No apparent role for the Wari insulator in transcriptional regulation of the endogenous white gene of Drosophila melanogaster

Chromatin insulators have been proposed to play an important role in chromosome organization and local regulatory interactions. In; Drosophila; , one of these insulators is known as Wari. It is located immediately downstream of the 3' end of the; white; transcription unit. Wari has been proposed to interact with the; white; promoter region, thereby facilitating recycling of the RNA polymerase machinery. We have tested this model by deleting the Wari insulator at the endogenous; white; locus and could not detect a significant effect on eye pigmentation

Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic)

Appropriate reference intervals are essential when using laboratory test results to guide medical decisions. Conventional approaches for the establishment of reference intervals rely on large samples from healthy and homogenous reference populations. However, this approach is associated with substantial financial and logistic challenges, subject to ethical restrictions in children, and limited in older individuals due to the high prevalence of chronic morbidities and medication. We implemented an indirect method for reference interval estimation, which uses mixed physiological and abnormal test results from clinical information systems, to overcome these restrictions. The algorithm minimizes the difference between an estimated parametrical distribution and a truncated part of the observed distribution, specifically, the Kolmogorov-Smirnov-distance between a hypothetical Gaussian distribution and the observed distribution of test results after Box-Cox-transformation. Simulations of common laboratory tests with increasing proportions of abnormal test results show reliable reference interval estimations even in challenging simulation scenarios, when <20% test results are abnormal. Additionally, reference intervals generated using samples from a university hospital’s laboratory information system, with a gradually increasing proportion of abnormal test results remained stable, even if samples from units with a substantial prevalence of pathologies were included. A high-performance open-source C++ implementation is available at https://gitlab.miracum.org/kosmic

Begleitung und Auswertung der Erprobung trägerübergreifender Persönlicher Budgets: wissenschaftliche Begleitforschung zur Umsetzung des Neunten Buches Sozialgesetzbuch (SGB IX) - Rehabilitation und Teilhabe behinderter Menschen ; Abschlussbericht

"Im Jahr 2004 initiierte das damalige Bundesministerium für Gesundheit und Soziale Sicherung - jetzt Bundesministerium für Arbeit und Soziales - die bundesweite Erprobung trägerübergreifender Persönlicher Budgets unter wissenschaftlicher Begleitung in acht ausgewählten Modellregionen. Nach einer öffentlichen Ausschreibung wurde ein Forschungsverbund der Universitäten Tübingen (Z.I.E.L.), Dortmund (Rehabilitationssoziologie) und der Pädagogischen Hochschule Ludwigsburg (Fakultät für Sonderpädagogik in Reutlingen) mit der wissenschaftlichen Begleitung beauftragt. Nunmehr liegt der Abschlussbericht der wissenschaftlichen Begleitforschung vor. Im Rahmen der Modellerprobung wurde auch eine juristische und verwaltungsrechtliche Expertise erstellt. Beim Abschlussbericht der wissenschaftlichen Begleitforschung konnten insgesamt 494 Persönliche Budgets in den Modellregionen und weitere 353 Persönliche Budgets außerhalb der Modellregionen dokumentiert werden; d. h. insgesamt wurden 847 Persönliche Budgets dokumentiert. Die Zahl der bewilligten und dokumentierten Budgets nahm kontinuierlich im gesamten Zeitverlauf der Modellerprobung zu. Innerhalb eines Jahres (von Januar 2006 bis Januar 2007) hat sich die Gesamtzahl nahezu verdreifacht. Der Abschlussbericht der wissenschaftlichen Begleitforschung bestätigt das Ergebnis des Berichts der Bundesregierung zum Persönlichen Budget vom 21. Dezember 2006, dass die bestehenden gesetzlichen Regelungen ausreichen, um bundesweit die Leistungsform des Persönlichen Budgets umzusetzen. Es wird belegt, dass die neue Leistungsform des Persönlichen Budgets bundesweit auch über die Modellregionen hinaus in Anspruch genommen wird und die Nutzerzufriedenheit ausgesprochen hoch ist. Nach wie vor werden jedoch wenig trägerübergreifende Persönliche Budgets beantragt und bewilligt." (Autorenreferat

Biophysical Characterization of Pro-apoptotic BimBH3 Peptides Reveals an Unexpected Capacity for Self-Association

Bcl-2 proteins orchestrate the mitochondrial pathway of apoptosis, pivotal for cell death. Yet, the structural details of the conformational changes of pro- and antiapoptotic proteins and their interactions remain unclear. Pulse dipolar spectroscopy (double electron-electron resonance [DEER], also known as PELDOR) in combination with spin-labeled apoptotic Bcl-2 proteins unveils conformational changes and interactions of each protein player via detection of intra- and inter-protein distances. Here, we present the synthesis and characterization of pro-apoptotic BimBH3 peptides of different lengths carrying cysteines for labeling with nitroxide or gadolinium spin probes. We show by DEER that the length of the peptides modulates their homo-interactions in the absence of other Bcl-2 proteins and solve by X-ray crystallography the structure of a BimBH3 tetramer, revealing the molecular details of the inter-peptide interactions. Finally, we prove that using orthogonal labels and three-channel DEER we can disentangle the Bim-Bim, Bcl-xL-Bcl-xL, and Bim-Bcl-xL interactions in a simplified interactome.This work was funded by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC-2033—Projektnummer 390677874, the DFG Priority Program SPP1601 “New Frontiers in Sensitivity in EPR Spectroscopy” (to E.B.), DFG BO 3000/5-1 (to E.B.), SFB958 – Z04 (to E.B.), DFG grant INST 130/972-1 FUGG (to E.B.). P.E.C. is supported by an Australian NHMRC fellowship (1079700

Multidisciplinary Late Effects Clinics for Childhood Cancer Survivors in Germany - a Two-Center Study

Background: Childhood cancer survivors are at risk for therapy-related sequelae and, therefore, require long-term follow-up. At 2 university hospitals in Germany collaborative multidisciplinary late effects clinics were installed to provide specialized care and to evaluate the current health status of these patients in a clinical setting. Patients andMethods: Every patient who visited the late effects clinics at the university hospital in Lübeck and Erlangen over a period of 3 years and met the inclusion criteria was included in the study. Patients' characteristics as well as cancer diagnosis, treatment related factors and the prevalence of chronic health conditions were assessed. Results: 220 patients attended the late effects clinics during the observation period. The median follow-up period was 16 years (range 5-45 years). In total over 64% of the patients were affected by at least 1 chronic health condition, including endocrine disruptions in 19.1% of the patients. Moreover, secondary neoplasms occurred in 9.1% of the study participants. Conclusion: German childhood cancer survivors are affected by multiple therapy-related sequelae. A comprehensive network of late effects clinics should be established to ensure specialized and risk-adapted care for every childhood cancer survivor in Germany

Mnemonic function in small vessel disease and associations with white matter tract microstructure.

Cerebral small vessel disease (SVD) is associated with deficits in working memory, with a relative sparing of long-term memory; function may be influenced by white matter microstructure. Working and long-term memory were examined in 106 patients with SVD and 35 healthy controls. Microstructure was measured in the uncinate fasciculi and cingula. Working memory was more impaired than long-term memory in SVD, but both abilities were reduced compared to controls. Regression analyses found that having SVD explained the variance in memory functions, with additional variance explained by the cingula (working memory) and uncinate (long-term memory). Performance can be explained in terms of integrity loss in specific white matter tract associated with mnemonic functions

Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5′ region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girl

The Ews-ERG Fusion Protein Can Initiate Neoplasia from Lineage-Committed Haematopoietic Cells

The EWS-ERG fusion protein is found in human sarcomas with the chromosomal translocation t(21;22)(q22;q12), where the translocation is considered to be an initiating event in sarcoma formation within uncommitted mesenchymal cells, probably long-lived progenitors capable of self renewal. The fusion protein may not therefore have an oncogenic capability beyond these progenitors. To assess whether EWS-ERG can be a tumour initiator in cells other than mesenchymal cells, we have analysed Ews-ERG fusion protein function in a cellular environment not typical of that found in human cancers, namely, committed lymphoid cells. We have used Ews-ERG invertor mice having an inverted ERG cDNA cassette flanked by loxP sites knocked in the Ews intron 8, crossed with mice expressing Cre recombinase under the control of the Rag1 gene to give conditional, lymphoid-specific expression of the fusion protein. Clonal T cell neoplasias arose in these mice. This conditional Ews gene fusion model of tumourigenesis shows that Ews-ERG can cause haematopoietic tumours and the precursor cells are committed cells. Thus, Ews-ERG can function in cells that do not have to be pluripotent progenitors or mesenchymal cells