Who Owns the Virtual Items?

Do you WoW? Because millions of people around the world do! Due to this increased traffic, virtual wealth amassed in MMORPGs are intersecting in our real world in unexpected ways. Virtual goods have real-life values and are traded in real-life markets. However, the market for trading in virtual items is highly inefficient because society has not created property rights for virtual items. This lack of regulation has a detrimental effect not just the market for virtual items, but actually the market for MMORPGs. Assuming we want to promote the production of MMORPGs as a market, society requires a set of distinct property rules to decrease the inefficiencies in the virtual market. In creating these regulation, we may be able to take cues from intellectual property laws, as many of the problems surrounding virtual goods are akin to intellectual property

Massively parallel cis-regulatory analysis in the mammalian central nervous system

Cis-regulatory elements (CREs, e.g., promoters and enhancers) regulate gene expression, and variants within CREs can modulate disease risk. Next-generation sequencing has enabled the rapid generation of genomic data that predict the locations of CREs, but a bottleneck lies in functionally interpreting these data. To address this issue, massively parallel reporter assays (MPRAs) have emerged, in which barcoded reporter libraries are introduced into cells, and the resulting barcoded transcripts are quantified by next-generation sequencing. Thus far, MPRAs have been largely restricted to assaying short CREs in a limited repertoire of cultured cell types. Here, we present two advances that extend the biological relevance and applicability of MPRAs. First, we adapt exome capture technology to instead capture candidate CREs, thereby tiling across the targeted regions and markedly increasing the length of CREs that can be readily assayed. Second, we package the library into adeno-associated virus (AAV), thereby allowing delivery to target organs in vivo. As a proof of concept, we introduce a capture library of about 46,000 constructs, corresponding to roughly 3500 DNase I hypersensitive (DHS) sites, into the mouse retina by ex vivo plasmid electroporation and into the mouse cerebral cortex by in vivo AAV injection. We demonstrate tissue-specific cis-regulatory activity of DHSs and provide examples of high-resolution truncation mutation analysis for multiplex parsing of CREs. Our approach should enable massively parallel functional analysis of a wide range of CREs in any organ or species that can be infected by AAV, such as nonhuman primates and human stem cell-derived organoids

Vacuum ultraviolet photoionization cross section of the hydroxyl radical

The absolute photoionization spectrum of the hydroxyl (OH) radical from 12.513 to 14.213 eV was measured by multiplexed photoionization mass spectrometry with time-resolved radical kinetics. Tunable vacuum ultraviolet (VUV) synchrotron radiation was generated at the Advanced Light Source. OH radicals were generated from the reaction of O(^1D) + H_2O in a flow reactor in He at 8 Torr. The initial O(^1D) concentration, where the atom was formed by pulsed laser photolysis of ozone, was determined from the measured depletion of a known concentration of ozone. Concentrations of OH and O(^3P) were obtained by fitting observed time traces with a kinetics model constructed with literature rate coefficients. The absolute cross section of OH was determined to be σ(13.436 eV) = 3.2 ± 1.0 Mb and σ(14.193 eV) = 4.7 ± 1.6 Mb relative to the known cross section for O(^3P) at 14.193 eV. The absolute photoionization spectrum was obtained by recording a spectrum at a resolution of 8 meV (50 meV steps) and scaling to the single-energy cross sections. We computed the absolute VUV photoionization spectrum of OH and O(^3P) using equation-of-motion coupled-cluster Dyson orbitals and a Coulomb photoelectron wave function and found good agreement with the observed absolute photoionization spectra

VUV Photoionization Cross Sections of HO_2, H_2O_2, and H_2CO

The absolute vacuum ultraviolet (VUV) photoionization spectra of the hydroperoxyl radical (HO_2), hydrogen peroxide (H_2O_2), and formaldehyde (H_2CO) have been measured from their first ionization thresholds to 12.008 eV. HO_2, H_2O_2, and H_2CO were generated from the oxidation of methanol initiated by pulsed-laser-photolysis of Cl_2 in a low-pressure slow flow reactor. Reactants, intermediates, and products were detected by time-resolved multiplexed synchrotron photoionization mass spectrometry. Absolute concentrations were obtained from the time-dependent photoion signals by modeling the kinetics of the methanol oxidation chemistry. Photoionization cross sections were determined at several photon energies relative to the cross section of methanol, which was in turn determined relative to that of propene. These measurements were used to place relative photoionization spectra of HO_2, H_2O_2, and H_2CO on an absolute scale, resulting in absolute photoionization spectra

The Origins of a Rich Absorption Line Complex in a Quasar at Redshift 3.45

We discuss the nature and origin of a rich complex of narrow absorption lines in the quasar J102325.31+514251.0 at redshift 3.447. We measure nine C IV(\lambda1548,1551) absorption line systems with velocities from -1400 to -6200 km/s, and full widths at half minimum ranging from 16 to 350 km/s. We also detect other absorption lines in these systems, including H I, C III, N V, O VI, and Si IV. Lower ionisation lines are not present, indicating a generally high degree of ionisation in all nine systems. The total hydrogen column densities range from <=10^{17.2} to 10^{19.1}cm^{-2}. We examine several diagnostics to estimate more directly the location and origin of each absorber. Four of the systems can be attributed to a quasar-driven outflow based on line profiles that are smooth and broad compared to thermal line widths. Several systems also have other indicators of a quasar outflow origin, including partial covering. Altogether there is direct evidence for 6 of the 9 systems forming in a quasar outflow. Consistent with a near-quasar origin, eight of the systems have metallicity values or lower limits in the range Z >= 1-8 Z_{sun}. The lowest velocity system, which has an ambiguous location, also has the lowest metallicity, Z <= 0.3 Z_{sun}, and might form in a non-outflow environment farther from the quasar. Overall, however, this complex of narrow absorption lines can be identified with a highly structured, multi-component outflow from the quasar. The high metallicities are similar to those derived for other quasars at similar redshifts and luminosities, and are consistent with evolution scenarios wherein quasars appear after the main episodes of star formation and metal enrichment in the host galaxies.Comment: 16 pages, 12 figures, Accepted to MNRAS, July 201

CRALBP supports the mammalian retinal visual cycle and cone vision

Mutations in the cellular retinaldehyde-binding protein (CRALBP, encoded by RLBP1) can lead to severe cone photoreceptor-mediated vision loss in patients. It is not known how CRALBP supports cone function or how altered CRALBP leads to cone dysfunction. Here, we determined that deletion of Rlbp1 in mice impairs the retinal visual cycle. Mice lacking CRALBP exhibited M-opsin mislocalization, M-cone loss, and impaired cone-driven visual behavior and light responses. Additionally, M-cone dark adaptation was largely suppressed in CRALBP-deficient animals. While rearing CRALBP-deficient mice in the dark prevented the deterioration of cone function, it did not rescue cone dark adaptation. Adeno-associated virus-mediated restoration of CRALBP expression specifically in Müller cells, but not retinal pigment epithelial (RPE) cells, rescued the retinal visual cycle and M-cone sensitivity in knockout mice. Our results identify Müller cell CRALBP as a key component of the retinal visual cycle and demonstrate that this pathway is important for maintaining normal cone-driven vision and accelerating cone dark adaptation

HEAD CIRCUMFERENCE AS PREDICTED BY FACIAL MEASURES IN MOUSE MODEL OF FASD

poster abstractIntrauterine exposure to ethanol produces a myriad of anomalies, many tied to the developing brain. Both dose and duration of exposure are suggested to have cumulative effects on brain growth; however, brain volume is difficult to obtain directly, so a commonly used indirect measure of brain volume has been the occipital frontal circumference (OFC) in humans (Malina and Bouchard). In this study, we investigated the relationship of craniofacial measurements and exposure histories against skull circumference in C57BL/6J (Jackson Laboratory) mice. Three alcohol treatment groups were used, which differed in dose of alcohol administered and/or the duration of treatment during gestation. All pups were surrogated at birth with normal dams and received microCT at postnatal day (P) 21. Individual measurement comparisons were made between treatment groups, a control sample of chow fed, and matching groups of pair-fed (isocalorically linked liquid diet). Linear craniofacial measurements were derived from micro-CT images, and a measure of head circumference was constructed using the MxView software (Philips). A multiple linear regression was used to evaluate the facial measurements that best predicted circumference. Variables explored were facial measurements as well as treatment and gender. The model, using a constant, mid facial depth, inner orbital width, and bigonial width predicted 68.8% of variance in circumference (N=164, R2=.688, p=.006). In conclusion, a small set of facial measurements can moderately predict circumference in mice. However, in a small exploratory study, there is an indication that alcohol exposure is a significant factor in the degree to which circumference relates to total brain volume. 2Department of Anthropology Indiana University Purdue University Indianapolis, Indianapolis, Indiana, 46202 3Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, Indiana, 46202 4Department of Radiology and Imaging Sciences Indiana University School of Medicine, Indianapolis, IN 46202 5Stark Neuroscience Research Institute, Indiana University School of Medicine Indianapolis, Indiana, 4620

Vacuum ultraviolet photoionization cross section of the hydroxyl radical

The absolute photoionization spectrum of the hydroxyl (OH) radical from 12.513 to 14.213 eV was measured by multiplexed photoionization mass spectrometry with time-resolved radical kinetics. Tunable vacuum ultraviolet (VUV) synchrotron radiation was generated at the Advanced Light Source. OH radicals were generated from the reaction of O(^1D) + H_2O in a flow reactor in He at 8 Torr. The initial O(^1D) concentration, where the atom was formed by pulsed laser photolysis of ozone, was determined from the measured depletion of a known concentration of ozone. Concentrations of OH and O(^3P) were obtained by fitting observed time traces with a kinetics model constructed with literature rate coefficients. The absolute cross section of OH was determined to be σ(13.436 eV) = 3.2 ± 1.0 Mb and σ(14.193 eV) = 4.7 ± 1.6 Mb relative to the known cross section for O(^3P) at 14.193 eV. The absolute photoionization spectrum was obtained by recording a spectrum at a resolution of 8 meV (50 meV steps) and scaling to the single-energy cross sections. We computed the absolute VUV photoionization spectrum of OH and O(^3P) using equation-of-motion coupled-cluster Dyson orbitals and a Coulomb photoelectron wave function and found good agreement with the observed absolute photoionization spectra

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematological tumors. We assessed intra-tumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status≥60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) pre-operatively (Arm A; N=8 patients). Patients not undergoing surgery received 50mg/m(2) (Arm B, N=24), or 60mg (Arm C, N=14) twice weekly, or 80mg once weekly (Arm D; N=30). Primary endpoint was six-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving pre-surgical selinexor was 105.4nM (range 39.7-291nM). In Arms B, C, and D, respectively, the PFS6 was 10% (95%CI, 2.79-35.9), 7.7% (95%CI, 1.17-50.6), and 17% (95%CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% (Arm B, 8.3% (95%CI, 1.0-27.0); C:7.7% (95%CI, 0.2-36.0); D:10% (95%CI, 2.1-26.5)), with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; one (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%) and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC=0.88). CONCLUSION: At 80mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198634

Factors associated with mortality in patients with drug-susceptible pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Tuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings.</p> <p>Methods</p> <p>Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.</p> <p>Results</p> <p>Of 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions.</p> <p>Conclusions</p> <p>In addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.</p