Biology subjects

Pap, I.

Publications and source records attributed to Pap, I..

6 recordsLinked to original sources

bioRxiv2026

Glutamine and GLS1 are key metabolic checkpoints that Limit T cell Infiltration and Function in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is characterized by poor survival and limited benefit from immune checkpoint blockade (ICB), underscoring the need to define targetable mechanisms of immune escape. In a prospective, patient-centered study, we investigated how tumor metabolic reprogramming impairs T cell function and drives ICB resistance. Targeted metabolomics identified two dominant and distinct tumor states: the Warburg phenotype and glutamine deprivation and revealed increased tumor-specific glutamine to glutamate turnover. Integrating spatial metabolic imaging with immunohistochemistry linked these states to immune-cold and immune-excluded tumor architectures. Metabolic states selectively reduced the expression of T cell chemokine receptors highly abundant and prognostic in HNSCC. Accordingly, T cell migration into tumor spheroids was reduced at lower glutamine concentrations. Interfering with glutamine metabolism by pharmacologic inhibition or genetic deletion of glutaminase-1 markedly increased tumor susceptibility to immune cell-mediated cytotoxicity in vitro and ex vivo and sensitized patient-derived tumor fragments (PDTFs) to ICB. This effect extended beyond glutamine restoration and involved disruption of glutathione-dependent ROS defense, impaired tumor proliferation, and increased MHC expression in tumor cells. Consistently, high expression of genes involved in glutamine and glutathione metabolism associated with reduced ICB response in patients. In contrast to HNSCC, other tumor entities including breast cancer show low glutaminase-1 expression. Accordingly, breast cancer PDTFs were not responsive to glutaminase-1 inhibition. Together, these data identify glutaminase-1 as a metabolic checkpoint driving immune escape in HNSCC, and support guided patient stratification for metabolism-targeted immunotherapy, similar to current precision approaches for mutation targeted drugs.

cancer biology↗

bioRxiv2025

Structural modelling and dynamics of the full-length Homer1 multimer

Abstract/SummaryHomer proteins are modular scaffold molecules that constitute an integral part of the protein network within the postsynaptic density. Full-length Homer1 forms a large homotetramer via a long coiled coil region, and can interact with proline-rich target sequences with its globular EVH1 domain. Here we report an atomistic model of the full-length Homer1 tetramer along with the NMR solution structure of its EVH1 domain. Compared to the already available EVH1 structures, our NMR ensemble exhibits subtle differences, mostly in and around its partner binding region, suggesting the presence of ligand-induced conformational transitions. Molecular dynamics simulations of the long coiled coil reveal distinct regions with different stability and flexibility, with the N-terminal part of the coiled coil exhibiting the largest motions. Interestingly, this segment is highly conserved, pointing to the functional relevance of the observed dynamical features. Our results indicate previously unexplored aspects of the flexibility of the full-length Homer1 tetramer that might contribute to the dynamic rearrangements of the postsynaptic protein network linked to its functional transitions.

molecular biology↗

bioRxiv2023

Improved detection of methylation in ancient DNA

Reconstructing premortem DNA methylation levels in ancient DNA (aDNA) has led to breakthrough studies such as the prediction of anatomical features of the Denisovan, as well as the castration status of ancient horses. These studies relied on computationally inferring methylation levels from damage signals in naturally deaminated cytosines. Because of statistical constraints, this inference requires high-coverage sequencing, and is thus not only expensive but also restricted to samples with exceptional DNA preservation. Instead, a method to directly measure methylation levels in aDNA, as exists in modern DNA samples, would open the door to a more thorough and cost effective ability to study ancient DNA methylation. We have tested two methods for direct methylation measurement developed for modern DNA based on either bisulfite or enzymatic methylation treatments. We find that both methods preserve sufficient DNA yields to allow for methylation measurement. Bisulfite treatment, combined with a single stranded library preparation, shows the least reduction in DNA yields compared to no methylation treatment, as well as the least biases during methylation conversion. In addition, we show that applying bisulfite treatment to [~]0.4-fold coverage sample provides a methylation signal that is comparable to, or even better, than the computationally inferred one. We thus present a method to directly measure methylation in ancient DNA that is cost effective and can be used on a wide variety of ancient samples.

genomics↗

bioRxiv2020

A Minimally Destructive Protocol for DNA Extraction from Ancient Teeth

Ancient DNA sampling methods--although optimized for efficient DNA extraction--are destructive, relying on drilling or cutting and powdering (parts of) bones and teeth. As the field of ancient DNA has grown, so have concerns about the impact of destructive sampling of the skeletal remains from which ancient DNA is obtained. Due to a particularly high concentration of endogenous DNA, the cementum of tooth roots is often targeted for ancient DNA sampling, but standard destructive sampling methods often result in the loss of at least one entire root. Here, we present a minimally destructive method for extracting ancient DNA from dental cementum present on the surface of tooth roots. This method does not require destructive drilling or grinding, and, following extraction, the tooth remains safe to handle and suitable for most morphological studies, as well as other biochemical studies, such as radiocarbon dating. We extracted and sequenced ancient DNA from 30 teeth (and 9 corresponding petrous bones) using this minimally destructive extraction method in addition to a typical tooth sampling method. We find that the minimally destructive method can provide ancient DNA that is of comparable quality to extracts produced from teeth that have undergone destructive sampling processes. Further, we find that a rigorous cleaning of the tooth surface combining diluted bleach and UV light irradiation seems sufficient to minimize external contaminants usually removed through the physical removal of a superficial layer when sampling through regular powdering methods.

evolutionary biology↗

bioRxiv2019

Human Auditory Ossicles as an Alternative Optimal Source of Ancient DNA

DNA recovery from ancient human remains has revolutionized our ability to reconstruct the genetic landscape of the past. Ancient DNA research has benefited from the identification of skeletal elements, such as the cochlear part of the osseous inner ear, that provide optimal contexts for DNA preservation; however, the rich genetic information obtained from the cochlea must be counterbalanced against the loss of valuable morphological information caused by its sampling. Motivated by similarities in developmental processes and histological properties between the cochlea and auditory ossicles, we evaluated the efficacy of ossicles as an alternative source of ancient DNA. We demonstrate that ossicles perform comparably to the cochlea in terms of DNA recovery, finding no substantial reduction in data quality, quantity, or authenticity across a range of preservation conditions. Ossicles can be sampled from intact skulls or disarticulated petrous bones without damage to surrounding bone, and we argue that, when available, they should be selected over the cochlea to reduce damage to skeletal integrity. These results identify a second optimal skeletal element for ancient DNA analysis and add to a growing toolkit of sampling methods that help to better preserve skeletal remains for future research while maximizing the likelihood that ancient DNA analysis will produce useable results.

genomics↗

bioRxiv2018

Mitogenomic data indicate admixture components of Asian Hun and Srubnaya origin in the Hungarian Conquerors

It has been widely accepted that the Finno-Ugric Hungarian language, originated from proto Uralic people, was brought into the Carpathian Basin by the Hungarian Conquerors. From the middle of the 19th century this view prevailed against the deep-rooted Hungarian Hun tradition, maintained in folk memory as well as in Hungarian and foreign written medieval sources, which claimed that Hungarians were kinsfolk of the Huns. In order to shed light on the genetic origin of the Conquerors we sequenced 102 mitogenomes from early Conqueror cemeteries and compared them to sequences of all available databases. We applied novel population genetic algorithms, named Shared Haplogroup Distance and MITOMIX, to reveal past admixture of maternal lineages. Phylogenetic and population genetic analysis indicated that more than one third of the Conqueror maternal lineages were derived from Central-Inner Asia and their most probable ultimate sources were the Asian Huns. The rest of the lineages most likely originated from the Bronze Age Potapovka-Poltavka-Srubnaya cultures of the Pontic-Caspian steppe, which area was part of the later European Hun empire. Our data give support to the Hungarian Hun tradition and provides indirect evidence for the genetic connection between Asian and European Huns. Available data imply that the Conquerors did not have a major contribution to the gene pool of the Carpathian Basin, raising doubts about the Conqueror origin of Hungarian language.

genetics↗