Betaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular ...risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk?
Plasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days).
High and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1-7.1) for death, 4.0 (1.6-9.8) for myocardial infarction, 4.6 (2.0-10.7) for heart failure, 9.1 (2.8-29.7) for unstable angina and 2.0 (1.1-3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6-4.8) and heart failure, HR 1.9 (1.1-3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine.
Elevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.
Chemical analyses of three Martian soil samples were performed using the Wet Chemistry Laboratories on the 2007 Phoenix Mars Scout Lander. One soil sample was obtained from the top ∼2 cm (Rosy Red) ...and two were obtained at ∼5 cm depth from the ice table interface (Sorceress 1 and Sorceress 2). When mixed with water in a ∼1:25 soil to solution ratio (by volume), a portion of the soil components solvated. Ion concentrations were measured using an array of ion selective electrodes and solution conductivity using a conductivity cell. The measured concentrations represent the minimum leachable ions in the soil and do not take into account species remaining in the soil. Described is the data processing and analysis for determining concentrations of seven ionic species directly measured in the soil/solution mixture. There were no significant differences in concentrations, pH, or conductivity, between the three samples. Using laboratory experiments, refinement of the surface calibrations, and modeling, we have determined a pH for the soil solution of 7.7(±0.3), under prevalent conditions, carbonate buffering, and PCO2 in the cell headspace. Perchlorate was the dominant anion in solution with a concentration for Rosy Red of 2.7(±1) mM. Equilibrium modeling indicates that measured Ca2+ at 0.56(±0.5) mM and Mg2+ at 2.9(±1.5) mM, are consistent with carbonate equilibrium for a saturated solution. The Na+ and K+ were 1.4(±0.6), and 0.36(±0.3) mM, respectively. Results indicate that the leached portion of soils at the Phoenix landing site are slightly alkaline and dominated by carbonate and perchlorate. However, it should be noted that there is a 5–15 mM discrepancy between measured ions and conductivity and another species may be present.
Pathogenesis of human B cell lymphomas Shaffer, 3rd, Arthur L; Young, Ryan M; Staudt, Louis M
Annual review of immunology,
01/2012, Letnik:
30
Journal Article
Recenzirano
Odprti dostop
The mechanisms that drive normal B cell differentiation and activation are frequently subverted by B cell lymphomas for their unlimited growth and survival. B cells are particularly prone to ...malignant transformation because the machinery used for antibody diversification can cause chromosomal translocations and oncogenic mutations. The advent of functional and structural genomics has greatly accelerated our understanding of oncogenic mechanisms in lymphomagenesis. The signaling pathways that normal B cells utilize to sense antigens are frequently derailed in B cell malignancies, leading to constitutive activation of prosurvival pathways. These malignancies co-opt transcriptional regulatory systems that characterize their normal B cell counterparts and frequently alter epigenetic regulators of chromatin structure and gene expression. These mechanistic insights are ushering in an era of targeted therapies for these cancers based on the principles of pathogenesis.
The Wet Chemistry Laboratory on the Phoenix Mars Lander performed aqueous chemical analyses of martian soil from the polygon-patterned northern plains of the Vastitas Borealis. The solutions ...contained approximately 10 mM of dissolved salts with 0.4 to 0.6% perchlorate (ClO₄) by mass leached from each sample. The remaining anions included small concentrations of chloride, bicarbonate, and possibly sulfate. Cations were dominated by Mg²⁺ and Na⁺, with small contributions from K⁺ and Ca²⁺. A moderately alkaline pH of 7.7 ± 0.5 was measured, consistent with a carbonate-buffered solution. Samples analyzed from the surface and the excavated boundary of the approximately 5-centimeter-deep ice table showed no significant difference in soluble chemistry.
Considerable evidence suggests that the time of day at which calories are consumed markedly impacts body weight gain and adiposity. However, a precise quantification of energy balance parameters ...during controlled animal studies enforcing time-of-day-restricted feeding is currently lacking in the absence of direct human interaction.
The purpose of the present study was therefore to quantify the effects of restricted feeding during the light (sleep)-phase in a fully-automated, computer-controlled comprehensive laboratory animal monitoring system (CLAMS) designed to modulate food access in a time-of-day-dependent manner. Energy balance, gene expression (within metabolically relevant tissues), humoral factors and body weight were assessed.
We report that relative to mice fed only during the dark (active)-phase, light (sleep)-phase fed mice: (1) consume a large meal upon initiation of food availability; (2) consume greater total calories per day; (3) exhibit a higher respiratory exchange ratio (indicative of decreased reliance on lipid/fatty acid oxidation); (4) exhibit tissue-specific alterations in the phases and amplitudes of circadian clock and metabolic genes in metabolically active tissues (greatest phase differences observed in the liver and diminution of amplitudes in epididymal fat, gastrocnemius muscle and heart); (5) exhibit diminished amplitude in humoral factor diurnal variations (for example, corticosterone); and (6) exhibit greater weight gain within 9 days of restricted feeding.
Collectively, these data suggest that weight gain following light (sleep)-phase restricted feeding is associated with significant alterations in energy balance, as well as dyssynchrony between metabolically active organs.
Nuclear membrane rupture during interphase occurs in a variety of cell contexts, both healthy and pathological. Membrane ruptures can be rapidly repaired, but these mechanisms are still unclear. Here ...we show BAF, a nuclear envelope protein that shapes chromatin and recruits membrane proteins in mitosis, also facilitates nuclear membrane repair in interphase, in part through recruitment of the nuclear membrane proteins emerin and LEMD2 to rupture sites. Characterization of GFP-BAF accumulation at nuclear membrane rupture sites confirmed BAF is a fast, accurate, and persistent mark of nucleus rupture whose kinetics are partially dictated by membrane resealing. BAF depletion significantly delayed nuclear membrane repair, with a larger effect on longer ruptures. This phenotype could be rescued by GFP-BAF, but not by a BAF mutant lacking the LEM-protein binding domain. Depletion of the BAF interactors LEMD2 or emerin, and to a lesser extent lamin A/C, increased the duration of nucleus ruptures, consistent with LEM-protein binding being a key function of BAF during membrane repair. Overall our results suggest a model where BAF is critical for timely repair of large ruptures in the nuclear membrane, potentially by facilitating membrane attachment to the rupture site. Media: see text.
Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated ...B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.
► Lenalidomide kills ABC DLBCLs by decreasing expression of IRF4 and SPIB ► IRF4 and SPIB maintain ABC DLBCL viability ► IRF4 and SPIB block toxic IFNβ production while enhancing prosurvival NF-κB activity ► Lenalidomide and BCR pathway drugs synergize to inhibit IRF4 and kill ABC DLBCLs
Behavioural interventions incorporating features that are culturally salient to African American women have emerged as one approach to address the high rates of obesity in this group. Yet, the ...systematic evaluation of this research is lacking. This review identified culturally adapted strategies reported in behavioural interventions using a prescribed framework and examined the effectiveness of these interventions for diet and weight outcomes among African American women. Publications from 1 January 1990 through 31 December 2012 were retrieved from four databases, yielding 28 interventions. Seventeen of 28 studies reported significant improvements in diet and/or weight change outcomes in treatment over comparison groups. The most commonly identified strategies reported were ‘sociocultural’ (reflecting a group's values and beliefs) and ‘constituent involving’ (drawing from a group's experiences). Studies with significant findings commonly reported constituent‐involving strategies during the formative phases of the intervention. Involving constituents early on may uncover key attributes of a target group and contribute to a greater understanding of the heterogeneity that exists even within racial/ethnic groups. Available evidence does not, however, explain how culturally adapted strategies specifically influence outcomes. Greater attention to defining and measuring cultural variables and linking them to outcomes or related mediators are important next steps.
The importance of understanding the genetic and biochemical basis of B-cell receptor (BCR) survival signaling in diffuse large B-cell lymphoma (DLBCL) is underscored by the recent clinical success of ...agents that target the BCR pathway. DLBCL is composed of multiple distinct molecular subtypes with divergent clinical outcomes. The activated B-cell-like (ABC) subtype is the most aggressive form of DLBCL and is often resistant to standard chemotherapies. ABC DLBCL expresses numerous genes found in antigen-activated B cells, and genetic and pharmacologic studies have demonstrated that ABC DLBCL tumors are addicted to NF-κB activity. The origins of this NF-κB activity remained obscure until RNA interference screens established that the majority of ABC DLBCL cell lines rely on expression of BCR components and downstream signaling effectors for NF-κB activation. Pharmacological inhibition with ibrutinib of Bruton's tyrosine kinase, a kinase that is required for BCR signaling to engage NF-κB, is selectively toxic for ABC DLBCL tumors; a finding that has now been translated to the clinic. These novel targets not only offer a promising new therapy option for ABC DLBCL, but also demonstrate the value of a deep molecular understanding of oncogenic signaling pathways.
We study the volume-limited and nearly mass-selected (stellar mass M
stars 6 × 109 M) ATLAS3D sample of 260 early-type galaxies (ETGs, ellipticals Es and lenticulars S0s). We construct detailed ...axisymmetric dynamical models (Jeans Anisotropic MGE), which allow for orbital anisotropy, include a dark matter halo and reproduce in detail both the galaxy images and the high-quality integral-field stellar kinematics out to about 1R
e, the projected half-light radius. We derive accurate total mass-to-light ratios (M/L)
e
and dark matter fractions f
DM, within a sphere of radius
centred on the galaxies. We also measure the stellar (M/L)stars and derive a median dark matter fraction f
DM = 13 per cent in our sample. We infer masses M
JAM ≡ L × (M/L)
e
2 × M
1/2, where M
1/2 is the total mass within a sphere enclosing half of the galaxy light. We find that the thin two-dimensional subset spanned by galaxies in the
coordinates system, which we call the Mass Plane (MP) has an observed rms scatter of 19 per cent, which implies an intrinsic one of 11 per cent. Here,
is the major axis of an isophote enclosing half of the observed galaxy light, while σ
e
is measured within that isophote. The MP satisfies the scalar virial relation
within our tight errors. This show that the larger scatter in the Fundamental Plane (FP) (L, σ
e
, R
e) is due to stellar population effects including trends in the stellar initial mass function (IMF). It confirms that the FP deviation from the virial exponents is due to a genuine (M/L)
e
variation. However, the details of how both R
e and σ
e
are determined are critical in defining the precise deviation from the virial exponents. The main uncertainty in masses or M/L estimates using the scalar virial relation is in the measurement of R
e. This problem is already relevant for nearby galaxies and may cause significant biases in virial mass and size determinations at high redshift. Dynamical models can eliminate these problems. We revisit the (M/L)
e
-σ
e
relation, which describes most of the deviations between the MP and the FP. The best-fitting relation is
(r band). It provides an upper limit to any systematic increase of the IMF mass normalization with σ
e
. The correlation is more shallow and has smaller scatter for slow rotating systems or for galaxies in Virgo. For the latter, when using the best distance estimates, we observe a scatter in (M/L)
e
of 11 per cent, and infer an intrinsic one of 8 per cent. We perform an accurate empirical study of the link between σ
e
and the galaxies circular velocity V
circ within 1R
e (where stars dominate) and find the relation max (V
circ) 1.76 × σ
e
, which has an observed scatter of 7 per cent. The accurate parameters described in this paper are used in the companion Paper XX (Cappellari et al.) of this series to explore the variation of global galaxy properties, including the IMF, on the projections of the MP.
PDF
