Strange metal electrodynamics across the phase diagram of Bi_2-<i>x</i>Pb_<i>x</i>Sr_2-<i>y</i>La_<i>y</i>CuO_6+<i>δ</i> cuprates

Unlocking the mystery of the strange metal state has become the focal point of high-Tcresearch, not because of its importance for superconductivity, but because it appears to represent a truly novel phase of matter dubbed "quantum supreme matter. " Detected originally through high magnetic field, transport experiments, signatures of this phase have now been uncovered with a variety of probes. Our high resolution optical data of the low-Tccuprate superconductor, Bi2-xPbxSr2-yLayCuO6+delta allows us to probe this phase over a large energy and temperature window. We demonstrate that the optical signatures of the strange metal phase persist throughout the phase diagram. The strange metal signatures in the optical conductivity are twofold: (i) a low energy Drude response with Drude width on the order of temperature and (ii) a high energy conformal tail with a doping dependent power-law exponent. While the Drude weight evolves monotonically throughout the entire doping range studied, the spectral weight contained in the high energy conformal tail appears to be doping and temperature independent. Our analysis further shows that the temperature dependence of the optical conductivity is completely determined by the Drude parameters. Our results indicate that there is no critical doping level inside the superconducting dome where the carrier density starts to change drastically and that the previously observed "return to normalcy " is a consequence of the increasing importance of the Drude component relative to the conformal tail with doping. Importantly, both the doping and temperature dependence of the resistivity are largely determined by the Drude width

Soziale Bedingungen von Schulleistungen: Zur Erfassung von Kontextmerkmalen durch Schüler-, Schul- und Elternfragebögen [Elektronische Ressource]

Author's comment: sine ann

The endoplasmic reticulum Ca2+-ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis

This is the peer reviewed version of the following article: Morales-Ropero JM, Arroyo-Urea S, Neubrand VE, Martín-Oliva D, Marín-Teva JL, Cuadros MA, Vangheluwe P, Navascués J, Mata AM, Sepúlveda MR. The endoplasmic reticulum Ca2+ -ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis. Glia. 2021 Apr;69(4):842-857, which has been published in final form at https://onlinelibrary.wiley.com/doi/10.1002/glia.23931. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.The accepted version is under embargo until April 2022.Activation of microglia is an early immune response to damage in the brain. Although a key role for Ca2+ as trigger of microglial activation has been considered, little is known about the molecular scenario for regulating Ca2+ homeostasis in these cells. Taking into account the importance of the endoplasmic reticulum as a cellular Ca2+ store, the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2b) is an interesting target to modulate intracellular Ca2+ dynamics. We found upregulation of SERCA2b in activated microglia of human brain with Alzheimer´s disease and we further studied the participation of SERCA2b in microglial functions by using the BV2 murine microglial cell line and primary microglia isolated from mouse brain. To trigger microglia activation, we used the bacterial lipopolysaccharide (LPS), which is known to induce an increase of cytosolic Ca2+. Our results showed an upregulated expression of SERCA2b in LPS-induced activated microglia likely associated to an attempt to restore the increased cytosolic Ca2+ concentration. We analyzed SERCA2b contribution in microglial migration by using the specific SERCA inhibitor thapsigargin in scratch assays. Microglial migration was strongly stimulated with thapsigargin, even more than with LPS-induction, but delayed in time. However, phagocytic capacity of microglia was blocked in the presence of the SERCA inhibitor, indicating the importance of a tight control of cytosolic Ca2+ in these processes. All together, these results provide for the first time compelling evidence for SERCA2b as a major player regulating microglial functions, affecting migration and phagocytosis in an opposite manner.Grant mP_BS_35-2014 from CEI BioTic GranadaPP2016-PJI05 from University of GranadaA1-CTS-324-UGR18 from FEDER-Junta de Andalucía, SpainPP2016-PIP08 from University of GranadaBFU2017-85723-P from Spanish Ministry of Economy and Competitiveness co-financed with FEDERG044212N from Flanders Research Foundatio

The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma

BACKGROUND: Paediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints. RESULTS: We report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG - CSGALNACT2:RET and the complex fusion DHX57:TMEM178:MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG. CONCLUSIONS: These data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.We are grateful for support from the Rosetrees Trust, the Brain Tumour Charity and Fundacao para a Ciencia e Tecnologia, Portugal (PhD Studentship SFRH/BD/33473/2008). DC, AM, LB and CJ acknowledge NHS funding to the Biomedical Research Centre

Kidins220/ARMS Is a Novel Modulator of Short-Term Synaptic Plasticity in Hippocampal GABAergic Neurons

Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin Repeat-rich Membrane Spanning) is a scaffold protein highly expressed in the nervous system. Previous work on neurons with altered Kidins220/ARMS expression suggested that this protein plays multiple roles in synaptic function. In this study, we analyzed the effects of Kidins220/ARMS ablation on basal synaptic transmission and on a variety of short-term plasticity paradigms in both excitatory and inhibitory synapses using a recently described Kidins220 full knockout mouse. Hippocampal neuronal cultures prepared from embryonic Kidins220−/− (KO) and wild type (WT) littermates were used for whole-cell patch-clamp recordings of spontaneous and evoked synaptic activity. Whereas glutamatergic AMPA receptor-mediated responses were not significantly affected in KO neurons, specific differences were detected in evoked GABAergic transmission. The recovery from synaptic depression of inhibitory post-synaptic currents in WT cells showed biphasic kinetics, both in response to paired-pulse and long-lasting train stimulation, while in KO cells the respective slow components were strongly reduced. We demonstrate that the slow recovery from synaptic depression in WT cells is caused by a transient reduction of the vesicle release probability, which is absent in KO neurons. These results suggest that Kidins220/ARMS is not essential for basal synaptic transmission and various forms of short-term plasticity, but instead plays a novel role in the mechanisms regulating the recovery of synaptic strength in GABAergic synapses

Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development

The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75NTR. Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis

Methodology: We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-Angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-Angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis