Miracle-dz/UniFAR-FTUs huggingface dataset:
Employing a Gain-of-Function Factor IX Variant R338L to Advance the Efficacy and Safety of Hemophilia B Human Gene Therapy: Preclinical Evaluation Supporting an Ongoing Adeno-Associated Virus Clinical Trial

Abstract Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose–response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2–500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8+ T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX–/– mice 8–10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity, 100–500%). These preclinical studies demonstrate a safety:efficacy profile supporting an ongoing phase 1/2 human clinical trial of the scAAV8.FIXR338L vector (designated BAX335).
Rational Molecular Design of Complementary Self-Assembling Peptide Hydrogels

Rational molecular design of self- assembling peptide-based materials that spontaneously form self-supporting hydrogels shows potential in many healthcare applications. Binary peptides based on complementary charged sequences are developed, and the use of biophysical analysis and cell-based studies highlights that the charged interactions can influence the properties of peptide materials and ultimately affect biomaterial applications.
Ethanol's effect on intracellular signal pathways in prenatal rat cortical neurons is GABAB1 dependent

To confirm the modulation role of GABAB on ethanol' effects, we studied the effects of ethanol on the neuronal intracellular signals, protein kinase A (PKA) and cAMP‐response element binding protein (CREB), by using a system where GABAB1 receptors were specifically knocked down in the in vitro cultivated cortical neurons. The results showed that the PKA α subunit was increased with ethanol treatment, and could be further increased by administering baclofen and phaclofen. By contrast, baclofen and/or phaclofen could decrease ethanol's up‐regulation effects on PKA α subunit expression in primary cultured cortical neurons in which the GABAB1 receptor was specifically knocked down using GABAB1 receptor RNA interference. Furthermore, these effects could lead to changes of phospho (p)‐CREB expression, which showed the same expression pattern as PKA. Finally, we observed changes of GABAB1, PKA, and p‐CREB distribution within the same neuronal cells. These results showed that the GABAB receptors are critical to ethanol's cellular effects, which occur via modulating the PKA and CREB transcription pathway, and may be an underlying cause of ethanol's effects. Synapse 61:622–628, 2007. © 2007 Wiley‐Liss, Inc.
Role of Garlic Usage in Cardiovascular Disease Prevention: An Evidence-Based Approach

Introduction. Rapidly growing prevalence of cardiovascular disease is a major threat for the developed as well as developing world warranting urgent need of intervention. Complementary and alternative medicines are gaining popularity among general population because of their safety profile and easy administration. Garlic, in particular, is considered to be one of the best disease-preventive foods because of its potent and widespread effects. This study was done to find out the role of garlic usage in cardiovascular disease prevention. Methodology. Major databases including Google, PubMed, MEDLINE, and Cochrane library view were used for the literature search. Clinical trials conducted on humans assessing role of garlic usage in cardiovascular disease prevention and the possible mechanisms responsible for such therapeutic actions were assessed. Results. Various clinical trials and meta-analyses conducted have shown positive impact of garlic in cardiovascular-disease prevention especially its effects on lipid levels; however, some contradictory results are also reported. Similarly, its effects on hypertension control, and platelet are also mild with limited data availability. The possible reason for these inconsistent results is the difference in preparations with diverse composition, variations in sulphur content present in different garlic preparations used, and methodological variations in subject recruitment, duration of study, dietary control and so forth. Conclusion. Garlic can be used as an adjuvant with lipid-lowering drugs for control of lipids, however, its role as a main therapeutic agent cannot be recommended and it is suggested that more meta-analyses using standardized preparations with a close watch on methodological shortfalls should be conducted to prove its role.
The bioenergetic costs of a gene

Significance A long-standing mystery in evolutionary genomics concerns the lineage-specific expansions of genome size in eukaryotes relative to prokaryotes. One argument is that the cellular complexity and elevated gene numbers in eukaryotes were impossible without a mitochondrion. However, the energetic burden of a gene is typically no greater, and generally becomes progressively smaller, in larger cells in both bacteria and eukaryotes, and this is true for costs measured at the DNA, RNA, and protein levels. These results eliminate the need to invoke an energetics barrier to genome complexity. An enduring mystery of evolutionary genomics concerns the mechanisms responsible for lineage-specific expansions of genome size in eukaryotes, especially in multicellular species. One idea is that all excess DNA is mutationally hazardous, but weakly enough so that genome-size expansion passively emerges in species experiencing relatively low efficiency of selection owing to small effective population sizes. Another idea is that substantial gene additions were impossible without the energetic boost provided by the colonizing mitochondrion in the eukaryotic lineage. Contrary to this latter view, analysis of cellular energetics and genomics data from a wide variety of species indicates that, relative to the lifetime ATP requirements of a cell, the costs of a gene at the DNA, RNA, and protein levels decline with cell volume in both bacteria and eukaryotes. Moreover, these costs are usually sufficiently large to be perceived by natural selection in bacterial populations, but not in eukaryotes experiencing high levels of random genetic drift. Thus, for scaling reasons that are not yet understood, by virtue of their large size alone, eukaryotic cells are subject to a broader set of opportunities for the colonization of novel genes manifesting weakly advantageous or even transiently disadvantageous phenotypic effects. These results indicate that the origin of the mitochondrion was not a prerequisite for genome-size expansion.
Scaling and characterizing database workloads: bridging the gap between research and practice

On-line transaction processing (OLTP) workloads are crucial benchmarks for the design and analysis of server processors. Typical cached configurations used by researchers to simulate OLTP workloads are orders of magnitude smaller than the fully scaled configurations used by OEM vendors to achieve world-record transaction processing throughput. The objective of this study is to discover the underlying relationships that characterize OLTP performance over a wide range of configurations. To this end, we have derived the "iron law" of database performance. Using our iron law, we show that both the average instructions executed per transaction (IPX) and the average cycles per instruction (CPI) are critical to the transaction-throughput performance. We use an extensive, empirical examination of an Oracle based commercial OLTP workload on an Intel Xeon multiprocessor system to characterize the scaling behaviour of both the IPX and the CPI. We demonstrate that across a wide range of configurations the IPX and CPI behaviour follows predictable trends, which can be accurately characterized by simple linear or piece-wise linear approximations. Based on our data, we propose a method for selecting a minimal, representative workload configuration from which behaviours of much larger OLTP configurations can be accurately extrapolated.
Hierarchical classification of Web content

This paper explores the use of hierarchical structure for classifying a large, heterogeneous collection of web content. The hierarchical structure is initially used to train different second-level classifiers. In the hierarchical case, a model is learned to distinguish a second-level category from other categories within the same top level. In the flat non-hierarchical case, a model distinguishes a second-level category from all other second-level categories. Scoring rules can further take advantage of the hierarchy by considering only second-level categories that exceed a threshold at the top level. We use support vector machine (SVM) classifiers, which have been shown to be efficient and effective for classification, but not previously explored in the context of hierarchical classification. We found small advantages in accuracy for hierarchical models over flat models. For the hierarchical approach, we found the same accuracy using a sequential Boolean decision rule and a multiplicative decision rule. Since the sequential approach is much more efficient, requiring only 14%-16% of the comparisons used in the other approaches, we find it to be a good choice for classifying text into large hierarchical structures.
Magnetic Resonance Imaging of Tuberculous Spondylitis

Study Design This retrospective study analyzed the magnetic resonance imaging characteristics of tuberculous spondylitis. Objective To describe the magnetic resonance imaging characteristics of tuberculous spondylitis and compare the diagnostic yield of magnetic resonance imaging versus other modalities. Summary of Background Data Tuberculous spondylitis is not an uncommon occurrence with extrapulmonary disease. It requires prompt diagnosis and management. In the pre-magnetic resonance imaging era, computed tomography was used to delineate the associated radiologic changes. Data are limited that describe the magnetic resonance imaging pattern of tuberculous spondylitis and the effect of post-contrast enhancement. Methods The magnetic resonance imaging characteristics of 28 vertebrae in 12 patients with tuberculous spondylitis were studied. Results The thoracic spine was the most commonly involved region, with involvement occurring in the thoracic spine alone in 12 vertebrae (43%) and with other areas of the spine in an additional five (18%). Partial involvement was detected in the majority of the vertebral lesions (24; 86%). Magnetic resonance imaging evidence of disc space involvement was apparent in only 46% of the lesions. Paraspinal abscess and epidural extension were documented by magnetic resonance imaging in 71% and 61% of lesions, respectively. Decreased signal intensity on T1-weighted images was demonstrated in 13 vertebrae (46%), with increased signal intensity on T2-weighted images seen only in five (18%). Conclusion Magnetic resonance imaging is a useful diagnostic modality for patients with suspected tuberculous spondylitis. Partial vertebral involvement and paraspinal and epidural extension were delineated. Study of the signal intensity on T1− and T2-weighted images revealed a pattern that may be dissimilar to that commonly reported. Post-contrast enhancement adds more certainty to the diagnosis of tuberculous spondylitis.
The role of estradiol withdrawal in the etiology of menstrual migraine

W There can be little doubt that migraine attacks are related to hormonal changes in some women. Attacks often begin at puberty and usually remit after the menopause. According to Friedman and Merritt,l the effect of pregnancy is striking, 80% of women either losing their headaches or improving during pregnancy. Occasionally, however, the opposite effect is observed.2 The widespread use of oral contraceptives has led to several reports of an increased incidence of migraine, suggesting that a casual relationship exists between synthetic estrogen-progestogen combinations and migraine.3-5 From a clinical study of women suffering from migraine while taking oral contraceptives, Whitty et a1.6 commented that many experienced migraine during the interval between courses of medication, that is, a t a time when one would expect plasma levels of these hormones to be declining or at their lowest level. They suggested that migraine in these women might be precipitated by the withdrawal of progestogen. The regular recurrence of migraine during the premenstrual and menstrual phases of the cycle in women not taking oral contraceptives suggests that the withdrawal of natural ovarian hormones may play a significant role in precipitating migraine in some women. In the natural menstrual cycle, the premenstrual phase is characterized by a diminishing secremone separately. The results of this technique applied to the study of the role of progesterone in menstrual migraine have been reported.9 It was concluded that progesterone treatment during the premenstrual phase had little protective effect and that progesterone withdrawal did not precipitate migraine. The aim of the current investigation was to study the role of estradiol in menstrual migraine.
Perception as an Inference Problem

Although the idea of thinking of perception as in inference problem goes back to Helmholtz, it is only recently that we have seen the emergence of neural models of perception that embrace this idea. Here I describe why inferential computations are necessary for perception, and how they go beyond traditional computational approaches based on deductive processes such as feature detection and classification. Neural models of perceptual inference rely heavily upon recurrent computation in which information propagates both within and between levels of representation in a bi- directional manner. The inferential framework shifts us away from thinking of 'receptive fields' and 'tuning' of individual neurons, and instead toward how populations of neurons interact via horizontal and top-down feedback connections to perform collective computations.
Response to Definitive Chemoradiotherapy and Survival in Patients with an Oesophageal Adenocarcinoma versus Squamous Cell Carcinoma: A Matched-Pair Analysis

Objectives: The impact of the histological tumour type in patients treated with definitive chemoradiotherapy (CRT) for an oesophageal cancer is not well established. The aim of this retrospective matched-pair analysis was to evaluate the clinical complete response (CCR) to definitive CRT and the outcome between 2 groups of patients. Methods: Fifty-seven patients with an oesophageal adenocarcinoma (ADC) were matched according to the tumour stage and the WHO performance as well as the CRT regimen status including 57 patients with an oesophageal squamous cell carcinoma (SCC). CRT was based on radiotherapy combined with a cisplatin-based chemotherapy. Results: A CCR was observed in 40 patients (70.2%) with an SCC as compared with 26 patients (45.6%) with an ADC (p = 0.013). SCC patients received significantly more of planned cisplatin and radiotherapy doses than ADC patients (82.0 vs. 67.7%, p = 0.042, and 92.5 vs. 84.5%, p = 0.023, respectively). In responders to CRT, local recurrence was significantly more frequent in SCC patients (52.5 vs. 26.9%, p = 0.046). Median survival in all patients as well as in responders to CRT was not different between the 2 groups. Conclusion: Our study showed that treatment completion and CCR to definitive CRT were more frequent in SCC with, however, more local recurrences in these patients. Further studies are required to confirm this difference in response rate to definitive CRT according to histological type of the tumour in oesophageal cancer.
Contamination Grades Recognition of Ceramic Insulators Using Fused Features of Infrared and Ultraviolet Images

In order to realize the non-contact measurement of ceramic insulator contamination severity, a method based on feature level fusion of infrared (IR) and ultraviolet (UV) image information is proposed in this paper. IR and UV images of artificially polluted insulators were obtained from high voltage experiments at 80%, 85% and 90% RH. After the preprocessing of images, IR and UV features were calculated, respectively. Then, feature selection based on Fisher criterion was adopted to gain features, which have the ability to distinguish different contamination grades effectively. In feature level fusion section, kernel principal component analysis (KPCA) was applied to the dimensionality reduction fusion of IR and UV features and obtain three-dimensional fused features. A particle swarm optimized back propagation neural network (PSO-BPNN) classifier was constructed and trained to recognize the contamination grades. Experimental results indicate that the feature level fusion of IR and UV information based on KPCA has capability to characterize the contamination grades comprehensively. Compared with recognition using IR or UV features separately, recognition based on the feature level fusion is more accurate and effective. This study provides a new methodology for the measurement of insulator contamination severity at working condition.
Intensionality was only alleged: On adjective-noun composition in distributional semantics

We acknowledge the support of Spanish MICINN grant FFI2010-09464-E (McNally, Boleda), the ICREA Foundation (McNally), Catalan AGAUR grant 2010BP-A00070, MICINN grant TIN2009-14715-C04-04, EU grant PASCAL2, FP7-ICT-216886, the DARPA DEFT program under AFRL grant FA8750-13-2-0026 (Boleda) and the ERC under the 2011 Starting Independent Research Grant 283554 to the COMPOSES project (Baroni, Pham). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the view of DARPA, AFRL or the US government.
An Example of Maximizing Survey Return Rates

Obtaining a high response rate in survey research can bolster statistical power, reduce sampling error, and enhance the generalizability of the results to the population surveyed. We describe a mail survey designed to achieve a high return rate of completed questionnaires from members of the American Psychological Association who were engaged in clinical practice. We adapted the Total Design Method for survey research and were able to achieve a high response rate (68%) among health professionals. This was not an experiment in which we assessed the best method to increase survey response rates, hence we cannot empirically evaluate how each of the steps influenced our overall response rate. Future research is needed to identify the relative effectiveness of each of these principles in enhancing survey response rates. Research is also needed to distinguish general principles that apply across populations fromthose that must be tailored to spe cific subpopulations.
Employed family caregivers of cognitively impaired elderly: An examination of role strain and depressive symptoms

This paper compares employed and non-employed caregivers of cognitively impaired elderly family members. Using two competing positions derived from role theory, role conflict and role expansion, we explored whether holding the positions of both caregiver and worker led to greater role overload and psychological role conflict, or provided an outlet that helps caregivers better manage the demands placed on them. We found no differences between employed and non-employed caregivers on measures of role overload, worry and strain, and depression. For working caregivers, however, greater conflict on the job was associated with higher role overload and worry and strain while beneficial work experiences were only weakly associated with lower role overload and worry and strain. There was an interaction effect between positive work experiences and role overload when predicting depressive symptoms. These results provide some support for role conflict, but also suggest that caregivers may vary considerably in how they adapt to multiple roles.
Characterization of erasin (UBXD2): a new ER protein that promotes ER-associated protein degradation

Ubiquitin regulator-X (UBX) is a discrete protein domain that binds p97/valosin-containing protein (VCP), a molecular chaperone involved in diverse cell processes, including endoplasmic-reticulum-associated protein degradation (ERAD). Here we characterize a human UBX-containing protein, UBXD2, that is highly conserved in mammals, which we have renamed erasin. Biochemical fractionation, immunofluorescence and electron microscopy, and protease protection experiments suggest that erasin is an integral membrane protein of the endoplasmic reticulum and nuclear envelope with both its N- and C-termini facing the cytoplasm or nucleoplasm. Localization of GFP-tagged deletion derivatives of erasin in HeLa cells revealed that a single 21-amino-acid sequence located near the C-terminus is necessary and sufficient for localization of erasin to the endoplasmic reticulum. Immunoprecipitation and GST-pulldown experiments confirmed that erasin binds p97/VCP via its UBX domain. Additional immunoprecipitation assays indicated that erasin exists in a complex with other p97/VCP-associated factors involved in ERAD. Overexpression of erasin enhanced the degradation of the ERAD substrate CD3δ, whereas siRNA-mediated reduction of erasin expression almost completely blocked ERAD. Erasin protein levels were increased by endoplasmic reticulum stress. Immunohistochemical staining of brain tissue from patients with Alzheimer's disease and control subjects revealed that erasin accumulates preferentially in neurons undergoing neurofibrillary degeneration in Alzheimer's disease. These results suggest that erasin may be involved in ERAD and in Alzheimer's disease.