Stephan Lorenzen - Academia.edu (original) (raw)

Papers by Stephan Lorenzen

Additional file 3: Suppl. Figure 3. a-b. There was no correlation between patient survival and ly... more Additional file 3: Suppl. Figure 3. a-b. There was no correlation between patient survival and lymphocyte cytogenetic damage. The Kaplan-Meier survival curves depict the cancer-specific survival (Suppl. Fig. 3a), the recurrence-free survival, the local recurrence-free survival, and the distant metastasis-free survival (Suppl. Fig. 3b). Patients were stratified according to the median of micronuclei (MN) or of nucleoplasmatic bridges (NPB), respectively, counted in binucleated lymphocytes (BNL/BL) after 50.4 Gy of radiochemotherapy (RCT). The endpoint for cancer-specific survival was any death related to tumor recurrence. Significance tests were performed using the Cox proportional hazards model.

Since protein complex crystallization is expensive and time-consuming, computational docking tool... more Since protein complex crystallization is expensive and time-consuming, computational docking tools provide a valuable method to investigate protein interactions. While the sampling of possible docked conformers of two proteins can be performed efficiently by Fast Fourier Transform (FFT) methods, the selection of near-native decoys from the pool of thousands of possible decoys is still far from being solved. Here, a new approach for docking decoy selection by Monte Carlo stability analysis is presented. In the course of replica exchange Monte Carlo simulations (REMC), replica from near-native decoys show a significantly lower structural diversity than replica from non-native decoys. The effect is successfully applied to rank docking decoys in a benchmark set of 59 protein complexes.

Biosystems, 2010

Circadian rhythms regulate a wide range of cellular, physiological, metabolic and behavioral acti... more Circadian rhythms regulate a wide range of cellular, physiological, metabolic and behavioral activities in mammals. The complexity of tissue- and day-time specific regulation of thousands of clock controlled genes (CCGs) suggests that many transcriptional regulators are involved. Our bioinformatic analysis is based on two published DNA-array studies from mouse liver. We search overrepresented transcription factor binding sites in promoter regions of CCGs using GC-matched controls. Analyzing a large set of CCG promoters, we find known motifs such as E-boxes, D-boxes and cAMP responsive elements. In addition, we find overrepresented GC-rich motifs (Sp1, ETF, Nrf1), AT-rich motifs (TBP, Fox04, MEF-2), Y-box motifs (NF-Y, C/EBP) and cell cycle regulators (E2F, Elk-1). In a subset of system-driven genes, we find overrepresented motifs of the serum response factor SRF and the estrogen receptor ER. The analysis of published ChIP data reveals that some of our predicted regulators (C/EBP, E2F, HNF-1, Myc, MEF-2) target relatively many clock controlled genes. Our analysis of CCG promoters contributes to an understanding of the complex transcriptional regulation of circadian rhythms in liver.

Age and Ageing, 2012

Background: Extended-spectrum beta-lactamases-producing Enterobacterales (ESBL-E) are disseminati... more Background: Extended-spectrum beta-lactamases-producing Enterobacterales (ESBL-E) are disseminating worldwide especially in Intensive Care Units (ICUs) and are responsible for increased health costs and mortality. The aims of this work were to study ESBL-E dissemination in ICU and to assess the impact of ESBL-E fecal carriage on subsequent infections during a non-outbreak situation. Methods: We therefore screened every patient at admission then once a week in a medical ICU between January and June 2015. Each ESBL-E isolate was characterized by ESBL genes PCR amplification and the clonal dissemination was assessed by Pulsed-Field Gel Electrophoresis (PFGE). Results: Among the 608 screened patients, 55 (9%) were colonized by ESBL-E. Forty-four isolates were available for further analysis. Most of them (43/44, 98%) contained a ESBL gene from the CTX-M group. Only one case of ESBL-E cross-transmission occurred, even for acquired ESBL-E colonization. Subsequent infection by ESBL-E occurred in 6/55 (11%) patients and infecting ESBL-E strains were the colonizing ones. ESBL-E faecal carriage had a negative predictive value of 100% and a positive predictive value of 40% to predict ESBL-E ventilator associated-pneumonia (VAP). Alternatives to carbapenems consisting in piperacillin-tazobactam, ceftolozane-tazobactam and ceftazidime-avibactam were all active on this panel of ESBL-E. Conclusions: ESBL-E expansion and acquisition in ICU in a non-outbreak situation are not any more fully explained by cross-transmission. Mechanisms underlying ESBL-E dissemination in ICU are still to investigate. Interestingly, as far as we know, our study demonstrates for the first time by PFGE that the colonizing strain is indeed the infecting one in case of subsequent ESBL-E infection. Nevertheless, subsequent ESBL-E infection remains a rare event conferring poor positive predictive value for ESBL-E colonization to predict ESBL-E VAP. Relevance of systematic ESBL-E faecal screening at ICU admission and during ICU stay needs further investigation.

Journal of Theoretical Biology, 2011

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service... more This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Membrane proteins span a large variety of different functions such as cell-surface re-ceptors, re... more Membrane proteins span a large variety of different functions such as cell-surface re-ceptors, redox proteins, ion channels, and transport-ers. Proteins with functional pores show different characteristics of helix–helix packing as other helical membrane proteins. We found that the helix–helix contacts of 13 nonhomologous high-resolution struc-tures of membrane channels and transporters are mainly accomplished by weakly polar amino acids (G> S> T> F) that preferably create contacts every fourth residue, typical for right-handed helix cross-ings. There is a strong correlation between the now available biological hydrophobicity scale and the pro-pensities of the weakly polar and hydrophobic resi-dues to be buried at helix–helix interfaces or to be

In proteins and peptides, the vast majority of peptide bonds occurs in trans conforma-tion, but a... more In proteins and peptides, the vast majority of peptide bonds occurs in trans conforma-tion, but a considerable fraction (about 5%) of X-Pro bonds adopts the cis conformation. Here we study the conservation of cis prolyl residues in evolution-ary related proteins. We find that overall, in con-trast to local, protein sequence similarity is a clear indicator for the conformation of prolyl residues. We observe that cis prolyl residues are more often conserved than trans prolyl residues, and both are more conserved than the surrounding amino acids, which show the same extent of conservation as the whole protein. The pattern of amino acid exchanges differs between cis and trans prolyl residues. Also, the cis prolyl bond is maintained in proteins with sequence identity as low as 20%. This finding empha-sizes the importance of cis peptide bonds in protein structure and function. Proteins 2005;58:589–595.

Cells, 2021

Infections with the deadliest malaria parasite, Plasmodium falciparum, are accompanied by a stron... more Infections with the deadliest malaria parasite, Plasmodium falciparum, are accompanied by a strong immunological response of the human host. To date, more than 30 cytokines have been detected in elevated levels in plasma of malaria patients compared to healthy controls. Endothelial cells (ECs) are a potential source of these cytokines, but so far it is not known if their cytokine secretion depends on the direct contact of the P. falciparum-infected erythrocytes (IEs) with ECs in terms of cytoadhesion. Culturing ECs with plasma from malaria patients (27 returning travellers) resulted in significantly increased secretion of IL-11, CXCL5, CXCL8, CXCL10, vascular endothelial growth factor (VEGF) and angiopoietin-like protein 4 (ANGPTL4) if compared to matching controls (22 healthy individuals). The accompanying transcriptome study of the ECs identified 43 genes that were significantly increased in expression (≥1.7 fold) after co-incubation with malaria patient plasma, including cxcl5 an...

Methods in molecular biology, 2021

During malaria infection, the endothelial lining of the small blood vessels of the brain and othe... more During malaria infection, the endothelial lining of the small blood vessels of the brain and other vital organs is strongly stimulated. This leads to fatal complications and poor prognosis of the infection. It is believed that two main reasons are responsible for this pathology, namely the cytoadhesion of Plasmodium falciparum-infected erythrocytes (IEs) on the one hand and the proinflammatory products released by the IEs which activate the endothelial cells (ECs) on the other hand. Until recently, most of the studies that characterized the activation of ECs were performed under static conditions, which do not reflect the real sequelae in vivo. In this chapter, we present a system, which allows authentic simulation of the IEs-ECs interactions during P. falciparum infection.The main idea of the system is to provide an adequate shear stress over the ECs during the cytoadhesion and stimulation with IEs, which provides a better basis for the investigation of the cytoadhesion pathology t...

BMC Cancer

Background The question whether lymphocyte radiosensitivity is representative of patients’ respon... more Background The question whether lymphocyte radiosensitivity is representative of patients’ response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients’ and RCT characteristics on cytogenetic damage, and tested for correlations with patients’ outcome in terms of tumor response, survival and treatment-related toxicity. Methods The cytokinesis-block micronucleus cytome (CBMNcyt) assay was performed on the peripheral blood lymphocytes (PBLCs) of 134 patients obtained before, during, at the end of RCT, and during the 2-year follow-up. A subset of PBLCs obtained before RCT was irradiated in-vitro with 3 Gy. RCT included 50.4 Gy of pelvic RT with 5-fluorouracil (5-FU) alone (n = 78) or 5-FU plu...

Genome Informatics Series, 2007

Emerging infectious diseases, Dec 1, 2017

In 2015, we identified an avian hepatitis B virus associated with hepatitis in a group of captive... more In 2015, we identified an avian hepatitis B virus associated with hepatitis in a group of captive elegant-crested tinamous (Eudromia elegans) in Germany. The full-length genome of this virus shares <76% sequence identity with other avihepadnaviruses. The virus may therefore be considered a new extant avian hepadnavirus.

Scientific Reports

Leishmania donovani is a trypanosomatidic parasite and causes the lethal kala-azar fever, a negle... more Leishmania donovani is a trypanosomatidic parasite and causes the lethal kala-azar fever, a neglected tropical disease. The Trypanosomatida are devoid of transcriptional gene regulation and rely on gene copy number variations and translational control for their adaption to changing conditions. To survive at mammalian tissue temperatures, L. donovani relies on the small heat shock protein HSP23, the loss of which renders the parasites stress sensitive and impairs their proliferation. Here, we analysed a spontaneous escape mutant with wild type-like in vitro growth. Further selection of this escape strains resulted in a complete reversion of the phenotype. Whole genome sequencing revealed a correlation between stress tolerance and the massive amplification of a six-gene cluster on chromosome 35, with further analysis showing over expression of the casein kinase 1.2 gene as responsible. In vitro phosphorylation experiments established both HSP23 and the related P23 co-chaperone as subs...

Blood

B cell antigen receptors (BCR) transduce signals and thereby control important cell fate decision... more B cell antigen receptors (BCR) transduce signals and thereby control important cell fate decisions of the B-lineage including differentiation, proliferation and B cell survival. The intracellular signaling networks are complex and mainly regulated through reversible protein phosphorylation on tyrosine, serine or threonine residues. This process is highly controlled to ensure regular B cell function. However, dysregulation of BCR signaling can induce immunodeficiency, autoimmune disorders and malignant transformation. Recently, it was demonstrated that besides chronic lymphocytic leukemia and diffuse large B cell lymphomas of the activated B cell-type also subgroups of Burkitt lymphomas (BL) critically depend on BCR signaling that is enhanced due to TCF3 or ID3mutations. Thus, targeting of BCR signaling pathways by small molecule inhibitors is a promising therapeutic strategy for BCR-dependent BL. In order to identify putative novel drug targets, comprehensive knowledge about BCR eff...

mBio

During its intraerythrocytic development, the malaria parasite Plasmodium falciparum exposes vari... more During its intraerythrocytic development, the malaria parasite Plasmodium falciparum exposes variant surface antigens (VSAs) on infected erythrocytes to establish and maintain an infection. One family of small VSAs is the polymorphic STEVOR proteins, which are marked for export to the host cell surface through their PEXEL signal peptide. Interestingly, some STEVORs have also been reported to localize to the parasite plasma membrane and apical organelles, pointing toward a putative function in host cell egress or invasion. Using deep RNA sequencing analysis, we characterized P. falciparum stevor gene expression across the intraerythrocytic development cycle, including free merozoites, in detail and used the resulting stevor expression profiles for hierarchical clustering. We found that most stevor genes show biphasic expression oscillation, with maximum expression during trophozoite stages and a second peak in late schizonts. We selected four STEVOR variants, confirmed the expected e...

Veterinary pathology, Mar 1, 2018

Feline panleukopenia virus (FPV) infections are typically associated with anorexia, vomiting, dia... more Feline panleukopenia virus (FPV) infections are typically associated with anorexia, vomiting, diarrhea, neutropenia, and lymphopenia. In cases of late prenatal or early neonatal infections, cerebellar hypoplasia is reported in kittens. In addition, single cases of encephalitis are described. FPV replication was recently identified in neurons, although it is mainly found in cells with high mitotic activity. A female cat, 2 months old, was submitted to necropsy after it died with neurologic deficits. Besides typical FPV intestinal tract changes, multifocal, randomly distributed intracytoplasmic vacuoles within neurons of the thoracic spinal cord were found histologically. Next-generation sequencing identified FPV-specific sequences within the central nervous system. FPV antigen was detected within central nervous system cells, including the vacuolated neurons, via immunohistochemistry. In situ hybridization confirmed the presence of FPV DNA within the vacuolated neurons. Thus, FPV sho...

CNS neuroscience & therapeutics, Jan 31, 2018

Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environme... more Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a psychosocial stress model based on resident-intruder confrontations to study the brain corticostriatal-function, since deregulation of corticostriatal circuitries has been reported in many psychiatric disorders. CB receptors are widely expressed in the central nervous system and particularly, in both cortex and striatum brain structures. The investigation presented here is addressed to assess the impact of repeated stress following acute cannabinoid exposure on behavior and corticostriatal brain physiology by assessing mice behavior, the concentration of endocannabinoid and endocannabinoid-like molecules and changes in the transcriptome. Stressed animals urinated frequently; showed exacerbated scratching activity, lower striatal N-arachidonylethanolamine (AEA) levels and higher cortical expression of cholinergic receptor nicot...

mSphere

The emerging bunyavirus Rift Valley fever virus (RVFV) is transmitted to humans and livestock by ... more The emerging bunyavirus Rift Valley fever virus (RVFV) is transmitted to humans and livestock by a large number of mosquito species. RNA interference (RNAi) has been characterized as an important innate immune defense mechanism used by mosquitoes to limit replication of positive-sense RNA flaviviruses and togaviruses; however, little is known about its role against negative-strand RNA viruses such as RVFV. We show that virus-specific small RNAs are produced in infected mosquito cells, in Drosophila melanogaster cells, and, most importantly, also in RVFV vector mosquitoes. By addressing the production of small RNAs in adult Aedes sp. and Culex quinquefasciatus mosquitoes, we showed the presence of virus-derived Piwi-interacting RNAs (piRNAs) not only in Aedes sp. but also in C. quinquefasciatus mosquitoes, indicating that antiviral RNA interference in C. quinquefasciatus mosquitoes is similar to the described activities of RNAi in Aedes sp. mosquitoes. We also show that these have an...

Nature Structural & Molecular Biology, 2016