The CCAAT/enhancer binding protein (C/EBP) δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide

<p>Abstract</p> <p>Background</p> <p>The transcription factors CCAAT/enhancer binding proteins (C/EBP) α, β and δ have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor κB (NF-κB). In general, C/EBPα is down-regulated, whereas both C/EBPβ and δ are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD) one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-β (Aβ) deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Aβ deposits with the aim of defining new therapeutic targets.</p> <p>Methods</p> <p>Here we have investigated the effects of Aβ on expression of C/EBP family members with a focus on C/EBPδ in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar Aβ deposits (tg-ArcSwe) by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBPδ and NF-κB was investigated by analyzing binding to a κB site using a biotin streptavidin-agarose pull-down assay.</p> <p>Results</p> <p>We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of Aβ inhibit up-regulation of C/EBPδ expression in interleukin-1β-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBPα was significantly down-regulated and C/EBPβ was significantly up-regulated. C/EBPδ, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar Aβ deposits. In contrast, no difference in expression levels of C/EBPδ between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1β-induced C/EBPδ DNA binding activity to both C/EBP and κB sites is abolished after exposure to Aβ.</p> <p>Conclusions</p> <p>These data suggest that both expression and function of C/EBPδ are dysregulated in Alzheimer's disease. C/EBPδ seems to be differently regulated in response to different conformations of Aβ. We propose that Aβ induces an imbalance between NF-κB and C/EBP transcription factors that may result in abnormal responses to inflammatory stimuli.</p

Rationing of nursing care and its relationship to patient outcomes: the Swiss extension of the International Hospital Outcomes Study

Objectives To explore the association between implicit rationing of nursing care and selected patient outcomes in Swiss hospitals, adjusting for major organizational variables, including the quality of the nurse practice environment and the level of nurse staffing. Rationing was measured using the newly developed Basel Extent of Rationing of Nursing Care (BERNCA) instrument. Additional data were collected using an adapted version of the International Hospital Outcomes Study questionnaire. Design Multi-hospital cross-sectional surveys of patients and nurses. Setting Eight Swiss acute care hospitals Participants Nurses (1338) and patients (779) on 118 medical, surgical and gynecological units. Main outcome measures Patient satisfaction, nurse-reported medication errors, patient falls, nosocomial infections, pressure ulcers and critical incidents involving patients over the previous year. Results Generally, nurses reported rarely having omitted any of the 20 nursing tasks listed in the BERNCA over their last 7 working days. However, despite relatively low levels, implicit rationing of nursing care was a significant predictor of all six patient outcomes studied. Although the adequacy of nursing resources was a significant predictor for most of the patient outcomes in unadjusted models, it was not an independent predictor in the adjusted models. Low nursing resource adequacy ratings were a significant predictor for five of the six patient outcomes in the unadjusted models, but not in the adjusted ones. Conclusion As a system factor in acute general hospitals, implicit rationing of nursing care is an important new predictor of patient outcomes and merits further stud

Widespread recombination, reassortment, and transmission of unbalanced compound viral genotypes in natural arenavirus infections.

Arenaviruses are one of the largest families of human hemorrhagic fever viruses and are known to infect both mammals and snakes. Arenaviruses package a large (L) and small (S) genome segment in their virions. For segmented RNA viruses like these, novel genotypes can be generated through mutation, recombination, and reassortment. Although it is believed that an ancient recombination event led to the emergence of a new lineage of mammalian arenaviruses, neither recombination nor reassortment has been definitively documented in natural arenavirus infections. Here, we used metagenomic sequencing to survey the viral diversity present in captive arenavirus-infected snakes. From 48 infected animals, we determined the complete or near complete sequence of 210 genome segments that grouped into 23 L and 11 S genotypes. The majority of snakes were multiply infected, with up to 4 distinct S and 11 distinct L segment genotypes in individual animals. This S/L imbalance was typical: in all cases intrahost L segment genotypes outnumbered S genotypes, and a particular S segment genotype dominated in individual animals and at a population level. We corroborated sequencing results by qRT-PCR and virus isolation, and isolates replicated as ensembles in culture. Numerous instances of recombination and reassortment were detected, including recombinant segments with unusual organizations featuring 2 intergenic regions and superfluous content, which were capable of stable replication and transmission despite their atypical structures. Overall, this represents intrahost diversity of an extent and form that goes well beyond what has been observed for arenaviruses or for viruses in general. This diversity can be plausibly attributed to the captive intermingling of sub-clinically infected wild-caught snakes. Thus, beyond providing a unique opportunity to study arenavirus evolution and adaptation, these findings allow the investigation of unintended anthropogenic impacts on viral ecology, diversity, and disease potential

“I Think Writing is…” A Multi-State Study of Teacher Candidates’ Changing Beliefs about Writing

While writing scholarship framed by sociocultural theory illuminates the complexity of writing, writing in schools is frequently presented in simplistic ways. For this to change, teacher educators must support future teachers to develop complex understandings of writing. The purpose of this multi-state study was to investigate teacher candidates’ changing beliefs about writing and to consider the implications for teacher preparation. Data sources were written responses from 113 teacher candidates to questions about good writing and the purposes of writing that were collected at the beginning and end of semester-long literacy courses in six institutions across the United States. The responses were examined using thematic and discourse analysis. Findings indicate that, almost all teacher candidates changed their beliefs related to writing as a social, personal, and/or school practice, although changes were minor. Responses centering writing as a school activity were pervasive, and certain key sociocultural understandings, such as the connections between writing, context, culture, and power, were absent. Implications highlight ways that teacher educators might work to disrupt and broaden teacher candidates’ beliefs about writing, so teacher candidates might expand how writing is taught in their future classrooms

Characterization of Scale-Free Properties of Human Electrocorticography in Awake and Slow Wave Sleep States

Like many complex dynamic systems, the brain exhibits scale-free dynamics that follow power-law scaling. Broadband power spectral density (PSD) of brain electrical activity exhibits state-dependent power-law scaling with a log frequency exponent that varies across frequency ranges. Widely divergent naturally occurring neural states, awake and slow wave sleep (SWS), were used to evaluate the nature of changes in scale-free indices of brain electrical activity. We demonstrate two analytic approaches to characterizing electrocorticographic (ECoG) data obtained during awake and SWS states. A data-driven approach was used, characterizing all available frequency ranges. Using an equal error state discriminator (EESD), a single frequency range did not best characterize state across data from all six subjects, though the ability to distinguish awake and SWS ECoG data in individual subjects was excellent. Multi-segment piecewise linear fits were used to characterize scale-free slopes across the entire frequency range (0.2–200 Hz). These scale-free slopes differed between awake and SWS states across subjects, particularly at frequencies below 10 Hz and showed little difference at frequencies above 70 Hz. A multivariate maximum likelihood analysis (MMLA) method using the multi-segment slope indices successfully categorized ECoG data in most subjects, though individual variation was seen. In exploring the differences between awake and SWS ECoG data, these analytic techniques show that no change in a single frequency range best characterizes differences between these two divergent biological states. With increasing computational tractability, the use of scale-free slope values to characterize ECoG and EEG data will have practical value in clinical and research studies

The Teacher’s Role in Writing: A Study of Teacher Candidates’ Perceptions

A team of teacher education researchers conducted a qualitative study to explore how teacher candidates viewed the teacher’s role in teaching students to write. Participants (N = 107) enrolled in writing-focused methods courses across four universities completed a reflective quick write near the end of the course. Since writing is a complex and multidimensional activity, these responses were analyzed through the theoretical framework of social cognitive theory. When describing the role of the teacher, the data indicated candidates across all institutions primarily focused on the affective aspects of teaching writing, specifically supporting and developing students’ confidence in writing. Some mentioned the need for explicit instruction such as developing students’ writing skills and use of strategies. A smaller percentage included both the importance of affective and explicit instruction. Many candidates indicated the significance of the role that teachers play in students learning to write. Implications for writing pedagogy support within and beyond teacher preparation are discussed

Measurement of H₂O₂ within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix

Hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; in vivo. Here we report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; correlates with aging, it may not be causative

Learning as acquiring a discursive identity through participation in a community: improving student learning in engineering education

This is an Accepted Manuscript of an article published by Taylor & Francis in African Journal of Research in Mathematics Science and Technology Education on 2009, available online: http://www.tandfonline.com/10.1080/03043790902989457.In this paper, we propose that learning in engineering involves taking on the discourse of an engineering community, which is intimately bound up with the identity of being a member of that community. This leads to the notion of discursive identity, which emphasises that students' identities are constituted through engaging in discourse. This view of learning implies that success in engineering studies needs to be defined with particular reference to the sorts of identities that students develop and how these relate to identities in the world of work. In order to achieve successful learning in engineering, we need to recognise the multiple identities held by our students, provide an authentic range of engineering-related activities through which students can develop engineering identities and make more explicit key aspects of the discourse of engineering of which lecturers are tacitly aware. We include three vignettes to illustrate how some of the authors of this paper (from across three different institutions) have applied this perspective of learning in their teaching practice

Less Traditional Diets in Chinese Mothers and Children Are Similarly Linked to Socioeconomic and Cohort Factors but Vary with Increasing Child Age

Global shifts toward an increasingly Western diet and rises in nutrition-related noncommunicable diseases necessitate systematic examination of dietary change in adults and children. This study longitudinally examined mother and child dietary intakes and their relationship with socioeconomic factors across 4 mutually exclusive cohorts followed over 6- to 7-y time periods (cohort A: 1991–1997, cohort B: 1993–2000, cohort C: 1997–2004, cohort D: 2000–2006). The cohorts included 966 mother-child pairs (children 3–5 y at baseline) from the China Health and Nutrition Survey. Dietary intake was assessed using 24-h recall and household food consumption data; dietary variables were the percentage of total energy from animal-source foods (ASF), fats/oils, and grains. Mother-child comparison of dietary variables used average annual change measures, Spearman partial correlations, random effects models, and seemingly unrelated regression models and estimation. Whereas children were earlier adopters and maintainers of a less traditional Chinese diet, mothers experienced greater shifts away from the traditional Chinese diet with increasing child age. Mother-child correlations for the dietary variables ranged from 0.46 to 0.89 (P < 0.001). Similar increased intake of ASF and decreased intake of grains were reported for mothers and children of urban (vs. rural) residence and with higher levels of maternal education (P < 0.001). A comparable cohort effect was shown, with mothers and children consuming a less traditional Chinese diet in the later (C and D) compared to earlier (A and B) cohorts (P < 0.05). Our findings provide insight into dietary changes in mothers and children within the context of a rapidly changing nutrition and socioeconomic environment

Eph-Dependent Tyrosine Phosphorylation of Ephexin1 Modulates Growth Cone Collapse

SummaryEphs regulate growth cone repulsion, a process controlled by the actin cytoskeleton. The guanine nucleotide exchange factor (GEF) ephexin1 interacts with EphA4 and has been suggested to mediate the effect of EphA on the activity of Rho GTPases, key regulators of the cytoskeleton and axon guidance. Using cultured ephexin1−/− mouse neurons and RNA interference in the chick, we report that ephexin1 is required for normal axon outgrowth and ephrin-dependent axon repulsion. Ephexin1 becomes tyrosine phosphorylated in response to EphA signaling in neurons, and this phosphorylation event is required for growth cone collapse. Tyrosine phosphorylation of ephexin1 enhances ephexin1’s GEF activity toward RhoA while not altering its activity toward Rac1 or Cdc42, thus changing the balance of GTPase activities. These findings reveal that ephexin1 plays a role in axon guidance and is regulated by a switch mechanism that is specifically tailored to control Eph-mediated growth cone collapse