Miracle-dz/UniFAR-FTUs huggingface dataset:
Enhancement of Spontaneous Activity by HCN4 Overexpression in Mouse Embryonic Stem Cell-Derived Cardiomyocytes - A Possible Biological Pacemaker

Background Establishment of a biological pacemaker is expected to solve the persisting problems of a mechanical pacemaker including the problems of battery life and electromagnetic interference. Enhancement of the funny current (I f) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and attenuation of the inward rectifier K+ current (I K1) flowing through inward rectifier potassium (Kir) channels are essential for generation of a biological pacemaker. Therefore, we generated HCN4-overexpressing mouse embryonic stem cells (mESCs) and induced cardiomyocytes that originally show poor I K1 currents, and we investigated whether the HCN4-overexpressing mESC-derived cardiomyocytes (mESC-CMs) function as a biological pacemaker in vitro. Methods and Results The rabbit Hcn4 gene was transfected into mESCs, and stable clones were selected. mESC-CMs were generated via embryoid bodies and purified under serum/glucose-free and lactate-supplemented conditions. Approximately 90% of the purified cells were troponin I-positive by immunostaining. In mESC-CMs, expression level of the Kcnj2 gene encoding Kir2.1, which is essential for generation of I K1 currents that are responsible for stabilizing the resting membrane potential, was lower than that in an adult mouse ventricle. HCN4-overexpressing mESC-CMs expressed about a 3-times higher level of the Hcn4 gene than did non-overexpressing mESC-CMs. Expression of the Cacna1h gene, which encodes T-type calcium channel and generates diastolic depolarization in the sinoatrial node, was also confirmed. Additionally, genes required for impulse conduction including Connexin40, Connexin43, and Connexin45 genes, which encode connexins forming gap junctions, and the Scn5a gene, which encodes sodium channels, are expressed in the cells. HCN4-overexpressing mESC-CMs showed significantly larger I f currents and more rapid spontaneous beating than did non-overexpressing mESC-CMs. The beating rate of HCN4-overexpressing mESC-CMs responded to ivabradine, an I f inhibitor, and to isoproterenol, a beta-adrenergic receptor agonist. Co-culture of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with aggregates composed of mESC-CMs resulted in synchronized contraction of the cells. The beating rate of hiPSC-CMs co-cultured with aggregates of HCN4-overexpressing mESC-CMs was significantly higher than that of non-treated hiPSC-CMs and that of hiPSC-CMs co-cultured with aggregates of non-overexpressing mESC-CMs. Conclusions We generated HCN4-overexpresssing mESC-CMs expressing genes required for impulse conduction, showing rapid spontaneous beating, responding to an I f inhibitor and beta-adrenergic receptor agonist, and having pacing ability in an in vitro co-culture system with other excitable cells. The results indicated that these cells could be applied to a biological pacemaker.
Saudi children’s thoughts on inclusive education

ABSTRACT Saudi Arabia has followed the global trend towards inclusive education; however, few researchers have examined the lived reality of inclusion in Saudi schools. In this study, we interviewed 31 girls and 34 boys in grades 5 and 6 who attended an inclusive school in Saudi. The overarching research question was, ‘How do Saudi children perceive social exclusion or inclusion among their classmates with learning difficulties? ’ We followed a phenomenological approach, reporting descriptions in the participants’ own words. We identified two overarching groupings of responses that related to beliefs and behaviours. Students in our study voiced a variety of beliefs about why children with learning difficulties might be socially accepted or not accepted. More boys than girls believed that students with learning difficulties were socially accepted. Students gave examples of inclusionary behaviour they had witnessed or been involved in, and these examples emerged more strongly than examples of exclusionary behaviour. Inclusionary behaviours included friendship, helping with schoolwork, and including in play.
The molecular basis of quantitative genetic variation in central and secondary metabolism in Arabidopsis.

To find the genes controlling quantitative variation, we need model systems where functional information on physiology, development, and gene regulation can guide evolutionary inferences. We mapped quantitative trait loci (QTLs) influencing quantitative levels of enzyme activity in primary and secondary metabolism in Arabidopsis. All 10 enzymes showed highly significant quantitative genetic variation. Strong positive genetic correlations were found among activity levels of 5 glycolytic enzymes, PGI, PGM, GPD, FBP, and G6P, suggesting that enzymes with closely related metabolic functions are coregulated. Significant QTLs were found influencing activity of most enzymes. Some enzyme activity QTLs mapped very close to known enzyme-encoding loci (e.g., hexokinase, PGI, and PGM). A hexokinase QTL is attributable to cis-acting regulatory variation at the AtHXK1 locus or a closely linked regulatory locus, rather than polypeptide sequence differences. We also found a QTL on chromosome IV that may be a joint regulator of GPD, PGI, and G6P activity. In addition, a QTL affecting PGM activity maps within 700 kb of the PGM-encoding locus. This QTL is predicted to alter starch biosynthesis by 3.4%, corresponding with theoretical models, suggesting that QTLs reflect pleiotropic effects of mutant alleles.
Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

Factors providing trophic support to diverse enteric neuron subtypes remain poorly understood. We tested the hypothesis that hepatocyte growth factor (HGF) and the HGF receptor MET might support some types of enteric neurons. HGF and MET are expressed in fetal and adult enteric nervous system. In vitro, HGF increased enteric neuron differentiation and neurite length, but only if vanishingly small amounts (1 pg/ml) of glial cell line-derived neurotrophic factor were included in culture media. HGF effects were blocked by phosphatidylinositol-3 kinase inhibitor and by MET-blocking antibody. Both of these inhibitors and MEK inhibition reduced neurite length. In adult mice, MET was restricted to a subset of calcitonin gene-related peptide-immunoreactive (IR) myenteric plexus neurons thought to be intrinsic primary afferent neurons (IPANs). Conditional MET kinase domain inactivation (Metfl/fl; Wnt1Cre+) caused a dramatic loss of myenteric plexus MET-IR neurites and 1–1′-dioctodecyl-3,3,3′,3′-tetramethylindocarbocyamine perchlorate (DiI) labeling suggested reduced MET-IR neurite length. In vitro, Metfl/fl; Wnt1Cre+ mouse bowel had markedly reduced peristalsis in response to mucosal deformation, but normal response to radial muscle stretch. However, whole-bowel transit, small-bowel transit, and colonic-bead expulsion were normal in Metfl/fl; Wnt1Cre+ mice. Finally, Metfl/fl; Wnt1Cre+ mice had more bowel injury and reduced epithelial cell proliferation compared with WT animals after dextran sodium sulfate treatment. These results suggest that HGF/MET signaling is important for development and function of a subset IPANs and that these cells regulate intestinal motility and epithelial cell proliferation in response to bowel injury. SIGNIFICANCE STATEMENT The enteric nervous system has many neuronal subtypes that coordinate and control intestinal activity. Trophic factors that support these neuron types and enhance neurite growth after fetal development are not well understood. We show that a subset of adult calcitonin gene-related peptide (CGRP)-expressing myenteric neurons produce MET, the receptor for hepatocyte growth factor, and that loss of MET activity affects peristalsis in response to mucosal stroking, reduces MET-immunoreactive neurites, and increases susceptibility to dextran sodium sulfate-induced bowel injury. These observations may be relevant for understanding and treating intestinal motility disorders and also suggest that enhancing the activity of MET-expressing CGRP neurons might be a useful strategy to reduce bowel inflammation.
Presuppositions as anaphors : towards a full understanding of partial matches

Van der Sandt's theory of presuppositions-as-anaphors is widely considered to be the empirically most adequate theory of presupposition projection on the market. One of the main differences between Van der Sandt's approach and its main competitor, the `contextual satisfaction ' approach, lies in the treatment of the so-called partial match phenomenon. In this paper, we take a closer look at partial matches. We show that the distinction between partial and full matches should be a central element of any theory of presupposition projection. However, we also argue that Van der Sandt's own formal theory, as it stands, does not offer an adequate treatment of partial matches. We then propose a number of modifications of his formal theory and apply the modified algorithm to definite (and other) NPs. The resulting modified version of the presuppositions-as-anaphors theory is argued to be more general, formally more precise, and empirically more adequate than its predecessor.
A pilot study: a computer game-based assessment of visual perspective taking of four children with autism with high support needs

High support need and minimally verbal individuals with autism have received less attention in research in comparison to so-called higher functioning individuals with autism. As computers motivate individuals with autism, a game with a positive user experience was altered into a level 1 perspective-taking task in which advancement was contingent on eye contact. A case-controls design was used to see whether participants had impaired perspective taking and would they benefit from additional cues. Four high support need and minimally verbal children with autism played the game in their school environment. It was found that only one child with autism made more errors than controls using the eye cues. No child with autism benefitted from the additional cues, whereas the control group did. The results suggest that positive contexts may reveal more about individuals and their skills, and that individual level analysis can provide insights about autism and about the individuals with autism.
Self-Regulation Programs for At-Risk Youth: Are Teachers Affected Too?

ABSTRACT This study examines changes experienced by teachers of youth at socioeconomic risk during and after conducting self-regulation programs with their students. Participants' self-reports were classified into 3 change models. Teachers in the 1st model reported changes in their interaction with the school, their role with the students, and their own self-regulation. Those in the 2nd model experienced a partial process centered mainly on their handling of the classroom and on changes in themselves. In the 3rd model teachers reported virtually no change as a result of implementing the program. The implications for teachers of at-risk youth are examined.
Dietary phyto-oestrogens and the risk of ovarian and endometrial cancers: findings from two Australian case–control studies

Phyto-oestrogens have been suggested to have a protective effect on hormone-sensitive cancers. However, few studies have investigated the association between dietary phyto-oestrogens and gynaecological cancers. In the present study, we analysed data from two population-based case–control studies of ovarian (1366 cases and 1414 controls) and endometrial (1288 cases and 1435 controls) cancers. Dietary intake information was obtained using a 135-item FFQ, and phyto-oestrogen intake was estimated using published food composition databases. Unconditional logistic regression was used to estimate adjusted OR and 95 % CI. In multivariable analyses, there was a suggestive pattern of inverse associations between increasing intakes of total phyto-oestrogens, isoflavones and enterolignans and the risk of ovarian cancer. However, the results only reached statistical significance for the lignan compounds matairesinol and lariciresinol, where the OR for the highest v. the lowest intake category was 0·72 (95 % CI 0·54, 0·96; P for trend = 0·02) for matairesinol and 0·72 (95 % CI 0·55, 0·96; P for trend = 0·03) for lariciresinol. When the risk of ovarian cancer was assessed by subtype, there was an indication that increasing intakes of phyto-oestrogens may be associated with a decreased risk of mucinous (cases n 158) ovarian tumours (OR for the highest v. the lowest intake category: 0·47 (95 % CI 0·24, 0·93); P for trend = 0·04). However, there were no significant associations with other histological subtypes. In contrast, dietary phyto-oestrogens (total or any subclass) were unrelated to the risk of endometrial cancer cases overall or by subtype.
MDL-1, a growth- and tumor-suppressor, slows aging and prevents germline hyperplasia and hypertrophy in C. elegans

In C. elegans, increased lifespan in daf-2 insulin/IGF-1 receptor mutants is accompanied by up-regulation of the MDL-1 Mad basic helix-loop-helix leucine zipper transcription factor. Here we describe the role of mdl-1 in C. elegans germline proliferation and aging. The deletion allele mdl-1(tm311) shortened lifespan, and did so significantly more so in long-lived daf-2 mutants implying that mdl-1(+) contributes to effects of daf-2 on lifespan. mdl-1 mutant hermaphrodites also lay increased numbers of unfertilized oocytes. During aging, unfertilized oocytes in the uterus develop into tumors, whose development was accelerated by mdl-1(tm311). Opposite phenotypes were seen in daf-2 mutants, i.e. mdl-1 and daf-2 mutant germlines are hyperplastic and hypoplastic, respectively. Thus, MDL-1, like its mammalian orthologs, is an inhibitor of cell proliferation and growth that slows progression of an age-related pathology in C. elegans (uterine tumors). In addition, intestine-limited rescue of mdl-1 increased lifespan but not to wild type levels. Thus, mdl-1 likely acts both in the intestine and the germline to influence age-related mortality.
Prevalence and Molecular Identification of Nematode and Dipteran Parasites in an Australian Alpine Grasshopper (Kosciuscola tristis)

In alpine Australia, Orthoptera are abundant, dominant herbivores, important prey species, and hosts for parasites and parasitoids. Despite the central role of orthopterans in alpine ecosystems, the impact of parasites on orthopteran populations is under-explored. In this study we describe the relationship between parasite prevalence and host sex, body size and year of collection. We accessed an existing, preserved collection of 640 Kosciuscola tristis collected from across its range between 2007 and 2011. Upon dissection we collected juvenile parasites and used molecular tools to identify them to three families (Nematoda; Mermithidae, and Arthropoda: Diptera: Tachinidae and Sarcophagidae). The prevalence of nematodes ranged from 3.5% to 25.0% and dipterans from 2.4% to 20.0%. Contrary to predictions, we found no associations between parasite prevalence and grasshopper sex or size. Although there was an association between prevalence of both nematodes and dipterans with year of collection, this is likely driven by a small sample size in the first year. Our results provide a foundation for future studies into parasite prevalence within the alpine environment and the abiotic factors that might influence these associations.
Comment on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity"

Herbert et al. (Reports, 14 April 2006, p. 279) found that the rs7566605 genetic variant, located upstream of the INSIG2 gene, was consistently associated with increased body mass index. However, we found no evidence of association between rs7566605 and body mass index in two large ethnically homogeneous population-based cohorts. On the contrary, an opposite tendency was observed.
Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study

Published guidelines recommend spirometry to accurately diagnose chronic obstructive pulmonary disease (COPD). However, even spirometry-based COPD prevalence estimates can vary widely. We compared properties of several spirometry-based COPD definitions using data from the international Burden of Obstructive Lung Disease (BOLD)study. 14 sites recruited population-based samples of adults aged ≥40 yrs. Procedures included standardised questionnaires and post-bronchodilator spirometry. 10,001 individuals provided usable data. Use of the lower limit of normal (LLN) forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio reduced the age-related increases in COPD prevalence that are seen among healthy never-smokers when using the fixed ratio criterion (FEV1/FVC <0.7) recommended by the Global Initiative for Chronic Obstructive Lung Disease. The added requirement of an FEV1 either <80% predicted or below the LLN further reduced age-related increases and also led to the least site-to-site variability in prevalence estimates after adjusting for potential confounders. Use of the FEV1/FEV6 ratio in place of the FEV1/FVC yielded similar prevalence estimates. Use of the FEV1/FVC<LLN criterion instead of the FEV1/FVC <0.7 should minimise known age biases and better reflect clinically significant irreversible airflow limitation. Our study also supports the use of the FEV1/FEV6 as a practical substitute for the FEV1/FVC.
Concentrations of amino acids and urea in the plasma of the preruminant calf and estimation of the amino acid requirements

1. A study was made of factors affecting the plasma concentrations of free amino acids (PAA) and urea (PU) in calves receiving liquid diets 2. When calves were given whole milk (approximately 0·05 kg/kg live weight) at 10·00 and 17·00 hours there were marked decreases in PAA and slight decreases in PU for about 3–4 h after the morning feed. Both PAA and PU thereafter increased slightly and then remained constant for the next 10 h. In subsequent comparative experiments samples were taken 3 h after the morning feed. The variation in plasma methionine, isoleucine, leucine, phenylalanine, tyrosine and total PAA was apparently greater between than within animals 3. In calves transferred from a diet of whole milk to one consisting of diluted whole milk supplemented with appropriate nutrients, including amino acids, but deficient in methionine, PU increased markedly and plasma methionine decreased 4. Two calves (50–60 kg live weight) given the latter diet supplemented to give an intake of more than 4·5 g L-methionine/d together with 0·3 g cystine/d showed marked increases in plasma methionine. This was considered to correspond with the point at which methionine requirements were met and that under these conditions the methionine requirement for these calves (mean value ± SE) was 4·5 ± 0·2 g/d. In the same two calves PU decreased markedly with increasing levels of methionine supplementation up to 3·9 g/d and the estimated methionine requirement (mean value ± SE) was 3·9 ± 0·4 g/d.
Management of Partially Safe Buffers

Safe RAM is RAM which has been made as reliable as a disk. We consider the problem of buffer management in partially safe buffers, i.e., buffers which contain both safe RAM and volatile RAM. Buffer management techniques for partially safe buffers explicitly consider the safety of memory in deciding which data to place in the buffer, where to place it, and when to copy updates back to the disk. We present techniques for managing such buffers and study their performance using trace-driven simulations. >
Are Chinese Growth and Inflation Too Smooth? Evidence from Engel Curves

China has experienced remarkably stable growth and inflation in recent years according to official statistics. We construct alternative estimates using detailed information on Chinese household purchasing patterns. As households become richer, a smaller fraction of total expenditures are spent on necessities such as grain and a larger fraction on luxuries such as eating out. We use systematic discrepancies between cross-sectional and time-series Engel curves to construct alternative estimates of Chinese growth and inflation. Our estimates suggest that official statistics present a smoothed version of reality. Official inflation rose in the 2000's, but our estimates indicate that true inflation was still higher and consumption growth was overstated over this period. In contrast, inflation was overstated and growth understated during the low-inflation 1990's. Similar patterns emerge from the data whether we base our estimates on major categories such as food or clothing as a fraction of total expenditures or subcategories such as grain as a fraction of food expenditures or garments as a fraction of clothing expenditures.
The Game Genre Map: A Revised Game Classification

The existing common video game genres lack clarity as well as consistency and thus cannot serve as a solid reference to inform the research on digital educational games (DEG), which are increasingly used as learning tools. To address this basic issue of game classification, we have developed a web-based survey to collect data on how people play and perceive video games that they know well. The survey is grounded in our Game Elements-Attributes Model (GEAM). 321 valid responses were analysed using established hierarchical clustering methods and a novel mapping technique that computes the degree of relevance of individual game attributes to game types and visualises them with hues of grey. The game genre map so obtained can improve the existing game classification.
A longitudinal study of antimicrobial resistant faecal bacteria in sediments collected from a hospital wastewater system

Objective: The objective with this study was to determine and follow antimicrobial resistance in faecal bacteria over time in hospital wastewater pipe sediment. A further aim was to determine bacterial growth rates of sensitive, intermediate and resistant intestinal enterococci in different ciprofloxacin concentrations as a measure of bacterial fitness. Methods: A system enabling the collection of settled particles over time was installed at Kalmar County Hospital. Samples were collected bi-monthly for a 14-month period. Coliform bacteria and enterococci were isolated from the sediment with standard methods and investigated for resistance to ciprofloxacin (CIP), imipenem (IMI), trimetroprim-sulfamethoxazole (TS), ampicillin (AMP) and vancomycin (VAN) by the disc diffusion method. Resistant isolates were further typed with the PhenePlateTM system. Growth assessments were performed with an automated spectrophotometer. Results: The rate of intestinal enterococci resistance was <0.6, 1.3, 1.9 and 13% to VAN, IMI, AMP and CIP respectively. Coliform resistance frequencies were 1.1, 2.2 and 2.2% to CIP, IMI and TS respectively. At two sampling occasions, significantly higher rates of ciprofloxacin resistant enterococci were found and the establishment of a resistant clone in the sewer was indicated by the PhP-analysis. Ciprofloxacin resistant intestinal enterococci had a significantly longer lag-phase time than sensitive isolates, but from 500 µg ml−1 (half MIC) resistant isolates had a competitive advantage in terms of significantly faster generation time. Discussion: Despite high concentration of antimicrobials in the sediment, resistance frequencies were generally low. This can depend on limited growth possibilities for faecal bacteria. However, the establishment of a resistant clone shows that hospital sewers can serve as a reservoir for antibiotic resistant bacteria.