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

Survival of, and competition between, oligodendrocytes expressing different alleles of the Plp gene

Mutations in the X-linked Plp gene lead to dysmyelinating phenotypes and oligodendrocyte cell death. Here, we exploit the X inactivation phenomenon to show that a hierarchy exists in the influence of different mutant Plp alleles on oligodendrocyte survival. We used compound heterozygote mice to study the long-term fate of oligodendrocytes expressing either the jimpy or rumpshaker allele against a background of cells expressing a Plp-null allele. Although mutant and null oligodendrocytes were generated in equal numbers, the proportion expressing the mutant allele subsequently declined, but whereas those expressing the rumpshaker allele formed a reduced but stable population, the number of jimpy cells fell progressively. The age of decline in the jimpy cells in different regions of the CNS correlated with the temporal sequence of myelination. In compound heterozygotes expressing rumpshaker and jimpy alleles, oligodendrocytes expressing the former predominated and were more abundant than when the rumpshaker and null alleles were in competition. Thus, oligodendrocyte survival is not determined solely by cell intrinsic factors, such as the conformation of the misfolded PLP, but is influenced by neighboring cells, possibly competing for cell survival factors

Vastus lateralis/vastus medialis cross-sectional area ratio impacts presence and degree of knee joint abnormalities and cartilage T2 determined with 3T MRI – an analysis from the incidence cohort of the Osteoarthritis Initiative

SummaryObjectiveTo study the role of vastus lateralis/vastus medialis cross-sectional area CSA ratio (VL/VM CSA ratio) in preclinical knee osteoarthritis (OA) using magnetic resonance imaging (MRI)-based cartilage T2 mapping technique and morphological analysis at 3.0T in non-symptomatic, middle-aged subjects.Material and methods174 non-symptomatic individuals aged 45–55 years with OA risk factors were selected from the Osteoarthritis Initiative (OAI) incidence cohort. OA-related knee abnormalities were analyzed using the whole-organ magnetic resonance imaging score (WORMS). Knee cartilage T2 maps were generated using sagittal 2D multi-echo spin-echo images of the right knee. CSA of thigh muscles was measured using axial T1W images of the right mid thigh. Spline-based segmentation of cartilage and muscles was performed on a SUN/SPARC workstation. Muscle measurements were normalized to body size using body surface area (BSA). Statistical significance was determined using Student’s t-test, Pearson correlation test, and multiple regression models. To correct for multiple testing, Bonferroni adjustments were applied across all tests within each of the primary results tables (Tables III–VII).ResultsHigher T2 values were associated with increased prevalence and severity of cartilage degeneration. In our study, male and female subjects with higher VL/VM CSA ratio demonstrated significantly lower mean cartilage T2 values (all compartments combined) (mean 44.10 vs 45.17, P=0.0017), and significantly lower WORMS scores (mean 14.12 vs 18.68, P=0.0316). Regression analyses of combined mean cartilage T2 using VL/VM CSA ratio as a continuous predictor showed a significant curvilinear relationship between these two variables (P=0.0082).ConclusionOur results suggested that higher VL/VM CSA ratio is associated with lower T2 values and decreased presence and severity of OA-related morphological changes. Additional studies will be needed to determine causality

Localized spin ordering in Kondo lattice models

Using a non-Abelian density matrix renormalization group method we determine the phase diagram of the Kondo lattice model in one dimension, by directly measuring the magnetization of the ground-state. This allowed us to discover a second ferromagnetic phase missed in previous approaches. The phase transitions are found to be continuous. The spin-spin correlation function is studied in detail, and we determine in which regions the large and small Fermi surfaces dominate. The importance of double-exchange ordering and its competition with Kondo singlet formation is emphasized in understanding the complexity of the model.Comment: Revtex, 4 pages, 4 eps figures embedde

Prevalence of HIV and disease outcomes on the medical and surgical wards at Kamuzu Central Hospital, Lilongwe, Malawi

Introduction: The World Health Organization (WHO) recommends HIV Counseling and Testing (HCT) in a range of clinical settings. We describe the characteristics of patients diagnosed with HIV on the medical and surgical wards at a tertiary care hospital in Malawi. Methods: Under the universal opt-out HCT protocol we characterized the number of new HIV/AIDS infections and associated clinical features among hospitalized surgical and medical patients diagnosed during the course of admission. Results: All 2985 and 3959 medical and surgical patients, respectively, admitted between April 2012 and January 2013 were screened for HCT. 62% and 89% of medical and surgical patients, respectively, had an unknown status on admission and qualified for testing. Of the patients with an unknown status, a new HIV diagnosis was made in 20% and 7% of medical and surgical patients, respectively. Of the newly diagnosed patients with a CD4 count recorded, 91% and 67% of medical and surgical patients, respectively, had a count less than 350, qualifying for ART by Malawi ART guidelines. Newly HIV-diagnosed medical and surgical patients had an inpatient mortality of 20% and 2%, respectively. Discussion: While newly diagnosed HIV-positive medical patients had high inpatient mortality and higher rates of WHO stage 3 or 4 conditions, surgical patients presented with less advanced HIV, though still meeting ART initiation guidelines. The medical inpatient wards are an obvious choice for implementing voluntary counseling and testing (VCT), but surgical patients present with less advanced disease and starting treatment in this group could result in more years of life gained