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1. Electron micrographs of ultra-thin sections of Staphylococcus aureus and Micrococcus lysodeikticus in Vestopal as embedding medium disclose a multiplicity of DNA containing threads with varying interparticular distances.
2. The diameter of these threads is about one tenth of the average optimal section thickness.
3. This section thickness inevitably is implicated in the visualization of the internal distances between the threads as well as in some common trends in the DNA pool, a fact that has to be accounted for in the analysis of the macromolecules.
4. By spreading lysozyme protoplasts of M. lysodeikticus on a water-air interface in a Langmuir trough and by transferring this surface layer to carbon supported Formvar films, two-dimensional systems can be demonstrated which as a thread of constant width comprise the total DNA content of one microorganism each.
5. Such a macromolecular system shows equally shaped, coiled loops in a peripheral zone and many crossings towards the center. Branching of threads never has been observed so far.
From this evidence we conlude:
a) Intracellular DNA in these bacteria seems to exist in one pool as a “woolen ball” which is centered in the cytoplasm as a more or less dense object.
b) This “woolen ball“ embodies the total amount of DNA most probably as one single threadlike unit.
6. Partial destruction of the thread system of protoplasts will result upon changing optimal spreading conditions.
7. The same kind of destruction is shown upon isolation of the DNA from protoplasts, the length of the threads being an inverse function of the number of precipitation steps showing purification.
ß-Hydroxybutyrate (BHB) is a ketone body formed in high amounts during lipolysis and fasting. Ketone bodies and the ketogenic diet were suggested as neuroprotective agents in neurodegenerative disease. In the present work, we induced transient ischemia in mouse brain by unilaterally occluding the middle cerebral artery for 90 min. BHB (30 mg/kg), given immediately after reperfusion, significantly improved the neurological score determined after 24 h. In isolated mitochondria from mouse brain, oxygen consumption by the complexes I, II and IV was reduced immediately after ischemia but recovered slowly over 1 week. The single acute BHB administration after reperfusion improved complex I and II activity after 24 h while no significant effects were seen at later time points. After 24 h, plasma and brain BHB concentrations were strongly increased while mitochondrial intermediates (citrate, succinate) were unchanged in brain tissue. Our data suggest that a single administration of BHB may improve mitochondrial respiration for 1–2 days but not for later time points. Endogenous BHB formation seems to complement the effects of exogenous BHB administration.
Zinc finger proteins (ZNF) are a large group of transcription factors with diverse functions. We recently discovered that endothelial cells harbour a specific mechanism to limit the action of ZNF354C, whose function in endothelial cells is unknown. Given that ZNF354C has so far only been studied in bone and tumour, its function was determined in endothelial cells. ZNF354C is expressed in vascular cells and localises to the nucleus and cytoplasm. Overexpression of ZNF354C in human endothelial cells results in a marked inhibition of endothelial sprouting. RNA-sequencing of human microvascular endothelial cells with and without overexpression of ZNF354C revealed that the protein is a potent transcriptional repressor. ZNF354C contains an active KRAB domain which mediates this suppression as shown by mutagenesis analysis. ZNF354C interacts with dsDNA, TRIM28 and histones, as observed by proximity ligation and immunoprecipitation. Moreover, chromatin immunoprecipitation revealed that the ZNF binds to specific endothelial-relevant target-gene promoters. ZNF354C suppresses these genes as shown by CRISPR/Cas knockout and RNAi. Inhibition of endothelial sprouting by ZNF354C is dependent on the amino acids DV and MLE of the KRAB domain. These results demonstrate that ZNF354C is a repressive transcription factor which acts through a KRAB domain to inhibit endothelial angiogenic sprouting.
Iron deficiency (ID) is a common manifestation of inflammatory bowel disease (IBD), arising primarily due to chronic inflammation and/or blood loss. There is no gold standard for ID diagnosis, which is often complicated by concomitant inflammation. Zinc protoporphyrin (ZnPP) correlates with parameters of iron homeostasis and has been identified as a promising marker for ID, irrespective of inflammation. We investigated the diagnostic performance of ZnPP in ID, iron deficiency anemia, anemia of chronic disease and mixed anemia in a cross-sectional study in 130 patients with IBD. Different parameters were compared by receiver operator characteristic (ROC) analysis as detectors of iron-restricted erythropoiesis (IRE). IRE was detected in 91 patients (70.0%); fifty-nine (64.8%) had absolute ID and 23 (25.4%) functional ID. When inflammation was present, ZnPP was a more reliable sole biomarker of IRE than MCV, transferrin saturation (TSAT) or ferritin (AUC; 0.855 vs. 0.763, 0.834% and 0.772, respectively). The specificity of TSAT was significantly lower than ZnPP when inflammation was present (38% vs. 71%, respectively). We conclude that ZnPP is a reliable biomarker of functional ID in patients with IBD and more dependable than ferritin or TSAT, which are influenced by chronic inflammation. We propose that ZnPP may also have utility in patients with other chronic diseases.
The traffic AAA-ATPase PilF is essential for pilus biogenesis and natural transformation of Thermus thermophilus HB27. Recently, we showed that PilF forms hexameric complexes containing six zinc atoms coordinated by conserved tetracysteine motifs. Here we report that zinc binding is essential for complex stability. However, zinc binding is neither required for pilus biogenesis nor natural transformation. A number of the mutants did not exhibit any pili during growth at 64 °C but still were transformable. This leads to the conclusion that type 4 pili and the DNA translocator are distinct systems. At lower growth temperatures (55 °C) the zinc-depleted multiple cysteine mutants were hyperpiliated but defective in pilus-mediated twitching motility. This provides evidence that zinc binding is essential for the role of PilF in pilus dynamics. Moreover, we found that zinc binding is essential for complex stability but dispensable for ATPase activity. In contrast to many polymerization ATPases from mesophilic bacteria, ATP binding is not required for PilF complex formation; however, it significantly increases complex stability. These data suggest that zinc and ATP binding increase complex stability that is important for functionality of PilF under extreme environmental conditions.
Glial cell line-derived neurotrophic factor (GDNF) is a ligand that activates, through co-receptor GDNF family receptor alpha-1 (GFRα1) and receptor tyrosine kinase “RET”, several signaling pathways crucial in the development and sustainment of multiple neuronal populations. We decided to study whether non-mammalian orthologs of these three proteins have conserved their function: can they activate the human counterparts? Using the baculovirus expression system, we expressed and purified Danio rerio RET, and its binding partners GFRα1 and GDNF, and Drosophila melanogaster RET and two isoforms of co-receptor GDNF receptor-like. Our results report high-level insect cell expression of post-translationally modified and dimerized zebrafish RET and its binding partners. We also found that zebrafish GFRα1 and GDNF are comparably active as mammalian cell-produced ones. We also report the first measurements of the affinity of the complex to RET in solution: at least for zebrafish, the Kd for GFRα1-GDNF binding RET is 5.9 μM. Surprisingly, we also found that zebrafish GDNF as well as zebrafish GFRα1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF, unlike E. coli-produced human proteins. These results contradict previous studies suggesting that mammalian GFRα1 and GDNF cannot bind and activate non-mammalian RET and vice versa.
Zebrafish
(2019)
Glioblastoma is the most common and most aggressive type of brain tumor in adults. In contrast to epithelial cancers, glioblastomas do not metastasize. While the major treatment challenge in epithelial cancers is not the primary tumor but metastasis, glioblastoma patients die of the primary tumor.
However, there is a common theme which underlies the malignant properties of progressed epithelial cancers and glioblastoma: invasion from the primary tumor into the surrounding tissue. In the case of epithelial cancers this is the first and necessary step to metastasis, whereas invasion leads inevitably to tumor recurrence after resection in the case of glioblastoma, causing it to be incurable.
A cellular program which has been described in detail to promote the invasive phenotype in epithelial tumors, is the epithelial-mesenchymal-transition (EMT). Differentiated neural cells are not epithelial, thus, strictly speaking, EMT does not occur in glioblastoma. However, the traits acquired in the process of EMT, especially invasiveness and stemness, are highly relevant to glioblastoma. One of the key transcription factors known to induce EMT in epithelial cancers is ZEB1, which has been described only marginally in the central nervous system so far. Here, I investigate the expression and function of ZEB1 in glioblastoma and during human fetal neural development.
ZEB1 mRNA was significantly upregulated in all histological types of glioma, including glioblastoma, when compared to normal brain. There was no correlation between ZEB1 mRNA levels and tumor grade. Immunohistochemical staining of glioma samples demonstrated that ZEB1 was highly expressed in the great majority of tumor cells. In the developing human brain, intense staining for ZEB1 could be observed in the ventricular and subventricular zone, where stem- and progenitor cells reside. ZEB1 positive cells included cells stained with stem- and progenitor markers like PAX6, GFAP and Nestin. In contrast, ZEB1 was never found in early neuronal cells as identified by TUBB3 staining.
To gain insight into ZEB1 function I generated a human fetal neural stem cell line and a glioblastoma cell line with ZEB1 knockdown, which were compared with their respective control cell lines. First, I found that ZEB1 does not regulate the micro RNA 200 family in either cell line, which has been described as an essential ZEB1 target in epithelial cancers. Second, regulated target genes were identified with a genome wide microarray. The third approach was to directly identify genomic binding sites of ZEB1 by chromatin immunoprecipitation sequencing (ChIP-seq). All three approaches showed that the ZEB1 transcriptional program is surprisingly similar in the neural stem cell line and the glioblastoma cell line. In contrast, it bears only little resemblance to the program described in epithelial cancers.
The most interesting, previously unrecognized ZEB1 target gene identified in this study is integrin b1. It was regulated after ZEB1 knockdown detected by microarray analysis, and has a ZEB1 binding site in its promoter region detected by ChIP-seq. Finally, I addressed the question whether ZEB1 influences tumor growth and invasiveness in a glioblastoma model. After intracranial xenotransplantation in mice, ZEB1 knockdown glioblastoma cells formed significantly smaller and less invasive tumors than control glioblastoma cells.
This study demonstrates that ZEB1 is widely expressed in glioma and relevant for glioblastoma growth and invasion. In contrast to what is known about ZEB1 function in epithelial cancers, ZEB1 is not associated with glioma progression, but instead seems to be an early and necessary event in tumorigenesis. Also with regard to ZEB1 target genes, ZEB1 functions differently in glioblastoma than in epithelial cancers. The two most important ZEB1 targets in epithelial cancers are E-cadherin and the miR-200 family members. Both are not relevant to ZEB1 function in glioblastoma. Interestingly, while the ZEB1 transcriptional program is different from the one described in epithelial cancers, it is highly similar in glioblastoma cells and fetal neural stem cells. This suggests that an embryonic pathway restricted to stem- and progenitor cells during development is reactivated in glioblastoma.
Previously known ZEB1 target genes were tissue specific and therefore seemed unlikely to mediate ZEB1 function in the central nervous system. However, the newly identified ZEB1 target gene integrin b1 is well known to play pivotal roles in both glioblastoma tumorigenesis and invasion as well as in neural stem cells. Additionally, integrin b1 is widely expressed and seems a likely ZEB1 target in other organs than the brain.
Taken together, I demonstrate that ZEB1 is a new regulator of glioblastoma growth and invasion. The transcriptional program of ZEB1 differs from the one in epithelial cancers but is strikingly similar to the one in neural stem cells. The newly identified ZEB1 target gene integrin b1 is likely to mediate crucial ZEB1 functios. Thus, this study identifies ZEB1 as a yet unrecognized player in glioblastoma and neural development. Furthermore, it sets the stage for more research which will help to deepen our understanding of ZEB1 function in the central nervous system and beyond.
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.
Z-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2021)
Measurement of Z-boson production in p-Pb collisions at sNN−−−√=8.16 TeV and Pb-Pb collisions at sNN−−−√=5.02 TeV is reported. It is performed in the dimuon decay channel, through the detection of muons with pseudorapidity −4<ημ<−2.5 and transverse momentum pμT>20 GeV/c in the laboratory frame. The invariant yield and nuclear modification factor are measured for opposite-sign dimuons with invariant mass 60<mμμ<120 GeVc2 and rapidity 2.5<yμμcms<4. They are presented as a function of rapidity and, for the Pb-Pb collisions, of centrality as well. The results are compared with theoretical calculations, both with and without nuclear modifications to the Parton Distribution Functions (PDFs). In p-Pb collisions the center-of-mass frame is boosted with respect to the laboratory frame, and the measurements cover the backward (−4.46<yμμcms<−2.96) and forward (2.03<yμμcms<3.53) rapidity regions. For the p-Pb collisions, the results are consistent within experimental and theoretical uncertainties with calculations that include both free-nucleon and nuclear-modified PDFs. For the Pb-Pb collisions, a 3.4σ deviation is seen in the integrated yield between the data and calculations based on the free-nucleon PDFs, while good agreement is found once nuclear modifications are considered.
Z-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2020)
Measurement of Z-boson production in p-Pb collisions at sNN−−−√=8.16 TeV and Pb-Pb collisions at sNN−−−√=5.02 TeV is reported. It is performed in the dimuon decay channel, through the detection of muons with pseudorapidity −4<ημ<−2.5 and transverse momentum pμT>20 GeV/c in the laboratory frame. The invariant yield and nuclear modification factor are measured for opposite-sign dimuons with invariant mass 60<mμμ<120 GeVc2 and rapidity 2.5<yμμcms<4. They are presented as a function of rapidity and, for the Pb-Pb collisions, of centrality as well. The results are compared with theoretical calculations, both with and without nuclear modifications to the Parton Distribution Functions (PDFs). In p-Pb collisions the center-of-mass frame is boosted with respect to the laboratory frame, and the measurements cover the backward (−4.46<yμμcms<−2.96) and forward (2.03<yμμcms<3.53) rapidity regions. For the p-Pb collisions, the results are consistent within experimental and theoretical uncertainties with calculations that include both free-nucleon and nuclear-modified PDFs. For the Pb-Pb collisions, a 3.4σ deviation is seen in the integrated yield between the data and calculations based on the free-nucleon PDFs, while good agreement is found once nuclear modifications are considered.
Z-boson production in p-Pb collisions at √sNN = 8.16 TeV and Pb-Pb collisions at √sNN = 5.02 TeV
(2020)
Measurement of Z-boson production in p-Pb collisions at sNN−−−√ = 8.16 TeV and Pb-Pb collisions at sNN−−−√ = 5.02 TeV is reported. It is performed in the dimuon decay channel, through the detection of muons with pseudorapidity −4 < ημ < −2.5 and transverse momentum pμT > 20 GeV/c in the laboratory frame. The invariant yield and nuclear modification factor are measured for opposite-sign dimuons with invariant mass 60 < mμμ < 120 GeV/c2 and rapidity 2.5 < yμμcms < 4. They are presented as a function of rapidity and, for the Pb-Pb collisions, of centrality as well. The results are compared with theoretical calculations, both with and without nuclear modifications to the Parton Distribution Functions (PDFs). In p-Pb collisions the center-of-mass frame is boosted with respect to the laboratory frame, and the measurements cover the backward (−4.46 < yμμcms < −2.96) and forward (2.03 < yμμcms < 3.53) rapidity regions. For the p-Pb collisions, the results are consistent within experimental and theoretical uncertainties with calculations that include both free-nucleon and nuclear-modified PDFs. For the Pb-Pb collisions, a 3.4σ deviation is seen in the integrated yield between the data and calculations based on the free-nucleon PDFs, while good agreement is found once nuclear modifications are considered.
You reap what you sow! differences in knowledge exchange effectiveness between communication types
(2014)
FOR KNOWLEDGE-INTENSIVE ORGANIZATIONS IN THE FINANCE INDUSTRY, AN EFFECTIVE KNOWLEDGE EXCHANGE AMONG EMPLOYEES IS CRUCIAL FOR THE COMPETITIVE PERFORMANCE. THEREFORE, COMPANIES INCREASINGLY RELY ON SOCIAL MEDIA PLATFORMS TO FACILITATE COMMUNICATION AND COLLABORATION. TO ENHANCE OUR UNDERSTANDING OF SUCCESSFUL COMMUNICATION IN ENTERPRISE SOCIAL MEDIA, WE APPLY HUMAN CODING AND QUANTITATIVE ANALYSIS TO THE CONTENT AND TONE OF 15,505 ENTERPRISE MICROBLOGGING MESSAGES CREATED BY 1,166 EMPLOYEES OF AN INTERNATIONAL FINANCIAL SERVICE PROVIDER. OUR RESULTS SUGGEST THAT A MORE FACTUAL-ORIENTED COMMUNICATION TYPE BENEFITS FROM A HIGHER KNOWLEDGE EXCHANGE EFFECTIVENESS COMPARED TO A PRIMARILY SELF-DISCLOSING COMMUNICATION TYPE.