Biology subjects

Burban, E.

Publications and source records attributed to Burban, E..

6 recordsLinked to original sources

bioRxiv2023

Optimization of neuromuscular blockade protocols in cynomolgus macaques: monitoring, doses and antagonism

BackgroundNeuromuscular blocking agents (NMBAs) are a crucial component of anaesthesia and intensive care. NMBAs are a family of molecules defined by their ability to compete with acetylcholine for binding to the acetylcholine receptor at the neuromuscular junction. This functional homology relies on the presence of ammonium groups in all NMBAs that, however, display vastly different chemical structures. Among animal models, non-human primates (NHP) are an essential model for a great diversity of human disease models but remain poorly characterized for the effectiveness of the diverse NMBAs. MethodsSeven healthy male cynomolgus macaques were randomly assigned to this study. Experiments using macaques were approved by the local ethical committee (CEtEA #44). All animals were anaesthetized according to institutional guidelines, with ketamine and medetomidine, allowing IV line placement and tracheal intubation. Anaesthesia was maintained with isofluorane. Either rocuronium bromine or atracurium besylate was evaluated, with reversal with sugammadex. Monitoring was performed with two devices, TOF-Watch(R) and ToFscan(R), measuring the T4/T1 and the T4/Tref ratios, respectively. Nonparametric Mann-Whitney statistical analyses were done when indicated. ResultsNMBA monitoring required adaptation compared to humans, such as stimulus intensity and electrodes placement, to be efficient and valid in Cynomolgus macaques. When administered, both NMBAs induced deep and persistent neuro-muscular blockade at equivalent doses to clinical doses in humans. Rocuronium-induced profound neuromuscular blockade could be reverted using the cyclodextrin sugammadexs reversal agent. We report no adverse effects in these models by clinical observation, blood chemistry, or complete blood count. ConclusionThese results support the use of non-human primate models for neuromuscular blockade monitoring and testing novel NMBA or their reversal agents.

pathology↗

bioRxiv2023

RIDGE, a tool tailored to detect gene flow barriers across species pairs

Characterizing the processes underlying reproductive isolation between diverging lineages is central to understanding speciation. Here, we present RIDGE - Reproductive Isolation Detection using Genomic polymorphisms - a tool tailored for quantifying gene flow barrier proportions and identifying the corresponding genomic regions. RIDGE relies on an Approximate Bayesian Computation with a model-averaging approach to accommodate diverse scenarios of lineage divergence. It captures heterogeneity in effective migration rate along the genome while accounting for variation in linked selection and recombination. The barrier detection test relies on numerous summary statistics to compute a Bayes factor, offering a robust statistical framework that facilitates cross-species comparisons. Simulations revealed that RIDGE is particularly efficient both at capturing signals of ongoing migration and at identifying barrier loci, including for recent divergence times (~0.1 2Ne generations). Applying RIDGE to four published crow datasets, we validated our tool by identifying a well-known large genomic region associated with mate choice patterns. We identified additional barrier loci between species pairs, which have shown, on the one hand, that depending on the biological, demographic, and selection contexts, different combinations of summary statistics are informative for the detection of signals. On the other hand, these analyses also highlight the value of our newly developed outlier statistics in challenging detection conditions.

evolutionary biology↗

bioRxiv2023

A novel adjuvant formulation induces robust Th1/Th17 memory and mucosal recall responses in Non-Human Primates

After clean drinking water, vaccination is the most impactful global health intervention. However, development of new vaccines against difficult-to-target diseases is hampered by the lack of diverse adjuvants for human use. Of particular interest, none of the currently available adjuvants induce Th17 cells. Here, we develop and test an improved liposomal adjuvant, termed CAF(R)10b, that incorporates a TLR-9 agonist. In a head-to-head study in non-human primates (NHPs), immunization with antigen adjuvanted with CAF(R)10b induced significantly increased antibody and cellular immune responses compared to previous CAF(R) adjuvants, already in clinical trials. This was not seen in the mouse model, demonstrating that adjuvant effects can be highly species specific. Importantly, intramuscular immunization of NHPs with CAF(R)10b induced robust Th17 responses that were observed in circulation half a year after vaccination. Furthermore, subsequent instillation of unadjuvanted antigen into the skin and lungs of these memory animals led to significant recall responses including transient local lung inflammation observed by Positron Emission Tomography-Computed Tomography (PET-CT), elevated antibody titers, and expanded systemic and local Th1 and Th17 responses, including >20% antigen-specific T cells in the bronchoalveolar lavage. Overall, CAF(R)10b demonstrated an adjuvant able to drive true memory antibody, Th1 and Th17 vaccine-responses across rodent and primate species, supporting its translational potential.

immunology↗

bioRxiv2021

Sonogenetic stimulation of the brain at a spatiotemporal resolution suitable for vision restoration

Remote, precisely controlled activation of the brain is a fundamental challenge in the development of brain-machine interfaces providing feasible rehabilitation strategies for neurological disorders. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain1-7, but this approach lacks spatial resolution and cellular selectivity and loads the brain with high levels of acoustic energy. The combination of the expression of ultrasound-sensitive proteins with ultrasound stimulation ( sonogenetic stimulation) can provide cellular selectivity and higher sensitivity, but such strategies have been subject to severe limitations in terms of spatiotemporal resolution in vivo8-10, precluding their use for real-life applications. We used the expression of large-conductance mechanosensitive ion channels (MscL) with high-frequency ultrasonic stimulation for a duration of milliseconds to activate neurons selectively at a relatively high spatiotemporal resolution in the rat retina ex vivo and the primary visual cortex of rodents in vivo. This spatiotemporal resolution was achieved at low energy levels associated with negligible tissue heating and far below those leading to complications in ultrasound neuromodulation6,11. We showed, in an associative learning test, that sonogenetic stimulation of the visual cortex generated light perception. Our findings demonstrate that sonogenetic stimulation is compatible with millisecond pattern presentation for visual restoration at the cortical level. They represent a step towards the precise transfer of information over large distances to the cortical and subcortical regions of the brain via an approach less invasive than that associated with current brain-machine interfaces and with a wide range of applications in neurological disorders.

neuroscience↗

bioRxiv2021

Gene network simulations provide testable predictions for the molecular domestication syndrome

The domestication of plant species lead to repeatable morphological evolution, often referred to as the phenotypic domestication syndrome. Domestication is also associated with important genomic changes, such as the loss of genetic diversity compared to adequately large wild populations, and modifications of gene expression patterns. Here, we explored theoretically the effect of a domestication-like scenario on the evolution of gene regulatory networks. We ran population genetics simulations in which individuals were featured by their genotype (an interaction matrix encoding a gene regulatory network) and their gene expressions, representing the phenotypic level. Our domestication scenario included a population bottleneck and a selection switch mimicking human-mediated directional and canalizing selection, i.e., change in the optimal gene expression level and selection towards more stable expression across environments. We showed that domestication profoundly alters genetic architectures. Based on four examples of plant domestication scenarios, our simulations predict (i) a drop in neutral allelic diversity, (ii) a change in gene expression variance that depends upon the domestication scenario, (iii) transient maladaptive plasticity, (iv) a deep rewiring of the gene regulatory networks, with a trend towards gain of regulatory interactions, and (v) a global increase in the genetic correlations among gene expressions, with a loss of modularity in the resulting coexpression patterns and in the underlying networks. We provide empirically testable predictions on the differences of genetic architectures between wild and domesticated forms. The characterization of such systematic evolutionary changes in the genetic architecture of traits contributes to define a molecular domestication syndrome.

evolutionary biology↗

bioRxiv2021

In vivo optogenetic stimulation of the primate retina activates the visual cortex after long-term transfection

Over the last 15 years, optogenetics has changed fundamental research in neuroscience, and is now reaching toward therapeutic applications. Vision restoration strategies using optogenetics are now at the forefront of these new clinical opportunities. But applications to human patients suffering from retinal diseases leading to blindness rise important concerns on the long-term functional expression of optogenes and the efficient signal transmission to higher visual centers. Here we demonstrate in non-human primates, continued expression and functionality at the retina level [~]20 months after delivery of our construct. We also performed in-vivo recordings of visually evoked potentials in the primary visual cortex of anaesthetized animals. Using synaptic blockers, we isolated the in-vivo cortical activation resulting from the direct optogenetic stimulation of primate retina. In conclusion, our work indicates long-term transgene expression and transmission of the signal generated in the macaque retina to the visual cortex, two important features for future clinical applications.

neuroscience↗