Miracle-dz/UniFAR-FTUs huggingface dataset:
Domain organization and function in GluK2 subtype kainate receptors

Glutamate receptor ion channels (iGluRs) are excitatory neurotransmitter receptors with a unique molecular architecture in which the extracellular domains assemble as a dimer of dimers. The structure of individual dimer assemblies has been established previously for both the isolated ligand-binding domain (LBD) and more recently for the larger amino terminal domain (ATD). How these dimers pack to form tetrameric assemblies in intact iGluRs has remained controversial. Using recently solved crystal structures for the GluK2 kainate receptor ATD as a guide, we performed cysteine mutant cross-linking experiments in full-length tetrameric GluK2 to establish how the ATD packs in a dimer of dimers assembly. A similar approach, using a full-length AMPA receptor GluA2 crystal structure as a guide, was used to design cysteine mutant cross-links for the GluK2 LBD dimer of dimers assembly. The formation of cross-linked tetramers in full-length GluK2 by combinations of ATD and LBD mutants which individually produce only cross-linked dimers suggests that subunits in the ATD and LBD layers swap dimer partners. Functional studies reveal that cross-linking either the ATD or the LBD inhibits activation of GluK2 and that, in the LBD, cross-links within and between dimers have different effects. These results establish that kainate and AMPA receptors have a conserved extracellular architecture and provide insight into the role of individual dimer assemblies in activation of ion channel gating.
Sequential Activation of Rac-1, SEK-1/MKK-4, and Protein Kinase Cδ Is Required for Interleukin-6-induced STAT3 Ser-727 Phosphorylation and Transactivation*

Activation of signal transducer and activator of transcription 3 (STAT3) by interleukin-6 (IL-6) involves phosphorylation of Tyr-705 and Ser-727, both of which are critical for STAT3 transactivation. Here, we demonstrate that IL-6 activates Rac-1 and SEK-1/MKK-4 of the stress-activated protein kinase pathway, as well as protein kinase Cδ (PKCδ), as indicated by PKCδ Thr-505 phosphorylation. However, JNK-1, the end point kinase of the stress-activated protein kinase pathway signal transduction cascade, is not activated by IL-6. PKCδ was found to be associated with SEK-1/MKK-4 in unstimulated HepG2 cells but rapidly dissociates from SEK-1/MKK-4 upon IL-6 stimulation to become associated with STAT3. Inhibition of PKCδ using rottlerin (6 μm) or by overexpression of dominant negative PKCδ demonstrates that PKCδ kinase activity is required for STAT3 Ser-727 phosphorylation and transactivation but not for STAT3 Tyr-705 phosphorylation or nuclear import. PKCδ signals downstream of Rac-1 and SEK-1/MKK-4, because enhanced STAT3 transactivation induced by overexpression of constitutive active RacV12 was strongly abrogated by rottlerin, whereas IL-6-induced SEK-1/MKK-4 Thr-223 phosphorylation was not affected under these conditions. Studying the kinetics of STAT3 and PKCδ phosphorylation in cytoplasmic and nuclear fractions revealed that STAT3 Tyr-705 phosphorylation and nuclear translocation precedes PKCδ Thr-505 and STAT3 Ser-727 phosphorylation. Furthermore, the IL-6-induced PKCδ Thr-505 and STAT3 Ser-727 phosphorylation were only observed in nuclear fractions of HepG2 cells. These results demonstrate that IL-6-induced STAT3 transactivation involves the sequential activation of Rac-1 and SEK-1/MKK-4, which leads to nuclear translocation of PKCδ by release from a SEK-1/MKK-4-containing complex. Our results further indicate that PKCδ-mediated STAT3 Ser-727 phosphorylation is mainly a nuclear event.
Intravenous Administration of Substance P Attenuates Mechanical Allodynia Following Nerve Injury by Regulating Neuropathic Pain-Related Factors

This study aimed to investigate the analgesic effect of substance P (SP) in an animal model of neuropathic pain. An experimental model of neuropathic pain, the chronic constriction injury (CCI) model, was established using ICR mice. An intravenous (i.v.) injection of SP (1 nmole/kg) was administered to the mice to examine the analgesic effects of systemic SP on neuropathic pain. Behavioral testing and immunostaining was performed following treatment of the CCI model with SP. SP attenuated mechanical allodynia in a time-dependent manner, beginning at 1 h following administration, peaking at 1 day post-injection, and decaying by 3 days post-injection. The second injection of SP also increased the threshold of mechanical allodynia, with the effects peaking on day 1 and decaying by day 3. A reduction in phospho-ERK and glial fibrillary acidic protein (GFAP) accompanied the attenuation of mechanical allodynia. We have shown for the first time that i.v. administration of substance P attenuated mechanical allodynia in the maintenance phase of neuropathic pain using von Frey’s test, and simultaneously reduced levels of phospho-ERK and GFAP, which are representative biochemical markers of neuropathic pain. Importantly, glial cells in the dorsal horn of the spinal cord (L4–L5) of SP-treated CCI mice, expressed the anti-inflammatory cytokine, IL-10, which was not seen in vehicle saline-treated mice. Thus, i.v. administration of substance P may be beneficial for improving the treatment of patients with neuropathic pain, since it decreases the activity of nociceptive factors and increases the expression of anti-nociceptive factors.
SCID‐repopulating activity of human umbilical cord blood–derived hematopoietic stem and/or progenitor cells in a nonobese diabetic/Shi‐SCID mice serial xenotransplantation model and immune cell activities in vitro: a comparative study of the filter method and the hydroxyethyl starch method

BACKGROUND: A novel filter system was developed for umbilical cord blood (UCB) volume reduction. The aim of this study was to compare the functions of cryopreserved UCB cells processed by the filter and by the hydroxyethyl starch (HES) sedimentation method from the aspect of the graft quality.
Non-Touch Aseptic Technique Maintains Sterility of Antibiotic-Admixed Peritoneal Dialysis Fluid

There is a paucity of data on the sterility of peritoneal dialysis fluid (PDF) after drug admixture. International Society for Peritoneal Dialysis (ISPD) guidelines suggest using sterile technique when admixing antibiotics; however, the degree of sterility remains unclear. This issue is most pertinent when preparing take-home PDF for outpatient treatment of peritonitis. This study compares the sterility of PDF admixed with antibiotics using a non-touch aseptic technique (NTAT) versus sterile technique. Groups of 8 PDF mixtures (1.5% Dianeal or Icodextrin [Baxter International Inc., Spring Grove, IL, USA]) were admixed with 1 g/L ceftazidime and vancomycin, or 20 mL saline, either by a pharmacist using sterile technique in a sterile suite, or a nurse in a clinical room using NTAT. Dianeal inoculated with 1 × 106 colony-forming units (CFU)/L of coagulase-negative Staphylococcus (CNS), with and without antibiotics, served as positive controls. Admixed PDFs were left at room temperature for 72 hours, then cultured using the BacT/ALERT system. A positive culture by day 5 constituted a contamination. Differences in proportion of contamination between groups were assessed using the Chi-squared test. Eighty PDF bags underwent microbiological testing. Sterility was maintained in all bags, independent of technique (NTAT versus sterile technique), type of PDF (Dianeal versus Icodextrin), or whether antibiotics were admixed. Of the positive controls, CNS-inoculated PDFs without antibiotics were all culture positive; however, when inoculated into antibiotic-admixed PDFs, only S. haemolyticus remained culture-positive (p < 0.0001). In conclusion, PDF sterility can be maintained using NTAT for up to 3 days at room temperature. Currently, there is insufficient evidence to adopt sterile technique in sterile suites when admixing take-home PDF.
Reliability study on high-k bi-layer dielectrics

As electronic devices get smaller, reliability issues pose new challenges due to unknown underlying physics of failure mechanisms. This necessitates the development of new reliability analysis approaches related to nano-scale devices. One of the most important nano-devices is the transistor, and it is subject to various failure mechanisms. For such devices, dielectric breakdown is the most critical failure mode and has become a major barrier for reliable circuit design in nanoscale. Due to aggressive needs for the downscaling of transistors, dielectric films are made extremely thin. This has led to adopting high permittivity (k) dielectrics as an alternative to previously widely used SiO2, in recent years. Since most time-dependent dielectric breakdown test data on high-k bi-layer stacks significantly deviate from the Weibull trend, we propose a new approach to modeling the corresponding time-to-breakdown in this paper. A marked space-time self-exciting point process is employed in modeling defect generation rate. A simulation algorithm is used to generate defects within the dielectric space, and an optimization algorithm is developed to minimize the Kullback-Leibler divergence between the empirical distributions of real and simulated data to find the best set of the parameters and predict the total time-to-failure. The novelty of the presented approach lies in using a conditional intensity for trap generation in dielectrics that is a function of the times, locations and sizes of previous defects.
Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells.

Although there is no definitive evidence of the association of human cytomegalovirus (HCMV) infection with human cancers, the oncogenic potential of HCMV has been well established by in vitro studies demonstrating the ability of UV-irradiated or infectious virus to transform a variety of cells. After prolonged passaging the transformed cell type was maintained while HCMV DNA sequences were no more detectable. Three morphological transforming regions (mtr) of HCMV have been identified. The effects of HCMV on cellular functions which may be associated with the malignant phenotype include the expression of oncogenes and transcriptional activation of growth factors and interleukin synthesis. In infected cells, HCMV induces cytoskeletal alterations and changes in expression of cell surface receptors for extracellular matrix proteins which could result in increased motility and dissemination of cancer cells. Several human neuroblastoma cell lines undergo maturation in different neural crest derived cell types upon treatment with oncogenic potential agents, i.e. retinoic acid. The persistent HCMV infection of neuroblastoma cells (> 1 year) is accompanied by the increased expression of oncoproteins (i.e. N-myc) and decreased expression of tyrosine hydroxylase and dopamine-beta-hydroxylase. The activation of the cellular metabolism is due to HCMV binding to cellular receptors (prior to virus gene expression) and to the activity of HCMV immediate early (IE) gene products. IE proteins act directly as transcriptional activators or their activity is mediated by a variety of cellular transcription factors. HCMV infection may result in activation of promoters of cellular genes coding for cytokines, replication enzymes, proto-oncogenes and viral promoters. Recently it has been demonstrated that HCMV IE proteins block apoptosis probably by suppressing the ability of the antioncogene p53 to activate a reporter gene. The interactions of HCMV with tumor suppressor proteins such as p53 or retinoblastoma (pRb) susceptibility protein are reminiscent of those mediated by the oncoproteins of DNA tumor viruses. The acquisition of a fully malignant phenotype by normal cells is thought to require several mutations in a number of cellular genes. In this connection, HCMV may play the role of a nonobligate either direct or indirect cofactor for tumor genesis, e.g. by blocking apoptosis, which may be an essential requirement for tumor progression. Due to the stimulation of growth factors and/or inhibition of antioncogenes by its gene products, HCMV may modulate the malignant potential for tumor cells.
Iranian student nurses' experiences of clinical placement.

BACKGROUND Nursing as a practice-based profession requires that student nurses learn how to become professional in the clinical environment. Many studies have addressed student nurses' clinical learning and related problems, but few have explored the whole clinical experience of being a student nurse. AIM To understand and gain deeper insight into Iranian student nurses' lived experience of clinical placement. METHOD Five student nurses were interviewed about their clinical experience during clinical placement. The researchers analysed the verbatim transcripts using van Manen's phenomenological methodology, keeping in mind the recommended six research activities. FINDINGS Five themes emerged by which the phenomenon of clinical experience could be illustrated. These themes were: caring-orientated relationships, attractive aspects of clinical experience, finding oneself in the clinical milieu, being supportive to classmates, and actualizing potential. Fourteen subthemes expanded and clarified the meaning of these themes. CONCLUSION The attention paid and acknowledgement given to 'caring' and 'knowledge' by the student nurses showed that they are progressing toward their ultimate goal of being professional nurses. The student nurses' awareness of 'what is going on there? ' and also support from other significant people facilitates the students' adaptation process and guarantees this progress.
The Chinese Stroke Association scientific statement: intravenous thrombolysis in acute ischaemic stroke

The most effective medical treatment for acute ischaemic stroke (AIS) is to offer intravenous thrombolysis during the ultra-early period of time after the onset. Even based on the Consensus of Chinese Experts on Intravenous Thrombolysis for AIS in 2012 and 2014 Chinese Guidelines on the Diagnosis and Treatment of AIS, the rate of thrombolysis for AIS in China remained around 2.4%, and the rate of intravenous tissue plasminogen activator usage was only about 1.6% in real world. The indication of thrombolysis for AIS has been expanded, and contraindications have been reduced with recently published studies. In order to facilitate the standardisation of treating AIS, improve the rate of thrombolysis and benefit patients who had a stroke, Chinese Stroke Association has organised and developed this scientific statement.
Inadvertent exposure to xenoestrogens in children

This article reviews previous studies and presents new data on pesticide exposure in order to provide some indications of the extent and significance of childhood exposure to xenoestrogens, including pesticides, epoxy resins, and polycarbonates. After more than four decades of pesticide use, little is known about their adverse effects on health. There is a need to address the potential risks associated with the current contamination of water, soils, and foods in many agricultural areas. In southeastern Spain, along the Mediterranean coast, extensive areas alongside residential zones are devoted to intensive farming in plastic greenhouses, with the use of large amounts of pesticides. Human tissue samples have been investigated for pesticide residues. Samples of fat from children living in farm areas contained a total of 14 pesticides, including lindane, HCH, heptachlor, aldrin, dieldrin, endrin, endosulfan, o,p′-DDE, and o,p′-DDD, among others. Of the 113 samples studied, 43 were positive for one or more pesticides, some of which have estrogenic activity. The number of new substances that mimic the action of endogenous estrogens is increasing rapidly. These endocrine-disrupting chemicals are not restricted to pesticides. Several different compounds used in the food industry, in plasticizers, and in dental restorations are also estrogenic. The few studies that have investigated their effects in humans all indicate that concerns are warranted. If there is indeed an association between zexposure to substances with hormone-disruptive activity and certain disorders of sexual maturation, the incidence of such disorders should be greater in areas where exposure to agents with this activity is high. We used a spatial ecological design to search for variations in orchidopexy rates and to analyze relationships between these differences and geographical variations in exposure to pesticides. Our results are compatible with a hypothetical association between exposure to hormone-disruptive chemicals and the induction of cryptorchidism. Several methodological limitations in the study design make it necessary to evaluate the results with caution. In conclusion, a closer scrutiny is required to determine whether epoxy resins and polycarbonates contribute, together with estrogenic pesticides, to the exposure of human consumers, especially children, to xenoestrogens.
Phase I/II study of irinotecan (CPT-11) and S-1 in the treatment of advanced gastric cancer

A phase I/II study to determine the recommended dose for combination therapy with CPT-11 (irinotecan hydrochloride) and S-1 (tegafur, gimestat and otastat potassium) for advanced or recurrent gastric cancer, and to assess the safety and efficacy of this therapy. In the phase I portion of the study, S-1 was administered from day 1 to 14 at a fixed dose approved in Japan (80 mg/m2/day), and CPT-11 was administered on days 1 and 8, with its dose being escalated to 100 from 80 mg/m2. This regimen was repeated at 3-week intervals. The phase II portion of the study assessed the efficacy and safety of this regimen at the recommended dose determined in the phase I portion of the study. Seven patients were enrolled in the phase I portion of the study. The dose-limiting toxicity was the delay of administration owing to adverse reactions (leucopenia and diarrhea). The maximum tolerated dose of CPT-11 was 100 mg/m2 and the recommended dose was determined to be 80 mg/m2. In the phase II portion of the study, 10 patients with no prior chemotherapy regimen were enrolled. The median number of treatment cycles given was 4.5, the response rate was 20.0% (2/10) in all patients, the tumor control rate stable disease or better response was 60% (6/10) and the mean survival time was 311 days. Major adverse reactions included a decreased hemoglobin level, diarrhea, nausea and anorexia of grade 3 or worse (each occurred in 10% of the patients). Other adverse reactions were slight and well tolerated. The present combination therapy with CPT-11 and S-1 produced a low response rate but a high tumor control rate (stable disease or better response) and slight prolongation of survival time. This is a well-tolerated ambulatory regimen for advanced gastric cancer.
BSR and BHPR guideline for the treatment of systemic sclerosis.

SCOPE AND PURPOSE: SSc is a complex, multi-organ disease that requires a comprehensive multidisciplinary guideline. This is a short summary of the guideline, which is available in full as supplementary material at Rheumatology Online. Each recommendation is graded for level of evidence (I-IV) and strength (A-D). ELIGIBILITY AND EXCLUSION CRITERIA: Patients are classified as having SSc based on current classification criteria (ACR/EULAR 2013 [1]). Other scleroderma spectrum diseases are not included in this document.
Sex‐determined resistance against Leishmania mexicana is associated with the preferential induction of a Th1‐like response and IFN‐γ production by female but not male DBA/2 mice

Female DBA/2 mice are relatively resistant to infection with Leishmania mexicana compared with male mice. Following subcutaneous infection with 5 × 106 L. mexicana, amastigotes lesion growth in male and female DBA/2 mice was measured and the developing immune responses were monitored both in vitro and in vivo. Over the 10 week duration of the experiment all male DBA/2 mice developed rapidly growing non‐healing lesions while female mice either developed no lesions whatsoever or developed smaller slower growing lesions than males. Both male and female mice produced parasite specific IgG2a during the course of the disease. However, significant titres of parasite specific IgG1 antibodies could be detected only in male mice indicating a Th2‐influenced response in this sex. Furthermore, female mice, unlike male mice, developed significant parasite induced cutaneous delayed‐type hypersensitivity footpad responses, indicating a Th1‐influenced response in female mice. Although both male and female DBA/2 mice infected with L. mexicana displayed a significant increase in the number of cells in their draining lymph nodes at week 10 post‐infection, no significant differences could be observed in the numbers of CD4+, CD8+ T cells as well as B cells between male and female DBA/2 mice. However, following in vitro stimulation, the lymph node cells from female mice displayed significantly higher antigen specific proliferative responses than the males and produced significant amounts of IFN‐γ which could not be detected in the equivalent culture supernatants from male mice. There were no significant differences in the levels of Th2‐associated cytokines IL‐4 and IL‐5, produced by the lymph node cells of both sexes. Treatment of female DBA/2 mice with IFN‐γ neutralizing antibody following L. mexicana infection resulted in lesion growth equivalent to male mice. Conversely, intralesional injections of murine recombinant IFN‐γ significantly inhibited lesion growth in male mice.
The Influence of Surface Oil on C-and Ku-Band Ocean Backscatter

A comparative study of ocean backscatter depression due to surface oil has been carried out using Ku-and C-band scatterometers supported by some X-and C-band synthetic aperture radar (SAR) imagery. The depression of radar backscatter for both C-and Ku-band HH-polarized radiation has been measured for the incidence angle range from 20° to 50° on two days, September 16 and 17, 1983 on which the average wind and wave height conditions were 3-6 m/s, 0.3 m and ~10-14 m/s, 1.2 m, respectively. Results show that the depression in Ku-band backscatter increases from approximately 3-5 dB at 20° to ~10 dB or more at 30°-40° and then decreases at the larger incidence angles. Generally, the angular dependence of C-band backscatter depression was similar to that at Ku-band, but the peak depression was shifted to slightly larger angles and usually exceeded Ku peak 1-2 dB. The Ku-band results are in good agreement with previous work [9] that tentatively explained the angular results of backscatter depression on the basis of a selective damping of the first-order Bragg resonant waves by the oil film. This explanation, however, is inconsistent with the results of the present work when both C-and Ku-band are considered. The significance of the data is discussed in the context of present and future radar systems (e. g., the ESA ERS-1 SAR and the Radarsat SAR).