Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation into drug release from colon‐specific azoreductase‐activated steroid prodrugs using in‐vitro models

Objectives The aim of this study was to investigate drug release from a double steroid prodrug, OPN501, which incorporates a phenylpropionate linker, and its phenylacetate analogue. The prodrugs, which were designed to deliver prednisolone to the colon for the treatment of inflammatory bowel disease, are based on a novel design that requires sequential azoreductase activity and cyclization of an amino ester to trigger drug release. We sought to explain the divergent effects of the two compounds in anti‐inflammatory models and to justify the selection of OPN‐501 for clinical development.
Clinical and psychosocial outcomes of borderline personality disorder in childhood and adolescence: a systematic review

Background While there is a growing body of research on borderline personality disorder (BPD) in children and adolescents, controversy remains regarding the validity and diagnosis of the disorder prior to adulthood. Method MEDLINE, EMBASE, Psych INFO and PubMed databases were systematically searched for articles pertaining to the clinical and psychosocial outcomes (i.e. predictive validity) of BPD first diagnosed in childhood or adolescence (i.e. prior to 19 years of age). All primary empirical studies were included in the review. A narrative synthesis of the data was completed. Results A total of 8200 abstracts were screened. Out of 214 full-text articles, 18 satisfied the predetermined inclusion criteria. Quality assessment indicated that most studies had high risk of bias in at least one study domain. Consistent with the adult literature, the diagnostic stability of BPD prior to the age of 19 years was low to moderate, and mean-level and rank-order stability, moderate to high. Individuals with BPD symptoms in childhood or adolescence had significant social, educational, work and financial impairment in later life. Conclusions Studies indicate that borderline pathology prior to the age of 19 years is predictive of long-term deficits in functioning, and that a considerable proportion of individuals continue to manifest borderline symptoms up to 20 years later. These findings provide some support for the clinical utility of the BPD phenotype in younger populations, and suggest that an early intervention approach may be warranted. Further prospective studies are needed to delineate risk (and protective) factors pertinent to the chronicity of BPD across the lifespan.
Physical characterization of MxiH and PrgI, the needle component of the type III secretion apparatus from Shigella and Salmonella

Shigella and Salmonella use similar type III secretion systems for delivering effector proteins into host cells. This secretion system consists of a base anchored in both bacterial membranes and an extracellular “needle” that forms a rod‐like structure exposed on the pathogen surface. The needle is composed of multiple subunits of a single protein and makes direct contact with host cells to facilitate protein delivery. The proteins that make up the needle of Shigella and Salmonella are MxiH and PrgI, respectively. These proteins are attractive vaccine candidates because of their essential role in virulence and surface exposure. We therefore isolated, purified, and characterized the monomeric forms of MxiH and PrgI. Their far‐UV circular dichroism spectra show structural similarities with hints of subtle differences in their secondary structure. Both proteins are highly helical and thermally unstable, with PrgI having a midpoint of thermal unfolding (Tm) near 37°C and MxiH having a value near 42°C. The two proteins also have comparable intrinsic stabilities as measured by chemically induced (urea) unfolding. MxiH, however, with a free energy of unfolding (ΔG°0,un) of 1.6 kcal/mol, is slightly more stable than PrgI (1.2 kcal/mol). The relatively low m‐values obtained for the urea‐induced unfolding of the proteins suggest that they undergo only a small change in solvent‐accessible surface area. This argues that when MxiH and PrgI are incorporated into the needle complex, they obtain a more stable structural state through the introduction of protein–protein interactions.
Upregulation of microRNA-876 Induces Endothelial Cell Apoptosis by Suppressing Bcl-Xl in Development of Atherosclerosis

Background/Aims: The injury and apoptotic cell death of endothelial cells hallmark the development of atherosclerosis (AS), characterized by dysregulation of lipid homeostasis, immune responses, and formation of coronary plaques. However, the mechanisms underlying the initiation of endothelial cell apoptosis remain ill-defined. Recent evidence suggests a role of microRNAs in the processes of AS-associated endothelial cell apoptosis. Thus, we studied this question in the current study. Methods: AS was developed in ApoE (-/-) mice suppled with high-fat diet (HFD), compared to ApoE (-/-) mice suppled with normal diet (ND). Mouse endothelial cells were isolated from the aortic arch using flow cytometry based on their expression of Pecam-1. Oxidized low-density lipoprotein (ox-LDL) were used to treat human aortic endothelial cells (HAECs) as an in vitro model for AS. Gene expression was quantified by RT-qPCR and protein levels were analyzed by Western blotting. Apoptosis was evaluated by FITC Annexin V Apoptosis essay and by TUNEL staining. Prediction of the binding between miRNAs and 3'-UTR of mRNA from the target gene was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. Results: HFD mice, but not ND mice, developed AS in 12 weeks. Significantly reduced endothelial cell marks and significantly increased mesenchymal cell marks were detected in the aortic arch of the HFD mice, compared to the ND mice. The endothelial cell apoptosis was significantly higher in HFD mice, seemingly due to functional suppression of protein translation of anti-apoptotic Bcl-Xl protein through upregulation of miR-876. Similar results were obtained from in vitro study. Inhibition of miR-876 abolished the effects of ox-LDL-induced apoptotic cell death of HAECs. Conclusion: AS-associated endothelial cell apoptosis may partially result from downregulation of Bcl-Xl, through upregulation of miR-876 that binds and suppresses translation of Bcl-Xl mRNA.
Empowerment in School Nursing Practice: A Grounded Theory Approach

Professional empowerment is vital to nurses’ productivity and job satisfaction. A grounded theory study was conducted to describe the basic social process experienced by school nurses in relation to professional empowerment. Interviews with 10 school nurses led to the development of a situation-specific theory of school nurse empowerment, Making a Difference: The Role of the School Nurse in the Health of Children in Schools. This theory was derived from four theoretical constructs: (a) enlisting support, (b) getting through the day, (c) maintaining control over practice, and (d) adjusting to challenges. Interviews revealed that knowing at the end of each school day that they made a difference in the health of children resulted in feelings of empowerment. Participants cited various areas in which their sense of empowerment was limited, including salaries and workload. Despite these issues, they believed they had a positive impact on the health of children, leading to job satisfaction and feelings of value.
Plasma degradation of platelet‐activating factor in severely ill patients with clinical sepsis

ObjectiveTo study the plasma degradation of platelet-activating factor in severely ill patients with clinical sepsis. DesignA prospective, nonrandomized control study. SettingIntensive care unit in a university hospital. PatientsThirteen critically ill male patients with clinical sepsis, due to medical or surgical illness, and ten normal male volunteers were studied. Measurements were repeated in seven patients who survived. Measurements and Main ResultsThe plasma activity of acetylhydrolase, the lipoprotein-associated enzyme that hydrolyses platelet-activating factor to its biologically inactive lyso-derivative was determined using an optimized enzyme assay. The plasma half-life of platelet-activating factor was also measured, along with phospholipase A2 activity, lyso-platelet-activating factor, and serum lipid concentrations. Patient results were compared with those results of normal controls and followed once in survivors. Acetylhydrolase activity in the patient group was significantly lower than in normal subjects (median 34, interquartile range 17 to 54 nmol/min/mL vs. median 60, interquartile range 56 to 80 nmol/min/mL; p < .002), while overall, the plasma half-life of platelet-activating factor did not differ significantly between the groups. However, the half-life of platelet-activating factor in six patients who died (median 3.3, range 3.3 to 4.3 mins) was significantly greater than in either survivors (median 2.1, range 1.4 to 2.9 mins; p < .001) or the normal group (median 2.5, range 2.2 to 2.8 mins; p < .001). Consistent with theoretical prediction, a significant linear relationship existed between platelet-activating factor half-life and the reciprocal of acetylhydrolase activity in the patient group (p < .05). Plasma phospholipase A2 activity was markedly increased in the patient group, while plasma lyso-platelet-activating factor and serum lipid concentrations were severely decreased. ConclusionsDepression of acetylhydrolase activity was consistent with the concentration of lipids with which it is associated. Platelet-activating factor half-life was relatively well preserved because of the nature of its relationship with enzyme activity. The half-life was prolonged in those patients with the worst outcome and the breakdown in plasma degradation of platelet-activating factor could have contributed to pathophysiology in these subjects. (Crit Care Med 1994; 22:204–212)
Relationship between the Right Internal Jugular Vein and Carotid Artery at Ipsilateral Head Rotation

Ultrasound-guided right internal jugular vein catheterization (RIJV) should be the first choice to decrease the catheter-related complications in high-risk hemodialysis patients. For this procedure, clinicians should identify the optimum positions of the RIJV, including its lower overlap with the carotid artery (CA) and high cross-sectional area of the vein. The aim of this prospective randomized study to evaluate the effects of mild ipsilateral head rotation combined with Trendelenburg position on RIJV cross-sectional area and its relation to the CA in adult patients. Forty ASA I–II patients who were undergoing elective surgery were enrolled for this study. The subjects were asked to remain supine in the 15–20° Trendelenburg position. Two-dimensional ultrasound was then used to measure the degree of overlap between the RIJV and CA, the cross-sectional area of the RIJV. These measurements were compared between head rotation to the >30° left, <30° left, neutral, and <30° right positions. When the head was in the >30° left position, overlap was seen in 38 of 40 patients (95%). As the head was rotated from >30° left to <30° right, the CA-RIJV overlap (from 95% to 57.5%), and the cross-sectional area (from 14.2 mm to 8.7 mm) significantly decreased. In conclusion, when the head was turned to <30° right, the CA-RIJV overlap significantly decreased, and the cross-sectional area also decreased. When clinicians determine the optimal head position before RIJV cannulation, it is important to consider the advantages and disadvantages of the different head positions from >30° left to <30° right.
A cost effective color gamut mapping architecture for digital TV color reproduction enhancement

A cost effective three-dimensional color gamut mapping architecture is described. The conventional three-dimensional reduced resolution look-up table is considered and the concept of three-dimensional reduced resolution difference look-up table is introduced for cost effective and real-time color gamut mapping. The overall architecture uses one-dimensional memory decomposition of three-dimensional gamut mapping look-up table and three-dimensional interpolation and simple adding operation for generating the final gamut mapped colors. The required computational cost is greatly reduced by look-up table resolution adjustment and further reduced by the gamut mapping rule modification. The proposed architecture greatly reduces the required memory size and hardware complexity compared to the conventional methods and it is suitable for real-time applications. The proposed hardware architecture is suitable for FPGA and ASIC implementation and could be applied to the real-time display quality enhancement purposes.
Far upstream initiation sites for adenovirus early region 1A transcription are utilized after the onset of viral DNA replication

Adenovirus early region 1A (E1A) is the first transcription unit expressed after infection. It encodes a protein which controls the expression of all other early viral genes. The E1A mRNAs have one major capped 5' terminus which maps 31 nucleotides downstream from a T-A-T-A sequence (C. Baker and E. Ziff. J. Mol. Biol. 149:189-221, 1981). In addition, a minor set of E1A mRNAs are observed during the early phase of infection which have 5' termini mapping at approximately -160, -185, and -230 relative to the major cap site (Osborne et al., Cell 29:139-148, 1982). Here we report the occurrence of another set of minor E1A mRNAs which were observed exclusively after the initiation of viral DNA replication. These late specific E1A mRNAs had cap sites which mapped at approximately -300, -325, -360, and -375 relative to the major cap site. The appearance of these minor late E1A mRNAs was blocked by the DNA synthesis inhibitor cytosine arabinoside. These same late specific E1A mRNAs were synthesized from E1A-containing plasmids which replicate in monkey cells. This demonstrated that neither late specific adenovirus proteins nor adenovirus-specific chromatin structure was required for the production of the late specific E1A mRNAs. Adenovirus mutants in which the E1A T-A-T-A box region had been deleted also synthesized the corresponding deleted forms of the late specific mRNAs after initiation of DNA replication. These results indicate that the process of DNA replication alters the specificity of E1A transcription initiation in a promoter region which is at least 375 nucleotides in length.
Association between endothelial dysfunction and otoneurological symptoms in children with sickle cell disease

ABSTRACT Objective: To evaluate the association between endothelial dysfunction and otoneurological symptoms and vaso-occlusive phenomena in children with sickle cell disease (SCD). Methods: Cross-sectional study with 54 children, aged between 6 and19 years of age, of whom 28 had genotype SS and 26 apparently healthy (AA genotype) whose parents or guardians, or the children themselves, filled out a questionnaire designed to assess their otoneurological symptoms. All the individuals were submitted assessment of endothelial function by flow-mediated dilation (FMD) percentage with reactive hyperemia of brachial artery Doppler. Results: Otoneurological symptoms (tinnitus and/or vertigo) predominated in the SCD group (46.4 vs. 15.4%; p = 0.006). A negative correlation was observed between FMD percentage and time of evolution of vertigo SCD (r = −0.432; p = 0.022) and the linear regression analysis demonstrated that for every reduction in FMD percentage there was an increase in time of evolution of vertigo of 1.79 months (β = −1.79; p = 0.022). The positive correlation between episodes of painful crisis and time of evolution of vertigo (r = 0.3; p = 0.04). Discussion: The presence of vascular endothelial damage in the labyrinthine artery in patients with SCD is capable of compromising the semicircular canals, shown by clinical expression of otoneurological symptoms, such as vertigo. In the present study, an association was observed between endothelial dysfunction with otoneurological symptoms and otoneurological symptoms and vaso-occlusive phenomena in SCD.
Evaluation of the Interlaboratory Concordance in Quantification of Human Immunodeficiency Virus-Specific T Cells with a Gamma Interferon Enzyme-Linked Immunospot Assay

ABSTRACT The gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay is a reference method for the ex vivo monitoring of antigen-specific T cells and a primary tool for assessing clinical trials of human immunodeficiency virus (HIV) or cancer vaccines. Four experienced laboratories in Paris compared their results with this method by exchanging frozen blood samples from eight HIV-seronegative and eight HIV-seropositive subjects. Each laboratory measured the IFN-γ-producing cells specific for HIV, Epstein-Barr virus, cytomegalovirus, and influenza using the same set of peptides and the same ELISPOT reader but its own ELISPOT technique. The cutoff values for positive responses (50 or 100 spot-forming cells/106 peripheral blood mononuclear cells over background) were consistent with the binomial statistic criterion. The global qualitative concordance, as assessed by the kappa index, ranged from 0.38 to 0.92, that is, moderate to excellent, and was better for non-HIV 9-mer peptide pools than for HIV 15-mer peptide pools. The interlaboratory coefficient of variation for the frequency of virus-specific T cells was 18.7% (data are expressed on a log scale). Clustering analysis of HIV-positive subjects showed qualitative agreement for ELISPOT results from all four laboratories. Overall, the good interlaboratory qualitative concordance of IFN-γ ELISPOT assays with only the peptide source and ELISPOT reader in common suggests that a qualitative comparison of interlaboratory findings is feasible. Nonetheless, a single set of standard operating procedures should be used in multicenter trials to improve standardization.
The influence of inhibitory afferents on the development of postsynaptic dendritic arbors

The growth and maintenance of dendritic form is dependent on normally functioning excitatory afferents. We have now examined the development of dendritic arbors in the gerbil lateral superior olive (LSO), following contralateral cochlear removal at postnatal day 7, a manipulation that substantially eliminates driven inhibitory transmission. Previous studies have demonstrated that the morphology of LSO dendritic arbors varies with tonotopic position and becomes more restricted with age.
Molecular dissection of the ILK-PINCH-parvin triad reveals a fundamental role for the ILK kinase domain in the late stages of focal-adhesion maturation

Integrin-linked kinase (ILK) and cytoplasmic adaptors of the PINCH and parvin families form a ternary complex, termed IPP, that localizes to integrin adhesions. We show here that deletion of the genes encoding ILK or PINCH1 similarly blocks maturation of focal adhesions to tensin-rich and phosphotyrosine-poor fibrillar adhesions (FBs) by downregulating expression or recruitment of tensin and destabilizing α5β1-integrin–cytoskeleton linkages. As IPP components are interdependent for integrin targeting and protein stability, functional dissection of the complex was achieved by fusing ILK, PINCH, parvin or their individual motifs to the cytoplasmic tail of β3 integrin, normally excluded from FBs. Using this novel gain-of-function approach, we demonstrated that expression of the C-terminal kinase domain of ILK can restore tensin recruitment and prompt focal-adhesion maturation in IPP-null cells. Debilitating mutations in the paxillin- or ATP-binding sites of ILK, together with α-parvin silencing, revealed a determinant role for ILK-parvin association, but not for direct paxillin binding, in this function. We propose a model in which the C-terminal domain of ILK promotes integrin sorting by reinforcing α5β1-integrin–actin linkage and controls force transmission by targeting tensin to maturing adhesions.
Oxidation of Vinyl Carbamate and Formation of 1,N6-Ethenodeoxyadenosine in Murine Lung

Vinyl carbamate (VC) is derived from ethyl carbamate, a carcinogen formed in fermentation of food and alcoholic products. We have undertaken studies to test the hypothesis that an epoxide generated from VC oxidation leads to formation of 1,N6-ethenodeoxyadenosine (ϵdAS). We have developed approaches using liquid chromatography-mass spectrometry and liquid chromatographytandem mass spectrometry for identification and quantitation of ϵdAS. Scanning and fragment ion analyses confirmed the identity of ϵdAS based on the molecular ion [M + H]+ m/z 276 and the specific fragment ion m/z 160. Chemical oxidation of VC in reactions containing 2′-deoxyadenosine produced ϵdAS with 1H NMR, chromatographic, and mass spectral characteristics identical to those of the authentic ϵdAS, suggesting DNA alkylation by the VC epoxide. Subsequent studies evaluated formation of ϵdAS in incubations of murine lung microsomes or recombinant CYP2E1 with VC. The formation of ϵdAS in incubations of lung microsomes or recombinant CYP2E1 with VC was dependent on protein concentrations, CYP2E1 enzyme levels, and incubation time. The rates of ϵdAS formation were highly correlated with VC concentrations. Peak rates were produced by lung microsomes and recombinant CYP2E1 at 3.0 and 2.5 mM VC, respectively. In inhibitory studies, incubations of VC were performed using lung microsomes from mice treated with the CYP2E1 inhibitor diallyl sulfone (100 mg/kg, p.o.). Results from these studies showed significantly decreased ϵdAS formation in microsomes incubated with VC, with an inhibition of 70% at 3.0 mM. These findings suggested that CYP2E1 is a major enzyme mediating VC oxidation, leading to the formation of a metabolite that alkylates DNA to form the ϵdAS adduct.
URATE HOMEOSTASIS IN POLYCYSTIC KIDNEY DISEASE: COMPARISON WITH CHRONIC GLOMERULONEPHRITIC KIDNEY

Autosomal dominant polycystic kidney disease (ADPKD) might affect urate homeostasis and clearance. Renal tubular urate transport was studied by means of probenecid (PB) and pyrazinamide (PZA) tests in individuals with ADPKD and normal renal function as well as various degrees of renal failure (49 patients). Comparisons were made between polycystic and chronic glomerulonephritic kidney (CGNK), as well as with controls (men with normal renal function). Patients with ADPKD and normal renal function showed plasma urate levels within normal range and normal renal urate handling. In contrast higher plasma urate levels comparing to controls were found in patients with CGNK and normal renal function. During the evolution of renal failure ADPKD patients showed lower urate plasma levels and higher renal clearance as well as, fractional urate excretion, comparing to CGNK patients with the same degree of renal failure. In conclusion patients with ADPKD and normal renal function have normal urate handling and plasma urate levels within normal range. With increasing severity of disease and during evolution of renal failure CGNK patients showed higher urate plasma levels and lower clearances comparing to ADPKD patients. When renal disease becomes more advanced there was no difference in renal urate handling between ADPKD and CGNK patients.