IgE antibodies may be protective in parasite immunity, but their aberrant production can lead to allergic disease and life-threatening anaphylaxis. Despite the importance of IgE regulation, few ...studies have directly examined the B cells that express IgE, because these cells are rare and difficult to detect. Here, we describe fluorescent IgE reporter mice and validate a flow cytometry procedure to allow sensitive and specific identification of IgE-expressing B cells in vivo. Similar to IgG1+ cells, IgE+ B cells differentiated into germinal center (GC) B cells and plasma cells (PCs) during primary immune responses to a T cell-dependent hapten-protein conjugate and the helminth Nippostrongylus brasiliensis. However, the participation of IgE+ B cells in GCs was transient. IgE+ B cells had an atypical propensity to upregulate the transcription factor Blimp-1 and undergo PC differentiation. Most IgE+ PCs were short lived and showed reduced affinity maturation, revealing intrinsic mechanisms that restrict the IgE antibody response.
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► Reporter mice and intracellular staining can reliably detect IgE+ B cells in vivo ► IgE+ B cells can differentiate into GC B cells, but participation in GCs is limited ► IgE+ B cells exhibit elevated Blimp-1 expression and PC differentiation ► IgE+ B cells tend to become short-lived PCs, thus restraining cell numbers
Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the ...contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13—expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.
Inappropriate Sinus Tachycardia Olshansky, Brian, MD; Sullivan, Renee M., MD
Journal of the American College of Cardiology,
02/2013, Letnik:
61, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Inappropriate sinus tachycardia (IST) is a syndrome in which the sinus heart rate is inexplicably faster than expected and associated symptoms are present. The heart rate at rest, even in a supine ...position, can exceed 100 beats/min; minimal activity accelerates the rate rapidly and substantially. Patients with IST may require restriction from physical activity. Mechanisms responsible for IST are understood incompletely. It is important to distinguish IST from so-called appropriate sinus tachycardia and from postural orthostatic tachycardia syndrome, with which overlap may occur. Because the long-term outcome seems to be benign, treatment may be unnecessary or may be as simple as physical training. However, for patients with intolerable symptoms, therapeutic measures are warranted. Even at high doses, β-adrenergic blockers, the first-line therapy, often are ineffective; the same is true for most other medical therapies. In rare instances, catheter- or surgically- based right atrial or sinus node modification may be helpful, but even this is fraught with limited efficacy and potential complications. Overtreatment, in an attempt to reduce symptoms, can be difficult to avoid, but is discouraged.
The ε4 allele of the apolipoprotein E (
) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our ...current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human
(5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti-Aβ antibody had no effect on CAA. Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.
A superconducting interfaceInterfaces between materials can harbor quantum states that belong to neither of the materials. A classic example is the superconducting interface between two insulating ...oxides, LaAlO3 and SrTiO3, with a critical temperature of around 200 millikelvin. Liu et al. observed superconductivity at a different interface—formed between KTaO3 as a substrate and an overlayer of either EuO or LaAlO3—at a considerably higher temperature of about 2 kelvin. Transport measurements displayed anisotropy, which may indicate an unusual superconducting state.Science, this issue p. 716The distinctive electronic structure found at interfaces between materials can allow unconventional quantum states to emerge. Here we report on the discovery of superconductivity in electron gases formed at interfaces between (111)-oriented KTaO3 and insulating overlayers of either EuO or LaAlO3. The superconducting transition temperature, as high as 2.2 kelvin, is about one order of magnitude higher than that of the LaAlO3/SrTiO3 system. Notably, similar electron gases at KTaO3 (001) interfaces remain normal down to 25 millikelvin. The critical field and current-voltage measurements indicate that the superconductivity is two-dimensional. In EuO/KTaO3 (111) samples, a spontaneous in-plane transport anisotropy is observed before the onset of superconductivity, suggesting the emergence of a distinct “stripe”-like phase, which is also revealed near the critical field.
Summary Background Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the ...condition, and to provide a framework for researchers to assess new risk markers. Methods We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45–95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine echocardiographic measurements (5152 participants, 7156 examinations) to reclassify the risk of atrial fibrillation and to assess whether these measurements improved risk prediction. Findings 457 (10%) of the 4764 participants developed atrial fibrillation. Age, sex, body-mass index, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, and heart failure were associated with atrial fibrillation and incorporated in a risk score (p<0·05, except body-mass index p=0·08), clinical model C statistic 0·78 (95% CI 0·76–0·80). Risk of atrial fibrillation in 10 years varied with age: more than 15% risk was recorded in 53 (1%) participants younger than 65 years, compared with 783 (27%) older than 65 years. Additional incorporation of echocardiographic measurements to enhance the risk prediction model only slightly improved the C statistic from 0·78 (95% CI 0·75–0·80) to 0·79 (0·77–0·82), p=0·005. Echocardiographic measurements did not improve risk reclassification (p=0·18). Interpretation From clinical factors readily accessible in primary care, our risk score could help to identify risk of atrial fibrillation for individuals in the community, assess technologies or markers for improvement of risk prediction, and target high-risk individuals for preventive measures. Funding US National Institutes of Health.
Over the past century, many of the world's major rivers have been modified for the purposes of flood mitigation, power generation and commercial navigation. Engineering modifications to the ...Mississippi River system have altered the river's sediment levels and channel morphology, but the influence of these modifications on flood hazard is debated. Detecting and attributing changes in river discharge is challenging because instrumental streamflow records are often too short to evaluate the range of natural hydrological variability before the establishment of flood mitigation infrastructure. Here we show that multi-decadal trends of flood hazard on the lower Mississippi River are strongly modulated by dynamical modes of climate variability, particularly the El Niño-Southern Oscillation and the Atlantic Multidecadal Oscillation, but that the artificial channelization (confinement to a straightened channel) has greatly amplified flood magnitudes over the past century. Our results, based on a multi-proxy reconstruction of flood frequency and magnitude spanning the past 500 years, reveal that the magnitude of the 100-year flood (a flood with a 1 per cent chance of being exceeded in any year) has increased by 20 per cent over those five centuries, with about 75 per cent of this increase attributed to river engineering. We conclude that the interaction of human alterations to the Mississippi River system with dynamical modes of climate variability has elevated the current flood hazard to levels that are unprecedented within the past five centuries.
Abstract
The formation of the first stars in the high-redshift Universe is a sensitive probe of the small-scale, particle physics nature of dark matter (DM). We carry out cosmological simulations of ...primordial star formation in ultralight, axion-like particle DM cosmology, with masses of 10−22 and 10−21 eV, with de Broglie wavelengths approaching galactic scales (∼ kpc). The onset of star formation is delayed, and shifted to more massive host structures. For the lightest DM particle mass explored here, first stars form at z ∼ 7 in structures with ∼109 M⊙, compared to the standard minihalo environment within the Λ cold dark matter (ΛCDM) cosmology, where z ∼ 20–30 and ∼105–106 M⊙. Despite this greatly altered DM host environment, the thermodynamic behaviour of the metal-free gas as it collapses into the DM potential well asymptotically approaches a very similar evolutionary track. Thus, the fragmentation properties are predicted to remain the same as in ΛCDM cosmology, implying a similar mass scale for the first stars. These results predict intense starbursts in the axion cosmologies, which may be amenable to observations with the James Webb Space Telescope.
One reason librarians are confident they have a role to play in fighting misinformation is the level of trust in libraries as institutions. Exactly how they might leverage that trust remains unclear ...and untested. Building on recent work in correcting health misperceptions on social media, this study tests whether libraries can leverage trust to combat misinformation online. Using a misperception about the influenza vaccine as a test case, an experiment (n = 625) was conducted in fall 2018 using Amazon's Mechanical Turk. Results suggest that the misperception can be reduced, but not by library institutions. An unsuccessful follow-up (n = 600) suggests that the effectiveness of the correction is season dependent and opens the possibility that libraries may yet play a role, but not necessarily because they are trusted. Future library proposals for combating misinformation need to be developed and tested within a broader contemporary misinformation research program.
•Librarians are confident they have a role to play in fighting misinformation, but their solutions remain untested.•This study tests whether libraries can leverage trust online to reduce a misperception about the influenza vaccine.•Results suggest that the misperception can be reduced, but perhaps not by library institutions and not because of trust.•The study introduces a research tool (Amazon's MTurk) and initiates a new misinformation research program.•Future work needs to demonstrate the effectiveness of library solutions within that research program.
High-quality collections of Type II supernova (SN) light curves are scarce because they evolve for hundreds of days, making follow-up observations time consuming and often extending over multiple ...observing seasons. In light of these difficulties, the diversity of SNe II is not fully understood. Here we present ultraviolet and optical photometry of 12 SNe II monitored by the Las Cumbres Observatory Global Telescope Network during 2013 to 2014, and compare them with previously studied SNe having well-sampled light curves. We explore SN II diversity by searching for correlations between the slope of the linear light-curve decay after maximum light (historically used to divide SNe II into IIL and IIP) and other measured physical properties. While SNe IIL are found to be on average more luminous than SNe IIP, SNe IIL do not appear to synthesize more 56Ni than SNe IIP. Finally, optical nebular spectra obtained for several SNe in our sample are found to be consistent with models of red supergiant progenitors in the 12–16 M⊙ range. Consequently, SNe IIL appear not to account for the deficit of massive red supergiants as SN II progenitors.
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