A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis

Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting approximately 2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20-30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24-q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.     

Integrating Quarterly Data into a Dynamic Factor Model of US Monthly GDP

This paper develops and estimates a dynamic factor model in which estimates for unobserved monthly US Gross Domestic Product (GDP) are consistent with observed quarterly data. In contrast to existing approaches, the quarterly averages of our monthly estimates are exactly equal to the Bureau of Economic Analysis (BEA) quarterly estimates. The relationship between our monthly estimates and the quarterly data is therefore the same as the relationship between quarterly and annual data. The study makes use of Bayesian Markov chain Monte Carlo and data augmentation techniques to simulate values for the logarithms on monthly US GDP. The imposition of the exact linear quarterly constraint produces a non‐standard distribution, necessitating the implementation of a Metropolis simulation step in the estimation. Our methodology can be easily generalized to cases where the variable of interest is monthly GDP and in such a way that the final results incorporate the statistical uncertainty associated with the monthly GDP estimates. We provide an example by incorporating our monthly estimates into a Markov switching model of the US business cycle. Copyright © 2016 John Wiley & Sons, Ltd.     

Benjamin Moore,Science, and Medical Planning in early Twentieth-Century Britain

Benjamin Moore (1867–1922), physiologist and biochemist, was an eminent member of the British scientific and medical community in the early twentieth century. As a founder and president of the State Medical Services Association (SMSA) from its establishment in 1912 until his untimely death in 1922, Moore was a prominent medical services activist and planner in a period of intense debate on health services reform. As a medical scientist, Moore was also a participant in the campaign by laboratory scientists to obtain a larger role in clinical education, research, and medicine in this period. This article examines the medical services activism and ideas of Benjamin Moore. In particular, it seeks to demonstrate how his health services proposals and those he influenced, including SMSA and Labour Party plans, sought to advance the interests of laboratory scientists.     

Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair

The genetic determinants of hair texture in humans are largely unknown. Several human syndromes exist in which woolly hair comprises a part of the phenotype; however, simple autosomal recessive inheritance of isolated woolly hair has only rarely been reported. To identify a gene involved in controlling hair texture, we performed genetic linkage analysis in six families of Pakistani origin with autosomal recessive woolly hair (ARWH; OMIM 278150). All six families showed linkage to chromosome 13q14.2-14.3 (Z = 17.97). In all cases, we discovered pathogenic mutations in P2RY5, which encodes a G protein-coupled receptor and is a nested gene residing within intron 17 of the retinoblastoma 1 (RB1) gene. P2RY5 is expressed in both Henle's and Huxley's layers of the inner root sheath of the hair follicle. Our findings indicate that disruption of P2RY5 underlies ARWH and, more broadly, uncover a new gene involved in determining hair texture in humans.     

Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1

To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.     

Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease

Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.     

From Cutting Nature at Its Joints to Measuring It: New Kinds and New Kinds of People in Biology

In the received version of the development of science, natural kinds are established in the preliminary stages (natural history) and made more precise by measurement (exact science). By examining the move from nineteenth- to twentieth-century biology, this paper unpacks the notion of species as ‘natural kinds’ and grounds for discourse, questioning received notions about both kinds and species. Life sciences in the nineteenth century established several ‘monster-barring’ techniques to block disputes about the precise definition of species. Counterintuitively, precision and definition brought dispute and disrupted exchange. Thus, any attempt to add precision was doomed to failure. By intervening and measuring, the new experimental biology dislocated the established links between natural kinds and kinds of people and institutions. New kinds were built in new places. They were made to measure from the very start. This paper ends by claiming that there was no long-standing ‘species problem’ in the history of biology. That problem is a later construction of the ‘modern synthesis’, well after the disruption of ‘kinds’ and kinds of people. Only then would definitions and precision matter. A new, non-linguistic, take on the incommensurability thesis is hinted at.     

The Concept of Sustainability in the Evolutionary Guidance of an Educational Institution

Sustainability has been introduced at Ithaca College as a potential guiding theme for a wide range of development efforts. How these efforts will shape the institution's future is unclear, particularly when one places them in the context of recent changes in the College's approach to governance and planning. Countering rather primitive applications of systems thinking in the popular literature on sustainability, a case is made that sustainability principles can be reframed within Banathy's [Banathy, B. H. (1989). Syst. Res. 6(4), 289–296.] notion of an evolutionary guidance system, and this could lead to the next evolutionary stage of the institution.     

Retinal light adaptation--evidence for a feedback mechanism

Light adaptation is the adjustment of retinal response properties to variations in ambient illumination. It enables the encoding of visual information over a millionfold intensity range, from moonlight to broad daylight, despite the relatively small dynamic range of response of visual neurones. We have studied the effects of light adaptation on the dynamics and sensitivity of visual responses of neurones in the turtle retina, by measuring the responses of horizontal cells in the retina to light which was modulated with a sinusoidal time course around various mean levels. As a quantitative measure of the transduction from light to neural signals, we calculated the gain of response at each frequency. Gain is defined as the amplitude of the modulated response component divided by the amplitude of light modulation. We report here that the gain (mV photon-1) at low temporal frequencies decreased as the mean light level increased. Over a 2 log-unit range of mean light levels, low-frequency gain was inversely proportional to the mean light level, as in Weber's law. However, at high temporal frequencies, the gain was almost independent of mean light level. Our results are reminiscent of Kelly's results on human temporal-frequency sensitivity in various states of light adaptation. We found that a family of horizontal-cell temporal frequency responses, measured at various mean light levels, could be accounted for by a negative feedback model in which the feedback strength is proportional to mean light level.