Miracle-dz/UniFAR-FTUs huggingface dataset:
Cystic fibrosis: unenhanced CT description of the appendix in asymptomatic adults.

OBJECTIVE The purpose of this study was to describe the unenhanced CT appearance of the appendix in adults with cystic fibrosis. SUBJECTS AND METHODS Among adults with cystic fibrosis undergoing follow-up at our hospital, 71 patients (35 women, 36 men; mean age, 33 years; range, 18-59 years) without a history of appendectomy or current abdominal pain were prospectively included in this study and underwent unenhanced abdominopelvic MDCT. Two readers coded visualization of the appendix, measured the diameter of the appendix, and described the attenuation of its contents in relation to the intestinal wall. They also coded the presence of colonic wall redundancy, pancreatic fatty replacement, and cirrhosis. Lung transplant status and CFTR gene mutations were recorded. Analysis of variance, linear regression analysis, Student t test, and Pearson test were used. RESULTS The appendix was detected in all patients. The mean diameter was recorded as 10.6 ± 3.5 mm. The mean diameter was larger when the appendix contained hyperattenuating material (p = 0.001). There was no association between diameter and the other coded CT findings (p = 0.076-0.466), transplant status (p = 0.788), or CFTR mutation (p = 0.078). In 75% of the patients, the appendix contained hyperattenuating material with a higher proportion in homozygous ΔF508 mutation (p = 0.029) without any significant effect of the other CT features (p = 0.056-0.392), or transplant status (p = 1.000). CONCLUSION The appendix is larger in adults with cystic fibrosis than in those without it and appears hyperattenuating at unenhanced CT in 75% of patients, more commonly in those with ΔF508 homozygous mutation.
Nature and uses of fluorescent dyes for drug transporter studies

Introduction: Drug transporters are now recognized as major players involved in pharmacokinetics and toxicology. Methods for assessing their activity are important to consider, particularly owing to regulatory requirements with respect to inhibition of drug transporter activity and prediction of drug–drug interactions. In this context, the use of fluorescent-dye-based transport assays is likely to deserve attention. Areas covered: This review provides an overview of the nature of fluorescent dye substrates for ATP-binding cassette and solute carrier drug transporters. Their use for investigating drug transporter activity in cultured cells and clinical hematological samples, drug transporter inhibition, drug transporter imaging and drug transport at the organ level are summarized. Expert opinion: A wide range of fluorescent dyes is now available for use in various aspects of drug transporter studies. The use of these dyes for transporter analyses may, however, be hampered by classic pitfalls of fluorescence technology, such as quenching. Transporter-independent processes such as passive diffusion of dyes through plasma membrane or dye sequestration into subcellular compartments must also be considered, as well as the redundant handling by various distinct transporters of some fluorescent probes. Finally, standardization of dye-based transport assays remains an important on-going issue.
Integrin‐linked kinase regulates oligodendrocyte cytoskeleton, growth cone, and adhesion dynamics

Integrin‐linked kinase (ILK), a focal adhesion protein, brokers the link between cytoskeleton, cell membrane, and extracellular environment. Here, we demonstrate a role for ILK in laminin‐2‐mediated adhesion in primary murine oligodendrocytes (OLs) – with ILK loss leading to severe defects in process branching and outgrowth. These defects were partially recovered when the ILK‐depleted OLs were instead grown on the non‐integrin‐activating substrate poly‐l‐lysine. Intriguingly, ILK loss on the neutral poly‐l‐lysine substrate led to swelling at the tips of OL processes, which we identified as enlarged growth cones. Employing the bloated ILK‐depleted growth cones as template, we demonstrate the appearance of distinct cytoskeletal domains within OL growth cones bearing classic neuronal growth cone architecture. Further, microtubule organization was severely perturbed following ILK loss, with centripetal microtubule looping and failure to bundle occurring in a laminin‐2‐independent manner. Together, our work highlights differences in specific aspects of OL biology as driven by laminin‐2‐dependent or independent ILK governed mechanisms. We also reinforce the idea of OLs as growth cone bearing cells and describe the neuronal‐like cytoskeleton therein. Finally, we demonstrate a role for ILK in OL growth cone maturation through microtubule regulation, the loss of which translates to decreased process length and myelin production capacity.
Structure activity relationship of plumbagin in BRCA1 related cancer cells

It has been shown earlier that plumbagin, a naturally occurring naphthaquinone has specific anticancer activity in BRCA1 blocked ovarian cancer cells. Plumbagin can induce estrogen dependent cell signaling and apoptosis in BRCA1 blocked ovarian cancer cells. Being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has immense potential as a promising anticancer agent. In this study we analyzed whether there would be increased anticancer activity if the positions of the functional groups on plumbagin were altered and further to analyze the detailed molecular mechanism of action of the lead molecule. Methods like MTT assay, apoptosis analysis by flow cytometry, assessment of mitochondrial membrane potential‐Δψm, suppression subtractive hybridization, microarray, molecular docking and estrogen receptor–DNA binding activity by electrophoresis mobility shift assay (EMSA) were adopted for assessing the anticancer activity. Consequently we found that, plumbagin was the most potent anticancer agent when compared to structurally related compounds. The anti‐cancer activities were in the order plumbagin > 1,4‐naphthaquinone > juglone > lawsone > menadione. Molecular docking studies showed that plumbagin could be well docked in the receptor ligand complex of TRAIL–DR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ERα, we speculated that plumbagin interferes with the binding of ERα to ERE and we confirmed this by EMSA. This study clearly indicates that plumbagin can induce multiple pathways of apoptosis and cell cycle arrest in BRCA1 blocked cells compared to unblocked cells. © 2012 Wiley Periodicals, Inc.
Potential exposure to Australian bat lyssavirus is unlikely to prevent future bat handling among adults in South East Queensland

Despite ongoing public health messages about the risks associated with bat contact, the number of potential exposures to Australian bat lyssavirus (ABLV) due to intentional handling by members of the general public in Queensland has remained high. We sought to better understand the reasons for intentional handling among these members of the public who reported their potential exposure to inform future public health messages. We interviewed adults who resided in a defined geographic area in South East Queensland and notified potential exposure to ABLV due to intentional handling of bats by telephone between 1 January 2012 and 31 December 2013. The participation rate was 54%. Adults who reported they had intentionally handled bats in South East Queensland indicated high levels of knowledge and perception of a moderately high risk associated with bats with overall low intentions to handle bats in the future. However, substantial proportions of people would attempt to handle bats again in some circumstances, particularly to protect their children or pets. Fifty‐two percent indicated that they would handle a bat if a child was about to pick up or touch a live bat, and 49% would intervene if a pet was interacting with a bat. Future public health communications should recognize the situations in which even people with highrisk perceptions of bats will attempt to handle them. Public health messages currently focus on avoidance of bats in all circumstances and recommend calling in a trained vaccinated handler, but messaging directed at adults for circumstances where children or pets may be potentially exposed should provide safe immediate management options.
Prediction of Human Metabolism of FK3453 by Aldehyde Oxidase Using Chimeric Mice Transplanted with Human or Rat Hepatocytes

During drug development, it is important to predict the activities of multiple metabolic enzymes, not only cytochrome P450 (P450) but also non-P450 enzymes, such as conjugative enzymes and aldehyde oxidase (AO). In this study, we focused on prediction of AO-mediated human metabolism and pharmacokinetics (PK) of 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) (Astellas Pharma Inc.), the development of which was suspended due to extremely low exposure in human, despite good oral bioavailability in rat and dog. We examined species difference in oxidative metabolism of the aminopyrimidine moiety of FK3453, catalyzed by AO, using human-chimeric mice with humanized liver (h-PXB mice) and rat-chimeric mice (r-PXB mice) transplanted with rat hepatocytes. AO activity of h-PXB mouse hepatocytes was higher than that of r-PXB mouse hepatocytes. Moreover, higher concentrations of human-specific AO-generated FK3453 metabolite A-M were detected in urine and feces after administration of FK3453 to h-PXB mice versus r-PXB mice. The total clearance of h-PXB mice was 2-fold higher than that of r-PXB mice. These results agreed reasonably well with the metabolism and PK profiles of FK3453 in human and rat. Our results indicated that h-PXB mice should be helpful for predicting the metabolic profile of drugs in humans, and the use of both h-PXB and r-PXB mice should be helpful for evaluation of species differences of AO metabolic activity.
Functional Characterization of Human Myosin-18A and Its Interaction with F-actin and GOLPH3*

Background: Class-18A myosins share a unique N-terminal extension comprising a PDZ module and a KE-rich region. Results: Human myosin-18A binds F-actin via its motor domain in a nucleotide-dependent manner and via the KE-rich region, modulated by direct interaction between the PDZ module and GOLPH3. Conclusion: Myosin-18A binds F-actin and recruits interaction partners to the cytoskeleton. Significance: This work establishes a molecular basis for myosin-18A mediated membrane-cytoskeleton interplay. Molecular motors of the myosin superfamily share a generic motor domain region. They commonly bind actin in an ATP-sensitive manner, exhibit actin-activated ATPase activity, and generate force and movement in this interaction. Class-18 myosins form heavy chain dimers and contain protein interaction domains located at their unique N-terminal extension. Here, we characterized human myosin-18A molecular function in the interaction with nucleotides, F-actin, and its putative binding partner, the Golgi-associated phosphoprotein GOLPH3. We show that myosin-18A comprises two actin binding sites. One is located in the KE-rich region at the start of the N-terminal extension and appears to mediate ATP-independent binding to F-actin. The second actin-binding site resides in the generic motor domain and is regulated by nucleotide binding in the absence of intrinsic ATP hydrolysis competence. This core motor domain displays its highest actin affinity in the ADP state. Electron micrographs of myosin-18A motor domain-decorated F-actin filaments show a periodic binding pattern independent of the nucleotide state. We show that the PDZ module mediates direct binding of myosin-18A to GOLPH3, and this interaction in turn modulates the actin binding properties of the N-terminal extension. Thus, myosin-18A can act as an actin cross-linker with multiple regulatory modulators that targets interacting proteins or complexes to the actin-based cytoskeleton.
Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection1

Because GALT is a major portal of entry for HIV-1 and reservoir for viral replication, we hypothesized that an ineffective cellular immune response in intestinal mucosa might partially explain the failure of immune control in AIDS. In this study, we demonstrate that the vast majority of CD8+ T cells in rectal tissue, including HIV-1-specific cells, fail to express the cytolytic protein, perforin. However, rectal CD8+ T cells do express granzyme A, and are also capable of releasing IFN-γ upon stimulation with cognate peptide. Confocal microscopy showed that granzyme A was located in intracellular granules in the absence of perforin. The majority of rectal CD8+ T cells exhibit an effector memory phenotype, expressing CD45RO but not CCR7. Quantitative real-time PCR analysis demonstrated that perforin RNA is expressed in rectal CD8+ T cells from healthy and HIV-1-positive individuals. In HIV-1-positive individuals, similar amounts of perforin RNA were detected in CD8+ T cells from rectal tissue and PBMC, despite a relative absence of perforin protein in rectal tissue. These findings demonstrate an important difference in perforin expression between CD8+ T cells in blood and mucosa. Furthermore, the relative absence of armed effector cells may serve to protect the integrity of rectal mucosa under normal conditions, but might also provide an early advantage to HIV-1 and other sexually transmitted viruses.
Structure and Seasonality of Nearctic Culex pipiens Populations

Abstract: The abundance and structure of urban autogenous and anautogenous populations of Culex pipiens mosquitoes were documented systematically in Boston, MA, during three successive years. Autogenous larvae become abundant mainly in enclosed sites and anautogenous larvae in sites that provide free access and egress. Both populations begin to proliferate when the water temperature exceeds 15°C during June. Larval anautogenous mosquitoes increase in abundance 10‐fold in two weeks and autogenous in three weeks. Although anautogenous larvae rapidly disappear after mid‐August when winter diapause commences, the abundance of autogenous larvae continues to increase until mid‐October. The forms generally are reproductively isolated in nature but occasionally hybridize during August and thereafter. Anautogenous females feed mainly on birds; autogenous females generally never feed on blood; and hybrid females appear to feed indiscriminately on avian or mammalian hosts. Such northern C. p. pipiens mosquitoes range as far south as 33°N. Taken together, these observations suggest that C. p. pipiens‐borne pathogens may proliferate in the northern United States until mid‐August and affect human hosts thereafter. Intensity of transmission decreases toward the south.
Quantitative measurement of blood‐brain barrier permeability in human using dynamic contrast‐enhanced MRI with fast T1 mapping

Breakdown of the blood‐brain barrier (BBB), occurring in many neurological diseases, has been difficult to measure noninvasively in humans. Dynamic contrast‐enhanced magnetic resonance imaging measures BBB permeability. However, important technical challenges remain and normative data from healthy humans is lacking. We report the implementation of a method for measuring BBB permeability, originally developed in animals, to estimate BBB permeability in both healthy subjects and patients with white matter pathology. Fast T1 mapping was used to measure the leakage of contrast agent Gadolinium diethylene triamine pentaacetic acid (Gd‐DTPA) from plasma into brain. A quarter of the standard Gd‐DTPA dose for dynamic contrast‐enhanced magnetic resonance imaging was found to give both sufficient contrast‐to‐noise and high T1 sensitivity. The Patlak graphical approach was used to calculate the permeability from changes in 1/T1. Permeability constants were compared with cerebrospinal fluid albumin index. The upper limit of the 95% confidence interval for white matter BBB permeability for normal subjects was 3 × 10−4 L/g min. MRI measurements correlated strongly with levels of cerebrospinal fluid albumin in those subjects undergoing lumbar puncture. Dynamic contrast‐enhanced magnetic resonance imaging with low dose Gd‐DTPA and fast T1 imaging is a sensitive method to measure subtle differences in BBB permeability in humans and may have advantages over techniques based purely on the measurement of pixel contrast changes. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.
Macrophage Migration Inhibitory Factor and Host Innate Immune Responses to Microbes

Among innate immune cells, macrophages play an essential role in the sensing and elimination of invasive microorganisms. Binding of microbial products to pathogen-recognition receptors stimulates macrophages to release cytokines and other effector molecules that orchestrate the host innate and adaptive immune responses. Recently, the protein known as macrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity. First identified as a T-cell cytokine, MIF was rediscovered as a protein released by pituitary cells after exposure to endotoxin [lipopolysaccharide (LPS)] or bacteria and in response to stress. Monocytes, macrophages and lymphocytes constitutively express MIF, which is rapidly released after stimulation with bacterial endotoxins and exotoxins, and cytokines. MIF induces powerful proinflammatory biological responses and has been shown to be an important effector molecule of septic shock. High levels of MIF have been detected in the circulation of patients with severe sepsis and septic shock. Inhibition of MIF activity with neutralizing anti-MIF antibodies or deletion of the Mif gene led to a marked reduction in cytokine production and protected mice from lethal bacterial sepsis and toxic shock induced by Gram-negative endotoxin or Gram-positive exotoxins. Investigations into the mechanisms whereby MIF modulates innate immune responses to endotoxin and Gram-negative bacteria have shown that MIF up-regulates the expression of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex. Thus, MIF enables cells, such as the macrophage, that are at the forefront of the host antimicrobial defences, to sense promptly the presence of invading Gram-negative bacteria and mount an innate immune response. Given that it is a pivotal regulator of innate immune responses to bacterial infections, MIF appears to be a perfect target for novel therapeutic interventions in patients with severe sepsis.
Influence of Day and Night Wear on Surface Properties of Silicone Hydrogel Contact Lenses and Bacterial Adhesion

Purpose: The aim of this study was to determine the effect of continuous wear on physicochemical surface properties of silicone hydrogel (S-H) lenses and their susceptibility to bacterial adhesion. Methods: In this study, volunteers wore 2 pairs of either "lotrafilcon A" or "balafilcon A" S-H contact lenses. The first pair was worn continuously for a week and the second pair for 4 weeks. One lens of each pair was used for surface characterization and the other one for bacterial adhesion experiments. Lens surfaces were characterized by examination of their wettability, roughness, elemental composition, and proteins attached to their surfaces. Adhesion of Staphylococcus aureus 835 and Pseudomonas aeruginosa #3 to a lens was studied using a parallel plate flow chamber. Results: Before use, the lotrafilcon A lens was rougher than the balafilcon A lens and had a lower water contact angle and a higher affinity for S. aureus 835. After wear, both lens types had similar water contact angles, whereas the differences in elemental surface composition decreased as well. S. aureus 835 adhered in higher numbers to worn balafilcon A lenses, whereas the opposite was seen for P. aeruginosa #3. The initial deposition rates of both bacterial strains to lotrafilcon A lenses decreased by wearing and were found to correlate significant (P < 0.001) with the surface roughness of worn lenses. Conclusions: In this study, the differences in surface properties between 2 types of S-H lenses were found to change after 1 week of continuous wear. Generally, bacteria adhered in lower numbers and less tenaciously to worn lenses, except S. aureus 835, adhering in higher numbers to worn balafilcon A lenses.
Influence of ABCB1 polymorphisms and serum concentrations on venlafaxine response in patients with major depressive disorder

Abstract Background: The pharmacokinetics and the pharmacodynamics of antidepressants show large inter-individual variations which result in unpredictable clinical responses. Aim: The aim of the study was to examine the effect of ABCB1 polymorphisms and the serum concentrations on the efficacy and tolerability of venlafaxine in patients with major depressive disorder (MDD). Methods: Fifty-two outpatients who met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for MDD were recruited for the study. The severity of depression was assessed using the 17-item Hamilton Rating Scale for Depression scale (HDRS17) and tolerability was assessed based on a query regarding side-effects for 6 weeks. The ABCB1 C3435T/A and G2677T/A polymorphisms were genotyped by PCR/RFLP and steady-state serum venlafaxine concentrations were measured by high-performance liquid chromatography. Results: Patients with the TT genotype for the C3435T and the TT/TA genotype for the G2677T/A polymorphism showed significantly higher frequencies in venlafaxine-induced akathisia. This relationship was not observed for efficacy. As regards serum venlafaxine concentrations, patient groups showed no significant differences in efficacy and tolerability. Conclusion: The results suggest that individuals with the TT-TT/TA genotypes for the C3435T-G2677T/A polymorphisms of ABCB1 may be pre-disposed to a risk of akathisia.
Reduced tract integrity of the model for social communication is a neural substrate of social communication deficits in autism spectrum disorder

BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental disorder with social communication deficits as one of the core symptoms. Recently, a five-level model for the social communication has been proposed in which white matter tracts corresponding to each level of the model are identified. Given that the model for social communication subserves social language functions, we hypothesized that the tract integrity of the model for social communication may be reduced in ASD, and the reduction may be related to social communication deficits. METHODS Sixty-two right-handed boys with ASD and 55 typically developing (TD) boys received clinical evaluations, intelligence tests, the Social Communication Questionnaire (SCQ), and MRI scans. Generalized fractional anisotropy (GFA) was measured by diffusion spectrum imaging to indicate the microstructural integrity of the tracts for each level of the social communication model. Group difference in the tract integrity and its relationship with the SCQ subscales of social communication and social interaction were investigated. RESULTS We found that the GFA values of the superior longitudinal fasciculus III (SLF III, level 1) and the frontal aslant tracts (FAT, level 2) were decreased in ASD compared to TD. Moreover, the GFA values of the SLF III and the FAT were associated with the social interaction subscale in ASD. CONCLUSIONS The tract integrity of the model for social communication is reduced in ASD, and the reduction is associated with impaired social interaction. Our results support that reduced tract integrity of the model for social communication might be a neural substrate of social communication deficits in ASD.