration of cells can be properly estimated by discussing the VACFs of trajectory projected to the primary and non-primary directions.

Enhanced vibrational resonance in a single neuron with chemical autapse for signal detection

Many animals can detect the multi-frequency signals from their external surroundings.The understanding for underlying mechanism of signal detection can apply the theory of vibrational resonance,in which the moderate high frequency driving can maximize the nonlinear system's response to the low frequency subthreshold signal.In this work,we study the roles of chemical autapse on the vibrational resonance in a single neuron for signal detection.We reveal that the vibrational resonance is strengthened significantly by the inhibitory autapse in the neuron,while it is weakened typically by the excitatory autapse.It is generally believed that the inhibitory synapse has a suppressive effect in neuronal dynamics.However,we find that the detection of the neuron to the low frequency subthreshold signal can be improved greatly by the inhibitory autapse.Our finding indicates that the inhibitory synapse may act constructively on the detection of weak signal in the brain and neuronal system.

The RIP3-RIP1-NF-κB signaling axis is dispensable for necroptotic cells to elicit cross-priming of CD8^(+) T cells

Apoptosis and necroptosis are two types of programmed cell death with distinct morphological features.Necroptosis has been assumed to be more inflammatory than apoptosis,but a recent paper1 concluded that necroptotic cells cannot elicit cross-priming of CD8^(+)T cells and that NF-κB activation in necroptotic cells is required for maximal CD8^(+)T-cell cross-priming.

TBK1:a new target for overcoming cancer immunotherapy resistance

In a recent study published in Nature,Sun et al.(2023)discovered that targeting TANK-binding kinase 1(TBK1)can successfully overcome resistance to immune checkpoint blockade(ICB)treatment and the study revealed its potential mechanism.The authors provided evidence that the disruption of TBK1 signal enhances the blockade of programmed cell death protein-1(PD-1)and promotes anti-tumor immunity in the tumor microenvironment(TME).Tumor cells rely on Janus kinase(JAK)and signal transducer as well as activator of transcription(STAT)signals to elicit an immune response by perceiving tumor necrosis factorα(TNF-α)and interferon-γ(IFN-γ),resulting in receptor-interacting protein kinase(RIPK)-caspase-mediated cell death in tumor cells(Figure 1).

Advancing clinical-basic-clinical research: exploring novel immunotargets for ovarian cancer

In a recent paper published in Cell,1 Luo and colleagues performed a multi-omics analysis of a prospective phase Ⅱ clinical trial and elucidated the effector regulatory T cells(eTregs)as novel immunotarget for ovarian cancer with homologous recombination deficiency(HRD),analyzing for the first time at the clinical level how poly(ADP-ribose)polymerase(PARP)inhibitors reshape the ovarian cancer microenvironment.The implications of targeting eTregs and combining PARP inhibitors could pave the way for more effective therapies clinically,which is also a typical example of practicing the concept of reverse transformation medicine(RTM)(Fig.1).

Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling

Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFN？ and IL4 productions from NKT cells, and more profound influence on IFN？ was observed. By adjusting the pH of culture medium we fiu-ther showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin （roTOR） signaling and nuclear translocation of promyelocytic leukemia zinc-finger （PLZF）. Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.

Cuproptosis:a new v form of programmed cell death

A recent study by Tsvetkov et al.was published in Science and proposed a novel form of copper-induced cell death.Tsvetkov et al.revealed that excess intracellular copper induces the aggregation of lipoylated dihydrolipoamide S-acetyltransferase(DLAT),which is associated with the mitochondrial tricarboxylic acid(TCA)cycle,resulting in proteotoxic stress and leading to a novel form of cell death termed cuproptosis[1].

Dual mechanisms of Bcl-2 regulation in IP_(3)-receptor-mediated Ca^(2+)release:A computational study

Inositol 1,4,5-trisphosphate receptors(IP_(3)R)-mediated calcium ion(Ca^(2+))release plays a central role in the regulation of cell survival and death.Bcl-2 limits the Ca^(2+)release function of the IP3R through a direct or indirect mechanism.However,the two mechanisms are overwhelmingly complex and not completely understood.Here,we convert the mechanisms into a set of ordinary differential equations.We firstly simulate the time evolution of Ca^(2+)concentration under two different levels of Bcl-2 for the direct and indirect mechanism models and compare them with experimental results available in the literature.Secondly,we employ one-and two-parameter bifurcation analysis to demonstrate that Bcl-2 can suppress Ca^(2+)signal from a global point of view both in the direct and indirect mechanism models.We then use mathematical analysis to clarify that the indirect mechanism is more efficient than the direct mechanism in repressing Ca^(2+)signal.Lastly,we predict that the two mechanisms restrict Ca^(2+)signal synergistically.Together,our study provides theoretical insights into Bcl-2 regulation in IP_(3)R-mediated Ca^(2+)release,which may be instrumental for the successful development of therapies to target Bcl-2 for cancer treatment.

Quantitative modeling of bacterial quorum sensing dynamics in time and space

Quorum sensing (QS) refers to the cell communication through signaling molecules that regulate many important biological functions of bacteria by monitoring their population density. Although a wide spectrum of studies on the QS system mechanisms have been carried out in experiments, mathematical modeling to explore the QS system has become a powerful approach as well. In this paper, we review the research progress of network modeling in bacterial QS to capture the system's underlying mechanisms. There are four types of QS system models for bacteria: the Gram-negative QS system model, the Gram-positive QS system model, the model for both Gram-negative and Gram-positive QS system, and the synthetic QS system model. These QS system models are mostly described by the ordinary differential equations (ODE) or partial differential equations (PDE) to study the changes of signaling molecule dynamics in time and space and the cell population density variations. Besides the deterministic simulations, the stochastic modeling approaches have also been introduced to discuss the noise effects on kinetics in QS systems. Taken together, these current modeling efforts advance our understanding of the QS system by providing systematic and quantitative dynamics description, which can hardly be obtained in experiments.

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new “coexisting” state in single cells is proposed when GSDMD acts as the driving force of the landscape. The “seesaw model” is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.

PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

Metabolic reprogramming is a hallmark of cancer,including lung cancer.However,the exact underlying mechanism and therapeutic potential are largely unknown.Here we report that protein arginine methyltransferase 6(PRMT6)is highly expressed in lung cancer and is required for cell metabolism,tumorigenicity,and cisplatin response of lung cancer.PRMT6 regulated the oxidative pentose phosphate pathway(PPP)flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phosphogluconate dehydrogenase(6PGD)and a-enolase(ENO1).Furthermore,PRMT6 methylated R324 of 6PGD to enhancing its activity;while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate(2-PG)binding to ENO1,respectively.Lastly,targeting PRMT6 blocked the oxidative PPP flux,glycolysis pathway,and tumor growth,as well as enhanced the antitumor effects of cisplatin in lung cancer.Together,this study demonstrates that PRMT6 acts as a posttranslational modification(PTM)regulator of glucose metabolism,which leads to the pathogenesis of lung cancer.It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Biexponential distribution of open times of a toy channel model

The biexponential distributions of open times are observed in various types of ion channels. In this paper, by discussing a simple channel model, we show that there are two different schemes to understand the biexponential distribution of open times. One scheme is mathematically strict based on generator matrix theory, while the other one has a clear physical explanation according to an approximation process with numerical simulation of Markovian channel dynamics. Our comparison results suggest that even for biologically complex channels, in addition to carrying out a stochastic simulation, the strict theoretical analysis should be considered to understand the multiple exponential distributions of open times.

The DDB1-DCAF2 complex is essential for B cell development because it regulates cell cycle progression

B cell development in the bone marrow is critical for producing numerous B cells that play an essential role in the adaptive immune response.B cells develop from common lymphoid progenitors(CLPs),which then differentiate through a series of stages,which include prepro-B cells,pro-B cells,pre-B cells,immature B cells,and mature B cells.

Development of a novel method for rapid cloning of shRNA vectors, which successfully knocked down CD44 in mesenchymal triple-negative breast cancer cells

Dear Editor,Since the discovery of short hairpin RNA(shRNA)vec-tor-mediated RNA interference(RNAi),this technology has been widely used in cancer research for its specific-ity,potency,and convenience.However,researchers may find it costly to purchase commercial vectors from bio-companies or time-and labor-consuming to construct their own shRNA vectors using traditional method by inserting annealed duplex into digested vectors.Despite intensive efforts to accelerate shRNA vector cloning in laboratories,the development of a reliable,rapid,conven-ient,and cost-effective method is still in great demand.To this end,we developed a novel method named SuperSH(Super rapid cloning of shRNA vector)for the effective and rapid construction of shRNA-expressing vectors based on high-performance DNA polymerase and seamless cloning technique[1](Additional file 1:Fig-ure S1a;the detailed methods can be found in Additional file 1).In our SuperSH method,the shRNA sequences are introduced into the vector via a pair of polymerase chain reaction(PCR)primers rather than via annealed duplex.In detail,the 3′ends of the primers are designed to bind the template to initiate a PCR to amplify the vector back-bone,and the 5′portions are designed to introduce the sequences of interest as well as to form a short homol-ogous arm for subsequent recombination via seamless cloning[1].

The loss of epigenetic information:not only consequences but a cause of mammalian aging

In a recent study published in Cell,Yang et al.revealed that changes in epigenetic landscapes caused by faithful DNA repair are key drivers accelerating aging of mammalian organs or tissues.1 Impressively,changes in H3K27ac landscape during aging process influence cell identity maintenance,and this aging process can be reversed by the inducible expression of pioneer transcription factors,Oct4,Sox2,and Klf4(OSK)in the living mammals.In mammals,global and local changes of DNA methylation occur in the genome during aging.Additionally,general loss of histones and global chromatin remodeling have been observed in all aging models,while in reverse reprograming of cell fate can lead to global changes in the epigenetic and rejuvenated epigenome,suggesting the potential of reprogramming for the reversal of aging.2 However,as no systematic studies revealed the characteristics of epigenomic changes during aging,it remains unclear whether the changes in epigenetic landscape are the consequences(marks)or direct cause of aging.

三维电子显微镜和单分子追踪技术揭示内质网和线粒体接触部位的动态变化

Mammalian cells are highly compartmented. Different organelles fulfill diverse cellular functions at the same time coordinate with each other through the exchange of materials and information. Physical contacts play pivotal roles in communication between organelles [1].

Dear-DIA^(XMBD): Deep Autoencoder Enables Deconvolution of Data-Independent Acquisition Proteomics

Data-independent acquisition(DIA)technology for protein identification from mass spectrometry and related algorithms is developing rapidly.The spectrum-centric analysis of DIA data without the use of spectra library from data-dependent acquisition data represents a promising direction.In this paper,we proposed an untargeted analysis method,Dear-DIA^(XMBD),for direct analysis of DIA data.Dear-DIA^(XMBD) first integrates the deep variational autoencoder and triplet loss to learn the representations of the extracted fragment ion chromatograms,then uses the k-means clustering algorithm to aggregate fragments with similar representations into the same classes,and finally establishes the inverted index tables to determine the precursors of fragment clusters between precursors and peptides and between fragments and peptides.We show that Dear-DIA^(XMBD) performs superiorly with the highly complicated DIA data of different species obtained by different instrument platforms.

NKT cells in liver diseases

Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CDld-expressing cells or bystander cells.

Challenges of NK cell-based immunotherapy in the new era

Natural killer cells （NKs） have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells （PBMCs）, stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.