Biology subjects

Bach, A.

Publications and source records attributed to Bach, A..

6 recordsLinked to original sources

bioRxiv2026

Sulforaphane targets Leishmania promastigotes to inhibit parasite motility and alters host autophagy to suppress parasite replication in macrophages

Visceral leishmaniasis (VL) is a neglected tropical disease caused by the protozoan parasites Leishmania infantum (LI) and Leishmania donovani (LD). VL disproportionately affects populations that live in extreme poverty and those affected by climate change. Treatment options are limited, fiscally prohibitive, and toxic to some that receive treatment. In cases where VL remains untreated, death is inevitable. Although disease prevalence is increasing in affluent countries with robust research capabilities, there remains little economic incentive to search for new, more accessible non-toxic treatments, emphasizing the neglected tropical aspect of this disease. Our previous results indicate that sulforaphane (SFN) inhibits VL promastigote and amastigote growth through an unknown mechanism. The current study extends the anti-parasitic effects of SFN establishing SFN's efficacy against multiple Leishmania parasites including L. tropica, L. mexicana, L. panamensis and L. amazonesis. Moreover, SFN was an effective therapy post-infection as stably infected macrophages treated with SFN (10 M for 48 hours) had a significant reduction in the number of infected cells and the number of amastigotes per cell against Leishmania species that cause both VL and cutaneous leishmaniasis (CL). Moreover, SFN led to a reduction of motility within 6 hours of treatment indicating a direct interaction with the parasite. Alkynyl SFN (A-SFN) was subsequently synthesized to determine the specific binding target of SFN. Interestingly, A-SFN was more effective than SFN in decreasing parasite viability and inhibiting motility against VL and CL parasite species at equivalent concentrations. Immunofluorescence analysis utilizing click chemistry indicated A-SFN binds to cytosolic promastigote components and colocalized only minimally with KMP-11. The binding of SFN to KMP-11 could not be confirmed in vitro. In terms of intracellular host effects, SFN treatment increased the induction of nonselective macroautophagy by increased lysosomal acidification as quantified by DALGreen and FITC-dextran staining in infected macrophages. The induction of autophagy occurred simultaneously with the upregulation of expression of cytoprotective, antioxidant and autophagy-related genes via the NRF2 transcription factor. These data provide robust evidence that SFN is an excellent lead compound against Leishmania that initiates multiple innate immune pathways that enable enhanced parasite killing. Future studies will focus on the in vivo efficacy of SFN against CL.

microbiology↗

bioRxiv2021

Models as games: a novel approach for 'gamesourcing' parameter data and communicating complex models

1O_LIModels have become indispensable tools in conservation science in the face of increasingly rapid loss of biodiversity through anthropogenic habitat loss and natural resource exploitation. In addition to their ecological components, accurately representing human decision-making processes in such models is vital to maximise their utility. This can be problematic as modelling complexity increases, making them challenging to communicate and parameterise. C_LIO_LIGames have a long history of being used as science communication tools, but are less widely used as data collection tools, particularly in videogame form. We propose a novel approach to (1) aid communication of complex social-ecological models, and (2) "gamesource" human decision-making data, by explicitly casting an existing modelling framework as an interactive videogame. C_LIO_LIWe present players with a natural resource management game as a front-end to a social-ecological modelling framework (Generalised Management Strategy Evaluation, GMSE). Players actions replace a model algorithm making management decisions about a population of wild animals, which graze on crops and can thus lower agricultural yield. A number of non-player agents (farmers) respond through modelled algorithms to the players management, taking actions that may affect their crop yield as well as the animal population. Players are asked to set their own management goal (e.g. maintain the animal population at a certain level or improve yield) and make decisions accordingly. Trial players were also asked to provide any feedback on both gameplay and purpose. C_LIO_LIWe demonstrate the utility of this approach by collecting and analysing game play data from a sample of trial plays, in which we systematically vary two model parameters, and allowing trial players to interact with the model through the game interface. As an illustration, we show how variations in land ownership and the number of farmers in the system affects decision-making patterns as well as population trajectories (extinction probabilities). C_LIO_LIWe discuss the potential and limitations of this model-game approach in the light of trial player feedback received. In particular, we highlight how a common concern about the game framework (perceived lack of "realism" or relevance to a specific context) are actually criticisms of the underlying model, as opposed to the game itself. This further highlights both the parallels between games and models, as well as the utility of model-games to aid in communicating complex models. We conclude that videogames may be an effective tool for conservation and natural resource management, and that although they provide a promising means to collect data on human decision-making, it is vital to carefully consider both external validity and potential biases when doing so. C_LI

scientific communication and education↗

bioRxiv2021

Intervene or wait? Modelling the timing of intervention in conservation conflicts adaptive management under uncertainty.

The timing of biodiversity managers interventions can be critical to the success of conservation, especially in situations of conflict between conservation objectives and human livelihood, i.e., conservation conflicts. Given the uncertainty associated with complex social-ecological systems and the potentially irreversible consequences of delayed action for biodiversity and livelihoods, managers tend to simply intervene as soon as possible by precaution. However, refraining from intervening when the situation allows it can be beneficial, notably by saving critical management resources. Here, we introduce a strategy for managers to decide, based on monitoring, whether intervention is required or if waiting is possible. This study evaluates the performance of this waiting strategy compared to a strategy of unconditional intervention at every opportunity. We built an individual-based model of conservation conflict between a manager aiming to conserve an animal population and farmers aiming to maximize yield by protecting their crop from wildlife damage. We then simulated a budget-constrained adaptive management over time applying each strategy, while accounting for uncertainty around population dynamics and around decision-making of managers and farmers. Our results showed that when the decision for the manager to intervene was based on a prediction of population size trajectory, the waiting strategy performed at least as well as unconditional intervention while also allowing managers to save resources by avoiding unnecessary interventions. Under difficult budgetary constraints on managers, this waiting strategy ensured as high yields as unconditional intervention while significantly improving conservation outcomes by compensating managers lack of resources with the benefits accrued over waiting periods. This suggests that waiting strategies are worth considering in conservation conflicts, as they can facilitate equitable management with a more efficient use of management resources, which are often limiting in biodiversity conservation.

ecology↗

bioRxiv2020

GHB confers neuroprotection by stabilizing the CaMKIIα hub domain

Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII) is an abundant neuronal signaling protein involved in synaptic plasticity and memory formation1,2. The central hub domain regulates the activity of CaMKII by organizing the holoenzyme complex into functional oligomers3-6. Recent findings have suggested that the hub is also an allosteric determinant of kinase activity7, and is thus an emerging target for therapies to correct CaMKII dysregulation8,9. However, pharmacological modulation of the hub domain has never been demonstrated. Here we show that stabilization of the CaMKII hub domain confers neuroprotection. By combining photoaffinity labeling and chemical proteomics using small molecule analogs of the natural metabolite {gamma}-hydroxybutyrate (GHB)10 we reveal that CaMKII is the selective target for GHB. We further find that these GHB analogs bind to the hub interior by solving a 2.2 [A] crystal structure of CaMKII with bound ligand. Using differential scanning fluorimetry, we show that binding of ligands to the hub interior increases the thermal stability of hub oligomers in a concentration-dependent manner. Moreover, we demonstrate the functional significance of this hub stabilization by showing substantial neuroprotective effects in cellular excitotoxicity assays and in a mouse model of cerebral ischemia. Together, our results reveal that CaMKII hub stabilization is the mechanism by which GHB provides endogenous neuroprotection and that small-molecule CaMKII-selective ligands have therapeutic potential.

biochemistry↗

bioRxiv2020

Molecular recognition and dynamics of linear poly-ubiquitins: integrating coarse-grain simulations and experiments

Poly-ubiquitin chains are flexible multidomain proteins, whose conformational dynamics enable their molecular recognition by a large number of partners in multiple biological pathways. By using alternative linkage, it is possible to obtain poly-ubiquitin molecules with different dynamical properties. This flexibility is further increased by the possibility to tune the length of poly-ubiquitin chains. Characterizing the dynamics of poly-ubiquitins as a function of their length is thus relevant to understand their biology. Structural characterization of poly-ubiquitin conformational dynamics is challenging both experimentally and computationally due to increasing system size and conformational variability. Here, by developing highly efficient and accurate small-angle X-ray scattering driven Martini coarse-grain simulations, we characterize the dynamics of linear M1-linked di-, tri- and tetra-ubiquitin chains. Our data show that the behavior of the di-ubiquitin subunits is independent of the presence of additional ubiquitin modules. We propose that the conformational space sampled by linear poly-ubiquitins, in general, may follow a simple self-avoiding polymer model. These results, combined with experimental data from small angle X-ray scattering, biophysical techniques and additional simulations show that binding of NEMO, a central regulator in the NF-{kappa}B pathway, to linear poly-ubiquitin obeys a 2:1 (NEMO:poly-ubiquitin) stoichiometry in solution, even in the context of four ubiquitin units. Eventually, we show how the conformational properties of long poly-ubiquitins may modulate the binding with their partners in a length-dependent manner. SignificanceProtein conformational dynamics plays an essential role in molecular recognition mechanisms. The characterization of conformational dynamics is hampered by the conformational averaging of observable in experimental structural biology techniques and by the limitations in the accuracy of computational methods. By developing an efficient and accurate approach to combine small-angle X-ray scattering solution experiments and coarse-grain Martini simulations, we show that the conformational dynamics of linear poly-ubiquitins can be efficiently determined and to rationalize the role of poly-ubiquitin dynamic in the molecular recognition of the UBAN domain upon binding to the signaling regulator NEMO. The analysis of the conformational ensembles allows us to propose a general model of the dynamics of linear poly-ubiquitin chains where they can be described as a self-avoiding polymer with a characteristic length associated with their specific linkage.

biophysics↗

bioRxiv2019

Long reads from Nanopore sequencing as a tool for animal microbiome studies

In the era of bioinformatics and metagenomics, the study of the ruminal microbiome has gained considerable relevance in the field of animal breeding, since the composition of the rumen microbiota significantly impacts production and the environment. Illumina sequencing is considered the gold standard for the analysis of microbiomes, but it is limited by obtaining only short DNA sequences to analyze. As an alternative, Oxford Nanopore Technologies (ONT) has developed a new sequencing technique based on nanopores that can be carried out in the MinION, a portable device with a low initial cost which long DNA readings can be obtained with. The aim of this study was to compare the performance of both types of sequencing applied to samples of ruminal content using a similar pipeline. The ONT sequencing provided similar results to the Illumina sequencing, although it was able to classify a greater number of readings at the species level, possibly due to the increase in the read size. The results also suggest that, due to the size of the reads, it would be possible to obtain the same amount of information in a smaller number of hours. However, detection of archaeal and eukaryotic species is still difficult to accomplish due to their low abundance in the rumen compared to bacteria, suggesting different pipelines and strategies are needed to obtain a whole representation of the less abundant species in the rumen microbiota.

microbiology↗