Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway.

A systematic evaluation of the influence of sex on transduction by recombinant adeno-associated viral vector (rAAV) indicated that transgene expression after liver-targeted delivery of vector particles was between 5- to 13-fold higher in male mice compared with female mice, irrespective of the proviral promoter or cDNA and mouse strain. Molecular analysis revealed that the rAAV genome was stably retained in male liver at levels that were 7-fold higher than those observed in females. Further, the sex difference in transduction was observed with AAV-2- and AAV-5-based vectors, which use distinct receptor complexes for infection. In concordance with the differences in AAV transduction, gel shift analysis with nuclear extracts derived from the liver of mice and humans revealed substantially higher binding of host nuclear protein to the rep-binding site (RBS) of AAV inverted terminal repeat (ITR) in males compared with females. Transduction efficiency and binding of nuclear protein to RBS was dramatically reduced in male mice by castration. In contrast, although oophorectomy did not significantly influence rAAV transduction, administration of 5alpha dihydrotestosterone, prior to gene transfer, increased stable hepatocyte gene transfer in females to levels observed in male mice, implying that androgens significantly influence hepatocyte gene transfer. Interestingly, sex did not have a significant effect on AAV gene transfer into nonhepatic tissue, indicating that there are distinct tissue- and sex-specific differences in the mechanisms responsible for efficient transduction with this vector. These results have significant implications for gene therapy of autosomal and acquired disorders affecting the liver

Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques

The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 × 1012 vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B. © 2002 by The American Society of Hematology

Who needs nature? The influence of employee speciesism on nature-based need satisfaction and subsequent work behavior

Scholars have long upheld the notion that exposure to nature benefits individuals. Recently, organizational researchers have theorized that these benefits extend to the workplace, leading to calls for organizations to incorporate contact with nature into employees’ jobs. However, it is unclear whether the effects of nature are strong enough to meaningfully impact employee performance, thereby justifying organizations’ investments in it. In this research, we draw on self-determination theory to develop a theoretical model predicting that exposure to nature at work satisfies employees’ psychological needs (i.e., needs for autonomy, relatedness, and competence), and positively affects their subsequent task performance and prosocial behavior. In addition, we theorize that the effects of nature on need satisfaction are weaker in employees higher on speciesism (i.e., the belief that humans are superior to other forms of life). We test these predictions with a mixed-method approach comprised of an online experiment in the United States (Study 1), a field experiment in Hong Kong (Study 2), a multi-wave, multi-source field study in Taiwan (Study 3), and a multi-wave, multi-source field study (with objective performance scores) in New Zealand (Study 4). Overall, our findings largely support our theoretical model

A preclinical study on the combination therapy of everolimus and transarterial chemoembolization in hepatocellular carcinoma

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Effects of electron-electron interactions on the electronic Raman scattering of graphite in high magnetic fields

We report the observation of strongly temperature-dependent, asymmetric spectral lines in electronic Raman scattering spectra of graphite in a high magnetic field up to 45 T applied along the c-axis. The magnetic field quantizes the in-plane motion, while the out-of-plane motion remains free, effectively reducing the system dimension from three to one. Optically created electron-hole pairs interact with, or shake up, the one-dimensional Fermi sea in the lowest Landau subbands. Based on the Tomonaga-Luttinger liquid theory, we show that interaction effects modify the van Hove singularity to the form $(\omega-\Delta)^{2\alpha-1/2}$ at zero temperature. At finite temperature, we predict a thermal broadening factor that increases linearly with the temperature. Our model reproduces the observed temperature-dependent line-shape, determining $\alpha$ to be $\sim$0.05 at 40 T

Magnetophonon resonance in graphite: High-field Raman measurements and electron-phonon coupling contributions

We perform Raman scattering experiments on natural graphite in magnetic fields up to 45 T, observing a series of peaks due to interband electronic excitations over a much broader magnetic field range than previously reported. We also explore electron-phonon coupling in graphite via magnetophonon resonances

Direct healthcare costs of Rome IV or Rome III-defined irritable bowel syndrome in the United Kingdom

Background Previous studies have demonstrated a substantial economic impact of irritable bowel syndrome (IBS). Aims To provide contemporaneous estimates of direct healthcare costs of IBS in the United Kingdom. Methods We collected demographic, gastrointestinal and psychological symptoms, quality of life and healthcare usage data from adults with Rome IV or Rome III IBS in the United Kingdom. We calculated the mean annual direct healthcare costs of IBS per person and used contemporaneous IBS prevalence data, together with census data, to estimate annual direct costs of IBS. We also examined predictors of higher costs. Results The mean annual direct cost of IBS per person among 752 individuals with Rome IV IBS was £556.65 (SD £1023.92) and £474.16 (SD £897.86) for 995 individuals with Rome III IBS. We estimate the annual direct healthcare cost of IBS in the United Kingdom is £1.27 billion if the Rome IV criteria are used to define IBS, and £2.07 billion using Rome III. Among individuals with Rome IV IBS, mean annual costs were higher in those with opiate use (£907.90 vs £470.58, p 5 years £501.60, p = 0.002), lower quality of life (p < 0.001 for trend), and higher depression, somatisation and gastrointestinal symptom-specific anxiety scores (P < 0.001 for trend for all). Conclusion We estimate annual direct healthcare costs of IBS of between £1.3 and £2 billion in the United Kingdom

Willingness to pay for medications among patients with Rome IV Irritable Bowel Syndrome

Background Little is known about willingness to pay for medications among individuals with irritable bowel syndrome (IBS). Methods We collected demographic, gastrointestinal symptom, psychological health, quality of life, and healthcare usage data from 752 adults with Rome IV-defined IBS. We examined willingness to pay for a hypothetical medication in return for improvement in IBS symptoms using a contingent valuation method, according to these variables. Results The median amount of money individuals was willing to pay was £1–£50 (IQR £0–£100) per month for a medication with a 100% chance of improving IBS symptoms. Women, compared with men, (92.7% willing to pay “£0,” 89.8% “£1–£50,” 87.3% “£51–£100,” 78.9% “£101–£200,” and 78.5% “more than £200,” p = 0.008) were less likely to be willing to pay for a pill with a 100% chance of improving IBS symptoms whilst those with an annual income of £30,000 or more (12.2% willing to pay “£0,” 25.2% “£1–£50,” 33.5% “£51–£100,” 40.2% “£101–£200,” and 35.1% “more than £200,” p = 0.002) were more likely. We observed a higher willingness to pay among those with lower IBS-related quality of life (p = 0.002 for trend). Of all 752 individuals, 92.7%, 74.5%, and 58.0% would be willing to pay for a medication that would give them a 100%, 50%, or 30% chance of improving IBS symptoms, respectively. Conclusion Patients with IBS are willing to pay for medications which improve IBS symptoms. Future studies should investigate the relative importance of medication pricing, efficacy, and side effect profile among individuals with IBS

Willingness to accept risk with medication in return for cure of symptoms among patients with Rome IV irritable bowel syndrome

Background Some drugs for irritable bowel syndrome (IBS) have serious side effects. Aims To examine the willingness of individuals with IBS to accept risks with medication in return for symptom cure. Methods We collected demographic, gastrointestinal symptoms, psychological health, quality of life and impact on work and daily activities data from 752 adults with Rome IV-defined IBS. We examined median willingness to accept death in return for cure with a hypothetical medication using a standard gamble, according to these variables. Results Participants would accept a median 2.0% (IQR 0.0%-9.0%) risk of death in return for a 98.0% (IQR 91.0%-100.0%) chance of permanent symptom cure. The median accepted risk of death was higher in men (5.0% vs 2.0%, P < 0.001), those with continuous abdominal pain (4.0% vs 1.0%, P < 0.001), more severe symptoms (P = 0.005 for trend), abnormal depression scores (P < 0.001 for trend), higher gastrointestinal symptom-specific anxiety (P < 0.001 for trend), and lower IBS-related quality of life (P < 0.001 for trend). Those willing to accept above median risk of death were more likely to be male (17.1% vs 9.1%, P < 0.001), take higher levels of risks in their daily life (P = 0.008 for trend), and report continuous abdominal pain (53.1% vs 39.4%, P < 0.001), and had higher depression (P = 0.004 for trend) and lower quality of life (P < 0.001 for trend) scores. Conclusion Patients are willing to accept significant risks in return for cure of their IBS symptoms