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Aims Prediction of mitral (MR) and tricuspid (TR) regurgitation progression on transthoracic echocardiography (TTE) is needed to personalize valvular surveillance intervals and prognostication. Methods and results Structured TTE report data at Beth Israel Deaconess Medical Center, 26 January 2000–31 December 2017, were used to determine time to progression (≥1+ increase in severity). TTE predictors of progression were used to create a progression score, externally validated at Massachusetts General Hospital, 1 January 2002–31 December 2019. In the derivation sample (MR, N = 34 933; TR, N = 27 526), only 5379 (15.4%) individuals with MR and 3630 (13.2%) with TR had progression during a median interquartile range) 9.0 (4.1–13.4) years of follow-up. Despite wide inter-individual variability in progression rates, a score based solely on demographics and TTE variables identified individuals with a five- to six-fold higher rate of MR/TR progression over 10 years (high- vs. low-score tertile, rate of progression; MR 20.1% vs. 3.3%; TR 21.2% vs. 4.4%). Compared to those in the lowest score tertile, those in the highest tertile of progression had a four-fold increased risk of mortality. On external validation, the score demonstrated similar performance to other algorithms commonly in use. Conclusion Four-fifths of individuals had no progression of MR or TR over two decades. Despite wide interindividual variability in progression rates, a score, based solely on TTE parameters, identified individuals with a five- to six-fold higher rate of MR/TR progression. Compared to the lowest tertile, individuals in the highest score tertile had a four-fold increased risk of mortality. Prediction of long-term MR/TR progression is not only feasible but prognostically important. [ABSTRACT FROM AUTHOR]

Tregs play a pivotal role in inducing and maintaining donorspecific transplant tolerance. The T cell immunoglobulin and mucin domain-3 protein (TIM-3) is expressed on many fully activated effector T cells. Along with program death 1 (PD-1), TIM-3 is used as a marker for exhausted effector T cells, and interaction with its ligand, galectin-9, leads to selective death of TIM-3+ cells. We report herein the presence of a galectin-9-sensitive CD4+FoxP3+TIM-3+ population of T cells, which arose from CD4+FoxP3 +TIM-3- proliferating T cells in vitro and in vivo and were often PD-1+. These cells became very prominent among graft-infiltrating Tregs during allograft response. The frequency and number of TIM-3+ Tregs peaked at the time of graft rejection and declined thereafter. Moreover, these cells also arise in a tolerance-promoting donorspecific transfusion model, representing a pool of proliferating, donorspecific Tregs. Compared with TIM-3- Tregs, TIM-3+ Tregs, which are often PD-1+ as well, exhibited higher in vitro effector function and more robust expression of CD25, CD39, CD73, CTLA-4, IL-10, and TGF-β but not galectin-9. However, these TIM-3+ Tregs did not flourish when passively transferred to newly transplanted hosts. These data suggest that a heretofore unrecognized graftinfiltrating, short-lived subset of Tregs can restrain rejection., Introduction A hallmark of an adaptive immune response is differentiation and clonal expansion of T effector cell (Teff) populations, including Th1, Th2, Th17 cells, and Tregs (1-4). T cell immunoglobulin [...]

Stem cells reside in a specialized regulatory microenvironment or niche (1,2), where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity (1-3). The niche may also protect stem cells from environmental insults (3) including cytotoxic chemotherapy and perhaps pathogenic immunity (4). The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression (4). We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche (1,2,5-7) in the bone marrow, a site where immune reactivity exists (8,9). We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T ([T.sub.reg]) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with [T.sub.reg] cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. [T.sub.reg] cells seem to participate in creating a localized zone where HSPCs reside and where [T.sub.reg] cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack., Despite rapid advances in our understanding of adult stem-cell biology, the immunological attributes of somatic stem-cell niches have remained largely unexplored. We hypothesized that the HSPC niche within the bone [...]

While many candidate type 1 diabetes (T1D) susceptibility genes have been identified, evidence suggests that environmental stimuli, such as viral infections, may also be involved in T1D pathogenesis. However, how viral infections may prevent or trigger the diabetogenic process remains unclear. In this issue of the JCI, Filippi et al. show that infection of NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus, neither of which directly destroys insulin-secreting pancreatic [beta] cells, triggers the activation of two distinct immunoregulatory mechanisms, involving both the innate and adaptive immune system, that protect against the development of T1D in these animals (see the related article beginning on page 1515)., Immune-mediated destruction of insulin-secreting pancreatic [beta] cells results in type 1 diabetes (T1D). Genetic factors, including genes that regulate facets of the immune response, influence the susceptibility of an individual [...]

Invasive insulitis is a destructive T cell-dependent autoimmune process directed against insulin-producing [beta] cells that is central to the pathogenesis of type 1 diabetes mellitus (T1DM) in humans and the clinically relevant nonobese diabetic (NOD) mouse model. Few therapies have succeeded in restoring long-term, drug-free euglycemia and immune tolerance to [beta] cells in overtly diabetic NOD mice, and none have demonstrably enabled enlargement of the functional [beta] cell mass. Recent studies have emphasized the impact of inflammatory cytokines on the commitment of antigen-activated T cells to various effector or regulatory T cell phenotypes and insulin resistance and defective insulin signaling. Hence, we tested the hypothesis that inflammatory mechanisms trigger insulitis, insulin resistance, faulty insulin signaling, and the loss of immune tolerance to islets. We demonstrate that treatment with [alpha]1-antitrypsin (AAT), an agent that dampens inflammation, does not directly inhibit T cell activation, ablates invasive insulitis, and restores euglycemia, immune tolerance to [beta] cells, normal insulin signaling, and insulin responsiveness in NOD mice with recent-onset T1DM through favorable changes in the inflammation milieu. Indeed, the functional mass of [beta] cells expands in AAT-treated diabetic NOD mice. autoimmunity | type 1 diabetes | inflammation

T cell Ig mucin (Tim) molecules modulate [CD4.sup.+] T cell responses. In keeping with the view that Tim-1 generates a stimulatory signal for [CD4.sup.+] T cell activation, we hypothesized that an agonist Tim-1-specific mAb would intensify the [CD4.sup.+] T cell--dependant allograft response. Unexpectedly, we determined that a particular Tim-1-specific mAb exerted reciprocal effects upon the commitment of alloactivated T cells to regulatory and effector phenotypes. Commitment to the Th1 and Th17 phenotypes was fostered, whereas commitment to the Treg phenotype was hindered. Moreover, ligation of Tim-1 in vitro effectively deprogrammed Tregs and thus produced Tregs unable to control T cell responses. Overall, the effects of the agonist Tim-1-specific mAb on the allograft response stemmed from enhanced expansion and survival of T effector cells; a capacity to deprogram natural Tregs; and inhibition of the conversion of naive [CD4.sup.+] T cells into Tregs. The reciprocal effects of agonist Tim-1-specific mAbs upon effector T cells and Tregs serve to prevent allogeneic transplant tolerance., Introduction T cell Ig mucin (Tim) molecules are structurally related to type I membrane glycoproteins expressed on T cells (1). Polymorphisms within the Tim gene locus are associated with susceptibility [...]

A field study was conducted to examine the turbulent properties of the flow around a naturally formed cluster bedform. This was carried out on a mountain river using a 3D acoustic Doppler velocimeter (ADV). Concurrent with this objective, the ability of the ADV to make measurements in a shallow flow over a cobble bed ([h.sub.o]/[d.sub.84] = 1.75) was examined. ADV measurements in natural clear-water shallow flows around obstacles are inherently difficult to obtain due to (1) signal interference between the acoustic reflections from the boundary and the ADV sample volume; (2) regions of high turbulent intensity, such as in local detached shear layers; and (3) low concentrations of suspended particles passing through the ADV sampling volume. These processes result in velocity time series that contain a significant amount of spikes, lower-than-average signal-to-noise ratios, and lower than average correlation values. A filtering process that optimized the removal of bad points while retaining a sufficient number of points to describe the velocity time series histogram was developed. In general, flow over the study section can be described by an inner roughness layer dominated by large roughness and detached flow, and an outer flow that exhibits a form of log scaling. It was found that the cluster acts to locally modify this structure by shifting the elevation of the roughness layer and the zone of primary production and dissipation of turbulent energy up towards the center of the water column. Mean and turbulent statistics, energy distributions, spectral properties, and a quadrant analysis are presented to characterize the flow around the cluster. CE Database subject headings: Turbulent flow; River beds; Bedforms; Gravel; Mountain streams; Measuring instruments; Flow measurement.

Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG)[sub.35-55]/IA[sup.b] (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3[sup.+] T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3[sup.+] T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4[sup.+]Foxp3[sup.+] T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation., Author(s): Thomas Korn [1]; Jayagopala Reddy [1]; Wenda Gao [2]; Estelle Bettelli [1]; Amit Awasthi [1]; Troels R Petersen [3]; B Thomas Backstrom [3]; Raymond A Sobel [4]; Kai W [...]

The present study examines the flow around a self-occurring cluster bed form and the use of general computation fluid dynamics methods for hydraulic and geophysical flow applications. This is accomplished through a comprehensive experimental/numerical investigation. In the laboratory, cluster bed forms are first formed from movable sediment, and laser Doppler velocimeter measurements of two-dimensional fluid velocity are then taken around a formed cluster. A three-dimensional (3D) Reynolds averaged Navier-Stokes simulation of the physical cluster and flow conditions is then conducted using near-wall, shear stress transport (SST) turbulence modeling with the inclusion of hydraulic roughness, [k.sub.s] (R = 31,150, [k.sub.s]/h = 0.1, [k.sup.+.sub.s] = 274, i.e., in the fully rough regime). SST near-wall modeling is advantageous compared to the more widely used wall functions approach for flows with significant roughness and flow separation because the model equations can be integrated down to the wall. Therefore, SST near-wall modeling makes no a priori assumption that the law of the wall is valid throughout the wall region of the flow. Additionally, it has the ability to intrinsically handle boundary roughness through the boundary condition for turbulent specific dissipation at the wall, allowing for wall functions to be bypassed in accounting for roughness effects. The study shows that in the wall region surrounding the cluster, flow is 3D and quite complex, with different scales of embedded flow structures dominating the cluster wake and leading to flow heterogeneities in pressure and bed-shear stress. Results also indicate that near-wall modeling with SST compared favorably with the experimental flow data without tuning of model constants. DOI: 10.1061/(ASCE)0733-9429(2007) CE Database subject headings: Bedforms; Microstructures; Turbulent flow; Numerical models; Simulation; Computational fluid dynamics technique; Hydraulic engineering.

Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private [alpha]-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor [beta]- and [gamma]-chains. The [gamma]-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the [gamma]-chain is called the common [gamma] or [gamma]-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the [gamma]-c expression. Decreased [gamma]-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo., Author(s): Xian Chang Li (corresponding author) [1]; Gulcin Demirci [1]; Sylvie Ferrari-Lacraz [1]; Chris Groves [2]; Anthony Coyle [2]; Thomas R. Malek [3]; Terry B. Strom [1] In contrast to [...]