An X-ray chimney extending hundreds of parsecs above and below the Galactic Centre.

Evidence has mounted in recent decades that outflows of matter and energy from the central few parsecs of our Galaxy have shaped the observed structure of the Milky Way on a variety of larger scales1. On scales of 15 parsecs, the Galactic Centre has bipolar lobes that can be seen in both the X-ray and radio parts of the spectrum2,3, indicating broadly collimated outflows from the centre, directed perpendicular to the Galactic plane. On larger scales, approaching the size of the Galaxy itself, γ-ray observations have revealed the so-called 'Fermi bubble' features4, implying that our Galactic Centre has had a period of active energy release leading to the production of relativistic particles that now populate huge cavities on both sides of the Galactic plane. The X-ray maps from the ROSAT all-sky survey show that the edges of these cavities close to the Galactic plane are bright in X-rays4-6. At intermediate scales (about 150 parsecs), radio astronomers have observed the Galactic Centre lobe, an apparent bubble of emission seen only at positive Galactic latitudes7,8, but again indicative of energy injection from near the Galactic Centre. Here we report prominent X-ray structures on these intermediate scales (hundreds of parsecs) above and below the plane, which appear to connect the Galactic Centre region to the Fermi bubbles. We propose that these structures, which we term the Galactic Centre 'chimneys', constitute exhaust channels through which energy and mass, injected by a quasi-continuous train of episodic events at the Galactic Centre, are transported from the central few parsecs to the base of the Fermi bubbles4.

Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Cav1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Cav1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Cav1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Cav1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.

Type 2 diabetes patients have accelerated cartilage matrix degeneration compared to diabetes free controls: data from the Osteoarthritis Initiative.

PURPOSE: Osteoarthritis (OA) and diabetes mellitus (DM) share common risk factors with a potential underlying relationship between both diseases. The purpose of this study was to investigate the longitudinal effects of DM on cartilage deterioration over 24-months with MR-based T2 relaxation time measurements. METHODS: From the Osteoarthritis Initiative (OAI) cohort 196 diabetics were matched in small sets for age, sex, BMI and Kellgren-Lawrence score with 196 non-diabetic controls. Knee cartilage semi-automatic segmentation was performed on 2D multi-slice multi-echo spin-echo sequences. Texture of cartilage T2 maps was obtained via grey level co-occurrence matrix analysis. Linear regression analysis was used to compare cross-sectional and changes in T2 and texture parameters between the groups. RESULTS: Both study groups were similar in age (63.3 vs 63.0 years, P = 0.70), BMI (30.9 vs 31.2 kg/m2, P = 0.52), sex (female 53.6% vs 54.1%, P = 0.92) and KL score distribution (P = 0.97). In diabetics, except for the patella, all compartments showed a significantly higher increase in mean T2 values when compared to non-diabetic controls. Global T2 values increased almost twice as much; 1.77ms vs 0.98ms (0.79ms [CI: 0.39,1.19]) (P < 0.001). Additionally, global T2 values showed a significantly higher increase in the bone layer (P = 0.006), and in a separate analysis of the texture parameters, diabetics also showed consistently higher texture values (P < 0.05), indicating a more disordered cartilage composition. CONCLUSION: Cartilage T2 values in diabetics show a faster increase with a consistently more heterogeneous cartilage texture composition. DM seems to be a risk factor for developing early OA with an accelerated degeneration of the articular cartilage in the knee.

Bragg coherent diffraction imaging and metrics for radiation damage in protein micro-crystallography.

The proliferation of extremely intense synchrotron sources has enabled ever higher-resolution structures to be obtained using data collected from smaller and often more imperfect biological crystals (Helliwell, 1984). Synchrotron beamlines now exist that are capable of measuring data from single crystals that are just a few micrometres in size. This provides renewed motivation to study and understand the radiation damage behaviour of small protein crystals. Reciprocal-space mapping and Bragg coherent diffractive imaging experiments have been performed on cryo-cooled microcrystals of hen egg-white lysozyme as they undergo radiation damage. Several well established metrics, such as intensity-loss and lattice expansion, are applied to the diffraction data and the results are compared with several new metrics that can be extracted from the coherent imaging experiments. Individually some of these metrics are inconclusive. However, combining metrics, the results suggest that radiation damage behaviour in protein micro-crystals differs from that of larger protein crystals and may allow them to continue to diffract for longer. A possible mechanism to account for these observations is proposed.

Observation of crack growth in a polycrystalline ferroelectric by synchrotron X-ray diffraction.

Pre-cracked samples of unpoled, polycrystalline, soft ferroelectric lead zirconate titanate were subjected to electrical and mechanical loading whilst using synchrotron X-ray diffraction to map strain-fields. Clear evidence is found of switching around the crack tip and development of a crack-wake. A J-integral estimate based on strain-field data provided a sensitive measure of strain changes during loading. Electrical loading did not cause crack advance or crack-tip switching; this provides evidence for electrically permeable crack models. There was also enhancement of electrically-driven switching in the crack-wake region. The results provide improved understanding and a resource for testing fracture models in ferroelectrics.

Laue-DIC: a new method for improved stress field measurements at the micrometer scale.

A better understanding of the effective mechanical behavior of polycrystalline materials requires an accurate knowledge of the behavior at a scale smaller than the grain size. The X-ray Laue microdiffraction technique available at beamline BM32 at the European Synchrotron Radiation Facility is ideally suited for probing elastic strains (and associated stresses) in deformed polycrystalline materials with a spatial resolution smaller than a micrometer. However, the standard technique used to evaluate local stresses from the distortion of Laue patterns lacks accuracy for many micromechanical applications, mostly due to (i) the fitting of Laue spots by analytical functions, and (ii) the necessary comparison of the measured pattern with the theoretical one from an unstrained reference specimen. In the present paper, a new method for the analysis of Laue images is presented. A Digital Image Correlation (DIC) technique, which is essentially insensitive to the shape of Laue spots, is applied to measure the relative distortion of Laue patterns acquired at two different positions on the specimen. The new method is tested on an in situ deformed Si single-crystal, for which the prescribed stress distribution has been calculated by finite-element analysis. It is shown that the new Laue-DIC method allows determination of local stresses with a strain resolution of the order of 10(-5).

Comparative transcriptomic analyses reveal activation of the epithelial-mesenchymal transition program in non-metastasizing low grade pseudomyxoma peritonei.

Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade pseudomyxoma peritonei (lgPMP) show local aggressiveness with very limited metastatic potential as opposed to CRC. To better understand the underlying processes that foster or impede metastatic spread, we compared LAMN, lgPMP, and CRC with respect to their molecular profile with subsequent pathway analysis. LAMN, lgPMP and (mucinous) CRC cases were subjected to transcriptomic analysis utilizing Poly(A) RNA sequencing. Successfully sequenced cases (LAMN n = 10, 77%, lgPMP n = 13, 100% and CRC n = 8, 100%) were investigated using bioinformatic and statistical tests (differential expression analysis, hierarchical clustering, principal component analysis and gene set enrichment analysis). We identified a gene signature of 28 genes distinguishing LAMN, lgPMP and CRC neoplasias. Ontology analyses revealed that multiple pathways including EMT, ECM interaction and angiogenesis are differentially regulated. Fifty-three significantly differentially regulated gene sets were identified between lgPMP and CRC followed by CRC vs. LAMN (n = 21) and lgPMP vs. LAMN (n = 16). Unexpectedly, a substantial enrichment of the EMT gene set was observed in lgPMP vs. LAMN (FDR=0.011) and CRC (FDR=0.004). Typical EMT markers were significantly upregulated (Vimentin, TWIST1, N-Cadherin) or downregulated (E-Cadherin) in lgPMP. However, MMP1 and MMP3 levels, associated with EMT, ECM and metastasis, were considerably higher in CRC. We show that the different tumor biological behaviour and metastatic spread pattern of midgut malignancies is reflected in a different gene expression profile. We revealed a strong activation of the EMT program in non-metastasizing lgPMP vs. CRC. Hence, although EMT is considered a key step in hematogenous spread, successful EMT does not necessarily lead to hematogenous dissemination. This emphasizes the need for further pathway analyses and forms the basis for mechanistic and therapy-targeting research.

New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is the most serious form of the autosomal recessive childhood-onset retinal dystrophies. Mutations in the gene encoding RPE65, a protein vital for regeneration of the visual pigment rhodopsin in the retinal pigment epithelium, account for 10-15% of LCA cases. Whereas previous studies of RPE65 deficiency in both animal models and patients attributed remaining visual function to cones, we show here that light-evoked retinal responses in fact originate from rods. For this purpose, we selectively impaired either rod or cone function in Rpe65-/- mice by generating double- mutant mice with models of pure cone function (rhodopsin-deficient mice; Rho-/-) and pure rod function (cyclic nucleotide-gated channel alpha3-deficient mice; Cnga3-/-). The electroretinograms (ERGs) of Rpe65-/- and Rpe65-/-Cnga3-/- mice were almost identical, whereas there was no assessable response in Rpe65-/-Rho-/- mice. Thus, we conclude that the rod system is the source of vision in RPE65 deficiency. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as a mechanism decreased rod sensitivity due to a reduction in rhodopsin content to less than 1%. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.

[Cancer through the handling of biological agents]. / Krebsdurch den Umgang mit Biostoffen.

In March 2012, the International Agency for Research on Cancer (IARC), an agency of the World Health Organization (WHO) issued a list. It lists 108 agents for which there is sufficient evidence of a carcinogenic effect in humans, depending on the cancer site. The vast majority of these actions can take place in the workplace. What is new in the list, in addition to the long-known cancer-causing chemical and physical agents now biomaterials have been added, such as hepatitis B virus, hepatitis C virus, Human papilloma virus, Helicobacter pylori. This paper gives an overview on the basis of identifying carcinogenic agents and can be displayed in certain cancer site and occupational exposure occupational diseases according to the occupational disease regulation.

In-vitro model to mimic T cell subset change in human PDAC organoid co-culture.

PURPOSE: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs). METHODS: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs. RESULTS: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4+, CD8+ and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids. CONCLUSION: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future.

Computation of Burgers vectors from elastic strain and lattice rotation data.

A theoretical framework for computation of Burgers vectors from strain and lattice rotation data in materials with low dislocation density is presented, as well as implementation into a computer program to automate the process. The efficacy of the method is verified using simulated data of dislocations with known results. A three-dimensional dataset retrieved from Bragg coherent diffraction imaging (BCDI) and a two-dimensional dataset from high-resolution transmission Kikuchi diffraction (HR-TKD) are used as inputs to demonstrate the reliable identification of dislocation positions and accurate determination of Burgers vectors from experimental data. For BCDI data, the results found using our approach show very close agreement to those expected from empirical methods. For the HR-TKD data, the predicted dislocation position and the computed Burgers vector showed fair agreement with the expected result, which is promising considering the substantial experimental uncertainties in this dataset. The method reported in this paper provides a general and robust framework for determining dislocation position and associated Burgers vector, and can be readily applied to data from different experimental techniques.

Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice.

Agonist-induced Ca2+ entry into cells by both store-operated channels and channels activated independently of Ca2+-store depletion has been described in various cell types. The molecular structures of these channels are unknown as is, in most cases, their impact on various cellular functions. Here we describe a store-operated Ca2+ current in vascular endothelium and show that endothelial cells of mice deficient in TRP4 (also known as CCE1) lack this current. As a consequence, agonist-induced Ca2+ entry and vasorelaxation is reduced markedly, showing that TRP4 is an indispensable component of store-operated channels in native endothelial cells and that these channels directly provide an Ca2+-entry pathway essentially contributing to the regulation of blood vessel tone.

Duration of wet work in hairdressers.

AIM OF THE STUDY: Occupational contact dermatitis caused by wet work is particularly common in hairdressers. Data on the duration of wet work (DWW) in the hairdresser's trade are not well known until now. A questionnaire or self-reported/estimated skin exposure are not suitable to get accurate information about DWW. According to the guidance of the German Federal Ministry for Labour and Social Affairs, employees with DWW > 2 h per day should get a possibility for targeted occupational-medical health examinations. Targeted occupational-medical health examinations are prescribed for employees with daily duration of wet work longer than 4 h. The aim of the study was to quantify the average daily exposition to wet work in hairdressers. MATERIALS AND METHODS: In our study, we used the direct observation as a standard method to analyse the work steps and to measure DWW in hairdressers. We developed the instrument for the analyses of activities in hairdresser salons and measurement of DWW in hairdressers during their 8-h shift. At the beginning of the study, 60 observers were intensively instructed and trained in the procedure of analysis. RESULTS: The mean of duration of wet work (DWW) in 106 8-h shifts analysed was 8,234 s (approx. 2 h 17 min). The minimum of DWW was 278 s and the maximum 21,135 s (approx. 6 h); the standard deviation was 3,826 s. In 37% of the analysed 8-h shifts, DWW was shorter than 2 h, in 58% between 2 and 4 h and in 5% longer than 4 h. Eighteen per cent of the DWW was caused by wearing water-resistant protective gloves. We found positive correlations between "DWW" and "DWW > 2 h", with the predictors "number of customers total", "number of long-haired people" and "number of female customers". CONCLUSION: According to the guidance of the German Federal Ministry for Labour and Social Affairs, hairdressers should get a possibility for targeted occupational-medical health examinations.

[Improvement strategy to increase vaccination rates in adolescents]. / Erfolgreiche Strategie zur Verbesserung der Impfraten bei Jugendlichen.

BACKGROUND: Vaccination rates in adolescents in Germany are not sufficient. An intervention programme, which has been launched by the community health centre in Essen, should significantly increase vaccination coverage. METHODS: In 2001 the Children and Youth Health Service at the Community Health Centre in Essen implemented a specific strategy to improve vaccination rates in adolescents. Vaccination rates were determined by control of vaccination certificates of all 6 (th) graders in Essen (n=5 589). After control of vaccination records the parents got a written, individual vaccination counselling for their child as well as a referral to the paediatrician to get the missing vaccinations. After 6 months the vaccination certificates were looked at again and vaccination coverage was determined. RESULTS: At the initial vaccination record control of 6 (th) graders in 2001 only 15% of the students, who presented their vaccination certificate, had an appropriate age related immunisation status. 84% of the students had had the tetanus/diphtheria and polio booster. But only 43% had been given a second measles, mumps and rubella (MMR) immunisation and only 24% had a complete hepatitis B coverage. The intervention programme (e. g., individual vaccination counselling) improved vaccination rates for hepatitis B and MMR by 16%. From 2001 to 2008 vaccination coverage in this age group could be improved from 43% to 87% for the second MMR vaccination and from 24% to 85% for hepatitis B. CONCLUSIONS: A remarkable improvement in vaccination coverage in children and adolescents could be achieved by a single, individual, written vaccination reminder. As a prerequisite a good cooperation between schools/paediatricians and the health authorities is needed.

Increased adhesion and aggregation of platelets lacking cyclic guanosine 3',5'-monophosphate kinase I.

Atherosclerotic vascular lesions are considered to be a major cause of ischemic diseases, including myocardial infarction and stroke. Platelet adhesion and aggregation during ischemia-reperfusion are thought to be the initial steps leading to remodeling and reocclusion of the postischemic vasculature. Nitric oxide (NO) inhibits platelet aggregation and smooth muscle proliferation. A major downstream target of NO is cyclic guanosine 3', 5'-monophosphate kinase I (cGKI). To test the intravascular significance of the NO/cGKI signaling pathway in vivo, we have studied platelet-endothelial cell and platelet-platelet interactions during ischemia/reperfusion using cGKI-deficient (cGKI-/-) mice. Platelet cGKI but not endothelial or smooth muscle cGKI is essential to prevent intravascular adhesion and aggregation of platelets after ischemia. The defect in platelet cGKI is not compensated by the cAMP/cAMP kinase pathway supporting the essential role of cGKI in prevention of ischemia-induced platelet adhesion and aggregation.

Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice.

In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.

Retrospective and consecutive analysis of the long-term outcomes of the SBG stem: a 15-year follow-up study.

BACKGROUND: In 1991, 230 cementless total hip arthroplasties (THAs) with anatomical Stolzalpe-Buchner-Graf (SBG) stems were implanted in 230 patients at our hospital. Patients were examined retrospectively and consecutively 15 years after the operations. METHODS: In total, 118 patients were available for follow-up (average 12.8 +/- 3.8 years postoperatively), with 44 examined clinically/radiologically at our hospital and 74 interviewed by telephone. Five THAs needed revision (stem explantation), three for aseptic loosening. Average patient age at the time of surgery was 61 years (27-91 years). For all THAs, we implanted ceramic-to-metal heads in combination with ultra-high molecular weight polyethylene inlay (ceramic/polyethylene and metal/polyethylene articulating components). RESULTS: The survival rate of the SBG stem was 98.13% (CI 94.32-99.39%) with aseptic loosening as the endpoint and 96.98% (CI 92.85-98.74%) with revision and stem explantation for any other reason as the endpoint. The average Harris Hip Score was 36.0 +/- 6.9 (range 22-45) preoperatively, increasing to 88.2 +/- 15.3 (30-100) for clinically evaluated patients and 80.3 +/- 11.3 (27-91) for telephone-interviewed patients at 15 years postoperatively. Osteolysis and radiolucent lines around the prosthetic stem were rarely observed (mainly at the proximal diaphysis). CONCLUSION: These follow-up results emphasize the excellent long-term outcomes associated with the SBG stem.

The roles of the subunits in the function of the calcium channel.

Dihydropyridine-sensitive voltage-dependent L-type calcium channels are critical to excitation-secretion and excitation-contraction coupling. The channel molecule is a complex of the main, pore-forming subunit alpha 1 and four additional subunits: alpha 2, delta, beta, and gamma (alpha 2 and delta are encoded by a single messenger RNA). The alpha 1 subunit messenger RNA alone directs expression of functional calcium channels in Xenopus oocytes, and coexpression of the alpha 2/delta and beta subunits enhances the amplitude of the current. The alpha 2, delta, and gamma subunits also have pronounced effects on its macroscopic characteristics, such as kinetics, voltage dependence of activation and inactivation, and enhancement by a dihydropyridine agonist. In some cases, specific modulatory functions can be assigned to individual subunits, whereas in other cases the different subunits appear to act in concert to modulate the properties of the channel.

Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II.

Cyclic guanosine 3',5'-monophosphate (cGMP)-dependent protein kinases (cGKs) mediate cellular signaling induced by nitric oxide and cGMP. Mice deficient in the type II cGK were resistant to Escherichia coli STa, an enterotoxin that stimulates cGMP accumulation and intestinal fluid secretion. The cGKII-deficient mice also developed dwarfism that was caused by a severe defect in endochondral ossification at the growth plates. These results indicate that cGKII plays a central role in diverse physiological processes.

Primary structure of the beta subunit of the DHP-sensitive calcium channel from skeletal muscle.

Complementary DNAs for the beta subunit of the dihydropyridine-sensitive calcium channel of rabbit skeletal muscle were isolated on the basis of peptide sequences derived from the purified protein. The deduced primary structure is without homology to other known protein sequences and is consistent with the beta subunit being a peripheral membrane protein associated with the cytoplasmic aspect of the sarcolemma. The protein contains sites that might be expected to be preferentially phosphorylated by protein kinase C and guanosine 3',5'-monophosphate-dependent protein kinase. A messenger RNA for this protein appears to be expressed in brain.