Das Leben des Buddha Śākyamuni am Holzportal des dKar chung Iha khang in Nako

In dem kleinen Dorf Nako, Oberes Kinnaur, im indischen Bundesstaat Himachal Pradesh befindet sich der beschnitzte Portalrahmen des dKar chung lha khang, des “Kleinen weißen Tempels“. Der einzige Teil des Portals, der trotz der starken Witterungseinflüsse noch etwas besser erhalten geblieben ist und auf dem noch figurative Beschnitzung zu erkennen ist, ist das Fries am Türsturz. Dieses Paneel ist in sieben Abschnitte unterteilt und zeigt acht Episoden aus dem Leben Buddha Sakyamuni die von links nach rechts zu lesen sind. Es dürfte sich dabei um folgenden Szenen handeln: Die Geburt des Buddha; die gleichzeitig zur Geburt stattgefundenen Tiergeburten; das Erste Bad und die Ersten Schritte, zusammen in einem Abschnitt; das Ankleiden vor dem Ersten Besuch im Tempel; der Weise Asita; die Vier Ausfahrten und ein Ringkampf mit seinem Cousin Devadatta. Das Ziel meiner Diplomarbeit war es die einzelnen auf dem Fries dargestellten Szenen genau zu analysieren und mit Hilfe von Textquellen zum Leben des Buddha Sakyamuni und Vergleichen mit anderen Portalen der Region zu klären ob es sich dabei überhaupt um Ereignisse aus seinem Leben handeln könnte. Im Lauf dieser Arbeit hat sich herausgestellt dass der Lalitavistara, die jüngste Sanskrit-Quelle zum Leben Buddha Sakyamuni´s aus vermutlich dem 8. Jhdt. n. Chr., als haupt-sächlich verwendete Quelle für diese acht Episoden gedient haben dürfte. Die Darstellung des gesamten Lebenszyklus des geschichtlichen Buddha scheint, vor allem während der Zeit der West-Tibetischen Könige, zwischen dem 10. und 12. Jhdt. n. Chr. ein fester Bestandteil der Dekoration der hölzernen Portale in der Region gewesen zu sein. Das Portal des dKar chung lha khang in Nako ist ein leider nur partiell erhaltenes, meiner Ansicht nach auch etwas jüngeres, Beispiel dieser künstlerisch hochwertigen Holzschnitz-Tradition.In the small village of Nako, Upper Kinnaur, Himachal Pradesh, the carved wooden door frame of the dKar chung lha khang, the “Small White Temple” of Nako, is located. Through the extreme weather conditions of the region the portal is already in a bad condition and the frieze on the lintel is the only part on which figurative carving can still be identified. This panel is divided into seven sections, clearly seperated from each other. It shows eight figurative episodes in more or less chronological order, to be read from left to right. The intention of my thesis was a detailed analysis of the episodes on the lintel frieze and comparisons with other wooden portals of the region to verify that different events out of the life of the historical Buddha are illustrated there and to clear up the question which episodes might be shown. The sections seem to show the following events (in the order from left to right): The Birth; the Simultaneous Births; the First Bath and the First Steps (together in one section); the ornamentation before the First Visit to the Temple; the Sage Asita; the Four Encounters and a wrestling match with Devadatta, a cousin of the Bodhisattva. In the course of the research it emerged that the Lalitavistara, the last of the Sanskrit sources on the life of Buddha Sakyamuni, presumably dating to the 8th century C.E., might have been the main source for the interpretations of these eight events. Mainly during the reign of the kings of West Tibet, from the 10th to the 12th centuries C.E. the depiction of the whole life story of the historical Buddha seems to have been common for the decoration of the wooden portals of the region. The portal of the dKar chung lha khang in Nako is sadly just a partially preserved example of this high quality wood carving tradition, and in my opinion should be dated to a slightly later time

cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node. The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses

cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node

Novel mutation in YMDD motif and direct neighbourhood in a child with chronic HBV-infection and clinical lamivudine and adefovir resistance - a scholarly case

<p>Abstract</p> <p>Context</p> <p>Chronic HBV infection is a major cause of hepatocellular carcinoma (HCC) which meanwhile has become the 5^thmost reason for a fatal outcome of cancer. Worldwide, approximately 350 million people are chronically HBV infected and as such of risk to develop HCC, of those an estimated high rate of children. Treatment of chronic infection is sufficient to reduce the rate of HCC but the rate of sustained virological response remains to low, not at least due to emergence of resistant virus strains. Less is known on HBV infection in children despite the extremely high rate of chronicity.</p> <p>Objective, Design, Setting, and Patient</p> <p>The case of a nine years old male with a 6 year history of chronic HBV infection, of those 5 years with antiviral treatment is described.</p> <p>Interventions and Main Outcome Measure(s)</p> <p>Before our lab was consulted, the patient was unsuccessfully treated with interferon, an obscure drug named Hepon, which should activate antiviral immune response, and Lamivudine, the latter most likely becoming ineffective due to the mergence of resistant subpopulations (rtL180 M, rtV207 M, two strains with stop codons at position rt188 and rt198, rtM204V (YVDD), rtM204K (YKDD)). Replacement of Lamivudine by adefovir displayed no advantage despite the lack of resistance mutations, thus no decrease in viremia was observed under adefovir treatment.</p> <p>Results and Conclusions</p> <p>Novel mutations in the YMDD motif and its direct neighbourhood were observed, both being compatible with Lamivudine resistance. No mutations were found that are associated with ADF resistance. Both, the clinical course of treatment and the genotypic resistance profile emphasize the need for systematic analyses of the HBV resistance mechanisms and structured therapy concept also for children chronically infected with HBV.</p

Diagnostic utility of small fiber analysis in skin biopsies from children with chronic pain

Introduction Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain. Methods Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data. Results Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders. Discussion Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options

CopR, a Global Regulator of Transcription to Maintain Copper Homeostasis in Pyrococcus furiosus

Although copper is in many cases an essential micronutrient for cellular life, higher concentrations are toxic. Therefore, all living cells have developed strategies to maintain copper homeostasis. In this manuscript, we have analyzed the transcriptome-wide response of Pyrococcus furiosus to increased copper concentrations and described the essential role of the putative copper-sensing metalloregulator CopR in the detoxification process. To this end, we employed biochemical and biophysical methods to characterize the role of CopR. Additionally, a copR knockout strain revealed an amplified sensitivity in comparison to the parental strain towards increased copper levels, which designates an essential role of CopR for copper homeostasis. To learn more about the CopR-regulated gene network, we performed differential gene expression and ChIP-seq analysis under normal and 20 μM copper-shock conditions. By integrating the transcriptome and genome-wide binding data, we found that CopR binds to the upstream regions of many copper-induced genes. Negative-stain transmission electron microscopy and 2D class averaging revealed an octameric assembly formed from a tetramer of dimers for CopR, similar to published crystal structures from the Lrp family. In conclusion, we propose a model for CopR-regulated transcription and highlight the regulatory network that enables Pyrococcus to respond to increased copper concentrations

Recruiting young pre-symptomatic children for a clinical trial in type 1 diabetes: insights from the Fr1da insulin intervention study

Background: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. Aim: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. Methods: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. Results: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. Conclusion: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed. Keywords: Type 1 diabetes, Trial recruitment, Trial enrollment, Infants, Children, Asymptomati

Report of the Workshop Evaluating the Nature of Midwater Mining Plumes and Their Potential Effects on Midwater Ecosystems

The International Seabed Authority (ISA) is developing regulations to control the future exploitation of deep-sea mineral resources including sulphide deposits near hydrothermal vents, polymetallic nodules on the abyssal seafloor, and cobalt crusts on seamounts. Under the UN Convention on the Law of the Sea the ISA is required to adopt are taking measures to ensure the effective protection of the marine environment from harmful effects arising from mining-related activities. Contractors are required to generate environmental baselines and assess the potential environmental consequences of deep seafloor mining. Understandably, nearly all environmental research has focused on the seafloor where the most direct mining effects will occur. However, sediment plumes and other impacts (e.g., noise) from seafloor mining are likely to be extensive in the water column. Sediment plumes created on the seafloor will affect the benthic boundary layer which extends 10s to 100s of meters above the seafloor. Separation or dewatering of ore from sediment and seawater aboard ships will require discharge of a dewatering plume at some depth in the water column. It is important to consider the potential impacts of mining on the ocean’s midwaters (depths from ~200 m to the seafloor) because they provide vital ecosystem services and harbor substantial biodiversity. The better known epipelagic or sunlit surface ocean provisions the rest of the water column through primary production and export flux (This was not the focus at this workshop as the subject was considered too large and surface discharges are unlikely). It is also home to a diverse community of organisms including commercially important fishes such as tunas, billfish, and cephalopods that contribute to the economies of many countries. The mesopelagic or twilight zone (200-1000 m) is dimly lit and home to very diverse and abundant communities of organisms. Mesopelagic plankton and small nekton form the forage base for many deep-diving marine mammals and commercially harvested epipelagic species. Furthermore, detritus from the epipelagic zone falls through the mesopelagic where it is either recycled, providing the vital process of nutrient regeneration, or sinks to greater depths sequestering carbon from short-term atmospheric cycles. The waters below the mesopelagic down to the seafloor (both the bathypelagic and abyssopelagic) are very poorly characterized but are likely large reservoirs of novel biodiversity and link the surface and benthic ecosystems. Great strides have been made in understanding the biodiversity and ecosystem function of the ocean’s midwaters, but large regions, including those containing many exploration license areas and the greater depths where mining plumes will occur, remain very poorly studied. It is clear that pelagic communities are distinct from those on the seafloor and in the benthic boundary layer. They are often sampled with different instrumentation. The fauna have relatively large biogeographic ranges and they are more apt to mix freely across stakeholder boundaries, reference areas and other spatial management zones. Pelagic organisms live in a three-dimensional habitat and their food webs and populations are vertically connected by daily or lifetime migrations and the sinking flux of detritus from the epipelagic. The fauna do not normally encounter hard surfaces, making them fragile, and difficult to capture and maintain for sensitivity or toxicity studies. Despite some existing general knowledge, ecological baselines for midwater communities and ecosystems that likely will be impacted by mining have not been documented. There is an urgent need to conduct more research and evaluate the midwater biota (microbes to fishes) in regions where mining is likely to occur. Deep-sea mining activities may affect midwater organisms in a number of ways, but it is still unclear at what scale perturbations may occur. The sediment plumes both from collectors on the seafloor and from midwater discharge will have a host of negative consequences. They may cause respiratory distress from clogged gills or respiratory surfaces. Suspension feeders, such as copepods, polychaetes, salps, and appendicularians, that filter small particles from the water and form an important basal group of the food web, may suffer from dilution of their food by inorganic sediments and/or clogging of their fragile mucous filter nets. Small particles may settle on gelatinous plankton causing buoyancy issues. Metals, including toxic elements that will enter the food web, will be released from pore waters and crushed ore materials. Sediment plumes will also absorb light and change backscatter properties, reducing visual communication and bioluminescent signaling that are very important for prey capture and reproduction in midwater animals. Noise from mining activities may alter the behaviors of marine mammals and other animals. Small particles have high surface area to volume ratios, high pelagic persistence and dispersal and as a result greater potential to result in pelagic impacts. All of these potential effects will result in mortality, migration (both horizontal and vertical), decreased fitness, and shifts in community composition. Depending on the scale and duration of these effects, there could be reduction in provisioning to commercial fish species, delivery of toxic metals to pelagic food webs and hence human seafood supply, and alterations to carbon transport and nutrient regeneration services. After four days of presentations and discussions, the workshop participants came to several conclusions and synthesized recommendations. 1. Assuming no discharge in the epipelagic zone, it is essential to minimize mining effects in the mesopelagic zone because of links to our human seafood supply as well as other ecosystem services provided by the mesopelagic fauna. This minimization could be accomplished by delivering dewatering discharge well below the mesopelagic/bathypelagic transition (below ~1000 m depth). 2. Research should be promoted by the ISA and other bodies to study the bathypelagic and abyssopelagic zones (from ~1000 m depths to just above the seafloor). It is likely that both collector plumes and dewatering plumes will be created in the bathypelagic, yet this zone is extremely understudied and contains major unknowns for evaluating mining impacts. 3. Management objectives, regulations and management actions need to prevent the creation of a persistent regional scale “haze” (enhanced suspended particle concentrations) in pelagic midwaters. Such a haze would very likely cause chronic harm to deep midwater ecosystem biodiversity, structure and function. 4. Effort is needed to craft suitable standards, thresholds, and indicators of harmful environmental effects that are appropriate to pelagic ecosystems. In particular, suspension feeders are very important ecologically and are likely to be very sensitive to sediment plumes. They are a high priority for study. 5. Particularly noisy mining activities such as ore grinding at seamounts and hydrothermal vents is of concern to deep diving marine mammals and other species. One way to minimize sound impacts would be to minimize activities in the sound-fixing-and-ranging (SOFAR) channel (typically at depths of ~1000 m) which transmits sounds over very long distances. 6. A Lagrangian (drifting) perspective is needed in monitoring and management because the pelagic ecosystem is not a fixed habitat and mining effects are likely to cross spatial management boundaries. For example, potential broad-scale impacts to pelagic ecosystems should be considered in the deliberations over preservation reference zones, the choice of stations for environmental baseline and monitoring studies and other area-based management and conservation measures. 7. Much more modeling and empirical study of realistic mining sediment plumes is needed. Plume models will help evaluate the spatial and temporal extent of pelagic (as well as benthic) ecosystem effects and help to assess risks from different technologies and mining scenarios. Plume modeling should include realistic mining scenarios (including duration) and assess the spatial-temporal scales over which particle concentrations exceed baseline levels and interfere with light transmission to elucidate potential stresses on communities and ecosystem services. Models should include both near and far field-phases, incorporating realistic near field parameters of plume generation, flocculation, particle sinking, and other processes. It is important to note that some inputs to these models such as physical oceanographic parameters are lacking and should be acquired in the near-term. Plume models need to be complemented by studies to understand effects on biological components by certain particle sizes and concentrations

GLI1(+) progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1(+) progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Glil-creER(T2)) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1(+) cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1(+) progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1(+) progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Foxl2) in response to GDX. These findings support the premise that GLI1(+) progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe