Molecular pathway-based classification of ectodermal dysplasias: first five-yearly update

To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term “ectodermal dysplasia”, referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options

Unique Features of a Global Human Ectoparasite Identified Through Sequencing of the Bed Bug Genome

The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host-symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human-bed bug and symbiont-bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite

Unique features of a global human ectoparasite identified through sequencing of the bed bug genome

The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host–symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human–bed bug and symbiont–bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite

New insights into circadian photoreception and the molecular regulation of the resetting of Drosophila�s circadian clock

Circadian rhythms are so widespread under the inhabitants of the earth that it is no wonder that circadian clocks are focus of investigation for a very long time. The many genetic and molecular possibilities of the model organism Drosophila melanogaster make the fruit fly the perfect organism for the investigation of the circadian clock on the molecular level. For this reason the current thesis deals with the investigation of the circadian clock of Drosophila with the focus on the circadian photoreception. In the first part of this work we investigated the gene lethal (2) 05510 or quasimodo (qsm). Our investigations revealed, that the qsm mRNA is rhythmically expressed under the control of the circadian clock. When this gene is down-regulated via RNAi technique in the crucial clock neurons of adult flies those animals still behave rhythmic under constant illumination. Constant light normally renders flies arrhythmic, because of a light dependent degradation of the important clock protein Timeless (TIM). Furthermore some neuronal groups still exhibited a rhythmic fluctuation of the Period (PER) protein under constant illumination � this was never detected in wild-type animals. We could show that QSM is expressed �at least partly- in clock neurons and in neurons in close proximity to those neurons. Whereas the localization and intensity of the protein changes with the time, surprisingly the troughs and peaks do not correlate with the mRNA troughs and peaks. Another interesting observation was the restored rhythmicity of per01animals when qsm was down regulated in constant light conditions in per01 background. Until now it was believed, that period is mandatory for circadian rhythm. The fact that per01;;qsmRNAi(16) animals are rhythmic under constant light condition or anticipate the evening under LD conditions brought us to rethink. What really renders those animals rhythmic in LL is still subject of investigation. We discussed in this context a separation of the circadian clock into several oscillators � one important for the control of the circadian clock in the darkness, one important for the control of the circadian clock in the light. In the �Light-clock� PER does not play the important role it holds in the �Dark-clock�. Furthermore we could reveal that the over-expression of the EP2586 insertion � a P-element insertion close to the qsm start - does not approach quasimodo but the miRNA cluster 310-313. This cluster is located in the promoter region of qsm. When those miRNAs are overexpressed in the clock neurons we could detect a different behavior under Light/Dark cycles. In those animals the release of the circadian neuropeptide PDF seems to be impaired. Because similar phenotypes are reported for animals where ion channels are over-expressed or down regulated we focused our search for the targets of the miRNAs to channel and channel like proteins. A good candidate for a target channel protein is Cg31547. First preliminary results still do not allow us to make a clear assertion. The second part of this work deals with a mutant fly that behaves rhythmic under LL conditions as well. We could show that in this mutant fly � called Veela - not one but two different factors are causing the abnormal behavior: Veela animals carry a mutation in the F-Box protein Jetlag (JET). jet is important for the light dependent degradation of TIM. Furthermore Veela animals carry a less light sensitive natural allelic variant of the Timeless protein � encoded by the so called ls-tim gene. Each factor alone impairs the circadian photoreception only to a minor extend. Hence only the combination of both leads to the observed phenotype under constant light conditions. We could reveal that the Jetlag protein has an additional function in the circadian clock. Jetlag also interacts with Cry in yeast and in Drosophila S2 cells in a light-dependent manner. After illumination Jetlag induces massive degradation of Cry which can be prevented in vitro and in vivo by adding Tim as an antagonist. We show that Jetlag causes light-dependant and sequential degradation of Tim and Cry. With this sophisticated mechanism the degradation of TIM and CRY and thus the resetting of the circadian clock in the light is regulated. Another protein that is intimately involved in the degradation of TIM and CRY is Shaggy. Recent observations demonstrate that Shaggy stabilizes Cryptochrome in the light. Our preliminary results could not affirm a stabilization effect of Shaggy on Cry. Here we discussed the possibility that the function of Shaggy is not located in the stabilization of Cry by binding to its C-terminus and thus acting as a repressor. We rather speculated that Shaggy phosphorylates Cry and facilitates thus the degradation of this protein

GSK-3 Beta Does Not Stabilize Cryptochrome in the Circadian Clock of Drosophila

Cryptochrome (CRY) is the primary photoreceptor of Drosophila’s circadian clock. It resets the circadian clock by promoting light-induced degradation of the clock protein Timeless (TIM) in the proteasome. Under constant light, the clock stops because TIM is absent, and the flies become arrhythmic. In addition to TIM degradation, light also induces CRY degradation. This depends on the interaction of CRY with several proteins such as the E3 ubiquitin ligases Jetlag (JET) and Ramshackle (BRWD3). However, CRY can seemingly also be stabilized by interaction with the kinase Shaggy (SGG), the GSK-3 beta fly orthologue. Consequently, flies with SGG overexpression in certain dorsal clock neurons are reported to remain rhythmic under constant light. We were interested in the interaction between CRY, Ramshackle and SGG and started to perform protein interaction studies in S2 cells. To our surprise, we were not able to replicate the results, that SGG overexpression does stabilize CRY, neither in S2 cells nor in the relevant clock neurons. SGG rather does the contrary. Furthermore, flies with SGG overexpression in the dorsal clock neurons became arrhythmic as did wild-type flies. Nevertheless, we could reproduce the published interaction of SGG with TIM, since flies with SGG overexpression in the lateral clock neurons shortened their free-running period. We conclude that SGG does not directly interact with CRY but rather with TIM. Furthermore we could demonstrate, that an unspecific antibody explains the observed stabilization effects on CRY

Platinum Priority -Testis Cancer Postchemotherapy Laparoscopic Retroperitoneal Lymph Node Dissection for Low-volume, Stage II, Nonseminomatous Germ Cell Tumor: First 100 Patients

E U R O P E A N U R O L O G Y X X X ( 2 0 1 2 ) X X X -X X X a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Article info Article history: Accepted September 14, 2012 Published online ahead of print on September 24, 2012 Keywords: Testicular neoplasm Germ cell tumor Retroperitoneal lymph node dissection Laparoscopy Abstract Background: Retroperitoneal lymph node dissection (RPLND) is indicated after chemotherapy in case of radiologic incomplete remission or teratomatous elements in orchiectomy specimens. Open RPLND is associated with considerable morbidity, but technical difficulty of postchemotherapy laparoscopic RPLND (L-RPLND) can be significant; therefore, literature concerning pc L-RPLND is sparse. Objective: To evaluate feasibility and long-term oncologic outcome of postchemotherapy L-RPLND for clinical stage II disease at a single institution. Design, setting, and participants: Records of patients with nonseminomatous germ cell tumor who underwent postchemotherapy L-RPLND between 1993 and 2010 were retrospectively reviewed. Unilateral template resection was used until a bilateral nerve-sparing approach was introduced in 2004. Follow-up investigations were performed at 3-mo intervals for the first 3 yr, every 6 mo for the next 2 yr, and annually thereafter. Outcome measurements and statistical analysis: This was a descriptive analysis. Results and limitations: The study cohort comprised 100 patients with stage II retroperitoneal disease (stage IIC: n = 16; IIB: n = 68; IIA with persisting tumor marker: n = 16). Mean diameter of retroperitoneal masses before and after chemotherapy was 3.5 cm and 1.4 cm, respectively. Unilateral and bilateral templates were resected in 71 and 29 patients, respectively. Surgery was successfully completed in all but one patient, whose procedure was converted to open surgery due to bleeding. Mean operation time for unilateral and bilateral resection was 241 and 343 min, respectively. Mean blood loss was 84 ml. Postoperative complications were a large lymphocele in one patient and chylous ascites in another. Mean postoperative hospital stay was 3.9 d. L-RPLND specimens showed teratoma in 38 patients and active tumor in 2 patients. During a mean follow-up of 74 mo, one patient recurred. No recurrence was observed inside the applied surgical field. No patient died of tumor progression. After bilateral nerve-sparing postchemotherapy L-RPLND, 95.2% of patients reported antegrade ejaculation. Conclusions: Postchemotherapy L-RPLND performed by experienced hands is feasible and associated with low morbidity and high oncologic efficacy

Stability of CRY in living <i>Drosophila</i> animals.

<p>Bioluminescence of adult <i>Drosophila</i> animals carrying a <i>Luc-dCry</i> reporter. Adult <i>Drosophila</i> transgenic male flies were measured in a Packard Topcount machine. The genotype of the flies is displayed on the right. Furthermore all animals carried one chromosomal copy of an <i>UAS</i>-<i>Luc-dCry</i> insertion. The x-axis indicates the time, the black and white bars at the bottom indicate the daily change of light and darkness (Light/Dark ratio 12:12 hrs). The y-axis indicates the bioluminescence level (in Counts per second CPS) and thus the luciferase amount. Per genotype 8 animals were investigated.</p

Rhythmic behaviour of male <i>Drosophila</i> flies in LL after SGG overexpression.

<p>Double-plotted actograms of representative single males of the rhythmic genotypes are shown. On the y-axis the LD or LL setting is marked. While the SGG overexpressing animals only show a very weak rhythm in LL, <i>cry</i>^<i>01</i> animals still behave strongly rhythmic under these conditions.</p

Behaviour in LD/DD conditions.

<p>Behaviour in LD/DD conditions.</p