Curve counting via stable pairs in the derived category

For a nonsingular projective 3-fold $X$, we define integer invariants virtually enumerating pairs $(C,D)$ where $C\subset X$ is an embedded curve and $D\subset C$ is a divisor. A virtual class is constructed on the associated moduli space by viewing a pair as an object in the derived category of $X$. The resulting invariants are conjecturally equivalent, after universal transformations, to both the Gromov-Witten and DT theories of $X$. For Calabi-Yau 3-folds, the latter equivalence should be viewed as a wall-crossing formula in the derived category. Several calculations of the new invariants are carried out. In the Fano case, the local contributions of nonsingular embedded curves are found. In the local toric Calabi-Yau case, a completely new form of the topological vertex is described. The virtual enumeration of pairs is closely related to the geometry underlying the BPS state counts of Gopakumar and Vafa. We prove that our integrality predictions for Gromov-Witten invariants agree with the BPS integrality. Conversely, the BPS geometry imposes strong conditions on the enumeration of pairs.Comment: Corrected typos and duality error in Proposition 4.6. 47 page

Wall-Crossing from Boltzmann Black Hole Halos

A key question in the study of N=2 supersymmetric string or field theories is to understand the decay of BPS bound states across walls of marginal stability in the space of parameters or vacua. By representing the potentially unstable bound states as multi-centered black hole solutions in N=2 supergravity, we provide two fully general and explicit formulae for the change in the (refined) index across the wall. The first, "Higgs branch" formula relies on Reineke's results for invariants of quivers without oriented loops, specialized to the Abelian case. The second, "Coulomb branch" formula results from evaluating the symplectic volume of the classical phase space of multi-centered solutions by localization. We provide extensive evidence that these new formulae agree with each other and with the mathematical results of Kontsevich and Soibelman (KS) and Joyce and Song (JS). The main physical insight behind our results is that the Bose-Fermi statistics of individual black holes participating in the bound state can be traded for Maxwell-Boltzmann statistics, provided the (integer) index \Omega(\gamma) of the internal degrees of freedom carried by each black hole is replaced by an effective (rational) index \bar\Omega(\gamma)= \sum_{m|\gamma} \Omega(\gamma/m)/m^2. A similar map also exists for the refined index. This observation provides a physical rationale for the appearance of the rational Donaldson-Thomas invariant \bar\Omega(\gamma) in the works of KS and JS. The simplicity of the wall crossing formula for rational invariants allows us to generalize the "semi-primitive wall-crossing formula" to arbitrary decays of the type \gamma\to M\gamma_1+N\gamma_2 with M=2,3.Comment: 71 pages, 1 figure; v3: changed normalisation of symplectic form 3.22, corrected 3.35, other cosmetic change

Baryogenesis and the New Cosmology

In this talk I begin with a brief review of the status of approaches to understanding the origin of the baryon asymmetry of the universe (BAU). I then describe a recent model unifying three seemingly-distict problems facing particle cosmology: the origin of inflation, the generation of the BAU and the nature of dark energy.Comment: 16 pages, RevTeX, Plenary talk presented at PASCOS-03, Mumbai, India; COSMO-02, Chicago, and at the Aspen Winter 2003 Conference on Particle Physics: At the Frontiers of Particle Physics, Aspen Center for Physics. To appear in the proceedings of PASCOS-0

Budding yeast ATM/ATR control meiotic double-strand break (DSB) levels by down-regulating Rec114, an essential component of the DSB-machinery

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or "DSB homeostasis", might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks

Evaluation of SMN Protein, Transcript, and Copy Number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

BACKGROUND: The universal presence of a gene (SMN2) nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA) has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early "biomarker" of treatment effect. METHODS: A cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS). Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age. RESULTS: SMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other. CONCLUSION: This is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an "early look" for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number. TRIAL REGISTRY: Clinicaltrials.gov NCT00756821

Cultivation of Human Corneal Endothelial Cells Isolated from Paired Donor Corneas

Consistent expansion of human corneal endothelial cells (hCECs) is critical in the development of tissue engineered endothelial constructs. However, a wide range of complex culture media, developed from different basal media have been reported in the propagation of hCECs, some with more success than others. These results are further confounded by donor-to-donor variability. The aim of this study is to evaluate four culture media in the isolation and propagation of hCECs isolated from a series of paired donor corneas in order to negate donor variability

Recent Advances in Modeling Stellar Interiors

Advances in stellar interior modeling are being driven by new data from large-scale surveys and high-precision photometric and spectroscopic observations. Here we focus on single stars in normal evolutionary phases; we will not discuss the many advances in modeling star formation, interacting binaries, supernovae, or neutron stars. We review briefly: 1) updates to input physics of stellar models; 2) progress in two and three-dimensional evolution and hydrodynamic models; 3) insights from oscillation data used to infer stellar interior structure and validate model predictions (asteroseismology). We close by highlighting a few outstanding problems, e.g., the driving mechanisms for hybrid gamma Dor/delta Sct star pulsations, the cause of giant eruptions seen in luminous blue variables such as eta Car and P Cyg, and the solar abundance problem.Comment: Proceedings for invited talk at conference High Energy Density Laboratory Astrophysics 2010, Caltech, March 2010, submitted for special issue of Astrophysics and Space Science; 7 pages; 5 figure

Effect of Interfacial Bonds on the Morphology of InAs QDs Grown on GaAs (311) B and (100) Substrates

The morphology and transition thickness (tc) for InAs quantum dots (QDs) grown on GaAs (311) B and (100) substrates were investigated. The morphology varies with the composition of buffer layer and substrate orientation. Andtcdecreased when the thin InGaAs was used as a buffer layer instead of the GaAs layer on (311) B substrates. For InAs/(In)GaAs QDs grown on high miller index surfaces, both the morphology andtccan be influenced by the interfacial bonds configuration. This indicates that buffer layer design with appropriate interfacial bonds provides an approach to adjust the morphologies of QDs grown on high miller surfaces

The Influence of Repair Pathways on the Cytotoxicity and Mutagenicity Induced by the Pyridyloxobutylation Pathway of Tobacco-Specific Nitrosamines

Tobacco-specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN), are considered to be human carcinogens. Both compounds are metabolized to pyridyloxobutylating intermediates that react with DNA to form adducts such as 7-[4-(3-pyridyl)-4-oxobut-1-yl]-guanine (7-pobG), O2-[4-(3-pyridyl)-4-oxobut-1-yl]-cytosine (O2-pobC), O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxythymidine (O2-pobdT), O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine (O6-pobdG) and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts. The role of specific DNA adducts in the overall genotoxic activity of the pyridyloxobutylation pathway is not known. One adduct, O6-pobdG, is mutagenic. To characterize the mutagenic and cytotoxic properties of pyridyloxobutyl DNA adducts, the impact of DNA repair pathways on the cytotoxic and mutagenic properties of the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) was investigated in Chinese hamster ovary (CHO) cell lines proficient or deficient in O6-alkylguanine DNA alkyltransferase (AGT), deficient in both AGT and base excision repair (BER), or deficient in both AGT and nucleotide excision repair (NER). The repair of the four pyridyloxobutyl DNA adducts was determined in the same cell lines via sensitive LC-MS/MS methods. NNKOAc was more cytotoxic in the cell lines lacking AGT, BER and NER repair pathways. It also induced more mutations in the hprt gene in the BER and NER deficient cell lines. However, AGT expression did not influence NNKOAc’s mutagenicity despite efficient repair of O6-pobdG. Analysis of the hprt mutational spectra indicated that NNKOAc primarily caused point mutations at AT base pairs. GC to AT transition mutations were a minor contributor to the overall mutation spectrum, providing a rationale for the observation that AGT does not protect against the overall mutagenic properties of NNKOAc in this model system. The only adduct affected by the absence of effective NER was O2-pobdT. Slower repair of O2-pobdT in NER deficient cells was associated with increased AT to TA transversion mutations, supporting the hypothesis that these mutations are caused by O2-pobdT. Together, these data support a hypothesis that the pyridyloxobutylation pathway generates multiple mutagenic and toxic adducts

Implementing health research through academic and clinical partnerships : a realistic evaluation of the Collaborations for Leadership in Applied Health Research and Care (CLAHRC)

Background: The English National Health Service has made a major investment in nine partnerships between higher education institutions and local health services called Collaborations for Leadership in Applied Health Research and Care (CLAHRC). They have been funded to increase capacity and capability to produce and implement research through sustained interactions between academics and health services. CLAHRCs provide a natural ‘test bed’ for exploring questions about research implementation within a partnership model of delivery. This protocol describes an externally funded evaluation that focuses on implementation mechanisms and processes within three CLAHRCs. It seeks to uncover what works, for whom, how, and in what circumstances. Design and methods: This study is a longitudinal three-phase, multi-method realistic evaluation, which deliberately aims to explore the boundaries around knowledge use in context. The evaluation funder wishes to see it conducted for the process of learning, not for judging performance. The study is underpinned by a conceptual framework that combines the Promoting Action on Research Implementation in Health Services and Knowledge to Action frameworks to reflect the complexities of implementation. Three participating CLARHCS will provide indepth comparative case studies of research implementation using multiple data collection methods including interviews, observation, documents, and publicly available data to test and refine hypotheses over four rounds of data collection. We will test the wider applicability of emerging findings with a wider community using an interpretative forum. Discussion: The idea that collaboration between academics and services might lead to more applicable health research that is actually used in practice is theoretically and intuitively appealing; however the evidence for it is limited. Our evaluation is designed to capture the processes and impacts of collaborative approaches for implementing research, and therefore should contribute to the evidence base about an increasingly popular (e.g., Mode two, integrated knowledge transfer, interactive research), but poorly understood approach to knowledge translation. Additionally we hope to develop approaches for evaluating implementation processes and impacts particularly with respect to integrated stakeholder involvement