Miracle-dz/UniFAR-FTUs huggingface dataset:
Presenilin-1 Mutations Reduce Cytoskeletal Association, Deregulate Neurite Growth, and Potentiate Neuronal Dystrophy and Tau Phosphorylation

Mutations in presenilin genes are linked to early onset familial Alzheimer's disease (FAD). Previous work in non-neuronal cells indicates that presenilin-1 (PS1) associates with cytoskeletal elements and that it facilitates Notch1 signaling. Because Notch1 participates in the control of neurite growth, cultured hippocampal neurons were used to investigate the cytoskeletal association of PS1 and its potential role during neuronal development. We found that PS1 associates with microtubules (MT) and microfilaments (MF) and that its cytoskeletal association increases dramatically during neuronal development. PS1 was detected associated with MT in the central region of neuronal growth cones and with MF in MF-rich areas extending into filopodia and lamellipodia. In differentiated neurons, PS1 mutations reduced the interaction of PS1 with cytoskeletal elements, diminished the nuclear translocation of the Notch1 intracellular domain (NICD), and promoted a marked increase in total neurite length. In developing neurons, PS1 overexpression increased the nuclear translocation of NICD and inhibited neurite growth, whereas PS1 mutations M146V, I143T, and deletion of exon 9 (D9) did not facilitate NICD nuclear translocation and had no effect on neurite growth. In cultures that were treated with amyloid β (Aβ), PS1 mutations significantly increased neuritic dystrophy and AD-like changes in tau such as hyperphosphorylation, release from MT, and increased tau protein levels. We conclude that PS1 participates in the regulation of neurite growth and stabilization in both developing and differentiated neurons. In the Alzheimer's brain PS1 mutations may promote neuritic dystrophy and tangle formation by interfering with Notch1 signaling and enhancing pathological changes in tau.
The experiences of diverse-gender tertiary students : structural discrimination and microaggressions

This paper documents forms of discrimination that students with diversegender identities face within the New Zealand tertiary environment, and reports on students’ suggestions for strategies to support the normalisation of gender diversity. Findings from this qualitative study are based on data collected via in-depth, semi-structured interviews with seven participants. They indicate that although participants did not generally experience discrimination through direct attacks or violence, the negative effects of gender-normativity and of administrative processes that were not suitable, as well as a lack of staff awareness about the needs of diverse-gender students, comprise discrimination through ever-present microaggressions. Findings also highlight the resilience of diverse-gender students and their ability to develop personal strategies to manage their experiences of being part of a marginalised group. Strategies that participants identified to help create authentic inclusive tertiary environments include increasing the visibility of diverse-gender identities within policies, processes and curricula, and developing educational programmes for staff on the unique needs of the diverse-gender population. This paper evidences structural discrimination that pervades most of society in relation to gender diversity, and suggests that it could be addressed fairly easily within the tertiary sector by those who manage its systems, pending education and awareness.
A Remote Sensing Method for Estimating Surface Air Temperature and Surface Vapor Pressure on a Regional Scale

This paper presents a method of estimating regional distributions of surface air temperature (Ta) and surface vapor pressure (ea), which uses remotely-sensed data and meteorological data as its inputs. The method takes into account the effects of both local driving force and horizontal advection on Ta and ea. Good correlation coefficients (R2) and root mean square error (RMSE) between the measurements of Ta/ea at weather stations and Ta/ea estimates were obtained; with R2 of 0.77, 0.82 and 0.80 and RMSE of 0.42K, 0.35K and 0.20K for Ta and with R2 of 0.85, 0.88, 0.88 and RMSE of 0.24hpa, 0.35hpa and 0.16hpa for ea, respectively, for the three-day results. This result is much better than that estimated from the inverse distance weighted method (IDW). The performance of Ta/ea estimates at Dongping Lake illustrated that the method proposed in the paper also has good accuracy for a heterogeneous surface. The absolute biases of Ta and ea estimates at Dongping Lake from the proposed method are less than 0.5Kand 0.7hpa, respectively, while the absolute biases of them from the IDW method are more than 2K and 3hpa, respectively. Sensitivity analysis suggests that the Ta estimation method presented in the paper is most sensitive to surface temperature and that the ea estimation method is most sensitive to available energy.
Rapid Translocation of Polarized MDCK Cell Monolayers by Leptospira interrogans, an Invasive but Nonintracellular Pathogen

ABSTRACT Pathogenic spirochetes of the genus Leptospira are a major cause of human zoonotic infectious disease worldwide. After gaining entry through the skin, the organism causes disease by hematogenously disseminating to multiple organs. The mechanism by which it penetrates the mammalian cell barriers to disseminate is not well understood. In this study, we used a low-passage-number isolate of Leptospira interrogans to elucidate the invasive potential of this spirochete. Quantification of bacteria by dark-field microscopy revealed that pathogenic spirochetes were able to translocate through polarized MDCK cell monolayers at a rate significantly greater than that of nonpathogenic Leptospira or a recognized invasive bacterial pathogen, Salmonella. In contrast to Salmonella, L. interrogans did not alter transepithelial electrical resistance during cell translocation. Both transmission and scanning electron microscopy revealed tight association of the extracellular spirochetes with the host cell plasma membrane, without membrane perturbations suggestive of cytoskeletal rearrangement. Spirochetes were not observed within intercellular junctions or membrane-bound compartments inside cells. They were found within the cytoplasm of only 8% of the counted cells. These results indicate that Leptospira is an invasive but not a facultative intracellular organism. We propose that the rapid translocation of mammalian cells by pathogenic Leptospira is a mechanism designed to evade killing by host cells that permits the organism to quickly reach the bloodstream and disseminate to multiple organs.
Medication adherence in resistant hypertension: An investigation of prevalence, psychological predictors and patient perspectives

Objectives. Medication non-adherence is a known behavioural contributor to poor blood pressure control that puts patients with hypertension at elevated cardiovascular risk. Studies of medication adherence for apparent treatment-resistant hypertension (aTRH) vary significantly with respect to design, methods, and setting; and as a result, have produced highly variable figures describing the prevalence of non-adherence. This review aimed to describe the prevalence and potential moderators of medication non-adherence estimates for aTRH. Methods. Systematic review and random effects meta-analysis. Results. From an initial discovery of 921 studies, we identified 24 studies that measured medication adherence for patients with uncontrolled blood pressure despite being prescribed three or more antihypertensive medications of different classes. Using a random effects model, the pooled prevalence of non-adherence was 31.2% (95% CI [20.2, 44.7], I = 99.50) with non-adherence rates ranging from 3.3–86.1%. The strongest contributor to variance in non-adherence rates was the method of adherence assessment used. Studies that
A global human rights approach to pre-service teacher education on LGBTIs

ABSTRACT Pre-service teacher education on LGBTI rights and inclusion is impacted by multiple conflicting education governance provisions carrying different risks and duties for teachers. Pre-service teacher education has an international reach – catering to both international pre-service teachers and domestic pre-service teachers destined for careers and travel abroad. This paper argues that pre-service teacher education efforts focussing solely on local education treatments of LGBTI rights may leave pre-service teachers sorely underprepared for the differing education contexts they may encounter. The article proposes that teacher educators should communicate relevant international human rights legislation provisions and education policies on LGBTIs. It provides overviews of LGBTI identities, laws and policies, and data across multiple contexts based on key informant interview data and desk-based research. It argues that some sources on LGBTIs are unreliable and informed by broader disruptive geopolitical efforts, and suggests why and how to train pre-service teachers to avoid them.
Molecular Dynamics of the Shewanella oneidensis Response to Chromate Stress*S

Temporal genomic profiling and whole-cell proteomic analyses were performed to characterize the dynamic molecular response of the metal-reducing bacterium Shewanella oneidensis MR-1 to an acute chromate shock. The complex dynamics of cellular processes demand the integration of methodologies that describe biological systems at the levels of regulation, gene and protein expression, and metabolite production. Genomic microarray analysis of the transcriptome dynamics of midexponential phase cells subjected to 1 mm potassium chromate (K2CrO4) at exposure time intervals of 5, 30, 60, and 90 min revealed 910 genes that were differentially expressed at one or more time points. Strongly induced genes included those encoding components of a TonB1 iron transport system (tonB1-exbB1-exbD1), hemin ATP-binding cassette transporters (hmuTUV), TonB-dependent receptors as well as sulfate transporters (cysP, cysW-2, and cysA-2), and enzymes involved in assimilative sulfur metabolism (cysC, cysN, cysD, cysH, cysI, and cysJ). Transcript levels for genes with annotated functions in DNA repair (lexA, recX, recA, recN, dinP, and umuD), cellular detoxification (so1756, so3585, and so3586), and two-component signal transduction systems (so2426) were also significantly up-regulated (p < 0.05) in Cr(VI)-exposed cells relative to untreated cells. By contrast, genes with functions linked to energy metabolism, particularly electron transport (e.g. so0902-03-04, mtrA, omcA, and omcB), showed dramatic temporal alterations in expression with the majority exhibiting repression. Differential proteomics based on multidimensional HPLC-MS/MS was used to complement the transcriptome data, resulting in comparable induction and repression patterns for a subset of corresponding proteins. In total, expression of 2,370 proteins were confidently verified with 624 (26%) of these annotated as hypothetical or conserved hypothetical proteins. The initial response of S. oneidensis to chromate shock appears to require a combination of different regulatory networks that involve genes with annotated functions in oxidative stress protection, detoxification, protein stress protection, iron and sulfur acquisition, and SOS-controlled DNA repair mechanisms.
‘Perceived social citizenship’: a comparative study between two different hukous

ABSTRACT In China, there are immense barriers to inclusive social citizenship because of the failure to overcome the institutional fragmentation of social security across the hukou division. The hukou system continues to be important in determining how social citizenship is granted in China; not only does it facilitate dual social citizenship, it imposes perceptions of deservingness that bolster these divisions. The aim of this paper is to build a social-citizenship-based framework, drawing upon the strengths of the capability approach, which is applicable to the complexity of the rural–urban divide in China. Referring to several data sources, the paper examines social citizenship as a subjective phenomenon. The paper highlights the social exclusion mechanisms embedded in the hukou system that might have an effect on social citizenship as a state of self-awareness.
A Comparative Approach to Teaching Malaysian School Boys Hockey Using Two Different Pedagogical Styles

Previous research has compared the two different models of TGfU and the technical model in hockey (Turner & Martinek, 1999). This study not only focused on hockey but also aimed to compare the effects of emphasizing two different teaching styles incorporated into the TGfU approach. As Metzler (2005) pointed out, separating teaching styles from instructional models is sometimes difficult, and the TGfU model can be value added by emphasizing particular teaching styles within it. The quasi-experimental study in this article examined the effectiveness of two different pedagogical styles, Style E Tactical (SET) and Style H Tactical (SHT), that combined teaching styles with the TGfU model for improving speed and accuracy in the execution of general hockey skills, declarative and procedural knowledge, ball control, decision making, and skill execution in three-on-three game play. Samples (n = 150, ±13-yearold lower secondary school boys) were divided equally into groups of highskilled boys (HSB), medium-skilled boys (MSB), and low-skilled boys (LSB). The findings indicate that both teaching styles were effective for all skill groups in improving speed and accuracy of skill execution, declarative knowledge, ball control, and decision making in three-on-three hockey games. However, based on mean score, SET is more effective in improving speed (especially for HSB and LSB) and accuracy (HSB, MSB and LSB) in executing hockey skills. SHT was very effective in improving declarative knowledge as well as ball control and decision making in three-on-three games for almost all skill groups, but further work needs to be done to validate the effectiveness of these two teaching styles.
Genotypic diversity and serotype distribution of group B streptococcus isolated from women before and after delivery.

BACKGROUND Most studies of the dynamics of maternal group B Streptococcus (GBS) colonization have relied on capsular serotyping to define GBS acquisition or loss. Newer molecular methods that distinguish GBS clones may expand our knowledge and influence vaccination strategies. We used multilocus sequence typing (MLST) and GBS capsular gene cluster (cps) genotyping to investigate the dynamics of perinatal GBS colonization. METHODS A total of 338 GBS isolates obtained from 212 colonized women who were enrolled in a prior prospective cohort study were serotyped and genotyped by MLST and cps typing before (visit 1) and 6 weeks after (visit 2) delivery. RESULTS Of the 212 women, 126 were colonized at both visits, whereas 66 lost and 20 acquired GBS by visit 2. MLST of the 338 strains identified 29 sequence types marking distinct bacterial clones. A change in sequence type or cps and serotype occurred in 23 (18.3%) of the 126 women who were colonized at both visits. Specific sequence types were associated with GBS loss and persistence. Older maternal age and exclusive intrapartum antibiotic use were associated with persistent colonization. CONCLUSIONS Although most GBS-positive pregnant women were stably colonized during the peripartum period, we detected changes in capsule expression and recolonization with antigenically distinct GBS clones over time by applying MLST. Combining the epidemiologic and molecular typing data revealed host factors and clones associated with persistent colonization, as well as a clone that was more readily lost. This knowledge is useful for the development of prevention and intervention strategies to reduce the likelihood of maternal GBS colonization.
Selective Small-Molecule Agonists of G Protein–Coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose in Mice

OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40. RESEARCH DESIGN AND METHODS— We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40−/−). RESULTS— Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40−/− mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40−/− mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet–induced obesity acutely and chronically. CONCLUSIONS— GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
Thoughts about Sexual Difficulties and Related Anxiety Among a Predominantly Female Sample of Adolescents

Abstract This qualitative data analysis examined adolescents’ thoughts and feelings about difficulties that can emerge during sexual experiences. The sample consisted of 53 sexually experienced, ethnically diverse, predominantly female, nonpregnant adolescents participating in a web-based sexual health intervention. As part of a message board discussion, adolescents described anxiety-enhancing attitudes and beliefs (e.g., men should be skilled sexually, women should express satisfaction even if they do not feel it). Several adolescents advocated for condom use despite potential difficulties when attempting to use them. Health professionals should equip adolescents with skills to communicate with partners about sexual difficulties and cope with related anxiety.
The Role and Potential Therapeutic Application of Myeloid-Derived Suppressor Cells in Allo- and Autoimmunity

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells. They have been identified as a cell population that may affect the activation of CD4+ and CD8+ T-cells to regulate the immune response negatively, which makes them attractive targets for the treatment of transplantation and autoimmune diseases. Several studies have suggested the potential suppressive effect of MDSCs on allo- and autoimmune responses. Conversely, MDSCs have also been found at various stages of differentiation, accumulating during pathological situations, not only during tumor development but also in a variety of inflammatory immune responses, bone marrow transplantation, and some autoimmune diseases. These findings appear to be contradictory. In this review, we summarize the roles of MDSCs in different transplantation and autoimmune diseases models as well as the potential to target these cells for therapeutic benefit.
A Comprehensive Evaluation of Biomarkers Predictive of Response to PI3K Inhibitors and of Resistance Mechanisms in Head and Neck Squamous Cell Carcinoma

The PI3K/AKT/mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), but pathway inhibition has variable efficacy. Identification of predictive biomarkers and mechanisms of resistance would allow selection of patients most likely to respond and novel therapeutic combinations. The purpose of this study was to extend recent discoveries regarding the PI3K/AKT/mTOR pathway in HNSCC by more broadly examining potential biomarkers of response, by examining pathway inhibitors with a diverse range of targets, and by defining mechanisms of resistance and potential combination therapies. We used reverse-phase protein arrays (RPPA) to simultaneously evaluate expression of 195 proteins; SNP array to estimate gene copy number; and mass array to identify mutations. We examined altered signaling at baseline and after pathway inhibition. Likewise, we examined the activation of the PI3K/AKT/mTOR pathway in HNSCC tumors by RPPA. Cell lines with PIK3CA mutations were sensitive to pathway inhibitors, whereas amplification status did not predict sensitivity. While we identified a set of individual candidate biomarkers of response to pathway inhibitors, proteomic pathway scores did not correlate with amplification or mutation and did not predict response. Several receptor tyrosine kinases, including EGFR and ERK, were activated following PI3K inhibition in resistant cells; dual pathway inhibition of PI3K and EGFR or MEK demonstrated synergy. Combined MEK and PI3K inhibition was markedly synergistic in HRAS-mutant cell lines. Our findings indicate that clinical trials of single-agent PI3K/AKT/mTOR pathway inhibitors in selected populations and of PI3K/EGFR or PI3K/MEK inhibitor combinations are warranted; we plan to conduct such trials. Mol Cancer Ther; 13(11); 2738–50. ©2014 AACR.
Adjective production by Russian-speaking children with developmental language disorder and Dutch–Russian simultaneous bilinguals: Disentangling the profiles

ABSTRACT Bilingual children with reduced exposure to one or both languages may have language profiles that are apparently similar to those of children with developmental language disorder (DLD). Children with DLD receive enough input, but have difficulty using this input for acquisition due to processing deficits. The present investigation aims to determine aspects of adjective production that are differentially affected by reduced input (in bilingualism) and reduced intake (in DLD). Adjectives were elicited from Dutch–Russian simultaneous bilinguals with limited exposure to Russian and Russian-speaking monolinguals with and without DLD. An antonym elicitation task was used to assess the size of adjective vocabularies, and a degree task was employed to compare the preferences of the three groups in the use of morphological, lexical, and syntactic degree markers. The results revealed that adjective–noun agreement is affected to the same extent by both reduced input and reduced intake. The size of adjective lexicons is also negatively affected by both, but more so by reduced exposure. However, production of morphological degree markers and learning of semantic paradigms are areas of relative strength in which bilinguals outperform monolingual children with DLD. We suggest that reduced input might be counterbalanced by linguistic and cognitive advantages of bilingualism.
Violent Victimization and Future Expectations: Results from a Longitudinal Study of At-Risk Youth

ABSTRACT The relationship between offending and expectations for the future is well documented. Despite the link between offending and victimization and the wealth of research documenting the negative effects of victimization, how victimization shapes expectations for the future has not been fully explored. The authors investigate this relationship using longitudinal data derived from the Pathways to Desistance study. Using fixed-effects regression models for panel data that account for the effects of excluded time-invariant covariates, the authors examine time-varying factors such as self-reported delinquency, gang membership, binge drinking and drug use, and peer delinquency. The authors find that expectations for the future are decreased in waves in which a person is violently victimized. This finding indicates a potential intervention strategy for those who have been victimized, focusing on cognitive assessments postvictimization that could be useful in reducing revictimization as well as reoffending.