Particle Motion and Scalar Field Propagation in Myers-Perry Black Hole Spacetimes in All Dimensions

We study separability of the Hamilton-Jacobi and massive Klein-Gordon equations in the general Myers-Perry black hole background in all dimensions. Complete separation of both equations is carried out in cases when there are two sets of equal black hole rotation parameters, which significantly enlarges the rotational symmetry group. We explicitly construct a nontrivial irreducible Killing tensor associated with the enlarged symmetry group which permits separation. We also derive first-order equations of motion for particles in these backgrounds and examine some of their properties.Comment: 16 pages, LaTeX2

Stationary strings near a higher-dimensional rotating black hole

We study stationary string configurations in a space-time of a higher-dimensional rotating black hole. We demonstrate that the Nambu-Goto equations for a stationary string in the 5D Myers-Perry metric allow a separation of variables. We present these equations in the first-order form and study their properties. We prove that the only stationary string configuration which crosses the infinite red-shift surface and remains regular there is a principal Killing string. A worldsheet of such a string is generated by a principal null geodesic and a timelike at infinity Killing vector field. We obtain principal Killing string solutions in the Myers-Perry metrics with an arbitrary number of dimensions. It is shown that due to the interaction of a string with a rotating black hole there is an angular momentum transfer from the black hole to the string. We calculate the rate of this transfer in a spacetime with an arbitrary number of dimensions. This effect slows down the rotation of the black hole. We discuss possible final stationary configurations of a rotating black hole interacting with a string.Comment: 13 pages, contains additianal material at the end of Section 8, also small misprints are correcte

Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.This work was supported by grants from the UK Multiple Sclerosis Society, Wellcome-Trust, NINDS/NIH Intramural Research Program, Health Research Board Scholars Program, Gates-Cambridge Scholarship, and Spanish Ministry of Economy and Competitiveness (SAF2012- 31483).S

Does ECG Predict Cardiac Hypertrophy in American-Style Football Athletes?

The accurate and cost effective identification of left ventricular (LV) hypertrophy is clinically relevant due to its association with cardiac mortality in the general population. PURPOSE: To determine if electrocardiographic (ECG) voltage criteria predicts LV mass measured with cardiac ultrasound in collegiate American-style football (ASF) players. METHODS: Over a 3-year period, standard resting, supine 12-lead ECG and echocardiographic (ECHO) procedures were performed on 76 collegiate ASF players first entering an NCAA Football Bowl Subdivision university as part of their preparticipation physical exams. Player demographics were: age=18±1 yr., height=186±7 cm, weight=100.1±22.0 kg, BMI=28.6±5.0 kg·m2, and BSA=2.24±0.25 m2. Linear regression was used to predict ECHO-derived LV mass and LV mass/BSA index from ECG precordial-lead voltage criteria [sum largest S (V1 or V2) + R (V5 or V6) ≥ 35 mm]. RESULTS: ECG voltage criteria did not significantly (p \u3e 0.05) predict ECHO LV mass (LV mass = -0.12x + 216.94, r = 0.024, R² = 0.0006), or LV mass/BSA index (LV mass/BSA = 0.3063x + 81.951, r = 0.17, R² = 0.0244). CONCLUSION: ECG precordial lead voltage was not clinically useful in diagnosing ECHO-derived LV hypertrophy in our sample of first-year collegiate ASF players. We suggest that new and more accurate algorithms for evaluating LV hypertrophy in ASF athletes be explored, possibly using demographic, body habitus, cardiovascular, and other ECG criteria

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene. Keyword: PIK3CA; 2OG; OGDH; TCA cycle; glycolysisDamon Runyon Cancer Research Foundation (HHMI Fellowship

Retinoid X Receptor activation reverses age-related deficiencies in myelin debris phagocytosis and CNS remyelination

Remyelination is a regenerative process that occurs through the formation of myelin sheaths by oligodendrocytes, which are recruited as oligodendrocyte progenitor cells (OPCs) after demyelination in diseases such as Multiple Sclerosis (MS).A key environmental factor regulating OPC differentiation is the fate of myelin debris generated during demyelination. Myelin debris contains inhibitors of OPC differentiation and thus its clearance by phagocytic macrophages is an important component of creating a lesion environment conducive to remyelination. The efficiency of debris clearance declines with age, contributing to the age-associated decline in remyelination. Therefore, understanding the mechanisms of the age-related decline in myelin debris phagocytosis is important for devising means to therapeutically reverse the decline in remyelination. The aim of this study was to determine the functional/molecular differences between young and old phagocytes involved in myelin debris clearance, thereby identifying therapeutically modifiable pathways associated with efficient myelin debris phagocytosis. In this study, we show that expression of genes involved in the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR) pathways are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages. Disruption of RXR and PPAR using synthetic antagonists in young macrophages mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα knockout mice revealed that loss of RXR function in young mice caused delayed myelin debris uptake and slowed remyelination. Alternatively, receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The FDA-approved agonists bexarotene and pioglitazone, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profiles in MS patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. Activation of these pathways also enhances immunoregulatory markers on monocytes from MS patients, further suggesting the regeneration-promoting capacity of activating these pathways in phagocytes. These results reveal the RXR/PPAR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.This work was supported by the Gates-Cambridge Scholarship and NIH-Cambridge Partnership Progra

Intranasal Delivery of E-Selectin Reduces Atherosclerosis in ApoE−/− Mice

Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or “tolerogenic” responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE−/− mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE−/− mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke

Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer

Tumor-associated dendritic cells are defective in their ability to cross-present antigens, and they accumulate lipid bodies. Here the authors show that this defect is due to an impaired trafficking of peptide-MHC class I caused by the interaction of electrophilic lipids with chaperone heat shock protein 70