Explore the vast range of titles available.

Pregnant women with mild chronic hypertension were randomly assigned to receive medication targeting a normal blood pressure (<140/90 mm Hg) or to receive no treatment unless severe hypertension (>160/105 mm Hg) developed. The incidence of adverse maternal and neonatal outcomes was significantly lower in the active-treatment group, without an increase in low birth weight.

Background. Crisscross heart (CCH) is a complex, rare, congenital, rotational, cardiac abnormality that accounts for <0.1% of congenital heart defects (CHD). CCH is characterized by the crossing of the inflow streams of the two ventricles due to an abnormal twisting of the heart. A case of maternal CCH has not been previously reported. Case. We report a case of a primigravida with a CCH, who was separated at birth from her thoracopagus conjoined twin. Pregnancy was managed by congenital cardiology, maternal-fetal medicine, anesthesiology, and obstetrics. She underwent a 39-week vaginal delivery without maternal or neonatal complication. Conclusion. A successful term pregnancy outcome was achieved in a patient with CCH using a multidisciplinary approach to address her cardiac condition.

RNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA three-dimensional structure prediction. With agreement from structural biologists, RNA structures are predicted by modeling groups before publication of the experimental structures. We report a large-scale set of predictions by 18 groups for 23 RNA-Puzzles: 4 RNA elements, 2 Aptamers, 4 Viral elements, 5 Ribozymes and 8 Riboswitches. We describe automatic assessment protocols for comparisons between prediction and experiment. Our analyses reveal some critical steps to be overcome to achieve good accuracy in modeling RNA structures: identification of helix-forming pairs and of non-Watson–Crick modules, correct coaxial stacking between helices and avoidance of entanglements. Three of the top four modeling groups in this round also ranked among the top four in the CASP15 contest. The results of the Fifth RNA-Puzzles contest highlights advances in RNA three-dimensional structure prediction and uncovers new insights into RNA folding and structure.

Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells 1 – 5 , and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell neoantigens 6 , 7 . Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αβ T cell receptor (TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential 8 (ILTCKs). These cells were broadly reactive to unmutated self-antigens, arose from distinct thymic progenitors following early encounter with cognate antigens, and were continuously replenished by thymic progenitors during tumour progression. Notably, expansion and effector differentiation of intratumoural ILTCKs depended on interleukin-15 (IL-15) expression in cancer cells, and inducible activation of IL-15 signalling in adoptively transferred ILTCK progenitors suppressed tumour growth. Thus, the antigen receptor self-reactivity, unique ontogeny, and distinct cancer cell-sensing mechanism distinguish ILTCKs from conventional cytotoxic T cells, and define a new class of tumour-elicited immune response. A survey of T cell populations in human and mouse tumours identifies a population of cancer-sensing IL-15-activated αβ T cell receptor-positive FCER1G-expressing innate-like T cells with high cytotoxic potential.

Contributors Indigo Esmonde, University of Toronto; Krishna Madhavan, Purdue University; Wolff‐Michael Roth, University of Victoria; Dan L. Schwartz and Jessica Tsang, Stanford University; Estrid Sørensen, Humboldt University and Aarhus University; Iris Tabak, Ben Gurion University of the Negev Background The field of engineering education research has seen substantial growth in the last five years but it often lacks theoretical and empirical work on engineering learning that could be supplied by the learning sciences. In addition, the learning sciences have focused very little on engineering learning to date. Purpose This article summarizes prior work in the learning sciences and discusses one perspective—situative learning— in depth. Situativity refers to the central role of context, including the physical and social aspects of the environment, on learning. Furthermore, it emphasizes the socially and culturally negotiated nature of thought and action of persons in interaction. The aim of the article is to provide a foundation for future work on engineering learning and to suggest ways in which the learning sciences and engineering education research communities might work to their mutual benefit. Scope/Method The article begins with a brief discussion of recent developments in engineering education research. After an initial overview of the field of learning sciences, situative learning is discussed and three analytical aspects of the perspective are outlined: social and material context, activities and interactions, and participation and identity. Relevant expert commentaries are interspersed throughout the article. The article concludes with an exploration of the potential for contributions from the learning sciences to understanding engineering learning. Conclusion There are many areas of mutual benefit for engineering education and the learning sciences and many potential areas of collaborative research that can contribute not only to engineering learning but to the learning sciences.

To describe the underlying processes involved in oceanic plankton dynamics is crucial for the determination of energy and mass flux through an ecosystem and for the estimation of biogeochemical element cycling. Many planktonic ecosystem models were developed to resolve major processes so that flux estimates can be derived from numerical simulations. These results depend on the type and number of parameterizations incorporated as model equations. Furthermore, the values assigned to respective parameters specify a model's solution. Representative model results are those that can explain data; therefore, data assimilation methods are utilized to yield optimal estimates of parameter values while fitting model results to match data. Central difficulties are (1) planktonic ecosystem models are imperfect and (2) data are often too sparse to constrain all model parameters. In this review we explore how problems in parameter identification are approached in marine planktonic ecosystem modelling. We provide background information about model uncertainties and estimation methods, and how these are considered for assessing misfits between observations and model results. We explain differences in evaluating uncertainties in parameter estimation, thereby also discussing issues of parameter identifiability. Aspects of model complexity are addressed and we describe how results from cross-validation studies provide much insight in this respect. Moreover, approaches are discussed that consider time- and space-dependent parameter values. We further discuss the use of dynamical/statistical emulator approaches, and we elucidate issues of parameter identification in global biogeochemical models. Our review discloses many facets of parameter identification, as we found many commonalities between the objectives of different approaches, but scientific insight differed between studies. To learn more from results of planktonic ecosystem models we recommend finding a good balance in the level of sophistication between mechanistic modelling and statistical data assimilation treatment for parameter estimation.

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients.

Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. We evaluated the specificity of Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic Ga-CBP8 PET/MRI, and five underwent follow up Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Ga-CBP8 showed specific binding to PDAC compared to non-binding Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher Ga-CBP8 uptake in tumor compared to pancreas (SUV : 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUV : 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUV (R = 0.54, P = 0.0007). This study demonstrates the specificity of Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.1% of cases. We find a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of CAKUT patients with diagnostic variants have neurodevelopmental or cardiac phenotypes. We identify 40 candidate genes, including CELSR1 , SSBP2, XPO1, NR6A1 , and ARID3A . Two are confirmed as CAKUT genes: ARID3A and NR6A1 . This study suggests that many yet-unidentified syndromes would be discoverable with larger cohorts and cross-phenotype analysis, leading to clarification of the genetic and phenotypic spectrum of developmental disorders. The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1 , along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.