On the Galois structure of Selmer groups

Let A be an abelian variety defined over a number field k and F a finite Galois extension of k. Let p be a prime number. Then under certain not-too-stringent conditions on A and F, we investigate the explicit Galois structure of the p-primary Selmer group of A over F. We also use the results so obtained to derive new bounds on the growth of the Selmer rank of A over extensions of k

On Mordell–Weil groups and congruences between derivatives of twisted Hasse–Weil L-functions

Let A be an abelian variety defined over a number field k and let F be a finite Galois extension of k. Let p be a prime number. Then under certain not-too-stringent conditions on A and F we compute explicitly the algebraic part of the p-component of the equivariant Tamagawa number of the pair (h1(A/F)(1),Z[Gal(F/k)]). By comparing the result of this computation with the theorem of Gross and Zagier we are able to give the first verification of the p-component of the equivariant Tamagawa number conjecture for an abelian variety in the technically most demanding case in which the relevant Mordell–Weil group has strictly positive rank and the relevant field extension is both non-abelian and of degree divisible by p. More generally, our approach leads us to the formulation of certain precise families of conjectural p-adic congruences between the values at s = 1 of derivatives of the Hasse–Weil L-functions associated to twists of A, normalised by a product of explicit equivariant regulators and periods, and to explicit predictions concerning the Galois structure of Tate–Shafarevich groups. In several interesting cases we provide theoretical and numerical evidence in support of these more general predictions

Characterization of VPS41 and Its Role in the Regulated Secretory Pathway

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific membrane proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine/neuronal granules. We now find that a stable pool of VPS41 exists outside of HOPS and is required for regulated insulin secretion. Loss of VPS41 leads to a reduction in insulin SG number and changes in their transmembrane protein composition, associated with defects in granule release properties. We further show that a human point mutation, identified in patients with neurological defects but no endocrine defects, enables isolation of the HOPS independent function of VPS41. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop a diabetic phenotype due to a defect in insulin secretion. Altogether our data suggest that VPS41 contributes significantly to glucose homeostasis

HID-1 controls formation of large dense core vesicles by influencing cargo sorting and trans-Golgi network acidification

Large dense core vesicles (LDCVs) mediate the regulated release of neuropeptides and peptide hormones. They form at the trans-Golgi network (TGN), where their soluble content aggregates to form a dense core, but the mechanisms controlling biogenesis are still not completely understood. Recent studies have implicated the peripheral membrane protein HID-1 in neuropeptide sorting and insulin secretion. Using CRISPR/Cas9, we generated HID-1 KO rat neuroendocrine cells, and we show that the absence of HID-1 results in specific defects in peptide hormone and monoamine storage and regulated secretion. Loss of HID-1 causes a reduction in the number of LDCVs and affects their morphology and biochemical properties, due to impaired cargo sorting and dense core formation. HID-1 KO cells also exhibit defects in TGN acidification together with mislocalization of the Golgi-enriched vacuolar H+-ATPase subunit isoform a2. We propose that HID-1 influences early steps in LDCV formation by controlling dense core formation at the TGN.</jats:p

Oncogenic Transformation by Herpes Simplex Virus

Many lines of evidence exist associating herpes simplex virus (HSV) with the development of carcinoma. Data from human studies includes seroepidemiologic studies of carcinoma patients and the localization of viral markers in human cancers. Experimental studies include in vitro transformation of cultured cells and viral induced alterations of host DNA. Much of this evidence is anecdotal or associative in nature and does not prove a cause and effect. The purpose of this research was to investigate the oncogenic potential of HSV type 2 (HSV-2) in vivo and in vitro. An in vivo mouse model for lib carcinogenesis was designed to combine HSV-2 infection, ultraviolet (UV) exposure and tetradecanyl-phorbolacetate (TPA) application. Preliminary studies showed that HSV-2 inoculation onto abraded mouse lips was capable of causing vesicular ulcerative lesions. These lesions healed completely after 10-14 days. Repeated herpetic lip infections failed to induce tumors. UV-irradiation delivered to the lesion site daily for 6 minutes at 42 ergs/mm2/s on days 3 through 6 postinfection caused hyperkeratosis, acanthosis and dysplasia to develop in several lips; while the same UV exposure delivered by itself failed to alter the histologic appearance. The addition of related TPA application to the HSV + UV regimen promoted tumor emergence. Thirty-two of 156 BALB/c mice developed tumors. Although the majority were papillomas, six were squamous cell carcinomas. These tumor bearing mice had increased HSV specific antibody titers. HSV antigens were shown to be present in outgrowths from explanted tumors as well as in tumor biopsies by immunoperoxidase staining with HSV specific antiseras. Another series of in vivo studies showed that HSV lip infection initiated prior to or during repeated chemical carcinogen (dimethylbenzanthracene/DMBA) application was capable of reducing the incidence of tumors as compared to DMBA application without superimposed HSV infection. Comparison of results from this system and those from the HSV + UV + TPA system emphasized the fact that the lytic capability of HSV must be inhibited for the virus to express its oncogenic potential. It was hypothesized that the in vivo UV-irradiated HSV acted as the inducer and TPA as the promoter, analogous to the classical two-state carcinogenesis model. Since neither the HSV infection by itself, the UV exposure by itself, the TPA application by itself nor any combination of two induced the development of squamous cell carcinomas, HSV was considered a carcinogen with UV-radiation. An analogous tripartite system was devised in vitro. Hamster embryo cells were infected with HSV-2 irradiated for 6, 7, or 8 minutes at 42 ergs/mm2/s. Twenty-one days postinoculation transformed foci had developed with frequencies (FFU/PFU) of 2.9 x 10 -7, and 3.9 x 10 -7, respectively. This represents 0.9, 3.0, and 1.3 FFU/10 6 cells. The 7 minute transformation frequencies were further increased to 1.7 x 10 -6 by the addition of TPA to the growth media (0.1 ug/ml) 48 hours postinoculation. This represents 5.1 FFU/10 6 cells. Thus, TPA was capable of tumor promotion in vivo and increasing transformation efficiency in vitro. Furthermore, TPA was shown by two dimensional gel electrophoresis to increase protein synthesis in transformed cells and by cell sorter analysis to increase cellular replicative activity. A transformed cell line, 3-26-7#1, derived from a UV-inactivated HSV transformation experiment, was shown to possess HSV antigens by immunoperoxidase staining with specific antisera and to be oncogenic when injected into newborn hamsters. Sera from the tumor bearing animals had HSV neutralizing antibodies and when used as the primary antisera in the immunoperoxidase stain could detect antigens in HSV infected cells and outgrowths from explanted hamster tumors. Another transformed cell line, 333-8-9, was shown by in situ hybridization to have HSV specific mRNA in its cytoplasm. These data reveal UV-irradiated HSV capable of tumor induction in vivo and of transforming hamster cell in vitro. In these systems, HSV can be considered a cocarcinogen

Structural Equation Modeling of Multiple-Indicator Multimethod-Multioccasion Data: A Primer

We provide a tutorial on how to analyze multiple-indicator multi-method (MM) longitudinal (multi-occasion, MO) data. Multiple-indicator MM-MO data presents specific challenges due to (1) different types of method effects, (2) longitudinal and cross-method measurement equivalence (ME) testing, (3) the question as to which process characterizes the longitudinal course of the construct under study, and (4) the issue of convergent validity versus method-specificity of different methods such as multiple informants. We present different models for multiple-indicator MM-MO data and discuss a modeling strategy that begins with basic single-method longitudinal confirmatory factor models and ends with more sophisticated MM-MO models. Our proposed strategy allows researchers to identify a well-fitting and possibly parsimonious model through a series of model comparisons. We illustrate our proposed MM-MO modeling strategy based on mother and father reports of inattention in a sample of N = 805 Spanish children

Examining Quadratic Relationships Between Traits and Methods in Two Multitrait-Multimethod Models

Multitrait-multimethod (MTMM) analysis is one of the most frequently employed methods to examine the validity of psychological measures. Confirmatory factor analysis (CFA) is a commonly used analytic tool for examining MTMM data through the specification of trait and method latent variables. Most contemporary CFA-MTMM models either do not allow estimating correlations between the trait and method factors or they are restricted to linear trait-method relationships. There is no theoretical reason why trait and method relationships should always be linear, and quadratic relationships are frequently proposed in the social sciences. In this article, we present two approaches for examining quadratic relations between traits and methods through extended latent difference and latent means CFA-MTMM models (Pohl et al., 2008; Pohl and Steyer, 2010). An application of the new approaches to a multi-rater study of the nine inattention symptoms of attention-deficit/hyperactivity disorder in children (N = 752) and the results of a Monte Carlo study to test the applicability of the models under a variety of data conditions are described

Applying and Interpreting Mixture Distribution Latent State-Trait Models

Latent state-trait (LST) models are commonly applied to determine the extent to which observed variables reflect trait-like versus state-like constructs. Mixture distribution LST (M-LST) models relax the assumption of population homogeneity made in traditional LST models, allowing researchers to identify subpopulations (latent classes) with differing trait- and state-like attributes. Applications of M-LST models are scarce, presumably because of the analysis complexity. We present a step-by-step tutorial for evaluating M-LST models based on an application to mother, father, and teacher reports of children’s inattention (n = 811). In the application, we found three latent classes for mother and father reports and four classes for teacher reports. All reporter solutions contained classes with very low, low, and moderate levels of inattention. The teacher solution also contained a class with high inattention. Comparable mother and father (but not teacher) classes exhibited similar levels of trait and state variance

Bud13 Promotes a Type I Interferon Response By Countering Intron Retention in Irf7

Intron retention (IR) has emerged as an important mechanism of gene expression control, but the factors controlling IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified BUD13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in BUD13 was associated with increased IR, decreased mature Irf7 transcript and protein levels, and consequently a dampened type I interferon response, which compromised the ability of BUD13-deficient macrophages to withstand vesicular stomatitis virus (VSV) infection. Global analysis of BUD13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a BUD13-dependent manner. Deficiency of BUD13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, BUD13 facilitates the expression of genes at which IR occurs

On Mordell–Weil groups and congruences between derivatives of twisted Hasse–Weil L-functions

Let A be an abelian variety defined over a number field k and let F be a finite Galois extension of k. Let p be a prime number. Then under certain not-too-stringent conditions on A and F we compute explicitly the algebraic part of the p-component of the equivariant Tamagawa number of the pair (h1(A/F)(1),Z[Gal(F/k)]). By comparing the result of this computation with the theorem of Gross and Zagier we are able to give the first verification of the p-component of the equivariant Tamagawa number conjecture for an abelian variety in the technically most demanding case in which the relevant Mordell–Weil group has strictly positive rank and the relevant field extension is both non-abelian and of degree divisible by p. More generally, our approach leads us to the formulation of certain precise families of conjectural p-adic congruences between the values at s = 1 of derivatives of the Hasse–Weil L-functions associated to twists of A, normalised by a product of explicit equivariant regulators and periods, and to explicit predictions concerning the Galois structure of Tate–Shafarevich groups. In several interesting cases we provide theoretical and numerical evidence in support of these more general predictions