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Schmidt, E.

Publications and source records attributed to Schmidt, E..

At least 19 recordsLinked to original sources

WrapEvoFS enables auditable feature compression with regret-constrained representative locking

WrapEvoFS provides a deterministic, auditable rule for choosing one feature set from repeated stochastic searches. It retains candidates within a prespecified development-score gap, selects the most representative set by feature overlap, and records the decision before held-out evaluation. A corrected genetic objective preserves score ordering lost through zero truncation. In a fully nested four-class cancer analysis, all 30 locked signatures met the 0.01 tolerance, and 11 differed from the highest-scoring candidate; every changed selection increased mean feature overlap within the eligible pool. Paired differences in area under the receiver operating characteristic curve against recursive feature elimination with cross-validation all had 95% intervals crossing zero. No selector dominated matched comparisons on feature count and predictive performance, and one-time evaluation of frozen signatures at held-out centers yielded heterogeneous effects. WrapEvoFS standardizes selection within a fixed candidate bank under an empirical score-gap constraint, enabling reproducible reporting of performance, compression, and feature-agreement trade-offs without implying predictive superiority or stability under changes in participant composition.

bioinformatics↗

Light-independent and pulsing-sensitive magnetic compass responses in planarians

Many animals can sense the Earth's magnetic field and use it for orientation. However, the mechanism underlying magnetoreception has not been identified, partially due to the lack of reproducible and genetically tractable model systems. Here, we establish a directional assay for planaria to test their responses to different magnetic fields. Girardia dorotocephala showed a preferred magnetic directionality in the horizontal plane in an Earth-strength magnetic field in the absence of visible light, which shifted if the azimuth was rotated and was absent when the magnetic field was cancelled. This directional preference differed between labs. Furthermore, the directional response was affected by a short but strong magnetic pulse, resulting in a random distribution. The effect of the pulse was temporary, with directional preferences recovering over several days. Taken together, these data are consistent with a magnetoreception mechanism in planarians that functions independently of light and relies on permanently magnetised material, such as single-domain magnetite. As planarians are genetically tractable and well-established, they are a promising invertebrate model organism that might offer insights into the mechanisms underlying magnetoreception in animals.

animal behavior and cognition↗

Phylogenetic Diversity and Venom Gland Transcriptomics of Palauan Cone Snails (Conidae)

Cone snails (genus Conus Linnaeus, 1758) represent one of the most species-rich lineages of venomous marine snails, producing diverse and highly specialized toxins. While Conus diversity is particularly high in the Indo-Pacific, some regions, such as the archipelago of Palau, remain poorly studied. Here, we combine mitochondrial marker gene sequencing (COI, 12S, and 16S) and venom-gland transcriptomics to investigate the phylogenetic relationships and venom gene diversity of Palauan Conus species. We sampled 27 species, recovering mitochondrial sequences for 34-41 individuals per gene. Maximum-likelihood phylogenetic analysis revealed that most individuals group with known species, although several lineages show notable divergence from reference sequences. We additionally sequenced venom gland transcriptomes from 21 individuals representing 14 species, including three species for which no previous venom data exist. Comparative analysis showed largely consistent expression patterns at the superfamily level within species collected from different biogeographical regions, supporting conserved venom gene expression profiles. These results contribute foundational data for future studies of Conus evolution, biogeography, and toxin diversification in an underexplored biodiversity hotspot.

evolutionary biology↗

Gut Microbiota Modulates and Predicts Disease Severity in Experimental Pemphigoid Disease

Pemphigoid diseases (PD) are autoimmune blistering diseases with reported alterations in skin and gut microbiota, though their causal contribution to disease pathophysiology remains unclear. Using a passive model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA), we compared C57BL/6J mice from two sources (in-house vs. Charles River) that differed in their baseline microbiota. Charles River mice developed significantly less severe disease. Co-housing led to partial homogenization of the gut microbiota, driven by asymmetric transfer of taxa from Charles River to in-house mice, which corresponded with reduced disease severity in the latter. The skin microbiota, however, showed limited exchange. Disease severity was inversely associated with gut microbial alpha diversity, with protective taxa such as Lactobacillus intestinalis and Parabacteroides distasonis enriched in Charles River mice, while pro-inflammatory taxa including Turicimonas muris and Muribaculum intestinale were enriched in in-house mice. A machine learning model further identified a gut taxon most closely matching the candidate genus Scatocola as a strong negative predictor of disease severity. Through experimental exposure and uptake of variable gut microbiota, these findings suggest a direct role of gut microbiota in mediating the severity of the experimental BP-like EBA and highlight the potential of microbiota-based strategies for therapeutic intervention in PD.

microbiology↗

Long-Term Potentiation and Closed-Loop Learning in Paired Brain Organoids for CNS Drug Discovery

Learning and memory, central to cognitive function and critical targets for drug discovery in neurological disorders, fundamentally rely on synaptic plasticity, such as long-term potentiation (LTP). We developed an embedded electrode array (EEA) capable of supporting paired CNS-3D brain organoids, derived from human, induced pluripotent stem cells (iPSCs), that were interconnected via guided axonal growth, as a novel functional biomarker model for probing learning-related plasticity in vitro. Using open-loop stimulation protocols, a robust, network-level LTP in trained organoids was demonstrated that was not observed in untrained organoids. Importantly, LTP was enhanced in the presence of elevated levels of brain-derived neurotrophic factor (BDNF), and it was prevented by the NMDA receptor antagonist AP5. Furthermore, a closed-loop "maze-game", inspired by Pac-Man(R), demonstrated that paired brain organoids could learn to perform better in the game when given reinforcement feedback, and that this effect depended on BDNF. This integrated platform provides a human-relevant in vitro model of synaptic plasticity and cognitive function, establishing a functional biomarker platform for central nervous system (CNS) drug discovery and linking game performance as a measurable readout of learning-related plasticity to the emerging field of organoid intelligence.

bioengineering↗

Human Peripheral Nerve-on-a-Chip on a Multiwell Microelectrode Array as a Scalable Preclinical Neurotoxicity Assay

Reliable human-relevant models of peripheral nerve function remain a critical unmet need in preclinical drug development, particularly for predicting neurotoxicity and bridging the gap to clinical translation. Here, we introduce a next generation Nerve-on-a-Chip, PNS-3D organoids, as a novel human-cell-based 3D peripheral nerve microphysiological system (MPS) that recapitulates key functional and structural features of native nerves, including long-distance axonal outgrowth, physiological myelination, and clinically translational population level electrophysiology. The platform integrates iPSC-derived human sensory neurons and primary human Schwann cells within a spatially organized 3D environment, coupled to a custom embedded electrode array that enables high-content, longitudinal, and clinically translatable functional assessments. As a proof of concept, we evaluated the platforms predictive power using vincristine, a chemotherapeutic agent known to cause chemotherapy-induced peripheral neuropathy (CIPN). PNS-3D organoids captured dose- and time-dependent deficits in nerve conduction velocity, compound action potential amplitude, and axonal degeneration, with IC values in line with human clinical exposures-- outperforming traditional 2D cultures and in vivo benchmarks. Transcriptomic and morphological analyses further revealed neuron-specific degeneration consistent with axonopathy. These results validate the platform as a human-relevant, clinically translation, and scalable solution, enabling mechanistic safety assessment and drug discovery for neurotoxic and neuroprotective therapeutics.

pharmacology and toxicology↗

SERPINB5-TGF-β signalling modulates desmoplakin membrane localization and ameliorates pemphigus vulgaris skin blistering

Impairment of desmosomal cell-cell adhesion leads to several life-threatening diseases such as the autoimmune skin blistering disorder pemphigus vulgaris (PV). Disease management strategies that stabilize intercellular adhesion, in addition to the existing immunosuppression therapies, may result in improved clinical outcomes. Previous findings showed that the serine protease inhibitor SERPINB5 promotes intercellular adhesion by binding to and regulating the localization of the desmosomal adapter molecule desmoplakin (DSP) at the plasma membrane. We here show that SERPINB5 overexpression prevents PV-IgG-mediated loss of cell-cell adhesion and the loss of DSP from the cell membrane. We mechanistically demonstrate that SERPINB5 loss deregulates TGF-{beta} signalling, a pathway known to destabilize DSP in keratinocytes. TGF-{beta} signalling was also activated in skin biopsies of PV patients and keratinocytes treated with PV autoantibodies, suggesting a contribution to disease. Inhibition of TGF-{beta} activation ameliorated PV-IgG-mediated loss of cell-cell adhesion, increased DSP membrane expression, and prevented PV-IgG-induced blister formation in a human ex-vivo skin model. Together, SERPINB5 modulates DSP and intercellular adhesion through the regulation of TGF-{beta} signalling. Further, TGF-{beta} signalling was identified as a potential target for pemphigus treatment.

cell biology↗

IgG autoantibodies in bullous pemphigoid directly induce a pathogenic MyD88-dependent pro-inflammatory response in keratinocytes:

AbstractWhile autoantibodies in bullous pemphigoid (BP) are known to activate the innate immune response, their direct effect on keratinocytes, and the contribution of BP-IgG autoantibody-dependent keratinocyte responses to BP pathology is largely unknown. Herein, we performed multiplex immunoassays and bulk RNA-seq on primary keratinocytes treated with IgG from BP patients or controls. We identified a pro-inflammatory and proteolytic response with release of several cytokines (IL-6, IL-24, TGF-{beta}1), chemokines (CXCL16, CTACK, MIP-3{beta}, RANTES), C1s, DPP4, and MMP-9. We further validated this response using spatial transcriptomics and scRNA-seq of diseased and control skin. Blistering itself appeared to be major driver of this inflammatory response, with attached BP skin and spongiotic dermatitis revealing highly similar transcriptomes. Based on elevated levels of MyD88 and MyD88-dependent cytokines, we studied the impact of MyD88 deficiency in keratinocytes and demonstrated that MyD88 regulates BP-IgG-induced expression of IL-8, IL-24, and MMP-9. Induction of experimental BP in mice with Krt14-specific Myd88 knockout revealed significantly decreased disease severity with decreased serum levels of IL-1{beta}, IL-4, and IL-9 indicating the contributory role of keratinocyte-derived skin inflammation towards systemic response. Our work demonstrates the key contributions of keratinocyte and MyD88 dependent signaling in response to autoantibodies in BP. Key Messages-IgG antibodies from bullous pemphigoid (BP) patients induce significant upregulation of several inflammatory markers in keratinocytes including cytokines (IL-6, IL-24, TGF-{beta}1), chemokines (CXCL16, CTACK, MIP-3{beta}, RANTES), C1s, DPP4, and MMP9. Several of these markers, including IL-8, IL-24, and MMP9 are regulated by MyD88. -Spatial transcriptomics reveals that BP patient blistered skin demonstrated similar transcriptomic profiles to BP-IgG-treated keratinocytes. With attached skin demonstrating a comparable transcriptome to that seen in spongiotic dermatitis. -In a mouse BP model, keratinocyte-specific MyD88 deficiency results in decreased disease severity with a subsequent decrease in serum IL-1{beta}, IL-4, and IL-9 levels. Capsule summaryIgG from patients with bullous pemphigoid (BP) induces a pro-inflammatory response in keratinocytes, indicating their direct role in driving the inflammatory response in BP.

immunology↗

Pseudomonas aeruginosa faces a fitness trade-off between mucosal colonization and antibiotic tolerance during airway infections

Pseudomonas aeruginosa causes antibiotic-resilient acute and chronic pneumonia, but the mechanisms by which it adapts to the airway environment are poorly understood. Here, we investigated P. aeruginosa pathoadaptive mechanisms in tissue-engineered human airway organoids. Using transposon sequencing in situ, we decoded how P. aeruginosa survives on the mucosal surface during antibiotic treatment. Biofilm formation emerged as a major driver of P. aeruginosa colonization. Mutants that extensively produce biofilms on mucus show limited exploratory behavior, which limits nutrient access, slowing down their growth. Conversely, biofilm-dwelling P. aeruginosa better tolerate antibiotics via biophysical mechanisms. Finally, biofilms can shelter less-tolerant but more cytotoxic strains, thereby contributing to genotypic heterogeneity. P. aeruginosa must therefore adapt to conflicting physical and biological selective pressures to initiate chronic infections.

microbiology↗

A Unified Atlas of T cell Glycophysiology

Glycans are emerging as important regulators of T cell function but remain poorly characterized across the functionally distinct populations that exist in vivo. Here, we couple single-cell analysis technologies with soluble lectins and chemical probes to interrogate glycosylation patterns on major T cell populations across multiple mouse and human tissues. Our analysis focused on terminal glycan epitopes with immunomodulatory functions, including sialoglycan ligands for Siglecs. We demonstrate that glycosylation patterns are diverse across the resting murine T cell repertoire and dynamically remodelled in response to antigen-specific stimulation. Surprisingly, we find that human T cell populations do not share the same glycoprofiles or glycan remodelling dynamics as their murine counterparts. We show that these differences can be explained by divergent regulation of glycan biosynthesis pathways between the species. These results highlight fundamental glycophysiological differences between mouse and human T cells and reveal features that are critical to consider for glycan-targeted therapies.

immunology↗

Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer

Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of "precarious balance", due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.

cancer biology↗

The structure of full-length AFPK supports the ACP linker in a role that regulates iterative polyketide and fatty acid assembly

We present the full structures of two animal fatty acid synthase (FAS)-like polyketide synthases (AFPKs), PKS1 and PKS2 from Elysia chlorotica. Unlike the related FAS enzymes that use malonate to produce reduced lipids, EcPKS1 and EcPKS2 accept methylmalonyl-CoA to produce oxidized polypropionate products. When incubated with inhibitory malonyl-CoA (MC), the resulting EcPKS2(MC) structure revealed MC bound to the acyltransferase active site and the phosphopantetheinylated acyl carrier protein (ACP-pPant) bound to the ketosynthase (KS) active site. Remarkably, the entire linker from one modifying region to the ACP was visible in full-length EcPKS2(MC), revealing an asymmetric mega-enzyme structure. Mutations disrupting the affinity between the ACP linker and modifying domains altered substrate selectivity and active site selection, despite an expectation that the interactions are transient and that the wild-type linker alternates between the observed ordered and disordered conformations during the competing catalytic cycles of the homodimeric protein. A second structure, EcPKS2(AC), was acylated both on the KS catalytic cysteine and on the ACP-pPant. The ACP was docked at the dehydratase site, revealing further interactions between ACP and these FAS-like enzymes. The results suggest an unexpected role for the ACP linker in the control of substrate and product selectivity across the AFPK/FAS clade in animals and highlight ACP interfaces and mega-enzyme dynamics over the course of the catalytic cycle.

biochemistry↗

Structural basis of dual BACH1 regulation by SCFFBXO22 and SCFFBXL17

BTB and CNC homolog 1 (BACH1) is a master transcriptional regulator of the cellular oxidative stress response and pro-metastatic oncogene. Post-translational stability of BACH1 is tightly regulated by distinct F-box ubiquitin ligases, including SCFFBXO22 and SCFFBXL17. However, the molecular details have been elusive. Here, we reveal a structural switch in FBXO22 that controls the recognition of a three-dimensional degron in the BACH1 BTB domain, thus explaining its specificity for dimeric BACH1. We describe how cancer-associated mutations in FBXO22 modulate binding and ubiquitylation of BACH1. Further, we reveal that cancer-related mutations or cysteine-modifications destabilize the BTB domain and redirect BACH1 to FBXL17, where it is recognized as a monomer. This explains how complementary ligases post-translationally regulate BACH1 depending on the state of its BTB domain. Our findings provide mechanistic insights into the regulation of the oxidative stress response and may spur therapeutic strategies to targeting oxidative stress-related disorders and metastatic cancers.

biophysics↗

A human-specific enhancer fine-tunes radial glia potency and corticogenesis

Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications1-3. Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to human-specific cortical development is largely unknown4,5. HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development6. Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices containing more neurons. By measuring neural dynamics in vivo we show these anatomical features correlate with increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using live imaging, lineage analysis, and single-cell RNA sequencing. This reveals Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

neuroscience↗

Multivalent DNA-encoded lectins on phage enable detecting compositional glycocalyx differences

Selective detection of disease-associated changes in the cellular glycocalyx is a foundation of modern targeted therapies. Detecting minor changes in the density and identity of glycans on the cell surface is a technological challenge exacerbated by lack of 1:1 correspondence between cellular DNA/RNA and glycan structures on cell surface. We demonstrate that multivalent displays of up to 300 lectins on DNA-barcoded M13 phage on a liquid lectin array (LiLA), detects subtle differences in composition and density of glycans on cells ex vivo and in immune cells or organs in animals. For example, constructs displaying 73 copies of diCBM40 lectin per 700x5 nm virion ({varphi}-CBM73) exhibit non-linear ON/OFF-like recognition of sialoglycans on the surface of normal and cancer cells. In contrast, a high-valency {varphi}-CBM290 display, or soluble diCBM40, exhibit canonical progressive scaling in binding with increased epitope density; these constructs cannot amplify the subtle differences detected by {varphi}-CBM73. Similarly, multivalent displays of diCBM40 and Siglec-7 detect differences in the glycocalyx between stem-like and non-stem populations in cancer cells that are not detected with soluble lectins. Multivalent display of lectins on M13 scaffold with protected DNA inside the phage offer non-destructive detection of minor differences in glycocalyx in cells in vitro and in vivo not feasible to currently available technologies.

biochemistry↗

Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection through aging

Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here, we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mt-genome in different tissues throughout aging. We used ultra-sensitive Duplex Sequencing to profile [~]2.5 million mt-genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloging [~]1.2 million mitochondrial somatic and ultra low frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the Light Strand Origin of Replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared to primates with a surfeit of reactive oxygen species-associated G>T/C>A mutations, and that somatic mutations in protein coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that "re-align" mito-nuclear ancestry within an organisms lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.

genomics↗

Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function.

Promoting brown adipose tissue (BAT) activity has been recognized as innovative therapeutic approach to improve obesity and metabolic disease. Whilst the molecular circuitry underlying thermogenic activation of BAT is well understood, the processes underlying rheostatic regulation of BAT to maintain homeostasis and avoid excessive energy dissipation remain ill-defined. Increasing cyclic AMP (cAMP) biosynthesis is key for BAT activation. Here, we demonstrate that ADCY3, an adenylyl cyclase whose expression is induced during cold exposure and regulates cAMP homeostasis in thermogenic fat, is dispensable for BAT function in lean mice, but becomes critical during obesity. Furthermore, by combining RNA-seq with epigenomic H3K4me3 profiling, we detected a novel, cold-inducible promoter that generates a 5 truncated Adcy3-at mRNA isoform, Adcy3-at. Mice lacking only Adcy3-at, but not full-length Adcy3, displayed increased energy expenditure already under lean conditions and were protected against obesity and ensuing metabolic imbalances. Subcellularly, translated ADCY3-AT proteins are retained in the endoplasmic reticulum (ER), did not translocate to the cell membrane, and lacked enzymatic activity. By interacting with ADCY3, ADCY3-AT retained ADCY3 in the ER and, thereby, reduced the plasma membrane pool of ADCYs available for G-protein mediated cAMP synthesis. Thereby, ADCY3-AT acts as a signaling rheostat in BAT, limiting adverse consequences of uncurbed cAMP activity after long-term BAT activation. Adcy3-at induction was driven by a cold-induced, truncated isoform of the transcriptional cofactor PPARGC1A (PPARG Coactivator 1 Alpha, PPARGC1A-AT). Expression of Ppargc1a-at and Adcy3-at are evolutionary conserved, indicating that transcriptional rewiring by commissioning of alternative promoters is key for thermogenic fat function.

cell biology↗

Apremilast prevents blistering in human epidermis by stabilization of keratinocyte adhesion in pemphigus.

Pemphigus vulgaris (PV) is a life-threatening blistering skin disease caused by autoantibodies (PV-IgG) destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used e.g. in psoriasis, prevents blistering in PV. Apremilast abrogated PV-IgG-induced loss of keratinocyte cohesion in ex-vivo epidermis and in vitro. This was paralleled by inhibition of keratin retraction and desmosome splitting but affected neither desmoglein (Dsg) depletion nor Dsg3 binding properties. Apremilast induced phosphorylation of plakoglobin at serine 665 - a mechanisms which is known to stabilize cardiomyocyte cohesion. Interestingly, keratinocytes phospho-deficient at this side showed altered organization of Dsg1, Dsg3 and keratin filaments and impaired adhesion, which was not rescued by apremilast. These data identified a new mechanism of desmosome regulation and propose that apremilast is protective in pemphigus by stabilizing keratinocyte cohesion.

cell biology↗