Biology subjects

Schmitt, C. A.

Publications and source records attributed to Schmitt, C. A..

6 recordsLinked to original sources

bioRxiv2022

Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive hematological malignancy often curable only by using intensive chemotherapy. Nonetheless, resistance/early relapses are frequent, underscoring the need to investigate the molecular events occurring shortly after chemotherapy. Therapy-induced senescence (TIS) is a fail-safe tumor suppressive mechanism that may elicit immune-mediated responses contributing to senescent cell clearance. Yet, TIS functional role in AML eradication and immune surveillance early post-chemotherapy remains ill-defined. By combining transcriptional and cellular-based evaluation of senescence markers in AML patient samples, we found upregulation of senescence-associated genes and interferon gene categories with concomitant induction of HLA class I and class II molecules, pointing to a causal link between TIS and leukemia immunogenicity. Consistently, senescence-competent AML samples activated autologous CD4+ and CD8+ T cells and improved leukemia recognition by both T-cell subsets. Lastly, the anti-leukemic activity of Immune Checkpoint Blockades (ICBs) was enhanced upon senescence engagement in AML. Altogether, our results identify senescence as a potent immune-related anti-leukemic mechanism that may rapidly translate into innovative senescence-based strategies to prevent AML relapse. STATEMENT OF SIGNIFICANCEOur findings uncover a novel link between senescence induction and leukemia immune recognition by T cells via upregulation of antigen presentation machinery components, providing the basis for conceptually novel senescence-based targeted immunotherapeutic regimens for AML patients.

cancer biology↗

bioRxiv2022

Evidence of selection in UCP1 gene region suggests local adaptation to irradiance rather than cold temperatures in savanna monkeys (Chlorocebus spp.)

The genus Chlorocebus is widely distributed throughout sub-Saharan Africa, and in the last 300 thousand years expanded from equatorial Africa into the southernmost latitudes of the continent. In these new environments, colder climate was a likely driver of natural selection. We investigated population-level genetic variation in the mitochondrial uncoupling protein 1 (UCP1) gene region - implicated in non-shivering thermogenesis within brown/beige adipocytes - in 73 wild savanna monkeys from three taxa representing this southern expansion (C. pygerythrus hilgerti, C. cynosuros, C. p. pygerythrus) ranging from Kenya to South Africa. We found 17 SNPs with extended haplotype homozygosity consistent with positive selective sweeps, 10 of which show no significant LD with each other. Phylogenetic generalized least squares modeling with ecological covariates suggest that most derived allele frequencies are significantly associated with solar irradiance and winter precipitation, rather than overall low temperatures. This selection and association with irradiance appears to be driven by a population isolate in the southern coastal belt of South Africa. We suggest that sunbathing behaviors common to savanna monkeys, in combination with strength of solar irradiance, may mediate adaptations to thermal stress via non-shivering thermogenesis among savanna monkeys. The variants we discovered all lie in non-coding regions, some with previously documented regulatory functions, calling for further validation and research.

genetics↗

bioRxiv2022

Expanded Distribution and Predicted Suitable Habitat for the Critically Endangered Yellow-tailed Woolly Monkey (Lagothrix flavicauda) in Peru

The Tropical Andes Biodiversity Hotspot holds a remarkable number of species at risk of extinction due to anthropogenic habitat loss, hunting and climate change. One of these species, the Critically Endangered yellow-tailed woolly monkey (Lagothrix flavicauda), was recently sighted in Junin region, 206 kilometres south of its previously known distribution. The range extension, combined with continued habitat loss, calls for a re-evaluation of the species distribution and available suitable habitat. Here, we present novel data from surveys at 53 sites in the regions of Junin, Cerro de Pasco, Ayacucho and Cusco. We encountered L. flavicauda at 9 sites, all in Junin, and the congeneric L. l. tschudii at 20 sites, but never in sympatry. Using these new localities along with all previous geographic localities for the species, we made predictive Species Distribution Models based on Ecological Niche Modelling using a generalized linear model and maximum entropy. Each model incorporated bioclimatic variables, forest cover, vegetation measurements, and elevation as predictor variables. Model evaluation showed >80% accuracy for all measures. Precipitation was the strongest predictor of species presence. Habitat suitability maps illustrate potential corridors for gene flow between the southern and northern populations, although much of this area is inhabited by L. l. tschudii. An analysis of the current protected area (PA) network showed [~]47% of remaining suitable habitat is unprotected. With this, we suggest priority areas for new protected areas or expansions to existing reserves that would conserve potential corridors between L. flavicauda populations. Further surveys and characterization of the distribution in intermediate areas, combined with studies on genetic flow, are still needed to protect this species.

ecology↗

bioRxiv2020

Anthropogenic food enhancement alters the timing of maturational landmarks among wild savanna monkeys (Chlorocebus pygerythrus)

ABSTRACTAnthropogenic landscapes are rapidly replacing natural nonhuman primate habitats. Yet, the access to anthropogenic resources on primate biology, health, and fitness remain poorly studied. Given their ubiquity across a range of human impacted landscapes, from cities to national parks, savanna monkeys (Chlorocebus spp.) provide an excellent study system in which to test these effects. We compared body condition and reproductive maturation in vervets (Chlorocebus pygerythrus) inhabiting a private farm in !Gariep Dam, with ample access to anthropogenic foods, and wild-foraging vervets in Soetdoring Nature Reserve, South Africa. Overall, vervets in !Gariep show significantly thicker skin folds, and higher BMI and body mass, than those in Soetdoring, suggesting increased fat deposition. Males in !Gariep have larger relative testis volumes at peri-pubescent ages compared to those in Soetdoring, suggesting early reproductive maturation associated with age-specific increases in body mass. Females from !Gariep showed evidence of an earlier onset of reproduction than those in Soetdoring, based on parity status as assessed by nipple length and evidence of lactation. Parity status at sub-adult dental ages was also strongly associated with body mass. These results are consistent with a positive effect of anthropogenic food-enhancement on body fat deposition, potentially linked to an earlier onset of reproductive maturation. Further investigation into primate responses to cultivated resources will inform our understanding of the broader effects of food enhancement on developmental plasticity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

zoology↗

bioRxiv2019

A novel IKK- and proteasome-independent mechanism of RelA activation triggers senescence associated secretome via transcriptional repression of NFKBIA

The I{kappa}B kinase (IKK) - NF-{kappa}B pathway is activated as part of the DNA damage response and controls both resistance to apoptosis and inflammation. How these different functions are achieved remained unknown. We demonstrate here that DNA double strand breaks elicit two subsequent phases of NF-{kappa}B activation in vivo and in vitro, which are mechanistically and functionally distinct. RNA-sequencing reveals that the first phase controls anti-apoptotic gene expression, while the second drives expression of senescence-associated secretory phenotype (SASP) genes. The first, rapidly activated phase is driven by the ATM-PARP1-TRAF6-IKK cascade, which triggers proteasomal destruction of I{kappa}B and is terminated through I{kappa}B (NFKBIA) re-expression. The second phase is activated days later in senescent cells but is independent of IKK and the proteasome. An altered phosphorylation status of p65, in part driven by GSK3{beta}, results in transcriptional silencing of NFKBIA and IKK-independent, constitutive activation of NF-{kappa}B in senescence. Collectively, our study reveals a novel physiological mechanism of NF-{kappa}B activation with important implications for genotoxic cancer treatment.

cell biology↗

bioRxiv2016

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

By analyzing multi-tissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalogue of expression quantitative trait loci (eQTLs) in a non-human primate model. This catalogue contains more genome-wide significant eQTLs, per sample, than comparable human resources, and reveals sex and age-related expression patterns. Findings include a master regulatory locus that likely plays a role in immune function, and a locus regulating hippocampal long non-coding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

genetics↗