Biology subjects

da Silva, J.

Publications and source records attributed to da Silva, J..

7 recordsLinked to original sources

bioRxiv2026

Stem Cell Divisions, Driver Mutations, and Carcinogenesis in Purebred Dogs

Most cancers are initiated by mutations that inactivate tumour-suppressor genes or activate oncogenes. Fitting a multistage model of carcinogenesis to the increase in cancer mortality with breed-specific size and lifespan in dogs has predicted that four somatic driver mutations are typically required to initiate cancer. This result is reconsidered here because it depends on the relationship between the number of at-risk cells and breed weight. Using a power function for this relationship results in higher quality models that support single driver mutations activating oncogenes. In addition, parameter estimates suggest that somatic mutation rates increase with weight, likely because of reduced investment in somatic maintenance. Regression of cancer mortality on body weight and lifespan shows that 56% of cancers in dogs are the result of mutations arising from somatic cell division, compared to 66% in humans. A further 7% of cancers may be due to inherited recessive mutations deactivating tumour suppressor genes, as indicated by the relationship between cancer mortality and breed germline homozygosity. Some of the remaining unexplained variation in cancer mortality may be explained by germline mutations underlying breed predispositions to specific cancers. Contrasting results with humans provide novel insights into the dynamics of carcinogenesis.

cancer biology↗

bioRxiv2026

Adaptive Cancer Suppression among Tissues through Reduced Stem Cell Mutation Rates

Since most cancers are initiated by driver mutations arising in somatic cells, the risk of cancer should be explained by the probability of driver mutations as a function of the product of the number of stem cells and the stem cell division rate for a tissue. However, such models of driver-mutation initiated carcinogenesis fail to adequately predict cancer risk. It has been suggested that the missing component is greater adaptive cancer suppression in large tissues with high rates of stem cell division. This 8 may manifest as either a greater number of driver mutations required to initiate cancer or a lower stem cell mutation rate. These hypotheses are tested here using nonlinear regression to fit models that incorporate variation in the number of driver mutations and the stem cell mutation rate to data on the tissue-specific cancer risk, number of stem cells, and stem cell division rate. The greatest concordance between predicted and observed cancer risks is obtained by single driver mutations across tissues and stem cell mutation rates that decline with increasing lifetime numbers of stem cell divisions. This provides evidence of adaptive cancer suppression among tissues.

cancer biology↗

bioRxiv2025

Life History Optimization and the Macroevolution of Mammal Body Size

Although body size is linked to nearly every aspect of an organisms biology, its evolution remains poorly understood. Here, an analytical life history model of optimal size is tested for the first time using unprecedented data on mammal life history and phylogeny and shown to explain several well-defined macroevolutionary patterns. The evolution of body size is explained in large part by life history optimization with respect to adult mortality under metabolic constraints on productivity. The model also explains plausible effects of climate change, diet, feeding mode, cursoriality, aquatic living, powered flight, and island endemicity on the evolution of body size. This study furthers our understanding of the relationship between micro- and macro-evolution.

evolutionary biology↗

bioRxiv2024

Circumferential actomyosin bundles drive endothelial cell deformations to constrict blood vessels

Following the formation of new blood vessels, vascular remodelling ensues to generate a hierarchical network of vascular tubes with optimal connections and diameters for efficient blood perfusion of tissues. How transitions in endothelial cell (EC) number and shape are coordinated to define vessel diameter during development remains an open question. In this study, we discovered EC deformations, rearrangements and transient formation of self-seam junctions as key mechanisms that explain a negative relationship between cell number and vessel diameter. High-resolution analysis of actin cytoskeleton organization disclosed the generation of tension-bearing, circumferential actomyosin bundles in the endothelial cortex that drive EC deformation and vessel constriction. Importantly, the loss of circumferential actin bundles in krit1/ccm1-deficient ECs causes cell enlargement and impaired vessel constriction that culminate in dilated vessels, characteristic of cerebral cavernous malformation. Our multiscale study therefore underpins circumferential actomyosin-driven EC deformations in controlling vessel size and in the prevention of vascular malformations.

cell biology↗

bioRxiv2021

Neutralizing antibody-independent immunity to SARS-CoV-2 in hamsters and hACE-2 transgenic mice immunized with a RBD/Nucleocapsid fusion protein

The nucleocapsid (N) and the receptor binding domain (RBD) of the Spike (S) proteins elicit robust antibody and T cell responses either in vaccinated or COVID-19 convalescent individuals. We generated a chimeric protein that comprises the sequences of RBD from S and N antigens (SpiN). SpiN was highly immunogenic and elicited a strong IFN{gamma} response from T cells and high levels of antibodies to the inactivated virus, but no neutralizing antibodies. Importantly, hamsters and the human Angiotensin Convertase Enzyme-2-transgenic mice immunized with SpiN were highly resistant to challenge with the wild type SARS-CoV-2, as indicated by viral load, clinical outcome, lung inflammation and lethality. Thus, the N protein should be considered to induce T-cell-based immunity to improve SARS-CoV-2 vaccines, and eventually to circumvent the immune scape by variants.

immunology↗

bioRxiv2020

Reporting to the Convention on Biology Diversity: How are countries assessing and protecting their genetic diversity?

Genetic diversity is critically important for all species-domesticated and wild- to adapt to environmental change, and for ecosystem resilience to extreme events. International agreements such as the Convention on Biological Diversity (CBD) have committed to conserve and sustainably and equitably use all levels of biodiversity-genes, species and ecosystems-globally. However, assessment and monitoring of genetic diversity are often overlooked, and there are large knowledge and policy gaps regarding genetic diversity conservation. In this study, we present the first quantitative analysis of genetic diversity assessments conducted by Parties to the CBD. We conducted a detailed, systematic analysis of 114 CBD 5th (submitted 2014) and 6th (submitted 2018) National Reports to quantitatively assess actions, progress on targets, values and indicators related to genetic diversity. First, we found that the importance of genetic diversity is recognised by most Parties to the CBD, and that recognition increased over time. However, genetic targets mainly addressed genetic diversity within cultivated plants, farm animals, and crop wild relatives, with little focus on other wild species. Also, actions for conserving genetic diversity primarily concerned ex-situ facilities and policy, rather than monitoring and intervention for maintaining genetic diversity in situ. The most commonly used indicators of genetic diversity status were the number of genetic resources in conservation facilities, number of threatened breeds, and Red List Index, which are not well correlated to genetic erosion in most species -- highlighting that genetic change is poorly monitored by current indicators. Lastly, analyses of genetic data observations, indigenous use and knowledge of genetic diversity, and strategies being developed and implemented to conserve genetic diversity are highly under-reported. We make several recommendations for the post-2020 CBD Biodiversity Framework to improve awareness, assessment, and monitoring, and facilitate consistent and complete reporting of progress of genetic diversity in future National Reports. Article Impact StatementAn analysis of genetic diversity in CBD National Reports neglects non-domesticated species and demonstrates need for sufficient indicators.

scientific communication and education↗

bioRxiv2018

Organometallic gold(III) Cl (L1 = SNS-donating thiosemicarbazone) complex protects mice against acute T. cruzi infection

Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs against Trypanosoma cruzi, we evaluated both the in vitro and in vivo activity of the organometallic gold(III) complex [Au(Hdamp)(L14)]Cl (L1 = SNS- donating thiosemicarbazone), which was denoted 4-Cl. Our results demonstrated that 4- Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and the intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In very-low-dose in vivo assays, 4-Cl reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage. All these changes resulted in the survival of 100% of the mice treated with 4-Cl during the acute phase. We hypothesised that 4-Cl can act directly on the parasite and may participate in the modulation of IFN-{gamma} production at the acute stage of the disease. Molecular docking simulations showed that the compound may interact with cruzain, a thiol protease considered a possible antiparasitic drug target, primarily by hydrophobic interactions. These analyses predicted that the Cys25 residue in the cruzain binding site is approximately 3.0 [A] away from the S and Au atoms of the gold compound, which could suggest formation of a possible covalent bond between cruzain and the inhibitor. Overall, we confirmed the potential of 4-Cl as a new candidate for Chagas disease treatment.

pharmacology and toxicology↗