Unified Quantum Mechanical Picture for Confined Spinons in Dimerized and Frustrated Spin S=1/2 Chains

A quantum mechanical picture is presented to describe the behavior of confined spinons in a variety of S=1/2 chains. The confinement is due to dimerization and frustration and it manifests itselfas a nonlinear potential V(x)~ |x|^b, centered at chain ends (b <= 1) or produced by modulation kinks (b > 1). The calculation extends to weak or zero frustration some previous ideas valid for spinons in strongly frustrated spin chains. The local magnetization patterns of the confined spinons are calculated. A (minimum) enhancement of the local moments of about 11/3 over a single S=1/2 is found. Estimates for excitation energies and binding lengths are obtained.Comment: 11.5 pages, Revtex, 10 figures included, accepted by Euro. Phys. J. B final version including some changes, several references adde

Genome-wide analysis of C99-overexpressing human neuroblastoma cells : effects of C99 cleavage products on gene expression, signal transduction and phosphorylation status

The human genome comprises approximately 20,000-25,000 genes. The genes known to be involved in Alzheimer’s disease (AD) are the amyloid precursor protein (AbetaPP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (APOE). However, which additional genes are involved in its etiology is a controversial topic. C99, the C-terminal cleavage product of AbetaPP is the direct, in vivo occurring, precursor of Abeta-peptides. It is proteolytically processed, resulting in the generation of several Abeta-peptides. In contrast to the form with 40 amino acids (Abeta40), which is regarded as the physiological form, the variant with 42 amino acids (Abeta42) is thought to be the pathogenic form triggering the pathophysiological cascade in AD. In order to produce different Abeta42 and Abeta40 levels, the Abeta precursors C99I45F and C99V50F (two C99 mutants, known to generate different amounts of Abeta42 and Abeta40) were overexpressed in human neuroblastoma cells. This resulted, due to varying intracellular cleavage by gamma-secretase, in different Abeta42 and Abeta40 levels accompanied by the generation of their respective APP intracellular domains (AICDs). The goal of this thesis was to obtain information about effects of the different C99 cleavage products. Therefore different C99 mutants were overexpressed in the human neuroblastoma cell line SH-SY5Y resulting in different Abeta42/Abeta40 levels and a genome-wide transcriptomic (Affymetrix) and proteomic response of these cells was monitored. As was expected, many genes previously reported to be associated with AD were found to be differentially expressed. Importantly, further genes, not yet linked to AD, have been identified and new cross-talk between genes/proteins has been suggested. The genes assumed to play a predominant role in response to altered C99 cleavage products are indicated in brackets and full gene names are to be found in Chapter 10, Abbreviations. In this thesis, it was demonstrated that an increased Abeta42/Abeta40 ratio, but not a decreased Abeta42/Abeta40 ratio, induced upregulation of the retinoic acid binding protein CRABP1 on the transcript level and on the protein level. This, in turn, reduced the responsiveness of SH-SY5Y cells to retinoic acid, which reduced their differentiation potential. Knockdown of the increased CRABP1 levels by siRNA rescued the differentiation potential of these cells. These findings, in conjunction with known functional properties of CRABP1, suggest that up-regulated CRABP1 might, possibly also in vivo, prevent the terminal differentiation of neural precursor cells into functional neurons (disturbed neurogenesis). Furthermore, the phosphorylation status of proteins was determined providing further insights into signal transduction pathways. The IGF2/IGF1R/PKC together with the PI3K/AKT survival pathway was found to be inversely regulated by an altered Abeta42/Abeta40 ratio (IGF2, IGFBP5, PKC, AKT1). The chromosomal locus 11p15.5 was identified as a hot spot: an increased Abeta42/Abeta40 ratio, in contrast to a decreased one, down-regulated the IGF2-H19 imprinted region (chr.11p15.5) indicating that imprinting may play a role in AD. In consequence of an increased Abeta42/Abeta40 ratio, GSK3beta was hyperphosphorylated on the activating site Y216, and tau441 showed stronger phosphorylation on S199/S202, two sites reported to turn tau, upon phosphorylation, into a protein with possible toxic properties. APLP2 was found to be up-regulated as a consequence of an increased Abeta42/Abeta40 ratio, whereas APLP1 was up-regulated in response to a decreased Abeta42/Abeta40 ratio, indicating inverse Abeta-dependent regulation of APLP1/2 expression. In response to an increased Abeta42/Abeta40 ratio, expression levels of a set of genes were altered in such a way that a tendency towards faster blood coagulation and reduced fibrinolysis could be recognized on the transcript level (PLAT, TFPI2, FGB, SERPINF1, SERPINE2). This view is supported by observations in AD patients who have a greater risk of strokes and diminished cerebral perfusion. As Abeta-inducible candidate kinases possibly involved in tau-phosphorylation, DYRK1, CDKL1, CDKL5, CDK6, DCAMKL1, ERK1 and PFKP were identified due to their altered expression levels (or phosphorylation status for ERK1). Indeed, previous studies demonstrated that Abeta42 induces tau hyperphosphorylation in animal models. PFKP, which plays a key role in glycolysis, was found to be dysregulated in consequence of a changed Abeta42/Abeta40 ratio and could possibly reflect disturbed regulation of glucose and ATP metabolism in brains of AD patients. A potential function was assigned to the hitherto uncharacterized KIAA0125, namely to be a counter player of neurogenin 2, which was co-regulated with C99 and neuronatin. Furthermore, the following areas were distinctly affected by a changed Abeta42/Abeta40 ratio (for most genes determined on the transcript level and for some additionally on the protein level): Copper transport/metabolism with special regard to ATP7A, several (metallo) proteases (ADAMTS9, ADAMTS3, MMP8, PREP, ECEL1, CTSD, PRSS12), metalloprotease inhibitors (TIMP3, TIMP1), extracellular matrix proteins or related enzymes thereof (RELN, COL4A1, COL4A2, HS3ST2), cytoskeletal proteins (ACTA2, ACTN1), mitochondrial respiratory chain components (NDUFB9), cytochromes (b-561 and b-245), dopamine, serotonin and glutamate -metabolism with special regard to DDC, HMP19 and GAD1. Effects of BDNF (non-catalytic isoform of TRKB), membrane fusion of neurotransmitter containing vesicles (STX3A, SYN2), Ca2+ influx (AMPA2), acetylcholine receptors (CHRNA7), Notch signaling (DNER, TLE1, TLE2, JAG1, CUTL2), TGFbeta signaling (TGFB2, TGFBR2, BAMBI, BMP7), WNT signaling (DKK2, DKK4), G protein signaling (RGS4) and ERK/MEK signaling (ERK1, MEK1). Growth cone guidance, synaptogenesis and dendritic branching are expected to be impaired as consequence of an increased Abeta42/Abeta40 ratio but improved as a result of a decreased one (SEMA3A, SEMA3C, L1CAM, PTN, SLIT1). Further genes involved in the following areas were distinctly influenced by a changed Abeta42/Abeta40 ratio: Glutamate/ammonia metabolism (GLUL, GLS), urea cycle (ASS), cell cycle regulation (CCND1, CDKN1A), glucocorticoid regulated kinase (SGK), receptors (PTGER2, EGFR, AMPA2, AMPA3, GRM7, GRM8c, GLRB, GABRB3), long term potentiation (CREB1), axonal transport (DNCLI2), angiogenesis (HGF, VEGF), T-cell receptors and connected transcription factors (T-cell receptor alpha and delta locus, GATA3), lipoprotein associated proteins or adaptor proteins hereof (LRP4, PDZK1), vesicular transport of organelles and microtubule association (VMP), transcription factors (PBX1, SHOX2) and stress-related factors (ADRB1). Taken together, the identified genes, proteins and pathways have given new and deeper insight into the effects of different C99 cleavage products and they have provided new hypotheses for the pathological mechanisms of AD. Furthermore they are possible candidates for genetic risk factors and may be helpful in explaining the mechanisms of non-genetic risk factors. The gene expression pattern, specific for an increased Abeta42/Abeta40 ratio, could be useful, together with clinical data, for the diagnosis of AD. Finally, some of the identified transcripts, proteins and pathways might turn out to be suitable drug targets

Genetic deletion of neuronal PPARγ enhances the emotional response to acute stress and exacerbates anxiety: An effect reversed by rescue of amygdala PPARγ function

PPARγ is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPARγ is activated by thiazolidinediones such as pioglitazone, and it is targeted to treat insulin resistance. PPARγ is densely expressed in brain areas involved in regulation of motivational and emotional processes.Here, we investigated the role of PPARγ in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPARγ by pioglitazone did not affect basal anxiety but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPARγ (PPARγ(NestinCre)), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPARγ antagonist, elicited a marked anxiogenic response in PPARγ wild-type (Wt) but not in PPARγ(NestinCre) KO mice. Using c-Fos immunohistochemistry we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala and the hippocampus of PPARγ(NestinCre) KO mice compared with Wt mice. No differences were found between Wt and KO mice in hypothalamic regions responsible for hormonal response to stress, nor in blood corticosterone levels. Microinjection of pioglitazone, into the amygdala but not into the hippocampus abolished the anxiogenic response elicited by acute stress. Results also showed that in both regions PPARγ co-localizes with GABAergic cells. These findings demonstrate that neuronal PPARγ is involved the regulation of the stress response, and that the amygdala is a key substrate for the anxiolytic effect of PPARγ

The microscopic spin-phonon coupling constants in CuGeO_3

Using RPA results, mean field theory, and refined data for the polarization vectors we determine the coupling constants of the four Peierls-active phonon modes to the spin chains of CuGeO_3. We then derive the values of the coupling of the spin system to the linear ionic displacements, the bond lengths and the angles between bonds. Our values are consistent with microscopic theories and various experimental results. We discuss the applicability of static approaches to the spin-phonon coupling. The c-axis anomaly of the thermal expansion is explained. We give the values of the coupling constants in an effective one-dimensional Hamiltonian.Comment: 11 pages, two figures, 13 tables, PRB 59 (in press

New Alzheimer Amyloid β Responsive Genes Identified in Human Neuroblastoma Cells by Hierarchical Clustering

Alzheimer's disease (AD) is characterized by neuronal degeneration and cell loss. Aβ42, in contrast to Aβ40, is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Aβ40 and Aβ42 levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids) in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Aβ40 and Aβ42 levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2) and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Aβ42/Aβ40 ratio. Importantly however, an increased Aβ42/Aβ40 ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Aβ42/Aβ40 ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Aβ42/Aβ40 ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes

Upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Aβ42 reduces their differentiation potential

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several β-amyloid peptides (Aβ) are generated. In contrast to the form with 40 amino acids (Aβ₄₀), the variant with 42 amino acids (Aβ₄₂) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Aβ effects have been studied extensively, little is known about specific genome-wide effects triggered by Aβ₄₂or Aβ₄₀derived from their direct precursor C99.</p> <p>Methods</p> <p>A combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Aβ peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference.</p> <p>Results</p> <p>Here we studied the transcriptomic and proteomic responses to increased or decreased Aβ₄₂and Aβ₄₀levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Aβ₄₂- and Aβ₄₀-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Aβ₄₂/Aβ₄₀ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Aβ₄₂/Aβ₄₀ratio, whereas a decreased ratio did not result in up-regulation of CRABP1.</p> <p>Conclusion</p> <p>We conclude that increasing the Aβ₄₂/Aβ₄₀ratio up-regulates CRABP1, which in turn reduces the differentiation potential of the human neuroblastoma cell line SH-SY5Y, but increases cell proliferation. This work might contribute to the better understanding of AD neurogenesis, currently a controversial topic.</p

A time-resolved proteomic and prognostic map of COVID-19.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19