Circulating granulocyte lifespan in compensated alcohol-related cirrhosis: a pilot study.

Although granulocyte dysfunction is known to occur in cirrhosis, in vivo studies of granulocyte lifespan have not previously been performed. The normal circulating granulocyte survival half-time (G - t½), determined using indium-111 ((111)In)-radiolabeled granulocytes, is ~7 h. In this pilot study, we aimed to measure the in vivo G - t½ in compensated alcohol-related cirrhosis. Sequential venous blood samples were obtained in abstinent subjects with alcohol-related cirrhosis over 24 h post injection (PI) of minimally manipulated (111)In-radiolabeled autologous mixed leukocytes. Purified granulocytes were isolated from each sample using a magnetic microbead-antibody technique positively selecting for the marker CD15. Granulocyte-associated radioactivity was expressed relative to peak activity, plotted over time, and G - t½ estimated from data up to 12 h PI This was compared with normal neutrophil half-time (N - t½), determined using a similar method specifically selecting neutrophils in healthy controls at a collaborating center. Seven patients with cirrhosis (six male, aged 57.8 ± 9.4 years, all Child-Pugh class A) and seven normal controls (three male, 64.4 ± 5.6 years) were studied. Peripheral blood neutrophil counts were similar in both groups (4.6 (3.5 - 5.5) × 10(9)/L vs. 2.8 (2.7 - 4.4) × 10(9)/L, respectively, P = 0.277). G - t½ in cirrhosis was significantly lower than N - t½ in controls (2.7 ± 0.5 h vs. 4.4 ± 1.0 h, P = 0.007). Transient rises in granulocyte and neutrophil-associated activities occurred in four patients from each group, typically earlier in cirrhosis (4-6 h PI) than in controls (8-10 h), suggesting recirculation of radiolabeled cells released from an unidentified focus. Reduced in vivo granulocyte survival in compensated alcohol-related cirrhosis is a novel finding and potentially another mechanism for immune dysfunction in chronic liver disease. Larger studies are needed to corroborate these pilot data and assess intravascular neutrophil residency in other disease etiologies.Asthma UK (08/2011) MRC (MR/J00345X/1)This is the final version of the article. It first appeared from the American Physiological Society via http://dx.doi.org/10.14814/phy2.1283

Mechanical behaviour of rapidly solidified copper: effects of undercooling and strain rate

In this paper we present the results, from what we believe is the first ever attempt to study the mechanical behaviour of pure highly undercooled Cu specimens. The data revealed that the strength of the studied system increases not only with an increase of the level of undercooling, but also with the rate of testing. Microstructural analysis demonstrated that at undercoolings above 200 K the specimens underwent a transition from dendritic to a grain refined structure, accompanied with a break in the stress-undercooling relationship. It is suggested that on this occasion the transition was the result of two competing mechanisms: dendrite fragmentation and recrystallization. Finally, the relationship between the resultant grain sizes and measured stresses is compared against the Hall-Petch Law

Scaling properties of protein family phylogenies

One of the classical questions in evolutionary biology is how evolutionary processes are coupled at the gene and species level. With this motivation, we compare the topological properties (mainly the depth scaling, as a characterization of balance) of a large set of protein phylogenies with a set of species phylogenies. The comparative analysis shows that both sets of phylogenies share remarkably similar scaling behavior, suggesting the universality of branching rules and of the evolutionary processes that drive biological diversification from gene to species level. In order to explain such generality, we propose a simple model which allows us to estimate the proportion of evolvability/robustness needed to approximate the scaling behavior observed in the phylogenies, highlighting the relevance of the robustness of a biological system (species or protein) in the scaling properties of the phylogenetic trees. Thus, the rules that govern the incapability of a biological system to diversify are equally relevant both at the gene and at the species level.Comment: Replaced with final published versio

Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells

Phosphoinositide 3-kinases (PI-3Ks) are enzymes that generate lipid second messenger molecules, resulting in the activation of multiple intracellular signalling cascades. These events regulate a broad array of cellular responses including survival, activation, differentiation and proliferation and are now recognised to have a key role in a number of physiological and pathophysiological processes in the lung. PI-3Ks contribute to the pathogenesis of asthma by influencing the proliferation of airways smooth muscle and the recruitment of eosinophils, and affect the balance between the harmful and protective responses in pulmonary inflammation and infection by the modulation of granulocyte recruitment, activation and apoptosis. In addition they also seem to exert a critical influence on the malignant phenotype of small cell lung cancer. PI-3K isoforms and their downstream targets thus provide novel therapeutic targets for intervention in a broad spectrum of respiratory diseases

Evolution from XIST-Independent to XIST-Controlled X-Chromosome Inactivation: Epigenetic Modifications in Distantly Related Mammals

X chromosome inactivation (XCI) is the transcriptional silencing of one X in female mammals, balancing expression of X genes between females (XX) and males (XY). In placental mammals non-coding XIST RNA triggers silencing of one X (Xi) and recruits a characteristic suite of epigenetic modifications, including the histone mark H3K27me3. In marsupials, where XIST is missing, H3K27me3 association seems to have different degrees of stability, depending on cell-types and species. However, the complete suite of histone marks associated with the Xi and their stability throughout cell cycle remain a mystery, as does the evolution of an ancient mammal XCI system. Our extensive immunofluorescence analysis (using antibodies against specific histone modifications) in nuclei of mammals distantly related to human and mouse, revealed a general absence from the mammalian Xi territory of transcription machinery and histone modifications associated with active chromatin. Specific repressive modifications associated with XCI in human and mouse were also observed in elephant (a distantly related placental mammal), as was accumulation of XIST RNA. However, in two marsupial species the Xi either lacked these modifications (H4K20me1), or they were restricted to specific windows of the cell cycle (H3K27me3, H3K9me2). Surprisingly, the marsupial Xi was stably enriched for modifications associated with constitutive heterochromatin in all eukaryotes (H4K20me3, H3K9me3). We propose that marsupial XCI is comparable to a system that evolved in the common therian (marsupial and placental) ancestor. Silent chromatin of the early inactive X was exapted from neighbouring constitutive heterochromatin and, in early placental evolution, was augmented by the rise of XIST and the stable recruitment of specific histone modifications now classically associated with XCI

Examining the Evidence for Chytridiomycosis in Threatened Amphibian Species

Extinction risks are increasing for amphibians due to rising threats and minimal conservation efforts. Nearly one quarter of all threatened/extinct amphibians in the IUCN Red List is purportedly at risk from the disease chytridiomycosis. However, a closer look at the data reveals that Batrachochytrium dendrobatidis (the causal agent) has been identified and confirmed to cause clinical disease in only 14% of these species. Primary literature surveys confirm these findings; ruling out major discrepancies between Red List assessments and real-time science. Despite widespread interest in chytridiomycosis, little progress has been made between assessment years to acquire evidence for the role of chytridiomycosis in species-specific amphibian declines. Instead, assessment teams invoke the precautionary principle when listing chytridiomycosis as a threat. Precaution is valuable when dealing with the world's most threatened taxa, however scientific research is needed to distinguish between real and predicted threats in order to better prioritize conservation efforts. Fast paced, cost effective, in situ research to confirm or rule out chytridiomycosis in species currently hypothesized to be threatened by the disease would be a step in the right direction. Ultimately, determining the manner in which amphibian conservation resources are utilized is a conversation for the greater conservation community that we hope to stimulate here