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91.
Ester Lovsin Barle Gian Christian Winkler Peter Ulrich Christopher Perino Martin Kuster Alessandro Probst Silke Thielen Rudolf Bechter 《Regulatory toxicology and pharmacology : RTP》2014
During the chemical and pharmaceutical production of active pharmaceutical substances which are intended for immunosuppressive therapy, the employees may be exposed to these substances via inhalation. Immunosuppressants are linked to development of certain types of cancers e.g., lymphoma or skin cancer in transplant patients. The development of these cancers in patients is linked to the level of immunosuppression needed for transplantation in order to avoid organ rejection. Below these levels, with the immune system functioning uninhibited, cancer is unlikely to develop. 相似文献
92.
Dr. Silke Kuhn Dr. Jens Kalke Sven Buth Dr. Philipp Hiller Prof. Dr. Jens Reimer 《Pr?vention und Gesundheitsf?rderung》2014,9(2):104-110
Objective
Based on the initial survey of the project “Strengthen parents for dealing with the alcohol consumption of their children” parental style was quantified. The survey addressed the following issues: 1. The parents information of the alcohol consumption of their adolescents. 2. Adequate rules when dealing with the alcohol consumption of their children. 3. Parent?s reactions to a potential intoxication of their children.Method
2,793 parents of students in grades 8–10 were surveyed in Baden-Württemberg, Berlin, Saxony and Schleswig-Holstein. The questionnaires were passed back through the teachers. The questionnaires were collected by the teachers.Results
The results show that parents feel well informed about alcohol related education of children. 71?% use the internet as an information source. Approx. 95?% of the parents have talked with their children about alcohol consumption, particularly adviced them of health damages and development of dependence. Those rules of behavior guaranteeing a safe way home are favored by parents. In response to rule violations the parents talk with their children first. The comparison with current youth surveys shows that parents underestimate their children?s drinking.Conclusions
Alcohol and its consequences are a topic of conversation among parents and children. The parents need support to argue objectively and according to youth. The Internet should be used for drug prevention education activities. 相似文献93.
94.
Analysis of promoter methylation in stool: a novel method for the detection of colorectal cancer. 总被引:12,自引:0,他引:12
Konstanze Lenhard Guido T Bommer Silke Asutay Rolf Schauer Thomas Brabletz Burkhard G?ke Rolf Lamerz Frank T Kolligs 《Clinical gastroenterology and hepatology》2005,3(2):142-149
BACKGROUND & AIMS: Detection of tumor-derived DNA alterations in stool is an intriguing new approach with high potential for the noninvasive detection of colorectal cancer (CRC). Because of heterogeneity of tumors, usually multiple markers distributed throughout the human genome need to be analyzed. This is labor intensive and does not allow for high through-put screening. Therefore, markers with high sensitivity and good specificity are needed. We explored the potential of a single epigenetic marker in comparison with fecal occult blood testing (FOBT) for the discrimination of patients with CRCs and adenomas from those without. METHODS: Methylation-specific polymerase chain reaction (PCR) was performed to analyze hypermethylated in cancer 1 (HIC1) promoter methylation status in a blinded fashion in stool samples from 26 patients with CRC, 13 with adenoma > or =1 cm, 9 with hyperplastic polyps, 9 with chronic inflammatory bowel disease, and 32 with endoscopically normal colon. RESULTS: Ninety-seven percent of the stool samples contained amplifiable DNA. Forty-two percent of the samples from patients with CRC and 31% of the samples from patients with colorectal adenoma > or =1 cm were positive for HIC1 promoter methylation. No methylated HIC1 promoter DNA was detected in the fecal DNA from patients with endoscopically normal colon or hyperplastic polyps. CONCLUSIONS: The epigenetic marker HIC1 promoter methylation carries high potential for the remote detection of CRCs. We postulate that a panel of merely a few genetic and epigenetic markers will be required for the highly sensitive and specific detection of CRCs and adenomas in fecal samples from affected patients. 相似文献
95.
Joanne M. Hildebrand Maria C. Tanzer Isabelle S. Lucet Samuel N. Young Sukhdeep K. Spall Pooja Sharma Catia Pierotti Jean-Marc Garnier Renwick C. J. Dobson Andrew I. Webb Anne Tripaydonis Jeffrey J. Babon Mark D. Mulcair Martin J. Scanlon Warren S. Alexander Andrew F. Wilks Peter E. Czabotar Guillaume Lessene James M. Murphy John Silke 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(42):15072-15077
Necroptosis is considered to be complementary to the classical caspase-dependent programmed cell death pathway, apoptosis. The pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) is an essential effector protein in the necroptotic cell death pathway downstream of the protein kinase Receptor Interacting Protein Kinase-3 (RIPK3). How MLKL causes cell death is unclear, however RIPK3–mediated phosphorylation of the activation loop in MLKL trips a molecular switch to induce necroptotic cell death. Here, we show that the MLKL pseudokinase domain acts as a latch to restrain the N-terminal four-helix bundle (4HB) domain and that unleashing this domain results in formation of a high-molecular-weight, membrane-localized complex and cell death. Using alanine-scanning mutagenesis, we identified two clusters of residues on opposing faces of the 4HB domain that were required for the 4HB domain to kill cells. The integrity of one cluster was essential for membrane localization, whereas MLKL mutations in the other cluster did not prevent membrane translocation but prevented killing; this demonstrates that membrane localization is necessary, but insufficient, to induce cell death. Finally, we identified a small molecule that binds the nucleotide binding site within the MLKL pseudokinase domain and retards MLKL translocation to membranes, thereby preventing necroptosis. This inhibitor provides a novel tool to investigate necroptosis and demonstrates the feasibility of using small molecules to target the nucleotide binding site of pseudokinases to modulate signal transduction.Programmed necrosis or “necroptosis” has emerged in the past 5 years as a cell death mechanism that complements the conventional cell death pathway, apoptosis, in multicellular organisms. In contrast to apoptosis, necroptosis does not appear to serve an important role in multicellular organism development (1–3) but participates in the defense against pathogens and is a likely culprit in destructive inflammatory conditions (4–7). Receptor Interacting Protein Kinase-3 (RIPK3) was identified as a key effector of necroptosis in 2009 (4, 5) and its substrate, the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL), in 2012 (8, 9), but the molecular events following RIPK3-mediated phosphorylation of MLKL required to induce cell death are unclear. The RIPK1/RIPK3/MLKL necrosome has been proposed to activate PGAM5 (phosphoglycerate mutase 5) and Drp1 (Dynamin-related protein 1) to cause mitochondrial fragmentation and cell death (10), but the requirement for PGAM5, Drp1, and mitochondria for necroptosis has been questioned (1, 11–13).We described the structure of mouse MLKL revealing that MLKL contains a C-terminal pseudokinase domain and an N-terminal four-helix bundle (4HB) domain connected by a two-helix linker (the “brace” helices) (1). Based on our mutational and biochemical analyses, we proposed that the catalytically inactive pseudokinase domain functions as a molecular switch and that RIPK3-mediated phosphorylation triggers this switch by inducing a conformational change in MLKL (1, 14).Recently it has been proposed that the 4HB domain is the death effector domain within MLKL and that the killing function of MLKL relies on its oligomerization and plasma membrane association (15–18). The stoichiometry of the oligomer is, however, contentious and has been reported to contain three (15), four (16), and possibly six (17) MLKL protomers. Furthermore, several mechanisms for how this oligomer causes cell death have been proposed: Cai et al. proposed it activates the calcium channel protein Tprm7 and promotes calcium influx (15), Chen et al. showed it increased sodium influx (16), and Wang et al. proposed that the oligomerized form of MLKL has the ability to bind negatively charged lipids, including phosphoinositides and cardiolipin, which facilitates its disruption of membrane integrity (17), a model supported by a subsequent paper (18).Here, we show that the MLKL 4HB domain is sufficient to induce necroptosis and identify several charged residues clustered on two faces that are required for this function. Surprisingly the polarity of several of these charged residues is not conserved between mouse and human MLKL, and alanine substitution of negatively charged residues on the α4 helix of the 4HB domain disrupted function. This finding challenges the importance of phospholipid binding to the killing activity of the 4HB domain and illustrates that membrane association cannot solely be attributed to the interaction of poorly conserved basic residues within the MLKL 4HB domain. Intriguingly, mutation of a second cluster of residues on the 4HB domain did not preclude membrane localization or oligomerization but did prevent cell death, illustrating that additional function(s) beyond membrane translocation are required for the 4HB domain to induce cell death. MLKL oligomerization and membrane translocation were also inhibited by a small molecule, compound 1, which we identified on the basis of its affinity for the nucleotide binding site of the MLKL pseudokinase domain. These data support a model for MLKL function whereby the pseudokinase domain of MLKL holds the 4HB domain in check until phosphorylated by RIPK3, which causes a conformational change in the pseudokinase domain to unleash the 4HB domain to oligomerize and associate with membranes. Activation of MLKL can be thwarted by a small MLKL binding molecule, indicating the feasibility of targeting the nucleotide binding or “pseudoactive” sites of pseudokinases, a hitherto unexplored class of therapeutic targets. 相似文献
96.
Felix Schnarwiler Moritz Niemann Nicholas Doiron Anke Harsman Sandro K?ser Jan Mani Astrid Chanfon Caroline E. Dewar Silke Oeljeklaus Christopher B. Jackson Mascha Pusnik Oliver Schmidt Chris Meisinger Sebastian Hiller Bettina Warscheid Achim C. Schnaufer Torsten Ochsenreiter André Schneider 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(21):7624-7629
Mitochondria cannot form de novo but require mechanisms allowing their inheritance to daughter cells. In contrast to most other eukaryotes Trypanosoma brucei has a single mitochondrion whose single-unit genome is physically connected to the flagellum. Here we identify a β-barrel mitochondrial outer membrane protein, termed tripartite attachment complex 40 (TAC40), that localizes to this connection. TAC40 is essential for mitochondrial DNA inheritance and belongs to the mitochondrial porin protein family. However, it is not specifically related to any of the three subclasses of mitochondrial porins represented by the metabolite transporter voltage-dependent anion channel (VDAC), the protein translocator of the outer membrane 40 (TOM40), or the fungi-specific MDM10, a component of the endoplasmic reticulum–mitochondria encounter structure (ERMES). MDM10 and TAC40 mediate cellular architecture and participate in transmembrane complexes that are essential for mitochondrial DNA inheritance. In yeast MDM10, in the context of the ERMES, is postulated to connect the mitochondrial genomes to actin filaments, whereas in trypanosomes TAC40 mediates the linkage of the mitochondrial DNA to the basal body of the flagellum. However, TAC40 does not colocalize with trypanosomal orthologs of ERMES components and, unlike MDM10, it regulates neither mitochondrial morphology nor the assembly of the protein translocase. TAC40 therefore defines a novel subclass of mitochondrial porins that is distinct from VDAC, TOM40, and MDM10. However, whereas the architecture of the TAC40-containing complex in trypanosomes and the MDM10-containing ERMES in yeast is very different, both are organized around a β-barrel protein of the mitochondrial porin family that mediates a DNA–cytoskeleton linkage that is essential for mitochondrial DNA inheritance.Mitochondria are a hallmark of all eukaroytic cells. They derive from an endosymbiontic event between a free-living bacterium and a presumably prokaryotic host cell. More than 1.5 billion years of evolution resulted in a great diversification of mitochondria. As a consequence, the shape and number of organelles per cell as well as size, content, copy number, and organization of their genomes vary greatly between different taxons (1). However, all eukaryotes must be able to faithfully transmit mitochondria to their offspring (2, 3).Unlike most other eukaryotes, the parasitic protozoa Trypanosoma brucei has a single mitochondrion throughout its life and its cell cycle. Due to the single-unit nature of the mitochondrion, its duplication must be coordinated with the duplication of the nucleus (4). The mitochondrial genome of T. brucei, termed kinetoplast DNA (kDNA), is essential for growth of both the procyclic insect stage and the bloodstream form of the parasite (5). It consists of a disk-shaped single-unit kDNA network that localizes to a distinct region within the mitochondrial matrix (6). The kDNA is physically connected with the cytosolic basal body, the organizing center of the eukaryotic flagellum, via a high-order transmembrane structure termed tripartite attachment complex (TAC) (7) of which only few components have been identified (8–10). Replication of the kDNA network occurs at a defined stage of the cell cycle shortly before the onset of the nuclear S phase. After replication, the kDNA networks need to be correctly positioned so that during cell and mitochondrial division each daughter cell receives a single organelle with a single kDNA network. This process requires an intact TAC and is mediated by the movement of the basal body: one kDNA network remains connected to the basal body of the old flagellum whereas the other one segregates with the basal body of the new flagellum (7, 11).Unlike trypanosomes, Saccharomyces cerevisiae propagates by budding and contains highly dynamic mitochondria that constantly divide and fuse (12, 13). Mitochondrial inheritance in budding yeast therefore requires a mechanism to move mitochondria and their genomes from the mother cell into the growing bud. The protein-associated mitochondrial genomes of S. cerevisiae, termed nucleoids, localize to dozens of globular foci that are distributed all over the organelles. Most actively replicating nucleoids are associated with a protein complex that includes the outer membrane (OM) protein MDM10 as a central unit, as well as the proteins MDM12, MDM34, and MMM1 (14–16). The protein complex forms the endoplasmic reticulum (ER)–mitochondria encounter structure (ERMES) tethering the ER to the mitochondrion (17). The ERMES has also been suggested to connect to cytosolic actin fibers that mediate the movement of mitochondria to the bud of dividing yeast cells (14, 18, 19). Besides its role in mitochondrial inheritance, the ERMES has been implicated in maintenance of mitochondrial morphology and in phospholipid and calcium exchange as well as in the assembly of the protein translocase of the mitochondrial OM (TOM) (20, 21). Some of the proposed ERMES functions are controversial and there is evidence that some of them might be due to secondary effects caused by the drastically altered mitochondrial morphology (22).The central ERMES subunit, the β-barrel protein MDM10 belongs to the mitochondrial porin superfamily, which comprises the three members voltage-dependent anion channel (VDAC), Tom40, and MDM10. Whereas VDAC and Tom40 have so far been found in all eukaryotes, including T. brucei (23, 24), MDM10 is specific to the fungal clade.In this study we identify a mitochondrial OM protein of T. brucei as a novel component of the TAC. We show that the protein defines a novel subclass of the mitochondrial porin superfamily that is specialized in mitochondrial DNA inheritance. 相似文献
97.
Svenja Taubner Stefanie Ulrich-Manns Jennifer Klasen Christian Curth Heidi Möller Silke Wolter 《Psychotherapie Forum》2014,19(1):2-12
In this paper first results of a study about competence development of psychotherapists in training in Germany are presented. In particular, the current mental processing of early relationship experiences and adversive childhood experiences of 90 trainees from three psychotherapies were examined at the beginning of their training. The internal working models of attachment and adversive early childhood experiences were assessed with the Adult Attachment Interview (AAI). The quantitative data analysis was supplemented by qualitative content analysis of four interviews to examine how trainees have dealt with adversive experiences and to work out if and how those are related to their decision to become psychotherapists. The AAIs analysis with respect to the attachment representation revealed by a first analysis of 50 interviews an overrepresentation of secure attachment patterns (78?%) and thus a significantly higher proportion of secure internal working models in comparison to former studies. Psychotherapists in training seem as burdened as the general population in terms of adversive childhood experiences. The qualitative analysis suggests a high degree of self-efficacy-enhancing parentification. The results are discussed in relation to previous psychotherapy experience, therapeutic school, age and sex of trainees. 相似文献
98.
Lisa Lynn ten Bergen Aleksandra Petrovic Anders Krogh Aarebrot Silke Appel 《Scandinavian journal of immunology》2020,92(4):e12945
In the past decades, clinical and experimental evidence has demonstrated that psoriasis is an immune-mediated inflammatory disease of the skin that occurs in genetically susceptible individuals. Psoriasis also shows clear autoimmune pathomechanisms, but specific cellular targets for the onset and maintenance of psoriatic lesions were not established until 2014. Since then, four psoriasis autoantigens were discovered, namely cathelicidin LL-37, melanocytic ADAMTSL5, lipid antigen PLA2G4D and keratin 17. Autoreactive T cells against these autoantigens were found in a number of patients with moderate-to-severe plaque psoriasis. Moreover, the discovery of autoantibodies against LL-37 and ADAMTSL5 and their strong association with psoriatic arthritis (PsA) suggest a potential role of these autoantibodies in the pathogenesis of PsA. This review discusses the current studies on psoriatic autoantigens and the associated circulating autoantibodies and their mechanisms involved in the development and maintenance of psoriatic plaques. Recent autoimmune evidence fuelled the discussion on psoriasis as an autoimmune skin disorder and has the potential to develop new treatment strategies with protective and therapeutic antigen-targeted methods. 相似文献
99.
Nanchao Wang Kai Zhang Xue Shen Yuan Wang Jing Li Chengcai Li Jietai Mao Aleksey Malinka Chuanfeng Zhao Lynn M. Russell Jianping Guo Silke Gross Chong Liu Jing Yang Feitong Chen Lingyun Wu Sijie Chen Ju Ke Da Xiao Yudi Zhou Jing Fang Dong Liu 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(10)
Aerosol–cloud interaction (ACI) is complex and difficult to be well represented in current climate models. Progress on understanding ACI processes, such as the influence of aerosols on water cloud droplet formation, is hampered by inadequate observational capability. Hitherto, high-resolution and simultaneous observations of diurnal aerosol loading and cloud microphysical properties are challenging for current remote-sensing techniques. To overcome this conundrum, we introduce the dual-field-of-view (FOV) high-spectral-resolution lidar (HSRL) for simultaneously profiling aerosol and water cloud properties, especially water cloud microphysical properties. Continuous observations of aerosols and clouds using this instrument, verified by the Monte Carlo simulation and coincident observations of other techniques, were conducted to investigate the interactions between aerosol loading and water cloud microphysical properties. A case study over Beijing highlights the scientific potential of dual-FOV HSRL to become a significant contributor to the ACI investigations. The observed water cloud profiles identify that due to air entrainment its vertical structure is not perfectly adiabatic, as assumed by many current retrieval methods. Our ACI analysis shows increased aerosol loading led to increased droplet number concentration and decreased droplet effective radius—consistent with expectations—but had no discernible increase on liquid water path. This finding supports the hypothesis that aerosol-induced cloud water increase caused by suppressed rain formation can be canceled out by enhanced evaporation. Thus, these observations obtained from the dual-FOV HSRL constitute substantial and significant additions to understanding ACI process. This technique is expected to represent a significant step forward in characterizing ACI.Aerosol–cloud interaction (ACI) is a crucial aspect of atmospheric research and one of the primary sources of uncertainties in climate predictions (1–3). To assess the credibility of climate projections, it is imperative to improve our understanding of how aerosols interact with clouds (4–6). It has been well known that aerosols can serve as cloud condensation nuclei (CCN) to form cloud droplets, which can further influence the initiation of precipitation (7). However, quantifying the impact of natural and anthropogenic aerosols on the growth and the evolution of water clouds is still challenging (8, 9). The short lifetime, high temporal variability, and complex vertical structure of water cloud layers lead to a major difficulty for ACI studies (3, 10, 11). Despite the advances in the characterization of ACI by ground-based measurements (12–21), satellite retrieved products (22–25), and airborne in situ measurements (26–28), uncertainties remain in the effects of the aerosols on the water cloud properties. The reason for this gap in our knowledge is closely linked to the inadequate observations of the water cloud microphysical properties under various aerosol conditions (3). Current satellites can estimate cloud properties but not the typical aerosol nucleation region beneath clouds (22–25). Moreover, they also bring challenges for ACI studies that the typical revisit time of satellite-based sensors is much longer than the temporal scales of cloud variability (29, 30). Quintessential ground-based remote-sensing techniques for retrieving cloud properties, such as the cloud radar and the microwave radiometer, cannot provide simultaneous aerosol observations for ACI studies. Therefore, ground-based measurements commonly combine those with other remote-sensing or in situ aircraft instruments for characterizing aerosol loading beneath clouds (12–20). However, given the high variability of clouds, differences in perspective or mismatched sampling in space and time would raise uncertainty and bias in the characterization of ACI (15).Lidar, a powerful tool for profiling optical properties of aerosols and clouds, has been widely used in atmospheric studies (31–33). Yet, further progress with lidar-based techniques for ACI studies is hampered by limited observations of the water cloud microphysical properties, mainly due to the difficulties of quantifying the multiple scattering within water clouds (34). The multiple scattering has a significant impact on the water cloud observations of the extinction as well as the depolarization ratio, which is related to the receiver field of view (FOV). In brief, a retrieval of water cloud microphysical properties for lidar-based techniques relies on utilizing different receiver FOVs to provide the necessary observations for characterizing the multiple-scattering effect caused by the water droplets (34, 35). The first multiple-FOV lidars were aimed at investigating the multiple-scattering effect and measured Mie scattering by water droplets (36). However, a complicated behavior of the Mie phase function makes the quantifying of the multiple scattering become an arduous task. It naturally leads to the use of Raman scattering of atmospheric nitrogen, which has an isotropic phase function practically in the backward direction, to allow developing a feasible algorithm for the retrieval of water cloud microphysical properties (35). Moreover, the dual-FOV Raman lidar technique for profiling cloud properties has been experimentally demonstrated (37). With this technique in conjunction with an incoherent Doppler lidar, the ACI findings have been obtained with an ACI index versus vertical air motion (21, 38). However, nitrogen Raman signals are so weak that the observations are usually restricted to nighttime hours, and the signal has to be averaged over tens of minutes to deliver reliable lidar products, while the typical temporal scale of cloud variability is much shorter than that (29). Recently, a dual-FOV polarization lidar technique was reported, which continued and further developed the concept of the dual-FOV Mie lidar (39). However, to assess ACI this method requires a priori assumptions about the lidar ratio and subadiabatic cloud conditions. The impact of the a priori assumptions on the aerosol and cloud retrievals has been widely discussed (10, 40, 41). In general, all existing multiple-FOV lidar-based techniques have their advantages and also limitations.To overcome this conundrum, a dual-FOV high-spectral-resolution lidar (HSRL) technique for profiling aerosol and cloud properties simultaneously is introduced here. It provides lateral observations of aerosols and clouds with high vertical and temporal resolutions during daytime and nighttime. Neither assumptions on thermodynamic conditions nor lidar ratio are required. This work benefited from the range-resolved observations of water clouds with high resolution, revealing that the observed profiles of low-level water cloud microphysical properties are not perfectly adiabatic as assumed by many current retrievals (42–46). Furthermore, the ACI analysis supports the hypothesis that aerosol-induced water decrease by enhanced evaporation can cancel out the increase caused by suppressed rain formation (6, 47), while most current global general circulation models (GCMs) suggest that increased aerosol loading typically causes increased cloud water content (19, 48). Thus, these observations obtained from the dual-FOV HSRL can constitute a substantial and significant addition to our understanding of ACI studies. We believe that this versatile system will not only benefit the quality monitoring of aerosol and cloud properties but also serve as a powerful tool for ACI studies. 相似文献
100.