Miracle-dz/UniFAR-FTUs huggingface dataset:
Critical Role for Gi/o-Protein Activity in the Dorsal Striatum in the Reduction of Voluntary Alcohol Intake in C57Bl/6 Mice

The transition from non-dependent alcohol use to alcohol dependence involves increased activity of the dorsal striatum. Interestingly, the dorsal striatum expresses a large number of inhibitory G-protein-coupled receptors (GPCRs), which when activated may inhibit alcohol-induced increased activity and can decrease alcohol consumption. Here, we explore the hypothesis that dorsal striatal Gi/o-protein activation is sufficient to reduce voluntary alcohol intake. Using a voluntary, limited-access, two-bottle choice, drink-in-the-dark model of alcohol (10%) consumption, we validated the importance of Gi/o signaling in this region by locally expressing neuron-specific, adeno-associated-virus encoded Gi/o-coupled muscarinic M4 designer receptors exclusively activated by designer drugs (DREADD) in the dorsal striatum and observed a decrease in alcohol intake upon DREADD activation. We validated our findings by activating Gi/o-coupled delta-opioid receptors (DORs), which are natively expressed in the dorsal striatum, using either a G-protein biased agonist or a β-arrestin-biased agonist. Local infusion of TAN-67, an in vitro-determined Gi/o-protein biased DOR agonist, decreased voluntary alcohol intake in wild-type and β-arrestin-2 knockout (KO) mice. SNC80, a β-arrestin-2 biased DOR agonist, increased alcohol intake in wild-type mice; however, SNC80 decreased alcohol intake in β-arrestin-2 KO mice, thus resulting in a behavioral outcome generally observed for Gi/o-biased agonists and suggesting that β-arrestin recruitment is required for SNC80-increased alcohol intake. Overall, these results suggest that activation Gi/o-coupled GPCRs expressed in the dorsal striatum, such as the DOR, by G-protein biased agonists may be a potential strategy to decrease voluntary alcohol consumption and β-arrestin recruitment is to be avoided.
Deletion of the p85alpha regulatory subunit of phosphoinositide 3-kinase in cone photoreceptor cells results in cone photoreceptor degeneration.

PURPOSE Downregulation of the retinal insulin/mTOR pathway in mouse models of retinitis pigmentosa is linked to cone cell death, which can be delayed by systemic administration of insulin. A classic survival kinase linking extracellular trophic/growth factors with intracellular antiapoptotic pathways is phosphoinositide 3-kinase (PI3K), which the authors have shown to protect rod photoreceptors from stress-induced cell death. The role of PI3K in cones was studied by conditional deletion of its p85α regulatory subunit. METHODS Mice expressing Cre recombinase in cones were bred to mice with a floxed pi3k gene encoding the p85α regulatory subunit of the PI3K and were back-crossed to ultimately generate offspring with cone-specific p85α knockout (cKO). Cre expression and cone-specific localization were confirmed by Western blot analysis and immunohistochemistry (IHC), respectively. Cone structural integrity was determined by IHC using peanut agglutinin and an M-opsin-specific antibody. Electroretinography (ERG) was used to assess rod and cone photoreceptor function. Retinal structure was examined by light and electron microscopy. RESULTS An age-related cone degeneration was found in cKO mice, evidenced by a reduction in photopic ERG amplitudes and loss of cone cells. By 12 months of age, approximately 78% of cones had died, and progressive disorganization of synaptic ultrastructure was noted in surviving cone terminals in cKO retinas. Rod viability was unaffected in p85α cKO mice. CONCLUSIONS The present study suggests that PI3K signaling pathway is essential for cone survival in the mouse retina.
Simplified Footprint-Free Cas9/CRISPR Editing of Cardiac-Associated Genes in Human Pluripotent Stem Cells

Modeling disease with human pluripotent stem cells (hPSCs) is hindered because the impact on cell phenotype from genetic variability between individuals can be greater than from the pathogenic mutation. While “footprint-free” Cas9/CRISPR editing solves this issue, existing approaches are inefficient or lengthy. In this study, a simplified PiggyBac strategy shortened hPSC editing by 2 weeks and required one round of clonal expansion and genotyping rather than two, with similar efficiencies to the longer conventional process. Success was shown across four cardiac-associated loci (ADRB2, GRK5, RYR2, and ACTC1) by genomic cleavage and editing efficiencies of 8%–93% and 8%–67%, respectively, including mono- and/or biallelic events. Pluripotency was retained, as was differentiation into high-purity cardiomyocytes (CMs; 88%–99%). Using the GRK5 isogenic lines as an exemplar, chronic stimulation with the β-adrenoceptor agonist, isoprenaline, reduced beat rate in hPSC-CMs expressing GRK5-Q41 but not GRK5-L41; this was reversed by the β-blocker, propranolol. This shortened, footprint-free approach will be useful for mechanistic studies.
Phonatory Dysfunction as a Preclinical Symptom of Huntington Disease

Purpose Although dysphonia has been shown to be a common sign of Huntington disease (HD), the extent of phonatory dysfunction in gene positive premanifest HD individuals remains unknown. The aim of the current study was to explore the possible occurrence of phonatory abnormalities in prodromal HD. Method Sustained vowel phonations were acquired from 28 premanifest HD individuals and 28 healthy controls of comparable age. Data were analysed acoustically for measures of several phonatory dimensions including airflow insufficiency, aperiodicity, irregular vibration of vocal folds, signal perturbations, increased noise, vocal tremor and articulation deficiency. A predictive model was built to find the best combination of acoustic features and estimate sensitivity/specificity for differentiation between premanifest HD subjects and controls. The extent of voice deficits according to a specific phonatory dimension was determined using statistical decision making theory. The results were correlated to global motor function, cognitive score, disease burden score and estimated years to disease onset. Results Measures of aperiodicity and increased noise were able to significantly differentiate between premanifest HD individuals and controls (p<0.01). The combination of these aspects of dysphonia led to a sensitivity of 91.5% and specificity of 79.2% to correctly distinguish speakers with premanifest HD from healthy individuals. Some form of disrupted phonatory function was revealed in 68% of our premanifest HD subjects, where 18% had one affected phonatory dimension and 50% showed impairment of two or more dimensions. A relationship between pitch control and cognitive score was also observed (r = −0.50, p = 0.007). Conclusions Phonatory abnormalities are detectable even the in premotor stages of HD. Speech investigation may have the potential to provide functional biomarkers of HD and could be included in future clinical trials and therapeutic interventions.
Intraprocedural dataflow analysis for software product lines

Software product lines (SPLs) are commonly developed using annotative approaches such as conditional compilation that come with an inherent risk of constructing erroneous products. For this reason, it is essential to be able to analyze SPLs. However, as dataflow analysis techniques are not able to deal with SPLs, developers must generate and analyze all valid methods individually, which is expensive for non-trivial SPLs. In this paper, we demonstrate how to take any standard intraprocedural dataflow analysis and automatically turn it into a feature-sensitive dataflow analysis in three different ways. All are capable of analyzing all valid methods of an SPL without having to generate all of them explicitly. We have implemented all analyses as extensions of SOOT's intraprocedural dataflow analysis framework and experimentally evaluated their performance and memory characteristics on four qualitatively different SPLs. The results indicate that the feature-sensitive analyses are on average 5.6 times faster than the brute force approach on our SPLs, and that they have different time and space tradeoffs.
Comparing Feedback Types in Multimedia Learning of Speech by Young Children With Common Speech Sound Disorders: Research Protocol for a Pretest Posttest Independent Measures Control Trial

Children with speech sound disorders benefit from feedback about the accuracy of sounds they make. Home practice can reinforce feedback received from speech pathologists. Games in mobile device applications could encourage home practice, but those currently available are of limited value because they are unlikely to elaborate “Correct”/”Incorrect” feedback with information that can assist in improving the accuracy of the sound. This protocol proposes a “Wizard of Oz” experiment that aims to provide evidence for the provision of effective multimedia feedback for speech sound development. Children with two common speech sound disorders will play a game on a mobile device and make speech sounds when prompted by the game. A human “Wizard” will provide feedback on the accuracy of the sound but the children will perceive the feedback as coming from the game. Groups of 30 young children will be randomly allocated to one of five conditions: four types of feedback and a control which does not play the game. The results of this experiment will inform not only speech sound therapy, but also other types of language learning, both in general, and in multimedia applications. This experiment is a cost-effective precursor to the development of a mobile application that employs pedagogically and clinically sound processes for speech development in young children.
Hyaluronic Acid Enhances the Mechanical Properties of Tissue-Engineered Cartilage Constructs

There is a need for materials that are well suited for cartilage tissue engineering. Hydrogels have emerged as promising biomaterials for cartilage repair, since, like cartilage, they have high water content, and they allow cells to be encapsulated within the material in a genuinely three-dimensional microenvironment. In this study, we investigated the mechanical properties of tissue-engineered cartilage constructs using in vitro culture models incorporating human chondrocytes from osteoarthritis patients. We evaluated hydrogels formed from mixtures of photocrosslinkable gelatin-methacrylamide (Gel-MA) and varying concentrations (0–2%) of hyaluronic acid methacrylate (HA-MA). Initially, only small differences in the stiffness of each hydrogel existed. After 4 weeks of culture, and to a greater extent 8 weeks of culture, HA-MA had striking and concentration dependent impact on the changes in mechanical properties. For example, the initial compressive moduli of cell-laden constructs with 0 and 1% HA-MA were 29 and 41 kPa, respectively. After 8 weeks of culture, the moduli of these constructs had increased to 66 and 147 kPa respectively, representing a net improvement of 69 kPa for gels with 1% HA-MA. Similarly the equilibrium modulus, dynamic modulus, failure strength and failure strain were all improved in constructs containing HA-MA. Differences in mechanical properties did not correlate with glycosaminoglycan content, which did not vary greatly between groups, yet there were clear differences in aggrecan intensity and distribution as assessed using immunostaining. Based on the functional development with time in culture using human chondrocytes, mixtures of Gel-MA and HA-MA are promising candidates for cartilage tissue-engineering applications.
How Dark Are Radial Breathing Modes in Plasmonic Nanodisks?

Due to a vanishing dipole moment, radial breathing modes in small flat plasmonic nanoparticles do not couple to light and have to be probed with a near-field source, as in electron energy loss spectroscopy (EELS). With increasing particle size, retardation gives rise to light coupling, enabling probing breathing modes optically or by cathodoluminescence (CL). Here, we investigate single silver nanodisks with diameters of 150–500 nm by EELS and CL in an electron microscope and quantify the EELS/CL ratio, which corresponds to the ratio of full to radiative damping of the breathing mode. For the investigated diameter range, we find the CL signal to increase by about 1 order of magnitude, in agreement with numerical simulations. Due to reciprocity, our findings corroborate former optical experiments and enable a quantitative understanding of the light coupling of dark plasmonic modes.
Adsorption Behavior and Mechanism for the Uptake of Fluoride Ions by Reed Residues

The adsorption behavior and mechanism for the uptake of fluoride ions by untreated and desugared reed residues (roots, stems and leaves) were studied through adsorption experiments, elemental analysis, infrared spectroscopy and surface area analysis. The results showed that the adsorption capacity of untreated and desugared reeds followed the order: desugared roots 2136 mg/kg > desugared leaves 1825 mg/kg > desugared stems 1551 mg/kg > untreated roots 191 mg/kg > untreated stems 175 mg/kg > untreated leaves 150 mg/kg, so adsorption capacity of desugared reeds was larger than that of the untreated reeds. The adsorption kinetic of fluoride ions followed a pseudo-first-order model. A Langmuir model could be used to fit the isothermal adsorption process which was a spontaneous endothermic reaction involving mainly physical adsorption. The ΔG for the uptake of fluoride by the desugared reeds was more negative, so the degree of spontaneity was higher than for the use of the untreated reeds. After samples were desugared, the specific surface area and aromaticity of the reed increased, while the polarity and hydrophilicity decreased, which explained the adsorption amount of desugared reed was higher than that of the untreated. This study enriches techniques and methods of removing fluoride ions from water.
Use of factorial experimental approach and effect size on the CBR testing results for the usable dosages of wastewater sludge ash with coarse-grained material

There is an inadequate attempt to make a decision on the accuracy and reliability of the effectively usable dosage rates of sewage sludge ash (SSA) for replacement and improvement of coarse-grained soil. This study introduces an investigation on the effectively usable dosages of SSA for subbase construction by using factorial experimental approach and effect size estimation. California bearing ratio (CBR) tests have been carried out to measure the parameters of CBR value, energy absorption capacity (Ed) and ultimate bearing capacity (qu) of the soil + SSA mixtures for which proportions were 0, 5, 10, 15, 20, 30, 40, 50 and 60% by dry weight of the mixture. The effectively usable dosages of SSA for both improvement and substitute in highway construction, based on the foregoing parameters, have been assessed essentially using multiple comparison tests and effect size parameters (omega-squared, eta-squared and Cohen’s d). The results of statistical analysis demonstrate that while there is an insignificantly variation (increase or decrease) (p > .05 and Cohen’s d ≤ .41) at the dosage rates of 5 and 15% for CBR, 15% for Ed and 5, 20, 30 and 40% for qu, there is a significant decrease (p ≤ .05 and Cohen’s d > 2.7) in the values of CBR, Ed and qu due to the addition of SSA at the dosages of 50, 50 and 60%, respectively. Accordingly, it is suggested that SSA be introduced into sandy soil for improvement or replacement at the dosage rates less than 50% in the stabilisation applications. From the statistical analysis performed here, it is also found that multiple comparison tests and effect size estimates compare well in the decision-making.
Full genome analysis of swine genotype 3 hepatitis E virus isolated from eastern China

摘要目的扩增浙江地区基因3 型戊型肝炎病毒全基因组序 列,分析其分子特征及与国内外3 型戊型肝炎病 毒进行比较。 创新点首次分析报道浙江地区基因3 型猪戊型肝炎病毒 全序列。 方法利用套式PCR 和末端快速扩增法对分离自浙江地 区的戊型肝炎病毒进行分段扩增,经克隆测序后 拼接全基因组。 进一步利用生物信息学方法对基 因组结构、开放阅读框及其基因型等进行分析, 并与国内外戊型肝炎毒株进行比较分析。 结论浙江株戊型肝炎病毒(ZhJ-PJ050-3)基因组由7223 个核苷酸组成,其中3'非编码区含有23 个碱基的 poly(A)尾。 全基因组包含ORF1、ORF2 和ORF3 三个主要基因,长度分别为5109、1983 和342 bp。 进化分析显示,ZhJ-PJ050-3 为基因3 型,与国内 唯一报道的上海株3 型毒株以及多数日本毒株共 属3b 亚型。 与国内外戊型肝炎序列比对发现, ZhJ-PJ050-3 基因组共有24 个特有的点突变,且 在ORF1 中含有一个亮氨酸缺失。 这些分子特征 将为下一步的研究提供方向。
Efficient and Secure Multi-Keyword Search on Encrypted Cloud Data

As Cloud Computing becomes prevalent, sensitive information are being increasingly centralized into the cloud. For the protection of data privacy, sensitive data has to be encrypted before outsourcing, which makes effective data utilization a very challenging task. Although traditional searchable encryption schemes allow users to securely search over encrypted data through keywords, these techniques support only boolean search, without capturing any relevance of data files. This approach suffers from two main drawbacks when directly applied in the context of Cloud Computing. On the one hand, users, who do not necessarily have pre-knowledge of the encrypted cloud data, have to post process every retrieved file in order to find ones most matching their interest; On the other hand, invariably retrieving all files containing the queried keyword further incurs unnecessary network traffic, which is absolutely undesirable in today’s pay-as-you-use cloud paradigm. In this paper, for the first time we define and solve the problem of effective yet secure ranked keyword search over encrypted cloud data. Ranked search greatly enhances system usability by returning the matching files in a ranked order regarding to certain relevance criteria (e.g., keyword frequency), thus making one step closer towards practical deployment of privacy-preserving data hosting services in Cloud Computing. In this paper, for the first time, we define and solve the challenging problem of privacy-preserving multi-keyword ranked search over encrypted cloud data (MRSE), and establish a set of strict privacy requirements for such a secure cloud data utilization system to become a reality. Among various multi-keyword semantics, we choose the efficient principle of “coordinate matching”, i.e., as many matches as possible, to capture the similarity between search query and data documents, and further use “inner product similarity” to quantitatively formalize such principle for similarity measurement. We first propose a basic MRSE scheme using secure inner product computation, and then significantly improve it to meet different privacy requirements in two levels of threat models. Thorough analysis investigating privacy and efficiency guarantees of proposed schemes is given, and experiments on the real-world dataset further show proposed schemes indeed introduce low overhead on computation and communication.
Structure of Psb29/Thf1 and its association with the FtsH protease complex involved in photosystem II repair in cyanobacteria

One strategy for enhancing photosynthesis in crop plants is to improve their ability to repair photosystem II (PSII) in response to irreversible damage by light. Despite the pivotal role of thylakoid-embedded FtsH protease complexes in the selective degradation of PSII subunits during repair, little is known about the factors involved in regulating FtsH expression. Here we show using the cyanobacterium Synechocystis sp. PCC 6803 that the Psb29 subunit, originally identified as a minor component of His-tagged PSII preparations, physically interacts with FtsH complexes in vivo and is required for normal accumulation of the FtsH2/FtsH3 hetero-oligomeric complex involved in PSII repair. We show using X-ray crystallography that Psb29 from Thermosynechococcus elongatus has a unique fold consisting of a helical bundle and an extended C-terminal helix and contains a highly conserved region that might be involved in binding to FtsH. A similar interaction is likely to occur in Arabidopsis chloroplasts between the Psb29 homologue, termed THF1, and the FTSH2/FTSH5 complex. The direct involvement of Psb29/THF1 in FtsH accumulation helps explain why THF1 is a target during the hypersensitive response in plants induced by pathogen infection. Downregulating FtsH function and the PSII repair cycle via THF1 would contribute to the production of reactive oxygen species, the loss of chloroplast function and cell death. This article is part of the themed issue ‘Enhancing photosynthesis in crop plants: targets for improvement’.
The Influence of Milling and Spark Plasma Sintering on the Microstructure and Properties of the Al7075 Alloy

The compact samples of an Al7075 alloy were prepared by a combination of gas atomization, high energy milling, and spark plasma sintering. The predominantly cellular morphology observed in gas atomized powder particles was completely changed by mechanical milling. The continuous-like intermetallic phases present along intercellular boundaries were destroyed; nevertheless, a small amount of Mg(Zn,Cu,Al)2 phase was observed also in the milled powder. Milling resulted in a severe plastic deformation of the material and led to a reduction of grain size from several µm into the nanocrystalline region. The combination of these microstructural characteristics resulted in abnormally high microhardness values exceeding 300 HV. Consolidation through spark plasma sintering (SPS) resulted in bulk samples with negligible porosity. The heat exposition during SPS led to precipitation of intermetallic phases from the non-equilibrium microstructure of both gas atomized and milled powders. SPS of the milled powder resulted in a recrystallization of the severely deformed structure. An ultra-fine grained structure (grain size close to 500 nm) with grains divided primarily by high-angle boundaries was formed. A simultaneous release of stored deformation energy and an increase in the grain size caused a drop of microhardness to values close to 150 HV. This value was retained even after annealing at 425 °C.
Wikidatians are Born: Paths to Full Participation in a Collaborative Structured Knowledge Base

We investigated how participation evolves in Wiki- data as its editors become established members of the community. Originally conceived to support Wikipedia, Wikidata is a collaborative structured knowledge base, created and maintained by a large number of volunteers, whose data can be freely reused in other contexts. Just like in any other online social environment, understanding its contributors’ pathways to full participation helps Wikidata improve user experience and retention. We analysed how participation changes in time under the frameworks of legitimate peripheral participation and activity theory. We found out that as they engage more with the project, “Wikidatians” acquire a higher sense of responsibility for their work, interact more with the community, take on more advanced tasks, and use a wider range of tools. Previous activity in Wikipedia has varied effects. As Wikidata is a young community, future work should focus on volunteers with little or no expe- rience in similar projects and specify means to improve critical aspects such as engagement and data quality.