Biology subjects

Kaya, S.

Publications and source records attributed to Kaya, S..

5 recordsLinked to original sources

bioRxiv2026

In vitro effects of tensile strain on cancer-associated and matched normal fibroblasts derived from oral squamous cell carcinoma: an exploratory study

BackgroundMechanical forces, particularly tensile stress, influence tumor progression by modulating cancer-associated fibroblast (CAF) behaviour and extracellular matrix remodelling, yet their role in oral cancer remains insufficiently defined. To our knowledge, this is the first study investigating in vitro tensile stress responses in CAF and normal fibroblasts (NF) derived from oral squamous cell carcinoma (OSCC). ObjectiveTo assess how tensile stress affects fibroblast gap closure, proliferation, metabolic activity, and paracrine signalling relevant to tumor-stroma interactions. MethodsCAFs and NFs were isolated from OSCC tissue and matched healthy mucosa and exposed to cyclic tensile strain (3%, 0.02 Hz, 96 h) using the FX-6000T system. Gap closure was assessed by wound-healing assay, proliferation by cell counting, metabolic activity by AlamarBlue, and paracrine effects on A549 tumor cell gap closure using fibroblast-conditioned supernatants. ResultsTensile loading significantly increased CAF gap closure capacity compared with both stimulated NFs (p<0.0001) and unstimulated CAF controls (p=0.0167). Metabolic activity showed a non-significant trend toward higher values in CAFs. Proliferation did not differ between groups up to 48 h, arguing against a major early contribution of proliferation to the observed group differences in the fibroblast scratch assays; however, because proliferation was not inhibited and was not quantified beyond 48 h, later time points should be interpreted conservatively as composite gap closure. Supernatants from mechanically stimulated CAFs increased A549 gap closure by [~]40% compared with non-stimulated controls (p=0.0485), whereas stimulated NFs did not enhance the tumor cells capacity to close the cell-free gap. ConclusionsTensile strain was associated with increased fibroblast gap closure and enhanced gap-closure-promoting paracrine effects of oral CAFs under the conditions tested. These exploratory findings support the concept that biomechanical cues can modulate CAF functional behaviour in OSCC. Given the limited cohort size and inter-patient variability, these results should be interpreted as hypothesis-generating and require confirmation in larger studies. Mechanistic pathways were not interrogated in this study and should be addressed in future work using more complex tumor-stroma models. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/737904v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@d275c6org.highwire.dtl.DTLVardef@13249c5org.highwire.dtl.DTLVardef@8964b9org.highwire.dtl.DTLVardef@33e767_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

Loss-of-function phenomics, ncORFs, and ambiguity of mutant phenotypes in Medicago truncatula

Non-canonical open reading frames (ncORFs) are an emerging area of research that is quickly gaining momentum. Many peptides and proteins missed in initial annotation efforts (ncProts) were subsequently shown to be crucial for a wide range of biological processes. The discovery of ncORFs continues to improve the accuracy of loss-of-function studies because they often occupy the same genomic spaces as annotated ORFs. While databases of mutant phenotypes linked to genomic loci exist in a few species, none of these databases integrate the information on ncORFs present in already characterized loci. In this study, we introduce a nearly comprehensive loss-of-function phenomics dataset of Medicago truncatula (673 loci characterized over the past 30 years), which was integrated as a new track into the genome browser of this organism. This dataset helped critically analyze the potential contribution of ncORFs to published phenotypes. We detected mass spectrometry (MS)-validated ncORFs in 10 characterized genes, including major regulators of development and symbiotic relationships. We also found conserved ncORFs in 113 characterized genes, including four genes with highly conserved ncORFs. In some studies, the contribution of these ncORFs can be ruled out, while in others it cannot. Using real examples, we systematized ambiguities associated with ncORFs. Furthermore, we highlighted little-known trans effects of insertional mutagenesis on splicing as contributors to that ambiguity. Finally, our meta-analysis of published phenotypes revealed that different protein classes have significantly different (unique) proportions of unconditional, conditional, and neutral phenotypes, potentially reflecting their relative functional importance. Significance statementThis study is the first to merge a nearly comprehensive inventory of loss-of-function studies in a eukaryotic organism with the information on novel MS-validated and conserved ncORFs.

genetics↗

bioRxiv2025

Alzheimer's disease risk factor APOE4 exerts dimorphic effects on female bone

Individuals diagnosed with Alzheimers disease (AD) are at an increased risk of bone fractures. Conversely, a diagnosis of osteoporosis in women is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. Proteomic analysis of cortical bone from aged mice revealed neurological disease-associated proteins that are highly enriched in aged mouse bones, including apolipoprotein E (Apoe) and amyloid precursor protein. Further, Apoe localized specifically to bone-embedded osteocytes with expression twice as high in aged female bone as in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate APOE allelic roles in bone, we utilized a humanized APOE knock-in mouse model that expresses either the protective APOE2, the neutral APOE3, or the AD risk factor APOE4, and analyzed bone and hippocampus from the same mice. APOE4 exerted strong sex-specific effects on the bone transcriptome and proteome, relative to APOE2 or APOE3. Interestingly, the APOE4-associated perturbation in the female bone proteome was more pronounced than the corresponding alterations observed in the hippocampus. APOE4 protein causes bone fragility in females, but not males, even without changes in cortical bone structure. These bone quality deficits arose from suppression of osteocyte perilacunocanalicular remodeling. We find that APOE4 is a new molecular culprit capable of disrupting osteocyte maintenance of bone quality as early as midlife in a manner that disproportionately affects females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment, and treatment for bone fragility, in females.

molecular biology↗

bioRxiv2024

Discovery of diverse chimeric peptides in a eukaryotic proteome sets the stage for the experimental proof of the mosaic translation hypothesis

The high complexity of eukaryotic organisms enabled their evolutionary success, which became possible due to the diversification of eukaryotic proteomes. Various mechanisms contributed to this process. Alternative splicing had the largest known impact among these mechanisms: tens or hundreds of protein isoforms produced from a single genetic locus. Earlier, we hypothesized that along with alternative splicing, a different but conceptually similar mechanism creates novel versions of existing proteins in all eukaryotes. However, this mechanism acts at the level of translation, where the novelty of an amino acid sequence is achieved via multiple programmed ribosomal frameshifting. This mechanism, which is termed mosaic translation, is very difficult to demonstrate even with the most up-to-date molecular tools. Thus, it remained unnoticed so far. Using only a portion of all mass spectrometry proteomic data generated from various organs of the model plant Medicago truncatula, we attempted the first step toward the experimental proof of this hypothesis. Our original in silico approach resulted in the discovery of two candidates for mosaic proteins (homologs of EF1 and RuBisCo) and 154 candidates for chimeric peptides. Chimeric peptides and polypeptides are produced in the course of one ribosomal frameshifting event and may correspond to parts of mosaic proteins. In addition, our analysis reveals the possibility of translation of chimeric peptides from five ribosomal RNA transcripts, ten long non-coding RNA transcripts, and one transfer RNA transcript. These findings are very novel and will be the basis for experimental validation in future studies. In this work, we present multiple lines of indirect evidence that support the validity of our in silico data.

biochemistry↗

bioRxiv2021

Loss of adipocyte phospholipase gene PLAAT3 causes lipodystrophy and insulin resistance due to inactivated arachidonic acid-mediated PPAR signaling

PLAAT3 is a phospholipid modifying enzyme predominantly expressed in white adipose tissue (WAT). It is a candidate drug target as Plaat3 deficiency in mice protects against picornavirus infection and diet-induced obesity. We identified four patients with homozygous loss-of-function mutations in PLAAT3, presenting with partial lipodystrophy, severe insulin resistance and dyslipidemia. PLAAT3-deficient WAT showed a failure to liberate arachidonic acid (AA) from membrane phospholipids resulting in an inactive gene network downstream of adipogenesis master regulator and anti-diabetic drug target PPARG. These findings establish PLAAT3 deficiency in humans as a novel type of partial lipodystrophy due to an AA- and PPARG-dependent defect in WAT differentiation and function.

genetics↗