A case of mistaken identity: alcohol withdrawal, schizophrenia, or central pontine myelinolysis?

Demyelination is a hallmark of central pontine myelinolysis (CPM). Neuropsychiatric manifestations of this condition include weakness, quadriplegia, pseudobulbar palsy, mood changes, psychosis, and cognitive disturbances. These psychiatric symptoms are also associated with schizophrenia and alcohol withdrawal. Thus, it is clinically relevant to differentiate between CPM, schizophrenia, and alcohol withdrawal as the treatment and prognostic outcomes for each diagnosis are distinct. We present a series of events that led to a misdiagnosis of a patient admitted to the medical emergency center presenting with confusion, psychomotor agitation, and delirium who was first diagnosed with schizophrenia and alcohol withdrawal by emergency medical physicians and later discovered by the psychiatric consult team to have CPM. With a thorough psychiatric evaluation, a review of the laboratory results first showing mild hyponatremia (127 mmol/L), subsequent hypernatremia (154 mmol/L), and magnetic resonance brain imaging, psychiatrists concluded that CPM was the primary diagnosis underlying the observed neuropsychopathology. This patient has mild impairments in mood, cognition, and motor skills that remain 12 months after her emergency-center admission. This case report reminds emergency clinicians that abnormal sodium metabolism can have long-term and devastating psychopathological and neurological consequences. Differentiating between CPM, schizophrenia, and alcohol withdrawal using neuroimaging techniques and preventing the risks for CPM using slow sodium correction are paramount

Anisotropic Hall Effect in Single Crystal Heavy Fermion YbAgGe

Temperature- and field-dependent Hall effect measurements are reported for YbAgGe, a heavy fermion compound exhibiting a field-induced quantum phase transition, and for two other closely related members of the RAgGe series: a non-magnetic analogue, LuAgGe and a representative, ''good local moment'', magnetic material, TmAgGe. Whereas the temperature dependent Hall coefficient of YbAgGe shows behavior similar to what has been observed in a number of heavy fermion compounds, the low temperature, field-dependent measurements reveal well defined, sudden changes with applied field; in specific for $H \perp c$ a clear local maximum that sharpens as temperature is reduced below 2 K and that approaches a value of 45 kOe - a value that has been proposed as the $T = 0$ quantum critical point. Similar behavior was observed for $H \| c$ where a clear minimum in the field-dependent Hall resistivity was observed at low temperatures. Although at our base temperatures it is difficult to distinguish between the field-dependent behavior predicted for (i) diffraction off a critical spin density wave or (ii) breakdown in the composite nature of the heavy electron, for both field directions there is a distinct temperature dependence of a feature that can clearly be associated with a field-induced quantum critical point at $T = 0$ persisting up to at least 2 K.Comment: revised versio

Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases.

Ral GTPases have been implicated as critical drivers of cell growth and metastasis in numerous Ras-driven cancers. We have previously reported stapled peptides, based on the Ral effector RLIP76, that can disrupt Ral signaling. Stapled peptides are short peptides that are locked into their bioactive form using a synthetic brace. Here, using an affinity maturation of the RLIP76 Ral-binding domain, we identified several sequence substitutions that together improve binding to Ral proteins by more than 20-fold. Hits from the selection were rigorously analyzed to determine the contributions of individual residues and two 1.5 Å cocrystal structures of the tightest-binding mutants in complex with RalB revealed key interactions. Insights gained from this maturation were used to design second-generation stapled peptides based on RLIP76 that exhibited vastly improved selectivity for Ral GTPases when compared with the first-generation lead peptide. The binding of second-generation peptides to Ral proteins was quantified and the binding site of the lead peptide on RalB was determined by NMR. Stapled peptides successfully competed with multiple Ral-effector interactions in cellular lysates. Our findings demonstrate how manipulation of a native binding partner can assist in the rational design of stapled peptide inhibitors targeting a protein-protein interaction

Dynamic distribution of the replacement histone variant H3.3 in the mouse oocyte and preimplantation embryos

Upon fertilization, the gametes undergo a drastic reprogramming that includes changes in DNA methylation and histone modifications. Currently, it is not known whether replacement of the major histones by histone variants is also involved in these processes. Here we have examined the expression and localization of the histone variant H3.3 in early mouse embryogenesis. We show that H3.3 is present in the oocyte as a maternal factor. It is then incorporated preferentially into the male pronucleus before genome activation, pointing towards an asymmetry in histone composition between the two pronuclei. This is in line with the male pronucleus bearing transcriptional activation first. The same distribution was observed when we followed the localisation of a tagged version of H3.3. We detected H3.3 in the nuclei of mouse embryos in all of the stages analysed, from the zygote to the blastocyst stage, suggesting that the epigenetic mechanisms in the early embryo not only involve changes in histone modifications but may also include histone replacement

A lifeworld phenomenological study of the experience of living within ageing skin

Understanding people’s experience of skin ageing as it is lived can enable sensitive approaches to promoting healthy skin and to care in general. By understanding the insider perspective, what it is like for individuals, a way to sensitise practice for more humanly sensitive care is offered. Through interviews with seventeen, community-dwelling older people the essential meaning of living within ageing skin was illuminated as a state of managed inevitability. The skin is inevitably changing, ageing skin is a marker of change over time but the person within remains. Constituents of the phenomenon comprise: the experience of unfamiliar sights and sensations given by ageing skin; facing and accepting bodily changes and seeing this back and forth in family connections; taking care of the skin ‘to face’ the world and to present oneself to others and a different place in the world, same person, changed body. Findings point to why and how nurses can treat older people as persons by not over emphasising a view on ageing bodies or bodies with aged skin alone, but in tempering this view with deeper existential insights, meeting the older person with a skin care need as a person and not just as a physical entity

An NSTA Position Statement: Science-Technology-Society: Science Education for the 1980s

Science and technology influence every aspect of our lives. They are central to our welfare as individuals and to the welfare of our society. All around us are examples of the importance of science and technology for production of food, shelter, clothing, medicines, transportation, and various sources of energy. There are an increasing number of science- and technology-related societal problems as well as increasing societal benefits. Science and technology are central to our personal and cultural welfare and to many societal problems. We must insure appropriate science education for all citizens

Binding loci of RelA-containing nuclear factor-kappaB dimers in promoter regions of PHM1-31 myometrial smooth muscle cells.

Human parturition is associated with many pro-inflammatory mediators which are regulated by the nuclear factor-kappaB (NF-κB) family of transcription factors. In the present study, we employed a ChIP-on-chip approach to define genomic loci within chromatin of PHM1-31 myometrial cells that were occupied by RelA-containing NF-κB dimers in response to a TNF stimulation of 1 h. In TNF-stimulated PHM1-31 cells, anti-RelA serum enriched 13 300 chromatin regions; importantly, 11 110 regions were also enriched by anti-RelA antibodies in the absence of TNF. DNA sequences in these regions, from both unstimulated or TNF-stimulated PHM1-31 cultures, were associated with genic regions including IκBα, COX-2, IL6RN, Jun and KCNMB3. TNF-induced binding events at a consensus κB site numbered 1667; these were represented by 112 different instances of the consensus κB motif. Of the 1667 consensus κB motif occurrences, 770 (46.2%) were identified within intronic regions. In unstimulated PHM1-31 cells, anti-RelA-serum-enriched regions were associated with sequences corresponding to open reading frames of ion channel subunit genes including CACNB3 and KCNB1. Moreover, in unstimulated cells, the consensus κB site was identified 2116 times, being defined by 103 different sequence instances of this motif. Of these 2116 consensus κB motifs, 1089 (51.5%) were identified within intronic regions. Parallel expression array analyses in PHM1-31 cultures demonstrated that TNF stimulated a >2-fold induction in 51 genes and a fold repression of >1.5 in 18 others. We identified 14 anti-RelA-serum-enriched genomic regions that correlated with 17 TNF-inducible genes, such as COX2, Egr-1, Jun, IκBα and IL6, as well as five regions associated with TNF-mediated gene repression, including Col1A2

Human Activity Mediates a Trophic Cascade Caused by Wolves

Experimental evidence of trophic cascades initiated by large vertebrate predators is rare in terrestrial ecosystems. A serendipitous natural experiment provided an opportunity to test the trophic cascade hypothesis for wolves (Canis lupus) in Banff National Park, Canada. The first wolf pack recolonized the Bow Valley of Banff National Park in 1986. High human activity partially excluded wolves from one area of the Bow Valley (low-wolf area), whereas wolves made full use of an adjacent area (high-wolf area). We investigated the effects of differential wolf predation between these two areas on elk (Cervus elaphus) population density, adult female survival, and calf recruitment; aspen (Populus tremuloides) recruitment and browse intensity; willow (Salix spp.) production, browsing intensity, and net growth; beaver (Castor canadensis) density; and riparian songbird diversity, evenness, and abundance. We compared effects of recolonizing wolves on these response variables using the log response ratio between the low-wolf and high-wolf treatments. Elk population density diverged over time in the two treatments, such that elk were an order of magnitude more numerous in the low-wolf area compared to the high-wolf area at the end of the study. Annual survival of adult female elk was 62% in the high-wolf area vs. 89% in the low-wolf area. Annual recruitment of calves was 15% in the high-wolf area vs. 27% without wolves. Wolf exclusion decreased aspen recruitment, willow production, and increased willow and aspen browsing intensity. Beaver lodge density was negatively correlated to elk density, and elk herbivory had an indirect negative effect on riparian songbird diversity and abundance. These alternating patterns across trophic levels support the wolf-caused trophic cascade hypothesis. Human activity strongly mediated these cascade effects, through a depressing effect on habitat use by wolves. Thus, conservation strategies based on the trophic importance of large carnivores have increased support in terrestrial ecosystems. Read More: http://www.esajournals.org/doi/full/10.1890/04-126

Phenotypically distinct female castes in honey bees are defined by alternative chromatin states during larval development

The capacity of the honey bee to produce three phenotypically distinct organisms (two female castes; queens and sterile workers, and haploid male drones) from one genotype represents one of the most remarkable examples of developmental plasticity in any phylum. The queen-worker morphological and reproductive divide is environmentally controlled during post-embryonic development by differential feeding. Previous studies implicated metabolic flux acting via epigenetic regulation, in particular DNA methylation and microRNAs, in establishing distinct patterns of gene expression underlying caste-specific developmental trajectories. We produce the first genome-wide maps of chromatin structure in the honey bee at a key larval stage in which developmental canalization into queen or worker is virtually irreversible. We find extensive genome-wide differences in H3K4me3, H3K27ac, and H3K36me3, many of which correlate with caste-specific transcription. Furthermore, we identify H3K27ac as a key chromatin modification, with caste-specific regions of intronic H3K27ac directing the worker caste. These regions may harbor the first examples of caste-specific enhancer elements in the honey bee. Our results demonstrate a key role for chromatin modifications in the establishment and maintenance of caste-specific transcriptional programs in the honey bee. We show that at 96 h of larval growth, the queen-specific chromatin pattern is already established, whereas the worker determination is not, thus providing experimental support for the perceived timing of this critical point in developmental heterochrony in two types of honey bee females. In a broader context, our study provides novel data on environmentally regulated organismal plasticity and the molecular foundation of the evolutionary origins of eusociality.This work was funded by a grant to P.J.H. from the Biotechnology and Biological Sciences Research Council (BBSRC; BB/L023164/1). M.W. received funding from the William Harvey International Translational Research Academy COFUND Marie Curie Actions (WHRI-ACADEMY; PCOFUND-GA-2013-608765). Work in the Maleszka laboratory was supported by the Australian Research Council grant DP160103053