Direct BMP2/4 signaling through BMP receptor IA regulates fetal thymocyte progenitor homeostasis and differentiation to CD4+CD8+double-positive cell

BMP2/4 signaling is required for embryogenesis and involved in thymus morphogenesis and T-lineage differentiation. In vitro experiments have shown that treatment of thymus explants with exogenous BMP4 negatively regulated differentiation of early thymocyte progenitors and the transition from CD4−CD8− (DN) to CD4+CD8+ (DP). Here we show that in vivo BMP2/4 signaling is required for fetal thymocyte progenitor homeostasis and expansion, but negatively regulates differentiation from DN to DP cell. Unexpectedly, conditional deletion of BMPRIA from fetal thymocytes (using the Cre-loxP system and directing excision to hematopoietic lineage cells with the Vav promoter) demonstrated that physiological levels of BMP2/4 signaling directly to thymocytes through BMPRIA are required for normal differentiation and expansion of early fetal DN thymocytes. In contrast, the arrest in early thymocyte progenitor differentiation caused by exogenous BMP4 treatment of thymus explants is induced in part by direct signaling to thymocytes through BMPRIA, and in part by indirect signaling through non-hematopoietic cells. Analysis of the transition from fetal DN to DP cell, both by ex vivo analysis of conditional BMPRIA-deficient thymocytes and by treatment of thymus explants with the BMP4-inhibitor Noggin demonstrated that BMP2/4 signaling is a negative regulator at this stage. We showed that at this stage of fetal T-cell development BMP2/4 signals directly to thymocytes through BMPRIA

Recent Advances in Graph Partitioning

We survey recent trends in practical algorithms for balanced graph partitioning together with applications and future research directions

Stress Strengthens Memory of First Impressions of Others' Positive Personality Traits

Encounters with strangers bear potential for social conflict and stress, but also allow the formation of alliances. First impressions of other people play a critical role in the formation of alliances, since they provide a learned base to infer the other's future social attitude. Stress can facilitate emotional memories but it is unknown whether stress strengthens our memory for newly acquired impressions of other people's personality traits. To answer this question, we subjected 60 students (37 females, 23 males) to an impression-formation task, viewing portraits together with brief positive vs. negative behavior descriptions, followed by a 3-min cold pressor stress test or a non-stressful control procedure. The next day, novel and old portraits were paired with single trait adjectives, the old portraits with a trait adjective matching the previous day's behavior description. After a filler task, portraits were presented again and subjects were asked to recall the trait adjective. Cued recall was higher for old (previously implied) than the novel portraits' trait adjectives, indicating validity of the applied test procedures. Overall, recall rate of implied trait adjectives did not differ between the stress and the control group. However, while the control group showed a better memory performance for others' implied negative personality traits, the stress group showed enhanced recall for others' implied positive personality traits. This result indicates that post-learning stress affects consolidation of first impressions in a valence-specific manner. We propose that the stress-induced strengthening of memory of others' positive traits forms an important cue for the formation of alliances in stressful conditions

Modular Mass Spectrometric Tool for Analysis of Composition and Phosphorylation of Protein Complexes

The combination of high accuracy, sensitivity and speed of single and multiple-stage mass spectrometric analyses enables the collection of comprehensive sets of data containing detailed information about complex biological samples. To achieve these properties, we combined two high-performance matrix-assisted laser desorption ionization mass analyzers in one modular mass spectrometric tool, and applied this tool for dissecting the composition and post-translational modifications of protein complexes. As an example of this approach, we here present studies of the Saccharomyces cerevisiae anaphase-promoting complexes (APC) and elucidation of phosphorylation sites on its components. In general, the modular concept we describe could be useful for assembling mass spectrometers operating with both matrix-assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) ion sources into powerful mass spectrometric tools for the comprehensive analysis of complex biological samples

The individual and combined effects of obesity- and ageing-induced systemic inflammation on human skeletal muscle properties.

BACKGROUND/OBJECTIVES: The purpose of this study was to determine whether circulating pro-inflammatory cytokines, elevated with increased fat mass and ageing, were associated with muscle properties in young and older people with variable adiposity. SUBJECTS/METHODS: Seventy-five young (18-49 yrs) and 67 older (50-80 yrs) healthy, untrained men and women (BMI: 17-49 kg/m(2)) performed isometric and isokinetic plantar flexor maximum voluntary contractions (MVCs). Volume (Vm), fascicle pennation angle (FPA), and physiological cross-sectional area (PCSA) of the gastrocnemius medialis (GM) muscle were measured using ultrasonography. Voluntary muscle activation (VA) was assessed using electrical stimulation. GM specific force was calculated as GM fascicle force/PCSA. Percentage body fat (BF%), body fat mass (BFM), and lean mass (BLM) were assessed using dual-energy X-ray absorptiometry. Serum concentration of 12 cytokines was measured using multiplex luminometry. RESULTS: Despite greater Vm, FPA, and PCSA (P0.05), while IL-8 correlated with VA in older but not young adults (r⩾0.378, P⩽0.027). TNF-alpha correlated with MVC, lean mass, GM FPA and maximum force in older adults (r⩾0.458; P⩽0.048). CONCLUSIONS: The age- and adiposity-dependent relationships found here provide evidence that circulating pro-inflammatory cytokines may play different roles in muscle remodelling according to the age and adiposity of the individual.International Journal of Obesity accepted article preview online, 29 August 2016. doi:10.1038/ijo.2016.151

The Role of Response Elements Organization in Transcription Factor Selectivity: The IFN-β Enhanceosome Example

What is the mechanism through which transcription factors (TFs) assemble specifically along the enhancer DNA? The IFN-β enhanceosome provides a good model system: it is small; its components' crystal structures are available; and there are biochemical and cellular data. In the IFN-β enhanceosome, there are few protein-protein interactions even though consecutive DNA response elements (REs) overlap. Our molecular dynamics (MD) simulations on different motif combinations from the enhanceosome illustrate that cooperativity is achieved via unique organization of the REs: specific binding of one TF can enhance the binding of another TF to a neighboring RE and restrict others, through overlap of REs; the order of the REs can determine which complexes will form; and the alternation of consensus and non-consensus REs can regulate binding specificity by optimizing the interactions among partners. Our observations offer an explanation of how specificity and cooperativity can be attained despite the limited interactions between neighboring TFs on the enhancer DNA. To date, when addressing selective TF binding, attention has largely focused on RE sequences. Yet, the order of the REs on the DNA and the length of the spacers between them can be a key factor in specific combinatorial assembly of the TFs on the enhancer and thus in function. Our results emphasize cooperativity via RE binding sites organization

Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI.</p> <p>Results</p> <p>We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis.</p> <p>Conclusion</p> <p>Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing.</p

Ontogeny of Numerical Abilities in Fish

Background: It has been hypothesised that human adults, infants, and non-human primates share two non-verbal systems for enumerating objects, one for representing precisely small quantities (up to 3–4 items) and one for representing approximately larger quantities. Recent studies exploiting fish’s spontaneous tendency to join the larger group showed that their ability in numerical discrimination closely resembles that of primates but little is known as to whether these capacities are innate or acquired. Methodology/Principal Findings: We used the spontaneous tendency to join the larger shoal to study the limits of the quantity discrimination of newborn and juvenile guppies. One-day old fish chose the larger shoal when the choice was between numbers in the small quantity range, 2 vs. 3 fish, but not when they had to choose between large numbers, 4 vs. 8 or 4 vs. 12, although the numerical ratio was larger in the latter case. To investigate the relative role of maturation and experience in large number discrimination, fish were raised in pairs (with no numerical experience) or in large social groups and tested at three ages. Forty-day old guppies from both treatments were able to discriminate 4 vs. 8 fish while at 20 days this was only observed in fish grown in groups. Control experiments showed that these capacities were maintained after guppies were prevented from using non numerical perceptual variables that co-vary with numerosity. Conclusions/Significance: Overall, our results suggest the ability of guppies to discriminate small numbers is innate and i