Biology subjects

Perl, M.

Publications and source records attributed to Perl, M..

5 recordsLinked to original sources

bioRxiv2026

Tuning the mechanical properties of polymer-based surrogate materials for articular cartilage and vocal fold repair

The macroscopic biomechanical characteristics of soft and ultrasoft tissues, such as articular cartilage and vocal folds, significantly determine their physiological function. Treatments of widespread tissue degradations due to osteoarthritis in the knee or vocal fold impairment remain an unresolved challenge. For the design of implants for tissue repair after injury or disease, it is key to thoroughly understand the unique biomechanical properties of native tissues and potential substitute materials. We use multimodal mechanical testing methods combined with hyperelastic nonlinear continuum mechanics modeling, and finite element simulations to determine the macroscopic behavior of surrogate materials for human articular cartilage in the knee and human vocal folds. Our cyclic loading experiments reveal qualitative similarities for both tissues and their surrogates, including a nonlinear stress-strain behavior, hysteresis, and conditioning. We demonstrate the tunability of biomimetic and biosimilar stiffnesses of synthetic articular cartilage and vocal fold surrogates through tissue-specific process-material combinations. Our results demonstrate the feasibility of synthetic metamaterials in replicating essential passive biomechanical functions with great potential for future treatment options.

bioengineering↗

bioRxiv2026

Targeting ZC3H12C improves T cell persistence and antitumor function in adoptive T cell therapy

Adoptive T cell therapy (ACT) has achieved remarkable clinical responses in hematologic malignancies but remains limited by progressive T cell dysfunction under chronic antigen stimulation. Here, we identify ZC3H12C as a conserved feature of dysfunctional T cells and show that its disruption enhances the durability and antitumor activity of engineered T cells. By integrating single-cell chromatin accessibility and transcriptomic profiling of human tumor-infiltrating lymphocytes (TILs), we identified the ZC3H12C locus as selectively remodeled in exhausted T cells. ZC3H12C induction is largely absent across acute T cell activation contexts, indicating regulation that is specific to chronic antigen-driven dysfunction. Genetic disruption of ZC3H12C improves T cell expansion, cytotoxicity, and expression of effector molecules during repeated in vitro stimulation, translating into enhanced tumor control in vivo across both T cell receptor (TCR) and chimeric antigen receptor (CAR) T cell therapy platforms. Improved efficacy is observed in hematologic, solid, and metastatic tumor models and is accompanied by increased T cell persistence. Further, ZC3H12C is enriched in clinical pre-infusion CAR T cell products associated with non-response. Together, these findings identify ZC3H12C as a T cell dysfunction-specific target to improve ACT performance.

immunology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2025

Impact of mating strategies on life-history traits in the alien land snail Rumina decollata

AO_SCPLOWBSTRACTC_SCPLOWClimate change and global transport are driving species introductions worldwide, leading to economic and ecological consequences. Hermaphroditic organisms are able to reproduce with any conspecific, and some can self-fertilize, enhancing their potential for population establishment despite low initial densities in colonization events. This study examines how mating strategies influence the life history traits of the alien land snail Rumina decollata by comparing individuals subjected to facultative cross-fertilization or enforced self-fertilization over two laboratory-reared generations. Key life history traits--including size and age at first reproduction, fecundity, hatching time, and juvenile survival--were measured, alongside individual growth and shell morphometry. Self-fertilizing individuals exhibited higher body weight at first clutch but lower fecundity and delayed reproduction compared to cross-fertilizers. Selfing offspring (F2) took longer to hatch and had lower survival rates, indicating significant inbreeding depression. Selfed snails of F1 grew faster than outcrossers, but experienced a decline in growth in F2, consistent with inbreeding depression. Conversely, shell shape remained similar between mating treatments. Although selfing imposed fitness costs, 32% of self-fertilizing individuals produced viable offspring, highlighting their ability to establish in new environments. This study improves our understanding of how R. decollatas reproductive strategies shape life history traits under environmental constraints. SIMPLE SUMMARYSpecies are spreading to new regions due to climate change and global transport, often causing environmental and economic challenges. Hermaphrodite species that can reproduce by cross or self-fertilization can establish populations even when few individuals are present. In our study, we examined how these two reproductive strategies affect a land snails growth, reproduction, and survival. We found that self-fertilizing snails grew larger and heavier but laid fewer eggs and reproduced later than those that mated with others. Additionally, their offspring took longer to hatch and had lower survival rates. These results suggest that self-fertilization comes with costs, likely due to inbreeding depression, but it still allows the species to establish in new environments. Despite lower survival, one-third of the self-fertilizing snails produced viable offspring, showing that this strategy can support population growth when mates are scarce. As this species continues to expand into new areas, our findings help explain how it adapts to different environments. Understanding these reproductive strategies is important for predicting its spread and managing its potential impact on ecosystems.

evolutionary biology↗

bioRxiv2024

Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk

The microbiome is a complex host factor and key determinant of the outcome of antibody-based and cellular immunotherapy. Its postbiotics are a blend of soluble commensal byproducts that are released into the host environment and have been associated with the regulation of immune homeostasis, particularly through impacts on epigenetics and cell signaling. In this study, we show that the postbiotic pentanoate is metabolized to citrate within the TCA cycle via both the acetyl- and succinyl-CoA entry points, a feature uniquely enabled by the chemical structure of the C5 aliphatic chain. We identified ATP-citrate lyase as the crucial factor that redirects pentanoate-derived citrate from the succinyl-CoA route to the nucleus, thereby linking metabolic output and histone acetylation. This epigenetic-metabolic crosstalk mitigated T cell exhaustion and promoted naive-like differentiation in pentanoate-programmed chimeric antigen receptor (CAR) T cells. The predictive and therapeutic potential of pentanoate was corroborated in two independent patient cohorts and three syngeneic models of CAR T adoptive therapy. Our data demonstrate that postbiotics are integrated into mitochondrial metabolism and subsequently incorporated as epigenetic imprints. This bridge between microbial and mammalian interspecies communication can ultimately impact T cell differentiation and efficacy.

immunology↗