Grevelamm2855

We detect traces of extremely deep ancestry between some African populations, with around 1% of ancestry dating to divergences older than a million years ago.Systems Biology models reveal relationships between signaling inputs and observable molecular or cellular behaviors. The complexity of these models, however, often obscures key elements that regulate emergent properties. We use a Bayesian model reduction approach that combines Parallel Tempering with Lasso regularization to identify minimal subsets of reactions in a signaling network that are sufficient to reproduce experimentally observed data. The Bayesian approach finds distinct reduced models that fit data equivalently. A variant of this approach that uses Lasso to perform selection at the level of reaction modules is applied to the NF-κB signaling network to test the necessity of feedback loops for responses to pulsatile and continuous pathway stimulation. Taken together, our results demonstrate that Bayesian parameter estimation combined with regularization can isolate and reveal core motifs sufficient to explain data from complex signaling systems.Despite medical advances, the emergence and re-emergence of infectious diseases continue to pose a public health threat. Low-dimensional epidemiological models predict that epidemic transitions are preceded by the phenomenon of critical slowing down (CSD). This has raised the possibility of anticipating disease (re-)emergence using CSD-based early-warning signals (EWS), which are statistical moments estimated from time series data. buy Choline For EWS to be useful at detecting future (re-)emergence, CSD needs to be a generic (model-independent) feature of epidemiological dynamics irrespective of system complexity. Currently, it is unclear whether the predictions of CSD-derived from simple, low-dimensional systems-pertain to real systems, which are high-dimensional. To assess the generality of CSD, we carried out a simulation study of a hierarchy of models, with increasing structural complexity and dimensionality, for a measles-like infectious disease. Our five models included i) a nonseasonal homogeneous Susceptible-Exposed-Infectious-Recovered (SEIR) model, ii) a homogeneous SEIR model with seasonality in transmission, iii) an age-structured SEIR model, iv) a multiplex network-based model (Mplex) and v) an agent-based simulator (FRED). All models were parameterised to have a herd-immunity immunization threshold of around 90% coverage, and underwent a linear decrease in vaccine uptake, from 92% to 70% over 15 years. We found evidence of CSD prior to disease re-emergence in all models. We also evaluated the performance of seven EWS the autocorrelation, coefficient of variation, index of dispersion, kurtosis, mean, skewness, variance. Performance was scored using the Area Under the ROC Curve (AUC) statistic. The best performing EWS were the mean and variance, with AUC > 0.75 one year before the estimated transition time. These two, along with the autocorrelation and index of dispersion, are promising candidate EWS for detecting disease emergence.We present ProteoClade, a Python toolkit that performs taxa-specific peptide assignment, protein inference, and quantitation for multi-species proteomics experiments. ProteoClade scales to hundreds of millions of protein sequences, requires minimal computational resources, and is open source, multi-platform, and accessible to non-programmers. We demonstrate its utility for processing quantitative proteomic data derived from patient-derived xenografts and its speed and scalability enable a novel de novo proteomic workflow for complex microbiota samples.In the spinal cord, the central canal forms through a poorly understood process termed dorsal collapse that involves attrition and remodelling of pseudostratified ventricular layer (VL) cells. Here, we use mouse and chick models to show that dorsal ventricular layer (dVL) cells adjacent to dorsal midline Nestin(+) radial glia (dmNes+RG) down-regulate apical polarity proteins, including Crumbs2 (CRB2) and delaminate in a stepwise manner; live imaging shows that as one cell delaminates, the next cell ratchets up, the dmNes+RG endfoot ratchets down, and the process repeats. We show that dmNes+RG secrete a factor that promotes loss of cell polarity and delamination. This activity is mimicked by a secreted variant of Crumbs2 (CRB2S) which is specifically expressed by dmNes+RG. In cultured MDCK cells, CRB2S associates with apical membranes and decreases cell cohesion. Analysis of Crb2F/F/Nestin-Cre+/- mice, and targeted reduction of Crb2/CRB2S in slice cultures reveal essential roles for transmembrane CRB2 (CRB2TM) and CRB2S on VL cells and dmNes+RG, respectively. We propose a model in which a CRB2S-CRB2TM interaction promotes the progressive attrition of the dVL without loss of overall VL integrity. This novel mechanism may operate more widely to promote orderly progenitor delamination.Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize cargoes like cation-independent mannose 6-phosphate receptor (CI-MPR) and Insulin-like growth factor 1 receptor (IGF1R); however, it remains poorly understood how SNX-BARs select specific cargo proteins and whether they recognize additional ligands. Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. Using this motif, we identified over 70 putative SNX-BAR ligands, many of which play critical roles in apoptosis, cell adhesion, signal transduction, or metabolite homeostasis. Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.