Miracle-dz/UniFAR-FTUs huggingface dataset:
Liver-directed lentiviral gene therapy in a dog model of hemophilia B

Gene therapy with lentiviral vectors targeting transgene expression to hepatocytes provides stable reconstitution of clotting activity in dogs with hemophilia B and does not show genotoxicity in tumor-prone mice. Advancing gene therapy for hemophilia Hemophilia is an inherited bleeding disorder caused by a deficiency in a blood clotting factor. The current treatment requires lifelong intravenous administration of the missing clotting factor every few days, a costly and demanding regimen for patients with hemophilia. Gene therapy has the potential to provide a single-shot treatment option by replacing a functional gene in liver cells that naturally produce the factor. Cantore et al. now report a study of the efficacy and safety of liver-directed in vivo gene therapy in large and small animal models using lentiviral vectors. This gene therapy strategy with lentiviral vectors may complement the use of other gene therapy vectors for treating hemophilia. We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia.
One-Dimensional Markov-Functional Models Driven by Non-Gaussian Markov Processes

The class of Markov-functional models provide a framework that can be used to define interest-rate models of finite dimension calibrated to any arbitrage-free formula for caplet or swaption prices. Because of their computational efficiency one-factor Markov-functional models are of particular interest. So far the literature has been focused on models driven by a Gaussian process. The aim of this paper is to move away from this Gaussian assumption and to provide new algorithms that can be used to implement a Markov-functional model driven by a more general class of one-dimensional diffusion processes. We provide additional insight into the role of the driving process by presenting a simple copula-based criterion that can be used to distinguish between models. Finally we offer further insight into the dynamics of one-dimensional Markov-functional models by relating them to separable local-volatility LIBOR market models and demonstrate this with a practical example.
Evaluation of Quantitative RT-PCR Using Nonamplified and Amplified RNA

AbstractQuantitative reverse-transcription polymerase chain reaction (qRT-PCR) is a standard assay in molecular medicine for gene expression analysis. Samples from incisional/needle biopsies, laser-microdissected tumor cells and other biologic sources, normally available in clinical cancer studies, generate very small amounts of RNA that are restrictive for expression analysis. As a consequence, an RNA amplification procedure is required to assess the gene expression levels of such sample types. The reproducibility and accuracy of relative gene expression data produced by sensitive methodology as qRT-PCR when cDNA converted from amplified (A) RNA is used as template has not yet been properly addressed. In this study, to properly evaluate this issue, we performed 1 round of linear RNA amplification in 2 breast cell lines (C5.2 and HB4a) and assessed the relative expression of 34 genes using cDNA converted from both nonamplified (NA) and A RNA. Relative gene expression was obtained from β actin or glyceraldehyde 3-phosphate dehydrogenase normalized data using different dilutions of cDNA, wherein the variability and fold-change differences in the expression of the 2 methods were compared. Our data showed that 1 round of linear RNA amplification, even with suboptimal-quality RNA, is appropriate to generate reproducible and high-fidelity qRT-PCR relative expression data that have similar confidence levels as those from NA samples. The use of cDNA that is converted from both A and NA RNA in a single qRT-PCR experiment clearly creates bias in relative gene expression data.
Total Economic Valuation of the National Park Service Lands and Programs: Results of a Survey of the American Public

This paper presents the first-ever comprehensive estimate of the total economic value of the National Parks Service. The estimate covers administered lands, waters, and historic sites as well as NPS programs, which include protection of natural landmarks and historic sites, partnerships with local communities, recreational activities and educational programs. Our estimate of the total economic value to the American public is $92 billion. Two-thirds of this total ($62 billion) is for National Park lands, waters and historic sites; the remaining $30 billion is attributed to NPS Programs. The estimate, which is based on very conservative assumptions, includes not only the value attributed by visitors to the parks, but also a significant "non-use" or "existence" value. This is the value derived by the public from simply knowing that NPS assets are protected for current and future generations, regardless of whether or not they actually choose to visit. Our results are derived from a survey of a sample of U.S. households conducted for this study. Participants were asked whether they would be willing to pay specific amounts in increased annual federal income taxes over a ten-year period in order to retain the current National Parks and NPS Programs. This methodology is consistent with the techniques employed by numerous Federal agencies for economic valuation. The results reflect rational economic behavior--the higher the dollar amount in increased taxation, the less likely respondents were to pay. This indicates respondents were paying close attention to the payment amounts and gives us high confidence in our economic valuation. Overall, nearly 95% of responding households indicated that protecting National Parks, including historic sites, for current and future generations was important to them. This was largely independent of visitation; 85% of respondents felt that they personally benefitted from National Parks, regardless of whether they visited the parks or not. This paper describes our methodology in detail, including survey development techniques and implementation, as well as our statistical analysis. The paper also considers the policy implications of this first-ever analysis of NPS value. The study was conducted independently of the National Park Service. The research was funded through the generosity of the S.D. Bechtel Jr. Foundation, the Turner Foundation, Cody J. Smith of the Summit Foundation, the National Park Foundation.
Outdoor insulators: overview of in-service experience, inspection practice and future challenges

This paper, as a keynote contribution, provides an overview of the issues and challenges of applying ceramic and polymer insulators from a perspective of close academic cooperation with electrical utilities and insulator manufacturers. For polymer insulators, electrical stress, close to end fittings and across insulator leakage, remains an important design parameter. Also, for polymer insulators, methods for diagnosing the progress of aging and in-service degradation in response to excessive stress are presented. Future challenges in the life cycle cost of insulators, starting with harmonization of standards and ending with methods for recycling, are also outlined.
Sonographic Assessment of Facial HIV‐Related Lypoatrophy

OBJECTIVE To investigate the utility of ultrasonography (US) for assessing and grading facial lypoatrophy (FLA) in patients with HIV. DESIGN The social effect of FLA is huge and may reduce antiretroviral therapy adherence. Strategies for the early detection of FLA are crucial, because complete correction of FLA in late stages is unlikely. METHODS Fifty‐two HIV‐positive patients undergoing highly active antiretroviral therapy underwent US with nasogenian transversal scan using a high‐frequency broadband transducer (5–17 MHz) to detect FLA. Intra‐ and interobserver variability were calculated to assess US reproducibility. Concerning FLA grading, patients were categorized in five clinical classes and four US classes. RESULTS Our results regarding inter‐ and intraobserver coefficients of variation permit the validation of US as a reproducible technique (p<.001), and a high correlation between US and clinical classification was obtained, with complete concordance for more advanced FLA classes. CONCLUSIONS The lack of a reference objective method to quantify subcutaneous fat is a major difficulty in measuring HIV‐related FLA. Our results, in accordance with data from the literature, suggest that US is an ideal tool for assessing and grading FLA. Furthermore, US may be suitable for routine evaluation in HIV‐infected patients for early detection of FLA and to select its optimal management. The authors have indicated no significant interest with commercial supporters.
An Approach to Optimized Resource Scheduling Algorithm for Open-Source Cloud Systems

Based on the deep research on Infrastructure as a Service (IaaS) cloud systems of open-source, we propose an optimized scheduling algorithm to achieve the optimization or sub-optimization for cloud scheduling problems. In this paper, we investigate the possibility to allocate the Virtual Machines (VMs) in a flexible way to permit the maximum usage of physical resources. We use an Improved Genetic Algorithm (IGA) for the automated scheduling policy. The IGA uses the shortest genes and introduces the idea of Dividend Policy in Economics to select an optimal or suboptimal allocation for the VMs requests. The simulation experiments indicate that our dynamic scheduling policy performs much better than that of the Eucalyptus, Open Nebula, Nimbus IaaS cloud, etc. The tests illustrate that the speed of the IGA almost twice the traditional GA scheduling method in Grid environment and the utilization rate of resources always higher than the open-source IaaS cloud systems.
An Oblique Effect of Chromatic Gratings Measured by Color-Mixture Thresholds

Contrast sensitivity is lower for obliquely oriented achromatic gratings than for vertical or horizontal gratings at high spatial and low temporal frequencies. Although this response is suggestive of mediation by P-pathway cortical correlates, no clear sensory (ie class 1) oblique effect has been demonstrated with isoluminant chromatic stimuli. In the present experiment, a two-alternative forced-choice detection task was used to measure observers' sensitivity to spatio-temporal sinusoids varying in orientation and color contrast. A maximum-likelihood method fit ellipses to the thresholds, with the length of each ellipse taken as a measure of chromatic contrast sensitivity at isoluminance, and the width as luminance contrast threshold. A chromatic oblique effect was observed at about 3 cycles deg−1 suggesting an orientation bias within the cortical stream conveying P-cell activity.
Fourier transform infrared spectroscopy analysis of the conformational quality of recombinant proteins within inclusion bodies

The solubility of recombinant proteins produced in bacterial cells is considered a key issue in biotechnology as most overexpressed polypeptides undergo aggregation in inclusion bodies, from which they have to be recovered by solubilization and refolding procedures. Physiological and molecular strategies have been implemented to revert or at least to control aggregation but they often meet only partial success and have to be optimized case by case. Recent studies have shown that proteins embedded in inclusion bodies may retain residual structure and biological function and question the former axiom that solubility and activity are necessarily coupled. This allows for a switch in the goals from obtaining soluble products to controlling the conformational quality of aggregated proteins. Central to this approach is the availability of analytical methods to monitor protein structure within inclusion bodies. We describe here the use of Fourier transform infrared spectroscopy for the structural analysis of inclusion bodies both purified from cells and in vivo. Examples are reported concerning the study of kinetics of aggregation and structure of aggregates as a function of expression levels, temperature and co‐expression of chaperones.
SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma

Cyclophosphamide–dacarbazine–vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation‐wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression‐free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m2/d for 5 days every 28 days. Median PFS was 13.3 months after a median follow‐up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation‐wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB‐related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB‐mutated tumours may explain this finding.
A /spl Sigma//spl Delta/ modulation based analog BIST system with a wide bandwidth fifth-order analog response extractor for diagnosis purpose

A wide bandwidth /spl Sigma/-/spl Delta/ modulation based analog built-in self-test (BIST) system that can diagnose the prototype is presented. It consists of a low-cost design-for-testability (DJT) switched-capacitor filter as the circuit under test (CUT) and a wide bandwidth analog response extractor (ARE) to digitize the analog responses for final DSP analysis. The first stage of the DJT CUT is reconfigured to accept a repetitive /spl Sigma/-/spl Delta/ modulated bit-steam as its stimulus. This DJT technique reuses every original component and thus provides the advantages of lowering the testing cost, increasing the fault coverage as well as the accuracy, and being able to perform the at-speed tests. The ARE is a cascaded 2-1-1-I fifth-order /spl Sigma/-/spl Delta/ modulator equipped with single-bit quantizers to extend the testing bandwidth while retaining moderate tolerance of circuit imperfections. Our measurement results show that this ARE is able to provide a -95 dB spurious free dynamic range over 1 MHz bandwidth when operates at 30 MHz- A multi-tone test is performed to manifest the wide bandwidth and high accuracy of our BIST system. Based on the BIST results, a method of diagnosing the prototype to speed up the time-to-market is also proposed and demonstrated by our BIST system.
Zipper-Like Internalization of Dr-Positive Escherichia coli by Epithelial Cells Is Preceded by an Adhesin-Induced Mobilization of Raft-Associated Molecules in the Initial Step of Adhesion

ABSTRACT We undertook a study of the mechanism by which Dr-positive bacteria invade epithelial cells. Our findings show that Dr-positive bacteria enter via a zipper-like mechanism that is independent of the Dr-induced mobilization of F-actin and of the signaling molecules that control Dr-induced F-actin rearrangements. We also observed that Dr-positive IH11128 bacteria entered cells that were positive for the caveola marker VIP21/caveolin (HeLa and Caco-2/Cav-1 cells) to the same extent as those that were not (parental Caco-2 cells). Using fluorescence labeling and confocal laser scanning microscopy, we provide evidence that during the adhesion step, the α5β1 integrin, which plays a pivotal role in Afa/Dr diffusely adhering Escherichia coli bacterial entry, is mobilized around adhering Dr-positive bacteria. We show that the receptor for Afa/Dr adhesins, glycosylphosphatidylinositol-anchored CD55; the raft marker, ganglioside GM1; and VIP21/caveolin are all recruited around adhering Dr-positive bacteria. We also observed that extracting membrane cholesterol with methyl-β-cyclodextrin (MBCD) did not affect the recruitment of CD55, GM1, or β1 integrin to adhering Dr-positive bacteria. In contrast, extracting or changing membrane-bound cholesterol by means of drugs that modify lipid rafts (MBCD, filipin III, or mevalonate plus lovastatin plus MBCD) inhibited the entry of Dr-positive IH11128 both into cells that expressed VIP21/caveolin (HeLa and Caco-2/Cav-1 cells) and into those that did not (parental Caco-2 cells). Finally, restoring cholesterol within the cell membrane of MBCD-treated cells restored Dr-positive IH11128 internalization.
Compiler-Guided Parallelism Adaption Based on Application Partition for Power-Gated ILP Processor

Instruction-level parallelism (ILP) processors have been widely used to improve speed for several decades. However, the requirement of parallelism changes between applications, even within an application. Fixed high parallelism could result in poor utilization and extra leakage energy. Designing energy-efficient ILP processors to trade off power/speed has been a critical issue in current research. In this paper, a compiler-guided parallelism adaption based on an application partition algorithm is proposed to implement parallelism adaption with applications running on ILP processors. The aim is to minimize energy consumption without degrading the execution time. The main idea is described as follows: 1) partition the application into several power gating regions (PGRs); 2) assign adapted parallelism for each region by analyzing the requirements of resources and energy efficiency; and 3) reschedule each region with its own parallelism and insert power-gating instructions into the application to control hardware ON/OFF. The experimental results of evaluation with the CoreMarkPro benchmark suits show the expected savings of leakage energy. Our algorithm could reduce the leakage energy in register files by 30.46% and 64.06% for applications with high variance on software-inherent parallelism. Furthermore, the overhead energy originated from state transition is much lower than Tabkhi’s algorithm.
ZCSD: a Computational Storage Device over Zoned Namespaces (ZNS) SSDs

The Big Data trend is putting strain on modern storage systems, which have to support high-performance I/O accesses for the large quantities of data. With the prevalent Von Neumann computing architecture, this data is constantly moved back and forth between the computing (i.e., CPU) and storage entities (DRAM, Non-Volatile Memory NVM storage). Hence, as the data volume grows, this constant data movement between the CPU and storage devices has emerged as a key performance bottleneck. To improve the situation, researchers have advocated to leverage computational storage devices (CSDs), which offer a programmable interface to run user-defined data processing operations close to the storage without excessive data movement, thus offering performance improvements. However, despite its potential, building CSD-aware applications remains a challenging task due to the lack of exploration and experimentation with the right API and abstraction. This is due to the limited accessibility to latest CSD/NVM devices, emerging device interfaces, and closed-source software internals of the devices. To remedy the situation, in this work we present an open-source CSD prototype over emerging NVMe Zoned Namespaces (ZNS) SSDs and an interface that can be used to explore application designs for CSD/NVM storage devices. In this paper we summarize the current state of the practice with CSD devices, make a case for designing a CSD prototype with the ZNS interface and eBPF (ZCSD), and present our initial findings. The prototype is available at https://github.com/Dantali0n/qemu-csd.
An improved particle swarm optimization algorithm for geometric constraint solving problem

Geometric constraint problem is equivalent to the problem of solving a set of nonlinear equations substantially. The constraint problem can be transformed to an optimization problem. We can solve the problem by an improved PSO algorithm (IPSO), which is based on the “alldifferent” constraint. It combines the particle swarm optimization algorithm with genetic operators together effectively. When a particle is going to stagnate, the mutation operator is used to search its neighborhood. The experiment indicates that the algorithm can be used to solve geometric constraint problem effectively.
IMPACT OF MACROECONOMIC INDICATORS ON DIFFERENT CAPITAL MARKETS IN PAKISTAN

This research is about determining the relationship of macroeconomic variables with different capital market indices of Pakistan. Therefore, for this purpose ARDL (Autoregressive Distributed Lagged Model) approach to co-integration has been applied to determine the long run relationship and Toda-Yamamoto causality test to determine the uni-directional relationship. It is found that the impact of different macro-economic variables is not exactly the same on different capital market indices. According to ARDL results, Money supply (M2) and GDP has positive significant, whereas discount rate has negative significant impact on KSE100 index.In case of Lahore stock exchange, none of the macroeconomic variable has significant impact on LSE25 index. According to the results of Toda-Yamamoto causality, only inflation has causal relationship with KSE100 and LSE25 index.
The role of an EMU unemployment insurance scheme on income protection in case of unemployment

The aim of this paper is to explore the potential of an EMU unemployment insurance scheme (EMU-UI) to improve the income protection available to individuals and their families in case of unemployment. Our analysis uses an illustrative EMU-UI scheme, which has a common design across member states and can therefore be considered as a benchmark with respect to which gaps in national unemployment insurance schemes are assessed. We make use of EUROMOD, the EU-wide tax-benefit microsimulation model, to simulate entitlement to the national and EMU-UI and calculate their effect on household disposable income for all individuals currently in work and those with the highest unemployment risk, in case they would become unemployed. Our results show that the EMU-UI has the potential to reduce current gaps in coverage where these are sizeable due to stringent eligibility conditions, to increase generosity where current unemployment benefits are low relative to earnings and to extend duration where this is shorter than twelve months. The illustrative EMU-UI would reduce the risk of poverty for the potentially new unemployed and would have a positive effect on household income stabilization. The extent of these effects varies in size across EMU member states for two main reasons: differences in the design of national unemployment insurance schemes and differences in labor force characteristics across member states.