Androgen-independent events in penile development in humans and animals.

The common view on penile development is that it is androgen-dependent, based first and foremost on the fact that the genital tubercle forms a penis in males and a clitoris in females. However, critical examination of the complex processes involved in human penile development reveals that many individual steps in development of the genital tubercle are common to both males and females, and thus can be interpreted as androgen-independent. For certain developmental events this conclusion is bolstered by observations in androgen-insensitive patients and androgen receptor mutant mice. Events in genital tubercle development that are common to human males and females include: formation of (a) the genital tubercle, (b) the urethral plate, (c) the urethral groove, (d) the glans, (e) the prepuce and (f) the corporal body. For humans 6 of 13 individual developmental steps in penile development were interpreted as androgen-independent. For mice 5 of 11 individual developmental steps were found to be androgen-independent, which were verified through analysis of androgen-insensitive mutants. Observations from development of external genitalia of other species (moles and spotted hyena) provide further examples of androgen-independent events in penile development. These observations support the counter-intuitive idea that penile development involves both androgen-independent and androgen-dependent processes

Comparison of boreal ecosystem model sensitivity to variability in climate and forest site parameters

Ecosystem models are useful tools for evaluating environmental controls on carbon and water cycles under past or future conditions. In this paper we compare annual carbon and water fluxes from nine boreal spruce forest ecosystem models in a series of sensitivity simulations. For each comparison, a single climate driver or forest site parameter was altered in a separate sensitivity run. Driver and parameter changes were prescribed principally to be large enough to identify and isolate any major differences in model responses, while also remaining within the range of variability that the boreal forest biome may be exposed to over a time period of several decades. The models simulated plant production, autotrophic and heterotrophic respiration, and evapotranspiration (ET) for a black spruce site in the boreal forest of central Canada (56°N). Results revealed that there were common model responses in gross primary production, plant respiration, and ET fluxes to prescribed changes in air temperature or surface irradiance and to decreased precipitation amounts. The models were also similar in their responses to variations in canopy leaf area, leaf nitrogen content, and surface organic layer thickness. The models had different sensitivities to certain parameters, namely the net primary production response to increased CO2 levels, and the response of soil microbial respiration to precipitation inputs and soil wetness. These differences can be explained by the type (or absence) of photosynthesis-CO2 response curves in the models and by response algorithms of litter and humus decomposition to drying effects in organic soils of the boreal spruce ecosystem. Differences in the couplings of photosynthesis and soil respiration to nitrogen availability may also explain divergent model responses. Sensitivity comparisons imply that past conditions of the ecosystem represented in the models\u27 initial standing wood and soil carbon pools, including historical climate patterns and the time since the last major disturbance, can be as important as potential climatic changes to prediction of the annual ecosystem carbon balance in this boreal spruce forest

Redundant Function of REV-ERBα and β and Non-Essential Role for Bmal1 Cycling in Transcriptional Regulation of Intracellular Circadian Rhythms

The mammalian circadian clockwork is composed of a core PER/CRY feedback loop and additional interlocking loops. In particular, the ROR/REV/Bmal1 loop, consisting of ROR activators and REV-ERB repressors that regulate Bmal1 expression, is thought to “stabilize” core clock function. However, due to functional redundancy and pleiotropic effects of gene deletions, the role of the ROR/REV/Bmal1 loop has not been accurately defined. In this study, we examined cell-autonomous circadian oscillations using combined gene knockout and RNA interference and demonstrated that REV-ERBα and β are functionally redundant and are required for rhythmic Bmal1 expression. In contrast, the RORs contribute to Bmal1 amplitude but are dispensable for Bmal1 rhythm. We provide direct in vivo genetic evidence that the REV-ERBs also participate in combinatorial regulation of Cry1 and Rorc expression, leading to their phase-delay relative to Rev-erbα. Thus, the REV-ERBs play a more prominent role than the RORs in the basic clock mechanism. The cellular genetic approach permitted testing of the robustness of the intracellular core clock function. We showed that cells deficient in both REV-ERBα and β function, or those expressing constitutive BMAL1, were still able to generate and maintain normal Per2 rhythmicity. Our findings thus underscore the resilience of the intracellular clock mechanism and provide important insights into the transcriptional topologies underlying the circadian clock. Since REV-ERB function and Bmal1 mRNA/protein cycling are not necessary for basic clock function, we propose that the major role of the ROR/REV/Bmal1 loop and its constituents is to control rhythmic transcription of clock output genes

The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src

The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src

Detection of heterozygous deletions and duplications in the MECP2 gene in Rett syndrome by Robust Dosage PCR (RD-PCR)

Fifty to eighty percent of Rett syndrome (RTT) cases have point mutations in the gene encoding methyl-CpG-binding protein-2 (MECP2). A fraction of MECP2 negative classical RTT patients has large heterozygous deletions. Robust Dosage PCR (RD-PCR) assays were developed as a rapid, convenient and accurate method to detect large heterozygous deletions and duplications. A blinded analysis was performed for 65 RTT cases from Portugal by RDPCR in the coding exons 2-4 of the MECP2 gene. Neither the patients with point mutations nor the non-classical RTT patients without point mutation had a deletion or duplication. One of remaining eight female patients with classical RTT without point mutation had a heterozygous deletion. This is the first report of a deletion spanning the entire MECP2 gene. The deletion was confirmed by southern blotting analysis and the deletion junction was localized 37kb upstream from exon 1 and 18kb downstream from exon 4. No duplications were detected. Our results suggest that RD-PCR is an accurate and convenient molecular diagnostic method

PCA-based lung motion model

Organ motion induced by respiration may cause clinically significant targeting errors and greatly degrade the effectiveness of conformal radiotherapy. It is therefore crucial to be able to model respiratory motion accurately. A recently proposed lung motion model based on principal component analysis (PCA) has been shown to be promising on a few patients. However, there is still a need to understand the underlying reason why it works. In this paper, we present a much deeper and detailed analysis of the PCA-based lung motion model. We provide the theoretical justification of the effectiveness of PCA in modeling lung motion. We also prove that under certain conditions, the PCA motion model is equivalent to 5D motion model, which is based on physiology and anatomy of the lung. The modeling power of PCA model was tested on clinical data and the average 3D error was found to be below 1 mm.Comment: 4 pages, 1 figure. submitted to International Conference on the use of Computers in Radiation Therapy 201

Radiocarbon Dating of Charcoal and Bone Collagen Associated with Early Pottery at Yuchanyan Cave, Hunan Province, China

Yuchanyan Cave in Daoxian County, Hunan Province (People's Republic of China), yielded fragmentary remains of 2 or more ceramic vessels, in addition to large amounts of ash, a rich animal bone assemblage, cobble and flake artifacts, bone tools, and shell tools. The artifacts indicate that the cave was a Late Paleolithic foragers' camp. Here we report on the radiocarbon ages of the sediments based on analyses of charcoal and bone collagen. The best-preserved charcoal and bone samples were identified by prescreening in the field and laboratory. The dates range from around 21,000 to 13,800 cal BP. We show that the age of the ancient pottery ranges between 18,300 and 15,430 cal BP. Charcoal and bone collagen samples located above and below one of the fragments produced dates of around 18,000. These ceramic potsherds therefore provide some of the earliest evidence for pottery making in China.Anthropolog

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

The spectra and energies of classical double radio lobes

We compare two temporal properties of classical double radio sources: i) radiative lifetimes of synchrotron-emitting particles and ii) dynamical source ages. We discuss how these can be quite discrepant from one another, rendering use of the traditional spectral ageing method inappropriate: we contend that spectral ages give meaningful estimates of dynamical ages only when these ages are << 10^7 years. In juxtaposing the fleeting radiative lifetimes with source ages which are significantly longer, a refinement of the paradigm for radio source evolution is required. The changing spectra along lobes are explained, not predominantly by synchrotron ageing but, by gentle gradients in a magnetic field mediated by a low-gamma matrix which illuminates an energy-distribution of particles, controlled largely by classical synchrotron loss in the high magnetic field of the hotspot. The energy in the particles is an order of magnitude higher than that inferred from the minimum-energy estimate, implying that the jet-power is of the same order as the accretion luminosity produced by the quasar central engine. This refined paradigm points to a resolution of the findings of Rudnick et al (1994) and Katz-Stone & Rudnick (1994) that both the Jaffe-Perola and Kardashev-Pacholczyk model spectra are invariably poor descriptions of the curved spectral shape of lobe emission, and indeed that for Cygnus A all regions of the lobes are characterised by a `universal spectrum'. [abridged]Comment: LaTeX, 4 figures. To appear in A