Miracle-dz/UniFAR-FTUs huggingface dataset:
Preferential Phosphorylation of R-domain Serine 768 Dampens Activation of CFTR Channels by PKA

CFTR (cystic fibrosis transmembrane conductance regulator), the protein whose dysfunction causes cystic fibrosis, is a chloride ion channel whose gating is controlled by interactions of MgATP with CFTR's two cytoplasmic nucleotide binding domains, but only after several serines in CFTR's regulatory (R) domain have been phosphorylated by cAMP-dependent protein kinase (PKA). Whereas eight R-domain serines have previously been shown to be phosphorylated in purified CFTR, it is not known how individual phosphoserines regulate channel gating, although two of them, at positions 737 and 768, have been suggested to be inhibitory. Here we show, using mass spectrometric analysis, that Ser 768 is the first site phosphorylated in purified R-domain protein, and that it and five other R-domain sites are already phosphorylated in resting Xenopus oocytes expressing wild-type (WT) human epithelial CFTR. The WT channels have lower activity than S768A channels (with Ser 768 mutated to Ala) in resting oocytes, confirming the inhibitory influence of phosphoserine 768. In excised patches exposed to a range of PKA concentrations, the open probability (Po) of mutant S768A channels exceeded that of WT CFTR channels at all [PKA], and the half-maximally activating [PKA] for WT channels was twice that for S768A channels. As the open burst duration of S768A CFTR channels was almost double that of WT channels, at both low (55 nM) and high (550 nM) [PKA], we conclude that the principal mechanism by which phosphoserine 768 inhibits WT CFTR is by hastening the termination of open channel bursts. The right-shifted Po-[PKA] curve of WT channels might explain their slower activation, compared with S768A channels, at low [PKA]. The finding that phosphorylation kinetics of WT or S768A R-domain peptides were similar provides no support for an alternative explanation, that early phosphorylation of Ser 768 in WT CFTR might also impair subsequent phosphorylation of stimulatory R-domain serines. The observed reduced sensitivity to activation by [PKA] imparted by Ser 768 might serve to ensure activation of WT CFTR by strong stimuli while dampening responses to weak signals.
An evaluation of the potential of linear and nonlinear skin permeation models for the prediction of experimentally measured percutaneous drug absorption

Objectives The developments in combinatorial chemistry have led to a rapid increase in drug design and discovery and, ultimately, the production of many potential molecules that require evaluation. Hence, there has been much interest in the use of mathematical models to predict dermal absorption. Therefore, the aim of this study was to test the performance of both linear and nonlinear models to predict the skin permeation of a series of 11 compounds.
An Ultra Scale-Down Analysis of the Recovery by Dead-End Centrifugation of Human Cells for Therapy

An ultra scale‐down method is described to determine the response of cells to recovery by dead‐end (batch) centrifugation under commercially defined manufacturing conditions. The key variables studied are the cell suspension hold time prior to centrifugation, the relative centrifugal force (RCF), time of centrifugation, cell pellet resuspension velocities, and number of resuspension passes. The cell critical quality attributes studied are the cell membrane integrity and the presence of selected surface markers. Greater hold times and higher RCF values for longer spin times all led to the increased loss of cell membrane integrity. However, this loss was found to occur during intense cell resuspension rather than the preceding centrifugation stage. Controlled resuspension at low stress conditions below a possible critical stress point led to essentially complete cell recovery even at conditions of extreme centrifugation (e.g., RCF of 10000 g for 30 mins) and long (~2 h) holding times before centrifugation. The susceptibility to cell loss during resuspension under conditions of high stress depended on cell type and the age of cells before centrifugation and the level of matrix crosslinking within the cell pellet as determined by the presence of detachment enzymes or possibly the nature of the resuspension medium. Changes in cell surface markers were significant in some cases but to a lower extent than loss of cell membrane integrity. Biotechnol. Bioeng. 2015;112: 997–1011. © 2014 Wiley Periodicals, Inc.
Embryonic chick corneal epithelium: A model system for exploring cell–matrix interactions

In her initial research, Elizabeth D. Hay studied amphibian limb regeneration, but later switched her focus, and for the remainder of her career addressed the role of the extracellular matrix (ECM) in regulating embryonic morphogenesis. Much of that work used the embryonic chick corneal epithelial model. This review highlights many of the discoveries that she made using this model. Hay was the first to show that embryonic corneal epithelial cells produce fibrillar collagen. Her lab was among the first to demonstrate that corneal epithelial cells respond to a collagenous substrate by increasing ECM production, and that purified ECM molecules, added to cultures of epithelial sheets, induce a reorganization of the actin cytoskeleton. These data led to the first theories of cell–matrix interactions, illustrated in a ‘hands across the membrane’ sketch drawn by Hay. Recent work with the epithelial sheet model system has elucidated many of the signal transduction pathways required for actin reorganization in response to the ECM. In all, this body of work has amply supported Hay's belief that the embryonic corneal epithelium is a powerful model system for exploring the role of the ECM in regulating the cytoskeleton, in directing cell migration, and in profoundly influencing cell growth and differentiation during development. Developmental Dynamics 237:2667–2675, 2008. © 2008 Wiley‐Liss, Inc.
Plate Mode Velocities in Graphite/Epoxy Plates

Measurements of the velocities of the extensional and flexural plate modes were made along three directions of propagation in four graphite/epoxy composite plates. The acoustic signals were generated by simulated acoustic emission events (pencil lead breaks or Hsu-Neilsen sources) and detected by broad band ultrasonic transducers. The first arrival of the extensional plate mode, which is nond ispersive at low frequencies, was measured at a number of different distances from the source along the propagation direction of interest. The velocity was det ermined by plotting the distance versus arrival time and computing its slope. Because of the large dispersion of the flexural mode, a Fourier phase velocity technique was used to characterize this mode. The velocity was measured up to a frequency of 160 kHz. Theoretical predictions of the velocities of these modes were also made and compared with experimental observations. Classical plate theory yielded good agreement with the measured extensional velocities. For predictions of the dispersion of the flexural mode, Mindlin plate theory, which includes the effects of shear deformation and rotatory inertia was shown to give better agreement with the experimental measurements.
Breast-specific gamma imaging with Tc-99m-sestamibi in the diagnosis of breast cancer and its semiquantitative index correlation with tumor biologic markers, subtypes, and clinicopathologic characteristics

ObjectivesTo determine the sensitivity of breast-specific gamma imaging (BSGI) in diagnosing breast cancer and assess the potential correlation between the semiquantitative index of BSGI and biologic markers, molecular subtypes, and clinicopathologic characteristics of breast cancer. Materials and methodsThe sensitivity of BSGI for breast cancer was retrospectively assessed in 102 female breast cancer patients who underwent BSGI before surgery and was compared with that of ultrasonography and mammography. BSGI was visually graded on the basis of the Society of Nuclear Medicine and Molecular Imaging guideline. Tracer uptake in the cancer as the lesion to nonlesion ratio (L/N) was calculated semiquantitatively and was subsequently correlated to tumor biologic markers, molecular subtypes, and clinicopathologic characteristics. ResultsThe sensitivity of BSGI for breast cancer by visual analysis was 94.1% (96/102) in our cohort, which was 100% (47/47) in the subgroup of patients with a tumor size more than 2.0 cm and 89.1% (49/55) in the subgroup of patients with a size less than or equal to 2.0 cm. The sensitivity of BSGI was significantly higher than that of ultrasonography of 84.2% (85/101) (P=0.022) and mammography of 84.5% (60/71) (P=0.037). There was no significant correlation between the L/N and expressions of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and antigen Ki-67, and the subtypes or histologic grade of the cancer (P>0.05). However, the value of L/N was associated with infiltration degree (P=0.005), axillary lymph node status (P=0.029), and tumor size (P=0.002). Multivariate analysis further indicated that the value of L/N was correlated with infiltration degree (P=0.016) and tumor size (P=0.002). ConclusionBSGI has a high sensitivity for detecting primary breast cancer. The value of L/N on BSGI was independently related to infiltration degree and tumor size of breast cancer, but not to expression of tumor receptor markers and histologic grade.
Toxicity of lanthanum oxide (La2O3) nanoparticles in aquatic environments.

This study demonstrates the acute toxicity of lanthanum oxide nanoparticles (La2O3 NP) on two sentinel aquatic species, fresh-water microalgae Chlorella sp. and the crustacean Daphnia magna. The morphology, size and charge of the nanoparticles were systematically studied. The algal growth inhibition assay confirmed absence of toxic effects of La2O3 NP on Chlorella sp. , even at higher concentration (1000 mg L(-1)) after 72 h exposure. Similarly, no significant toxic effects were observed on D. magna at concentrations of 250 mg L(-1) or less, and considerable toxic effects were noted in higher concentrations (effective concentration [EC50] 500 mg L(-1); lethal dose [LD50] 1000 mg L(-1)). In addition, attachment of La2O3 NP on aquatic species was demonstrated using microscopy analysis. This study proved to be beneficial in understanding acute toxicity in order to provide environmental protection as part of risk assessment strategies.
Unusual presentation of anaplastic large cell lymphoma with clinical course mimicking fever of unknown origin and sepsis: autopsy study of five cases.

AIM To describe a subset of cases with the unusual clinical and histomorphological presentation of anaplastic large cell lymphoma (ALCL) mimicking fever of unknown origin (FUO) and sepsis. METHODS A pathology database was searched using full term Systematized Nomenclature of Medicine codes for ALCL to identify 23ALCL cases from the period 1999-2006. Of those, five cases that did not have a correct premortem diagnosis were further analyzed to elucidate the reasons for delayed and incorrect pre-mortem diagnosis. The analyzed data included clinical presentation, duration of symptoms, duration of hospital stay, premortem presumed cause of death, white blood cell count, platelet count, anion gap and blood pH, liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase), lactate, coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen, D-dimers), microbiology cultures, and radiology and surgical pathology reports. Autopsy reports were reviewed for description of major gross findings, initial clinical diagnosis, and cause of death. RESULTS Five fatal and pre-mortem unrecognized ALCL cases were characterized by rapid decline, with histologic findings showing predominantly extranodal involvement, intravascular lymphomatosis, and hemophagocytosis. The cases were also characterized by unusual clinical manifestations including a FUO, sepsis, and disseminated intravascular coagulation-like picture, lactic acidosis, hepatosplenomegaly, and absence of significant peripheral adenopathy. CONCLUSIONS There is a distinct group of ALCLs with unique and specific clinical, gross autopsy, and histopathologic findings. Recognition of this clinical variant may facilitate early detection and potentially timely diagnosis and therapy.
Current Management of Postherpetic Neuralgia

BACKGROUND–The herpes zoster rash occurs when a dormant varicella zoster virus reactivates in dorsal root and cranial nerve ganglia. Pain that persists in the region where this rash occurred after the cutaneous lesions have healed is termed postherpetic neuralgia (PHN). A wide variety of therapies has been used with varying degrees of success to prevent the occurrence of PHN and to reduce pain with established PHN. REVIEW SUMMARY–In this review, we discuss the clinical presentation of PHN, current strategies for the prevention and management of this disease, and observations that have increased our understanding of the neural mechanisms involved in PHN. CONCLUSIONS–Several classes of drugs are effective in attenuating the pain and hyperalgesia caused by PHN, but no single drug leads to the complete relief of symptoms. Additional research is needed to improve treatment strategies and define the role of invasive pain management techniques in cases where PHN is associated with intractable pain.
Active Learning for Crowd-Sourced Databases

Crowd-sourcing has become a popular means of acquiring labeled data for a wide variety of tasks where humans are more accurate than computers, e.g., labeling images, matching objects, or analyzing sentiment. However, relying solely on the crowd is often impractical even for data sets with thousands of items, due to time and cost constraints of acquiring human input (which cost pennies and minutes per label). In this paper, we propose algorithms for integrating machine learning into crowd-sourced databases, with the goal of allowing crowd-sourcing applications to scale, i.e., to handle larger datasets at lower costs. The key observation is that, in many of the above tasks, humans and machine learning algorithms can be complementary, as humans are often more accurate but slow and expensive, while algorithms are usually less accurate, but faster and cheaper. Based on this observation, we present two new active learning algorithms to combine humans and algorithms together in a crowd-sourced database. Our algorithms are based on the theory of non-parametric bootstrap, which makes our results applicable to a broad class of machine learning models. Our results, on three real-life datasets collected with Amazon's Mechanical Turk, and on 15 well-known UCI data sets, show that our methods on average ask humans to label one to two orders of magnitude fewer items to achieve the same accuracy as a baseline that labels random images, and two to eight times fewer questions than previous active learning schemes.
AFTERNOON GLUCOSE TOLERANCE TESTING: A KEY TO THE PATHOGENESIS, EARLY DIAGNOSIS AND PROGNOSIS OF DIABETOGENIC HYPERINSULINISM

Conventional glucose tolerance testing performed during the morning is a valuable and time-proved procedure. The following limitations of this test however, have been repeatedly observed with reference to diabetogenic hyperinsulinism (2-6): (a) failure to demonstrate impaired glucose tolerance in patients with “functional” hyperinsulinism who exhibit other features highly suggestive of diabetes mellitus (e.g., a history of diabetes among several immediate relatives, repeated birth of large babies, the presence of micro-aneurysms and other retinal changes, neurologic features consistent with diabetic neuropathy, narcolepsy ( 2 4 ) , hypercholesterolemia, and glucosuria or hyperglycemia on random testing); and ( b ) failure to demonstrate convincingly low blood glucose concentrations in patients who are manifesting the unequivocal symptoms of reactive hypoglycemia, with or without impaired glucose tolerance. The foregoing reservations are further underscored by: 1) The necessity for introduction of the intravenous glucose tolerance test, the cortisone glucose tolerance test, and tolbutamide tests (oral and intravenous routes) in an effort to overcome this blind spot in diagnosing “early” diabetes mellitus. 2) The writer’s estimate that the incidence of diabetes mellitus (recognized and unrecognized) in the United States is probably in the order of 15-20 million cases-not 5 million. 3) The potential false-negative pattern that can be introduced when abnormal morning glucose tolerance is brought to normal in patients with “chemical diabetes” due to self-imposed restriction of sugar once the possibility of diabetes mellitus has been raised. 4) The extraordinary importance of detecting the presence of “diabetes premellitus” before overt biochemical decompensation occurs, since it is during this period that dietary measures aimed at checking diabetogenic hyperinsulinism are of the greatest value in preventing clinical diabetes mellitus . * Consulting Staff, Good Samaritan Hospital and St Mary’s Hospital, West Palm
Wafer-fused optoelectronics for switching

Wafer fusion technique for realization of compact waveguide switches and three-dimensional (3-D) photonic integrated circuits is investigated theoretically and experimentally. Calculations based on beam propagation method show that very short vertical directional couplers with coupling lengths from 40 to 220 /spl mu/m and high extinction ratios from 20 to 32 dB can be realized. These extinction ratios can be further improved using a slight asymmetry in waveguide structure. The optical loss at the fused interface is investigated. Comparison of the transmission loss in InGaAsP-based ridge-loaded waveguide structures with and without a fused layer near the core region, reveals an excess loss of 1.1 dB/cm at 1.55 /spl mu/m wavelength. Fused straight vertical directional couplers have been fabricated and characterized. Waveguides separated by 0.6 /spl mu/m gap layer exhibit a coupling length of 62 /spl mu/m and a switching voltage of about 2.2 V. Implications for GaAs-based fused couplers for 850 nm applications will also be discussed.
Apathy Towards the Integration of Usability Work: A Case of System Justification

In this article we report from a case study of a software development organization and we study in particular the developers’ and product managers’ attitudes towards integrating usability work into software development. We offer explanations based on system justification theory illuminating what would-be integrators might be up against. The analysis shows how the developers only pay lip service to usability work and how they treat users superficially. It further shows how that leads to stereotyping of usability designers and users in order to preserve status quo, and how internalization of inequality between the developers and usability designers rationalizes the preservation of status quo. These findings will have significant implications for managers of software development.
Delineation of Myotoxicity Induced by 3-Hydroxy-3-methylglutaryl CoA Reductase Inhibitors in Human Skeletal Muscle Cells

The 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are widely used and well tolerated cholesterol-lowering drugs. In rare cases, side effects occur in skeletal muscle, including myositis or even rhabdomyolysis. However, the molecular mechanisms are not well understood that lead to these muscle-specific side effects. Here, we show that statins cause apoptosis in differentiated human skeletal muscle cells. The prototypical representative of statins, simvastatin, triggered sustained intracellular Ca2+ transients, leading to calpain activation. Intracellular chelation of Ca2+ completely abrogated cell death. Moreover, ryanodine also completely prevented the simvastatin-induced calpain activation. Nevertheless, an activation of the ryanodine receptor by simvastatin could not be observed. Downstream of the calpain activation simvastatin led to a translocation of Bax to mitochondria in a caspase 8-independent manner. Consecutive activation of caspase 9 and 3 execute apoptotic cell death that was in part reversed by the coadministration of mevalonic acid. Conversely, the simvastatin-induced activation of calpain was not prevented by mevalonic acid. These data delineate the signaling cascade that leads to muscle injury caused by statins. Our observations also have implications for improving the safety of this important medication and explain to some extent why physical exercise aggravates skeletal muscle side effects.
Household and occupational exposure to pesticides and risk of breast cancer

The association between breast cancer in women and the use of household or occupational pesticides was examined in a population-based case-control study. This study was conducted in Western Australia in 2009–2011and included 1,789 controls and 1,205 cases. Information on household pesticide exposure was collected from questionnaires. For occupational pesticide exposure, job-specific modules (JSMs) were used. To evaluate potential recall bias, we stratified the analysis by belief about whether pesticides contribute to breast cancer. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Women’s exposures to pesticides in households and workplaces were not related to increased risk of breast cancer (OR = 1.10; CI: 0.86–1.37) and (OR = 0.77; CI: 0.45–1.32), respectively. The prevalence of occupational exposure to pesticides among women in our study was low. In the stratified analyses, the odd ratios associated with household pesticide use were similar among participants who believed pesticides increased breast cancer risk and those who did not. The results of our study did not show associations between breast cancer and household or occupational exposure to pesticides.