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We developed three bathochromic, green-light activatable, photolabile protecting groups based on a nitrodibenzofuran (NDBF) core with D-π-A push–pull structures. Variation of donor substituents (D) at the favored ring position enabled us to observe their impact on the photolysis quantum yields. Comparing our new azetidinyl-NDBF (Az-NDBF) photolabile protecting group with our earlier published DMA-NDBF, we obtained insight into its excitation-specific photochemistry. While the “two-photon-only” cage DMA-NDBF was inert against one-photon excitation (1PE) in the visible spectral range, we were able to efficiently release glutamic acid from azetidinyl-NDBF with irradiation at 420 and 530 nm. Thus, a minimal change (a cyclization adding only one carbon atom) resulted in a drastically changed photochemical behavior, which enables photolysis in the green part of the spectrum.
The KASCADE-Grande experiment has significantly contributed to the current knowledge about the energy spectrum and composition of cosmic rays for energies between the knee and the ankle. Meanwhile, post-LHC versions of the hadronic interaction models are available and used to interpret the entire data set of KASCADE-Grande. In addition, a new, combined analysis of both arrays, KASCADE and Grande, was developed significantly increasing the accuracy of the shower observables. First results of the new analysis with the entire data set of the KASCADE-Grande experiment will be the focus of this contribution.
Using CORSIKA for simulating extensive air showers, we study the relation between the shower characteristics and features of hadronic multiparticle production at low energies. We report about investigations of typical energies and phase space regions of secondary particles which are important for muon production in extensive air showers. Possibilities to measure relevant quantities of hadron production in existing and planned accelerator experiments are discussed.
Emotional instability, difficulties in social adjustment, and disinhibited behavior are the most common symptoms of the psychiatric comorbidities in juvenile myoclonic epilepsy (JME). This psychopathology has been associated with dysfunctions of mesial-frontal brain circuits. The present work is a first direct test of this link and adapted a paradigm for probing frontal circuits during empathy for pain. Neural and psychophysiological parameters of pain empathy were assessed by combining functional magnetic resonance imaging (fMRI) with simultaneous pupillometry in 15 JME patients and 15 matched healthy controls. In JME patients, we observed reduced neural activation of the anterior cingulate cortex (ACC), the anterior insula (AI), and the ventrolateral prefrontal cortex (VLPFC). This modulation was paralleled by reduced pupil dilation during empathy for pain in patients. At the same time, pupil dilation was positively related to neural activity of the ACC, AI, and VLPFC. In JME patients, the ACC additionally showed reduced functional connectivity with the primary and secondary somatosensory cortex, areas fundamentally implicated in processing the somatic cause of another's pain. Our results provide first evidence that alterations of mesial-frontal circuits directly affect psychosocial functioning in JME patients and draw a link of pupil dynamics with brain activity during emotional processing. The findings of reduced pain empathy related activation of the ACC and AI and aberrant functional integration of the ACC with somatosensory cortex areas provide further evidence for this network's role in social behavior and helps explaining the JME psychopathology and patients' difficulties in social adjustment.
Recent advances in the diagnostic of myeloproliferative neoplasms (MPNs) discovered CALRETICULIN (CALR) mutations as a major driver in these disorders. In contrast to JAK2 mutations being mainly associated with polycythaemia vera, CALR mutations are only associated with primary myelofibrosis (PMF) and essential thrombocythaemia (ET). CALR mutations are present in the majority of PMF and ET patients lacking JAK2 and MPL mutations. As these CALR mutations are absent from reactive bone marrow (BM) lesions their presence indicates ET or PMF. So far these mutations are detectable only by molecular assays. Their molecular detection is cumbersome because of the great CALR mutation heterogeneity. Therefore, the availability of a simple assay would be of great help. All CALR mutations reported lead to a frameshift generating a new 36 amino-acid C-terminus. We generated a monoclonal antibody (CAL2) to this C-neoterminus by immunizing mice with a representative peptide and compared its performance with Sanger sequencing data in 173 MPNs and other BM diseases. There was a 100% correlation between the molecular and the CAL2 immunohistochemical (IHC) assays. Thus, the detection of CALR mutations by the CAL2 IHC is a specific, sensitive, rapid, simple and low-cost method.
Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis
(2014)
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK’s C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK’s stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/CCdc20 pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.
RITA, the RBP‐J interacting and tubulin‐associated protein, has been reported to be related to tumor development, but the underlying mechanisms are not understood. Since RITA interacts with tubulin and coats microtubules of the cytoskeleton, we hypothesized that it is involved in cell motility. We show here that depletion of RITA reduces cell migration and invasion of diverse cancer cell lines and mouse embryonic fibroblasts. Cells depleted of RITA display stable focal adhesions (FA) with elevated active integrin, phosphorylated focal adhesion kinase, and paxillin. This is accompanied by enlarged size and disturbed turnover of FA. These cells also demonstrate increased polymerized tubulin. Interestingly, RITA is precipitated with the lipoma‐preferred partner (LPP), which is critical in actin cytoskeleton remodeling and cell migration. Suppression of RITA results in reduced LPP and α‐actinin at FA leading to compromised focal adhesion turnover and actin dynamics. This study identifies RITA as a novel crucial player in cell migration and invasion by affecting the turnover of FA through its interference with the dynamics of actin filaments and microtubules. Its deregulation may contribute to malignant progression.
Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.
Function of p21 (Cip1/Waf1/CDKN1A) in migration and invasion of cancer and trophoblastic cells
(2019)
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.