There are several lung ultrasound scores (LUS) for evaluating lung aeration in critically ill adults with restrictive lung disorders. A modified LUS adapted for neonates correlates well with ...oxygenation and is able to be used to predict the need for surfactant in preterm neonates with respiratory distress syndrome (RDS). However, no data are available for extremely preterm neonates for whom timely surfactant administration is especially important. We hypothesized that LUS might be reliable in extremely preterm neonates with RDS who are treated with continuous positive airway pressure. We aimed to determine the diagnostic accuracy of LUS in predicting the need for surfactant treatment and re-treatment in this population.
We performed a prospective cohort diagnostic accuracy study between 2015 and 2016 in a tertiary-care academic center. Inborn neonates at ≤30 weeks' gestation with RDS treated with continuous positive airway pressure were eligible. Surfactant was given on the basis of oxygen requirement thresholds derived from European guidelines, and a LUS was not used to guide surfactant treatment. We calculated the LUS after admission and analyzed its diagnostic accuracy to predict surfactant treatment and re-treatment.
We enrolled 133 infants; 68 (51%) received 1 dose of surfactant and 19 (14%) received 2 surfactant doses. A LUS is significantly correlated with oxygenation index (ρ = 0.6;
< .0001) even after adjustment for gestational age (
< .0001). A LUS can be used to accurately predict the need for the first surfactant dose (area under the curve = 0.94; 95% confidence interval: 0.90-0.98;
< .0001) and also the need for surfactant redosing (area under the curve = 0.803; 95% confidence interval: 0.72-0.89;
< .0001). The global accuracy for the prediction of surfactant treatment and re-treatment is 89% and 72%, respectively.
LUS may be used to predict the need for surfactant replacement in extremely preterm neonates with RDS.
G protein–coupled receptors (GPCRs) are the largest gene family of cell membrane–associated molecules mediating signal transmission, and their involvement in key physiological functions is ...well-established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and sensory perception (e.g. vision, odor, and taste), is largely due to the diversity of these receptors and the layers of their downstream signaling circuits. Dysregulated expression and aberrant functions of GPCRs have been linked to some of the most prevalent human diseases, which renders GPCRs one of the top targets for pharmaceutical drug development. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Recent studies have shown that GPCRs can contribute to the many facets of tumorigenesis, including proliferation, survival, angiogenesis, invasion, metastasis, therapy resistance, and immune evasion. Indeed, GPCRs are widely dysregulated in cancer and yet are underexploited in oncology. We present here a comprehensive analysis of GPCR gene expression, copy number variation, and mutational signatures in 33 cancer types. We also highlight the emerging role of GPCRs as part of oncocrine networks promoting tumor growth, dissemination, and immune evasion, and we stress the potential benefits of targeting GPCRs and their signaling circuits in the new era of precision medicine and cancer immunotherapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
GPCRs are master regulators of cell signaling by transducing extracellular stimuli into the cell via selective coupling to intracellular G-proteins. Here we present a computational analysis of the ...structural determinants of G-protein-coupling repertoire of experimental and predicted 3D GPCR-G-protein complexes. Interface contact analysis recapitulates structural hallmarks associated with G-protein-coupling specificity, including TM5, TM6 and ICLs. We employ interface contacts as fingerprints to cluster G
vs G
complexes in an unsupervised fashion, suggesting that interface residues contribute to selective coupling. We experimentally confirm on a promiscuous receptor (CCKAR) that mutations of some of these specificity-determining positions bias the coupling selectivity. Interestingly, G
-GPCR complexes have more conserved interfaces, while G
proteins adopt a wider number of alternative docking poses, as assessed via structural alignments of representative 3D complexes. Binding energy calculations demonstrate that distinct structural properties of the complexes are associated to higher stability of G
than G
complexes. AlphaFold2 predictions of experimental binary complexes confirm several of these structural features and allow us to augment the structural coverage of poorly characterized complexes such as G
.
Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood.
To update the panel of single genes mutations involved in familial ...cholestasis.
PubMed search for “familial intrahepatic cholestasis” alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses.
PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer.
There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Wordom is a versatile, user-friendly, and efficient program for manipulation and analysis of molecular structures and dynamics. The following new analysis modules have been added since the ...publication of the original Wordom paper in 2007: assignment of secondary structure, calculation of solvent accessible surfaces, elastic network model, motion cross correlations, protein structure network, shortest intra-molecular and inter-molecular communication paths, kinetic grouping analysis, and calculation of mincut-based free energy profiles. In addition, an interface with the Python scripting language has been built and the overall performance and user accessibility enhanced. The source code of Wordom (in the C programming language) as well as documentation for usage and further development are available as an open source package under the GNU General Purpose License from http://wordom.sf.net.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Human islets of Langerhans are composed mostly of glucagon-secreting α cells and insulin-secreting β cells closely intermingled one another. Current methods for identifying α and β cells ...involve either fixing islets and using immunostaining or disaggregating islets and employing flow cytometry for classifying α and β cells based on their size and autofluorescence. Neither approach, however, allows investigating the dynamic behavior of α and β cells in a living and intact islet. To tackle this issue, we present a machine-learning-based strategy for identification α and β cells in label-free infrared micrographs of living human islets without immunostaining. Intrinsic autofluorescence is stimulated by infrared light and collected both in intensity and lifetime in the visible range, dominated by NAD(P)H and lipofuscin signals. Descriptive parameters are derived from micrographs for ~ 10 3 cells. These parameters are used as input for a boosted decision-tree model (XGBoost) pre-trained with immunofluorescence-derived cell-type information. The model displays an optimized-metrics performance of 0.86 (i.e. area under a ROC curve), with an associated precision of 0.94 for the recognition of β cells and 0.75 for α cells. This tool promises to enable longitudinal studies on the dynamic behavior of individual cell types at single-cell resolution within the intact tissue.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We developed a mixed Protein Structure Network (PSN) and Elastic Network Model-Normal Mode Analysis (ENM-NMA)-based strategy (i.e. PSN-ENM) to investigate structural communication in ...biomacromolecules. The approach starts from a Protein Structure Graph and searches for all shortest communication pathways between user-specified residues. The graph is computed on a single preferably high-resolution structure. Information on system's dynamics is supplied by ENM-NMA. The PSN-ENM methodology is made of multiple steps both in the setup and analysis stages, which may discourage inexperienced users. To facilitate its usage, we implemented WebPSN, a freely available web server that allows the user to easily setup the calculation, perform post-processing analyses and both visualize and download numerical and 3D representations of the output. Speed and accuracy make this server suitable to investigate structural communication, including allosterism, in large sets of bio-macromolecular systems.
The WebPSN server is freely available at http://webpsn.hpc.unimore.it.
There are relatively few data about the ultrasound evaluation of pleural line in patients with respiratory failure. We measured the pleural line thickness during different phases of the respiratory ...cycle in neonates with and without acute respiratory failure as we hypothesized that this can significantly change.
Prospective, observational, cohort study performed in an academic tertiary neonatal intensive care unit recruiting neonates with transient tachypnoea of the neonate (TTN), respiratory distress syndrome (RDS) or neonatal acute respiratory distress syndrome (NARDS). Neonates with no lung disease (NLD) were also recruited as controls. Pleural line thickness was measured with high-frequency ultrasound at end-inspiration and end-expiration by two different raters.
Pleural line thickness was slightly but significantly higher at end-expiration (0.53 0.43-0.63 mm) than at end-inspiration (0.5 0.4-0.6 mm; p = 0.001) for the whole population. End-inspiratory (NLD: 0.45 0.38-0.53, TTN: 0.49 0.43-0.59, RDS: 0.53 0.41-0.62, NARDS: 0.6 0.5-0.7 mm) and -expiratory (NLD: 0.47 0.42-0.56, TTN: 0.48 0.43-0.61, RDS: 0.53 0.46-0.65, NARDS: 0.61 0.54-0.72 mm) thickness were significantly different (overall p = 0.021 for both), between the groups although the absolute differences were small. The inter-rater agreement was optimal (ICC: 0.95 (0.94-0.96)). Coefficient of variation was 2.8% and 2.5% for end-inspiratory and end-expiratory measurements, respectively. These findings provide normative data of pleural line thickness for the most common forms of neonatal acute respiratory failure and are useful to design future studies to investigate possible clinical applications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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