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Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
The interaction of Eph receptor tyrosine kinases with their transmembrane ligands; the ephrins, is important for the regulation of cell-cell communication. Ephrin-Eph signaling is probably best known for the discrimination of arterial and venous territories by repulsion of venous endothelial cells away from those with an arterial fate. Ultimately, cell repulsion is mediated by initiating the collapse of the actin cytoskeleton in membrane protrusions. Here, we investigated the role of the Ena/VASP family of actin binding proteins in endothelial cell repulsion initiated by ephrin ligands. Human endothelial cells dynamically extended sheet-like lamellipodia over ephrin-B2 coated surfaces. While lamellipodia of control siRNA transfected cells rapidly collapsed, resulting in a pronounced cell repulsion from the ephrin-B2 surfaces, the knockdown of Ena/VASP proteins impaired the cytoskeletal collapse of membrane protrusions and the cells no longer avoided the repulsive surfaces. Mechanistically, ephrin-B2 stimulation elicited the EphB-mediated tyrosine phosphorylation of VASP, which abrogated its interaction with the focal adhesion protein Zyxin. Nck2 was identified as a novel VASP binding protein, which only interacted with the tyrosine phosphorylated VASP protein. Nck links Eph-receptors to the actin cytoskeleton. Therefore, we hypothesize that Nck-Ena/VASP complex formation is required for actin reorganization and/or Eph receptor internalization downstream of ephrin-Eph interaction in endothelial cells, with implications for endothelial navigation and pathfinding.
Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. Endothelial-specific deletion of EVL, a member of the mammalian Ena/VASP protein family, reduced the expression of the tip cell marker protein endothelial cell specific molecule-1 (Esm1) and compromised the radial sprouting of the vascular plexus in the postnatal mouse retina. The latter effects could at least partly be attributed to reduced VEGF receptor 2 (VEGFR2) internalization and signaling but the underlying mechanisms(s) are not fully understood. In the present study, we revealed that the expression of the long non-coding RNA H19 was significantly reduced in endothelial cells from postnatal EVL-/- mice and in siRNA-transfected human endothelial cells under hypoxic conditions. H19 was recently shown to promote VEGF expression and bioavailability via Esm1 and hypoxia inducible factor 1α (HIF-1α). Similar to EVL-/- mice, the radial outgrowth of the vascular plexus was significantly delayed in the postnatal retina of H19-/- mice. In summary, our data suggests that loss of EVL not only impairs VEGFR2 internalition and downstream signaling, but also impairs VEGF expression and bioavailability in the hypoxic retina via downregulation of lncRNA H19.
The family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65-70 meV, about eight times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3-Ce3Bi4Pd3-Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the d orbitals at the Fermi energy. To understand under which condition topological states form in these materials is a topic for future studies.
he family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65–70 meV, about eight times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3−Ce3Bi4Pd3−Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the 𝑑 orbitals at the Fermi energy. This work opens the possibility to investigate the conditions under which topological states develop in this series of strongly correlated 3-4-3 materials.
The family of cubic noncentrosymmetric 3-4-3 compounds has become a fertile ground for the discovery of novel correlated metallic and insulating phases. Here, we report the synthesis of a new heavy fermion compound, Ce3Bi4Ni3. It is an isoelectronic analog of the prototypical Kondo insulator Ce3Bi4Pt3 and of the recently discovered Weyl-Kondo semimetal Ce3Bi4Pd3. In contrast to the volume-preserving Pt-Pd substitution, structural and chemical analyses reveal a positive chemical pressure effect in Ce3Bi4Ni3 relative to its heavier counterparts. Based on the results of electrical resistivity, Hall effect, magnetic susceptibility, and specific heat measurements, we identify an energy gap of 65-70 meV, about 8 times larger than that in Ce3Bi4Pt3 and about 45 times larger than that of the Kondo-insulating background hosting the Weyl nodes in Ce3Bi4Pd3. We show that this gap as well as other physical properties do not evolve monotonically with increasing atomic number, i.e., in the sequence Ce3Bi4Ni3-Ce3Bi4Pd3-Ce3Bi4Pt3, but instead with increasing partial electronic density of states of the d orbitals at the Fermi energy. To understand under which condition topological states form in these materials is a topic for future studies.
Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine‐based L‐45 (dubbed L‐Moses) as the first potent, selective, and cell‐active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished L‐45 in enantiopure form. L‐45 was shown to disrupt PCAF‐Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co‐crystal structure of L‐45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L‐45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell‐permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
Cell-free expression represents an attractive method to produce large quantities of selectively labeled protein for NMR applications. Here, cell-free expression was used to label specific regions of the growth hormone secretagogue receptor (GHSR) with NMR-active isotopes. The GHSR is a member of the class A family of G protein-coupled receptors. A cell-free expression system was established to produce the GHSR in the precipitated form. The solubilized receptor was refolded in vitro and reconstituted into DMPC lipid membranes. Methionines, arginines, and histidines were chosen for 13C-labeling as they are representative for the transmembrane domains, the loops and flanking regions of the transmembrane α-helices, and the C-terminus of the receptor, respectively. The dynamics of the isotopically labeled residues was characterized by solid-state NMR measuring motionally averaged 1H-13C dipolar couplings, which were converted into molecular order parameters. Separated local field DIPSHIFT experiments under magic-angle spinning conditions using either varying cross polarization contact times or direct excitation provided order parameters for these residues showing that the C-terminus was the segment with the highest motional amplitude. The loop regions and helix ends as well as the transmembrane regions of the GHSR represent relatively rigid segments in the overall very flexible receptor molecule. Although no site resolution could be achieved in the experiments, the previously reported highly dynamic character of the receptor concluded from uniformly 13C labeled receptor samples could be further specified by this segmental labeling approach, leading to a more diversified understanding. of the receptor dynamics under equilibrium conditions
In 2010, the Conference of the Parties of the Convention on Biological Diversity agreedon the Strategic Plan for Biodiversity 2011–2020 in Aichi Prefecture, Japan. As this planapproaches its end, we discussed whether marine biodiversity and prediction studieswere nearing the Aichi Targets during the 4th World Conference on Marine Biodiversityheld in Montreal, Canada in June 2018. This article summarises the outcome of a five-day group discussion on how global marine biodiversity studies should be focusedfurther to better understand the patterns of biodiversity. We discussed and reviewedseven fundamental biodiversity priorities related to nine Aichi Targets focusing onglobal biodiversity discovery and predictions to improve and enhance biodiversitydata standards (quantity and quality), tools and techniques, spatial and temporal scaleframing, and stewardship and dissemination. We discuss how identifying biodiversityknowledge gaps and promoting efforts have and will reduce such gaps, including via theuse of new databases, tools and technology, and how these resources could be improvedin the future. The group recognised significant progress toward Target 19 in relationto scientific knowledge, but negligible progress with regard to Targets 6 to 13 whichaimed to safeguard and reduce human impacts on biodiversity.
Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.
On 20th January 1964, at the Colito Army Barracks just outside Dar es salaam, 15 officers of the Tanganyika Army that was inherited from the colonial state led a mutiny against the independent Tanganyika government. One group went to the State House with the intention of forcing President Julius Nyerere to accept their demands. What would have happened if they had succeeded in entering the State House and if President Nyerere had refused to accept their demands, as he most likely would have done? Anything could have happened and in the worst case scenario Tanzanias history and indeed the history of the whole of Africa would have been seriously affected. This book is about the courage and quick thinking of Peter Bwimbo, the then head of the Presidential Protection Unit and Nyereres Chief Body Guard who, alone, planned and executed an ingenious and successful evacuation of President Nyerere and Vice President Rashid Kawawa, whisking them away from the State House before the mutineers got there. By a clever ruse he convinced the ferry operators on duty before dawn to ferry them across the Kigamboni Creek. From there they walked several miles to a hiding place in a house that was offered by an ordinary citizen and where they stayed until the situation was normalised several days later.
12 hepatics and 32 mosses are reported new to Uganda, 1 moss being also new to Africa, and 1 liverwort new to mainland Africa. Ectropothecium plumigerum (Broth.) Hedenäs is a new combination (basionym: Isopterygium plumigerum Broth.) with a new synonym Taxicaulis plumirameus Müll.Hal. nom. nud., and Taxiphyllum maniae (Renauld & Paris) M. Fleisch. is a new synonym of Taxiphyllum taxirameum (Mitt.) M.Fleisch. Three mosses are removed from the Uganda list.