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Publications
Effective Latent Differential Equation Models via Attention and Multiple Shooting
For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuro… (voir plus)nal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in thirteen neurodegenerative conditions, including early-and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and three clinical variants of frontotemporal lobar degeneration (behavioural variant, semantic and non-fluent primary progressive aphasia) along with associated 3-repeat and 4-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorders pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.
Throughout the SARS-CoV-2 pandemic, several variants of concern (VOCs) have been identified, many of which share recurrent mutations in the … (voir plus)spike glycoprotein’s receptor-binding domain (RBD). This region coincides with known epitopes and can therefore have an impact on immune escape. Protracted infections in immunosuppressed patients have been hypothesized to lead to an enrichment of such mutations and therefore drive evolution towards VOCs. Here, we present the case of an immunosuppressed patient that developed distinct populations with immune escape mutations throughout the course of their infection. Notably, by investigating the co-occurrence of substitutions on individual sequencing reads in the RBD, we found quasispecies harboring mutations that confer resistance to known monoclonal antibodies (mAbs) such as S:E484K and S:E484A. These mutations were acquired without the patient being treated with mAbs nor convalescent sera and without them developing a detectable immune response to the virus. We also provide additional evidence for a viral reservoir based on intra-host phylogenetics, which led to a viral substrain that evolved elsewhere in the patient’s body, colonizing their upper respiratory tract (URT). The presence of SARS-CoV-2 viral reservoirs can shed light on protracted infections interspersed with periods where the virus is undetectable, and potential explanations for long-COVID cases.
Throughout the SARS-CoV-2 pandemic, several variants of concern (VOCs) have been identified, many of which share recurrent mutations in the … (voir plus)spike glycoprotein’s receptor-binding domain (RBD). This region coincides with known epitopes and can therefore have an impact on immune escape. Protracted infections in immunosuppressed patients have been hypothesized to lead to an enrichment of such mutations and therefore drive evolution towards VOCs. Here, we present the case of an immunosuppressed patient that developed distinct populations with immune escape mutations throughout the course of their infection. Notably, by investigating the co-occurrence of substitutions on individual sequencing reads in the RBD, we found quasispecies harboring mutations that confer resistance to known monoclonal antibodies (mAbs) such as S:E484K and S:E484A. These mutations were acquired without the patient being treated with mAbs nor convalescent sera and without them developing a detectable immune response to the virus. We also provide additional evidence for a viral reservoir based on intra-host phylogenetics, which led to a viral substrain that evolved elsewhere in the patient’s body, colonizing their upper respiratory tract (URT). The presence of SARS-CoV-2 viral reservoirs can shed light on protracted infections interspersed with periods where the virus is undetectable, and potential explanations for long-COVID cases.
Real-world decision-making problems involve Type 1 decision-dependent uncertainty, where the probability distribution of the stochastic proc… (voir plus)ess depends on the model decisions. However, few studies focus on two-stage stochastic programs with this type of endogenous uncertainty, and those that do lack general methodologies. We thus propose herein a general method for solving a class of these programs based on the transformation of random variables, a technique widely employed in probability and statistics. The proposed method is tailored to large-scale problems with discrete or continuous endogenous random variables. The random variable transformation allows the use of the sample average approximation (SAA) method, which provides optimality convergence guarantees under certain conditions. We show that, for some classical distributions, the proposed method reduces to solving mixed-integer linear or convex programs. Finally, we validate this method by applying it to a network design and facility-protection problem, considering distinct decision-dependent distributions for the random variables. Whereas most distributions result in a nonlinear nonconvex deterministic equivalent program, the proposed method solves mixed-integer linear programs in all cases. In addition, it produces attractive performance estimators for the SAA method in a reasonable computational time and outperforms the case in which the endogenous distribution defines a mixed-integer deterministic equivalent.
Hi-C is one of the most widely used approaches to study three-dimensional genome conformations. Contacts captured by a Hi-C experiment are r… (voir plus)epresented in a contact frequency matrix. Due to the limited sequencing depth and other factors, Hi-C contact frequency matrices are only approximations of the true interaction frequencies and are further reported without any quantification of uncertainty. Hence, downstream analyses based on Hi-C contact maps (e.g., TAD and loop annotation) are themselves point estimations. Here, we present the Hi-C interaction frequency sampler (HiCSampler) that reliably infers the posterior distribution of the interaction frequency for a given Hi-C contact map by exploiting dependencies between neighboring loci. Posterior predictive checks demonstrate that HiCSampler can infer highly predictive chromosomal interaction frequency. Summary statistics calculated by HiCSampler provide a measurement of the uncertainty for Hi-C experiments, and samples inferred by HiCSampler are ready for use by most downstream analysis tools off the shelf and permit uncertainty measurements in these analyses without modifications.
