MarrowQuant 2.0: A Digital Pathology Workflow Assisting Bone Marrow Evaluation in Experimental and Clinical Hematology.

Bone marrow (BM) cellularity assessment is a crucial step in the evaluation of BM trephine biopsies for hematologic and nonhematologic disorders. Clinical assessment is based on a semiquantitative visual estimation of the hematopoietic and adipocytic components by hematopathologists, which does not provide quantitative information on other stromal compartments. In this study, we developed and validated MarrowQuant 2.

Mammalian adipogenesis regulator (Areg) cells use retinoic acid signalling to be non- and anti-adipogenic in age-dependent manner.

Adipose stem and precursor cells (ASPCs) give rise to adipocytes and determine the composition and plasticity of adipose tissue. Recently, several studies have demonstrated that ASPCs partition into at least three distinct cell subpopulations, including the enigmatic CD142 cells. An outstanding challenge is to functionally characterise this population, as discrepant properties, from adipogenic to non- and anti-adipogenic, have been reported for these cells.

Shared acute phase traits in effector and memory human CD8 T cells.

CD8 T cells have multiple functional properties that mediate acute phase and long-term immune protection. Several effector and memory CD8 T cell subsets have been described with diverse functionalities and marker profiles. In contrast to the many comprehensive mouse studies, most human studies lack samples from the acute infection phase, a major reason why current knowledge of human T cell subsets and differentiation remains incomplete, particularly with regard to the T cell heterogeneity early during the immune response.

A minimalistic cyclic ice-binding peptide from phage display.

Developing molecules that emulate the properties of naturally occurring ice-binding proteins (IBPs) is a daunting challenge. Rather than relying on the (limited) existing structure-property relationships that have been established for IBPs, here we report the use of phage display for the identification of short peptide mimics of IBPs. To this end, an ice-affinity selection protocol is developed, which enables the selection of a cyclic ice-binding peptide containing just 14 amino acids.

Site-Specific Phosphorylation of Huntingtin Exon 1 Recombinant Proteins Enabled by the Discovery of Novel Kinases.

Post-translational modifications (PTMs) within the first 17 amino acids (Nt17) of exon 1 of the Huntingtin protein (Httex1) play important roles in modulating its cellular properties and functions in health and disease. In particular, phosphorylation of threonine and serine residues (T3, S13, and/or S16) has been shown to inhibit Htt aggregation in vitro and inclusion formation in cellular and animal models of Huntington's disease (HD). In this paper, we describe a new and simple methodology for producing milligram quantities of highly pure wild-type or mutant Httex1 proteins that are site-specifically phosphorylated at T3 or at both S13 and S16.

De novo development of proteolytically resistant therapeutic peptides for oral administration.

The oral administration of peptide drugs is hampered by their metabolic instability and limited intestinal uptake. Here, we describe a method for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases. By using phage display to screen large libraries of genetically encoded double-bridged peptides on protease-resistant fd bacteriophages, we generated a peptide inhibitor of the coagulation Factor XIa with nanomolar affinity that resisted gastrointestinal proteases in all regions of the gastrointestinal tract of mice after oral administration, enabling more than 30% of the peptide to remain intact, and small quantities of it to reach the blood circulation.

cis-regulatory variation modulates susceptibility to enteric infection in the Drosophila genetic reference panel.

Background: Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in the Drosophila Genetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants affect different molecular mechanisms to determine gut immunocompetence is still limited.

Results: To address this, we perform a systems genetics analysis of the gut transcriptomes from 38 DGRP lines that were orally infected with Pseudomonas entomophila.

Sex-dependent and sex-independent regulatory systems of size variation in natural populations.

Size of organs/organisms is a polygenic trait. Many of the growth-regulatory genes constitute conserved growth signaling pathways. However, how these multiple genes are orchestrated at the systems level to attain the natural variation in size including sexual size dimorphism is mostly unknown.

A stromal cell population that inhibits adipogenesis in mammalian fat depots.

Adipocyte development and differentiation have an important role in the aetiology of obesity and its co-morbidities. Although multiple studies have investigated the adipogenic stem and precursor cells that give rise to mature adipocytes, our understanding of their in vivo origin and properties is incomplete. This is partially due to the highly heterogeneous and unstructured nature of adipose tissue depots, which has proven difficult to molecularly dissect using classical approaches such as fluorescence-activated cell sorting and Cre-lox lines based on candidate marker genes.

Reversible De-differentiation of Mature White Adipocytes into Preadipocyte-like Precursors during Lactation.

Adipose tissue in the mammary gland undergoes dramatic remodeling during reproduction. Adipocytes are replaced by mammary alveolar structures during pregnancy and lactation, then reappear upon weaning. The fate of the original adipocytes during lactation and the developmental origin of the re-appearing adipocyte post involution are unclear.

Augmenting Research, Education, and Outreach with Client-Side Web Programming.

The evolution of computing and web technologies over the past decade has enabled the development of fully fledged scientific applications that run directly on web browsers. Powered by JavaScript, the lingua franca of web programming, these 'web apps' are starting to revolutionize and democratize scientific research, education, and outreach.

Extension of least squares spectral resolution algorithm to high-resolution lipidomics data.

Lipidomics, which focuses on the global study of molecular lipids in biological systems, has been driven tremendously by technical advances in mass spectrometry (MS) instrumentation, particularly high-resolution MS. This requires powerful computational tools that handle the high-throughput lipidomics data analysis. To address this issue, a novel computational tool has been developed for the analysis of high-resolution MS data, including the data pretreatment, visualization, automated identification, deconvolution and quantification of lipid species.

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production.

Outcome of the First wwPDB Hybrid/Integrative Methods Task Force Workshop.

Structures of biomolecular systems are increasingly computed by integrative modeling that relies on varied types of experimental data and theoretical information. We describe here the proceedings and conclusions from the first wwPDB Hybrid/Integrative Methods Task Force Workshop held at the European Bioinformatics Institute in Hinxton, UK, on October 6 and 7, 2014. At the workshop, experts in various experimental fields of structural biology, experts in integrative modeling and visualization, and experts in data archiving addressed a series of questions central to the future of structural biology.

Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding.

Protein-protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at high resolution. Here we exploited ubiquitin's noncovalent dimerization equilibrium to assess the potential of atomistic simulations to reproduce reversible protein-protein binding, by running submicrosecond simulations of systems with multiple copies of the protein at millimolar concentrations. The simulations essentially fail because they lead to aggregates, yet they reproduce some specificity in the binding interfaces as observed in known covalent and noncovalent ubiquitin dimers.

The importance of dynamics in integrative modeling of supramolecular assemblies.

Revealing the atomistic architecture of supramolecular complexes is a fundamental step toward a deeper understanding of cellular functioning. To date, this formidable task is facilitated by an emerging array of integrative modeling approaches that combine experimental data from different sources. One major challenge these methods have to face is the treatment of the dynamic rearrangements of the individual subunits upon assembly.