OpenNAU:An open-source platform for normalizing,analyzing,and visualizing cancer untargeted metabolomics data

Objective:As an important part of metabolomics analysis,untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also poses great challenges to data analysis,from the extraction of raw data to the identification of differential metabolites.To date,a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research.The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data.Our goal is to establish an easily operated platform and obtain a repeatable analysis result.Methods:We used the R language basic environment to construct the preprocessing system of the original data and the LAMP(Linux+Apache+MySQL+PHP)architecture to build a cloud mass spectrum data analysis system.Results:An open-source analysis software for untargeted metabolomics data(openNAU)was constructed.It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks.A reference metabolomics database based on public databases was also constructed.Conclusions:A complete analysis system platform for untargeted metabolomics was established.This platform provides a complete template interface for the addition and updating of the analysis process,so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions.The source code can be downloaded from https://github.com/zjuRong/openNAU.

Harvesting the fruits of the first stage of the Primate Genome Project

Primates are highly successful mammals with significant morphological,behavioral,and physiological diversity.Studying the genomes of non-human primates,as the closest relative of humans,can provide insights into human evolution,genetic structure,and potential drug targets relevant to human health,thus making important contributions to medical research.Additionally,primate genome research can support ecological balance and resource conservation and promote sustainable development and human well-being.Despite the existence of more than 500 primate species belonging to 80 genera and 16 families worldwide,with new species still being discovered in recent years(Fan et al.,2017;Khanal et al.,2021;Roos et al.,2020),genome sequencing efforts have been limited to a relatively small number of species from only 22 genera(Ensembl v103).Notably,approximately 72%of primate genera remain unsequenced,leading to significant knowledge gaps in our understanding of their evolutionary history.This situation presents considerable challenges for the development,utilization,and protection of primate genetic resources.It is for these compelling reasons that we initiated the Primate Genome Project(PGP)(Wu et al.,2022).

Tissue Engineering in Neuroscience: Applications and Perspectives

Neurological disorders have always been a threat to human physical and mental health nowadays,which are closely related to the nonregeneration of neurons in the nervous system(NS).The damage to the NS is currently difficult to repair using conventional therapies,such as surgery and medication.Therefore,repairing the damaged NS has always been a vast challenge in the area of neurology.Tissue engineering(TE),which integrates the cell biology and materials science to reconstruct or repair organs and tissues,has widespread applications in bone,periodontal tissue defects,skin repairs,and corneal transplantation.Recently,tremendous advances have been made in TE regarding neuroscience.In this review,we summarize TE’s recent progress in neuroscience,including pathological mechanisms of various neurological disorders,the concepts and classification of TE,and the most recent development of TE in neuroscience.Lastly,we prospect the future directions and unresolved problems of TE in neuroscience.

Combination of CRISPR/Cas9 System and CAR-T Cell Therapy:A New Era for Refractory and Relapsed Hematological Malignancies

Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.

Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation

Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of mice.After the mice were sacrificed,the hippocampus was excised for further analysis.Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte.Western blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory cytokines.Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus.Absence of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD.However,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.

Macroencapsulation Devices for Cell Therapy

Macroencapsulation has been widely used in cell therapy due to its capability to provide immune-privileged sites for implanted allogeneic or xenogeneic cells.Macroencapsulation also serves to provide mechanical and physiochemical support for maintaining cell expansion and promoting therapeutic func-tions.Macroencapsulation devices such as membrane-controlled release systems,hydrogels,micronee-dle(MN)array patches,and three-dimensional(3D)stents have shown promising in-lab and preclinical results in the maintenance of long-term cell survival and the strengthening of treatment effi-cacy.Recent studies focus on expanding the applications of these devices to new cell-based areas such as chimeric antigen receptor(CAR)-T cell delivery,cardiovascular disease therapy,and the exploration of new materials,construction methods,and working principles to augment treatment efficacy and prolong therapy duration.Here,we survey innovative platforms and approaches,as well as translation outcomes,for advancing the performance and applications of macrodevices for cell-based therapies.A discussion and critique regarding future opportunities and challenges is also provided.

Insights from TARGET-seq:Inflammation drives TP53-mediated clonal evolution

Approximately 10%–20%myeloproliferative neoplasms(MPNs)can progress into blast-phase MPNs,also termed secondary acute myeloid leukemias(sAMLs),presenting dismal prognoses.sAML exhibits a distinctive clinical and pathological profile compared to de novo AML,marked by a higher incidence of erythroid leukemias and reduced responsive to conventional chemotherapies,resulting in a median survival of approximately 6 months.TP53 alterations are prevalent adverse events in leukemic transformation(LT),occurring in around one-third of sAML subjects.

Advances of nanoparticles in transmucosal drug delivery

Transmucosal drug administration represents a potential strategy for enhancing treatment efficacy and reducing side effects by avoiding the first-pass effect into the systemic circulation and delivering therapeutics directly to the target disease site.However,many challenges still remain in its clinical application,including low drug availability and limited retention time in the mucosa.The burgeoning advancement of nanotechnologies offers great potential to overcome the above limitations,leveraging their distinct advantages of high drug-loading capacity and strong permeability.In this review,the latest developments of nanoparticles(NPs)in transmucosal drug delivery as well as their clinical applications are discussed.

Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke

With the escalating prevalence of global heat waves,heat stroke has become a prominent health concern,leading to substantial liver damage.Unlike other forms of liver injury,heat strokeinduced damage is characterized by heat cytotoxicity and heightened inflammation,directly contributing to elevated mortality rates.While clinical assessments have identified elevated bilirubin levels as indicative of Kupffer cell dysfunction,their specific correlation with heat stroke liver injury remains unclear.Our hypothesis proposes the involvement of Kupffer cell ferroptosis during heat stroke,initiating IL-1bmediated inflammation.Using single-cell RNA sequencing of murine macrophages,a distinct and highly susceptible Kupffer cell subtype,Clec4Ft/CD206t,emerged,with heme oxygenase 1(HMOX-1)playing a pivotal role.Mechanistically,heat-induced HMOX-1,regulated by early growth response factor 1,mediated ferroptosis in Kupffer cells,specifically in the Clec4F t/CD206 t subtype(KC2),activating phosphatidylinositol 4-kinase beta and promoting PI4P production.This cascade triggered NLRP3 inflammasome activation and maturation of IL-1b.These findings underscore the critical role of targeted therapy against HMOX-1 in ferroptosis within Kupffer cells,particularly in Clec4F t/CD206 t KCs.Such an approach has the potential to mitigate inflammation and alleviate acute liver injury in the context of heat stroke,offering a promising avenue for future therapeutic interventions.

Inflammation and aging:signaling pathways and intervention therapies

Aging is characterized by systemic chronic inflammation,which is accompanied by cellular senescence,immunosenescence,organ dysfunction,and age-related diseases.Given the multidimensional complexity of aging,there is an urgent need for a systematic organization of inflammaging through dimensionality reduction.

Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit

Mannose is a naturally occurring sugar widely consumed in the daily diet;however,mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking.Herein,we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery.Macrophage-secreted inflammatory cytokines,particularly TNF-α,induced pathological endoplasmic reticulum stress(ERS)in intestinal epithelial cells(IECs),which was prevented by mannose via normalization of protein N-glycosylation.By preserving epithelial integrity,mannose reduced the inflammatory activation of colonic macrophages.On the other hand,mannose directly suppressed macrophage TNF-αproduction translationally by reducing the glyceraldehyde 3-phosphate level,thus promoting GAPDH binding to TNF-αmRNA.Additionally,we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease.Finally,we revealed that activating PMM2 activity with epalrestat,a clinically approved drug for the treatment of diabetic neuropathy,elicited further sensitization to the therapeutic effect of mannose.Therefore,mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages,thereby normalizing aberrant immunometabolism in the gut.

FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes

Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia.However,the regulatory complexity of cytokine and cellular networks still needs to be investigated.Here,we show that the expression of FXYD3,a member of the FXYD domain-containing regulators of Na+/K+ATPases family,is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod(IMQ)-induced psoriasis.IL-17A,a cytokine important for the development of psoriatic lesions,contributes to FXYD3 expression in human primary keratinocytes.FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model.Importantly,FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes.This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors.Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation.Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.

Engineering SIRPα cellular membrane-based nanovesicles for combination immunotherapy

Immune checkpoint inhibitors(ICIs)have revolutionized cancer treatment for their unprecedented clinical efficacy.Signal regulatory proteinα(SIRPα)is a phagocytic checkpoint expressed on macrophages,dendritic cells,other myeloid cells.Cancer cells inhibit macrophage phagocytosis through the interaction of the CD47-SIRPαaxis.Disrupting the CD47-SIRPαaxis has therefore been a promising strategy in restoring the immune attack against cancer.Herein,we engineered cellular membrane nanovesicles(NVs)presenting SIRPαreceptors for phagocytosis checkpoint blockade to augment the antitumor immune response.Furthermore,zebularine(Zeb),an inhibitor of DNA methyltransferase,was encapsulated into SIRPαNVs to reprogram the immunosuppressive tumor microenvironment together with blockade of phagocytosis checkpoint.It is demonstrated that SIRPα@Zeb can improve tumor immunogenicity,the polarization of tumor-associated macrophages to the M1 phenotype,increase the infiltration of CD8^(+)T lymphocytes in tumors.The robust antitumor immune response induced by SIRPα@Zeb significantly suppressed tumor growth and extended mice-bearing melanoma xenograft survival.

Generating hematopoietic cells from human pluripotent stem cells:approaches,progress and challenges

Human pluripotent stem cells(hPSCs)have been suggested as a potential source for the production of blood cells for clinical application.In two decades,almost all types of blood cells can be successfully generated from hPSCs through various differentiated strategies.Meanwhile,with a deeper understanding of hematopoiesis,higher efficiency of generating progenitors and precursors of blood cells from hPSCs is achieved.However,how to generate large-scale mature functional cells from hPSCs for clinical use is still difficult.In this review,we summarized recent approaches that generated both hematopoietic stem cells and mature lineage cells from hPSCs,and remarked their efficiency and mechanisms in producing mature functional cells.We also discussed the major challenges in hPSC-derived products of blood cells and provided some potential solutions.Our review summarized efficient,simple,and defined methodologies for developing good manufacturing practice standards for hPSC-derived blood cells,which will facilitate the translation of these products into the clinic.

Correction:Generating hematopoietic cells from human pluripotent stem cells:approaches,progress and challenges

Correction:Cell Regen 12,31(2023).https://doi.org/10.1186/s13619-023-00175-6 Following publication of the original article(Zheng et al.2023),the authors reported that Figs.1 and 2 were in the wrong order.The correct Figs.1 and 2 have been provided in this Correction.The original article(Zheng et al.2023)has been corrected.

Characterization of the chemical fungicides-responsive and bacterial pathogen-preventing Bacillus licheniformis in rice spikelet

Seed-borne bacterial pathogens cause severe yield loss and biotoxin contamination in rice,leading to increasing concern on the global food supply and environmental safety.Plant native microbes play an important role in defending against diseases,but their actions are often influ-enced by the chemical fungicides applied in the field.Here,Bacillus licheniformis mmj was isolated from rice spikelet,which uniquely showed not only fungicide-responsiveness but also broad-spectrum antimicrobial activity against major rice bacterial pathogens including Xanthomonas oryzae pv.oryzae,Burkholderia plantari and Burkholderia glumae.To understand the hallmark underlying the environmental adaptation and anti-microbial activity of B.licheniformis mmj,the genome sequence was determined by SMRT and subjected to bioinformatics analysis.Genome sequence analysis enabled the identification of a set of antimicrobial-resistance and antibacterial activity genes together with an array of harsh environment-adaptive genes.Moreover,B.licheniformis mmj metabolites were analyzed with gas chromatography coupled to triple quadrupole mass spectrometry,and the volatile components that were linked with the antimicrobial activity were preliminarily profiled.Collectively,the present findings reveal the genomic and metabolic landscapes underlying fungicide-responsive B.licheniformis,which offers a new opportunity to design harsh environment-adaptive biopesticides to cope with prevalent bacterial phytopathogens.

Sense to Tune: Engaging Microglia with Dynamic Neuronal Activity

Microglia,the primary resident immune cells in the central nervous system(CNS),continuously survey the microenvironment via their ramified and motile processes to maintain brain homeostasis[1].As immune sentinels,microglia detect exogenous pathogens,elicit inflammation,promote tissue repair,and engage in the onset and progression of brain diseases[1].

Therapeutic targets and biomarkers of tumor immunotherapy:response versus non-response

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response.The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression.Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors.Represented by immune checkpoint blockade and adoptive cell transfer,tumor immunotherapy has seen tremendous success in the clinic,with the capability to induce long-term regression of some tumors that are refractory to all other treatments.Among them,immune checkpoint blocking therapy,represented by PD-1/PD-L1 inhibitors(nivolumab)and CTLA-4 inhibitors(ipilimumab),has shown encouraging therapeutic effects in the treatment of various malignant tumors,such as non-small cell lung cancer(NSCLC)and melanoma.In addition,with the advent of CAR-T,CAR-M and other novel immunotherapy methods,immunotherapy has entered a new era.At present,evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect.However,the overall clinical response rate of tumor immunotherapy still needs improvement,which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents.Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future.In this article,we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully understood.Here,using unbiased drug screening approaches,we discover Metformin,a drug that is commonly the first medication prescribed for type 2 diabetes,can induce CMA.We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA,Hsc70,and its activation.Notably,we find that amyloid-beta precursor protein(APP)is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner.The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity.Importantly,we find that in the APP/PS1 mouse model of Alzheimer's disease(AD),activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβplaque levels and reverses the molecular and behavioral AD phenotypes.Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases,such as AD,where such therapeutic intervention could be beneficial.

Alternative approaches to target Myc for cancer treatment

The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological processes,including cell proliferation,differentiation,survival,and apoptosis.Myc modulates about 15%of the global transcriptome,and its deregulation rewires the cellular signaling modules inside tumor cells,thereby acquiring selective advantages.The deregulation of Myc occurs in>70%of human cancers,and is related to poor prognosis;hence,hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades.Nevertheless,no specific drug is currently available to directly target Myc,mainly because of its"undruggable"properties:lack of enzymatic pocket for conventional small molecules to bind;inaccessibility for antibody due to the predominant nucleus localization of Myc.Although the topic of targeting Myc has actively been reviewed in the past decades,exciting new progresses in this field keep emerging.In this review,after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer,we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.