Miracle-dz/UniFAR-FTUs huggingface dataset:
Ventricular Ectopy and QTc‐Interval Prolongation Associated with Dronedarone Therapy

Amiodarone is an effective treatment for atrial and ventricular arrhythmias, but its use is limited by a toxic adverse‐effect profile. Although dronedarone has been touted as an antiarrhythmic agent devoid of both solid organ toxicity and proarrhythmic properties, its potential for prolonging ventricular repolarization may augment triggered ectopy. We describe a 66‐year‐old man who began dronedarone 400 mg twice/day for new‐onset paroxysmal atrial fibrillation; he had no left ventricular dysfunction or clinical heart failure. Three months after starting the drug, he complained of malaise, fatigue, and rare palpitations. Twenty four–hour Holter monitoring revealed increased premature ventricular complexes, and the rate‐corrected QT (QTc) interval was prolonged (range 525–760 msec). Dronedarone was discontinued and the patient's symptoms gradually resolved over the next 3 weeks. Holter monitoring revealed a marked reduction in ventricular ectopy burden, and the QTc interval decreased to his baseline values. Even in the absence of documented symptomatic torsade de pointes, this case suggests that caution should be exercised when prescribing dronedarone and that serial QTc interval monitoring may be appropriate. In addition, clinicians should have a low threshold to perform Holter monitoring if symptoms develop during dronedarone therapy.
Deubiquitinating enzyme USP37 regulating oncogenic function of 14-3-3γ

14-3-3 is a family of highly conserved protein that is involved in a number of cellular processes. In this study, we identified that the high expression of 14-3-3γ in various cancer cell lines correlates with the invasiveness of the cancer cells. Overexpression of 14-3-3γ causes changes to the morphologic characteristics of cell transformation, and promotes cell migration and invasion. The cells overexpressed with 14-3-3γ have been shown to stimulate foci and tumor formation in SCID-NOD mice in concert with signaling components as reported with the 14-3-3β. In our previous study, we demonstrated that 14-3-3γ inhibits apoptotic cell death and mediates the promotion of cell proliferation in immune cell lines. Earlier, binding partners for 14-3-3γ were defined by screening. We found that USP37, one of deubiquitinating enzymes (DUBs), belongs to this binding partner group. Therefore, we investigated whether 14-3-3γ mediates proliferation in cancer cells, and 14-3-3γ by USP37 is responsible for promoting cell proliferation. Importantly, we found that USP37 regulates the stability of ubiquitin-conjugated 14-3-3γ through its catalytic activity. This result implies that the interactive behavior between USP37 and 14-3-3γ could be involved in the regulation of 14-3-3γ degradation. When all these findings are considered together, USP37 is shown to be a specific DUB that prevents 14-3-3γ degradation, which may contribute to malignant transformation via MAPK signaling pathway, possibly providing a new target for therapeutic objectives of cancer.
Distribution of the Lactase Persistence-Associated Variant Alleles -13910*T and -13915*G among the People of Oman and Yemen

Abstract The high prevalence of lactase persistence (LP) among the people of Saudi Arabia is associated with the -13915*G variant allele upstream of the lactase gene (LCT). We, therefore, examined the frequency of the commonly known LP associated SNPs among randomly collected samples from Omani and Yemeni adult populations and obtained further data on the distribution of the two most common LP-associated variants, -13910*T and -13915T*G, in the Arabian Peninsula. The DNA fragment containing all the reported LP- associated SNPs was amplified and genotyped. The frequency of the -13915*G allele was highest among Dhofari Arabs of southern Oman (0.72) followed by Yemeni Arabs (0.54) and Arabs of northern Oman (0.14). It was not detected in Omanis of Asian origin. The frequency of the -13910*T allele was extremely low in Arabs of northern and southern Oman (0.00–0.01) and Yemenis (0.002). However, it had a frequency of 0.160 among Omanis of Asian origin. Results show that the highest frequency of the LCT -13915*G variant allele appears to be in the south of the Arabian Peninsula with clinal decrease within the Peninsula and further out in surrounding countries.
Robust on-line monitoring for univariate processes based on two sample goodness-of-fit test

On-line monitoring of quality variables and data streams raises attention in fields of quality management and statistical process control. Though much work has been dedicated on it in the literature, some challenges associated with designing distribution-free on-line control schemes are yet to be addressed well. This paper proposes a new distribution-free control chart for detecting both mean shifts and variance shifts in a univariate process based on nonparametric two sample goodness-of-fit test. It also integrates the self-starting feature by using data-dependent control limits set on-line instead of predetermined limits. Simulation study shows that the chart has satisfactory in-control run length performance given desired ARL and robust detection capability for general out-of-control changes, and is especially useful in short-run processes or start-up stages.
Mobile elements and inverted rearrangements in Trimerotropis pallidipennis (Orthoptera: Acrididae)

Abstract Mobile elements are ubiquitous and extremely active agents of genome variability and evolution. They contribute the bulk of DNA in most eukaryotic genomes, and promote various chromosomal rearrangements more efficiently and often more specifically than other cellular processes (i.e. deletions, duplications and inversions). The Class II element mariner is present from fungal genomes to invertebrates and vertebrates. In this paper, the identification and chromosomal localization of a new mariner-like element is reported in the genome of Trimerotropis pailidipennis, a grasshopper species with a high incidence of polymorphic inverted rearrangements with adaptive significance. This element was detected by FISH in centromeric and telomeric regions of most autosomes with pericentric inversions, and also in the X-chromosomes. These chromosome regions coincide in most cases with the extremes of inversions, suggesting a possible role mariner element played in the origin of inverted rearrangements in T. pallid-ipennis.
Pipelining in multi-query optimization

Database systems frequently have to execute a set of related queries, which share several common subexpressions. Multi-query optimization exploits this, by finding evaluation plans that share common results. Current approaches to multi-query optimization assume that common subexpressions are materialized. Significant performance benefits can be had if common subexpressions are pipelined to their uses, without being materialized. However, plans with pipelining may not always be realizable with limited buffer space, as we show. We present a general model for schedules with pipelining, and present a necessary and sufficient condition for determining validity of a schedule under our model. We show that finding a valid schedule with minimum cost is NP-hard. We present a greedy heuristic for finding good schedules. Finally, we present a performance study that shows the benefit of our algorithms on batches of queries from the TPCD benchmark.
Interventions to promote upper limb recovery in stroke survivors with severe paresis: a systematic review

Purpose. To investigate the effect of interventions that promote upper limb (UL) recovery in stroke survivors with severe paresis. Methods. A systematic search of the scientific literature from January 1970 to March 2009 was conducted using CINAHL, Cochrane, PEDro, Pubmed and Web of Science. keywords used included stroke, severe, hemiplegia, UL, task-oriented, robot, non-robot and electrical stimulation. Methodological quality of the studies was assessed using the PEDro rating scale. Studies were grouped into one of three intervention categories: robotic therapy, electrical stimulation or ‘other’ therapy. Results. Seventeen randomised controlled trials met the inclusion criteria. A ‘best evidence synthesis’ indicated strong evidence that robotic therapy provides a large beneficial effect and limited evidence that electrical stimulation and ‘other’ interventions provide a large beneficial effect on function. There is no evidence that these interventions influence use of the arm in everyday tasks. Conclusion. There are a number of newly developed interventions that enable stroke survivors with severe paresis to actively participate in task-oriented practice to promote UL recovery. While these interventions offer some promise for stroke survivors with severe paresis, ultimately, the effectiveness of these interventions will be dependent on whether they lead to restoration of function to the point at which the stroke survivor can practice everyday tasks.
The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene

The NR4A3 nuclear receptor is implicated in the development of extraskeletal myxoid chondrosarcoma (EMC), primitive sarcoma unrelated to conventional chondrosarcomas, through a specific fusion with EWSR1 resulting in an aberrant fusion protein that is thought to disrupt the transcriptional regulation of specific target genes. We performed an expression microarray analysis of EMC tumours expressing the EWSR1/NR4A3 fusion protein, comparing their expression profiles to those of other sarcoma types. We thereby identified a set of genes significantly overexpressed in EMC relative to other sarcomas, including PPARG and NDRG2. Western blot or immunohistochemical analyses confirm that PPARG and NDRG2 are expressed in tumours positive for EWSR1/NR4A3. Bioinformatic analysis identified a DNA response element for EWSR1/NR4A3 in the PPARG promoter, and band‐shift experiments and transient transfections indicate that EWSR1/NR4A3 can activate transcription through this element. Western blots further show that an isoform of the native NR4A3 receptor lacking the C‐terminal domain is very highly expressed in tumours positive for EWSR1/NR4A3, and co‐transfections of this isoform along with EWSR1/NR4A3 indicate that it may negatively regulate the activity of the fusion protein on the PPARG promoter. These results suggest that the overall expression of PPARG in EMC may be regulated in part by the balance between EWSR1/NR4A3 and NR4A3, and that PPARG may play a crucial role in the development of these tumours. The specific up‐regulation of PPARG by EWSR1/NR4A3 may also have potential therapeutic implications. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Multi-Cellular Logistics of Collective Cell Migration

During development, the formation of biological networks (such as organs and neuronal networks) is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic) blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes “collective migration,” whereas strong noise from non-migratory cells causes “dispersive migration. ” Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.
Direct Observation of Hierarchical Folding in Single Riboswitch Aptamers

Riboswitches regulate genes through structural changes in ligand-binding RNA aptamers. With the use of an optical-trapping assay based on in situ transcription by a molecule of RNA polymerase, single nascent RNAs containing pbuE adenine riboswitch aptamers were unfolded and refolded. Multiple folding states were characterized by means of both force-extension curves and folding trajectories under constant force by measuring the molecular contour length, kinetics, and energetics with and without adenine. Distinct folding steps correlated with the formation of key secondary or tertiary structures and with ligand binding. Adenine-induced stabilization of the weakest helix in the aptamer, the mechanical switch underlying regulatory action, was observed directly. These results provide an integrated view of hierarchical folding in an aptamer, demonstrating how complex folding can be resolved into constituent parts, and supply further insights into tertiary structure formation.
Associations between serum testosterone levels, cell proliferation and progesterone receptor content in normal and malignant breast tissue in postmenopausal women

Progestogens and progesterone receptors (PR) may play an important role in increased breast proliferation following combined estrogen/progestogen hormone therapy, while androgens may counteract this effect. In 50 untreated healthy postmenopausal women and 48 untreated postmenopausal breast cancer patients, we measured serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estrone (E1) and adrenal androgens; and additionally, in the breast cancer patients, cortisol and corticosteroid-binding globulin and endocrine data related to breast proliferation (assessed using the Ki-67/MIB-1 monoclonal antibody) and PR levels (determined by enzyme immunoassay) in the breast cancer tissue. In the healthy women the percentage of MIB-1+ cells showed significant negative correlations with serum levels of total T, calculated free T (fT) and the fT/E1 ratio; while in the breast cancer patients PR content showed significant negative correlations with fT level, the fT/E1 ratio and the T/SHBG ratio. No other correlations were found in any of the groups. Our findings in healthy women confirm previous reports of an antiproliferative effect of androgens in breast tissue and our finding in breast cancer patients suggests that this antiproliferative effect may be mediated via downregulation of PR.
Identification of Salmonella for public health surveillance using whole genome sequencing

In April 2015, Public Health England implemented whole genome sequencing (WGS) as a routine typing tool for public health surveillance of Salmonella, adopting a multilocus sequence typing (MLST) approach as a replacement for traditional serotyping. The WGS derived sequence type (ST) was compared to the phenotypic serotype for 6,887 isolates of S. enterica subspecies I, and of these, 6,616 (96%) were concordant. Of the 4% (n = 271) of isolates of subspecies I exhibiting a mismatch, 119 were due to a process error in the laboratory, 26 were likely caused by the serotype designation in the MLST database being incorrect and 126 occurred when two different serovars belonged to the same ST. The population structure of S. enterica subspecies II–IV differs markedly from that of subspecies I and, based on current data, defining the serovar from the clonal complex may be less appropriate for the classification of this group. Novel sequence types that were not present in the MLST database were identified in 8.6% of the total number of samples tested (including S. enterica subspecies I–IV and S. bongori) and these 654 isolates belonged to 326 novel STs. For S. enterica subspecies I, WGS MLST derived serotyping is a high throughput, accurate, robust, reliable typing method, well suited to routine public health surveillance. The combined output of ST and serovar supports the maintenance of traditional serovar nomenclature while providing additional insight on the true phylogenetic relationship between isolates.
Long-Term Therapy with Oral Treprostinil in Pulmonary Arterial Hypertension Failed to Lead to Improvement in Important Physiologic Measures: Results from a Single Center

Sustained-release oral treprostinil, an oral prostacyclin, led to significant improvement in 6-minute walk distance (6MWD) versus placebo in treatment-naive patients with pulmonary arterial hypertension (PAH) but failed to lead to significant improvement in two 16-week trials in patients receiving background PAH therapies (FREEDOM studies). Long-term studies are lacking. Our objective was to evaluate 6MWD, functional class, hemodynamics, and other long-term outcomes during oral treprostinil administration in PAH. Patients receiving oral treprostinil through the FREEDOM studies at our institution were included and were followed for up to 7 years. The primary end point was change in pulmonary vascular resistance (PVR) at first follow-up catheterization. Other end points included 6MWD, functional class, and other hemodynamic results. Thirty-seven patients received oral treprostinil for a median of 948 days, with 81%, 61%, and 47% continuing therapy at 1, 2, and 3 years, respectively. Mean treprostinil dose at 3, 12, and 24 months was 4.3 ± 2.3, 8.6 ± 3.2, and 11.7 ± 5.8 mg/24 h, respectively. Compared with pretreatment values, there was no significant change in 6MWD at 3 or 12 months, no improvement in functional class at 12 months, and no significant change in hemodynamics at the first follow-up catheterization (N = 34). Oral treprostinil dose was inversely associated with change in PVR (r = −0.42, P < 0.05), and change in PVR was numerically better among patients in the highest dosing quartile. No significant improvement in 6MWD, functional class, or hemodynamics versus pretreatment values was seen with long-term oral treprostinil therapy, potentially because of inability to achieve a clinically effective dose.
The current need for family and replacement donation in sub‐Saharan Africa should not hide the difficulties of its management

Dear Sir, Family replacement donation was initially described as a type of donation which is more risky than the voluntary not remunerated (VNR) donation and even during the last decade (Cunha et al., 2007; Mbanya & Tayou, 2005). For many years, this has consolidated WHO in the promotion of VNR donation (WHO, 2001, 2004). Currently, the majority of the countries having chosen exclusively the strategy of supply from VNR donation still do not have sufficient blood supply, in spite of the considerable assistance of international partners (Tagny et al., 2011). Family replacement donation still constitutes for several countries, an essential source of blood, notably when VNR blood donors are not available during school or university holidays. Blood supply from family replacement donation reduces the significant needs caused particularly by infectious diseases, anaemia from traumatic or obstetrical origins. Moreover, the cost of the exclusive supply from VNR donation remains hard to bear by the limited budget of the countries which adopted it. Indeed, the cost of a blood bag from a VNR donation is two to four times higher than that of a unit from a family replacement donation because of a high cost of the activities of promotion, mobile collection and quality system (Allain, 2011; Bates et al., 2007). Recently, some studies also asserted a weighty argument in favour of the family replacement donation: contrary to preceding information, it would be as much at risk as the VNR donation in first time donors (Allain, 2011). Only regular donation, family replacement as well as voluntary non-remunerated, are more capable to provide a supply at low risk. The combined use of the two types of donation is necessary but must gradually leave the place to a pool of regular donors capable to provide sustainable supply at lower risk. So, currently the family replacement donation remains useful; however, its daily management is problematic.
A Direct Interaction between the Sigma-1 Receptor and the hERG Voltage-gated K+ Channel Revealed by Atomic Force Microscopy and Homogeneous Time-resolved Fluorescence (HTRF®)*

Background: The sigma-1 receptor modulates the function of numerous ion channels. Results: We studied the interaction between the sigma-1 receptor and hERG. Conclusion: The interaction has a 4:1 stoichiometry and occurs at the plasma membrane. Significance: The sigma-1 receptor may bind to hERG in the endoplasmic reticulum, aiding its assembly and trafficking to the plasma membrane. The sigma-1 receptor is an endoplasmic reticulum chaperone protein, widely expressed in central and peripheral tissues, which can translocate to the plasma membrane and modulate the function of various ion channels. The human ether-à-go-go-related gene encodes hERG, a cardiac voltage-gated K+ channel that is abnormally expressed in many human cancers and is known to interact functionally with the sigma-1 receptor. Our aim was to investigate the nature of the interaction between the sigma-1 receptor and hERG. We show that the two proteins can be co-isolated from a detergent extract of stably transfected HEK-293 cells, consistent with a direct interaction between them. Atomic force microscopy imaging of the isolated protein confirmed the direct binding of the sigma-1 receptor to hERG monomers, dimers, and tetramers. hERG dimers and tetramers became both singly and doubly decorated by sigma-1 receptors; however, hERG monomers were only singly decorated. The distribution of angles between pairs of sigma-1 receptors bound to hERG tetramers had two peaks, at ∼90 and ∼180° in a ratio of ∼2:1, indicating that the sigma-1 receptor interacts with hERG with 4-fold symmetry. Homogeneous time-resolved fluorescence (HTRF®) allowed the detection of the interaction between the sigma-1 receptor and hERG within the plane of the plasma membrane. This interaction was resistant to sigma ligands, but was decreased in response to cholesterol depletion of the membrane. We suggest that the sigma-1 receptor may bind to hERG in the endoplasmic reticulum, aiding its assembly and trafficking to the plasma membrane.
Parents of Children With Cancer: At-Risk or Resilient?

OBJECTIVE To examine adjustment in parents of children with cancer using a design that minimizes focusing effects and allows for direct comparison with parents of healthy children. METHOD Parents of 305 children with cancer and a demographically similar sample of 231 parents of healthy children were evaluated using diagnostic interviews for posttraumatic stress disorder (PTSD), and questionnaire measures of posttraumatic stress symptoms (PTSS) and psychological growth (PG), as well as measures of global psychological functioning. RESULTS Rates of current and lifetime PTSD in parents of children with cancer were low, and did not differ from comparison parents. Likewise, levels of PTSS were not significantly different from comparison parents, but differed as a function of time since diagnosis, with parents of children who were ≥ 5 years from diagnosis reporting significantly lower PTSS than comparison parents. PG was higher in parents of children with cancer than in comparison parents regardless of time since diagnosis. CONCLUSION Parents of children with cancer demonstrate resilience to this challenge.