Tumour necrosis factor alpha, interferon gamma and substance P are novel modulators of extrapituitary prolactin expression in human skin.

Human scalp skin and hair follicles (HFs) are extra-pituitary sources of prolactin (PRL). However, the intracutaneous regulation of PRL remains poorly understood. Therefore we investigated whether well-recognized regulators of pituitary PRL expression, which also impact on human skin physiology and pathology, regulate expression of PRL and its receptor (PRLR) in situ. This was studied in serum-free organ cultures of microdissected human scalp HFs and skin, i.e. excluding pituitary, neural and vascular inputs. Prolactin expression was confirmed at the gene and protein level in human truncal skin, where its expression significantly increased (p = 0.049) during organ culture. There was, however, no evidence of PRL secretion into the culture medium as measured by ELISA. PRL immunoreactivity (IR) in female human epidermis was decreased by substance P (p = 0.009), while neither the classical pituitary PRL inhibitor, dopamine, nor corticotropin-releasing hormone significantly modulated PRL IR in HFs or skin respectively. Interferon (IFN) gamma increased PRL IR in the epithelium of human HFs (p = 0.044) while tumour necrosis factor (TNF) alpha decreased both PRL and PRLR IR. This study identifies substance P, TNFalpha and IFNgamma as novel modulators of PRL and PRLR expression in human skin, and suggests that intracutaneous PRL expression is not under dopaminergic control. Given the importance of PRL in human hair growth regulation and its possible role in the pathogenesis of several common skin diseases, targeting intracutaneous PRL production via these newly identified regulatory pathways may point towards novel therapeutic options for inflammatory dermatoses

The cultural and geopolitical dimensions of nation-building in the Ukraine

Ukraine belongs among those young countries where the beginnings of democratisation and nation-building approximately coincided. While the development of nation states in Central Europe was usually preceded by the development of nations, the biggest dilemma in the Ukraine is whether a nation-state programme — parallel to the aim of state-building — is able to bring unfinished nation-building to completion. Ukraine sways between the EU and Russia with enormous amplitude. The alternating orientation between the West and the East can be ascribed to superpower ambitions reaching beyond Ukraine. Eventually, internal and external determinants are intertwined and mutually interact with one another. The aim of the paper is to explain the dilemmas arising from identity problems behind the Ukraine’s internal and external orientation

Regulation of TRPC6 ion channels in podocytes — Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases

The glomerular filtration barrier is a highly specialized tri-layer structure with unique functional properties. Podocyte dysfunction and cytoskeletal disorganization leads to disruption of the slit diaphragma, and proteinuria. Inflammatory diseases involving the kidney as well as inherited podocytopathies or diabetic nephropathy cause injury of the podocyte network. Focal segmental glomerulosclerosis (FSGS) is a pathologic entity that is a common cause of nephrotic syndrome with severe proteinuria in both adults and children. Several causative genes have been identified in the pathogenesis of FSGS. Mutations of the transient receptor potential canonical-6 (TRPC6), a non-selective cation channel that is directly activated by diacylglycerol (DAG), cause a particularly aggressive form of FSGS. Angiotensin II, acting through its AT1 receptor, plays a critical role in generation of proteinuria and progression of kidney injury in a number of kidney diseases, including FSGS. Mounting evidence suggest the central role of TRPC6 and perhaps other TRPC channels in the pathogenesis of FSGS as well as of acquired forms of proteinuria such as diabetic nephropathy or hypertension. Identification of signaling pathways downstream of TRPC6 may provide novel targets for the treatment of proteinuria and prevent progression of podocyte injury

In vivo imaging of Aminopeptidase N (CD13) receptors in experimental renal tumors using the novel radiotracer 68Ga-NOTA-c(NGR)

Purpose: Aminopeptidase N (APN/CD13) plays an important role in tumor neoangiogenic process and the development of metastases. Furthermore, it may serve as a potential target for cancer diagnosis and therapy. Previous studies have already shown that asparagine–glycine–arginine (NGR) peptides specifically bind to APN/CD13. The aim of the study was to synthesize and investigate the APN/CD13 specificity of a novel 68Ga-labeled NOTA-c(NGR) molecule in vivo using miniPET. Methods: c[KNGRE]-NH2 peptide was conjugated with p-SCN-Bn-NOTA and was labeled with Ga-68 (68Ga-NOTA-c(NGR)). Orthotopic and heterotopic transplanted mesoblastic nephroma (NeDe) bearing Fischer-344 rats were prepared, on which biodistribution studies and miniPET scans were performed for both 68Ga-NOTA-c(NGR) and amb3 integrin selective 68Ga-NODAGA-[c(RGD)]2 tracers. APN/CD13 receptor expression of NeDe tumors and metastases was analyzed by western blot. Results: 68Ga-NOTA-c(NGR) was produced with high specific activity (5.13–5.92 GBq/lmol) and with excellent radiochemical purity (95%<), at all cases. Biodistribution studies in normal rats showed that uptake of the 68Ga-NOTA-c(NGR) was significantly (p 6 0.05) lower in abdominal organs in comparison with 68Ga-NODAGA-[c(RGD)]2. Both radiotracers were mainly excreted from the kidney. In NeDe tumor bearing rats higher 68Ga-NOTA-c(NGR) accumulation was found in the tumors than that of the 68Ga-NODAGA-[ c(RGD)]2. Using orthotopic transplantation, metastases were developed which showed specific 68Ga-NOTA-c(NGR) uptake. Western blot analysis confirmed the presence of APN/CD13 expression in NeDe tumors and metastases

Testing SNe Ia distance measurement methods with SN 2011fe

The nearby, bright, almost completely unreddened Type Ia supernova 2011fe in M101 provides a unique opportunity to test both the precision and the accuracy of the extragalactic distances derived from SNe Ia light curve fitters. We apply the current, public versions of the independent light curve fitting codes MLCS2k2 and SALT2 to compute the distance modulus of SN 2011fe from high-precision, multi-color (BVRI) light curves. The results from the two fitting codes confirm that 2011fe is a "normal" (not peculiar) and only slightly reddened SN Ia. New unreddened distance moduli are derived as 29.21 +/- 0.07 mag (D ~ 6.95 +/- 0.23$ Mpc, MLCS2k2), and 29.05 +/- 0.07 mag (6.46 +/- 0.21 Mpc, SALT2). Despite the very good fitting quality achieved with both light curve fitters, the resulting distance moduli are inconsistent by 2 sigma. Both are marginally consistent (at ~1 sigma) with the HST Key Project distance modulus for M101. The SALT2 distance is in good agreement with the recently revised Cepheid- and TRGB-distance to M101. Averaging all SN- and Cepheid-based estimates, the absolute distance to M101 is ~6.6 +/- 0.5 Mpc.Comment: 8 pages, 7 figures, accepted for publication in A&

Ancient genomic time transect from the Central Asian Steppe unravels the history of the Scythians

The Scythians were a multitude of horse-warrior nomad cultures dwelling in the Eurasian steppe during the first millennium BCE. Because of the lack of first-hand written records, little is known about the origins and relations among the different cultures. To address these questions, we produced genome-wide data for 111 ancient individuals retrieved from 39 archaeological sites from the first millennia BCE and CE across the Central Asian Steppe. We uncovered major admixture events in the Late Bronze Age forming the genetic substratum for two main Iron Age gene-pools emerging around the Altai and the Urals respectively. Their demise was mirrored by new genetic turnovers, linked to the spread of the eastern nomad empires in the first centuries CE. Compared to the high genetic heterogeneity of the past, the homogenization of the present-day Kazakhs gene pool is notable, likely a result of 400 years of strict exogamous social rules.Introduction Results - The IA transition in the Kazakh Steppe - Admixture modeling of IA steppe populations - Post-IA genetic turnovers in the Kazakh Steppe - Dating ancient admixture - Present-day Kazakhs Discussion Material and methods - Radiocarbon dating - DNA extraction, library preparations, and sequencing - Modern DNA genotyping and quality controls - Ancient DNA data processing -- Raw data -- Authentication and contamination estimate -- Genotyping -- Sex determination -- Genetic relatedness estimation - Uniparental haplogroup assignment - Population structure analyses - Individual labeling and population grouping criteria - F-statistics and ancestry modeling - Admixture dating - CHROMOPAINTER and fineSTRUCTURE analyse

Interferometric Observations of the Hierarchical Triple System Algol

Algol is a triple stellar system consisting of a close semidetached binary orbited by a third object. Due to the disputed spatial orientation of the close pair, the third body perturbation of this pair is a subject of much research. In this study, we determine the spatial orientation of the close pair orbital plane using the CHARA Array, a six-element optical/IR interferometer located on Mount Wilson, and state-of-the-art e-EVN interferometric techniques. We find that the longitude of the line of nodes for the close pair is \Omega_1=48\degr\pm2\degr and the mutual inclination of the orbital planes of the close and the wide pairs is 95\degr\pm3\degr. This latter value differs by 5\degr from the formerly known 100\degr which would imply a very fast inclination variation of the system, not borne out by the photometric observations. We also investigated the dynamics of the system with numerical integration of the equations of motions using our result as an initial condition. We found large variations in the inclination of the close pair (its amplitude \sim 170\degr) with a period of about 20 millennia. This result is in good agreement with the photometrically observed change of amplitude in Algol's primary minimum.Comment: ApJ, in press. This is the accepted version; will be changed with the final version later (minor language corrections

Systems of Differential Algebraic Equations in Computational Electromagnetics

Starting from space-discretisation of Maxwell's equations, various classical formulations are proposed for the simulation of electromagnetic fields. They differ in the phenomena considered as well as in the variables chosen for discretisation. This contribution presents a literature survey of the most common approximations and formulations with a focus on their structural properties. The differential-algebraic character is discussed and quantified by the differential index concept