The role of GLIS2 in maintenance of genome integrity in the development of nephronophthisis

Nephronophthisis (NPH) is an autosomal-recessive inherited ciliopathy and the most common genetically determined cause of end-stage renal disease in early childhood. Kidney failure is due to the development of excessive fibrosis and cysts at the corticomedullary border in the kidneys of these patients, which replace the functional kidney tissue. Today mutations in ≥20 different genes have been identified to cause NPH. The pathogenesis of NPH seems to be complex and to differ among the NPH subtypes, as well as the exact mechanisms remain largely unknown so far. One unifying concept is the presence of almost all NPH proteins at the base of or in primary cilia. In 2012 the first link between two NPH proteins (ZNF423 and CEP164) and the DDR pathway was identified, providing a new perspective on the pathogenesis of NPH. This finding led to the hypothesis that the DDR in cells lacking one of those NPH proteins is impaired, making the cell more susceptible to genotoxic influences like extracellular genotoxic substances or replication stress leading to the accumulation of DNA damage. This accumulation of DNA damage leads to the induction of cellular programs such as apoptosis and cellular senescence. Furthermore, DNA damage is also a trigger for the innate immune response, which might cause immune cell infiltration in the kidney tissue, providing a profibrotic environment for the tubule epithelial cells in the context of NPH, thus promoting EMT. Seven NPH proteins have been linked to roles in the DDR so far. We focused on GLIS2, which has been identified as NPHP7 7. Because of its primary localization in the nucleus, its known functions in the regulation of transcription, and the finding of activated DDR in GLIS2 knock-out cells, it was reasonable to assume that GLIS2 also plays a crucial role in the DDR. We generated the first GLIS2 interactome derived from mass spectrometry-based analysis of immunoprecipitates from stable cell lines expressing low levels of wild-type GLIS2 and two truncations. Interestingly, this revealed key components of DDR pathways like PARP1, DNA-PKcs, and RAD50. These data support a potential role of GLIS2 in the DDR and thus in the maintenance of genome integrity. Furthermore, many ciliary proteins were also found in this interactome, providing evidence for a ciliary localization of GLIS2

Zur Akzeptanz von Fassadenbegrünung

Die vorliegende Arbeit, die im Rahmen des an der Universität zu Köln eingerichteten Sonderforschungsbereiches (SFB) 419/Teilprojekt A4 angefertigt wurde, ging der Frage nach, welche Einstellungen gegenüber Fassadenbegrünung in der Bevölkerung vorherrschen und inwieweit dieses Mittel der Stadtgestaltung von den Bürgern akzeptiert wird. Zu diesem Zweck wurde gefragt, welche positiven wie negativen Auswirkungen Kölner Bürger mit begrünten Fassaden verbinden und welche Bedeutung sie den einzelnen Vor- bzw. Nachteilen zuschreiben. Um die Akzeptanz von Fassadenbegrünung empirisch 'messen' zu können, wurde ein allgemeines Akzeptanzmodell aufgestellt, in dem die Akzeptanz von Fassadengrün von vier übergeordneten Bereichen (1. ökologische, 2. optisch-ästhetische sowie psychosoziale, 3. bauphysikalische und 4. finanz- und zeitökonomische Aspekte) und von einer Vielzahl untergeordneter Faktoren abhängig ist. Dieses Modell wurde vor allem aus Ergebnissen der Akzeptanzforschung betriebswissenschaftlicher Richtung abgeleitet, während die Bestimmung der Einflussbereiche und -faktoren aus den Forschungsbefunden zum Thema 'Fassadenbegrünung' resultierte. Zur Akzeptanzmessung wurden in 24 Kölner Stadtteilen im Spätsommer 1999 zeitgleich zwei schriftliche Befragungen durchgeführt. Die beiden Umfragen richteten sich an Personen, die in Häusern mit bzw. ohne begrünte Fassaden leben. Aus den Umfragen geht hervor, dass eine Mehrheit beider Personengruppen Fassadengrün insgesamt betrachtet positiv gegenüberstehen (84% bzw. 68%). Ferner ergibt sich, dass die Ansicht der beiden Probandengruppen über begrünte Fassaden von einer Reihe gleicher Faktoren abhängig ist, bei den Bewohnern begrünter Häuser aber von weniger Faktoren beeinflusst wird als bei den Bewohnern unbegrünter Gebäude. Bei beiden Probandengruppen kann beobachtet werden, dass eine positive Gesamtbewertung von Fassadenbegrünung i.d.R. mit einer positiven Beurteilung der optisch-ästhetisch und psychosozialen Auswirkungen begrünter Fassaden einhergeht, während die Bewertung der anderen drei Bereiche weniger stark mit dem Gesamturteil korreliert. Für eine negative Gesamtbewertung sind bei den Bewohnern begrünter Häuser hauptsächlich Faktoren verantwortlich, die mit dem natürlichen Wuchsverhalten der Kletterpflanzen im Zusammenhang stehen (z.B. Laubanfall). Bei den Bewohnern unbegrünter Gebäude kommen noch die Bedenken hinsichtlich der Zunahme von Insekten hinzu. Aus den vorliegenden Befunden können einige Gründe für das bisher ungenutzte Gestaltungs- und Flächenpotential von Fassadengrün abgeleitet werden (z.B. die fehlende Anerkennung der gemeinnützigen Bewohneraktivität). Darüber hinaus ergeben sich einige Konsequenzen für die vermehrte Begrünung von Vertikalflächen und damit für eine optimierte Begrünungspraxis (z.B. praktische Hilfe bei der Anlegung und Pflege durch kommunale Stellen)

Prenatal ultrasound screening for fetal anomalies and outcomes in high-risk pregnancies due to maternal HIV infection : a retrospective study

Objective: To assess the prevalence of prenatal screening and of adverse outcome in high-risk pregnancies due to maternal HIV infection. Study design: The prevalence of prenatal screening in 330 pregnancies of HIV-positive women attending the department for prenatal screening and/or during labour between January 1, 2002 and December 31, 2012, was recorded. Screening results were compared with the postnatal outcome and maternal morbidity, and mother-to-child transmission (MTCT) was evaluated. Results: One hundred of 330 women (30.5%) had an early anomaly scan, 252 (74.5%) had a detailed scan at 20–22 weeks, 18 (5.5%) had a detailed scan prior to birth, and three (0.9%) had an amniocentesis. In seven cases (2.12%), a fetal anomaly was detected prenatally and confirmed postnatally, while in eight (2.42%) an anomaly was only detected postnatally, even though a prenatal scan was performed. There were no anomalies in the unscreened group. MTCT occurred in three cases (0.9%) and seven fetal and neonatal deaths (2.1%) were reported. Conclusion: The overall prevalence of prenatal ultrasound screening in our cohort is 74.5%, but often the opportunity for prenatal ultrasonography in the first trimester is missed. In general, the aim should be to offer prenatal ultrasonography in the first trimester in all pregnancies. This allows early reassurance or if fetal disease is suspected, further steps can be taken

Sozialmedizinisches Outcome von Patienten mit Fibromyalgiesyndrom nach einer psychosomatischen Rehabilitation

Fragestellung: Ziel der Studie war es, Unterschiede zwischen Patienten mit Fibromyalgiesyndrom (FMS), die nach einer Rehabilitationsmaßnahme arbeitsfähig werden und solchen, die es nicht werden, herauszufiltern und möglichst Prädiktoren für das Outcome zu finden. Als Mögliche Unterschiede wurden Depressivität, Coping, Beeinträchtigung durch die Schmerzen sowie arbeitsbezogenes Verhalten untersucht. Als Kontrollgruppe diente eine Gruppe von Patienten mit anhaltender somatoformer Schmerzstörung (ASS). Methoden: Als Stichprobe diente die Gruppe der FMS – Patienten, die in den Jahren 2004-2008 an einer Rehabilitationsmaßnahme in den MediClin Kliniken Blieskastel teil genommen hatten. Dazu wurde eine eine 100% weibliche Kontrollgruppe aus ASS – Patienten bezüglich Alter und Jahr, in dem die Rehabilitationsmaßnahme statt fand, gematcht. Die Probanden erhielten zuerst einen Kurzfragebogen mit Fragen zur Rehabilitation und dem arbeitsrechtlichen Status und dann bei entsprechender Zustimmung ein Fragebogenheft, das die Fragebögen HEALTH, CSQ, AVEM und PDI enthielt. Außerdem wurden aus den Entlassbriefen im Archiv die Daten des HEALTH heraus gesucht, der bereits im Rahmen des stationären Aufenthaltes durchgeführt wurde. Ergebnisse: Von 579 FMS – Patienten antworteten 221, was einer Rücklaufquote von 38,17% entspricht. Von den 261 ASS – Patienten antworteten 89, was einer Rücklaufquote von 34,1% entspricht. Die FMS – Patienten waren durchschnittlich 53,49 ± 6,07 Jahre alt und zu 95,9 % weiblich. Die ASS – Patienten waren durchschnittlich 52,47± 6,85 Jahre alt und zu 100% weiblich. Von den FMS – Patienten waren jeweils 20,6% Vollzeit und Teilzeit erwerbstätig, 6,1% hatten einen Minijob, 10,1 % waren arbeitssuchend und 40,40 % waren nicht erwerbstätig. Bei den ASS – Patienten waren 34,10 % Vollzeit arbeitend, 19,30% Teilzeit arbeitend, 4,5% hatten einen Minijob, 3,4% waren arbeitssuchend und 35,20% waren nicht erwerbstätig. Die Auswertung der Fragebögen ergab, dass sich Depressivität bei den FMS – Patienten negativ auf die Arbeitsfähigkeit auswirkt. Jedoch zeigte sich kein Unterschied bezüglich des Einflusses der Depressivität auf die Arbeitsfähigkeit zwischen FMS- und ASS – Gruppe. Auch änderte sich die Depressivität zwischen Zeitpunkt T0 (Anfang der Rehabilitationsmaßnahme) bis T2 (Zeitpunkt, zu dem das Fragebogenheft geschickt wurde) nicht signifikant. Zudem zeigte sich, dass sich FMS – Patienten von ASS – Patienten bezüglich der AVEM – Skala „Lebenszufriedenheit“ voneinander unterscheiden. Die Skala „subjektive Bedeutsamkeit der Arbeit“ des AVEM hat bei FMS – Patienten einen Einfluss auf die Arbeitsfähigkeit nach der Rehabilitation. Arbeitsunfähige Patienten hatten hier einen signifikant niedrigeren Wert als solche, die arbeitsfähig waren. Unterschiede zwischen FMS und ASS – Gruppe zeigten sich auch noch in den Skala „Schmerzverhalten“ des CSQ sowie den Skalen „Familien und häusliche Verpflichtungen“ und „soziale Aktivitäten“ des PDI (dort aber nur bei arbeitsunfähigen Probanden). Bei FMS – Patienten haben die Gesamtskala sowie die Skalen „Familien und häusliche Verpflichtungen “, „Erholung“, „soziale Aktivität“, „Beruf“ und „Selbstversorgung“ einen Einfluss mit der Arbeitsfähigkeit. Diskussion: Der einzige echte Prädiktor für eine Arbeitsunfähigkeit bei FMS – Patienten war in der vorliegenden Studie die Skala „Depressivität“ des HEALTH. Die sonstigen Unterschiede stellen lediglich Beschreibungen da, ohne dass klar ist, ob dies Ursache oder Folge der Arbeitsunfähigkeit ist. Weitere prospektive Studien sind hier nötig. Überraschend war, dass sich bezüglich der Beeinträchtigung durch die Schmerzen deutlich mehr Unterschiede zwischen arbeitsfähigen und arbeitsunfähigen FMS – Patienten fanden als in Bezug auf das Copingverhalten , was bedeuten könnte, dass es sich hier um den besseren Prädiktor handelt. Insgesamt zeigten sich deutlich weniger Unterschiede als Gemeinsamkeiten zwischen der FMS – und der ASS – Gruppe, was für eine Konzeptualisierung des FMS in der Nähe der somatoformen Störungen spricht. Die Ergebnisse der Studie sind allerdings limitiert durch eine hohe Dropoutquote und hieraus resultierende geringe Fallzahlen.Introduction: The Aim of this study was to determine differences between those patients with fibromyalgia syndrome (FMS) that are able to work after taking part in an rehabilitation program and those that are not and to find out more about predictors for the outcome. We examined depression, coping, pain disability as well as work related behaviour as possble differences. The control group consisted of patients with persistend somatoform pain disorder (PSPD). Methods: Sample was a group of FMS patients that participated in a rehabilitation program at the MediClin Bliestal Kliniken Blieskastel (Germany) in the years 2004 – 2008. We matched this group according to age and year in which the rehabilitation programm took place with a 100% female control group of PSPD patients. Patients first got a short questionnaire containing questions about rehabilitation and their socioeconomic status. When the patients agreed to it, they also got a larger questionnaire booklet including the questionnaires HEALTH, CSQ, AVEM and PDI. We also retrieved the results of HEALTH from the discharge letters in the hospital's archive if it had already been answered during the stay in the hospital. Results: Out of 579 patients with FMS 221 answered, corresponding to a return rate of 38,17%. Out of the 261 patients with PSPD 89 answered, corresponding to a return rate of 34,1%. FMS – patients were average 52,47± 6,85 years old and 95,9% female. ASS – patients were average 52,47± 6,85 years old and 100% female. Out of the FMS – patients 20% worked full time and 20% worked half time, 6,1% had a „Minijob“, 10,1% were looking for work and 40,4% were unable to work. Out of the PSPD – patients, 34,1% worked full time, 19,3% worked part time, 4,5% had a „Minijob“, 3,4% were looking for work and 35,2% were unable to work. Analysis of the questionnaires showed that depression had a negative effect on working ability in FMS patients. But we did not find a difference in the effect of depression on working ability between FMS and PSPD patients. Depression did not change significantly between T0 (start of the rehabilitation program) and T2 (point on which the questionnaire booklet was sent). The different groups of patients showed differences concerning the AVEM – scale „satisfaction with life“. The AVEM - scale „subjective importance of work“ showed an effect on working ability in FMS – patients after the rehabilitation. Patients unable to work had significantly lower results than those able to work. There were also differences found between the group of FMS – patients and that of PSPD – patients in scales „pain behaviour“ of CSQ as well as scales „family and domestic responsibilities“ and „social activities“ of PDI (only in subjects unable to work). In FMS patients the complete scale as well as the scales „family and domestic responsibilities“, „recreation“, „social activities“, „occupation“ and „self – care“ have an impact on working ability. Discussion: The only true predictor for inability to work in FMS – patients found in this study was the scale „depression“ of the HEALTH questionnaire. The other differences are sole descriptions. It stays unclear if these differences are causes or consequences of the inability to work. Further prospect studies are needed. It was surprising that we found more differences between those FMS - Patients able to work and those unable to work when looking at the pain disability than when looking at the coping strategies. This could signify that pain disability is a better predictor than coping strategies. Overall, we found more similarities than differences between FMS and PSPD patients which argues for a conceptualization of FMS in the vicinity of the somatic disorders. But the results of this study are limited due to high drop out rates and resulting low number of cases

Relaxation kinetics in two-dimensional structures

We have studied the approach to equilibrium of islands and pores in two dimensions. The two-regime scenario observed when islands evolve according to a set of particular rules, namely relaxation by steps at low temperature and smooth at high temperature, is generalized to a wide class of kinetic models and the two kinds of structures. Scaling laws for equilibration times are analytically derived and confirmed by kinetic Monte Carlo simulations.Comment: 6 pages, 7 figures, 1 tabl

A supersonic crowdion in mica: Ultradiscrete kinks with energy between 40^{40}K recoil and transmission sputtering

In this chapter we analyze in detail the behaviour and properties of the kinks found in an one dimensional model for the close packed rows of potassium ions in mica muscovite. The model includes realistic potentials obtained from the physics of the problem, ion bombardment experiments and molecular dynamics fitted to experiments. These kinks are supersonic and have an unique velocity and energy. They are ultradiscrete involving the translation of an interstitial ion, which is the reason they are called 'crowdions'. Their energy is below the most probable source of energy, the decay of the $^{40}$K isotope and above the energy needed to eject an atom from the mineral, a phenomenon that has been observed experimentallyComment: 28 pages, 15 figure

Fluctuations of an Atomic Ledge Bordering a Crystalline Facet

When a high symmetry facet joins the rounded part of a crystal, the step line density vanishes as sqrt(r) with r denoting the distance from the facet edge. This means that the ledge bordering the facet has a lot of space to meander as caused by thermal activation. We investigate the statistical properties of the border ledge fluctuations. In the scaling regime they turn out to be non-Gaussian and related to the edge statistics of GUE multi-matrix models.Comment: Version with major revisions -- RevTeX, 4 pages, 2 figure

Misfit-Dislocation-Mediated Heteroepitaxial Island Diffusion

Scanning tunneling microscopy combined with molecular dynamics simulations reveal a dislocation-mediated island diffusion mechanism for Cu on Ag(111), a highly mismatched system. Cluster motion is tracked with atomic precision at multiple temperatures and diffusion barriers and prefactors are determined from direct measurements of hop rates. The non-monotonic size dependence of the diffusion barrier is in good agreement with simulations and can lead to enhanced mass transport upon coarsening, in surprising contrast to the traditional island diffusion models where diffusivity reduces with cluster size

Cell type-specific transcriptomics of esophageal adenocarcinoma as a scalable alternative for single cell transcriptomics

Single-cell transcriptomics have revolutionized our understanding of the cell composition of tumors and allowed us to identify new subtypes of cells. Despite rapid technological advancements, single-cell analysis remains resource-intense hampering the scalability that is required to profile a sufficient number of samples for clinical associations. Therefore, more scalable approaches are needed to understand the contribution of individual cell types to the development and treatment response of solid tumors such as esophageal adenocarcinoma where comprehensive genomic studies have only led to a small number of targeted therapies. Due to the limited treatment options and late diagnosis, esophageal adenocarcinoma has a poor prognosis. Understanding the interaction between and dysfunction of individual cell populations provides an opportunity for the development of new interventions. In an attempt to address the technological and clinical needs, we developed a protocol for the separation of esophageal carcinoma tissue into leukocytes (CD45+), epithelial cells (EpCAM+), and fibroblasts (two out of PDGFRα, CD90, anti-fibroblast) by fluorescence-activated cell sorting and subsequent RNA sequencing. We confirm successful separation of the three cell populations by mapping their transcriptomic profiles to reference cell lineage expression data. Gene-level analysis further supports the isolation of individual cell populations with high expression of CD3, CD4, CD8, CD19, and CD20 for leukocytes, CDH1 and MUC1 for epithelial cells, and FAP, SMA, COL1A1, and COL3A1 for fibroblasts. As a proof of concept, we profiled tumor samples of nine patients and explored expression differences in the three cell populations between tumor and normal tissue. Interestingly, we found that angiogenesis-related genes were upregulated in fibroblasts isolated from tumors compared with normal tissue. Overall, we suggest our protocol as a complementary and more scalable approach compared with single-cell RNA sequencing to investigate associations between clinical parameters and transcriptomic alterations of specific cell populations in esophageal adenocarcinoma

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches