Biology subjects

Dokmak, S.

Publications and source records attributed to Dokmak, S..

3 recordsLinked to original sources

bioRxiv2026

Distinct Progression Paths Underlie the Diversity of Pancreatic Papillary Cystic Neoplasms

Surgical decisions for intraductal papillary mucinous neoplasms (IPMNs), precursors of pancreatic cancer, depend on distinguishing low- from high-grade dysplasia, a distinction that molecular markers could refine. We microdissected 433 tumor regions from 135 patients and integrated transcriptomics, deep-learning histology, and KRAS/GNAS RNA-called variants. RNA programs and morphological motifs separated lesions by phenotype, intestinal versus others, rather than by dysplasia grade. Along gastric IPMN trajectories, low-grade lesions recapitulated the pit-chief polarity of normal gastric glands, whereas high-grade lesions were indistinguishable from pancreatobiliary lesions in morphology, RNA programs, and driver mutations. Intestinal IPMNs arose through two routes: a canonical GNAS-associated pathway and a KRAS-associated shift from low-grade gastric features, with lesions sharing driver mutations retaining common programs across phenotypes. Resolving these phenotypic trajectories clarified distinct progression paths and enabled phenotype-specific prediction of high-grade dysplasia in mucus aspirated from 94 resected lesions. These findings support a promising fluid-based assessment of IPMN status.

cancer biology↗

bioRxiv2024

Proteostasis and metabolic dysfunction in a distinct subset of storage-induced senescent erythrocytes targeted for clearance

Although refrigerated storage slows the metabolism of volunteer donor RBCs, cellular aging still occurs throughout this in vitro process, which is essential in transfusion medicine. Storage-induced microerythrocytes (SMEs) are morphologically-altered senescent RBCs that accumulate during storage and which are cleared from circulation following transfusion. However, the molecular and cellular alterations that trigger clearance of this RBC subset remain to be identified. Using a staining protocol that sorts long-stored SMEs (i.e., CFSEhigh) and morphologically-normal RBCs (CFSElow), these in vitro aged cells were characterized. Metabolomics analysis identified depletion of energy, lipid-repair, and antioxidant metabolites in CFSEhigh RBCs. By redox proteomics, irreversible protein oxidation primarily affected CFSEhigh RBCs. By proteomics, 96 proteins, mostly in the proteostasis family, had relocated to CFSEhigh RBC membranes. CFSEhigh RBCs exhibited decreased proteasome activity and deformability; increased phosphatidylserine exposure, osmotic fragility, and endothelial cell adherence; and were cleared from the circulation during human spleen ex vivo perfusion. Conversely, molecular, cellular, and circulatory properties of long-stored CFSElow RBCs resembled those of short-stored RBCs. CFSEhigh RBCs are morphologically and metabolically altered, have irreversibly oxidized and membrane-relocated proteins, and exhibit decreased proteasome activity. In vitro aging during storage selectively alters metabolism and proteostasis in SMEs, targeting these senescent cells for clearance.

cell biology↗

bioRxiv2024

Malaria parasites undergo a rapid and extensive metamorphosis after invasion of the host erythrocyte

Within the human host, the symptoms of malaria are caused by the replication of malaria parasites within erythrocytes. Growth inside the erythrocyte exposes the parasites to the normal surveillance of erythrocytes by the host organism, in particular the clearance of erythrocytes in the spleen. Here we show that the malaria parasite Plasmodium falciparum undergoes a rapid, multi-step metamorphosis that transforms the invasive merozoite into an amoeboid-shaped cell within minutes after invading erythrocytes. This transformation involves an increase in the parasite surface area and is mediated by factors already present in the merozoite, including the parasite phospholipid transfer protein PV6. Parasites lacking PV6 do not assume an amoeboid form and instead are spherical and have a smaller surface area than amoeboid forms. Furthermore, erythrocytes infected with parasites lacking PV6 undergo a higher loss of surface area upon infection by P. falciparum, which affects the traversal of infected erythrocytes through the spleen. This is the first evidence that after invasion, the parasite undergoes a rapid, complex metamorphosis within the host erythrocyte that promotes survival in the host.

microbiology↗