Biology subjects

Nicolini, V.

Publications and source records attributed to Nicolini, V..

6 recordsLinked to original sources

bioRxiv2026

PD-1-Targeted IL-2v Expands a Novel Stem-like T Cell Subset Distinct from Anti-PD-1 Therapy to Enhance Effector Differentiation

Tumor-draining lymph nodes serve as critical sites for the generation, maintenance and differentiation of stem-like CD8 T cells during antitumor immune responses. Recent evidence has shown that delivering interleukin-2 to PD1 stem-like CD8 T cells using PD1-IL2v, an immunocytokine combining PD-1 blockade and IL-2R agonism, promotes their differentiation into potent effector cells with enhanced tumor-killing capacity. However, it remains unclear how targeted interleukin-2 therapies imprint early stem-like T-cell differentiation programs. Here, using single-cell transcriptomics and T-cell receptor sequencing in murine pancreatic tumor models, we demonstrate that PD1-IL2v induces an early bifurcation in the differentiation of stem-like CD8 T cells within tumor-draining lymph nodes. We identify an effector-primed stem-like population characterized by the expression of interferon-response genes, natural killer cell receptor genes, and Cx3cr1, consistent with activation of interleukin-2 and STAT5-associated programs. Clonal tracking revealed substantial overlap between these lymph node-derived cells and intratumoral effector populations, supporting a developmental relationship between early priming in lymph nodes and downstream effector differentiation. In contrast, an alternative stem-like state that displayed features associated with T-cell exhaustion, including increased Tox expression, was observed upon PD-1 therapy. Together, these findings identify an early branch point in stem-like T-cell differentiation and provide mechanistic insight into how PD1-IL2v circumvents exhaustion pathways to preferentially generate functional antitumor immunity.

immunology↗

bioRxiv2026

From prehistory to present-day: How isolation shaped the distinct genomic makeup of Italian Alpine valleys

Historically, the eastern Italian Alps have provided crucial geographic corridors for cultural and genetic exchange between the Mediterranean region and Central and Northern Europe. Although recent archaeogenomic data suggest a strong regional persistence of Anatolian Neolithic ancestry followed by the arrival of Yamnaya-related components during the Bronze Age, the genomic landscape of modern Alpine populations remains largely unmapped. In this study, we verified the persistence of these signals in the present-day Rendena and Ledro Valleys by integrating novel complete mitochondrial genomes (N=185) and genome-wide SNP data (N=96), the latter combined with a novel Italian genomic dataset (N=139). Our findings show that the Rendena and Ledro populations form a distinct "modern Alpine" genomic group, which retains a significant proportion of early European Neolithic ancestry, aligning with ancient eastern Italian Alpine individuals and modern Sardinians. More recently, geographic isolation and localized genetic drift appear to have shaped the two valleys differently. Demographic reconstructions reveal asynchronous population declines over the past two millennia, followed by a sharp, synchronized bottleneck 200-300 years ago, which coincided with historical plague outbreaks. Remarkably, this structured drift persisted at an extremely fine microgeographic scale within the valleys, resulting in internal genetic subclusters that directly correlate with local topography. This micro-differentiation was likely maintained by steep geographic barriers and/or local endogamous practices. This study ultimately underscores how geographic barriers and isolation can preserve ancient genomic components and shape highly localized genetic structures over centuries even to the modern day.

evolutionary biology↗

bioRxiv2026

DNA Traces on the Shroud of Turin: Metagenomics of the 1978 Official Sample Collection

This research provides original insights into the diversity of DNA extracted from samples collected in 1978 from the Turin Shroud, revealing its biological complexity through rigorous DNA and metagenomic analyses. Our findings highlight its preservation conditions and environmental interactions, offering valuable perspectives into the identified genetic variants, which originated from multiple biological sources. Several human mitochondrial DNA (mtDNA) lineages were identified, including K1a1b1a, which matches the 1978 official collectors mitogenome, H2a2 (i.e. the lineage of the mtDNA reference sequence rRCS), H1b, which is common in Western Eurasia, and H33, which is prevalent in the Near East and frequent among the Druze. Moreover, the reconstructed microbiome of the Shroud reveals a rich tapestry of multiple microbes commonly found on the human epidermis, as well as archaeal communities adapted to high salinity, and fungi including molds. This is indicative of the Shrouds preservation conditions over the centuries. Additionally, the presence of abundant Mediterranean endemic red coral, various cultivated plants (e.g. carrot, wheat, corn, bananas, and peanuts) and domesticated animals (e.g. cattle, pigs, chickens, dogs, and cats) provide a fascinating glimpse into the diverse biological sources of the contaminants that have accumulated on the Turin Shroud over time. Finally, radiocarbon dating of two distinct threads collected from the reliquary provides evidence of their use to repair the Shroud in the years 1534 and 1694 of the Common Era (CE). Significance statementAn in-depth metagenomic analysis was conducted on several linen strands collected from different areas of the body image of the Man of the Shroud during the official sampling in 1978. Our analyses revealed several human mtDNA lineages, including one common in Western Eurasia and another prevalent in the Near East. Additionally, the diversity of animal and plant species identified details the significant environmental contamination of the Shroud that likely occurred in recent centuries, particularly following the voyages of Marco Polo and Christopher Columbus. Radiocarbon dating of two distinct textile residuals from the Shrouds reliquary indicated a time range between 1451 and 1800 CE, overlapping with the period of its repair interventions.

genomics↗

bioRxiv2025

Ancient genomes from the siege and destruction of Middle Bronze Age Roca Vecchia (Apulia, Italy) shed light on Aegean contacts and conflicts

BackgroundRoca Vecchia, an iconic Bronze Age stronghold in Apulia, Southern Italy, was completely destroyed during a siege between the end of the 15th century BCE and the beginning of the 14th century BCE. During the siege, seven of the local people hid within the stronghold walls. Two others, who could have been as well attackers as defenders, were found under the ruins of the main gate. The material culture found at Roca Vecchia and associated with the period of the siege includes Minoan-type pottery produced from local clay, imported Aegean pottery and an Aegean-type dagger, pointing to an established relationship between the site and the Minoan civilization. Therefore, the site offers an unprecedented opportunity to characterise the genetic components of the population inhabiting an indigenous settlement with increasing contacts with the Aegean world, and to shed light on the demic or cultural modes of the Minoan presence in the central Mediterranean. ResultsWith our work, we sampled six out of nine available unburied Middle Bronze Age individuals, contemporary with the siege and destruction of the site, and obtained genome-wide information for two individuals. When compared with available Minoan, Apulian and broadly Mediterranean genomes, the individuals showed a characteristic Bronze/Iron Age Italian peninsula genetic signature, with limited contribution from Minoans. ConclusionsWe conclude that the local population of Roca Vecchia, at the moment of the siege, was predominantly autochthonous, with a minoritarian Minoan component. A Minoan genetic signal is indeed likely present in one out of two analysed individuals who were certainly part of the dwellers of Roca Vecchia. This confirms previous hypotheses supposing that a nucleus of "foreigners" coming from the Minoan world was living in the site and mixed with locals. Archaeological data suggest that the Roca Vecchia Aegean population component probably increased in the following centuries.

genetics↗

bioRxiv2024

Disrupting USP39 deubiquitinase Function Impairs the Survival and Migration of Multiple Myeloma Cells through ZEB1 Degradation

RationaleMultiple Myeloma (MM) stands as the second most common hematological malignancy characterized by the accumulation of monoclonal plasmocytes within the bone marrow. Despite the introduction of proteasome inhibitors, immunomodulatory agents and CD38-targeting antibodies which have extended survival rates, the disease remains incurable for most patients due to the emergence of resistant clones and frequent relapses. The efficacy of the proteasome inhibitor bortezomib (BTZ) in MM treatment underscores the critical role of the ubiquitin proteasome system (UPS) in this cancer. Deubiquitinases (DUBs), a class of enzymes governing the stability, interactions or localization of cellular proteins by removing ubiquitin modifications, have emerged as promising therapeutic targets across various cancers, including MM. MethodsThrough an exhaustive loss-of-function approach, we have identified for the first time USP39 DUB as a pivotal survival determinant for MM cells. ResultsOur analysis reveals a direct correlation between heightened USP39 mRNA levels and shorter survival in MM patients. Additionally, robust USP39 protein expression is observed in MM patient plasmocytes compared to healthy counterparts. Knockdown of Usp39 not only impedes clonogenic capabilities, but also induces apoptosis, triggers cell cycle arrest and overcomes BTZ resistance. Complementary gain-of-function assays, further elucidate how USP39, by stabilizing the transcription factor ZEB1, enhances the trans-migratory potential of MM cells. ConclusionsIn summary, our findings underscores the pivotal role of the deubiquitinase USP39, suggesting that targeting the USP39/ZEB1 axis hold promise as a prospective diagnostic marker and therapeutic target in MM.

cancer biology↗

bioRxiv2021

Human immunocompetent Choroid-on-Chip: a novel tool for studying ocular effects of biological drugs

Disorders of the eye leading to visual impairment are a major issue that affects millions of people. On the other side ocular toxicities were described for e.g. molecularly targeted therapies in oncology and may hamper their development. Current ocular model systems feature a number of limitations affecting human-relevance and availability. To find new options for pharmacological treatment and assess mechanisms of toxicity, hence, novel complex model systems that are human-relevant and readily available are urgently required. Here, we report the development of a human immunocompetent Choroid-on-Chip (CoC), a human cell-based in vitro model of the choroid layer of the eye integrating melanocytes and microvascular endothelial cells, covered by a layer of retinal pigmented epithelial cells. Immunocompetence is achieved by perfusion of peripheral immune cells. We demonstrate controlled immune cell recruitment into the stromal compartments through a vascular monolayer and in vivo-like cytokine release profiles. To investigate applicability for both efficacy testing of immunosuppressive compounds as well as safety profiling of immunoactivating antibodies, we exposed the CoCs to cyclosporine and tested CD3 bispecific antibodies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/443846v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@506402org.highwire.dtl.DTLVardef@1d5cdd3org.highwire.dtl.DTLVardef@1bc09d3org.highwire.dtl.DTLVardef@2909de_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

bioengineering↗