Biology subjects

Peng, M.

Publications and source records attributed to Peng, M..

At least 19 recordsLinked to original sources

bioRxiv2026

DPF3a couples H3K36me2-dependent chromatin remodeling to genome architecture during myogenesis

Chromatin remodelers are generally thought to regulate gene expression through nucleosome mobilization and modulation of local chromatin accessibility. Whether these complexes can instead control transcription through higher-order chromatin organization remains poorly understood. Here we identify the BAF subunit DPF3a as an essential regulator of skeletal muscle regeneration and myogenic differentiation. DPF3a functions through association with the H3K36me2/3 reader HRP2 and preferentially localizes to a distinctive chromatin state characterized by focal depressions within broad H3K36me2 domains. Biochemical reconstitution demonstrates that H3K36 methylation directly enhances remodeling activity of the DPF3a-containing cBAF complex. Unexpectedly, despite profound transcriptional defects, loss of DPF3a produces minimal changes in local chromatin accessibility. Instead, DPF3a is required for long-range chromatin looping associated with activation of myogenic genes. Together, our findings uncover a non-canonical mechanism whereby a chromatin remodeler regulates transcription primarily through three-dimensional genome organization rather than local accessibility control, and establish histone modification-guided chromatin remodeling as a key principle in gene regulation.

molecular biology↗

bioRxiv2026

Targeted modulation of IGFBP5/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma

Primary mitochondrial diseases (PMD) have limited disease-modifying therapies, currently applicable to only 3 of over 400 discrete gene disorders. Cycloheximide (CHX) is a global cytosolic translation inhibitor we previously reported to rescue PMD preclinical models, although its toxicity precluded clinical development. To identify specific mediators underlying CHX treatment benefit in PMD, SOMAscan-based proteomics was performed in complex I deficient and genetic disease fibroblast cell line models grown in galactose. Thrombopoietin (THPO) and insulin-like growth factor binding protein 5 (IGFBP5) were the only two differentially regulated proteins, together with ERK/MAPK pathway dysregulation, identified upon CHX treatment in PMD versus healthy control cells. THPO inhibition by siRNA or pharmacologic approaches rescued stress-induced viability loss in patient fibroblasts having diverse PMD gene etiologies, and significantly improved mitochondrial stress, linear growth, and neuromuscular function in a classical ndufs2-/- C. elegans model. IGFBP5 overexpression by lentiviral or mRNA approaches rescued cell viability across distinct PMD gene etiologies, as did IGF1 pharmacologic inhibition across both PMD mutant and C. elegans models. MAPK pharmacologic inhibition rescued multiple distinct complex I disease cells survival, as well as mitochondrial stress in SLC25A46-/- C. elegans. Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models. Additionally, single or combined pharmacologic inhibition of THPO or IGF1 significantly enhanced primary and metastatic osteosarcoma cell death. Collectively, targeted small molecule and genetic modulation of THPO, IGF1, or MAPK recapitulated the significant therapeutic benefit of CHX in PMD, while avoiding global translation inhibition. These novel PMD therapies likely confer benefit by attenuating MAPK-driven autophagy and potentially promoting noncanonical glucose uptake, improving cellular energy balance. Overall, these glucose signaling cellular pathway targets hold broad therapeutic promise for PMD patients, warranting further clinical research development.

genetics↗

bioRxiv2026

A biointegrated living brain stimulator evokes specific neural signalling

Implanted brain stimulators play a crucial role in treating various neurological disorders, including Parkinsons disease (PD), Alzheimers disease, epilepsy, and depression. However, none of the existing implanted brain stimulators can realize specific neuromodulation due to fundamental disparities in signal transmission between electrical signal-induced neuronal responses and neurotransmitter-evoked neural signalling in natural neural circuits, leading to persistent challenges in biosafety and therapeutic effectiveness. Inspired by the dopaminergic neural circuit, we report a biointegrated living brain stimulator (BBS) that integrates ferroelectric bioelectronics, dopaminergic cells, and a gelatin hydrogel matrix, enabling dopamine neurotransmitter-evoked neural signalling. In contrast to conventional brain stimulators, the BBS are capable of programmed secretion of physiological-level dopamine, specifically activating nigral dopamine pathways and restoring motor function in a rodent PD model. By integrating the advantages of both bioelectronics and medicine, this lifelike BBS offers a great promise for next-generation bioelectronics, medicine, and brain-machine interfaces.

bioengineering↗

bioRxiv2026

Hypermorphic TaARF4 shapes wheat architecture by repressing SPL-mediated developmental timing

Integrating spatial morphogens with temporal developmental clocks is fundamental to optimizing plant architecture and crop yield, yet their molecular interface remains elusive. Here, we characterize Branched shoot 1 (Bsh1), a semi-dominant wheat mutant exhibiting non-canonical upper-aerial branching and aberrant spike development, caused by a T265I substitution in the DNA-binding domain of the auxin response factor TaARF4-A2. Unlike flanking mutations governing protein stability in basal land plants, this central substitution uniquely converts TaARF4-A2 into an auxin-insensitive hypermorphic repressor. The mutant protein disrupts auxin-cytokinin homeostasis and markedly enhances the native repression of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors, the core timers of developmental phase transitions. This spatial and temporal uncoupling unleashes upper axillary buds from dormancy, promoting aerial branching and diverting resources from reproductive development. Our findings demonstrate how a conserved spatial morphogen effector was evolutionarily rewired in polyploid wheat to dictate the temporal SPL clock, orchestrating species-specific shoot architectural innovation.

plant biology↗

bioRxiv2026

CAPZ, but not canonical autophagy, regulates the endosomal-exosomal trafficking of plasma membrane PD-L1

Programmed death-ligand 1 (PD-L1) undergoes continuous endocytosis and intracellular trafficking that regulate its degradation, recycling, and exosomal release. Although PD-L1 internalization is known to depend on RAB5-mediated endocytosis, whether canonical autophagy contributes to its subsequent endosomal trafficking remains unclear. Here we show that the endosomal and exosomal trafficking of cell surface PD-L1 occurs independently of the canonical autophagy machinery. Genetic disruption of core autophagy components, including LC3B, ATG4B, ATG5, and ATG7, did not impair trafficking of internalized PD-L1 to early endosomes, multivesicular bodies, late endosomes, or extracellular vesicles. Pharmacologic inhibition of autophagosome-lysosome fusion enhanced accumulation of PD-L1 within RAB5-and CD63-positive compartments, but this effect persisted in cells lacking LC3B, ATG5, or ATG7, indicating that PD-L1 trafficking through the endosomal-exosomal pathway does not require canonical autophagy. Instead, we identify the actin-capping protein CAPZ as a key regulator of an endosomal maturation checkpoint that controls PD-L1 sorting. Loss of CAPZ impaired progression of PD-L1 from early to late endosomal compartments, reduced PD-L1 incorporation into multivesicular bodies and extracellular vesicles, and redirected PD-L1 toward RAB11-dependent recycling, resulting in increased plasma membrane PD-L1 abundance. These findings establish that PD-L1 membrane fate is determined by CAPZ-dependent endosomal maturation rather than canonical autophagy and identify endosomal trafficking machinery as a critical regulator of immune checkpoint distribution.

cell biology↗

bioRxiv2026

Gut Microbiota Dysbiosis-Mediated Gut NLRP3 Inflammasome Activation Exacerbates Corticospinal Tract Injury After Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) causes severe neurological deficits, largely attributable to corticospinal tract (CST) injury. However, the underlying mechanism remains unclear, which hinders the development of effective treatment methods. Here, we found that CST injury is not only associated with the activation of NLRP3 inflammasome in the surrounding area of the hematoma as expected, and dysfunction of the blood-brain barrier, but also related to the severe imbalance of the gut microbiota, the activation of NLRP3 inflammasome in the gut and the impairment of gut barrier function after ICH. We therefore systematically investigated how the gut NLRP3 inflammasome and gut dysbiosis exacerbate CST injury after ICH. Knockdown of colon NLRP3 significantly attenuated CST injury and downregulated inflammasome signaling in both the peripheral circulation and the peri-hematomal brain. Consistently, antibiotic-mediated gut microbiota depletion suppressed NLRP3 activation in the gut and brain, improved neurological function, and reduced CST damage. Crucially, fecal microbiota transplantation (FMT) from ICH donors established that the exacerbation of CST injury is dependent on gut dysbiosis. While FMT induced severe pathology in control mice, this effect was improved in gut NLRP3 knockdown recipients, demonstrating that gut NLRP3 is essential for mediating the harmful effects of microbiota dysbiosis. Our findings described a causal gut-brain axis in ICH, wherein microbiota dysbiosis activates the gut NLRP3 inflammasome to exacerbate CST injury, thereby identifying the gut NLRP3 inflammasome as a promising therapeutic target.

neuroscience↗

bioRxiv2026

In vitro modeling of nutritional and mitochondria-targeted therapies for osteosarcoma

Osteosarcoma is the most common pediatric bone tumor yet has limited treatment options, especially for metastatic cases with a 20% adjusted 5-year survival rate. Current therapies are non-specific, involving primary tumor resection with DNA-damaging chemotherapies like methotrexate, doxorubicin, and cisplatin. Few effective treatment options exist for metastases. Targeting metabolism involving cancers reduced mitochondrial functionality remains underexplored in osteosarcoma. We investigated the therapeutic potential in human osteosarcoma primary and metastatic cell lines of metabolic modulating drugs including metformin, cycloheximide, mitochondrial ETC inhibitors (antimycin A, metformin), dichloroacetate, and imipridones (ONC201, ONC206) on mitochondrial function and cell viability, individually and combined under various nutrient conditions across our lines. Results confirmed osteosarcoma cells are more dependent on glucose than osteoblasts but also require mitochondrial function for survival, highlighting the therapeutic potential of metabolic pathways. Osteosarcoma cell viability was reduced when any metabolic drug treatment was combined with conditions forcing reliance on mitochondrial OXPHOS capacity. Combination metabolic therapies, particularly ONC201/ONC206/metformin in 143B cells, and to a lesser extent DCA and ONC201 with either ONC206 or antimycin A, showed enhanced cytotoxicity compared to single agents, with a good therapeutic index based on minimal toxicity to normal osteoblast cells. The degree of effectiveness varied across cell lines, underscoring the importance of personalized treatment strategies. RNA-Seq transcriptome analysis revealed that effective nutrient and metabolic drug treatments triggered widespread regulatory changes in osteosarcoma cells involving increased translation/splicing with decreased mitochondrial processes such as cholesterol biosynthesis. These results demonstrate the utility of developing combined metabolic and chemotherapeutic treatments for osteosarcoma.

cancer biology↗

bioRxiv2026

Organelle biogenesis on a synthetic bead

How cells build their many organelles remains poorly understood. Centrosomes are a striking example: structurally complex organelles built from more than one hundred different proteins. Here we show that a synthetic bead can generate centrosome-like particles (CLiPs) in early Drosophila embryos if it is programmed to recruit any one of five essential centrosome assembly proteins. CLiPs behave remarkably like centrosomes: organising centrosomal proteins, microtubules and actomyosin, forming spindle poles, and undergoing multiple rounds of duplication - all in synchrony with the embryonic cell cycle. The beads generate CLiPs because they recruit Plk4, the master regulator of centrosome biogenesis, in a specific manner that stimulates its assembly activity. Thus, recruiting a single protein to a synthetic surface is sufficient to seed the self-assembly of a complex, self-propagating entity. These findings suggest a general framework for organelle biogenesis in which simple localised molecular inputs can seed the self-assembly of highly complex cellular structures.

cell biology↗

bioRxiv2025

Gut metabolite IPA alleviates white matter injury post-ICH by enhancing myelin debris phagocytosis via Stap1 inhibition

BackgroundIntracerebral hemorrhage (ICH) causes neurological dysfunction and white matter injury (WMI) characterized by myelin loss, axonal injury and myelin debris accumulation. Microglia-mediated debris clearance is critical for WMI repair. The microbiota-gut-brain axis plays an essential role in the central nervous system diseases, one of the ways in which gut microbiota affects brain is via producing metabolites. Indole-3-proprionic acid (IPA), a tryptophan-derived metabolite that mainly produced by Clostridium sporogenes, exhibits anti-inflammatory and neuroprotective properties. However, its effect on ICH remains unclear. This study aims to investigate the IPA level after ICH and the therapeutic effects of IPA on neurological deficits and WMI, as well as the potential mechanisms underlying IPA-mediated neuroprotection. MethodsAn ICH model was established using C57BL/6 mice, which then received intragastric IPA (20 mg/kg/day). Fecal abundance of IPA-related genes and IPA levels in feces and plasma were measured by qPCR and UPLC-MS/MS. Behavioral tests, qPCR, and immunofluorescence staining were used to assess neurological function, myelin integrity, and axonal injury. In vitro, BV2 microglia, with or without Stap1 knockdown, were co-cultured with myelin debris to assess IPAs effects on phagocytosis. Additionally, targeted plasma IPA profiling was performed in 30 ICH patients and 30 matched healthy controls. ResultsThe relative abundance of IPA production-related genes and IPA levels in feces and plasma were significantly decreased after ICH and remained low into the chronical phase. After IPA administration, the neurological deficits, myelin loss and axonal injury of mice with ICH were significantly improved. In vitro, IPA increased BV2 microglia myelin debris phagocytosis by inhibiting Stap1 expression. IPA levels were significantly reduced in ICH patients, consistent with ICH mouse model. ConclusionsOur findings demonstrated that the gut microbiota-derived metabolite IPA could facilitate neurological deficits recovery and alleviate WMI, which could be a promising therapeutic strategy to improve ICH prognosis.

neuroscience↗

bioRxiv2025

Wounding activates the HSFA1 transcription factors to promote cellular reprogramming in Arabidopsis

Mechanical injury is a primary trigger for cellular reprogramming during organ regeneration, yet the molecular mechanisms that link wounding to reprogramming remain poorly understood. In this study we identify the Arabidopsis HEAT SHOCK FACTOR A1 (HSFA1) class of transcription factors, being key regulators of the heat stress response, as central players in wound-induced callus formation and shoot regeneration. Loss of HSFA1 function in the hsfa1abd triple mutants severely impairs cellular reprogramming, reducing callus formation from wounded hypocotyls, as well as shoot regeneration from explants. Conversely, overexpression of the HSFA1d gain-of-function variant markedly enhances regeneration. Time-series RNA-seq and ChIP-seq analyses revealed that HSFA1s directly activate the key reprogramming regulators WOUND-INDUCED DEDIFFERENTIATION 1 (WIND1), PLETHORA 3 (PLT3) and ZINC FINGER OF ARABIDOPSIS THALIANA 6 (ZAT6). Furthermore, we demonstrate that HSFA1d activity is attenuated by SIZ1-mediated SUMOylation, linking post-translational modification to the regulation of wound responses. Our findings establish HSFA1s as an early transcriptional hub that integrates wound signals with the activation of a broad gene network that drives cellular reprogramming, thereby providing a mechanistic framework for understanding how stress-responsive transcription factors control regeneration.

plant biology↗

bioRxiv2025

Effect Of Perinatal Perfluorinated Compounds (PFASs) Exposure On Behavior Of SD Rats

Perfluorinated compounds (PFASs) are persistent environmental pollutants recognized for their bioaccumulation and potential neurotoxic effects, particularly in relation to attention deficit hyperactivity disorder (ADHD). This study investigated the effects of perinatal PFAS exposure on Sprague-Dawley (SD) rats, with a focus on behavioral outcomes and dopamine metabolism in the prefrontal cortex (PFC). Pregnant rats were administered PFASs at concentrations of 1 mg/L, 3 mg/L, and 10 mg/L through drinking water during gestation and lactation, with a control group included for comparison. The offspring were subjected to behavioral assessments, including open field, marble burying, and jump tests, to evaluate locomotor activity, attention, and impulsivity. Neurochemical analyses were conducted to measure the expression of tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (DDC), and dopamine receptor D1 (Drd1) in the PFC using Western blotting and quantitative PCR (qPCR). The results indicated that high-dose PFAS exposure (10 mg/L) resulted in hyperactivity, attention deficits, and impulsive behavior (p < 0.05), along with decreased TH and DDC expression and altered Drd1 levels, suggesting disrupted dopamine metabolism. These findings imply that perinatal PFAS exposure leads to behavioral abnormalities and disruptions in dopamine-related processes.

animal behavior and cognition↗

bioRxiv2025

Infectome Analysis of Small Mammals in Southern China Reveals Ecological Associations and Emerging Threats from Diverse Pathogens

Small mammals harbor a diverse array of zoonotic pathogens. To date, however, metagenomic surveys of these species have primarily focused on viral diversity, with limited attention paid to bacteria and eukaryotic pathogens. Additionally, the ecological determinants of pathogen diversity within these mammals have not been systematically examined. Herein, we employed a metatranscriptomics approach to survey the pathogen infectome of 2,408 individual samples, representing lung, liver, and gut tissues from 858 animals collected throughout Guangdong province, China, with a study design that accounted for host species, tissue, season, and geographic location. We identified 76 pathogen species, including 29 RNA viruses, 12 DNA viruses, 5 bacteria, and 30 eukaryotic pathogens, 33 of which were newly discovered. Tissue distribution analysis revealed distinct organotropisms, suggesting varied transmission routes, while host distribution analysis showed that each animal carried an average of one pathogen, with 10 pathogens widely distributed among mammalian orders. Our characterization of the geographic and seasonal patterns revealed that pathogen richness was primarily influenced by region, host species, and season, while pathogen composition was largely shaped by host genetic distance. Collectively, these data provide the first comprehensive insight into the dynamics of the pathogen infectome in these key mammalian disease reservoirs, highlighting the major factors driving pathogen diversity and transmission.

microbiology↗

bioRxiv2024

Targeted protein degradation via CAR endocytosis of antigen in T cells

Targeted protein degradation (TPD) relies on molecules engaging host protein degradation machinery. Here, we developed a novel TPD platform based on antigen endocytosis and degradation by chimeric antigen receptor (CAR) T cells. T cells expressing a CAR with TNFR1 as the antigen-binding domain (TNFR1T) were able to bind, endocytose, and degrade TNF in vitro. To enhance in vivo expansion and persistence of TNFR1T cells, BCOR and ZC3H12A were depleted, generating TNFR1TIF cells. In a human TNF transgenic mouse model of rheumatoid arthritis, a single infusion of TNFR1TIF cells sustainably reduced serum hTNF to near wild-type levels, leading to long-term disease remission. This approach extends CAR T cell targets from cells to extracellular proteins, enabling long-term degradation of inflammatory cytokines and durable remission in chronic inflammatory diseases.

immunology↗

bioRxiv2024

Inhibition of pterygium cell fibrosis by the Rho kinase inhibitor

Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinases inhibitors are a potential post-surgical treatment to prevent pterygium recurrence.

pharmacology and toxicology↗

bioRxiv2024

N-Glycosylation of MRS2 balances aerobic and anaerobic energy production by reducing rapid mitochondrial Mg2+ influx in conditions of high glucose or impaired respiratory chain function

N-linked glycoproteins function in numerous biological processes, modulating enzyme activities as well as protein folding, stability, oligomerization, and trafficking. While N-glycosylation of mitochondrial proteins has been detected by untargeted MS-analyses, the physiological existence and roles of mitochondrial protein N-linked glycosylation remain under debate. Here, we report that MRS2, a mitochondrial inner membrane protein that functions as the high flux magnesium transporter, is N-glycosylated to various extents depending on cellular bioenergetic status. Both N-glycosylated and unglycosylated isoforms were consistently detected in mitochondria isolated from mouse liver, rat and mouse liver fibroblast cells (BRL 3A and AFT024, respectively) as well as human skin fibroblast cells. Immunoblotting of MRS2 showed it was bound to, and required stringent elution conditions to remove from, lectin affinity columns with covalently bound concanavalin A or Lens culinaris agglutinin. Following peptide:N-glycosidase F (PNGase F) digestion of the stringently eluted proteins, the higher Mr MRS2 bands gel-shifted to lower Mr and loss of lectin affinity was seen. BRL 3A cells treated with two different N-linked glycosylation inhibitors, tunicamycin or 6-diazo-5-oxo-L-norleucine, resulted in decreased intensity or loss of the higher Mr MRS2 isoform. To investigate the possible functional role of MRS2 N- glycosylation, we measured rapid Mg2+ influx capacity in intact mitochondria isolated from BRL 3A cells in control media or following treatment with tunicamycin or 6-diazo-5-oxo-L-norleucine. Interestingly, rapid Mg2+ influx capacity increased in mitochondria isolated from BRL 3A cells treated with either N-glycosylation inhibitor. Forcing reliance on mitochondrial respiration by treatment with either galactose media or the glycolytic inhibitor 2-deoxyglucose or by minimizing glucose concentration similarly reduced the N-glycosylated isoform of MRS2, with a correlated concomitant increase in rapid Mg2+ influx capacity. Conversely, inhibiting mitochondrial energy production in BRL 3A cells with either rotenone or oligomycin resulted in an increased fraction of N-glycosylated MRS2, with decreased rapid Mg2+ influx capacity. Collectively, these data provide strong evidence that MRS2 N-glycosylation is directly involved in the regulation of mitochondrial matrix Mg2+, dynamically communicating relative cellular nutrient status and bioenergetic capacity by serving as a physiologic brake on the influx of mitochondrial matrix Mg2+ under conditions of glucose excess or mitochondrial bioenergetic impairment.

biochemistry↗

bioRxiv2024

Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes

Mitotic centrosomes form when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, yet it can assemble and disassemble within minutes, leading to much debate about its physical nature. Here we show that Drosophila Spd-2 fluxes out from centrioles, recruiting Polo and Aurora A to catalyse the assembly of a solid-like Cnn-scaffold and a more liquid-like TACC-scaffold, respectively. Both scaffolds can assemble and recruit PCM proteins independently, but both are required for proper centrosome assembly, with the Cnn-scaffold providing mechanical strength, and the TACC-scaffold locally concentrating centriole and centrosome proteins. Recruiting Spd-2, but not Cnn or TACC, to the surface of synthetic beads injected into early embryos reconstitutes several aspects of mitotic centrosome assembly on the bead surface, and this depends on the ability of Spd-2 to recruit Polo and AurA. Thus, Spd-2 molecules flux out from the centriole recruiting Polo and AurA to promote the assembly of two scaffolds with distinct properties to support mitotic centrosome assembly in flies.

cell biology↗

bioRxiv2024

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Single-stranded DNA gaps are postulated to be fundamental to the mechanism of anti-cancer drugs. Gaining insights into their induction could therefore be pivotal for advancing therapeutic strategies. For poly (ADP-ribose) polymerase inhibitors (PARPi) to be effective, the presence of FANCJ helicase is required. However, the relationship between FANCJ dependent gaps and PARP1 catalytic inhibition or trapping--both linked to PARPi toxicity in BRCA deficient cells--is yet to be elucidated. Here, we find that the efficacy of PARPi is contingent on S-phase PARP1 activity, which is compromised in FANCJ deficient cells because PARP1, along with MSH2, is "sequestered" by G-quadruplexes. PARP1s replication activity is also diminished in cells missing a FANCJ-MLH1 interaction, but in such cells, depleting MSH2 can release sequestered PARP1, restoring PARPi-induced gaps and sensitivity. Our observations indicate that sequestered and trapped PARP1 are different chromatin-bound forms, with FANCJ loss increasing PARPi resistance in cells susceptible to canonical PARP1 trapping. However, in BRCA1 null cells, the loss of FANCJ mirrors the effects of PARP1 loss or inhibition, with the common detrimental factor being the loss of PARP1 activity during DNA replication, not trapping. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA deficient cells and emphasize the importance of understanding drug mechanisms for enhancing precision medicine.

molecular biology↗

bioRxiv2023

One infusion of engineered long-lasting and multifunctional T cells cures asthma in mice

The majority of common chronic human diseases are incurable, which affect a large portion of population and require life-long treatments that impose huge disease, economic and social burden. For example, asthma is the most common respiratory disease affecting over 300 million people and accounts for > 250,000 death annually, for which there is no cure. Unlike traditional therapyies, engineered T cells, such as chimeric antigen receptor CAR T (CAR-T) cells, function as living drugs and can cure some hematological malignancies, but whether engineered T cells can cure common diseases beyond cancer remains elusive. Here, we develop a curative therapy for asthma based on enginerred T cell. With IL-5 as the targeting domain and depletion of BCOR and ZC3H12A, we produce long-lasting CAR-T cells eradicating IL-5R+ eosinophils, termed Immortal-like and Functional IL-5 CAR-T cells (5TIF) cells. We further enginerred 5TIF cells to secrete an IL-4 mutein that blocks the singaling of both IL-4 and IL-13, two driver inflammatory cytokines in asthma, named as 5TIF4 cells. In multiple models of asthma, one infusion of 5TIF4 cells in fully immunocompetent mice, in the absence of any conditioning regimen, confers long-term depletion of pathological eosinophils and blockade of IL-4/IL-13 actions, resulting in sustained repression of type 2 inflammation and asthmatic symptoms. Furthurmore, 5TIF4 cells can also be induced in human T cells in NSG mice. Our data demonstrate that asthma, a common noncancerous disease, can be cured by a single infusion of engineered long-lasting and multifunctional T cells, which paves the way for curing common chronic diseases by engineered long-lived T cells.

immunology↗