Miracle-dz/UniFAR-FTUs huggingface dataset:
The highly selective CRF(2) receptor antagonist K41498 binds to presynaptic CRF(2) receptors in rat brain.

1. Novel analogues of antisauvagine-30 (aSvg-30), a selective antagonist for CRF(2) receptors, have been synthesized and characterized in vitro and in vivo. 2. The analogues were tested for their ability to compete for [(125)I-Tyr(0)]Svg binding and to inhibit Svg-stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF(1) (hCRF(1)), hCRF(2alpha) and hCRF(2beta) receptor. One analogue [D-Phe(11), His(12), Nle(17)]Svg(11-40), named K41498, showed high affinity binding to hCRF(2alpha) (K(i)=0.66+/-0.03 nM) and hCRF(2beta) (K(i)=0.62+/-0.01 nM) but not the hCRF(1) receptor (k(i)=425+50 nM) and decreased Svg-stimulated cAMP accumulation in hCRF(2) expressing cells. In conscious Wistar-Kyoto rats, K41498 (1.84 microg, i.v.) antagonized the hypotensive response to systemic urocortin (1.4 microg, i.v.), but did not block the pressor response to centrally administered urocortin (2.35 microg, i.c.v.). 3. K41498 was subsequently radio-iodinated, and in autoradiographic studies, specific (sensitive to rat urocortin, astressin and aSvg30, but insensitive to antalarmin) binding of (125)I-K41498 (100 pM) was detected in the heart and in selected brain regions including the nucleus tractus solitarius (NTS), spinal trigeminal nucleus, lateral septum and around the anterior and middle cerebral arteries. 4. Following unilateral nodose ganglionectomy, binding of (125)I-K41498 was reduced by 65% in the ipsilateral NTS, indicative of presynaptic CRF(2) receptors on vagal afferent terminals. 5. These data demonstrate that K41498 is a useful tool to study native CRF(2) receptors in the brain and periphery.
Bronchiolitis obliterans syndrome in adults after allogeneic stem cell transplantation-pathophysiology, diagnostics and treatment

ABSTRACT Introduction: Transplant-related complications are common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), including graft versus host disease (GVHD). The lungs are frequently affected during the course of allo-HSCT, and among the non-infectious pulmonary complications bronchiolitis obliterans syndrome (BOS) is the most common and considered the only diagnostic manifestation of pulmonary GVHD. BOS is an irreversible obstructive disease that affects the terminal bronchioles, and it is associated with high morbidity and mortality rates. Area covered: We discuss the features of chronic GVHD, including the pathophysiological and cytokine-mediated alteration in BOS. Early treatment, before structural and irreversible changes have occurred, is crucial to reduce disease morbidity and mortality. This is challenging, given the unspecific symptoms of early stage disease and the complexity of the disease pathophysiology, obstructing both the diagnostic workup and the initiation of treatment. We highlight the main issues regarding diagnostic challenges, and we discuss the treatment options with a focus on new therapeutic options and modalities. Expert commentary: BOS is one of the most serious late complications after allo-HSCT and remains a diagnostic and therapeutic challenge. Thus, new and more effective therapeutic alternatives are strongly warranted.
Heterologous Human Immunodeficiency Virus Type 1 Priming-Boosting Immunization Strategies Involving Replication-Defective Adenovirus and Poxvirus Vaccine Vectors

ABSTRACT We compared the human immunodeficiency virus type 1 (HIV-1)-specific cellular immune responses elicited in nonhuman primates by HIV-1 gag-expressing replication-defective adenovirus serotype 5 (Ad5) or poxvirus vectors, used either alone or in combination with each other. The responses arising from a heterologous Ad5 priming-poxvirus boosting regimen were significantly greater than those elicited by homologous regimens with the individual vectors or by a heterologous poxvirus priming-Ad5 boosting regimen. The heterologous Ad5 priming-poxvirus boosting approach may have potential utility in humans as a means of inducing high levels of cellular immunity.
Education and self-management for people newly diagnosed with type 2 diabetes: a qualitative study of patients' views

Objectives: We explored the perceptions, views and experiences of diabetes education in people with type 2 diabetes who were participating in a UK randomized controlled trial of methods of education. The intervention arm of the trial was based on DESMOND, a structured programme of group education sessions aimed at enabling self-management of diabetes, while the standard arm was usual care from general practices. Methods: Individual semi-structured interviews were conducted with 36 adult patients, of whom 19 had attended DESMOND education sessions and 17 had been randomized to receive usual care. Data analysis was based on the constant comparative method. Results: Four principal orientations towards diabetes and its management were identified: `resisters', `identity resisters, consequence accepters', `identity accepters, consequence resisters' and `accepters'. Participants offered varying accounts of the degree of personal responsibility that needed to be assumed in response to the diagnosis. Preferences for different styles of education were also expressed, with many reporting that they enjoyed and benefited from group education, although some reported ambivalence or disappointment with their experiences of education. It was difficult to identify striking thematic differences between accounts of people on different arms of the trial, although there was some very tentative evidence that those who attended DESMOND were more accepting of a changed identity and its implications for their management of diabetes. Discussion: No one single approach to education is likely to suit all people newly diagnosed with diabetes, although structured group education may suit many. This paper identifies varying orientations and preferences of people with diabetes towards forms of both education and self-management, which should be taken into account when planning approaches to education.
Adverse reactions to food and food allergy in young children in Iceland and Sweden.

OBJECTIVE To investigate the prevalence of adverse reactions to food and food allergy in Icelandic and Swedish 18-month-old children. DESIGN Prospective multicentre comparative study. SETTING Primary health care centres in Sweden and Iceland. SUBJECTS A total of 324 children in Iceland and 328 in Sweden who attended for regular 18-month check-up. MAIN OUTCOME MEASURES Adverse reaction to food according to questionnaire, and food allergy according to skin prick tests and double blind food challenge tests. RESULTS Adverse reactions to food were reported in 27% of children in Iceland and 28% in Sweden. Food allergy was confirmed in 2.0% in both countries. Allergy among other family members was reported in 45% of the Icelandic children and 62% in the Swedish (p < 0.001). Indoor smoking was reported by 30% of the Icelandic families and 3% of the Swedish. Respiratory infections were reported significantly more often in Icelandic children than Swedish. CONCLUSION Adverse reactions to food and food allergy were similar in Icelandic and Swedish children. At the age of 18 months one can expect to confirm food allergy in approximately one out of 15 children with reported adverse reactions to food.
Course of Maternal Serum Magnesium Levels in Low-Risk Gestations and in Preterm Labor and Delivery

Objectives: To describe the course of total and ionized magnesium and total calcium levels in maternal serum during low-risk pregnancies and to compare women who developed preterm labor and delivery with those who delivered at term. Methods: 209 women with low-risk pregnancies were enrolled in a prospective trial before the 18th week of gestation. No woman received oral magnesium supplementation. The ionized and total magnesium and total calcium levels in maternal serum were measured every 4–6 weeks. The data were grouped into 3 gestational periods (≤18, 19–27 and ≥28 weeks of gestation) for overall comparison and analyzed with the general linear model for repeated measurements and ANOVA. p values of < 0.05 were considered statistically significant. Results: 145 gestations were available for analysis. 27 women were hospitalized for preterm labor and in 16 of these preterm delivery occurred. Ionized and total magnesium and calcium levels were significantly lower after the 18th week of gestation than before. The cation levels in women with preterm labor and delivery did not differ from those with term delivery. Conclusion: Ionized and total magnesium and calcium levels decrease with increasing gestational age. Preterm labor and delivery do not seem to be related to changes in serum cation levels.
The Proton/Amino Acid Cotransporter PAT2 Is Expressed in Neurons with a Different Subcellular Localization than Its Paralog PAT1*

The new member of the mammalian amino acid/auxin permease family, PAT2, has been cloned recently and represents an electrogenic proton/amino acid symporter. PAT2 and its paralog, PAT1/LYAAT-1, are transporters for small amino acids such as glycine, alanine, and proline. Our immunodetection studies revealed that the PAT2 protein is expressed in spinal cord and brain. It is found in neuronal cell bodies in the anterior horn in spinal cord and in brain stem, cerebellum, hippocampus, hypothalamus, rhinencephalon, cerebral cortex, and olfactory bulb in the brain. PAT2 is expressed in neurons positive for the N-methyl-d-aspartate subtype glutamate receptor subunit NR1. PAT2 is not found in lysosomes, unlike its paralog PAT1, but is present in the endoplasmic reticulum and recycling endosomes in neurons. PAT2 has a high external proton affinity causing half-maximal transport activation already at a pH of 8.3, suggesting that its activity is most likely not altered by physiological pH changes. Transport of amino acids by PAT2 activity is dependent on membrane potential and can occur bidirectionally; membrane depolarization causes net glycine outward currents. Our data suggest that PAT2 contributes to neuronal transport and sequestration of amino acids such as glycine, alanine, and/or proline, whereby the transport direction is dependent on the sum of the driving forces such as substrate concentration, pH gradient, and membrane potential.
PU.1 Redirects Adenovirus to Lysosomes in Alveolar Macrophages, Uncoupling Internalization from Infection1

Adenovirus is endocytosed and efficiently destroyed by human and murine alveolar macrophages (AMs) and rapidly cleared from the lungs of wild-type but not GM-CSF−/− mice. We hypothesized that GM-CSF may regulate adenovirus clearance in AMs via the transcription factor PU.1 by redirecting virion trafficking from the nucleus to lysosomes. This hypothesis was tested in murine AM cell lines with altered GM-CSF and/or PU.1 expression including MH-S (GM-CSF+/+PU.1Pos), mAM (GM-CSF−/−/PU.1Neg), and mAMPU.1+ (GM-CSF−/−/PU.1Pos; PU.1-transduced mAM cells) and A549 (an epithelial-like cell line) using a human adenovirus expressing a β-galactosidase reporter. In PU.1Neg mAM and A549 cells, adenovirus efficiently escaped from endosomes, translocated to the nucleus, and expressed the viral reporter in most cells. In marked contrast, in PU.1Pos mAMPU.1+ and MH-S cells, adenovirus failed to escape from endosomes, colocalized exclusively with endosome/lysosome markers (Rab5, Rab7, and Lamp1), and rarely expressed the reporter. Retroviral expression of PU.1 in A549 cells blocked endosomal escape, nuclear translocation and reporter expression. Inhibition of endosome acidification also blocked escape, nuclear translocation, and reporter expression in PU.1Neg cells. The effect of PU.1 on viral trafficking and transduction could not be explained by an effect on endosome acidification or on differences in viral load. PU.1 reduced expression of integrin β5, a host factor important for endosomal escape of adenovirus, suggesting that PU.1 redirects adenoviral trafficking by modulating integrin signaling. These results demonstrate that PU.1 uncouples infection from internalization in AMs, providing a mechanism for AMs to avoid infection by adenovirus during clearance.
Increased neopterin concentrations in patients with cancer: indicator of oxidative stress?

In vitro, large amounts of neopterin are produced by human monocytes/macrophages upon stimulation with interferon-gamma. In vivo increased neopterin concentrations in human serum and urine indicate activation of cell-mediated (Th1-type) immune response, e.g., during virus infections, autoimmune diseases, allograft rejection and in certain types of malignancy. In various groups of patients with malignant diseases neopterin concentrations correlate to the stage of disease, and higher neopterin concentrations in serum, urine or ascitic fluid were shown to significantly predict worse prognosis regarding relapse and survival. The amounts of neopterin produced by activated monocytes/macrophages correlate with their capacity to release reactive oxygen species (ROS). With this background, neopterin concentrations in body fluids can be regarded as an indirect estimate of the degree of oxidative stress emerging during cell-mediated immune response. Moreover, recently neopterin was found itself to be capable of enhancing toxic effects induced by ROS. In vitro, neopterin derivatives were able to interfere with intracellular signal transduction pathways involved in, e.g., programmed cell death and the induction of proto-oncogene c-fos or nuclear factor-chi B. The data support the view that increased production of ROS--indicated by increased neopterin concentrations--could modulate the development, the proliferation and the survival of malignant cells.
Spintronics with multiferroics

In this paper, we review the recent research on the functionalization of multiferroics for spintronics applications. We focus more particularly on antiferromagnetic and ferroelectric BiFeO3 and its integration in several types of architectures. For instance, when used as a tunnel barrier, BiFeO3 allows the observation of a large tunnel magnetoresistance with Co and (La,Sr)MnO3 ferromagnetic electrodes. Also, its antiferromagnetic and magnetoelectric properties have been exploited to induce an exchange coupling with a ferromagnet. The mechanisms of such an exchange coupling open ways to electrically control magnetization and possibly the logic state of spintronics devices. We also discuss recent results concerning the use of ferromagnetic and ferroelectric (La,Bi)MnO3 as an active tunnel barrier in magnetic tunnel junctions with Au and (La,Sr)MnO3 electrodes. A four-resistance-state device has been obtained, with two states arising from a spin filtering effect due to the ferromagnetic character of the barrier and two resulting from the ferroelectric behavior of the (La,Bi)MnO3 ultrathin film. These results show that the additional degree of freedom provided by the ferroelectric polarization brings novel functionalities to spintronics, either as a extra order parameter for multiple-state memory elements, or as a handle for gate-controlled magnetic memories.
Impact of Coupling Techniques of an Active Middle Ear Device to the Round Window Membrane for the Backward Stimulation of the Cochlea

Hypothesis Interposed cartilage and the round window coupler (RWC) increase the efficiency of cochlea stimulation with the floating mass transducer (FMT) of a single active middle ear implant (AMEI) placed against the round window membrane. Background Treatment of mixed and conductive hearing loss with an AMEI attached to the round window is effective, yet the best placement technique of its FMT for the most efficient stimulation of the cochlea remains to be determined. Methods Experimental study on human temporal bones with the FMT placed against firstly the unaltered round window niche and then subsequently against the fully exposed round window membrane with and without interposed cartilage and the RWC. Cochlea stimulation is measured by the volume velocities of the stapes footplate using LASER vibrometry. Results At the undrilled round window niche, placement of the FMT by itself and with the RWC resulted in similar volume velocities. The response was significantly raised by interposing cartilage into the undrilled round window niche. Complete exposure of the round window membrane allowed for significantly increased volume velocities. Among these, coupling of the FMT with interposed cartilage yielded responses of similar magnitude compared with the RWC but significantly higher compared with the FMT by itself. Conclusion Good contact to the round window membrane is essential for efficient stimulation of the cochlea. Therefore, interposing cartilage into the undrilled round window niche is a viable option. At the drilled round window membrane, the FMT with interposed cartilage and attached to the RWC are similarly effective.
Protective effect of apocynin on antimycin A‐induced cell damage in osteoblastic MC3T3‐E1 cells

Apocynin is a naturally occurring methoxy‐substituted catechol, experimentally used as an inhibitor of NADPH‐oxidase. In the present study, we investigated the protective effects of apocynin on antimycin A (AMA)‐induced toxicicy in osteoblastic MC3T3‐E1 cells. Exposure of MC3T3‐E1 cells to AMA caused significant cell viability loss, as well as mitochondrial membrane potential (MMP) dissipation, complex IV inactivation, ATP loss, intracellular calcium ([Ca2+]i) elevation and oxidative stress. Pretreatment with apocynin prior to AMA exposure significantly reduced AMA‐induced cell damage by preventing MMP dissipation, complex IV inactivation, ATP loss, [Ca2+]i elevation and oxidative stress. These results suggest that apocynin has a protective effect against AMA‐induced cell damage by its antioxidant effects and the attenuation of mitochondrial dysfunction. Apocynin also induced the activation of PI3K (phosphoinositide 3‐kinase), Akt (protein kinase B) and CREB (cAMP‐response element‐binding protein) inhibited by AMA. All these data indicate that apocynin may reduce or prevent osteoblasts degeneration in osteoporosis or other degenerative disorders. Copyright © 2011 John Wiley & Sons, Ltd.
Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes

DNA methylation has a substantial impact on gene expression, affecting the prognosis of breast cancer (BC) patients dependent on molecular subtypes. In this study, we investigated the prognostic relevance of the expression of genes reported as aberrantly methylated, and the link between gene expression and DNA methylation in BC subtypes. The prognostic value of the expression of 144 aberrantly methylated genes was evaluated in ER+/HER2−, HER2+, and ER−/HER2− molecular BC subtypes, in a meta‐analysis of two large transcriptomic cohorts of BC patients (n = 1,938 and n = 1,640). The correlation between gene expression and DNA methylation in distinct gene regions was also investigated in an independent dataset of 104 BCs. Survival and Pearson correlation analyses were computed for each gene separately. The expression of 48 genes was significantly associated with BC prognosis (p < 0.05), and 32 of these prognostic genes exhibited a direct expression–methylation correlation. The expression of several immune‐related genes, including CD3D and HLA‐A, was associated with both relapse‐free survival (HR = 0.42, p = 3.5E‐06; HR = 0.35, p = 1.7E‐08) and overall survival (HR = 0.50, p = 5.5E‐04; HR = 0.68, p = 4.5E‐02) in ER‐/HER2‐ BCs. On the overall, the distribution of both positive and negative expression–methylation correlation in distinct gene regions have different effects on gene expression and prognosis in BC subtypes. This large‐scale meta‐analysis allowed the identification of several genes consistently associated with prognosis, whose DNA methylation could represent a promising biomarker for prognostication and clinical stratification of patients with distinct BC subtypes.
TOTO Binding Affinity Analysis Using Single-molecule Fluorescence Spectroscopy¶

Abstract The sequence dependence of the double-stranded DNA (dsDNA)–binding affinity of TOTO, a thiazole orange dimer that functions as a DNA-intercalating fluorophore, was measured using single-molecule methods. An analysis was performed of the distribution of excited-state lifetimes of single molecules of TOTO intercalated into dsDNA fragments containing four–base pair sequences shown previously to have high affinity for TOTO under conditions used in nuclear magnetic resonance (NMR) spectroscopy. For the current studies, the putative binding sites were located centrally in 30–base pair–long dsDNA fragments in which the remaining sequence was either all poly-AT or poly-GC. The lifetime of TOTO fluorescence when bound to these fragments was entirely determined by the background sequence, i.e. DNA fragments with a poly-AT background predominantly gave a fluorescence lifetime of 1.7 ns, whereas DNA fragments with a poly-GC background gave a lifetime of 2.0 ns, independent of the presence or absence of the putative binding sequence. By performing competitive binding experiments in which these DNA fragments competed for TOTO binding with pure poly-AT fragments and using single-molecule fluorescence methods to determine the number of each type of DNA fragment having a TOTO bound in an equilibrium mixture, the relative binding affinity of each putative binding site was determined. The results of these experiments showed clearly that TOTO has no preference for binding to the putative binding sites over binding poly-AT or poly-GC under the conditions of these measurements. This suggests that there is very little sequence dependence of TOTO binding under conditions that would likely predominate in most biological applications of this intercalating dye.
Use of morphine and 6-monoacetylmorphine in blood for the evaluation of possible risk factors for sudden death in 192 heroin users.

AIMS To detect risk factors for sudden death from heroin injection. DESIGN Evaluation of data from forensic investigations of all fatal cases of suspected heroin death in a metropolitan area. Only cases with detectable morphine and 6-monoacetylmorphine (6-MAM) in blood were included in order to select heroin intoxication cases. SETTING Stockholm, Sweden. MEASUREMENTS Autopsy investigation and toxicological analysis of blood and urine; and police reports. FINDINGS In two-thirds of the 192 cases, death occurred in public places, and mostly without any time delay. Blood concentrations of morphine ranged from 50 to 1200 ng/g, and of 6-MAM from 1 to 80 ng/g. Codeine was detected in 96% of the subjects. In the majority of cases the forensic investigation indicated polydrug use, the most common additional findings being alcohol and benzodiazepines. However, in one-quarter of the cases other drug combinations were found. Previous abstinence from heroin and use of alcohol were identified as risk factors. For 6-MAM there was also a correlation with the presence of THC and benzodiazepines. Despite a high frequency of heart abnormalities (e.g. myocarditis and focal myocardial fibrosis), these conditions did not correlate with morphine or 6-MAM blood concentrations. CONCLUSIONS We confirm that alcohol intake and loss of tolerance are risk factors for death from heroin use, whereas no connection to heart pathology was observed. Further, prospective, studies should focus on other possible risk factors.