Adaptive changes in the neuronal proteome: mitochondrial energy production, endoplasmic reticulum stress, and ribosomal dysfunction in the cellular response to metabolic stress

Impaired energy metabolism in neurons is integral to a range of neurodegenerative diseases, from Alzheimer’s disease to stroke. To investigate the complex molecular changes underpinning cellular adaptation to metabolic stress, we have defined the proteomic response of the SH-SY5Y human neuroblastoma cell line after exposure to a metabolic challenge of oxygen glucose deprivation (OGD) in vitro. A total of 958 proteins across multiple subcellular compartments were detected and quantified by label-free liquid chromatography mass spectrometry. The levels of 130 proteins were significantly increased (P<0.01) after OGD and the levels of 63 proteins were significantly decreased (P<0.01) while expression of the majority of proteins (765) was not altered. Network analysis identified novel protein–protein interactomes involved with mitochondrial energy production, protein folding, and protein degradation, indicative of coherent and integrated proteomic responses to the metabolic challenge. Approximately one third (61) of the differentially expressed proteins was associated with the endoplasmic reticulum and mitochondria. Electron microscopic analysis of these subcellular structures showed morphologic changes consistent with the identified proteomic alterations. Our investigation of the global cellular response to a metabolic challenge clearly shows the considerable adaptive capacity of the proteome to a slowly evolving metabolic challenge

MIPVU: A manual for identifying metaphor-related words

Language Use in Past and Presen

Lojasiewicz exponent of families of ideals, Rees mixed multiplicities and Newton filtrations

We give an expression for the {\L}ojasiewicz exponent of a wide class of n-tuples of ideals $(I_1,..., I_n)$ in \O_n using the information given by a fixed Newton filtration. In order to obtain this expression we consider a reformulation of {\L}ojasiewicz exponents in terms of Rees mixed multiplicities. As a consequence, we obtain a wide class of semi-weighted homogeneous functions $(\mathbb{C}^n,0)\to (\mathbb{C},0)$ for which the {\L}ojasiewicz of its gradient map $\nabla f$ attains the maximum possible value.Comment: 25 pages. Updated with minor change

Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use

Chronic lymphocytic leukaemia: the role of T cells in a B cell disease

Chronic lymphocytic leukaemia (CLL) has long been thought to be an immunosuppressive disease and abnormalities in T‐cell subset distribution and function have been observed in many studies. However, the role of T cells (if any) in disease progression remains unclear and has not been directly studied. This has changed with the advent of new therapies, such as chimeric antigen receptor‐T cells, which actively use retargeted patient‐derived T cells as “living drugs” for CLL. However complete responses are relatively low (~26%) and recent studies have suggested the differentiation status of patient T cells before therapy may influence efficacy. Non‐chemotherapeutic drugs, such as idelalisib and ibrutinib, also have an impact on T cell populations in CLL patients. This review will highlight what is known about T cells in CLL during disease progression and after treatment, and discuss the prospects of using T cells as predictive biomarkers for immune status and response to therapy

Constraints on the momentum dependence of rho-omega mixing

Within a broad class of models we show that the amplitude for rho^0-omega mixing must vanish at the transition from timelike to spacelike four momentum. Hence in such models the mixing is either zero everywhere or is necessarily momentum-dependent. This lends support to the conclusions of other studies of rho-omega mixing and calls into question standard assumptions about the role of rho-omega mixing in the theoretical understanding of charge-symmetry breaking in nuclear systems.Comment: 8 pages. Publication details added to title pag

Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis

SummaryIn this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy

Transverse spin effects in hadron-pair production from semi-inclusive deep inelastic scattering

First measurements of azimuthal asymmetries in hadron-pair production in deep-inelastic scattering of muons on transversely polarised ^6LiD (deuteron) and NH_3 (proton) targets are presented. The data were taken in the years 2002-2004 and 2007 with the COMPASS spectrometer using a muon beam of 160 GeV/c at the CERN SPS. The asymmetries provide access to the transversity distribution functions, without involving the Collins effect as in single hadron production. The sizeable asymmetries measured on the NH_ target indicate non-vanishing u-quark transversity and two-hadron interference fragmentation functions. The small asymmetries measured on the ^6LiD target can be interpreted as indication for a cancellation of u- and d-quark transversities.Comment: 13 pages, 4 figures, updated to the published versio

The Spin-dependent Structure Function of the Proton g_1^p and a Test of the Bjorken Sum Rule

The inclusive double-spin asymmetry, A_1^p, has been measured at COMPASS in deepinelastic polarised muon scattering off a large polarised NH3 target. The data, collected in the year 2007, cover the range Q2 > 1 (GeV/c)^2, 0.004 < x < 0.7 and improve the statistical precision of g_1^p(x) by a factor of two in the region x < 0.02. The new proton asymmetries are combined with those previously published for the deuteron to extract the non-singlet spin-dependent structure function g_1^NS(x,Q2). The isovector quark density, Delta_q_3(x,Q2), is evaluated from a NLO QCD fit of g_1^NS. The first moment of Delta_q3 is in good agreement with the value predicted by the Bjorken sum rule and corresponds to a ratio of the axial and vector coupling constants g_A/g_V = 1.28+-0.07(stat)+-0.10(syst).Comment: 12 pages, 5 figure