1Department of Medicine, University of Chicago, Chicago, IL, USA.
2Committee on Immunology, University of Chicago, Chicago, IL, USA.
3Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
4Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.
5Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
6Department of Translational Medical Sciences, Section of Pediatrics, University of Naples Federico II, and CeInGe–Biotecnologie Avanzate, Naples, Italy.
7Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, Netherlands.
8Department of Chemistry, Stanford University, Stanford, CA, USA.
9Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
10Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
11University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.
12Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
13Department of Microbiology, Infectiology, and Immunology, University of Montreal, and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Quebec, Canada.
14Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
15Stanford ChEM-H, Stanford University, Stanford, California, USA.
16Department of Genetics, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
17Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
18Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
19Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
20Department of Pathology, University of Chicago, Chicago, IL, USA.
Department of Medicine, University of Chicago, Chicago, IL, USA.Committee on Immunology, University of Chicago, Chicago, IL, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, University of Chicago, Chicago, IL, USA.Department of Translational Medical Sciences, Section of Pediatrics, University of Naples Federico II, and CeInGe–Biotecnologie Avanzate, Naples, Italy.
Department of Medicine, University of Chicago, Chicago, IL, USA.Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, Netherlands.
Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, Netherlands.
Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Medicine, University of Chicago, Chicago, IL, USA.University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.
University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
Department of Microbiology, Infectiology, and Immunology, University of Montreal, and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Quebec, Canada.
Department of Chemistry, Stanford University, Stanford, CA, USA.Department of Chemical Engineering, Stanford University, Stanford, CA, USA.Stanford ChEM-H, Stanford University, Stanford, California, USA.
Department of Genetics, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.Broad Institute of MIT and Harvard University, Cambridge, MA, USA.Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Medicine, University of Chicago, Chicago, IL, USA.Committee on Immunology, University of Chicago, Chicago, IL, USA.University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA.Department of Pathology, University of Chicago, Chicago, IL, USA.
Reoviruses commonly infect humans and mice asymptomatically. Bouziat et al. found that immune responses to two gut-infecting reoviruses take different paths in mice (see the Perspective by Verdu and Caminero). Both reoviruses invoked protective immune responses, but for one reovirus, when infection happened in the presence of a dietary antigen (such as gluten or ovalbumin), tolerance to the dietary antigen was lost. This was because this strain prevented the formation of tolerogenic T cells. Instead, it promoted T helper 1 immunity to the dietary antigen through interferon regulatory factor 1 signaling. Celiac disease patients also exhibited elevated levels of antibodies against reovirus.
Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.
Celiac disease (CeD) is a complex immune disorder with an autoimmune component in which genetically susceptible individuals expressing the human leukocyte antigen (HLA) DQ2 or DQ8 molecules display an inflammatory T helper 1 (TH1) immune response against dietary gluten present in wheat (1–3). The HLA-DQ2– or HLA-DQ8–restricted TH1 response against gluten is central to CeD pathogenesis and thought to precede development of villous atrophy (4). However, epidemiological and immunological observations support a role for additional genetic and environmental factors in CeD pathogenesis. Similar levels of wheat consumption and expression of CeD-predisposing HLA molecules can be accompanied by striking differences in CeD prevalence (1). A remarkable example supporting a role for environmental factors is the high frequency of CeD in Finnish Karelia (>2%), which contrasts with the low incidence of CeD in the adjacent Russian republic of Karelia (0.2%), two neighboring regions harboring genetically similar populations. Furthermore, the incomplete digestion of gluten by intestinal enzymes (2, 5) explains why gluten would be conducive to inducing intestinal T cell responses. However, it does not explain why CeD patients develop a gluten-specific TH1 response instead of a regulatory immune response, the default intestinal immune reaction to orally ingested protein, characterized by the induction of peripheral regulatory T cells (pTregs) expressing the transcription factor forkhead box P3 (Foxp3) (6).
Despite epidemiological evidence of associations between viral infections and the initiation of CeD (1), experimental evidence is lacking. Previous studies have implicated adenovirus, enteroviruses, hepatitis C virus, and rotavirus as triggers of CeD (7, 8). However, little is known about the mechanisms by which viruses evoke the disease. Viruses in the family Reoviridae are segmented, double-stranded RNA (dsRNA) viruses that infect humans frequently throughout their lifetime (9). Mammalian Orthoreovirus (reovirus) strains isolated from humans can infect mice via the oral route and activate innate immune pathways similar to the related rotavirus (10, 11). Two human reovirus isolates, type 1 Lang (T1L) and type 3 Dearing (T3D), differ in replication biology, apoptosis induction, innate immune response activation, cellular tropism, and pathogenesis (11). Furthermore, T1L infects the intestine and perturbs intestinal immune homeostasis (11, 12), whereas T3D is incapable of infecting the intestine (11). On the basis of the fundamental differences between T1L and T3D, we hypothesized that engineering a T3D reassortant virus capable of intestinal infection would yield two viruses with potentially different effects on tolerance to dietary antigen. Therefore, we recovered a T3D reassortant virus called T3D-RV by introducing the S1 and L2 gene segments of T1L into a T3D genetic background, thus allowing the virus to infect the intestine (fig. S1A) (13). Such reassortants arise naturally (10, 11) and can be readily recovered in the laboratory by using reverse genetics (11). We first established that the two viruses are similar in their capacity to replicate (fig. S1B) and infect the intestine (fig. S1, C and D). Furthermore, both viruses are cleared (fig. S1E) without inducing intestinal damage (fig. S1F). Although both viruses induced high antireovirus antibody titers, antibody levels observed after T1L infection were significantly higher than those after T3D-RV infection (fig. S1G). However, comparison of the host T cell response in sham- and virus-infected mice revealed that T1L and T3D-RV induced similar TH1 responses in Peyer's patches (PP) (fig. S1H), the site at which protective immunity to reovirus is induced (12).
Having established that the two strains infect and induce protective immunity in PP, we next investigated whether they affect immune responses to dietary antigens at inductive and effector sites of oral tolerance—mesenteric lymph nodes (mLN) and lamina propria (Lp) (14, 15), respectively. We took an unbiased approach, using transcriptional profiling to compare and contrast the dynamics of the virus-host interaction across multiple sites of the gut. The application of an unsupervised approach incorporating minimum spanning trees (MSTs) (16, 17) and multidimensional scaling (MDS) ordination (Fig. 1A) revealed transcriptional profile clusters that were strongly driven by differences in location (epithelium, Lp, PP, and mLN) and were influenced by reovirus infection in a location- and time-dependent manner, which is consistent with our understanding of mucosal immunity and intestinal structure and function. This strong location effect was directly evident and predominantly captured by dimension 1 in the MDS scaling operation, which together with dimension 2 also captured the virus-dependent differences. At the early time point (6 hours), both viruses have similar effects primarily on PP and the epithelial compartment (primary sites of infection) (12) and no effect on mLN (Fig. 1A). In contrast, at 48 hours, the viruses altered the transcriptional profile of mLN and Lp (inductive and effector sites of immune responses to dietary antigens) (14, 15), and response differences between the two viruses emerged (Fig. 1A). We therefore followed up this observation with in-depth factorial design analyses (FDAs) (fig. S2) to identify host genes that were differentially expressed in response to the two viruses, characterizing their expression in a time- and location-dependent manner. In both Lp and mLN at 48 hours, we observed a strong enrichment of immune, defense, and antiviral response pathways, including type-1 interferon (IFN) signaling, among genes that were differentially expressed after T1L or T3D-RV infection (fig. S3). Additionally, in mLN, the differential response to the viruses was also characterized by an overrepresentation of cytokine and mitogen-activated protein (MAP) kinase signaling pathways, as well as pathways associated with nutrient response, stress, and vesicle-mediated transport (fig. S3). The finding that T1L induced more extensive transcriptional changes (in the number and level of genes induced) in mLN and Lp at 48 hours compared with that of T3D-RV (Fig. 1A and figs. S2 to S4) raised the possibility that T1L might alter the response to dietary antigen.
Fig. 1 T1L blocks the differentiation of pTregs and promotes TH1 immunity to dietary antigen at inductive and effector sites of the gut.
(A) For each time point, WT mice were inoculated perorally with 1010 plaque forming units (PFU) of T1L (n = 3 mice; red circles), 1010 PFU of T3D-RV (n = 3 mice; blue circles), or phosphate-buffered saline (PBS) (sham, n = 3 mice; open circles) and euthanized 6 or 48 hours after inoculation. RNA of mLN, PP, epithelium, and Lp were isolated and analyzed by means of microarray. MST is represented on multidimensional scaling ordination. The MST traces a path of minimum weight through each vertex or node that represents the profile of differentially expressed genes for each sample state shown. The lengths of edges (or connecting paths) indicate the level of dissimilarity between samples. Each sample state and the distances between them are represented in two-dimensional space. The coordinates of each sample along each dimension are indicated by the two axes. (B) Mice were inoculated perorally with 108 PFU of T1L (n = 6 mice), 108 PFU of T3D-RV (n = 6mice), or PBS (sham, n = 5 mice) for 2 days. The expression of IL-12p40 on gated MHC-II+ CD11c+ CD103+ CD11b− CD8α+ mLN DCs was evaluated by means of flow cytometry. Representative dot plots and percentages of IL-12p40 in the mLN are shown in the CD103+ CD11b– CD8α+ DC subset. (Cand D) OT-II+ CD45.1+ CD4+ T cells were transferred into WT CD45.2+ mice. One day after transfer, mice were inoculated perorally with 1010 PFU of T1L (n = 4 to 16 mice), 1010 PFU of T3D-RV (n = 5 to 14 mice), or PBS (sham, n = 6 to 15 mice) and fed 1.5% OVA in the drinking water (filled circles) or an OVA-containing diet (open circles) for 6 days. The intracellular expression of Foxp3 and T-bet in transferred OT-II+ CD45.1+ CD4+ T cells in the mLN and in the Lp was evaluated by means of flow cytometry. Representative dot plots and percentages of Foxp3+ T-bet− and T-bet+ Foxp3− cells are shown in the mLN (C) and in Lp (D), respectively. [(B) to (D)] Graphs depict at least two independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way analysis of variance (ANOVA)/Tukey's multiple comparison.
To test this hypothesis, we first determined the effect of in vivo reovirus infection on mLN dendritic cells (DCs). The CD103+ CD11b– DC subset has the highest tolerogenic potential (18, 19) but also drives TH1 responses to intestinal infections (20–22). T1L induced more IL-12p40 than did T3D-RV in CD103+ CD11b– CD8α+ DCs (Fig. 1B), which was the subset that exhibited the highest level of ovalbumin (OVA) uptake after oral administration, irrespective of the virus used (fig. S5, A and B). However, both viruses induced similar levels of IL-12p40 in resident CD103– CD11b– CD8α+ DCs (fig. S5C), whereas no up-regulation of IL-12p40 was detectable in the other mLN DC subsets (fig. S5D). Furthermore, T1L up-regulated more substantially the costimulatory molecule CD86 as well as transcripts of interleukin-27 (IL-27), a cytokine produced by antigen-presenting cells (APCs) that promote TH1 immunity (fig. S5, E and F) (23, 24).
Having found that T1L, but not T3D-RV, induces a proinflammatory phenotype in DCs that take up OVA, we next investigated the effect of the two reoviruses on the T cell response to dietary antigen using an in vivo T cell conversion assay (fig. S6A). In accordance with its capacity to alter the tolerogenic phenotype of CD103+ CD11b– DCs, T1L infection significantly inhibited the conversion of OVA-specific OT-II CD4+ T cells into pTregs and instead promoted their differentiation into T-bet+ and IFNγ+ CD4+ T cells in mLN and Lp, respectively (Fig. 1, C and D, and fig. S6, B to D). In contrast, T3D-RV neither markedly blocked the induction of pTregs nor induced TH1 immune responses against dietary OVA (Fig. 1, C and D, and fig. S6, B to D). Although T1L and T3D-RV differed in their capacity to interfere with responses to dietary antigens, they induced similar host TH1 responses to viral infections in mLN and Lp (fig. S7, A to D).
Oral tolerance is defined as the establishment of peripheral immune tolerance through oral administration of antigen and is thought to be dependent on the induction of pTregs (6). As expected, T1L but not T3D-RV prevented induction of peripheral tolerance upon oral administration of OVA (fig. S7, E to G). Collectively, these results suggest that as a consequence of T1L-host interactions, the tolerogenic response to dietary antigens is abrogated and, instead, TH1 immunity to dietary antigens is induced.
We next sought to determine the mechanistic basis for the differential effect of T1L and T3D-RV infection on the response to dietary antigen. Type-1 IFNs are up-regulated in CeD and have been suggested to explain development of TH1 immunity against dietary gluten (25). RNA sequencing (RNA-seq) analysis of mLN from wild-type (WT) mice and mice in which type-1 IFN receptor has been knocked out (IFNAR−/−) 48 hours after T1L and T3D-RV infection revealed that among the 285 genes found to be differentially expressed between T1L- and T3D-RV–infected mice, 200 genes were regulated in a type-1 IFN-dependent manner (fig. S8), 58 were partially type-1 IFN–dependent, and 27 were type-1 IFN–independent, as assessed with FDA to examine differences in expression response. Further analysis in mLN confirmed that T1L induced higher levels of canonical type-1 IFN-inducible genes such as Mx1 and Isg15 than did T3D-RV (Fig. 2A and fig. S9A). This result was contrary to the in vitro data (fig. S9, B to D) and the reported capacity of T1L but not T3D to interfere with type-1 IFN signaling (26), suggesting that yet-to-be-determined differences in virus-host interactions displayed by T1L and T3D-RV can lead to alternative outcomes in mLN in vivo, and that type-1 IFN may be responsible for initiating TH1 immunity against dietary antigen in T1L-infected mice. To assess this possibility—but to avoid confounding factors associated with uncontrolled T1L replication in the absence of type-1 IFN signaling (27)—we analyzed DCs and OVA-specific T cell conversion at 48 hours, a time point at which viral titers in the ileum are similar in WT and IFNAR−/− mice (fig. S9E). Surprisingly, although CD86 was not induced in IFNAR−/− CD103+ CD11b– CD8α+ DCs (fig. S9F), up-regulation of IL-12p40 in DCs (Fig. 2B and fig. S9G) and Il27 mRNA in mLN (fig. S9H) occurred after T1L infection, suggesting that type-1 IFNs are not required for acquisition of an inflammatory phenotype by mLN APCs. Consistent with these findings, T1L infection induced comparable T-bet expression in OVA-specific CD4+ T cells in WT and IFNAR−/− mice (Fig. 2C and fig. S9I). At this early time point, neither Foxp3 nor IFN-γ can be detected in OVA-specific T cells in the mLN. To assess the role of type-1 IFN in pTreg conversion, an in vivo OT-II T cell conversion assay was performed in WT and IFNAR−/− mice injected intraperitoneally with the dsRNA analog polyinosinic:polycytidylic acid [poly(I:C)]. As shown in Fig. 2, D and E, and fig. S10, A to B, dsRNA was sufficient to block pTreg conversion in a type-1 IFN–dependent manner. Furthermore, type-1 IFNs blocked pTreg conversion comparable with infection with T1L (fig. S10C). In contrast, poly(I:C) (Fig. 2, F and G, and fig. S10D) and type-1 IFN (fig. S10C) were unable to promote TH1 immunity.
Fig. 2 Type-1 IFN is required for blockade of pTreg conversion but not for induction of TH1 immunity to dietary antigen.
(A) WT and IFNAR−/− mice were inoculated perorally with 108 PFU of T1L (n = 6 mice), 108 PFU of T3D-RV (n = 6 mice), or PBS (sham, n = 6 mice) for 2 days. Mx1 expression in the mLN was analyzed by means of reverse transcription polymerase chain reaction (RT-PCR). (B and C) OT-II+ CD45.1+ CD4+ T cells were transferred into WT CD45.2+ or IFNAR−/− CD45.2+ mice. One day after transfer, mice were inoculated perorally with 108 PFU of T1L (n = 6 mice) or PBS (sham, n = 4 or 5mice) and fed 1.5% OVA in the drinking water for 2 days. The expression of IL-12p40 on gated MHC-II+ CD11c+ CD103+ CD11b− CD8α+ mLN DCs (B) and T-bet in OT-II+ CD45.1+ CD4+ T cells (C) in the mLN was evaluated by means of flow cytometry. (D to G) OT-II+ CD45.1+ CD4+ T cells were transferred into WT CD45.2+ or IFNAR−/− CD45.2+ mice. One day after transfer, mice were inoculated with PBS (n = 7mice) or 50 μg of poly(I:C) (n = 7 mice) intraperitoneally or 1010 PFU of T1L (n = 5 mice) perorally and fed an OVA-containing diet for 6 days. The intracellular expression of Foxp3 and IFN-γ in OT-II+ CD45.1+ CD4+ T cells in the mLN was evaluated by means of flow cytometry. Percentages and absolute numbers of Foxp3 [(D) and (E)] and IFN-γ [(F) and (G)] are shown. [(A) to (G)] Graphs depict at least two independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way ANOVA/Tukey's multiple comparison.
To define the mechanism underlying T1L-induced TH1 immunity to dietary antigen, we interrogated the mLN RNA-seq data from T1L- and T3D-RV–infected WT and IFNAR−/− mice more deeply in order to identify genes that were differentially expressed in a type-1 IFN–independent manner, using FDA (fig. S11A). IL-15, previously shown to prevent pTreg conversion and induce TH1 immunity to dietary antigens (28), was not up-regulated after T1L infection in mLN of IFNAR−/− mice (fig. S11B). In contrast, interferon regulatory factor 1 (IRF1)—a transcription factor regulated at the transcriptional level (29) and implicated in multistage regulation of TH1 immune responses (30)—was significantly up-regulated after T1L infection in both WT and IFNAR−/− mice (Fig. 3A and fig. S11A). IRF1 was a particularly intriguing candidate because it is up-regulated in the mucosa of children with CeD (31). To determine whether IRF1 is required in T1L-mediated immunopathology, we analyzed DCs and OT-II T cell conversion in IRF1−/− mice. Viral titers were similar at 48 hours and 6 days after infection in WT and IRF1−/− mice (fig. S11, C and D), enabling us to analyze the response to dietary antigen after oral OVA administration at these two time points. We found that IL-12p40 (Fig. 3B and fig. S11E) and to a lesser extent CD86 (fig. S11F) showed significantly less induction in IRF1−/− mice relative to WT mice. Additionally, induction of Il12b and Il27 mRNA expression was significantly impaired in IRF1−/− mice (fig. S11, G and H). Consistent with preserved type-1 IFN up-regulation after T1L infection in IRF1−/− mice (fig. S11, I and J), absence of IRF1 failed to restore pTreg conversion (Fig. 3, C and D, and fig. S11K). However, whereas type-1 IFN signaling was dispensable at 48 hours (Fig. 2C), IRF1 was required for T1L-mediated TH1 immunity to oral antigen 48 hours (fig. S11, L to N) and 6 days (Fig. 3, E and F, and fig. S11O) after OVA feeding. This result is consistent with the role of IL-12 and IL-27 in TH1 immunity (23, 30, 32) and the abrogation of their up-regulation in IRF1−/− mice (Fig. 3B and fig. S11, G and H). Knowing that the T cell conversion experiments were performed by using OT-II T cells that were IRF1-proficient, we next investigated a role for IRF1 in DCs by performing in vitro T cell conversion assays with mLN DCs isolated 48 hours after T1L infection of WT and IRF1−/− mice. Because IRF1 deficiency skews differentiation of DC subsets (33), we adjusted the relative proportion of the main mLN DC subsets of IRF1−/− mice to approximate that of WT mice (fig. S12, A and B). In keeping with a critical role for IRF1 in DCs, we found that mLN DCs from T1L-infected mice failed to promote TH1 cell differentiation in the absence of IRF1 expression (fig. S12, C and D). Our studies cannot eliminate a potential T cell–intrinsic function of IRF1 in virus-mediated pTreg blockade (34). Furthermore, and in accordance with the defect in IL-12 induction observed in vivo (Fig. 3B and fig. S11G), IL-12 production was impaired in IRF1−/− mLN DCs relative to that in WT mLN DCs (fig. S12E). Last, in support of a direct role for IL-12 in T1L-mediated TH1 immunity to oral antigen, we found that blocking IL-12 in vitro impaired the capacity of T1L-infected WT mLN DCs to convert OT-II T cells into TH1 cells (fig. S12, C and D). These results are in agreement with studies reporting that IRF1 functions in TH1 immunity and IL-12 induction (32, 35). Last, in addition to IL-12, IRF1 is required for IL-27 up-regulation in vivo (fig. S11H), suggesting that it may also participate in the induction of TH1 immunity to dietary antigen upon T1L infection.
Fig. 3 A central role for IRF1 in reovirus-mediated TH1 immunity to dietary antigen.
(A) WT and IFNAR−/− mice were inoculated perorally with 108 PFU of T1L (n = 6 mice), 108 PFU of T3D-RV (n = 6 mice), or PBS (sham, n = 6 mice) for 2 days. Irf1 expression in the mLN was analyzed by means of RT-PCR. (B) OT-II+ CD45.1+ CD4+ T cells were transferred into WT CD45.2+ or IRF1−/− CD45.2+ mice. One day after transfer, mice were inoculated perorally with 108 PFU of T1L (n = 4 to 6 mice) or PBS (sham, n= 4 to 6 mice) and fed 1.5% OVA in the drinking water for 2 days. The expression of IL-12p40 on gated MHC-II+ CD11c+ CD103+ CD11b− CD8α+ mLN DCs was evaluated by means of flow cytometry. (C to F) OT-II+ CD45.1+ CD4+ T cells were transferred into WT CD45.2+ or IRF1−/− CD45.2+ mice. One day after transfer, mice were inoculated perorally with 1010 PFU of T1L (n = 5 or 6 mice) or PBS (sham, n = 4 to 6 mice) and fed 1.5% OVA in the drinking water for 6 days. Intracellular expression of Foxp3 and IFN-γ was evaluated by means of flow cytometry. Representative dot plots (C), percentages of Foxp3 (D), representative dot plots (E), and percentages of IFN-γ (F) are shown in transferred OT-II+ CD4+ T cells in the mLN. [(A) to (F)] Graphs depict two independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; one-way ANOVA/Tukey's multiple comparison.
Taken together, our studies analyzing the effect of T1L on the response to dietary antigen using OVA as a model antigen (fig. S13) suggest that two reovirus strains can induce similar antiviral TH1 responses in PP and yet display distinct immunopathological properties. We show that T1L, but not T3D-RV, promotes an inflammatory phenotype in DCs taking up dietary antigen. In addition, our results indicate that type-1 IFN signaling and IRF1 up-regulation are differentially implicated in blocking pTreg conversion and promoting TH1 immunity to dietary antigen after T1L infection. IRF1 functions in T1L-induced TH1 immunity to dietary antigen by promoting IL-12 and IL-27 in DCs. Although type-1 IFNs are not required (Fig. 3A), they likely contribute to IRF1 up-regulation (36) after reovirus infection in WT mice.
To determine the relevance of these findings to CeD, we analyzed the effect of T1L infection in transgenic mice expressing the CeD-predisposing HLA molecule DQ8 (DQ8tg mice) (28). First, we confirmed that Irf1 was up-regulated in DQ8tg mice after T1L infection (Fig. 4A). Next, we verified that like OVA-fed WT mice (Fig. 1B and fig. S5B), gluten peptides were preferentially found in CD103+ CD11b– CD8α+ DCs after gavage of sham- or T1L-infected DQ8tg mice (fig. S14, A to C). This DC subset up-regulated IL-12p40 (Fig. 4B and fig. S14D) and CD86 (fig. S14E). The pattern of IL-12p40 expression in the other mLN DC subsets of DQ8tg mice was also similar to that in WT mice (fig. S14F). In addition, Il27 was up-regulated (fig. S14G). In agreement with mLN DCs acquiring a proinflammatory phenotype, T1L infection induced loss of oral tolerance to gluten in DQ8tg mice as assessed by the presence of anti-gliadin IgG2c antibodies (Fig. 4C) and the development of a TH1-delayed hypersensitivity reaction (Fig. 4D and fig. S14H). In addition to intestinal environmental conditions favoring TH1 immunity against dietary antigens, transglutaminase 2 (TG2) activation is thought topromote CeD pathogenesis by increasing the affinity of gluten peptides for HLA-DQ2 and HLA-DQ8 molecules (1–3) through posttranslational modifications. T1L infection induced TG2 activation, as quantified by incorporation of 5-(biotinamido)-pentylamine (5BP), a small-molecule TG2 activity probe, in more than 60% of infected DQ8tg mice (Fig. 4E) without inducing detectable intestinal damage. Thus, in a CeD-relevant mouse model, T1L infection breaks oral tolerance to gluten and promotes TG2 activation, supporting the hypothesis that reovirus infection, despite being clinically silent, can initiate critical events that set the stage for development of CeD.
Fig. 4 Role of reovirus infection in loss of oral tolerance to gluten and TG2 activation.
(A and B) DQ8tg mice were inoculated perorally with 108 PFU of T1L (n = 5 mice) or PBS (sham, n = 5mice) for 2 days. (A) Levels of Irf1 expression in the mLN were analyzed by means of RT-PCR. (B) The expression of IL-12p40 on gated CD11c+ CD103+ CD11b− CD8α+ mLN DCs was evaluated by means of flow cytometry. (C and D) DQ8tg mice were inoculated perorally with 1010 PFU of T1L at the initiation of an oral tolerance/delayed type hypersensitivity protocol. Mice were fed orally with gliadin (Glia) for 2 days and then immunized subcutaneously with a CFA-Glia emulsion. (C) Levels of Glia-specific IgG2c antibodies in the serum were quantified at day 18 by means of enzyme-linked immunosorbent assay (ELISA). (D) On day 28, mice were challenged subcutaneously with Glia, and the degree of ear swelling was determined 24 hours after challenge. Sham, n = 4 or 5 mice; Glia, n = 6mice; and Glia + T1L, n = 5 mice. (E) DQ8tg mice were inoculated perorally with 1010 PFU of T1L (n= 8 mice) or PBS (sham, n = 4 mice). TG2−/− mice were inoculated perorally with 1010 PFU of T1L (n = 2 mice) and used as a negative control. Mice were euthanized at 18 hours after infection, and small intestines were collected and frozen in optimal cutting temperature compound. Representative images from stained frozen sections of the proximal small intestines are shown. Scale bars, 100 μm. Staining with 4′,6-diamidino-2-phenylindole (DAPI) is shown in blue, TG2 protein is shown in green, and TG2 enzymatic activity as assessed by means of 5BP cross-linking is shown in red. TG2 enzymatic activity normalized to TG2 protein levels was quantified for each villus. The mean enzymatic activity in the proximal small intestine per mouse is shown. [(A) to (E)] Graph depicts two independent experiments. (A), (B), and (E), **P < 0.01, ***P < 0.001; unpaired t test. (C) and (D), **P < 0.01; one-way ANOVA/Tukey's multiple comparison.
To directly investigate a role for reovirus in CeD, we compared anti-reovirus antibody titers in control individuals with those with active CeD and CeD patients on a gluten-free diet (GFD). CeD patients tended to have higher anti-reovirus antibody titers (P = 0.06) (Fig. 5A) and were significantly overrepresented among patients with very high titers (Fig. 5B). Furthermore, CeD patients on a GFD with high anti-reovirus titers (above the median of our samples) have significantly higher IRF1 levels in the small intestinal mucosa compared with that of individuals with low anti-reovirus titers (Fig. 5C). However, there was no direct correlation between the anti-reovirus antibody titers and the level of IRF1 expression, indicating that there is not a linear relationship between antibody titers and IRF1 levels. Together, these results suggest that the presence of anti-reovirus antibody titers above a certain threshold indicates an antecedent virus-host interaction that caused long-lasting changes in immune homeostasis associated with high IRF1 expression. This hypothesis is in agreement with the concept that viruses may leave a permanent mark on the transcriptional program of the host (37) and is consistent with our observation that mice infected with T1L have higher antibody titers than those of mice infected with T3D-RV (fig. S1G), which does not disrupt tolerance to dietary antigens, unlike T1L. A link between rotavirus infection and development of CeD was suggested in a longitudinal study in children (8). However, our study failed to show such an association (Fig. 5, D to F). Our results do not exclude a role for rotavirus in CeD pathogenesis and could be explained by rotavirus-host immune interactions that differ from those observed with reovirus and hence do not lead to the same immune signatures. Last, high anti-reovirus antibody titers in CeD patients did not correlate with either high anti-rotavirus (Fig. 5G) or high anti-herpes simplex virus type 1 (HSV-1) antibody titers (Fig. 5H), indicating that CeD patients displaying high anti-reovirus antibody titers do not mount generally high antibody responses against viruses. Taken together, these results suggest that reovirus infection can trigger the onset of CeD in a subset of CeD patients.
Fig. 5 Role of human reovirus infections in celiac disease pathogenesis.
(A and D) Boxplots showing levels of reovirus antibody titers (A) and rotavirus antibody titers (D) in control (n = 73) and CeD patients (n = 160). (Band E) Percentage of control patients (gray), active CeD patients (blue), CeD patients on a gluten-free diet (GFD) (orange), and active CeD and GFD patients combined (red) that have reovirus (B) or rotavirus (E) antibody titers above an increasingly higher cutoff (left to right). Cutoffs were determined by defining the deciles of the distribution of reovirus (B) or rotavirus (E) antibody titers observed in the patient samples analyzed. GFD and CeD (Active + GFD) patient groups are significantly overrepresented among individuals with reovirus titers above a PRNT60 = 156 (6th decile) and PRNT60 = 1597 (9th decile), respectively. (C and F) IRF1 expression in small intestinal biopsies of GFD patients (n = 38) was analyzed by means of RT-PCR. To avoid any confounding factors associated with increased inflammation, analysis of IRF1 expression was performed in CeD patients on a GFD who, unlike active CeD patients, display normal levels of IFN-γ. Relative expression level of IRF1 in GFD patients with low (left) and high (right) levels of reovirus (C) or rotavirus (F) antibody titers is shown. (C) Reovirus low and reovirus high were respectively defined as individuals with antibody titers below and above the median PRNT60 = 47 [(B), 5th decile]. (F) Rotavirus low and rotavirus high were respectively defined as individuals with antibody titers below and above the median PRNT60 = 53 [(E), 5th decile]. (G and H) Reovirus and rotavirus antibody titers in serum of patients were determined by means of plaque-reduction neutralization assay. Levels of HSV-1 antibody titers were determined by means of ELISA. Correlations between the levels of reovirus antibody titers and rotavirus antibody titers (G) or HSV-1 antibody titers (H) in GFD patients are shown. r, Pearson correlation. (A) to (F), *P < 0.05; Mann-Whitney U test.
This study provides support for the concept that viruses can disrupt intestinal immune homeostasis and initiate loss of oral tolerance and TH1 immunity to dietary antigen. Furthermore, our findngs suggest that an avirulent pathogen, such as reovirus, which is successfully cleared from the infected host, can nonetheless promote immunopathology. In support of this idea, clinically silent norovirus infections increase susceptibility to development of colitis (38). Our data also indicate that two viruses belonging to the same species can have substantially different immunopathological effects. Analysis of the transcriptional profiles induced in response to T1L and T3D-RV suggests that the capacity of a virus to trigger the loss of oral tolerance is associated with its capacity to disrupt immune homeostasis at sites where responses to oral antigens are initiated (fig. S13).
In addition to reovirus, it is probable that other enteric viruses, including viruses belonging to families detected by different immune sensors and involving different signaling pathways, also trigger loss of tolerance to dietary antigen. Expanding the concept of virotypes (37), we propose that viruses eliciting proinflammatory immune responses to dietary antigen alter immune homeostasis and in particular endow DCs with proinflammatory properties at sites where oral tolerance is induced (fig. S13). Identification of other viruses and defining key common features of virus-host interactions leading to the abrogation of oral tolerance will help to design vaccine strategies to prevent CeD and possibly other autoimmune disorders in at-risk populations. On the basis of our findings, even viruses that do not lead to overt clinical pathology could be candidates for such prophylactic intervention.
CeD is a complex disorder that likely requires several environmental perturbations to permanently disrupt tolerance to gluten. Indeed, epidemiological studies longitudinally monitoring genetically at-risk children report transient anti-gluten immune responses before development of fully developed CeD (39, 40) and suggest that anti-gluten antibodies precede anti-TG2 antibodies (41). Furthermore, induction of TH1 immunity to gluten, although required, is insufficient to cause villous atrophy, both in humans and mouse models of CeD (42–44). Our study indicates that although reovirus infections may trigger development of TH1 immunity to gluten as well as activation of TG2, additional events will be required for induction of anti-TG2 antibodies and villous atrophy. Furthermore, nonviral triggers, such as pathogenic members of the microbiota (45, 46), may have disease causing properties similar to reovirus, and the combination of different types of environmental factors likely will eventually lead to formation of a memory pool of TH1 anti-gluten T cells of sufficient magnitude to cause enduring CeD with villous atrophy.
T. S. Dermody, J. S. Parker, B. Sherry, Orthoreoviruses (Lippincott Williams & Wilkins, ed. 6, 2013), pp. 1304–1346.
, Culturing, storage, and quantification of rotaviruses. Curr. Protoc. Microbiol., chap. 15, unit 15C.3 (2009).
, Controlling the false discovery rate—A practical and powerful approach to multiple testing. J. R. Stat. Soc. B Met. 57, 289–300 (1995).
R. Sedgewick, K. D. Wayne, Algorithms (Addison-Wesley, ed. 4, 2011).
Acknowledgments: Library generation and sequencing was performed by the University of Chicago Genomics Facility (http://genomics.bsd.uchicago.edu). Data reported in this paper were deposited into the National Center for Biotechnology Information Gene Expression Omnibus database under the SuperSeries record GSE94604 containing the following SubSeries records: GSE94602 (RNA-seq data) and GSE94517 (Microarray data). Histological slides were generated by the Vanderbilt Translational Pathology Shared Resource supported by National Cancer Institute/National Institutes of Health Cancer Center Support Grant P30 CA068485 and the Vanderbilt Mouse Metabolic Phenotyping Center Grant U24 DK059637. Whole-slide imaging and quantification of immunostaining were performed in the Digital Histology Shared Resource at Vanderbilt University Medical Center (www.mc.vanderbilt.edu/dhsr). We thank P. Savage (University of Chicago) for providing OT-II mice. We thank D. Mucida and D. Esterhazy (The Rockefeller University) for expertise and reagents. We thank B. Xiang for technical assistance. We thank T. Golovkina for helpful suggestions and discussions. This work was supported by the following grants from the NIH: R01DK098435 to B.J., T.S.D., and R.J.X.; R01DK100619 and R01DK067180 to B.J.; R01AI038296 to T.S.D.; R01DK43351 to R.J.X.; F31DK108562 to J.J.B.; R01DK063158 to C.K.; and R01AI113333 and R01DK068181 to H.-C.R. Additional support includes a Cancer Center Support Grant P30CA014599 and Digestive Diseases Research Core Center P30 DK42086 at the University of Chicago to B.J.; an Investigator Start-up Fund, Department of Medicine, MGH to A.N.; an award from the Bettencourt Schueller Foundation to R.B.; a research fellowship from the Dutch Sophia Research Foundation to L.M.M.C.; and the Austrian Science Fund (FWF) J3408-B13 to R.H. Analysis of patient samples in this work was approved by the Institutional Review Board of the University of Chicago (protocol 12623B) and Vanderbilt University (protocol 151358). Last, we thank the CeD patients and their family members as well as the University of Chicago Celiac Disease Center for supporting our research.
A nonpathogenic virus can promote inflammatory immunity to dietary antigens and may be linked to the development of celiac disease.


My first experience programming was at the ripe old age of 10, when I hacked together little games in BASIC on the old Apple II's at school. Soon, I moved on to HyperTalk, and by 12, I was learning C with the help of a book called "The Black Art of Macintosh Game Programming".
Before long, I began mastering web technologies, and was possibly the youngest to have an official design (Outburst) selected for the venerable CSS Zen Garden, a site dedicated to spreading the good news about the end of spacer GIFs and table-based web layout.
The joy I found in building useful things with technology has only grown over the decades. From the startup scene in San Francisco, through periods of independent consulting, I've built innumerable software solutions using a wide range of technologies, including Ruby on Rails, native iOS apps, APIs, and single-page applications using React and other cutting-edge front-end frameworks.
I presently work as an independent consultant. To find out more about the skills I have to offer, and to get in touch, please see the Services page.
Machines Are for People is hand-crafted in Ruby on Rails. True to its name, the site has been designed with the reader in mind, with clear readability on any size screen, fast load times, simple navigation, full-story RSS entries, accessibility best practices, and a tracker- and cookie-free experience (unless night mode is used, which is also provided as a consideration to the reader).
I believe in the ability of technology to enhance human enjoyment and potential, both for users and makers of things. But this doesn't happen on its own! It requires a conscious effort working from a principled foundation.


St. Tammany Parish Hospital is an Accredited Chest Pain Center. Getting to the nearest accredited chest pain center when you think you may be having a heart attack could save your life.
Each of these procedures allows physicians to diagnose and treat diseases of the heart and other vascular structures of the body. To learn more about these procedures follow the links to Cardiac Cath & Peripheral Laboratories and Cardiology Non-Invasive.


text:
'Zimmerman Got Away with Murder'
MIAMI (AP) — The mother of Trayvon Martin says she's disappointed that federal prosecutors decided not to charge a neighborhood watch volunteer with a hate crime for killing her son three years ago.
Speaking with The Associated Press on Wednesday before the third anniversary of her 17-year-old son's death, Sybrina Fulton says she still believes George Zimmerman got away with murder.
"He took a life, carelessly and recklessly, and he shouldn't deserve to have his entire life walking around on the street free. I just believe that he should be held accountable for what he's done," Fulton said.
Zimmerman claimed he shot the unarmed teenager in self-defense after confronting Martin while volunteering for his neighborhood watch group. A jury acquitted him of second-degree murder the next year.
The case sparked a national conversation about race, bias and crime in part because Zimmerman, who identifies himself as Hispanic, was not immediately arrested after shooting Martin, who is black.
The U.S. Justice Department announced Tuesday that it found insufficient evidence to establish that Zimmerman willfully deprived Martin of his civil rights or killed him because of his race.
"The Justice Department is the top of the line here," Fulton said. "But what they found just wasn't enough."
Zimmerman, for his part, is relieved the case is closed, according to his attorney, Don West.
"This cloud he was under has been lifted," West told the AP, adding that he finds it misleading to suggest that charges weren't filed only because the legal standard for federal hate crime is so tough to meet.
"There simply was never any compelling evidence that this was a federal hate crime. Race played no role in it whatsoever," West said.
The February 2012 confrontation began after Zimmerman spotted Martin walking through the neighborhood, returning to his father's home after buying candy and a soft drink at a convenience store.
Zimmerman called 911 to report a suspicious person, and got out of his car to follow Martin despite being warned by the dispatcher not to. Zimmerman did not testify at his trial, but he told investigators he feared for his life as Martin straddled him and punched him during the ensuing fight.
Wearing a T-shirt bearing a black-and-white image of her son in a hoodie, Fulton said she still longs for Zimmerman to be held responsible.
"I want to see people held accountable for what they're doing. It's just upsetting to know that a person can shoot and kill someone and justify it," Fulton said.
Fulton now channels her grief into work with The Trayvon Martin Foundation, which reaches out to other families who have lost children to violence, awards scholarships and collects school supplies for poor students.
She's also watching to see how the Justice Department handles other high-profile killings of unarmed blacks. Decisions are pending on whether to charge police in New York and Ferguson, Missouri with depriving the victims of their civil rights by using excessive force in the course of duty.
"What we want is accountability, we want somebody to be arrested, we want somebody to go to jail, of course," Fulton said. "But … we have grand juries and special grand juries; they're making a decision to not even arrest a person."
Mike Schneider in Orlando contributed to this report. Follow Jennifer Kay at www.twitter.com/jnkay.
Tagscrimedepartment of justiceGeorge ZimmermanslideshowSybrina FultonTrayvon Martin
Because Erykah Badu is Hilarious
Obama Predicts Success on Immigration

redpajama_set_name: RedPajamaCommonCrawl


text:
By Binoy Viswam	 Last updated Sep 10, 2020
INDIA AND CHINA NEED PEACE IN THE REGION FOR SPEEDY DEVELOPMENT
Every life lost by the migrant labour in the wake of the lockdown must be considered a martyrdom in the country's defence against coronavirus. Their numbers must, therefore, be added to the figures strenuously doctored by the government machinery so as to make the total number of casualties due to the pandemic look less appalling.
The escalation of tension across India -China border is a matter of great concern for all peace-loving people. It took an unexpected turn when 20 Indian soldiers were killed at Galwan valley. Those martyrs will be remembered as heroes of the nation. We hope that their families will be taken care of by the government. Though the Chinese side did not reveal their casualties, reports say that they also had damages including loss of human lives. Cross border interventions by any neighbour could not be tolerated by any country with self-respect. Territorial encroachment is nothing but attempt for territorial expansionism. In the past also China had expressed her affinity to that.
That is the political psychology of yesteryears. In modern times whichever country who choose that path will only be termed as warmongers and expansionists. Politics of war is destructive and suicidal. India's tradition and philosophy stand against it.
Border disputes are nothing new in the trajectory of India- China relations. Due to obvious reasons, both sides used to contain it within limits. Disputes were never allowed to raise to confrontations. There was a mechanism established and practiced by both India and China. Present casualties could have been avoided had the mechanism and the resultant pacts been followed. Ground level talks were the thrust of the pact aimed at de-escalation of stand-off between the armies.
Talks between higher officials and even political level could have been undertaken in order to maintain peace and stability in the difficult terrain with sub -zero temperature on the border. But it took an unfortunate turn on the eventful night of 15-16 June. It is not known why the Government of India decided to keep mum after this very important incident. None from the political leadership of the government came out to explain to the nation about the real situation.
At such crucial times it is the duty of the leaders of the country to reach the people and tell the facts. The newly founded wisdom of Indian diplomacy guided by Prime Minister Narendra Modi choose to adopt a different course. The country wants its leaders to be reasonable and responsible to the basic interests of this great peace-loving nation and its suffering masses.
Ideologues of hyper nationalism have become overactive and their propaganda machines are put to over timework. They look at the border issue with a narrow unrealistic perspective. For them relations between neighbouring nations are matters of least significance. This adventuristic philosophy and its diplomatic guidelines have made India a country with minimum friends in the neighbourhood. Instead, it looks to America for every needed and not needed occasions. For such elements, military buildup in the Chinese border might be the easiest option. Their allies in the international arena would also appreciate such a move. Protagonists of war and merchants of death might see this stand- off between two powerful neighbours as an opportunity for their deals in arms, through whipping up tensions. They should not be allowed to lead India at this critical moment of decision making.
Every inch of Indian territory needs to be protected. The lives and dignity of our Jawans at the borders have to be safe guarded. But war is not the only option for it. India cannot think of such a large-scale military confrontation now, when the whole country is reeling under the clutches of the pandemic. Even otherwise, war should not be the choice for any sensible nation in the nuclear era. It will have no victors at the end and will only put further hardships on the masses. Same is the case with China, equally suffering under the pandemic attack. Dialogue at the political level is the need. Conversation between external affairs ministers of India and China is a promising step in this direction. Let that initiative grow to new and more meaningful levels and Peace be restored between the two great neighbours.
Binoy Viswam
ECONOMIC BOYCOTT OF CHINA IS EASIER SAID THAN DONE


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1. OPEN SKATE SEASON BEGINS AT WINTER WONDERLAND ICE RINK
(PARAMUS, NJ) – Bergen County Executive Jim Tedesco, the Bergen County Board of Commissioners, and the Bergen County Parks Department are pleased to announce the beginning of the open skate season at Winter Wonderland, which starts on Friday, January 7th at 4 p.m. in Van Saun County Park.
by post on 01/07/2022 09:18 am - Story - 927 Hits
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Hackensack, N.J. (January 3, 2022) – NAI James E. Hanson, the largest New Jersey-based full-service independent commercial real estate firm, announces it has negotiated the sale of a 5,000-square-foot industrial building located at 15 Van Orden Place in Hackensack, N.J. NAI James E Hanson's Dominic Fittizzi represented both the buyer, HVAC Mechanical ...
3. Best Friends Animal Society Suggests the Adoption Option This Holiday Season
Adoption Gift Certificates Are a Great Idea for Friends or Families Looking for a Pet
4. Two Join College Cabinet
PARAMUS, N.J. – As first-year Bergen Community College President Eric M. Friedman, Ph.D., continues to identify strategic opportunities to enhance the institution, he has welcomed two new members to the executive cabinet of organizational leaders.
5. BERGEN & PASSAIC TO ENTER INTO NEW CORRECTIONS SHARED SERVICE AGREEMENT
Win-Win shared services agreement for both counties Officials from the Counties of Bergen and Passaic have reached terms to a new agreement where the Bergen County Jail, will soon assume the care and custody of all Passaic County inmates.
6. The Community Chest Opens Annual Campaign to Support Nonprofit Agencies Delivering Critical Care Services to Our Neighbors in Need
(Eastern Bergen County, New Jersey; December 6, 2021) -- The Community Chest of Eastern Bergen County's 2021-2022 Annual Campaign is underway raising funds for grants to award to nonprofit agencies responding to rising need for critical services, which are outpacing available resources.
7. URBY LAUNCHES LEASING FOR NEW PHASE OF APARTMENTS IN HARRISON, NJ
Full Size Indoor Basketball Court, Inspired Apartments, and New Bistro Bolster Urby Lifestyle Offering Close to the PATH
8. Northern NJ Community Foundation Highlights Food Insecurity and Donates Turkeys for Struggling Families in Bergen County
(Hackensack, NJ; November 22, 2021) ─ The Northern New Jersey Community Foundation's (NNJCF) celebration of National Community Foundation Week from November 12 through November 18 highlighted the escalation of food insecurity in the region.
9. Applebee's? Recognizes Restaurant Performance, Innovation and Community Engagement at Annual Franchise Conference
The Bill Palmer Legacy Scholarship was unveiled to honor brand's late founder. The scholarship will provide access to continued learning for up to 100 team members and their children each year
10. VAN SAUN COUNTY PARK WILL BE NEW JERSEY'S PREMIER DESTINATION FOR WINTER FAMILY FUN
Bergen County's Winter Wonderland & New Holiday Lantern Spectacular Open on November 26 (PARAMUS, NJ) – Bergen County Executive Jim Tedesco and the Bergen County Board of Commissioners are excited to announce that Van Saun County Park in Paramus will soon become New Jersey's premier destination for winter family fun.
11. BERKELEY COLLEGE STUDENTS LEARN ABOUT INTELLIGENCE SHARING AMONG PUBLIC-PRIVATE PARTNERS DURING TOUR OF NEW JERSEY REGIONAL OPERATIONS & INTELLIGENCE CENTER
Berkeley College students pursuing degrees in Justice Studies, Legal Studies and Business learned how the New Jersey State Police shares intelligence with its public and private partners during a visit to the New Jersey Regional Operations & Intelligence Center (NJ ROIC) in Ewing, NJ, on November 18, 2021.
12. THE SALVATION ARMY NEW JERSEY DIVISION PROVIDES THOUSANDS OF THANKSGIVING MEALS TO THOSE IN NEED
Largest Disaster Relief Organization in The U.S. Donates Traditional Thanksgiving Fare to More than 15 Communities Throughout the State
13. ConnectOne Bank Awards Grant to The Community Chest of Eastern Bergen County
--The grant provided training for nonprofit leaders to help clients returning to the workplace after experiencing trauma during the COVID-19 pandemic.--
14. NAI James E. Hanson Helps NJ Legal Service Relocate to Upgraded Paterson Office Space
Paterson, N.J. (November 8, 2021) – NAI James E. Hanson, the largest New Jersey-based full-service independent commercial real estate firm, announces it has negotiated a lease for 12,530 square feet of office space at 100 Hamilton Plaza in Paterson, N.J. NAI James E Hanson's W. Joshua Levering, SIOR, represented the tenant, Northeast ...
15. Ribbon Cutting Marks New Chapter for Greater Alliance Federal Credit Union
It's official! Greater Alliance Federal Credit Union has cut the ribbon and opened its doors on Hudson Street in Hackensack.
16. Eric LeGrand Announced as Keynote Speaker for December 9, 2021, New Jersey Business Hall of FameTM
October 14, 2021, Edison, New Jersey – Junior Achievement of New Jersey (JANJ) announced Eric LeGrand -- motivational speaker, entrepreneur, sports analyst, philanthropist, and author -- as its keynote speaker for the upcoming 2021 New Jersey Business Hall of Fame (NJBHOF).
17. HARRISON URBY TO ADD 381 NEW UNITS, FULL SIZE INDOOR BASKETBALL COURT, AND CAFÉ THIS FALL
New phase of Harrison Urby will include Brand New Apartments and Exciting New Elements Close to the PATH Station
18. Greater Alliance Federal Credit Union Has Moved to Its New Home
Greater Alliance Federal Credit Union is excited to announce the opening of its new flagship Hackensack branch. Located in the heart of the City of Hackensack, the new facility is located at 100 Hudson St. The first official day in the new offices is Monday, September 27th. All customers are welcome ...
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Berkeley College has named Annetta Ramtahal Campus Operating Officer of Berkeley College Online. As Campus Operating Officer, Ramtahal oversees day-to-day operations, finances, student and staff retention and community outreach for a global population.
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22. BACK TO WORK: AS WORKERS RETURN TO THE OFFICE, NY WATERWAY CAN GET THEM THERE SAFELY
With recent restorations, more frequent ferries are running from 8 NJ terminals providing service to Wall Street, Brookfield Place and Midtown Manhattan.


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Q: How to Edit a MySQL Data base from a PHP Site I have built a database named "artStore" and a table within that database named "inventory". I've been able to figure out how to create a new entry to the database, but I'm trying to create a page that can edit those entries.
Here is "inventory" the table I created:
$sql = "CREATE TABLE inventory (
  id INT(6) AUTO_INCREMENT PRIMARY KEY,
  product VARCHAR(30),
  category VARCHAR(30),
  seller VARCHAR(30)
  )";

Here is what I'm currently trying:
<?php
    $resultProduct = "product";
    $resultCategory = "category";
    $resultSeller = "seller";

    if ($result->num_rows > 0) {
      while ($row = $result->fetch_assoc()) {
        $resultProduct = $row["product"];
        $resultCategory = $row["category"];
        $resultSeller = $row["seller"];
      }
    } else {
      echo "No Results";
    }
     ?>
    <form action="update.php" method="POST">

      Product
      <input id="product" type="text" name="product" value="<?php echo $resultProduct; ?>">

      Category:
      <input id="category" type="text" name="category" value="<?php echo $resultCategory; ?>">

      Seller:
      <input id="seller" type="text" name="seller" value="<?php echo $resultSeller; ?>">

      <input id="id" type="text" name="id" value="<?php echo $resultId; ?>" style="display:none;">
      <input type="submit" value="Update My Record">
    </form>

What I'm trying in update.php
$product = $_POST['product'];
$category = $_POST['category'];
$seller = $_POST['seller'];

$sql = "INSERT INTO inventory (product, category, seller) VALUES ('$product', '$category', '$seller')";

if ($connection->query($sql) === true) {
  echo "Inserted Successfully";
} else {
  echo "Error occured in the insert: " . $connection->error;
}

 $connection->close();

A: Try the below code I added hidden field on form and changes on your sql query
<?php
        $resultProduct = "product";
        $resultCategory = "category";
        $resultSeller = "seller";

        if ($result->num_rows > 0) {
          while ($row = $result->fetch_assoc()) {
            $resultProduct = $row["product"];
            $resultCategory = $row["category"];
            $resultSeller = $row["seller"];
            $resultId = $row["id"];
          }
        } else {
          echo "No Results";
        }
         ?>
        <form action="update.php" method="POST">
     <input  type="text" name="update_id" value="<?php echo $resultId; ?>">
          Product
          <input id="product" type="text" name="product" value="<?php echo $resultProduct; ?>">

          Category:
          <input id="category" type="text" name="category" value="<?php echo $resultCategory; ?>">

          Seller:
          <input id="seller" type="text" name="seller" value="<?php echo $resultSeller; ?>">

          <input id="id" type="text" name="id" value="<?php echo $resultId; ?>" style="display:none;">
          <input type="submit" value="Update My Record">
        </form>

In update.php
$product = $_POST['product'];
$category = $_POST['category'];
$seller = $_POST['seller'];
$updateId = $_POST['update_id'];

$sql = "UPDATE inventory set product = '$product',category='$category',seller='$seller' WHERE id = '$updateId'";

A: <?php
        $resultProduct = "product";
        $resultCategory = "category";
        $resultSeller = "seller";
        $resultId = "product_id";

        if ($result->num_rows > 0) {
          while ($row = $result->fetch_assoc()) {
            $resultProduct = $row["product"];
            $resultCategory = $row["category"];
            $resultSeller = $row["seller"];
            $resultid = $row["id"];
          }
        } else {
          echo "No Results";
        }
     ?>

You were using $resultId in the form but you have not declared and assigned a value to it in the loop.
<form action="update.php" method="POST">
  <input id="id" type="hidden" name="id" value="<?php echo $resultId; ?>">
  Product
  <input id="product" type="text" name="product" value="<?php echo $resultProduct; ?>">

  Category:
  <input id="category" type="text" name="category" value="<?php echo $resultCategory; ?>">

  Seller:
  <input id="seller" type="text" name="seller" value="<?php echo $resultSeller; ?>">

   <input type="submit" value="Update My Record">
</form>

<?php

    $product = $_POST['product'];
    $category = $_POST['category'];
    $seller = $_POST['seller'];
    $product_id = $_POST['id'];

    if($product_id!='')//MEANS WE HAVE TO UPDATE THE RECORD
    {
        // UPDATE QUERY WILL UPDATE THE SAME RECORD ONLY MATCHING THE UNIQUE PRODUCT ID
        $sql = "UPDATE inventory SET product = '$product', category = '$category', seller = '$seller' WHERE id = '$product_id' LIMIT 1";
        if ($connection->query($sql) === true) {
          echo "Updated Successfully";
        } else {
          echo "Error occured in the insert: " . $connection->error;
        }
    }
    else// If id is blank it means you have a new record
    {
        $sql = "INSERT INTO inventory (product, category, seller) VALUES ('$product', '$category', '$seller')";
        if ($connection->query($sql) === true) {
          echo "Inserted Successfully";
        } else {
          echo "Error occured in the insert: " . $connection->error;
        }
    }

    $connection->close();
  ?>

redpajama_set_name: RedPajamaStackExchange


Mission in Cuba – Ye watchers and ye holy ones . . .
I recently took part in a visit to Seminario Evangélico de Teología with a delegation from the Episcopal Diocese of Atlanta. The seminary invited my bishop, Robert Wright, to teach a course on Jesus and Leadership. Lay and clergy representatives from our diocesan global missions commission and several Hispanic congregations joined him – 1 deacon, 2 lay leaders, and 7 priests – a team representing all four orders of ministry.
At the Atlanta airport before take off – an airport chaplain came by to pray with us.
Fieles a Jesús, Matanzas (Faithful to Jesus – perhaps my favorite church name ever, so named because this is the oldest non-Roman church on the island. The founders wanted a name that would distinguish it from the Roman Catholic Church).
The Episcopal Church of Cuba today includes 40+ parishes and missions and around 30 clergy. Worship everywhere we visited is according to the Spanish language translation of the 1979 Book of Common Prayer. Many congregations meet in lovely church buildings (like the Cathedral, above). All are very involved with their communities. Most are very small (ASA 20 – 40). A few are larger (ASA 80 – 100).
They are like many churches in the US.
Except . . . This is Cuba, an island nation that endured colonialism, dictatorship, Marxist social revolution, a continuing US embargo, and a "special period" (Fidel Castro's term) of economic hardship in the wake of the dissolution of the Soviet Union.
These concrete Soviet water towers are everywhere.
And yet, the church endured. It endured a long season in which being Christian meant being denied access to certain careers and opportunities. It endured a rapidly changing economic system that provides for some needs (education, health care) but not others (clean water, transportation, internet). It continues to endure "extra-provincial" status within the Anglican Communion when The Episcopal Church backed away from Cuba due to complications of the US economic embargo.
These Episcopal Christians are still here. They are like the cars a few are fortunate to drive in Cuba – classic models held together by hard work, repaired with invented parts, and polished with love.
Isn't this a beauty! On a street in Matanzas.
Churches in Cuba have survived by inventing new ways to keep going. As a result, in some ways, they seem stronger than churches in the US, where faith is easier but perhaps less valued. They have much to teach. They have already taught me much about being the Church in a rapidly changing world.
Cuba has lots of beaches.
AND mountains. Sorry, this doesn't do justice to the view heading in to Matanzas.


text:
Seven suggestions made to the government during the consultation on pension taxation | HK Wealth
The Government has recently finished a consultation looking at how pension taxation could work in the future. The Chancellor, George Osborne, has said that he expects to reveal the findings and the direction he is going to take during the March Budget. But is there any way to take an advance look at the situation? What has the Chancellor considered and what might his decision be in March?
Whilst there are no certainties in this situation, Scottish Widows in particular has identified a number of key ingredients it believes could make the system successful. These ideas may well have made it into consultation responses, so it's this sort of thing that the Chancellor may well be debating over, as we type!
Employers must remain positively incentivised to play a central role. Employers account for 80% of savings in our pension system (excluding the State Pension), where National Insurance Contribution (NIC) relief encourages employers to be much more generous than the law requires and often also encourages employees to save more in order to unlock higher levels of employer contribution.
A pension should offer a superior return compared to any alternatives. Under any new system there will be winners and losers relative to the current system. However, this is largely irrelevant once the old system has gone. Whether or not an individual will put money away over the long term for retirement depends on the extent to which it is more beneficial to do so over other savings options available to them (including ISAs or buy to let property.)
Incentives should apply to both the employed and the self employed. Whilst statutory employer contributions now make workplace pensions attractive to most employees, there is less incentive for the self employed, who make up 15% of the working population. A modern system should provide similar incentives to the self employed.
Tax relief should be promoted and appreciated. Research from Scottish Widows showed that only 15% of people fully understand the current pension tax system. People in 'net pay' arrangements have the least understanding with many unaware of any tax relief applying at all. Moving all schemes and products to operate on a 'Relief At Source' type basis would make relief more visible and a re-branding of tax relief to say a 'Government Incentive' could assist in more effective promotion and increased appreciation.
A simple message that applies to everyone. With ISAs, it doesn't matter who you are, there is a simple annual allowance that applies to everyone, every year. In pensions, the complex interaction between annual allowances, lifetime allowances and tapers, prevent Government, employers and the pensions industry from effectively promoting a simple message which applies universally.
The system should encourage people to behave responsibly at retirement. The current tax arrangements act as a braking mechanism which prevent people taking all of their pension pot early and spending it too quickly. When people spend their pension pots too quickly it places additional pressure on taxpayers to sustain them in later retirement and therefore any new system needs to consider an appropriate braking mechanism.
Provide assurance against double taxation. Individuals will be wary of saving through a vehicle where they could bare tax on the same money more than once. This could be the case at an individual level where an individual's marginal rate of tax changes between the stages of accumulation and retirement. A carefully designed system will address this potential issue. There is also a concern that a future Government could be forced to tax retirement savings in times of economic necessity, although this could be addressed by assuring savers that in such extreme circumstances, pension assets would be no more at risk from taxation than any other form of savings.
Sources: www.scottishwidows.co.uk (Press release: 2016/01/08)


text:
Home / Research
Together, BBE and its affiliated laboratories provide outstanding opportunities to carry out cutting-edge work in fundamental, translational, and applied research across a broad spectrum of life sciences.
The science of biology is in the midst of a revolution. Application of the methods and concepts of mathematics, physics, chemistry, engineering, and information science are providing deep insight into classical biological problems such as the nature of heredity, the control of protein function, the regulation of gene expression in cells, the regulation of cellular activity, the mechanisms of growth and development, and the nature and interactions of nerve activity, brain function, and behavior. In addition, this confluence is nurturing new disciplines such as synthetic biology and systems biology.
Biochemistry, Structural, and Molecular Cell Biology offer a broad continuum of approaches to understand the fundamental basis for how protein and RNA molecules function and how their activities are regulated.
Biological engineering research at Caltech focuses on the application of engineering principles to the design, analysis construction, and manipulation of biological systems.
The broad fields of Developmental Biology and Genetics are highly interdisciplinary with a presence in all basic medical-science areas, as well as animal and plant biology.
We utilize microorganisms to explore basic biology and biochemistry problems, understand the physical principles governing biological systems, investigate mechanisms that underpin the robustness, stability, and design of complex networks, and explore the interactions among microbes in communities and between microbes and their environment.
Understanding the brain remains one of the great intellectual challenges for science, and it requires the integration of approaches from many disciplines. Caltech Neuroscience research spans a wide range of subjects: the molecular function of receptors; signaling organelles like the synapse; the structure and function of single neurons; the assembly and function of circuits of nerve cells; and the collective function of brain systems in controlling behavior, perception, memory, cognition, and emotion.
Systems Biology seeks to understand how the parts of biological systems are integrated to produce amazing machines, cells, organisms, and ecosystems that exist in our world. We thus seek to define general principles of biological systems. Part of understanding biological systems involves defining the relevant parts of a biological network and measuring how they change in a quantitative and comprehensive fashion as they carry out their functions; such network biology studies use the tools of genomics, proteomics, and bioinformatics.
Caltech has a long history of evolutionary and organismal biology, including Thomas Hunt Morgan's foundational contributions to population genetics and evolutionary theory, Seymour Benzer's groundbreaking work on the molecular biology of circadian rhythms and behavior in fruit flies, and pioneering neuroethological studies of birds by Marc Konishi. The strong tradition of evolutionary and organismal science at Caltech continues today in the laboratories of numerous faculty in the Division of Biology and Biological Engineering.
Faculty and Alumni
National Medals of
Faculty Members of the National
Members of Academy
of Arts & Sciences


text:
BOYS BASKETBALL: Renaissance brings Jordan, Jr. on board as new boys hoops coach
By: Scott Burnstein, June 28, 2013, 10:00 am
Detroit Renaissance is hoping that Venias (Vito) Jordan, Jr. is the man that leads the Phoenix back to the Promised Land on the boys basketball floor.
Jordan, Jr., only three months removed from leading Detroit Community into the Class B state championship game, was recently hired as Renaissance's new head coach, replacing Cameron Nichols.
While under Nichols the Phoenix were always one of the better teams in the PSL, they weren't at the very top of the heap in the state as they were in the 2000s with Mark White at the helm.
When White (currently head coach at Adrian College) held the clipboard, the program took home two state titles in a three-year span (2004 and 2006) and were pumping out high-grade Division I college recruits like Ricky Paulding (Missouri), Joe Crawford (Kentucky), Malik Hairston (Oregon) and Tajuan Porter (Oregon). Paulding, Crawford and Hairston were all drafted into the NBA.
Nichols was on the bench guiding the Phoenix for six years.
Renaissance hasn't made a deep run in the state tournament in a number of seasons.
Community lost to Birmingham Detroit Country Day, 57-49, in the state finals in March at the Breslin Center. Bo Ziegler, an athletic, versatile 6-foot-7 swingman and Jordan, Jr.'s best player this year, is headed off to play his college hoops at the University of South Florida.
Jordan, Jr. played basketball and football at Alma College.
The Phoenix will return six varsity lettermen for the 2014 campaign, including a pair of intriguing sophomores in center Aleric Jackson and guard Justin Turner. Incoming senior James Murray will be the club's captain.


At six weeks old, Amelia Jackson is thriving and it is all thanks to a special 'wallet' and the midwifery team at the town's hospital.
Pete and Bev Jackson, of Winteringham, are celebrating the birth of Amelia after the tragic loss of her big sister Alicia who was born sleeping in February last year.
It was thanks to a 50p plastic wallet, that is being given to all pregnant women who come through Scunthorpe, Grimsby and Goole hospitals, that Pete and Bev sought help.
Pete said: "I am in no doubt that the wallet, and the amazing staff saved Amelia's life. The wallet says to trust your instincts and that is exactly what we did. Bev had some pelvic pains so we went to the pregnancy assessment unit to get checked out.
The scan showed an abnormality with the placenta and Bev was rushed to the labour ward for further observations. Nick Kerry, bereavement midwife, had been caring for the couple through her rainbow clinic and came in on her day off to be with the couple.
Nick said: "Thankfully Pete and Bev had been in the hospital for an eye appointment. Bev had a niggling pain and acting on the information on the wallet popped into the midwifery unit.
The colourful plastic wallets, which have been bought by Scunthorpe and Grimsby League of Friends, feature easy to understand key advice regarding mum's health, and that of the baby.
Nick, who saw the wallets at an 'Our Angels' conference, called on the League of Friends at Grimsby and Scunthorpe to help fund the information wallets. They both jumped at the chance to help local families and handed over enough money for Nick to buy 4,500 of the MAMA Wellbeing Wallets.
Nick said: "The wallets are great for women to store notes, scan photos and leaflets. They are also a fantastic way for women to educate themselves about their pregnancy.
They both paid tribute to the staff who they met on their rainbow journey including Rick, the sonographer who they always saw for their scans, the midwives and reception staff.
Heidi Eldridge, chief executive of the stillbirth prevention charity, MAMA Academy, said: "After the tragic loss of my stillborn son, Aidan, I wish I had been told the signs and symptoms to look out for in case my baby was not well during my pregnancy.
"When I discovered the UK has one of the highest stillbirth rates in the developed world, I took action by setting up MAMA Academy and creating our Wellbeing Wallets to empower parents with essential information so they have the confidence to approach their maternity team with any concerns.


text:
Лідія Луківна Потарикіна (27 липня 1923, Київ — 13 серпня 2008, Київ) — українська радянська учений-юрист, доктор юридичних наук (з 1973), професор (з 1976). Державна премія УРСР в галузі науки і техніки 1981 року (за участь у створенні колективної монографії «Історія держави і права Української PCP»).

Життєпис
Народилася у Києві в родині робітника. Член КПРС з 1943 року. Учасниця Німецько-радянської війни.

1949 року закінчила юридичний факультет Київського університету. З 1949 року (від часу заснування Інституту держави і права) до 1973 року — молодший, згодом — старший науковий співробітник Сектора держави і права УРСР, потім Інституту держави і права АН УРСР. У 1973—1997 — професор кафедри теорії та історії держави і права юридичного факультету Київського національного університету ім. Тараса Шевченка. Від 1997 року — професор Інституту адвокатури при цьому університеті.

Автор наукових праць з історії держави і права, державного права. Нагороджена орденом Вітчизняної війни ІІ ст. та 8 медалями.

Основні праці
 Охорона соціалістичної власності — одна з основних функцій Радянської держави (Київ, 1955);
 Сільські Ради і соціально-культурне будівництво (Київ, 1955);
 Ревкоми України в 1918—1920 років (Київ, 1957);
 3 історії органів контролю УРСР (Київ, 1966);
 Ленінські принципи державного контролю (Київ, 1969);
 Органы государственного контроля Украинской ССР в условиях строительства социализма 1917-1934 гг. (Київ, 1972);
 Історія держави і права Української РСР (т. 1—2, 1987; у співавторстві).

Примітки

Джерела
 Українська радянська енциклопедія
В. П. Горбатенко.  Потарикіна  //
 Ковальчук О. М. Потарикіна Лідія Луківна

Українські правники
Доктори юридичних наук України
Уродженці Києва
Науковці Київського університету
Члени КПРС

redpajama_set_name: RedPajamaWikipedia


text:
1st Annual Pizza Prize
Contest Results
Kathy Bruce
Kathy Bruce is an Ithaca, New York-born artist based in Scotland. She received an MFA from Yale University and a certificate from The Pennsylvania Academy of the Fine Arts. Her work explores archetypal female and mythological forms within the context of poetry, literature, and the natural environment. Ms. Bruce is the recipient of numerous grants and awards including a Pollock-Krasner Foundation Fellowship, Pennsylvania Council on the Arts Individual Artist Grant, two Fulbright-Hayes scholar grants to Peru, and a Ford Foundation Grant. She has exhibited her work in the U.S. and internationally including in Senegal, Taiwan, Denmark, Peru, France, and Canada.
These images—with the exception of Feral Ecologies and What is Scotland—are from a new series of collages titled, What is Artificial in a World that Needs to be Authentic? in which I have been thinking about the notion of objectification of the female image in popular culture, particularly in the realm of Kitsch. The resulting images of women and girls portrayed as traditional figurines of presumably self-objectifying figures reflect classical standards of beauty no doubt derived from the male gaze. These reconfigured images are meant to bring up questions regarding the objectification of female identities in contemporary culture.
Feral Ecologies; Cover art
Interview with the Artist
When did you first begin making art? What was your first medium?
I always drew and painted throughout my entire childhood. I can't remember a time when I didn't make art. I'm not sure where the impulse came from except perhaps from my paternal grandmother who made everything by hand herself—clothing, crocheted table clothes, rugs. She gave my sister and me complete creative freedom in her home and dumped construction paper, magazines, rickrack, and buttons into a big pile on her dining room table where we spent hours playing with materials. I loved that. Once, at age four, I displayed all of my artwork on the living room couch and invited my family and friends to view the "art exhibition." I priced the works at 4-10 cents depending on the quality of the piece. I was insulted when a neighbor snatched one of the best works and paid me with a piece of Bazooka bubblegum instead of cash! Early lessons on the art market! Later, in art school, I studied painting but the limitations of paint as a medium sent me in the direction of sculpture which enabled me to work freely with a vast multitude of different materials that are more closely related to creating collages. It took me a long time before I realized that collage was an acceptable art form in its own right—as unique and serious as painting and sculpture.
Who were your early inspirations as an artist?
People assume that visual artists are influenced primarily by other visual artists but this isn't necessarily true. My early artistic inspirations came from listening to Beethoven's symphonies, running through fields and woods, reading biographies of famous women, and absorbing The Captain's Verses by Pablo Neruda. These ideas triggered my imagination. Later, while on a Fulbright scholar grant I was deeply affected by a year in Peru where every aspect of my life was affected by the art and culture. As a result, I eventually spent a year backpacking around South America—absorbing the astounding natural environment, ancient art, and architecture while cultivating my aesthetic vision.
What is Artificial in a World that Needs to be Authentic?
Who are your biggest inspirations today?
Poetry, literature, and the environment continue to be great catalysts for my creativity today; I think artists go through phases where certain artists resonate deeply in relationship to one's own creative process at the time. As a woman, I owe a deep debt to the Surrealist women artists: Mina Loy, Dorothea Tanning, and Leonora Carrington. Lifelong favorites continue to be Velazquez, Francis Bacon, William Blake, David Lynch, and, more recently, Alexander McQueen. Of course 18th C Spanish Colonial/ Peruvian religious Art is always a staple that has been the subject of an ongoing collage series, "Tapadas, Saints and other Heroines." Then there are many incredible contemporary artists that aren't necessarily famous or well known but who I am in awe of because we are all a part of this time in which we are living now.
What draws you to the subject matter you choose?
It is important to me as a woman that I am making images of women at a time when it's okay for me to do so and not ok for male artists because of the historical baggage of the "Male Gaze'. I feel extremely fortunate as a visual artist that all of my interests in life (Peru, women, medical biology, environmental, literary, historical) can be incorporated—like conducting an orchestra—into my work. I always feel excited and stimulated by the process.
What is Scotland?
What does the process of art-making look like for you? From what you consider the "beginning" of a piece to what you consider the "finished" piece?
In my collages, they begin with a scrap or fragment that is built upon until it reaches its organic borders. I never work on rectangular or predetermined sizes of paper. The result is irregular edges, I find it impossible to stay within a limited border. The backsides of the collages look like a patchwork quilt. I'm not sure how to explain when a piece is finished—it's intuitive I guess.
What draws you to collage? What other mediums, if any, do you work in, and what influences your choice of medium when beginning a new work?
I work in sculpture and collage. The building process is the same although the materials and scale are not. The only difference is that the collages are flat and the sculptures are 3-dimensional. The small scale allows me to incorporate more detail and colors while the sculptures require a more general approach to form because they are quite large.
Examination or Repairing the Damage
Where do you find your collage materials?
Anything paper has the potential to trigger a collage, finding materials isn't a methodical process. I usually search for materials related to my current interest at the time. At the moment, for example, I am interested in early porcelain figurines so I have been photographing them in antique shops and searching for images of them in old books.
Your work "explores archetypal female and mythological forms within the context of poetry, literature, and the natural environment." Do you intend to draw any conclusions in this exploration? If so, what might your work argue? And, either way, what questions do you hope to invoke for your audience?
Meaning to me is intrinsic, complex, multi-layered. I don't expect everyone to interpret the meaning in the same way as I do and that is okay. I am happy for people to interpret with what they bring to the images. I don't have any conclusions to draw regarding my work…I would agree with Francis Bacon who once said, "The job of the artist is always to deepen the mystery."
Is there anything else you'd like to share?
I'm thrilled to share that my collages have been recently published in the 2021 updated version of the Thames and Hudson World of Art Series, "Photomontage," by renowned art historian Dawn Ades. It is an honor to find my work in the art historical canon of collage greats.
Pride of Possession
© Variant Literature Inc 2021


text:
Home Business New Maruti WagonR Stingray to be launched on August 21, 2013 in...
New Maruti WagonR Stingray to be launched on August 21, 2013 in India
By Nicholas -
Indian auto giant Maruti is all set to launch its WagonR Stingray model on August 21, 2013, in Delhi. In addition to that, Internet has been flooded with leaked pictures of the new car, which show its exterior and interior.
solar panel systems
The pictures posted online have showed that the new interiors are quite similar to that of the current WagonR, except there is an addition of steering-mounted audio controls and an all-black. However, there are certain changes when it comes to the exterior, such as slim headlamps which house projector-beam units, a flat front bonnet, a slimmer chrome grille and a completely new bumper which has a larger air dam and slightly restyled fog-lamp housings.
The rear portion has slimmer tail-lamps with clear lens units, a new chrome strip over the license plate with bold WagonR Stingray badging and a rear spoiler. When it comes to mechanicals, the new model is expected to carry the same three-cylinder 67bhp 1.0-liter K10 series motor in the current WagonR.
It is essential that the new WagonR differs from the current WagonR and to sit above it. So far, nothing has been announced in terms of pricing, but it is expected that the upcoming model will be priced between Rs. 40,000 and Rs. 50,000 more than the current version.
Photo Credits: Car Toq
2013 wagon r
new wagon R
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text:
Q: AWS Cognito Identity Service Provider appears to store access token in local storage. Is this safe? We are developing an application that uses a React front end website hosted on AWS using Amplify. This communicates with a .NET Core 3.1 Web API running on EC2 / Elastic Beanstalk. Cognito is used for user authentication with the Web API configured to use JWT tokens.
It works OK, but we have noticed that the Cognito provider stores the JWT access token in the browser local storage. This is what we see using F12 in Chrome and inspecting local storage.

From what we have read, storing access tokens in local storage is not advised as it makes the application susceptible to XSS attacks. Strange then, that the Cognito identity provider chooses to store sensitive information here.
If this approach is not considered safe, can the provider be configured to store this information elsewhere, such as cookies?
Alternatively, as we control both front and back ends, is there an alternative method that can be used to secure the API that does not involve tokens? Obviously the API needs to know which user is logged on to the web application in order to perform authorization checks. [Note authorization in the application is record level and defined in database tables, so it goes beyond simple user profile attributes.]
Many thanks in advance for your advice.
Doug

A: Security is a spectrum not a feature so it really depends on your appetite for risk vs effort. Amplify is not a particularly nice codebase, it has 500+ issues and if you look at the code you might be fairly shocked at the quality of it.
If you are using Hosted-UI then you can write code to manage the tokens yourself rather than using amplify, although you will need to learn a bit about OAuth grants and OIDC.
Be aware that the Hosted UI lacks a huge amount of features, so if you are going to use it make sure you are happy with it. Off the top of my head

*

*no silent refresh capability in the hosted UI, so no safe way to store the refresh token.

*no support for custom auth flow in the hosted UI

*no passwordless support in the hosted UI

*no ability to pre-populate a field in the hosted UI (e.g. username)

*no ability to customise the plethora of obscure error messages in the custom UI

*fixed now, but for years the email addresses were case sensitive!

An alternative is also to just use the AWS SDK to get tokens directly using cognito-idp but this also has a bunch of issues:

*

*no code/PKCE/nonce capability so insecure in a mobile authsession

*no ability to set oauth scopes, so can't use them

*consequently not possible to use for OIDC

*the SRP implementation is bananas and so far off spec

*if you make device registration mandatory, it will deliver a working access tokens before the device is registered! (allows invisible devices for malicious logins)

We were using auth0 which was leagues ahead but we had to move to Cognito because of SMS OTP cost (min $25k per year at auth0).
I have been using AWS for over a decade now, Cognito is by far the worst service I have used, and I have used a lot! If you can avoid it, do so.
To answer the original question, yeah it's insecure. The best you can probably do is keep them in memory. If you wanted to you could probably put the hosted UI behind a cloudfront and use an lambda@edge to transform the token into a cookie instead. This has now opened you up to CSRF attacks though.

A: answering the original question: no, it is not safe at all.
Storing refreshtoken in any local storage accessable to any local app/script is not secure. So, the best way would be to store the refreshoten (and also the access token) in an httponly cookie or even better to store a one-time session token in httponly secure cookie could be used to get new access and refresh cookies - similarly as it is made by cognito hosted ui with XSRF-TOKEN.
See below how I would solve (and plan to solve) this issue:
Some background:
Due to GDPR regulations I think I can not use the cognito hosted ui - I have to make sure users read and accept the general terms and conditions (giving clear and auditable consent) and can review and accept cookie policies as well before they type in any user data for sign up. Nevertheless the built in hosted ui design is quite outdated and unflexible. I have an SPA website where I want to manage users, secure endpoints, etc.
So I have the following idea which is still not super secure but I think it is more secure one if you want to use js and ampify sdk and which also might answer your question:
I'll use amplify javascript sdk to let users sign up, change psw and log in (get tokenid, access token and refresh token), will make my own "hosted ui". I'll store the access token in memory only (not in local cookies and not in localstorage for sure). Access token will be used in header (bearer) to access apiGW endpoints. Access tokens will have very short expire dates.  (I'd also use httponly secure cookies sent back by the apigw, as well as in the body.., then compare at BE side..)
And here comes the trick: I'd cut the refresh token into two. (Don't forget it is just a string.) I'd store the first part of the string in a local cookie (javascript can read it, if browser is closed and opened again it will be still there) and will send the other half of the refresh token to an apiGW endpoint (accessable without authentication) which will store it in a dynamoDB table (with TTL) and will send back an httponly secure cookie to the browser with a randomly generated "storagetoken" in it (which will be a key in dynamodb). There will be another unauthenticated apigw endpoint which will be called by the client whenever the client needs the full refresh token. Calling this endpoint the browser will send in the httponly secure cookie as well (same domain), so the backend will get it. As it is issued by the BE and available only in the given browser it can not be stolen so the backend  will send back the stored half refreshtoken. The other half part of refreshtoken is stored in a simple cookie in the browser.
If the browser is closed and opened again client checks if there is any valid accesstoken and if not it checks if there is a half refeshtoken stored as cookie. Then ask the other part of refreshtoken assuming there is a httponlycookie also stored and it will get back the other part of the refreshtoken from the BE. In case of success the client tries to use the full refreshtoken to renew/get access token from cognito, in case of failure it will pop up the login screen.
Whenever refreshtoken is not in use it is deleted from the memory.
I know this is still not supersecure but might be a better solution than storing refresh token in localstorage.

A:
Alternatively, as we control both front and back ends, is there an alternative method that can be used to secure the API that does not involve tokens?

I don't know anything of Amplify but in AWS Cognito what you describe is the Implicit grant OAuth flow. In AWS Cognito it is possible to use Authorization code grant where you instead of the token get a code which you in the backend can exchange for a user pool token.
https://docs.aws.amazon.com/cognito/latest/developerguide/cognito-user-pools-configuring-app-integration.html