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The pT-differential production cross section of prompt Λ+c charmed baryons was measured with the ALICE detector at the Large Hadron Collider (LHC) in pp collisions at s√=7 TeV and in p-Pb collisions at sNN−−−√=5.02 TeV at midrapidity. The Λ+c and Λ¯¯¯¯−c were reconstructed in the hadronic decay modes Λ+c→pK−π+, Λ+c→pK0S and in the semileptonic channel Λ+c→e+νeΛ (and charge conjugates). The measured values of the Λ+c/D0 ratio, which is sensitive to the c-quark hadronisation mechanism, and in particular to the production of baryons, are presented and are larger than those measured previously in different colliding systems, centre-of-mass energies, rapidity and pT intervals, where the Λ+c production process may differ. The results are compared with the expectations obtained from perturbative Quantum Chromodynamics calculations and Monte Carlo event generators. Neither perturbative QCD calculations nor Monte Carlo models reproduce the data, indicating that the fragmentation of heavy-flavour baryons is not well understood. The first measurement at the LHC of the Λ+c nuclear modification factor, RpPb, is also presented. The RpPb is found to be consistent with unity and with that of D mesons within the uncertainties, and consistent with a theoretical calculation that includes cold nuclear matter effects and a calculation that includes charm quark interactions with a deconfined medium.
The pT-differential production cross section of prompt Λ +c charmed baryons was measured with the ALICE detector at the Large Hadron Collider (LHC) in pp collisions at s√=7 TeV and in p-Pb collisions at sNN−−−√=5.02 TeV at midrapidity. The Λ +c and Λ¯¯¯¯c¯¯¯ were reconstructed in the hadronic decay modes Λ +c → pK−π+, Λ +c → pK 0S and in the semileptonic channel Λ +c → e+νeΛ (and charge conjugates). The measured values of the Λ +c/D0 ratio, which is sensitive to the c-quark hadronisation mechanism, and in particular to the production of baryons, are presented and are larger than those measured previously in different colliding systems, centre-of-mass energies, rapidity and pT intervals, where the Λ +c production process may differ. The results are compared with the expectations obtained from perturbative Quantum Chromodynamics calculations and Monte Carlo event generators. Neither perturbative QCD calculations nor Monte Carlo models reproduce the data, indicating that the fragmentation of heavy-flavour baryons is not well understood. The first measurement at the LHC of the Λ +c nuclear modification factor, RpPb, is also presented. The RpPb is found to be consistent with unity and with that of D mesons within the uncertainties, and consistent with a theoretical calculation that includes cold nuclear matter effects and a calculation that includes charm quark interactions with a deconfined medium.
The production cross section of prompt Λ+c charmed baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
The production cross section of prompt Λ+c charm baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
The production cross section of prompt Λ+c charm baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
The production cross section of prompt Λ+c charmed baryons was measured with the ALICE detector at the LHC at midrapidity in proton-proton (pp) and proton-lead (p-Pb) collisions at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. The Λ+c and Λ¯¯¯¯−c baryons were reconstructed in the hadronic decay channels Λ+c→pK−π+ and Λ+c→pK0S and respective charge conjugates. The measured differential cross sections as a function of transverse momentum (pT) and the pT-integrated Λ+c production cross section in pp and in p-Pb collisions are presented. The Λ+c nuclear modification factor (RpPb), calculated from the cross sections in pp and in p-Pb collisions, is presented and compared with the RpPb of D mesons. The Λ+c/D0 ratio is also presented and compared with the light-flavour baryon-to-meson ratios p/π and Λ/K0S, and measurements from other LHC experiments. The results are compared to predictions from model calculations and Monte Carlo event generators.
A measurement of the production of prompt +c baryons in Pb–Pb collisions at √sNN = 5.02 TeV with the ALICE detector at the LHC is reported. The +c and − c were reconstructed at midrapidity (|y| < 0.5) via the hadronic decay channel +c → pK0 S (and charge conjugate) in the transverse momentum and centrality intervals 6 < pT < 12 GeV/c and 0–80%. The +c /D0 ratio, which is sensitive to the charm quark hadronisation mechanisms in the medium, is measured and found to be larger than the ratio measured in minimum-bias pp collisions at √s = 7 TeV and in p–Pb collisions at √sNN = 5.02 TeV. In particular, the values in p–Pb and Pb–Pb collisions differ by about two standard deviations of the combined statistical and systematic uncertainties in the common pT interval covered by the measurements in the two collision systems. The + c /D0 ratio is also compared with model calculations including different implementations of charm quark hadronisation. The measured ratio is reproduced by models implementing a pure coalescence scenario, while adding a fragmentation contribution leads to an underestimation. The + c nuclear modification factor, RAA, is also presented. The measured values of the RAA of + c , D+ s and non-strange D mesons are compatible within the combined statistical and systematic uncertainties. They show, however, a hint of a hierarchy (RD0 AA < RD+ s AA < R+ c AA ), conceivable with a contribution from coalescence mechanisms to charm hadron formation in the medium.
A measurement of the production of prompt Λ+c baryons in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the LHC is reported. The Λ+c and Λ¯¯¯¯−c were reconstructed at midrapidity (|y|<0.5) via the hadronic decay channel Λ+c→pK0S (and charge conjugate) in the transverse momentum and centrality intervals 6<pT<12 GeV/c and 0-80%. The Λ+c/D0 ratio, which is sensitive to the charm quark hadronisation mechanisms in the medium, is measured and found to be larger than the ratio measured in minimum-bias pp collisions at s√=7 TeV and in p-Pb collisions at sNN−−−√=5.02 TeV. In particular, the values in p-Pb and Pb-Pb collisions differ by about two standard deviations of the combined statistical and systematic uncertainties in the common pT interval covered by the measurements in the two collision system. The Λ+c/D0 ratio is also compared with model calculations including different implementations of charm quark hadronisation. The measured ratio is reproduced by models implementing a pure coalescence scenario, while adding a fragmentation contribution leads to an underestimation. The Λ+c nuclear modification factor, RAA, is also presented. The measured values of the RAA of Λ+c, Ds and non-strange D mesons are compatible within the combined statistical and systematic uncertainties. They show, however, a hint of a hierarchy (RD0AA<RDsAA<RΛ+cAA), conceivable with a contribution of recombination mechanisms to charm hadron formation in the medium.
A measurement of the production of prompt Λ+c baryons in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the LHC is reported. The Λ+c and Λ¯¯¯¯−c were reconstructed at midrapidity (|y|<0.5) via the hadronic decay channel Λ+c→pK0S (and charge conjugate) in the transverse momentum and centrality intervals 6<pT<12 GeV/c and 0-80%. The Λ+c/D0 ratio, which is sensitive to the charm quark hadronisation mechanisms in the medium, is measured and found to be larger than the ratio measured in minimum-bias pp collisions at s√=7 TeV and in p-Pb collisions at sNN−−−√=5.02 TeV. In particular, the values in p-Pb and Pb-Pb collisions differ by about two standard deviations of the combined statistical and systematic uncertainties. The Λ+c/D0 ratio is also compared with model calculations including different implementations of charm quark hadronisation. The measured ratio is reproduced by models implementing a pure coalescence scenario, while adding a fragmentation contribution leads to an underestimation. The Λ+c nuclear modification factor, RAA, is also presented. The measured values of the RAA of Λ+c, Ds and non-strange D mesons are compatible within the combined statistical and systematic uncertainties. They show, however, a hint of a hierarchy (RD0AA<RDsAA<RΛ+cAA), conceivable with a contribution of recombination mechanisms to charm hadron formation in the medium.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2021)
The prompt production of the charm baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charm-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charm-baryon production in hadronic collisions at LHC energies.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2021)
The prompt production of the charm baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charm-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charm-baryon production in hadronic collisions at LHC energies.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2021)
The prompt production of the charm baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charm-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charm-baryon production in hadronic collisions at LHC energies.
Λ+c production and baryon-to-meson ratios in pp and p–Pb collisions at √sNN = 5.02 TeV at the LHC
(2020)
The prompt production of the charmed baryon Λ+c and the Λ+c/D0 production ratios were measured at midrapidity with the ALICE detector in pp and p-Pb collisions at sNN−−−√=5.02TeV. These new measurements show a clear decrease of the Λ+c/D0 ratio with increasing transverse momentum (pT) in both collision systems in the range 2<pT<12 GeV/c, exhibiting similarities with the light-flavour baryon-to-meson ratios p/π and Λ/K0S. At low pT, predictions that include additional colour-reconnection mechanisms beyond the leading-colour approximation; assume the existence of additional higher-mass charmed-baryon states; or include hadronisation via coalescence can describe the data, while predictions driven by charm-quark fragmentation processes measured in e+e− and e−p collisions significantly underestimate the data. The results presented in this letter provide significant evidence that the established assumption of universality (colliding-system independence) of parton-to-hadron fragmentation is not sufficient to describe charmed-baryon production in hadronic collisions at LHC energies.
In April and May 2012 data on Au+Au collisions at beam energies of Ekin = 1.23A GeV were recorded with the High Acceptance Di-Electron Spectrometer, which is located at the GSI Helmholtz Center for Heavy Ion Research in Darmstadt, Germany. At this beam energy all hadrons containing strangeness are produced below their elementary production threshold. The required energy is not available in binary NN collisions but must be provided by the system e.g. through multi-particle interactions or medium effects like a modified in-medium potential (e.g. KN/ΛN potential). Thus, a high sensitivity to these medium effects is expected in the investigated system.
The baryon-dominated systems created in relativistic heavy-ion collisions (HIC) at SIS18 energies reach densities of about 2-3 times ground state density p0 and may be similar to the properties of matter expected in the inner core of neutron stars. It is in particular the behavior of hadrons containing strangeness, i.e. kaons and hyperons, and their potentials in the dense medium which may have severe implications on astrophysical objects and processes. As ab-initio calculations of quantum chromodynamics (QCD) cannot be performed rigorously on the lattice at finite baryo-chemical potentials due to the fermion sign problem, effective descriptions have to be used in order to model properties of dense systems and the involved particles. The only way to access the in-medium potential of strange hadrons above nuclear ground state density p0 is by comparing data from relativistic HIC to such effective microscopic models. Up to now, not much data on neutral kaons and Λ hyperons are available from heavy collision systems close to their NN production threshold. These two electromagnetically uncharged strange hadrons are in particular well suited to study their potential in a dense nucleon-dominated environment as their kinematic spectra are not affected by Coulomb interactions.
Although, during the past decades, substantial advances emerged in identifying major local and systemic factors contributing to initiation and progression of osteoarthritis (OA), some neuroendocrine mechanisms are still not understood or even neglected when thinking about novel therapeutic options. One of which is the sympathetic nervous system that exhibits various OA-promoting effects in different tissues of the joint. Interestingly, the β2-adrenoceptor (AR) mediates the majority of these effects as demonstrated by several in vitro, in vivo as well as in clinical studies. This review article does not only summarize studies of the past two decades demonstrating that the β2-AR plays an OA-promoting role in different tissues of the joint but also aims to encourage the reader to think about next-level research to discover novel and innovative preventive and/or therapeutic strategies targeting the β2-AR in OA.
Purpose: Recent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/-) mice after surgical OA induction.
Methods: OA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.
Results: WT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.
Conclusion: We propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.
No disease modifying therapy is currently available for Parkinson’s disease (PD), the second most common neurodegenerative disease. The long non-motor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By developing a mutant α-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which in turn reduces gastrointestinal motility which is a common, very early symptom of prodromal PD. We show for the first time a causal chain of events from α-synuclein via a biophysical dysfunction of specific neuronal populations to a clinically relevant prodromal symptom. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.
α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis
(2018)
Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET–miR200–Zeb1/CtBP1–MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.
Es werden Schwingkreismodelle angegeben, deren Säkulargleichungen mit denen formal identisch sind, die sich bei der Anwendung der Methode der Moleküleigenfunktionen auf das Problem der π -Elektronenzustände in Molekülen ungesättigter und aromatischer Kohlenwasserstoffe ergeben. Damit ergibt sich die Möglichkeit, die quantenmechanischen Säkularprobleme durch Messung der Eigenfrequenzen der Modelle zu bestimmen.
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.
You are what you eat!
(2019)
Nowadays almost everyone is aware of the link between high blood cholesterol levels and cardiovascular disease. There are effective treatments that target blood cholesterol. his overview highlights some well known and some new mediators implicated in cardiovascular disease with the common theme that all of them can be influenced by the diet.
Survivin is a drug target and its suppressant YM155 a drug candidate mainly investigated for high-risk neuroblastoma. Findings from one YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 had suggested that increased ABCB1 (mediates YM155 efflux) levels, decreased SLC35F2 (mediates YM155 uptake) levels, decreased survivin levels, and TP53 mutations indicate YM155 resistance. Here, the investigation of 10 additional YM155-adapted UKF-NB-3 sublines only confirmed the roles of ABCB1 and SLC35F2. However, cellular ABCB1 and SLC35F2 levels did not indicate YM155 sensitivity in YM155-naïve cells, as indicated by drug response data derived from the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) databases. Moreover, the resistant sublines were characterized by a remarkable heterogeneity. Only seven sublines developed on-target resistance as indicated by resistance to RNAi-mediated survivin depletion. The sublines also varied in their response to other anti-cancer drugs. In conclusion, cancer cell populations of limited intrinsic heterogeneity can develop various resistance phenotypes in response to treatment. Therefore, individualized therapies will require monitoring of cancer cell evolution in response to treatment. Moreover, biomarkers can indicate resistance formation in the acquired resistance setting, even when they are not predictive in the intrinsic resistance setting.
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.
Background: A number of scientific papers on yellow fever have been published but no broad scientometric analysis on the published research of yellow fever has been reported. The aim of the article based study was to provide an in-depth evaluation of the yellow fever field using large-scale data analysis and employment of bibliometric indicators of production and quantity.
Methods: Data were retrieved from the Web of Science database (WoS) and analyzed as part of the NewQis platform. Then data were extracted from each file, transferred to databases and visualized as diagrams. Partially by means of density-equalizing mapping makes the findings clear and emphasizes the output of the analysis.
Results: In the study period from 1900 to 2012 a total of 5,053 yellow fever-associated items were published by 79 countries. The United States (USA) having the highest publication rate at 42% (n = 751) followed by far from Brazil (n = 203), France (n = 149) and the United Kingdom (n = 113). The most productive journals are the "Public Health Reports", the "American Journal of Tropical Medicine and Hygiene" and the "Journal of Virology". The gender analysis showed an overall steady increase of female authorship from 1950 to 2011. Brazil is the only country of the five most productive countries with a higher proportion of female scientists.
Conclusions: The present data shows an increase in research productivity over the entire study period, in particular an increase of female scientists. Brazil shows a majority of female authors, a fact that is confirmed by other studies.
Human GLUTs represent a family of specialized transporters that facilitate the diffusion of hexoses through membranes along a concentration gradient. The 14 isoforms share high sequence identity but differ in substrate specificity and affinity, and tissue distribution. According to their structure similarity, GLUTs are divided into three classes, with class 1 comprising the most intensively studied isoforms GLUTs1 4. An abnormal function of different GLUT members has been related to the pathogenesis of various diseases, including cancer and diabetes. Hence, GLUTs are the subject of intensive research, and efforts concentrate on identifying GLUT-selective ligands for putative medical purposes and their application in studies aiming to further unravel the metabolic roles of these transporters.
The hexose transporter deficient (hxt0) yeast strain EBY.VW4000 is devoid of all its endogenous hexose transporters and unable to grow on glucose or related hexoses. This strain has proven to be a valuable platform to investigate heterologous transporters due to its easy handling, increased robustness, and versatile applications. However, the functional expression of GLUTs in yeast requires certain modifications. Single point mutations of GLUT1 and GLUT5 led to their functional expression in EBY.VW4000, whereas the native GLUT1 was actively expressed in EBY.S7, a hxt0 strain carrying the fgy1 mutation that putatively reduces the phosphatidylinositol-4-phosphate (PI4P) content in the plasma membrane. GLUT4 was only actively expressed in the hxt0 strain SDY.022, which also contains the fgy1 mutation and in which ERG4 is additionally deleted. Erg4 is one of the late enzymes in the ergosterol pathway, and therefore SDY.022 probably has an altered sterol composition in its membrane.
The goal of this thesis was to actively express GLUT2 and GLUT3 in a hxt0 yeast strain, providing a convenient system for their ligand screening. A PCR-derived amino acid exchange in the sequence of GLUT3 enabled its functional expression in EBY.VW4000 and the unmodified GLUT3 protein was active in EBY.S7. Functional expression of GLUT2 was achieved by rational design. The extracellular loop between the transmembrane regions 1 and 2 is significantly larger in GLUT2 than in other class 1 GLUTs. By truncating this loop by 34 amino acids and exchanging an alanine for a serine, a GLUT3-like loop was implemented. The resulting construct GLUT2∆loopS was functional in EBY.S7. With an additional point mutation in the transmembrane region 11, GLUT2∆loopS_Q455R was also actively expressed in EBY.VW4000. Inhibition studies with the known GLUT inhibitors phloretin and quercetin showed a reduced transporter activity for GLUT2 and GLUT3 in uptake assays and growth tests when inhibitors were present, demonstrating that both systems are amenable for ligand screening experiments.
The newly established GLUT2 yeast system was then used to screen a library of compounds pre-selected by in silico screening. Thereby, eleven identified GLUT2 inhibitors exhibited strong potencies with IC50 values ranging from 0.61 to 19.3 µM. By employing the other yeast systems, these compounds were tested for their effects on GLUT1, and GLUTs3-5, revealing that nine of the identified ligands were GLUT2-selective. In contrast, one was a pan-class 1 inhibitor (inhibiting GLUTs1-4), and one affected GLUT2 and GLUT5, the two fructose transporting isoforms. These compounds will serve as useful tools for investigations on the role of GLUT2 in metabolic diseases and might even evolve into pharmaceutical agents targeting GLUT2-associated diseases.
Due to the beneficial effect of the putatively changed sterol composition in SDY.022 (by ERG4 deletion) on the functional expression of GLUT4, it was hypothesized that the presence of the human sterol cholesterol, or cholesterol-like sterols, might have a beneficial effect on GLUT expression, too. Thus, it was attempted to generate hxt0 strains that synthesize these sterols by genetic modifications targeting the ergosterol pathway. In the scope of these experiments, several strains with different sterol compositions were generated. Drop tests on glucose medium with the different strains expressing GLUT1 or GLUT4 revealed that the deletion of ERG6 is clearly advantageous for a functional expression of GLUT1 (but not GLUT4). This indicates that the methyl group at the ergosterol side chain (introduced by Erg6 and reduced by Erg4) negatively influences GLUT1 activity. However, this effect on GLUT1 activity was less pronounced than the putative altered PI4P content in EBY.S7.
Additionally, in this thesis, a new tool to measure glucose transport rates of transporters expressed in the hxt0 yeast system was developed to facilitate their kinetic characterization. For this, the pH-sensitive GFP variant pHluorin was employed as a biosensor for the cytosolic pH (pHcyt) by measuring the ratio (R390/470) of emission intensities at 512 nm from two different excitation wavelengths (390 and 470 nm). Sugar-starved cells exhibit a slightly acidic pHcyt because ATP production is depleted, reducing the activity of ATP-dependent proton pumps.
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Progranulin deficiency in humans is associated with neurodegeneration. Its mechanisms are not yet fully understood. We performed a Yeast-2-Hybrid screen using human full-length progranulin as bait to assess the interactions of progranulin. Progranulin was screened against human fetal brain and human bone marrow libraries using the standard Matchmaker technology (Clontech). This article contains the full Y2H data table, including blast results and sequences, a sorted table according to selection criteria for likely positive, putatively positive, likely false and false preys, and tables showing the gene ontology terms associated with the likely and putative preys of the brain and bone marrow libraries. The interactions with autophagy proteins were confirmed and functionally analyzed in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016).
Ribosomal RNA undergoes various modifications to optimize ribosomal structure and expand the topological potential of RNA. The most common nucleotide modifications in ribosomal RNA (rRNA) are pseudouridylations and 2'-O methylations (Nm), performed by H/ACA box snoRNAs and C/D box snoRNAs, respectively. Furthermore, rRNAs of both ribosomal subunits also contain various base modifications, which are catalysed by specific enzymes. These modifications cluster in highly conserved areas of the ribosome. Although most enzymes catalysing 18S rRNA base modifications have been identified, little is known about the 25S rRNA base modifications. The m(1)A modification at position 645 in Helix 25.1 is highly conserved in eukaryotes. Helix formation in this region of the 25S rRNA might be a prerequisite for a correct topological framework for 5.8S rRNA to interact with 25S rRNA. Surprisingly, we have identified ribosomal RNA processing protein 8 (Rrp8), a nucleolar Rossman-fold like methyltransferase, to carry out the m(1)A base modification at position 645, although Rrp8 was previously shown to be involved in A2 cleavage and 40S biogenesis. In addition, we were able to identify specific point mutations in Rrp8, which show that a reduced S-adenosyl-methionine binding influences the quality of the 60S subunit. This highlights the dual functionality of Rrp8 in the biogenesis of both subunits.
Mutations in the clk-1 gene result in slower development and increased life span in Caenorhabditis elegans. The Saccharomyces cerevisiae homologue COQ7/CAT5 is essential for several metabolic pathways including ubiquinone biosynthesis, respiration, and gluconeogenic gene activation. We show here that Coq7p/Cat5p is a mitochondrial inner membrane protein directly involved in ubiquinone biosynthesis, and that the defect in gluconeogenic gene activation in coq7/cat5 null mutants is a general consequence of a defect in respiration. These results obtained in the yeast model suggest that the effects on development and life span in C. elegans clk-1 mutants may relate to changes in the amount of ubiquinone, an essential electron transport component and a lipid soluble antioxidant.
Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo.
Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1.
Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment.
Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.
Background and Aim. Spontaneous bacterial peritonitis (SBP) is one of the most common complications of liver cirrhosis. Antibiotics are the main treatment regimen of SBP. Traditional Chinese medicine Xuebijing injection has been used in such patients. Our study aimed to overview the efficacy of Xuebijing injection combined with antibiotics for the treatment of SBP.
Method. We searched the PubMed, Embase, China National Knowledge Infrastructure, VIP, and Wanfang databases. The search items included "Xuebijing", "peritonitis", "liver cirrhosis", and "random" to identify all relevant randomized controlled trials (RCTs). The Cochrane risk of bias tool was used to assess the study quality. The odd ratios (ORs) with 95% confidence intervals (CIs) were calculated by using a random-effect model. Heterogeneity was also calculated.
Results. A total of 9 RCTs were included. The study quality was unsatisfied. The overall (OR = 2.95, 95% CI = 1.97–4.42, p<0.00001) and complete (OR = 2.18, 95% CI = 1.57–3.04, p<0.00001) responses were significantly higher in the Xuebijing injection combined with antibiotics group than the antibiotics alone group. The incidence of cirrhosis related complications, including hepatic encephalopathy and hepatorenal syndrome, was lower in the Xuebijing injection combined with antibiotics group than the antibiotics alone group. No significant heterogeneity was observed among studies.
Conclusion. Additional use of Xuebijing injection may improve the efficacy of antibiotics for the treatment of SBP in liver cirrhosis. However, due to a low level of current evidence, we did not establish any recommendation regarding the use of Xuebijing injection for the treatment of SBP.
Germany has experienced a rise in xenophobic attacks since it began to welcome refugees from Syria and elsewhere. Sebastian Jäckle and Pascal D. König have mapped these attacks and drawn some striking conclusions about their causes. They were more common in regions with a strong far-right presence and fewer migrants. One attack also tended to spark others – as did condemnation of xenophobia by national leaders, and Islamist terror. Britain saw a similar spike in xenophobic crime after the referendum. The authors ask whether the UK can learn from Germany’s painful experience.
Xenocoumacin (Xcn) 1 and 2 are the major antibiotics produced by the insect-pathogenic bacterium Xenorhabdus nematophila. Although the antimicrobial activity of Xcns has been explored, research regarding their action on mammalian cells is lacking. We aimed to investigate the action of Xcns in the context of inflammation and angiogenesis. We found that Xcns do not impair the viability of primary endothelial cells (ECs). Particularly Xcn2, but not Xcn1, inhibited the pro-inflammatory activation of ECs: Xcn2 diminished the interaction between ECs and leukocytes by downregulating cell adhesion molecule expression and blocked critical steps of the NF-κB activation pathway including the nuclear translocation of NF-κB p65 as well as the activation of inhibitor of κBα (IκBα) and IκB kinase β (IKKβ). Furthermore, the synthesis of pro-inflammatory mediators and enzymes, nitric oxide (NO) production and prostaglandin E2 (PGE2), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), was evaluated in leukocytes. The results showed that Xcns reduced viability, NO release, and iNOS expression in activated macrophages. Beyond these anti-inflammatory properties, Xcn2 effectively hindered pro-angiogenic processes in HUVECs, such as proliferation, undirected and chemotactic migration, sprouting, and network formation. Most importantly, we revealed that Xcn2 inhibits de novo protein synthesis in ECs. Consequently, protein levels of receptors that mediate the inflammatory and angiogenic signaling processes and that have a short half-live are reduced by Xcn2 treatment, thus explaining the observed pharmacological activities. Overall, our research highlights that Xcn2 exhibits significant pharmacological in vitro activity regarding inflammation and angiogenesis, which is worth to be further investigated preclinically.
W±-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2022)
The production of the W± bosons measured in p−Pb collisions at a centre-of-mass energy per nucleon−nucleon collision sNN−−−−√=8.16 TeV and Pb−Pb collisions at sNN−−−−√=5.02 TeV with ALICE at the LHC is presented. The W± bosons are measured via their muonic decay channel, with the muon reconstructed in the pseudorapidity region −4<ημlab<−2.5 with transverse momentum pμT>10 GeV/c. While in Pb−Pb collisions the measurements are performed in the forward (2.5<yμcms<4) rapidity region, in p−Pb collisions, where the centre-of-mass frame is boosted with respect to the laboratory frame, the measurements are performed in the backward (−4.46<yμcms<−2.96) and forward (2.03<yμcms<3.53) rapidity regions. The W− and W+ production cross sections, lepton-charge asymmetry, and nuclear modification factors are evaluated as a function of the muon rapidity. In order to study the production as a function of the p−Pb collision centrality, the production cross sections of the W− and W+ bosons are combined and normalised to the average number of binary nucleon−nucleon collision ⟨Ncoll⟩. In Pb−Pb collisions, the same measurements are presented as a function of the collision centrality. Study of the binary scaling of the W±-boson cross sections in p−Pb and Pb−Pb collisions is also reported. The results are compared with perturbative QCD (pQCD) calculations, with and without nuclear modifications of the Parton Distribution Functions (PDFs), as well as with available data at the LHC. Significant deviations from the theory expectations are found in the two collision systems, indicating that the measurements can provide additional constraints for the determination of nuclear PDF (nPDFs) and in particular of the light-quark distributions.
W±-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2022)
The production of the W± bosons measured in p−Pb collisions at a centre-of-mass energy per nucleon−nucleon collision sNN−−−−√=8.16 TeV and Pb−Pb collisions at sNN−−−−√=5.02 TeV with ALICE at the LHC is presented. The W± bosons are measured via their muonic decay channel, with the muon reconstructed in the pseudorapidity region −4<ημlab<−2.5 with transverse momentum pμT>10 GeV/c. While in Pb−Pb collisions the measurements are performed in the forward (2.5<yμcms<4) rapidity region, in p−Pb collisions, where the centre-of-mass frame is boosted with respect to the laboratory frame, the measurements are performed in the backward (−4.46<yμcms<−2.96) and forward (2.03<yμcms<3.53) rapidity regions. The W− and W+ production cross sections, lepton-charge asymmetry, and nuclear modification factors are evaluated as a function of the muon rapidity. In order to study the production as a function of the p−Pb collision centrality, the production cross sections of the W− and W+ bosons are combined and normalised to the average number of binary nucleon−nucleon collision ⟨Ncoll⟩. In Pb−Pb collisions, the same measurements are presented as a function of the collision centrality. Study of the binary scaling of the W±-boson cross sections in p−Pb and Pb−Pb collisions is also reported. The results are compared with perturbative QCD (pQCD) calculations, with and without nuclear modifications of the Parton Distribution Functions (PDFs), as well as with available data at the LHC. Significant deviations from the theory expectations are found in the two collision systems, indicating that the measurements can provide additional constraints for the determination of nuclear PDF (nPDFs) and in particular of the light-quark distributions.
W±-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2023)
The production of the W± bosons measured in p−Pb collisions at a centre-of-mass energy per nucleon−nucleon collision sNN−−−−√=8.16 TeV and Pb−Pb collisions at √sNN=5.02 TeV with ALICE at the LHC is presented. The W± bosons are measured via their muonic decay channel, with the muon reconstructed in the pseudorapidity region −4<ημlab<−2.5 with transverse momentum pμT>10 GeV/c. While in Pb−Pb collisions the measurements are performed in the forward (2.5<yμcms<4) rapidity region, in p−Pb collisions, where the centre-of-mass frame is boosted with respect to the laboratory frame, the measurements are performed in the backward (−4.46<yμcms<−2.96) and forward (2.03<yμcms<3.53) rapidity regions. The W− and W+ production cross sections, lepton-charge asymmetry, and nuclear modification factors are evaluated as a function of the muon rapidity. In order to study the production as a function of the p−Pb collision centrality, the production cross sections of the W− and W+ bosons are combined and normalised to the average number of binary nucleon−nucleon collision ⟨Ncoll⟩. In Pb−Pb collisions, the same measurements are presented as a function of the collision centrality. Study of the binary scaling of the W±-boson cross sections in p−Pb and Pb−Pb collisions is also reported. The results are compared with perturbative QCD (pQCD) calculations, with and without nuclear modifications of the Parton Distribution Functions (PDFs), as well as with available data at the LHC. Significant deviations from the theory expectations are found in the two collision systems, indicating that the measurements can provide additional constraints for the determination of nuclear PDF (nPDFs) and in particular of the light-quark distributions.
W±-boson production in p–Pb collisions at √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV
(2023)
The production of the W± bosons measured in p–Pb collisions at a centreof-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV and Pb–Pb collisions at √sNN = 5.02 TeV with ALICE at the LHC is presented. The W± bosons are measured via their muonic decay channel, with the muon reconstructed in the pseudorapidity region −4 < ηµ lab < −2.5 with transverse momentum p µ T > 10 GeV/c. While in Pb–Pb collisions the measurements are performed in the forward (2.5 < yµ cms < 4) rapidity region, in p–Pb collisions, where the centre-of-mass frame is boosted with respect to the laboratory frame, the measurements are performed in the backward (−4.46 < yµ cms < −2.96) and forward (2.03 < yµ cms < 3.53) rapidity regions. The W− and W+ production cross sections, leptoncharge asymmetry, and nuclear modification factors are evaluated as a function of the muon rapidity. In order to study the production as a function of the p–Pb collision centrality, the production cross sections of the W− and W+ bosons are combined and normalised to the average number of binary nucleon–nucleon collision hNcolli. In Pb–Pb collisions, the same measurements are presented as a function of the collision centrality. Study of the binary scaling of the W±-boson cross sections in p–Pb and Pb–Pb collisions is also reported. The results are compared with perturbative QCD calculations, with and without nuclear modifications of the Parton Distribution Functions (PDFs), as well as with available data at the LHC. Significant deviations from the theory expectations are found in the two collision systems, indicating that the measurements can provide additional constraints for the determination of nuclear PDFs and in particular of the light-quark distributions.
Background: Patient information materials and decision aids are essential tools for helping patients make informed decisions and share in decision-making. The aim of this study was to investigate the quality of the written patient information materials available at general practices in Styria, Austria.
Methods: We asked general practitioners to send in all patient information materials available in their practices and to answer a short questionnaire. We evaluated the materials using the Ensuring Quality Information for Patients (EQIP-36) instrument.
Results: A total of 387 different patient information materials were available for quality assessment. These materials achieved an average score of 39 out of 100. The score was below 50 for 78% of all materials. There was a significant lack of information on the evidence base of recommendations. Only 9 % of the materials provided full disclosure of their evidence sources. We also found that, despite the poor quality of the materials, 89% of general practitioners regularly make active use of them during consultations with patients.
Conclusion: Based on international standards, the quality of patient information materials available at general practices in Styria is poor. The vast majority of the materials are not suitable as a basis for informed decisions by patients. However, most Styrian general practitioners use written patient information materials on a regular basis in their daily clinical practice. Thus, these materials not only fail to help raise the health literacy of the general population, but may actually undermine efforts to enable patients to make shared informed decisions. To increase health literacy, it is necessary to make high quality, evidence-based and easy-to-understand information material available to patients and the public. For this, it may be necessary to set up a centralized and independent clearinghouse.
Focused electron beam induced deposition (FEBID) is a direct-write nanofabrication technique able to pattern three-dimensional magnetic nanostructures at resolutions comparable to the characteristic magnetic length scales. FEBID is thus a powerful tool for 3D nanomagnetism which enables unique fundamental studies involving complex 3D geometries, as well as nano-prototyping and specialized applications compatible with low throughputs. In this focused review, we discuss recent developments of this technique for applications in 3D nanomagnetism, namely the substantial progress on FEBID computational methods, and new routes followed to tune the magnetic properties of ferromagnetic FEBID materials. We also review a selection of recent works involving FEBID 3D nanostructures in areas such as scanning probe microscopy sensing, magnetic frustration phenomena, curvilinear magnetism, magnonics and fluxonics, offering a wide perspective of the important role FEBID is likely to have in the coming years in the study of new phenomena involving 3D magnetic nanostructures.
In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.
Highlights
• We present a novel alternative to the die-in-the-cup experiment.
• Participants’ payoffs depend on their reported mothers’ birthdays.
• We find that subjects lied to obtain real monetary payoffs.
• The extent of lying is small and insensitive to several design variations.
Abstract
We ask a representative sample of German household decision-makers to enter their mother's birthday, with potential payments depending on the month and the day they state. Thus, we create an incentive to lie. Compared to the die-under-the-cup experiment, our alternative has a lower probability that the income-maximizing outcome is true. Furthermore, it is better suited for online surveys and samples in which gambling is socially stigmatized. We conduct different variations of this game to crystalize design recommendations for researchers interested in our tool. Participants lied to receive higher payoffs, but only with real monetary incentives and only to a relatively small extent. Our results are largely insensitive to several design elements that we vary, such as the probability of being paid and the magnitude of the payoffs.
Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusion: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.
Background: Despite the numerous associations of vitamin D with health and disease, vitamin D deficiency is still common from a global perspective. While basic research, clinical and preventive activities grow constantly in vitamin D research, there is no in-depth analysis of the related global scientific productivity available so far.
Methods: Density equalizing mapping procedures (DEMP) were combined with socioeconomic benchmarks using the NewQIS platform.
Results: A total of 25,992 vitamin D-related research articles were identified between 1900 to 2014 with a significant increase (r2 = .6541) from 1900 to 2014. Authors located in Northern America – especially in the USA – distributed the majority of global vitamin D research, followed by their Western European counterparts. DEMP-analysis illustrates that Africa and South America exhibit only minor scientific productivity. Among high-income group countries, Scandinavian nations such as Denmark or Finland (2147.9 and 1607.7 vitamin D articles per GDP in 1000 billion USD) were highly active with regard to socioeconomic figures.
Conclusion: Networks dedicated to vitamin D research are present around the world. Overall, the Northern American and Western European nations occupy prominent positions. However, South American, African and Asian countries apart from Japan only play a minor role in the global research production related to vitamin D. Since vitamin D deficiency is currently increasing in the Americas, Europe and parts of the Middle East, research in these regions may need to be encouraged.
Background: Depression and anxiety are the most prevalent mental health difficulties in the workplace, costing the global economy $1 trillion each year. Evidence indicates that symptoms may be reduced by interventions in the workplace. This paper is the first to systematically review psychosocial interventions for depression, anxiety, and suicidal ideation and behaviours in small-to medium-size enterprises (SMEs).
Methods: A systematic search following PRISMA guidelines, registered in PROSPERO (CRD42020156275), was conducted for psychosocial interventions targeting depression, anxiety, and suicidal ideation/behaviour in SMEs. The PubMed, PsycINFO, Scopus, and two specific occupational health databases were searched, as well as four databases for grey literature, without time limit until 2nd December 2019.
Results: In total, 1283 records were identified, 70 were retained for full-text screening, and seven met the inclusion criteria: three randomised controlled trials (RCTs), three before and after designs and one non-randomised trial, comprising 5111 participants. Study quality was low to moderate according to the Quality Assessment Tool for Quantitative Studies. Five studies showed a reduction in depression and anxiety symptoms using techniques based on cognitive behavioural therapy (CBT), two reported no significant change.
Limitations: Low number and high heterogeneity of interventions and outcomes, high attrition and lack of rigorous RCTs.
Conclusions: Preliminary evidence indicates CBT-based interventions can be effective in targeting symptoms of depression and anxiety in SME employees. There may be unique challenges to implementing programmes in SMEs. Further research is needed in this important area.
Congenitally blind individuals have been shown to activate the visual cortex during non-visual tasks. The neuronal mechanisms of such cross-modal activation are not fully understood. Here, we used an auditory working memory training paradigm in congenitally blind and in sighted adults. We hypothesized that the visual cortex gets integrated into auditory working memory networks, after these networks have been challenged by training. The spectral profile of functional networks was investigated which mediate cross-modal reorganization following visual deprivation. A training induced integration of visual cortex into task-related networks in congenitally blind individuals was expected to result in changes in long-range functional connectivity in the theta-, beta- and gamma band (imaginary coherency) between visual cortex and working memory networks. Magnetoencephalographic data were recorded in congenitally blind and sighted individuals during resting state as well as during a voice-based working memory task; the task was performed before and after working memory training with either auditory or tactile stimuli, or a control condition. Auditory working memory training strengthened theta-band (2.5-5 Hz) connectivity in the sighted and beta-band (17.5-22.5 Hz) connectivity in the blind. In sighted participants, theta-band connectivity increased between brain areas typically involved in auditory working memory (inferior frontal, superior temporal, insular cortex). In blind participants, beta-band networks largely emerged during the training, and connectivity increased between brain areas involved in auditory working memory and as predicted, the visual cortex. Our findings highlight long-range connectivity as a key mechanism of functional reorganization following congenital blindness, and provide new insights into the spectral characteristics of functional network connectivity.
Previous research on working memory (WM) in children with poor mathematical skills has yielded heterogeneous results, possibly due to inconsistent consideration of the IQ-achievement discrepancy and additional reading and spelling difficulties. To examine the impact of both, the WM of 68 average-achieving and 68 low-achieving third-graders in mathematics was assessed. Preliminary analyses showed that poor mathematical skills were associated with poor WM. Afterwards, children with isolated mathematical difficulties were separated from those with additional reading and spelling difficulties. Half of each group fulfilled the IQ-achievement discrepancy, resulting in a 2 (additional reading and spelling difficulties: yes/no) by 2 (IQ-achievement discrepancy: yes/no) factorial design. Analyses revealed that not fulfilling the IQ achievement discrepancy was associated with poor visual WM, whereas additional reading and spelling difficulties were associated with poor central executive functioning in children fulfilling the IQ-achievement discrepancy. Therefore, WM in children with poor mathematical skills differs according to the IQ-achievement discrepancy and additional reading and spelling difficulties.
BIOfid is a specialized information service currently being developed to mobilize biodiversity data dormant in printed historical and modern literature and to offer a platform for open access journals on the science of biodiversity. Our team of librarians, computer scientists and biologists produce high-quality text digitizations, develop new text-mining tools and generate detailed ontologies enabling semantic text analysis and semantic search by means of user-specific queries. In a pilot project we focus on German publications on the distribution and ecology of vascular plants, birds, moths and butterflies extending back to the Linnaeus period about 250 years ago. The three organism groups have been selected according to current demands of the relevant research community in Germany. The text corpus defined for this purpose comprises over 400 volumes with more than 100,000 pages to be digitized and will be complemented by journals from other digitization projects, copyright-free and project-related literature. With TextImager (Natural Language Processing & Text Visualization) and TextAnnotator (Discourse Semantic Annotation) we have already extended and launched tools that focus on the text-analytical section of our project. Furthermore, taxonomic and anatomical ontologies elaborated by us for the taxa prioritized by the project’s target group - German institutions and scientists active in biodiversity research - are constantly improved and expanded to maximize scientific data output. Our poster describes the general workflow of our project ranging from literature acquisition via software development, to data availability on the BIOfid web portal (http://biofid.de/), and the implementation into existing platforms which serve to promote global accessibility of biodiversity data.
Background: Only few studies deal with the workload of physical therapists and the health consequences, although this occupational group is quite important for the health care system in many industrialized countries (e.g. ca. 136 000 people are currently employed as physical therapists in Germany). Therefore, the current state of knowledge of work-related diseases and disorders of physical therapists is insufficient. The aim of the "Physical Therapist Cohort" (PTC) study is to analyze the association between work-related exposures and diseases among physical therapists in Germany. This article describes the protocol of the baseline assessment of the PTC study.
Methods/Design: A cross-sectional study will be conducted as baseline assessment and will include a representative random sample of approximately 300 physical therapists employed in Germany (exposure group), and a population-based comparison group (n = 300). The comparison group will comprise a sample of working aged (18–65 years) inhabitants of a German city. Variables of interest will be assessed using a questionnaire manual including questions regarding musculoskeletal, dermal, and infectious diseases and disorders as well as psychosocial exposures, diseases and disorders. In addition to subjective measures, a clinical examination will be used to objectify the questionnaire-based results (n = 50).
Discussion: The study, which includes extensive data collection, provides a unique opportunity to study the prospective association of work-related exposures and associated complaints of physical therapists. Baseline results will give first clues with regard to whether and how prevalent main exposures of physiotherapeutic work and typical work areas of physical therapists are associated with the development of work-related diseases. Thereby, this baseline assessment provides the basis for further investigations to examine causal relationships in accordance with a longitudinal design.
Background: The aim of this study was to investigate the acceptance and assessment of work shadowing carried out by students and dentists in dental practices. Furthermore, the extent to which students perceive an improvement in their specialised, communication and social competencies, was to be examined.
Methods: 61 dental students in their clinical semesters at a German university participated in work shadowing placements at 27 different general dental practices. Before beginning, they received checklists of various competencies that they self-assessed using school grades (from 1 = "very good", to 6 = "failed"), which they also repeated after completion. The dentists supplemented this with their external assessments. In addition, the students were requested to fill out a 54-item questionnaire and compose a freely-structured report after the work shadowing; the dentists filled out a questionnaire containing 16 items. The statistical analysis was carried out by means of the Friedman Test, including a post-hoc test (Bonferroni-Holm correction).
Results: The analysis showed a significant overall improvement in the students’ self-assessed competencies by 0.71* ± 0.43 grades. With an average of 0.33* ± 0.36, the dentists’ external assessment proved significantly higher than the self-assessment. The greatest improvements were perceived by the students in the areas of accounting (1.17* ± 0.77), practice organisation (1.05* ± 0.61) and dentist’s discussions (0.94* ±0.80) [*p < 0.05]. The students confirmed experiencing an expansion of knowledge, an improvement in their communication skills and indicated a high degree of satisfaction in regard to the dentists (school grade 1.58 ± 0.93). A maximum amount of satisfaction towards the work shadow students was demonstrated by the dentists, and this form of teaching was assessed with a school grade of 1.69 ± 0.89.
Conclusion: Both students and dental practitioners demonstrated a high level of satisfaction in regard to the work shadowing. The students felt their knowledge had increased, viewed the dentists as motivating role models and acknowledged a significant improvement in their specialised, communication and social competencies. Work shadowing in dental teaching practices presents a sensible addition to academic teaching at a university.
The information and communication technology (ICT) sector within the Netherlands is a major driver of globalization, the country’s economic growth and innovation. The Dutch ICT sector’s performance is increasingly becoming dependent upon employee driven innovations in order to address the needs of the sectors they service. In other words, the ICT sector within the Netherlands is largely dependent upon the performance and innovative capacity of its employees; both of which are functions of employee engagement. Given the high demand, and low supply of talent within this sector, ICT organizations need to develop innovative ways to enhance the performance capacities of its people. Developing an engaged and highly innovative workforce seems to be an efficient way to activate employees’ performance. As such, the aim of this paper was to investigate the mediating function of employee driven innovative work behaviors in the relationship between work engagement and task performance within the a Dutch ICT consulting firm. A cross-sectional survey-based research design, employing a census-based sampling method, was employed to obtain data from a global ICT consulting firm within the Netherlands (n = 232). The Utrecht Work Engagement Scale, the Innovative Work Behavior Scale and the Task Performance Scale was used to assess the associative subjective experiences of ICT employees. The results showed that work engagement is a significant driver for innovative work behaviors, which in turn affects the task performance of employees. Further, innovative work behaviors are therefore important to translate the engaging energies of employees into performance. This paper discusses the theoretical and practical implications of these findings.
We test two hypotheses, based on sexual selection theory, about gender differences in costly social interactions. Differential selectivity states that women invest less than men in interactions with new individuals. Differential opportunism states that women’s investment in social interactions is less responsive to information about the interaction’s payoffs. The hypotheses imply that women’s social networks are more stable and path dependent and composed of a greater proportion of strong relative to weak links. During their introductory week, we let new university students play an experimental trust game, first with one anonymous partner, then with the same and a new partner. Consistent with our hypotheses, we find that women invest less than men in new partners and that their investments are only half as responsive to information about the likely returns to the investment. Moreover, subsequent formation of students’ real social networks is consistent with the experimental results: being randomly assigned to the same introductory group has a much larger positive effect on women’s likelihood of reporting a subsequent friendship.
Background: Scientifically evaluated cognitive intervention programs are essential to meet the demands of our increasingly aging society. Currently, one of the “hottest” topics in the field is the improvement of working memory function and its potential impact on overall cognition. The present study evaluated the efficacy of WOME (WOrking MEmory), a theory-based working memory training program, in a double-blind, placebo-controlled, and randomized controlled trial (www.drks.de, DRKS00013162).
Methods: N = 60 healthy older adults were allocated to (1) the WOME intervention, (2) an active low-level intervention, or (3) a passive control group. Overall, the intervention groups practiced twelve sessions of 45 min within 4 weeks of their respective training. Transfer effects were measured via an extensive battery of neuropsychological tests and questionnaires both pre-/post-training and at a 3-month follow-up.
Results: WOME led to a significant improvement in working memory function, demonstrated on a non-trained near transfer task and on two different composite scores with moderate to large effect sizes. In addition, we found some indication of relevant impact on everyday life. The effects were short-term rather than stable, being substantially diminished at follow-up with only little evidence suggesting long-term maintenance. No transfer effects on other cognitive functions were observed.
Conclusion: WOME is an appropriate and efficient intervention specifically targeting the working memory system in healthy older adults.
Trial Registration: German Clinical Trials Register (DRKS), Identifier: DRKS00013162.
Reproducing the characteristics and the functional responses of the blood–brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.
This article aims to shed light on some core challenges of liberating social criticism. Its centerpiece is an intuitively attractive account of the nature and difficulty of critical social thought that nevertheless goes missing in many philosophical conversations about critique. This omission at bottom reflects the fact that the account presupposes a philosophically contentious conception of rationality. Yet the relevant conception of rationality does in fact inform influential philosophical treatments of social criticism, including, very prominently, a left Hegelian strand of thinking within contemporary Critical Theory. Moreover, it is possible to mount a defense of the conception by reconstructing, if with various qualifications and additions, an argument from classic—i.e., mid twentieth-century—Anglo-American philosophy of the social sciences, in particular, the argument that forms the backbone of Peter Winch’s The Idea of a Social Science. Winch draws his guiding insights from the later philosophy of Wittgenstein, and one of the payoffs of considering Winch’s Wittgenstein-inspired work against the backdrop of Hegel-inspired work in Critical Theory is to contest the artificial professional strictures that are sometimes taken to speak against reaching across the so-called ‘Continental Divide’ in philosophy. The larger payoff is advancing, by means of this philosophically ecumenical approach, the enterprise of liberating social thought.