Co-evolution is incompatible with the Markov assumption in phylogenetics

Markov models are extensively used in the analysis of molecular evolution. A recent line of research suggests that pairs of proteins with functional and physical interactions co-evolve with each other. Here, by analyzing hundreds of orthologous sets of three fungi and their co-evolutionary relations, we demonstrate that co-evolutionary assumption may violate the Markov assumption. Our results encourage developing alternative probabilistic models for the cases of extreme co-evolution.     

Purifying stem cell-derived red blood cells: a high-throughput label-free downstream processing strategy based on microfluidic spiral inertial separation and membrane filtration

Cell-based therapeutics, such as in vitro manufactured red blood cells (mRBCs), are different to traditional biopharmaceutical products (the final product being the cells themselves as opposed to biological molecules such as proteins) and that presents a challenge of developing new robust and economically feasible manufacturing processes, especially for sample purification. Current purification technologies have limited throughput, rely on expensive fluorescent or magnetic immunolabeling with a significant (up to 70%) cell loss and quality impairment. To address this challenge, previously characterized mechanical properties of umbilical cord blood CD34+ cells undergoing in vitro erythropoiesis were used to develop an mRBC purification strategy. The approach consists of two main stages: (a) a microfluidic separation using inertial focusing for deformability-based sorting of enucleated cells (mRBC) from nuclei and nucleated cells resulting in 70% purity and (b) membrane filtration to enhance the purity to 99%. Herein, we propose a new route for high-throughput (processing millions of cells/min and mls of medium/min) purification process for mRBC, leading to high mRBC purity while maintaining cell integrity and no alterations in their global gene expression profile. Further adaption of this separation approach offers a potential route for processing of a wide range of cellular products.     

Correction to: Exposing the hidden half: root research at the forefront of science

Plant and Soil - In the published version of this editorial paper, the sentence in the first paragraph should be corrected as shown below.     

Quantitative assessment of higher-order chromatin structure of the INK4/ARF locus in human senescent cells

Somatic cells can be reset to oncogene-induced senescent (OIS) cells or induced pluripotent stem (iPS) cells by expressing specified factors. The INK4/ARF locus encodes p15(INK4b) , ARF, and p16(INK4a) genes in human chromosome 9p21, the products of which are known as common key reprogramming regulators. Compared with growing fibroblasts, the CCCTC-binding factor CTCF is remarkably up-regulated in iPS cells with silencing of the three genes in the locus and is reversely down-regulated in OIS cells with high expression of p15(INK4b) and p16(INK4a) genes. There are at least three CTCF-enriched sites in the INK4/ARF locus, which possess chromatin loop-forming activities. These CTCF-enriched sites and the p16(INK4a) promoter associate to form compact chromatin loops in growing fibroblasts, while CTCF depletion disrupts the loop structure. Interestingly, the loose chromatin structure is found in OIS cells. In addition, the INK4/ARF locus has an intermediate type of chromatin compaction in iPS cells. These results suggest that senescent cells have distinct higher-order chromatin signature in the INK4/ARF locus.     

Determinants of Translation Elongation Speed and Ribosomal Profiling Biases in Mouse Embryonic Stem Cells

Ribosomal profiling is a promising approach with increasing popularity for studying translation. This approach enables monitoring the ribosomal density along genes at a resolution of single nucleotides.In this study, we focused on ribosomal density profiles of mouse embryonic stem cells. Our analysis suggests, for the first time, that even in mammals such as M. musculus the elongation speed is significantly and directly affected by determinants of the coding sequence such as: 1) the adaptation of codons to the tRNA pool; 2) the local mRNA folding of the coding sequence; 3) the local charge of amino acids encoded in the codon sequence. In addition, our analyses suggest that in general, the translation velocity of ribosomes is slower at the beginning of the coding sequence and tends to increase downstream.Finally, a comparison of these data to the expected biophysical behavior of translation suggests that it suffers from some unknown biases. Specifically, the ribosomal flux measured on the experimental data increases along the coding sequence; however, according to any biophysical model of ribosomal movement lacking internal initiation sites, the flux is expected to remain constant or decrease. Thus, developing experimental and/or statistical methods for understanding, detecting and dealing with such biases is of high importance.     

Effects of different forms of Acacia saligna leaves inclusion on feed intake, digestibility and body weight gain in lambs fed grass hay basal diet

The study was undertaken to determine the effects of different forms of Acacia saligna leaves inclusion on feed intake, digestibility and body weight gain in lambs fed grass hay basal diet. Twenty local ‘Farta’ yearling male lambs weighing 17.4 ± 0.10 kg (mean ± SD) were randomly allocated to four dietary treatments consisting of daily feeding of lambs in T1 with 700 g grass hay (dry matter basis), and daily free choice feeding of lambs in T2, T3, and T4 with 700 g grass hay + 700 g fresh, wilted, and dried A. saligna leaves, respectively. Inclusion of different forms of A. saligna leaves improved (P<0.01) the daily intake of total DM by 8–9% and that of OM and CP by 7 and 38%, respectively compared to the control. The daily intake of NDFom was lower (P<0.01) by 1–2.3%, whereas that of the ADFom intake declined (P<0.01) by 1.3–3.4% for lambs on wilted and dried forms of A. saligna leaves. Inclusion of A. saligna leaves replaced the intake of the grass hay by 26–27% of the total diet and reduced (P<0.05) apparent digestibility coefficient of the total DM by 9, 7, and 4%, OM by 7, 6 and 4%, and CP by 12, 12, and 9%, but improved (P<0.05) apparent digestibility coefficient of NDFom by 3–4% compared to the control diet. Dried A. saligna leaves improved (P<0.05) apparent digestibility of DM, OM and CP compared to fresh A. saligna leaves. Lambs fed on hay alone lost (P<0.05) body weight, while the lambs supplemented with A. saligna leaves gained (P<0.05) weight. The results of this study revealed that A. saligna leaves could be best included in the grass hay based feeding in dried form at the rate of 265 g/kg DM for improved nutrient utilization and growth performance of yearling lambs.     

Maximum likelihood of phylogenetic networks

MOTIVATION: Horizontal gene transfer (HGT) is believed to be ubiquitous among bacteria, and plays a major role in their genome diversification as well as their ability to develop resistance to antibiotics. In light of its evolutionary significance and implications for human health, developing accurate and efficient methods for detecting and reconstructing HGT is imperative. RESULTS: In this article we provide a new HGT-oriented likelihood framework for many problems that involve phylogeny-based HGT detection and reconstruction. Beside the formulation of various likelihood criteria, we show that most of these problems are NP-hard, and offer heuristics for efficient and accurate reconstruction of HGT under these criteria. We implemented our heuristics and used them to analyze biological as well as synthetic data. In both cases, our criteria and heuristics exhibited very good performance with respect to identifying the correct number of HGT events as well as inferring their correct location on the species tree. AVAILABILITY: Implementation of the criteria as well as heuristics and hardness proofs are available from the authors upon request. Hardness proofs can also be downloaded at http://www.cs.tau.ac.il/~tamirtul/MLNET/Supp-ML.pdf     

The average common substring approach to phylogenomic reconstruction.

We describe a novel method for efficient reconstruction of phylogenetic trees, based on sequences of whole genomes or proteomes, whose lengths may greatly vary. The core of our method is a new measure of pairwise distances between sequences. This measure is based on computing the average lengths of maximum common substrings, which is intrinsically related to information theoretic tools (Kullback-Leibler relative entropy). We present an algorithm for efficiently computing these distances. In principle, the distance of two l long sequences can be calculated in O(l) time. We implemented the algorithm using suffix arrays our implementation is fast enough to enable the construction of the proteome phylogenomic tree for hundreds of species and the genome phylogenomic forest for almost two thousand viruses. An initial analysis of the results exhibits a remarkable agreement with "acceptable phylogenetic and taxonomic truth." To assess our approach, our results were compared to the traditional (single-gene or protein-based) maximum likelihood method. The obtained trees were compared to implementations of a number of alternative approaches, including two that were previously published in the literature, and to the published results of a third approach. Comparing their outcome and running time to ours, using a "traditional" trees and a standard tree comparison method, our algorithm improved upon the "competition" by a substantial margin. The simplicity and speed of our method allows for a whole genome analysis with the greatest scope attempted so far. We describe here five different applications of the method, which not only show the validity of the method, but also suggest a number of novel phylogenetic insights.     

Light-sensitive lipid-based nanoparticles for drug delivery: design principles and future considerations for biological applications

Radiation-based therapies aided by nanoparticles have been developed for decades, and can be primarily categorized into two main platforms. First, delivery of payload of photo-reactive drugs (photosensitizers) using the conventional nanoparticles, and second, design and development of photo-triggerable nanoparticles (primarily liposomes) to attain light-assisted on-demand drug delivery. The main focus of this review is to provide an update of the history, current status and future applications of photo-triggerable lipid-based nanoparticles (light-sensitive liposomes). We will begin with a brief overview on the applications of liposomes for delivery of photosensitizers, including the choice of photosensitizers for photodynamic therapy, as well as the currently available light sources (lasers) used for these applications. The main segment of this review will encompass the details of strategies used to develop photo-triggerable liposomes for their drug delivery function. The principles underlying the assembly of photoreactive lipids into nanoparticles (liposomes) and photo-triggering mechanisms will be presented. We will also discuss factors that limit the applications of these liposomes for in vivo triggered drug delivery and emerging concepts that may lead to the biologically viable photo-activation strategies. We will conclude with our view point on the future perspectives of light-sensitive liposomes in the clinic.