Notch/Delta signaling constrains reengineering of pro-T cells by PU.1

PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through β-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo β-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment

Exceptional Collections and del Pezzo Gauge Theories

Stacks of D3-branes placed at the tip of a cone over a del Pezzo surface provide a way of geometrically engineering a small but rich class of gauge/gravity dualities. We develop tools for understanding the resulting quiver gauge theories using exceptional collections. We prove two important results for a general quiver gauge theory: 1) we show the ordering of the nodes can be determined up to cyclic permutation and 2) we derive a simple formula for the ranks of the gauge groups (at the conformal point) in terms of the numbers of bifundamentals. We also provide a detailed analysis of four node quivers, examining when precisely mutations of the exceptional collection are related to Seiberg duality.Comment: 26 pages, 1 figure; v2 footnote 2 amended; v3 ref adde

Supersymmetry Breaking from a Calabi-Yau Singularity

We conjecture a geometric criterion for determining whether supersymmetry is spontaneously broken in certain string backgrounds. These backgrounds contain wrapped branes at Calabi-Yau singularites with obstructions to deformation of the complex structure. We motivate our conjecture with a particular example: the $Y^{2,1}$ quiver gauge theory corresponding to a cone over the first del Pezzo surface, $dP_1$. This setup can be analyzed using ordinary supersymmetric field theory methods, where we find that gaugino condensation drives a deformation of the chiral ring which has no solutions. We expect this breaking to be a general feature of any theory of branes at a singularity with a smaller number of possible deformations than independent anomaly-free fractional branes.Comment: 32 pages, 6 figures, latex, v2: minor changes, refs adde

Subversion of T lineage commitment by PU.1 in a clonal cell line system

Specification of mammalian T lymphocytes involves prolonged developmental plasticity even after lineage-specific gene expression begins. Expression of transcription factor PU.1 may maintain some myeloid-like developmental alternatives until commitment. Commitment could reflect PU.1 shutoff, resistance to PU.1 effects, and/or imposition of a suicide penalty for diversion. Here, we describe subclones from the SCID.adh murine thymic lymphoma, adh.2C2 and adh.6D4, that represent a new tool for probing these mechanisms. PU.1 can induce many adh.2C2 cells to undergo diversion to a myeloid-like phenotype, in an all-or-none fashion with multiple, coordinate gene expression changes; adh.6D4 cells resist diversion, and most die. Diversion depends on the PU.1 Ets domain but not on known interactions in the PEST or Q-rich domains, although the Q-rich domain enhances diversion frequency. Protein kinase C/MAP kinase stimulation can make adh.6D4 cells permissive for diversion without protecting from suicide. These results show distinct roles for regulated cell death and another stimulation-sensitive function that establishes a threshold for diversion competence. PU.1 also diverts normal T-cell precursors from wild type or Bcl2-transgenic mice to a myeloid-like phenotype, upon transduction in short-term culture. The adh.2C2 and adh.6D4 clones thus provide an accessible system for defining mechanisms controlling developmental plasticity in early T-cell development

Brane Tilings and Exceptional Collections

Both brane tilings and exceptional collections are useful tools for describing the low energy gauge theory on a stack of D3-branes probing a Calabi-Yau singularity. We provide a dictionary that translates between these two heretofore unconnected languages. Given a brane tiling, we compute an exceptional collection of line bundles associated to the base of the non-compact Calabi-Yau threefold. Given an exceptional collection, we derive the periodic quiver of the gauge theory which is the graph theoretic dual of the brane tiling. Our results give new insight to the construction of quiver theories and their relation to geometry.Comment: 46 pages, 37 figures, JHEP3; v2: reference added, figure 13 correcte

Seiberg Duality is an Exceptional Mutation

The low energy gauge theory living on D-branes probing a del Pezzo singularity of a non-compact Calabi-Yau manifold is not unique. In fact there is a large equivalence class of such gauge theories related by Seiberg duality. As a step toward characterizing this class, we show that Seiberg duality can be defined consistently as an admissible mutation of a strongly exceptional collection of coherent sheaves.Comment: 32 pages, 4 figures; v2 refs added, "orbifold point" discussion refined; v3 version to appear in JHEP, discussion of torsion sheaves improve

T. brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat cardiomyocytes

Aims: African trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response. Methods and results: Using confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release (Ca2+ waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10–15% increase of SERCA activity but reduced SR Ca2+ content, suggesting a concomitant increased SR-mediated Ca2+ leak. This conclusion was supported by data demonstrating that TbCatL increased Ca2+ wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events. Conclusion: These data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function

Biological solutions to aortic root replacement: valve-sparing versus bioprosthetic conduit‡

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A Sedimentological Record of Early Miocene Ice Advance and Retreat, AND-2A drill hole, McMurdo Sound, Antarctica

The lowest 501 m (∼1139–638 m) of the AND-2A core from southern McMurdo Sound is the most detailed and complete record of early Miocene sediments in Antarctica and indicates substantial variability in Antarctic ice sheet activity during early Miocene time. There are two main pulses of diamictite accumulation recorded in the core, and three significant intervals with almost no coarse clasts. Each diamictite package comprises several sequences consistent with ice advance-retreat episodes. The oldest phase of diamictite deposition, Composite Sequence 1 (CS1), has evidence for grounded ice at the drill site and has been dated around 20.2–20.1 Ma. It likely coincides with cooling associated with isotope event Mi1aa. This is overlain by a diamictite-free, sandstone-dominated interval, CS2 that includes three coarsening-upward deltaic cycles, is inferred to mark substantial warming, and has an inferred age range between 20.1 and 20.05 Ma. Above this is an interval with variable amounts of diamictite (CS3), with indicators of ice grounding, that is inferred to record ice advance relative to CS2, and is overlain by an ∼100-m-thick mud-rich interval (CS4) with no sedimentological evidence for direct glacial influence at the drill site (ca. 19.4–18.7 Ma). A third overlying diamictite-rich interval (CS5) overlies an unconformity spanning 18.7–17.8 Ma (coinciding with isotope event Mi1b), and records a return to more ice-influenced conditions at the drill site in late early Miocene time. The overall picture for the early Miocene (spanning the period 20.2–17.35 Ma) is one of ice advance alternating with periods of ice retreat and hence significant global climate fluctuations after the permanent establishment of the Antarctic ice sheet at the Eocene/Oligocene boundary, and preceding the relative warmth of the middle Miocene climatic optimum (ca. 17.5–14.5 Ma). Sedimentary cyclicity in CS1 and CS2 is consistent with ∼21 k.y. precession but in CS3 the frequency is closer to 100 k.y. (consistent with eccentricity), with a possible change to 20 k.y. precession in CS4. CS5 cyclicity is consistent with obliquity forcing. Provenance data are consistent with local Transantarctic Mountains glacial activity under precessional control in CS1 and more southerly ice-cap build up under 100 k.y. eccentricity and obliquity control during CS3 and CS5, respectively

Healthy lifestyle and life expectancy with and without Alzheimer's dementia: population based cohort study.

OBJECTIVE To determine the impact of lifestyle factors on life expectancy lived with and without Alzheimer's dementia. DESIGN Prospective cohort study. SETTING The Chicago Health and Aging Project, a population based cohort study in the United States. PARTICIPANTS 2449 men and women aged 65 years and older. MAIN EXPOSURE A healthy lifestyle score was developed based on five modifiable lifestyle factors: a diet for brain health (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay-MIND diet score in upper 40% of cohort distribution), late life cognitive activities (composite score in upper 40%), moderate or vigorous physical activity (≥150 min/week), no smoking, and light to moderate alcohol consumption (women 1-15 g/day; men 1-30 g/day). MAIN OUTCOME Life expectancy with and without Alzheimer's dementia in women and men. RESULTS Women aged 65 with four or five healthy factors had a life expectancy of 24.2 years (95% confidence interval 22.8 to 25.5) and lived 3.1 years longer than women aged 65 with zero or one healthy factor (life expectancy 21.1 years, 19.5 to 22.4). Of the total life expectancy at age 65, women with four or five healthy factors spent 10.8% (2.6 years, 2.0 to 3.3) of their remaining years with Alzheimer's dementia, whereas women with zero or one healthy factor spent 19.3% (4.1 years, 3.2 to 5.1) with the disease. Life expectancy for women aged 65 without Alzheimer's dementia and four or five healthy factors was 21.5 years (20.0 to 22.7), and for those with zero or one healthy factor it was 17.0 years (15.5 to 18.3). Men aged 65 with four or five healthy factors had a total life expectancy of 23.1 years (21.4 to 25.6), which is 5.7 years longer than men aged 65 with zero or one healthy factor (life expectancy 17.4 years, 15.8 to 20.1). Of the total life expectancy at age 65, men with four or five healthy factors spent 6.1% (1.4 years, 0.3 to 2.0) of their remaining years with Alzheimer's dementia, and those with zero or one healthy factor spent 12.0% (2.1 years, 0.2 to 3.0) with the disease. Life expectancy for men aged 65 without Alzheimer's dementia and four or five healthy factors was 21.7 years (19.7 to 24.9), and for those with zero or one healthy factor life expectancy was 15.3 years (13.4 to 19.1). CONCLUSION A healthy lifestyle was associated with a longer life expectancy among men and women, and they lived a larger proportion of their remaining years without Alzheimer's dementia. The life expectancy estimates might help health professionals, policy makers, and stakeholders to plan future healthcare services, costs, and needs