Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study

Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). Methods: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques. Results: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person–trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person–trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person–trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person–trained interpreters and in 87.7% of scans for e-trained interpreters. Conclusion: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.
Cpx Signal Transduction Is Influenced by a Conserved N-Terminal Domain in the Novel Inhibitor CpxP and the Periplasmic Protease DegP

ABSTRACT In Escherichia coli, envelope stress can be overcome by three different envelope stress responses: the σE stress response and the Bae and Cpx two-component systems. The Cpx envelope stress response is controlled by the sensor kinase CpxA, the response regulator CpxR, and the novel periplasmic protein CpxP. CpxP mediates feedback inhibition of the Cpx pathway through a hypothetical interaction with the sensing domain of CpxA. No informative homologues of CpxP are known, and thus it is unclear how CpxP exerts this inhibition. Here, we identified six cpxP loss-of-function mutations using a CpxP-β-lactamase (CpxP′-′Bla) translational fusion construct. These loss-of-function mutations identified a highly conserved, predicted α-helix in the N-terminal domain of CpxP that affects both the function and the stability of the protein. In the course of this study, we also found that CpxP′-′Bla stability is differentially controlled by the periplasmic protease DegP in response to inducing cues and that mutation of degP diminishes Cpx pathway activity. We propose that the N-terminal α-helix is an important functional domain for inhibition of the Cpx pathway and that CpxP is subject to DegP-dependent proteolysis.
Selective amplification of simian immunodeficiency virus genotypes after intrarectal inoculation of rhesus monkeys

Animal models for sexual transmission of human immunodeficiency virus can define the influences of virus type, dose, and route of inoculation on infection and clinical outcome. We used an uncloned simian immunodeficiency virus stock (SIVmac) to inoculate cells in vitro and to inoculate rhesus monkeys by intravenous and intrarectal routes. The distribution of virus genotypes present in each of these infection examples was characterized by DNA sequence analysis of viral long terminal repeats (LTRs). Our analysis of LTR sequences from in vitro and in vivo infections revealed three main genotypes: one genotype was observed only for in vitro infection, and two other genotypes were recovered only from infected animals. By comparing animals inoculated with high intrarectal doses of SIVmac and those inoculated with low doses, we demonstrated that unique subsets of the stock were selected after intrarectal infection. Our findings indicate that minor genotypes present in the stock cross the rectal mucosa and are amplified selectively to become prominent in peripheral blood mononuclear cells from acutely infected animals. Studies with a molecular recombinant of SIV and human immunodeficiency virus type 1 sequences, SHIV, showed that viral LTR sequences do not undergo especially rapid sequence variation or rearrangement after intrarectal inoculation. The mucosal barrier exerts a significant influence on infection and disease progression by reducing the efficiency of SIVmac infection and by permitting distinct, pathogenic genotypes to become established in the host.
Live-Cell Imaging Reveals Multiple Interactions between Epstein-Barr Virus Nuclear Antigen 1 and Cellular Chromatin during Interphase and Mitosis

ABSTRACT Epstein-Barr virus (EBV) establishes a life-long latent infection in humans. In proliferating latently infected cells, EBV genomes persist as multiple episomes that undergo one DNA replication event per cell cycle and remain attached to the mitotic chromosomes. EBV nuclear antigen 1 (EBNA-1) binding to the episome and cellular genome is essential to ensure proper episome replication and segregation. However, the nature and regulation of EBNA-1 interaction with chromatin has not been clearly elucidated. This activity has been suggested to involve EBNA-1 binding to DNA, duplex RNA, and/or proteins. EBNA-1 binding protein 2 (EBP2), a nucleolar protein, has been proposed to act as a docking protein for EBNA-1 on mitotic chromosomes. However, there is no direct evidence thus far for EBP2 being associated with EBNA-1 during mitosis. By combining video microscopy and Förster resonance energy transfer (FRET) microscopy, we demonstrate here for the first time that EBNA-1 and EBP2 interact in the nucleoplasm, as well as in the nucleoli during interphase. However, in strong contrast to the current proposed model, we were unable to observe any interaction between EBNA-1 and EBP2 on mitotic chromosomes. We also performed a yeast double-hybrid screening, followed by a FRET analysis, that led us to identify HMGB2 (high-mobility group box 2), a well-known chromatin component, as a new partner for EBNA-1 on chromatin during interphase and mitosis. Although the depletion of HMGB2 partly altered EBNA-1 association with chromatin in HeLa cells during interphase and mitosis, it did not significantly impact the maintenance of EBV episomes in Raji cells.
An overexpressed gene transcript in senescent and quiescent human fibroblasts encoding a novel protein in the epidermal growth factor-like repeat family stimulates DNA synthesis

We carried out subtractive enrichment of a cDNA library derived from mRNA of senescent human diploid fibroblasts (HDF) established from a subject with Werner syndrome of premature aging. By differential screening, we isolated an overexpressed cDNA sequence (S1-5) that codes for a novel protein containing epidermal growth factor (EGF)-like domains which match the EGF-like consensus sequences within several known extracellular proteins that play a role in cell growth, development, and cell signalling. S1-5 mRNA is overexpressed in Werner syndrome and senescent normal HDF, is induced by growth arrest of young normal cells, but is significantly decreased by high serum, conditions which promote cellular proliferation. Paradoxically, microinjection into young HDF of two different lengths of S1-5 mRNA, containing different putative AUG translational start sites, consistently stimulated rather than inhibited DNA synthesis by an apparent autocrine/paracrine mechanism. Thus, the S1-5 gene product may represent a negative and/or positive factor whose ultimate activity is modulated by the cell environment as occurs with other members of EGF-like family.
Use of the New Solitaire™ AB Device for Mechanical Thrombectomy When Merci Clot Retriever Has Failed to Remove the Clot

The Merci Retrieval System™ (Concentric Medical, Mountain View, CA, USA) was approved in 2004 for restoring blood flow in patients experiencing an acute stroke who are otherwise ineligible for intravenous tPA, or in whom intravenous tPA treatment has failed. However, this treatment results in successful recanalization in less than 60% of treatable vessels (Multi MERCI trial). We describe the use of a novel device, the Solitaire™ AB Neurovascular Remodeling Device (ev3 Inc., Irvine, CA, USA) that received the CE Mark for the treatment of neurovascular disease in 2007 and can recanalize arteries when MERCI has failed. We describe a case of mechanical thrombectomy in which a new device, Solitaire™ AB, was used for acute cerebral ischemia in the setting of middle cerebral artery occlusion after unsuccessful recanalization with the MERCI® Retriever. Excellent angiographic and good clinical results were obtained without any complication. The Solitaire™ AB device was able to retrieve and remove clots efficiently from the middle cerebral artery when the MERCI system failed, thereby offering a new alternative in the treatment of acute ischemic stroke.
Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib

Sunitinib inhibits KIT and other members of the split‐kinase‐domain family of receptor tyrosine kinases. Sunitinib prolongs survival in adult patients with imatinib‐resistant gastrointestinal stromal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib.
Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree With Familial Dilated Cardiomyopathy

Background—Whole exome sequencing is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied whole exome sequencing to identify the causal variant in a large family with familial dilated cardiomyopathy of unknown pathogenesis. Methods and Results—A large family with autosomal dominant, familial dilated cardiomyopathy was identified. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool. Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency ⩽0.001 or not reported) in 2 public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result. Conclusions—Whole exome sequencing of remotely related dilated cardiomyopathy subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis.
Production of Retroviral Vectors for Gene Therapy with the Human Packaging Cell Line FLYRD18

The development of gene therapy is hampered by the difficulty of producing large stocks of retroviral vectors at high titer. This study aimed to improve culture conditions and to intensify the production of retroviruses by FLYRD18, a packaging cell line derived from the HT1080 human fibrosarcoma line. Batch virus production proved to be feasible in unsupplemented basal medium and provided significantly higher titers and productivities than medium supplemented with 10% serum. For longer‐term production, however, AIM‐V complete serum‐free medium and basal medium supplemented with 2% serum gave superior results. Serum supplementation should nevertheless be optimized to take into account the presence of inhibitors of viral production. In monolayer cultures with 0.2 mL/cm2, the cell concentration was increased up to 2 × 106 cells/mL without loss of cell productivity. A semicontinuous production process, which enables the collection of larger amounts of viruses from the same culture, has also been successfully used. Suspension culture processes were prevented by the anchorage dependency of the FLYRD18 cell line. Microcarrier cultures were able to produce viruses but will require further investigation and optimization for their performance to become competitive with monolayer cultures. In the course of this study, more than a 10‐fold increase of titer has been achieved.
Red Cell Preservation in Protein‐Poor Media: III. Protection Against in vitro Hemolysis

Red cells stored under blood bank conditions normally show less than 1% spontaneous in vitro hemolysis even after 5 weeks; larger hemolysis may be found if the cells are suspended and stored in a saline‐adenine‐glucose (SAG) solution with very little trapped plasma. Delay of the addition of the suspension medium, return of 25 ml plasma after a maximal plasma harvest, addition of mannitol 10–30 mmol.1‐1 to the suspension medium were alternative and effective ways of keeping the spontaneous lysis within normal limits. Mechanical traumatization (centrifugation or shaking) caused considerably more damage to the red cells when these were highly concentrated than when they were diluted. A cell suspension in SAG is a more suitable product for hemotherapy than strongly packed red cell concentrates.
Objectively measured night‐to‐night sleep variations are associated with body composition in very elderly women

This cross‐sectional study examined the association between objectively measured sleep patterns and body composition in very elderly community‐dwelling women. Participants included 191 community‐dwelling adults aged ≥ 80 years (mean age: 83.4 ± 2.6 years; age range: 80–92 years). Sleep and physical activity were monitored via accelerometer (ActiGraph GT3X+) during at least five consecutive 24‐h periods. Night‐to‐night sleep pattern variability across all nights of recording was assessed using standard deviations (SDs). Body composition was assessed using dual‐energy X‐ray absorptiometry. Simple and multivariable linear regression analyses were performed. The mean number of nights with usable actigraphy data was 7.3 ± 1.3. On average, participants went to bed at 22:57 hours (SD: 1.11 h) and rose from bed at 6:27 hours (SD: 1.01 h). Night‐to‐night bedtime, sleep duration and sleep timing mid‐point variations correlated slightly with the percentage body fat and percentage lean mass (P < 0.05). Multiple linear regression analysis revealed significant associations of night‐to‐night bedtime variations and inconsistent sleep–wake patterns with all body composition indices after adjusting for potential confounding factors, including mean nightly sleep duration, self‐reported nap duration and daily physical activity. After further adjusting for night‐to‐night wake time, sleep timing mid‐point and sleep duration variations, greater bedtime variability remained associated significantly with all body composition indices except lean/fat mass ratio. Inconsistent sleep–wake patterns were associated independently with an increased fat mass and decreased lean mass among very elderly women. These findings suggest that in most elderly individuals, sleep patterns might be an important modifiable factor associated with obesity and sarcopenia development.
Predictive control via set-membership state estimation for constrained linear systems with disturbances

This paper combines predictive control and set-membership state estimation techniques, for input/state hard constraints fulfilment. Linear systems with unknown but bounded disturbances and partial state information are considered. The adopted worst-case approach guarantees that the constraints are satisfied for all the states which are compatible with the available information and for all the disturbances within the given bounds. A stability result and simulative studies are reported.
Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts

Mesoangioblasts (MABs) are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle regeneration. Molecular circuits that regulate the myogenic commitment of MABs are still poorly characterized. The critical role of bone morphogenetic protein (BMP) signalling during proliferation and differentiation of adult myogenic precursors, such as satellite cells, has recently been established. We evaluated whether BMP signalling impacts on the myogenic potential of embryonic and adult MABs both in vitro and in vivo. Addition of BMP inhibited MAB myogenic differentiation, whereas interference with the interactions between BMPs and receptor complexes induced differentiation. Similarly, siRNA-mediated knockdown of Smad8 in Smad1/5-null MABs or inhibition of SMAD1/5/8 phosphorylation with Dorsomorphin (DM) also improved myogenic differentiation, demonstrating a novel role of SMAD8. Moreover, using a transgenic mouse model of Smad8 deletion, we demonstrated that the absence of SMAD8 protein improved MAB myogenic differentiation. Furthermore, once injected into α-Sarcoglycan (Sgca)-null muscles, DM-treated MABs were more efficacious to restore α-sarcoglycan (αSG) protein levels and re-establish functional muscle properties. Similarly, in acute muscle damage, DM-treated MABs displayed a better myogenic potential compared with BMP-treated and untreated cells. Finally, SMADs also control the myogenic commitment of human MABs (hMABs). BMP signalling antagonists are therefore novel candidates to improve the therapeutic effects of hMABs.
Evolution of code smells over multiple versions of softwares: An empirical investigation

The symptoms which reflect the poor design quality of code are known as code smells. Refactoring is one of the possible ways to remove code smells, but refactoring does not come for free to developer. So there is a need to have efficient refactoring strategies. For this purpose an empirical study on distribution of different code smells over different versions of projects is provided in this paper, so that refactoring strategies can be built keeping in a view that which smell is more effective and at which time during evolution of software. For experiment, different versions of Junit, GCviewer and Gitblit have been taken. To detect the smells and violations in code JDeodorant and PMD tools are used. Study shows that a) Latest version of software has more design issues than that of oldest ones; b) God smell and urgent violations have more contribution than other smells whereas instances having Type Checking smell are very less in all the versions. Study shows that initial version of project can be used as reference architecture for purpose of reverse Engineering. We also found that Gitblit has better code design than that of other two softwares.
EXPRESSION OF SARCOPLASMIC RETICULUM Ca2+‐ATPase mRNA IN THE HYPERTROPHIED HEART OF YOUNG SPONTANEOUSLY HYPERTENSIVE RATS

1. Recent evidence indicates that cardiac hypertrophy induced by pressure overload is associated with a decrease in sarcoplasmic reticulum (SR) Ca2+‐ATPase of myocytes, which may contribute to a diastolic dysfunction of the heart by causing intracellular Ca2+ overload. To elucidate whether or not this is also the case in genetic hypertension, we examined cardiac mRNA levels of SR Ca2+‐ATPase in 11 week old spontaneously hypertensive rats (SHR) by northern blot analysis.
Gelatin-albumin hybrid nanoparticles as matrix metalloproteinases-degradable delivery systems for breast cancer therapy.

AIM To develop matrix metalloproteinase-responsive gelatin-albumin hybrid nanoparticles encapsulating a selective tropomyosin receptor kinase A (TrkA) inhibitor GNF-5837 (Gel-Alb-GNF HNPs) and to demonstrate their anticancer effects in breast cancer. METHODS Gel-Alb-GNF HNPs were prepared using a pH-controlled complexation process from cationic gelatin, dextran sulfate and albumin-bound GNF-5837. The anticancer activities of Gel-Alb-GNF HNPs were tested in a panel of subtype-specific breast cancer cell lines. RESULTS Gel-Alb-GNF HNPs (∼130 nm) displayed excellent stability and matrix metalloproteinase-triggered drug release. Compared with GNF-5837 alone, Gel-Alb-GNF HNPs not only significantly enhanced the antiproliferative and anti-invasive effects but also restored the apoptosis of cancer cells. CONCLUSION Gel-Alb-GNF HNPs may be adaptable for stand-alone therapies or used in combination with traditional chemotherapies for breast cancer treatment.
Neck circumference as a marker of obesity and a predictor of cardiometabolic risk among Saudi subjects

Objectives: To determine the optimal cutoff value for neck circumference (NC) that define overweight/obesity and assess its predictive potential for cardiometabolic risks (CMR) among Saudi subjects. Methods: A cross sectional study of 785 adults recruited from a public health awareness campaign in Medina, Saudi Arabia during June 2015. Waist circumference (WC), NC, body mass index (BMI), blood pressure (BP), and random blood glucose (RBG) were assessed, and the presence of CMR were collected by a questionnaire. Pearson’s correlation coefficients were used to evaluate the associations of NC with other anthropometric indices and CMR. The optimal cutoff value for NC to identify overweight/obesity was determined by receiver operating characteristic (ROC) curves. Results: There were significant correlations between NC and BMI, weight, WC, age, RBG, and BP. The area under the curve for NC and WC in the ROC analysis was 0.86 for men and 0.77 for women, and NC ≥39.25 cm for men and ≥34.75 cm for women were the best cutoff levels for identifying subjects with central obesity with an 89% sensitivity and a 71% specificity for men and an 80% sensitivity and a 65% specificity for women. These cutoff levels for NC were associated with a significantly increased risk for diabetes, dyslipidemia, and hypertension. Conclusion: Neck circumference is positively correlated with BMI and WC, and can be used to identify overweight/obesity and predict CMR in Saudi individuals.