Miracle-dz/UniFAR-FTUs huggingface dataset:
A transporter-to-trap conversion: a disulfide bond formation in CRABP I mutant triggered by retinoic acid binding irreversibly locks the ligand inside the protein

Transport proteins must bind their ligands reversibly to enable release at the point of delivery, while irreversible binding is usually associated with the extreme cases of ligand sequestration. Protein conformational dynamics is an important modulator of binding kinetics, as increased flexibility in the regions adjacent to the binding site may facilitate both association and dissociation processes. Ligand entry to, and exit from, the internal binding site of the Cellular Retinoic Acid Binding Protein I (CRABP I) occurs via a flexible portal region, which functions as a dynamic aperture. We designed and expressed a CRABP I mutant (A35C/T57C), in which a small-scale conformational switch caused by the ligand binding event triggers formation of a disulfide bond in the portal region, thereby arresting structural fluctuations and effectively locking the ligand inside the binding cavity. At the same time, no formation of the disulfide bond is observed in the apo-form of the mutant, and most characteristics of the mutant, including protein stability, are very similar to those of the wild type protein in the absence of retinoic acid. The mutation does not alter the kinetic of retinoic acid binding to the protein, although the disulfide formation makes the binding effectively irreversible, as suggested by the absence of retinoic acid transfer from the holo-form of the mutant to lipid vesicles in the absence of a reducing agent. Taken together, these data suggest that the disulfide bond formation in the portal region arrests large-scale structural fluctuations, which are required for retinoic acid release from the protein. The unique properties of the CRABP I mutant described in this work can be used to inspire and guide a design of nanodevices for multiple tasks ranging from sequestering small-molecule toxins both in tissue and circulation to nutrient-deprivation of pathogens.
Nonmyeloablative HLA-Haploidentical BMT with High-Dose Posttransplantation Cyclophosphamide: Effect of HLA Disparity on Outcome

Although some reports have found increasing HLA disparity between donor and recipient to be associated with fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality. However, the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. We analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative, HLA-haploidentical transplantation. A retrospective analysis was performed on 185 patients with hematologic malignancies enrolled on three similar trials of nonmyeloablative, related donor, haploidentical BMT incorporating high-dose posttransplantation cyclophosphamide for GVHD prophylaxis. No significant association was found between the number of HLA mismatches (HLA-A, -B, -Cw, and -DRB1 combined) and risk of acute grade II– IV GVHD (hazard ratio .89, P = .68 for 3–4 versus fewer antigen mismatches). More mismatching also had no detrimental effect on event-free survival (on multivariate analysis, hazard ratio .60, P = .03 for 3–4 versus fewer antigen mismatches; hazard ratio .55, P = .03 for 3–4 versus fewer allele mismatches). Thus, greater HLA disparity does not appear to worsen overall outcomes after nonmyeloablative haploidentical BMT with high-dose posttransplantation cyclophosphamide.
WHO Group I Pulmonary Hypertension: Epidemiology and Pathophysiology

Synopsis Pulmonary arterial hypertension (PAH) is a debilitating disease characterized by pathological remodeling of the resistance pulmonary arteries, ultimately leading to right ventricular (RV) failure and death [1]. In this review, we discuss the definition of PAH, the initial epidemiology based on the NIH Registry and the updated epidemiology gleaned from contemporary registries, pathogenesis of pulmonary vascular dysfunction and proliferation, and RV failure in PAH.
Transplantation of Human Retinal Pigment Epithelial Cells in the Nucleus Accumbens of cocaine self-administering rats provides protection from reinstatement

Chronic exposure to drugs and alcohol leads to damage to dopaminergic neurons and their projections in the ‘reward pathway’ that originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). This damage is thought to contribute to the signature symptom of addiction: chronic relapse. In this study we show that bilateral transplants of human retinal pigment epithelial cells (RPECs), a cell mediated dopaminergic and trophic neuromodulator, into the medial shell of the NAc, rescue rats with a history of high rates of cocaine self-administration from drug-seeking when returned, after 2 weeks of abstinence, to the drug-associated chamber under extinction conditions (i.e., with no drug available). Excellent survival was noted for the transplant of RPECs in the shell and/or the core of the NAc bilaterally in all rats that showed behavioral recovery from cocaine seeking. Design based unbiased stereology of tyrosine hydroxylase (TH) positive cell bodies in the VTA showed better preservation (p<0.035) in transplanted animals compared to control animals. This experiment shows that RPEC grafts provide beneficial effects to prevent chronic relapse in drug addiction via its effects directly on the NAc and its neural network with the VTA.
A Conceptual Model of E-Government Adoption in Indonesia

This study aims to determine various factors are related with the process of e-Government adoption. Many researchers have traced the success factors of e-Government but are still partial. This research contributes not only in terms of technological factors but also the attitudes and behaviors of its users (personality traits) which is also influential in the process of technology adoption. In this research, will be developed an adoption model of technology in the context of e-Government. This model incorporates some best practices related to the diffusion of technology such as TRI, TAM, UTAUT, IS/IT Success Model, as well as other factors influencing the adoption of e-Government such as Trust and Compatibility based on previous research. The conceptual model proposed could bring better understanding about important issues especially in e-Government adoption process in Indonesia. Keywords— Adoption, User, E-Government, Conceptual, Model, Indonesia
National Trends in Resource Utilization Associated with Emergency Department Visits for Syncope

Background— Over the last 20 years, numerous research articles and clinical guidelines aimed at optimizing resource utilization for emergency department (ED) patients presenting with syncope have been published. Hypothesis— We hypothesized there would be temporal trends in syncope-related ED visits and associated trends in imaging, hospital admissions, and diagnostic frequencies. Methods— The ED component of National Hospital Ambulatory Medical Care Survey was analyzed from 2001 through 2010, comprising over 358,000 visits (representing an estimated 1.18 billion visits nationally). We selected ED visits with a reason for visit of syncope or fainting and calculated nationally representative weighted estimates for prevalence of such visits, and associated rates of advanced imaging utilization and admission. For admitted patients from 2005 to 2010, the most frequent hospital discharge diagnoses were tabulated. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosures There are no other conflicts of interest. Results— During the study period, there were over 3,500 actual ED visits (representing 11.9 million visits nationally) related to syncope, representing roughly 1% of all ED visits. Admission rates for syncope patients ranged from 27% to 35% and showed no significant downward trend (p=0.1). Advanced imaging rates increased from about 21% to 45% and showed a significant upward trend (p < 0.001). For admitted patients, the most common hospital discharge diagnosis was the symptomatic diagnosis of “syncope and collapse” (36.4%). Conclusions— Despite substantial efforts by medical researchers and professional societies, resource utilization associated with ED visits for syncope appears to have actually increased. There have been no apparent improvements in diagnostic yield for admissions. Novel strategies may be needed to change practice patterns for such patients.
Do Dose and Frequency of Antigen Injection Influence IgE Development in Young Children: A Comparison of Fire Ant Stings and Tetanus Immunizations

Dennis R. Ownby, M.D.a, Megan E. Partridge, M.D.b, Ganesa R. Wegienka, Ph.D.c, Kimberley J. Woodcroft, Ph.D., MPHc, Edward L. Peterson, Ph.D.c, Christine L. M. Joseph, Ph.D., MPHc, L. Keoki Williams, M.D., MPHc, and Christine C. Johnson, Ph.D., MPH.c aMedical College of Georgia, Department of Allergy and Immunology, 1120 15th Street BG 1019, Augusta, GA 30912 bThe Allergy, Asthma & Sinus Center, 5045 Old Hickory Blvd, Suite 201, Hermitage, TN 37076 cDepartment of Biostatistics and Research Epidemiology, Henry Ford Hospital, 1 Ford Place, Detroit, MI 48202, USA dDepartment of Pediatrics, Henry Ford Hospital, 1 Ford Place, Detroit, MI 48202, USA
The Endogenous Production of Reactive Oxygen Species Is Required For Stimulation of Human Articular Chondrocyte MMP Production by Fibronectin Fragments

The objective of the present study was to determine if reactive oxygen species (ROS) are required as secondary messengers for fibronectin fragment stimulated matrix metalloproteinase (MMP) production in human articular chondrocytes. Cultured cells were stimulated with 25 μ g/ml of the α 5 β 1 integrin-binding 110kDa fibronectin fragment (FN-f) in the presence and absence of various antioxidants including Mn(III) tetrakis(4-benzoic acid)porphyrin (MnTBAP). FN-f stimulation significantly increased intracellular levels of ROS in articular chondrocytes. Pretreatment of cells with 250 μ M MnTBAP or 40mM N-Acetyl-L-cysteine, but not inhibitors of nitric oxide synthase, completely prevented FN-f stimulated MMP-3, -10 and -13 production. MnTBAP also blocked FN-f induced phosphorylation of the MAP kinases and NF- κ B-associated proteins and blocked activation of an NF- κ B promoter-reporter construct. Overexpression of catalase, superoxide dismutase, or glutathione peroxidase also inhibited FN-f stimulated MMP-13 production. Pre-incubation of chondrocytes with rotenone, an inhibitor of the mitochondrial electron transport chain, or nordihydroguaiaretic acid (NDGA), a selective 5-lipoxygenase inhibitor, partially prevented FN-f stimulated MMP-13 production and decreased MAP kinase and NF- κ B phosphorylation. These results show that increased production of ROS but not nitric oxide are obligatory secondary messengers in the chondrocyte FN-f signaling pathway that leads to the increased production of MMPs, including MMP-13.
Change Management Strategies When Undertaking eLearning Initiatives in Higher Education

Although technology enhanced learning has been advocated as one way of meeting student needs more effectively and efficiently, a challenge for university senior management is how best to facilitate this development. While studies in these areas have revealed that, in times of change, people management skills are of critical importance there is evidence from the literature that university leaders can be insensitive, taking little account of academic staff who are fearful of the transition to proposed changes in professional practices. Other research has suggested that successful implementation of plans are promoted by adopting more of a social deterministic approach, with the strategies clearly explained to academic staff so that the latter can understand the rationale and their new roles. The outcomes can empower staff and encourage participation, aligning individual motivations and concerns with organisational goals to develop engaging policies and practices. Within education, the information age that was enabled by the Internet has now opened up significant competitive, commercial possibilities for Higher Education on the now vitally important global stage. It’s a move much applauded by governments and their quality assurance and funding agencies in the belief that these business-like areas of performability are an advantaged means of meeting student needs more effectively and efficiently and are far superior to the unbusiness-like ones – such as the discovery of truth – that operated in the past (McWilliam, 2004; Deem & Brehony, 2005; Land, 2006). Such a development can also be linked to a desire by university management and external agencies to exercise a wider monitoring of the institution and its personnel, a setting similar to that already often found in the corporate sector (Noble, 1998; D’Urso, 2006). Traditionally, universities exhibited a characteristic decentralised organisational structure where decision-making and knowledge creation was carried out within semi-autonomous and specialised units (Weick, 1976). In recent years however, as Boezerooy (2006) has commented, there has been a trend towards more centralised management structures and business-like approaches – whereby various types of decisions traditionally taken by academics individually are now being increasingly made by senior managers who no longer see themselves or act as academics.
Transport of glutathione, as y-glutamylcysteinylglycyl ester, into liver and kidney

Administration of y-glutamylcysteinylglycyl monomethyl (or monoethyl) ester to mice leads to substantial increases in the levels of glutathione in the liver and kidney. Mice depleted of glutathione by treatment with buthionine sulfoximine, a potent inhibitor of y-glutamylcysteine synthetase, exhibited about a 4-fold increase in liver and kidney glutathione levels after administration of glutathione monomethyl ester. This ester also prevented the marked decline in liver glutathione level found after giving mice acetaminophen, and it protected mice from toxicity due to this compound. The findings indicate that the monomethyl and monoethyl esters of glutathione are transported into 'cells and hydrolyzed to glutathione. Such esters may be useful in experimental work on glutathione metabolism and function and may provide a relatively safe method for protecting cells against damage by toxic compounds, oxygen, and radiation.
Role of Semaphorin 7a signaling in TGF- β 1 induced lung fibrosis and scleroderma-related interstitial lung disease

Objective— Semaphorin (Sema) 7a regulates TGF- β 1 induced fibrosis. Using a murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGF- β 1 gene is overexpressed in the lung, we tested the hypothesis that Sema-7a exerts its pro-fibrotic effects in part by promoting the tissue accumulation of CD45 + fibrocytes. Methods— Fibrosis and fibrocytes were evaluated in TGF- β 1 transgenic mice in which the Sema-7a locus had been disrupted. The effect of replacement or deletion of Sema-7a on bone marrow derived cells was ascertained using bone marrow transplantation. The role of the Sema-7a receptor β 1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGF- β 1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease. Results— The appearance of fibrocytes in the lungs in TGF- β 1 transgenic mice requires Sema-7a. Replacement of Sema-7a in bone marrow derived cells restores fibrosis and fibrocytes. Immunoneutralization of β 1 integrin reduces pulmonary fibrocytes and fibrosis. mononuclear from patients with scleroderma-related interstitial lung disease show Sema-7a 1 integrin, Sema-7a on collagen producing fibrocytes and CD19 + lymphocytes. outgrowth is enhanced in these mononuclear recombinant Sema-7a these β 1 integrin neutralization. in TGF– β 1 exposed murine lung and that these effects are mediated in part through β 1-integrin. We also demonstrate that the expression of Sema-7a and its receptors are increased in the circulation of patients with SSc-ILD, that exposure to exogenous Sema-7a induces fibrocyte differentiation in PBMCs obtained from normal controls, and that immunoneutralization of the β 1 integrin which functions as a receptor for Sema-7a abrogates fibrocyte outgrowth, while inhibition of Plexin C1 promotes fibrocyte accumulation in these subjects. Our data do not rule out a role
On the long-run behavior of equation-based rate control

We consider unicast equation-based rate control, where a source estimates the loss event ratio $p$, and, primarily at loss events, adjusts its send rate to $f(p)$. Function $f$ is assumed to represent the loss-throughput relation that TCP would experience. When no loss occurs, the rate may also be increased according to some additional mechanism. We assume that the loss event interval estimator is non-biased. If the loss process is deterministic, the control is TCP-friendly in the long-run, i.e, the average throughput does not exceed that of TCP. If, in contrast, losses are random, it is a priori not clear whether this holds, due to the non-linearity of $f$, and a phenomenon similar to Feller's paradox. Our goal is to identify the key factors that drive whether, and how far, the control is TCP friendly (in the long run). As TCP and our source may experience different loss event intervals, we distinguish between TCP-friendliness and conservativeness (throughput does not exceed $f(p)$). We give a representation of the long term throughput, and derive that conservativeness is primarily influenced by various convexity properties of $f$, the variability of loss events, and the correlation structure of the loss process. In many cases, these factors lead to conservativeness, but we show reasonable experiments where the control is clearly non-conservative. However, our analysis also suggests that our source should experience a higher loss event ratio than TCP, which would make non-TCP friendliness less likely. Our findings provide guidelines that help understand when an equation base control is indeed TCP-friendly in the long-run, and in some cases, excessively so. The effects of round trip time and its variations are not included in this study.
PROTON THERAPY FOR PROSTATE CANCER

Proton therapy has been used in the treatment of prostate cancer for several decades, and interest surrounding its use continues to grow. Proton-based treatment techniques have evolved significantly over this time period, and several centers now routinely utilize technologies such as pencil beam scanning. However, whether the theoretical dosimetric advantages of the proton beam translate into clinically meaningful improvements for prostate cancer patients is unknown, and outcomes from single-arm experiences using whole courses of proton beam therapy in the treatment of early-stage prostate cancer have shown mixed results when compared to contemporary IMRT. A randomized trial comparing proton beam to IMRT in early-stage disease is open, and will be important in defining the role for proton therapy in this setting. We review the available evidence and present the current state of proton beam therapy for prostate cancer. Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ASSOCIATION OF RISK FACTORS FOR CHOROIDAL NEOVASCULARIZATION IN AMD WITH DECREASED FOVEOLAR CHOROIDAL CIRCULATION

Purpose— To investigate the relationship between known risk factors for Age-related macular degeneration (AMD) progression and foveolar choroidal circulation in eyes with non-exudative AMD. Design— A cross-sectional study in non-exudative AMD. Methods— Laser Doppler Flowmetry (LDF) measurements of relative choroidal blood velocity (ChBVel), volume (ChBVol) and flow (ChBFlow) were obtained in the center of the fovea of 273 study eyes of 204 AMD patients investigated at the Scheie Eye Institute of the University of Pennsylvania Medical School. All study eyes had visual acuity of 20/40 or better, good fixation, no other intraocular pathology and no evidence of choroidal neovascularization. RPE hypertrophy was determined from color fundus photographs by trained masked graders at the Scheie Image Reading Center. Correlation analysis and multivariate linear regression analysis with adjustments for significant covariates were carried out. Results— A significant inverse correlation was observed between age and ChBFlow (r= − 0.36, p<0.0001), and ChBVol (r= − 0.28, p<0.0001), but not for ChBVel. A significant inverse correlation was observed between spherical equivalent and ChBFlow (r= − 0.21, p=0.006), and ChBVol (r= − 0.14, p=0.04) but not for ChBVel. ChBFlow and ChBVol were significantly lower in patients with a history of hypertension (p ≤ 0.003) and in eyes with RPE hypertrophy (p ≤ 0.04), respectively.
PSD-93 Deficiency Protects Cultured Cortical Neurons from NMDA Receptor-triggered Neurotoxicity

It has been reported that N-methyl-D-aspartate receptor (NMDAR)-triggered neurotoxicity is related to excessive Ca 2+ loading and an increase in nitric oxide (NO) concentration. However, the molecular mechanisms that underlie these events are not completely understood. NMDARs and neuronal NO synthase each binds to the scaffolding protein PSD-93 through its PDZ domains. In this study, we determined whether PSD-93 plays a critical role in NMDAR/Ca 2+ /NO-mediated neurotoxicity. We found that the targeted disruption of the PSD-93 gene attenuated the neurotoxicity triggered by NMDAR activation, but not by non-NMDAR activation, in cultured mouse cortical neurons. PSD-93 deficiency reduced the amount of NMDAR subunits NR2A and NR2B in synaptosomal fractions from the cortical neurons and significantly prevented NMDA-stimulated increases in cyclic guanosine 3 ′ ,5 ′ -monophosphate and Ca 2+ loading in the cortical neurons. These findings indicate that PSD-93 deficiency could block NMDAR-triggered neurotoxicity by disrupting the NMDAR-Ca 2+ -NO signaling pathway and reducing expression of synaptic NR2A and NR2B. Since NMDARs, Ca 2+ , and NO play a critical role during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal disorders.
A Newly Recognized Genetic Syndrome of Tetramelic Deficiencies, Ectodermal Dysplasia, Deformed Ears, and Other Abnormalities

Congenital limb deficiencies represent a highly heterogeneous group of disorders, both etiologically and clinically (Freire-Maia 1969). Phenotypically they range from minor structural deviations to the most severe defects including acheiropodia, tetraphocomelia, and total amelia. A few of these conditions are due to autosomal dominant or recessive mutations; a small group is unequivocally caused by a predominantly exogenous mechanism (thalidomide, maternal diabetes, etc.); and a small fraction may be caused by "complex" genetic mechanisms. However, the etiology of the large majority of limb deficiencies in man is unknown. Chromosomal aberrations seem to be of little importance in this class of malformations. This paper reports an apparently undescribed complex malformation syndrome which includes severe deficiencies of all limbs. The disorder was mentioned briefly in two preliminary notes (Freire-Maia et al. 1969, 1970).