Biology subjects

Kuhn, C.

Publications and source records attributed to Kuhn, C..

5 recordsLinked to original sources

bioRxiv2026

Characterization of the upper epithelial compartment of cervical HSIL

High-grade squamous intraepithelial lesions (HSIL) of the uterine cervix result from transformation by high-risk human papillomavirus (HR-HPV) and are considered precancerous lesions. Depending on the proportion of the epithelium occupied by dysplastic cells, commonly evidenced by a block-like p16INK4a staining pattern, HSIL are subdivided into CIN2 or CIN3. We used immunohistochemistry (IHC) and laser-capture microdissection (LCM) to further characterize these lesions. Broad suprabasal expression of S100A9, a component of the epidermal differentiation complex (EDC), which we had previously found to be up-regulated in genus-beta-HPV-positive skin lesions, was present in the normal exocervix and declined gradually with increasing CIN grade. In CIN2 in particular, the S100A9 staining pattern was nearly complementary to the block-like p16INK4a expression. However, it largely coincided with the expression of CD63, a marker showing strong expression in cervical crypts and in columnar cells within the normal transformation zone, also those overlying reserve cells. We then used LCM to analyze both the p16INK4a- and S100A9/CD63-positive compartments in HSIL separately. Notably, in all samples investigated, we detected the same HR-HPV type (either HPV16, 45 or 51) in both compartments of the same HSIL, while tissue samples dissected from normal exocervix or transformation zone were consistently HR-HPV-negative. Our data suggest that the upper, S100A9-positive maturing compartment of HSILs retaining weak CD63 expression may represent a residual, HR-HPV-infected columnar-cell-derived epithelium, rather than not-yet-transformed squamous epithelium that is progressively being replaced by dysplastic cells. The two-compartment architecture of these HSILs was reminiscent of the staining pattern in the normal transformation zone, where columnar cells overlie reserve cells, and compatible with HR-HPV infection of columnar-derived cells but transformation of reserve cells, the putative origin of cervical squamous cell carcinoma. Our findings have direct clinical implications. Since the upper and lower layers of HSIL appear to form distinct epithelial compartments, our study suggests that the extent and thickness of the HR-HPV-transformed lower compartment itself, rather than the proportion of the epithelium occupied by dysplastic layers, may be the decisive factor in determining the HSIL grade.

Cancer Biology↗

bioRxiv2026

FYCO1 improves postischemic cardiac remodeling via enhanced autophagic flux and attenuation of proinflammatory signaling

Acute myocardial infarction (MI) is associated with severe metabolic and oxidative stress that triggers cardiomyocyte death, pro-inflammatory signaling and progressive structural remodeling frequently culminating in heart failure. Although significant advances in reperfusion therapy improved acute survival in patients, therapeutic strategies that directly target intracellular processes in response to injury remain limited. One key response mechanism, autophagy, is rapidly activated to ameliorate ischemic stress. Yet, defective autophagic flux may exacerbate cardiomyocyte injury and maladaptive tissue remodeling. Here we identify FYCO1 as a cardiomyocyte-enriched key regulator of autophagy that enhances autophagic flux and promotes myocardial resilience following ischemic injury. Using cardiomyocyte-specific FYCO1 transgenic mice subjected to permanent coronary ligation, we demonstrate that FYCO1 overexpression limits infarct expansion, reduces cardiomyocyte injury, and preserves cardiac function during remodeling. In vivo RFP-EGFP-LC3 autophagy reporter analyses reveal that FYCO1 promotes a sustained increase of autophagic flux by coordinating autophagosome formation and efficient autolysosomal clearance. Transcriptomic profiling identifies a cardioprotective gene program in FYCO1-Tg animals subjected to MI, with suppression of proinflammatory, proapoptotic and stress-response pathways. Systemic serum cytokine and chemokine profiling as well as transcriptomic analyses of myocardium confirm reduced inflammatory signaling and subsequent reduction in macrophage recruitment into the infarct border zone. Together these findings position FYCO1 as a key regulator of cardiomyocyte autophagy and reveal a previously unrecognized link between autophagy and inflammation in shaping cardiac remodeling following myocardial infarction. FYCO1-mediated autophagy promotes myocardial preservation and functional recovery, highlighting autophagic flux as a promising target for cardioprotective interventions.

molecular biology↗

bioRxiv2024

Empowering bioinformatics communities with Nextflow and nf-core

Standardised analysis pipelines are an important part of FAIR bioinformatics research. Over the last decade, there has been a notable shift from point-and-click pipeline solutions such as Galaxy towards command-line solutions such as Nextflow and Snakemake. We report on recent developments in the nf-core and Nextflow frameworks that have led to widespread adoption across many scientific communities. We describe how adopting nf-core standards enables faster development, improved interoperability, and collaboration with the >8,000 members of the nf-core community. The recent development of Nextflow Domain-Specific Language 2 (DSL2) allows pipeline components to be shared and combined across projects. The nf-core community has harnessed this with a library of modules and subworkflows that can be integrated into any Nextflow pipeline, enabling research communities to progressively transition to nf-core best practices. We present a case study of nf-core adoption by six European research consortia, grouped under the EuroFAANG umbrella and dedicated to farmed animal genomics. We believe that the process outlined in this report can inspire many large consortia to seek harmonisation of their data analysis procedures.

bioinformatics↗

bioRxiv2022

Rapastinel Accelerates Loss of Withdrawal Signs after Repeated Morphine and Blunts Relapse to Conditioned Place Preference

The purpose of the present study was to evaluate the efficacy of rapastinel, an allosteric modulator of NMDA receptor function, to accelerate the loss of opioid withdrawal symptoms and blunt or prevent relapse to morphine conditioned place preference (CPP) in rats. Two studies were conducted. In study 1, adult and adolescent male and female rats were treated with increasing doses of morphine (5 mg/kg, bid to 25 mg/kg bid) for 5 days. On day 6 animals were treated with naloxone (1 mg/kg) and withdrawal was assessed. They were then treated with saline or rapastinel (5 mg/kg) on days 6 and 8, and withdrawal assessed on day 9. Rapastinel treated animals exhibited significantly lower levels of withdrawal signs on day 9. No sex or age differences were observed. In Study 2, CPP for morphine was established in adult rats (males and females) by 4 daily pairings with saline and morphine (am/pm alternation). They were tested for CPP on day 5, and then treated with rapastinel (5 mg/kg) or saline daily on days 6-10 of extinction. On day 11 they received a final dose of rapastinel or saline followed by extinction. On day 12, animals received 1 mg/kg of morphine and were tested for relapse. Rapastinel did not affect extinction of CPP, but rapastinel-treated animals spent significantly less time in the previously morphine-paired side than saline-treated animals during the relapse trial. These findings of accelerated loss of withdrawal signs and blunted relapse to CPP suggest that rapastinel could provide an adjunctive therapy for opioid dependence during initiation of pharmacotherapy for opioid dependence.

pharmacology and toxicology↗

bioRxiv2021

The central nucleus of the amygdala and gustatory cortex assess affective valence during CTA learning and expression in male and female rats

This study evaluated behavior (Boost(R) intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), task performance) and c-Fos activation during conditioned taste aversion (CTA), the reinforced task (Boost(R) task) and control task (cage only) to understand how male and female rats balance the relative danger or safety of a stimulus in learning and performing a task. Females drank more Boost(R) than males but showed similar aversive behaviors after LiCl treatment. Males produced 55 kHz USVs (indicating positive valence) when anticipating Boost(R) and inhibited these calls after pairing with LiCl. Females produced 55 kHz USVs based on their estrous cycle but were more likely to make 22 kHz USVs than males (indicating negative valence) after pairing with LiCl. c-Fos responses were similar in males and females after Boost(R) or LiCl. Females engaged the gustatory cortex and ventral tegmental area more than males during the Boost(R) task and males engaged the amygdala more than females in both the reinforcing and devalued tasks. Network analysis of correlated c-Fos responses across brain regions identified two unique networks characterizing the Boost(R) and LiCl (CTA) tasks, in both of which the VTA played a central role. RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost(R) and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.

animal behavior and cognition↗