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Echocardiographic assessment of left ventricular (LV) filling pressures is performed using a multi-parametric algorithm. Left atrial (LA) strain was recently found to accurately classify the degree of diastolic dysfunction. We hypothesized that LA strain could be used as a stand-alone marker and sought to identify and test a cutoff, which would accurately detect elevated LV pressures. We studied 76 patients with a spectrum of LV function who underwent same-day echocardiogram and invasive left-heart catheterization. Speckle tracking was used to measure peak LA strain. The protocol involved a retrospective derivation group (N = 26) and an independent prospective validation cohort (N = 50) to derive and then test a peak LA strain cutoff which would identify pre-A-wave LV diastolic pressure > 15 mmHg. The guidelines-based assessment of filling pressures and peak LA strain were compared side-by-side against invasive hemodynamic data. In the derivation cohort, receiver-operating characteristic analysis showed area under curve of 0.76 and a peak LA strain cutoff < 20% was identified as optimal to detect elevated filling pressure. In the validation cohort, peak LA strain demonstrated better agreement with the invasive reference (81%) than the guidelines algorithm (72%). The improvement in classification using LA strain compared to the guidelines was more pronounced in subjects with normal LV function (91% versus 81%). In summary, the use of a peak LA strain to estimate elevated LV filling pressures is more accurate than the current guidelines. Incorporation of LA strain into the non-invasive assessment of LV diastolic function may improve the detection of elevated filling pressures.

Current guidelines recommend that the atria be measured in 2D echocardiographic (2DE) apical views using the method-of-disks (MOD) or area-length (AL) technique as an alternative, although no definitive data exists that these are interchangeable. However, standard apical views maximize the long-axis of the left ventricle, rather than the dimensions of the atria, resulting in atrial foreshortening. We hypothesized that the increase in normal values of atrial volumes in the recent guidelines update was driven by data obtained using either the AL technique or dedicated atrial-focused views, which maximize the longitudinal dimension of the atria and thus provide larger volumes than the MOD measurements in standard apical views. We prospectively studied 30 patients (Philips iE33) to compare 2DE measurements of left and right atrial volumes (LAV, RAV) using the MOD and AL techniques in standard and atrial-focused views, against 3D echocardiography (3DE) derived volumes (QLab) as a reference. Compared to standard views, atrial-focused views provided significantly larger MOD volumes for both atria, which were in better agreement with 3DE, as reflected by higher correlation coefficients (LAV: r = 0.95 vs. 0.89; RAV: r = 0.89 vs. 0.84), smaller biases (LAV: −1 ml vs. 7 ml; RAV: 3 ml vs. 7 ml) and tighter limits of agreement. This was also the case for the AL measurements, which were minimally larger than the MOD values (NS) for both atria. In conclusion, atrial-focused views are a more accurate alternative to standard apical views, which provides larger volumes. This finding can explain the increase in the normal values in the recent guidelines update, which was mostly driven by the use of atrial-focused views, rather than by the differences between MOD and AL techniques. This understanding is essential in order to correctly integrate the revised normal values into clinical practice.

The importance of left ventricular (LV) global longitudinal strain (GLS) is increasingly recognized in multiple clinical scenarios. However, in patients with poor image quality, strain is difficult or impossible to measure without contrast enhancement. The feasibility of contrast-enhanced GLS measurement was recently demonstrated. We sought to determine: (1) whether contrast enhancement improves the accuracy of GLS measurements against cardiac magnetic resonance (CMR) reference, (2) their reproducibility compared to non-enhanced GLS, and (3) the dependence of accuracy and reproducibility on image quality. We prospectively enrolled 25 patients undergoing clinically indicated CMR imaging who subsequently underwent transthoracic echocardiography (TTE) with and without low-dose contrast injection (1–2 mL Optison/3–5 mL saline IV, GE Healthcare). GLS was measured from both non-contrast and contrast-enhanced images using speckle tracking (EchoInsight, Epsilon Imaging). These measurements were compared to each other and to CMR reference values obtained using feature tracking (SuiteHEART, NeoSoft). Inter-technique comparisons included linear regression and Bland–Altman analyses. A random subgroup of 15 patients was used to assess inter- and intra-observer variability using intra-class correlation (ICC). Contrast-enhanced GLS was in close agreement with non-enhanced GLS (r = 0.95; bias: − 0.2 ± 1.5%). Both inter-observer (ICC = 0.88 vs. 0.82) and intra-observer variability (ICC = 0.91 vs. 0.88) were improved by contrast enhancement. The agreement with CMR was better for contrast-enhanced GLS (r = 0.87; bias: 1.1 ± 2.2%) than for non-enhanced GLS (r = 0.80; bias: 1.3 ± 2.7%). In 12/25 patients with suboptimal TTE images that rendered GLS difficult to measure, contrast-enhanced GLS showed better agreement with CMR than non-enhanced GLS (r = 0.88 vs. 0.83) and also improved inter-observer (ICC = 0.83 vs. 0.76) and intra-observer variability (ICC = 0.88 vs. 0.82). In conclusion, contrast enhancement of TTE images improves the accuracy and reproducibility of GLS measurements, resulting in better agreement with CMR, even in patients with suboptimal acoustic windows. This approach may aid in the assessment of LV function in this patient population.

Transillumination (TI) is a new 3D rendering tool that uses a freely movable virtual light source to enhance depth, contours, and image detail. The TI model was recently modified to allow the operator adjust the degree of transparency of both cardiac and extra-cardiac structures. While the addition of transparency was shown to significantly improve quality in 3D transesophageal imaging, this has not yet been shown for transthoracic (TTE) imaging. We prospectively studied 35 patients who underwent clinically indicated TTE with standard 3D acquisition, as well as TI with and without transparency. Six experienced echocardiographers were shown images of all three display types in random order. Each image was scored independently using a Likert Scale while assessing each of the following aspects: ability to identify anatomy or pathology, depth perception, degree of anatomic detail, and border delineation. All experts perceived an incremental value of the transparency mode, compared to TI without transparency and standard 3D rendering, in terms of ability to identify anatomy or pathology (4.15 ± 0.97 vs. 3.88 ± 0.99 vs. 2.52 ± 1.41, p < 0.01), depth perception (4.33 ± 0.78 vs. 3.88 ± 0.82 vs. 2.29 ± 1.07, p < 0.01), degree of anatomic detail (4.08 ± 1.0 vs. 3.89 ± 0.79 vs. 2.31 ± 1.08, p < 0.01), and border delineation (4.44 ± 0.80 vs. 3.90 ± 0.78 vs. 2.42 ± 1.13, p < 0.01). Compared to standard 3D and TI renderings of TTE images, the addition of transparency significantly improves both image quality and diagnostic confidence.

Over 40% of Sun-like stars are bound in binary or multistar systems. Stellar remnants in edge-on binary systems can gravitationally magnify their companions, as predicted 40 years ago. By using data from the Kepler spacecraft, we report the detection of such a \"self-lensing\" system, in which a 5-hour pulse of 0.1% amplitude occurs every orbital period. The white dwarf stellar remnant and its Sun-like companion orbit one another every 88.18 days, a long period for a white dwarf–eclipsing binary. By modeling the pulse as gravitational magnification (microlensing) along with Kepler's laws and stellar models, we constrain the mass of the white dwarf to be ∼63% of the mass of our Sun. Further study of this system, and any others discovered like it, will help to constrain the physics of white dwarfs and binary star evolution.

Iron is indispensable for almost all forms of life but toxic at elevated levels 1 – 4 . To survive within their hosts, bacterial pathogens have evolved iron uptake, storage and detoxification strategies to maintain iron homeostasis 1 , 5 , 6 . Recent studies showed that three Gram-negative environmental anaerobes produce iron-containing ferrosome granules 7 , 8 . However, it remains unclear whether ferrosomes are generated exclusively by Gram-negative bacteria. The Gram-positive bacterium Clostridioides difficile is the leading cause of nosocomial and antibiotic-associated infections in the USA 9 . Here we report that C. difficile undergoes an intracellular iron biomineralization process and stores iron in membrane-bound ferrosome organelles containing non-crystalline iron phosphate biominerals. We found that a membrane protein (FezA) and a P 1B6 -ATPase transporter (FezB), repressed by both iron and the ferric uptake regulator Fur, are required for ferrosome formation and play an important role in iron homeostasis during transition from iron deficiency to excess. Additionally, ferrosomes are often localized adjacent to cellular membranes as shown by cryo-electron tomography. Furthermore, using two mouse models of C. difficile infection, we demonstrated that the ferrosome system is activated in the inflamed gut to combat calprotectin-mediated iron sequestration and is important for bacterial colonization and survival during C. difficile infection. Ferrosome organelles produced by Clostridioides difficile are required to support colonization of the inflamed gut, highlighting the potential of targeting ferrosome formation as an antimicrobial strategy against this important pathogen.

Recent research findings have contributed to an improved understanding and treatment of borderline personality disorder. This disorder is characterised by severe functional impairments, a high risk of suicide, a negative effect on the course of depressive disorders, extensive use of treatment, and high costs to society. The course of this disorder is less stable than expected for personality disorders. The causes are not yet clear, but genetic factors and adverse life events seem to interact to lead to the disorder. Neurobiological research suggests that abnormalities in the frontolimbic networks are associated with many of the symptoms. Data for the effectiveness of pharmacotherapy vary and evidence is not yet robust. Specific forms of psychotherapy seem to be beneficial for at least some of the problems frequently reported in patients with borderline personality disorder. At present, there is no evidence to suggest that one specific form of psychotherapy is more effective than another. Further research is needed on the diagnosis, neurobiology, and treatment of borderline personality disorder.

Natural killer (NK) cells are innate lymphoid cells (ILCs) that participate to the clearance of pathogen‐infected cells and tumour cells. NK cells and subsets of ILCs express the natural cytotoxicity receptors (NCRs) NKp46, NKp44 and NKp30 at their surface. NCRs have been shown to recognize a broad spectrum of ligands ranging from viral‐, parasite‐ and bacterial‐derived ligands to cellular ligands; however, the full identification of NCR ligands remains to be performed and will undoubtedly contribute to a better understanding of NK cell and ILC biology. The March 2014 issue contains a Special Feature on NK cell recognition of unconventional ligands. Natural Killer (NK) cells are bone marrow derived lymphocytes capable of mediating rapid effector responses following pathogen detection in mammals. The name “Natural Killer” derives from the ability of these cells to spontaneously lyse a large range of leukemia cell lines in vitro without prior sensitization. The reviews included in this Special Feature of Immunology and Cell Biology highlight the multifaceted roles of NK cells in detecting unconventional ligands and countering a large range of pathogens and malignancies. Covering a range of topics, including the way adhesion molecules and activating receptors are central to NK cell recognition of their targets, the reviews also highlight some of the challenges that lie ahead in harnessing NK cell function and advancing NK cell immunotherapy strategies to persistent infection, cancer and bone marrow transplantation. Immunology and Cell Biology thanks the coordinator of this Special Feature – Nicholas Huntington – for his planning and input. Further background information on this important topic is available through the accompanying web focus which links to related articles from across Nature Publishing Group.

Network models are widely applied to describe connectivity and flow in diverse systems. In contrast, the fact that many connected systems move through space as the result of dynamic restructuring has received little attention. Therefore, we introduce the concept of ‘traveling networks’, and we analyze a tree-based model where the leaves are stochastically manipulated to grow, branch, and retract. We derive how these restructuring rates determine key attributes of network structure and motion, enabling a compact understanding of higher-level network behaviors such as multiscale search. These networks self-organize to the critical point between exponential growth and decay, allowing them to detect and respond to environmental signals with high sensitivity. Finally, we demonstrate how the traveling network concept applies to real-world systems, such as slime molds, the actin cytoskeleton, and human organizations, exemplifying how restructuring rules and rates in general can select for versatile search strategies in real or abstract spaces. Complex networks are relevant to wide range of areas, from biology to social sciences and economics, however the aspect that networks can move through space has not been elaborated. The authors propose a concept of traveling networks that can dynamically restructure themselves in space and perform search tasks.

The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 A crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix alpha10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation.