Biology subjects

Maina, M. B.

Publications and source records attributed to Maina, M. B..

3 recordsLinked to original sources

bioRxiv2020

Nucleation-dependent aggregation kinetics of Yeast Sup35 fragment GNNQQNY

An N-terminal hepta-peptide sequence of yeast prion protein Sup35 with the sequence GNNQQNY serves as an ideal model for structural understanding of amyloid assembly and kinetics. In this study, we used a reproducible solubilisation protocol that allows the generation of homogenous monomeric solution of GNNQQNY to understand the molecular details of its self-assembly mechanism. The aggregation kinetics data show that the GNNQQNY sequences follow nucleation-dependent aggregation kinetics with a critical nucleus of size ~7 monomers and that the size and efficiency of nucleation was found to be inversely related to the reaction temperature. The generated nucleus reduces the thermodynamic energy barrier by acting as a template for further self-assembly and results in highly ordered amyloid fibrils. The fibers grown at different temperatures showed similar Thioflavin T positivity, Congo red binding and {beta}-sheet rich structures displaying a characteristic cross-{beta} diffraction pattern. These aggregates also share morphological and structural identity with those reported earlier. The mature GNNQQNY fibers exerted no significant oxidative stress or cytotoxicity upon incubating with differentiated SHSY5Y cells. To our knowledge, this is the first study to experimentally validate previous predictions based on theoretical and molecular dynamics simulations. These findings will provide the basis for understanding the kinetics and thermodynamics of amyloid nucleation and elongation of amyloidogenic systems associated with many systemic and neurodegenerative diseases.

biophysics↗

bioRxiv2020

20 years of African Neuroscience: Waking a sleeping giant

Understanding the function and dysfunction of the brain remains one of the key challenges of our time. However, an overwhelming majority of brain research is carried out in the Global North, by a minority of well-funded and intimately interconnected labs. In contrast, with an estimated one neuroscientist per million people in Africa, news about neuroscience research from the Global South remains sparse. Clearly, devising new policies to boost Africa’s neuroscience landscape is imperative. However, the policy must be based on accurate data, which is largely lacking. Such data must reflect the extreme heterogeneity of research outputs across the continent’s 54 countries distributed over an area larger than USA, Europe and China combined. Here, we analysed all of Africa’s Neuroscience output over the past 21 years. Uniquely, we individually verified in each of 12,326 publications that the work was indeed performed in Africa and led by African-based researchers. This step is critical: previous estimates grossly inflated figures, because many of Africa’s high-visibility publications are in fact the result of internationally led collaborations, with most work done outside of Africa. The remaining number of African-led Neuroscience publications was 5,219, on average only ~5 per country and year. From here, we extracted metrics such as the journal and citations, as well as detailed information on funding, international collaborations and the techniques and model systems used. We link these metrics to demographic data and indicators of mobility and economy. For reference, we also extracted the same metrics from 220 randomly selected publications each from the UK, USA, Australia, Japan and Brazil. Our unique dataset allows us to gain accurate and in-depth information on the current state of African Neuroscience research, and to put it into a global context. This in turn allows us to make actionable recommendations on how African research might best be supported in the future.Competing Interest StatementThe authors have declared no competing interest.View Full Text

scientific communication and education↗

bioRxiv2020

Dityrosine cross-link trapping of amyloid-β intermediates reveals that self-assembly is required for Aβ-induced cytotoxicity

Multiple chemical reactions, such as the production of reactive oxygen species (ROS) can lead to dityrosine (DiY) formation via the cross-linking of closely spaced tyrosine residues and this can serve as a marker for aging. Amyloid-{beta} (A{beta}) has been found to be DiY cross-linked in the brains of AD patients. In vitro, A{beta} forms DiY cross-links via metal-catalysed oxidation (Cu2+ and H202) (MCO) leading to the formation of fibrils that are resistant to formic acid denaturation. However, copper is well known to influence and enhance self-assembly. Here, to investigate the interplay between self-assembly and DiY cross-linking we have utilised a non-assembly competent variant of A{beta} (vA{beta}). MCO and UV oxidation experiments using vA{beta} and wild-type A{beta}, revealed that DiY cross-linking stabilises, but does not induce or promote A{beta} assembly. Cu2+ alone, without H202, facilitates the formation and DiY cross-linking of wild-type A{beta} into long-lived oligomers. Our work reveals DiY formation halts further A{beta} self-assembly. DiY cross-linked A{beta} is non-toxic to neuroblastoma cells at all stages of self-assembly in contrast to oligomeric non-cross-linked A{beta}. These findings point to a mechanism of toxicity that necessitates continuing self-assembly of the A{beta} peptide, whereby trapped DiY A{beta} assemblies and assembly incompetent variant A{beta} are unable to result in cell death.

biochemistry↗