475 research outputs found
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alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo
The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) before the onset of plaques. Expression of human APPsw exclusively in olfactory sensory neurons also perturbs connectivity with associated reductions in odour-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctly in mice overexpressing wild-type human amyloid precursor protein throughout the brain and in mice overexpressing M671V human APP, a missense mutation that reduces amyloid beta production, exclusively in olfactory sensory neurons. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta
Phylogenetic placement of environmental sequences using taxonomically reliable databases helps to rigorously assess dinophyte biodiversity in Bavarian lakes (Germany).
1. Reliable determination of organisms is a prerequisite to explore their spatial
and temporal occurrence and to study their evolution, ecology, and dispersal. In
Europe, Bavaria (Germany) provides an excellent study system for research on the
origin and diversification of freshwater organisms including dinophytes, due to
the presence of extensive lake districts and ice age river valleys. Bavarian freshwater
environments are ecologically diverse and range from deep nutrientâpoor
mountain lakes to shallow nutrientârich lakes and ponds.
2. We obtained amplicon sequence data (V4 region of small subunitârRNA, c. 410 bp
long) from environmental samples collected at 11 sites in Upper Bavaria. We
found 186 operational taxonomic units (OTUs) associated with Dinophyceae that
were further classified by means of a phylogenetic placement approach.
3. The maximum likelihood tree inferred from a wellâcurated reference alignment comprised
a systematically representative set of 251 dinophytes, covering the currently
known molecular diversity and OTUs linked to type material if possible. Environmental
OTUs were scattered across the reference tree, but accumulated mostly in freshwater
lineages, with 79% of OTUs placed in either Apocalathium, Ceratium, or Peridinium,
the most frequently encountered taxa in Bavaria based on morphology.
4. Twentyâone Bavarian OTUs showed identical sequences to already known and
vouchered accessions, two of which are linked to type material, namely Palatinus
apiculatus and Theleodinium calcisporum. Particularly within Peridiniaceae, delimitation
of Peridinium species was based on the intraspecific sequence variation.
5. Our approach indicates that highâthroughput sequencing of environmental samples
is effective for reliable determination of dinophyte species in Bavarian lakes.
We further discuss the importance of wellâcurated reference databases that remain
to be developed in the future
Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: Absence of structural mutations in five patients with brody disease
Sarcolipin (SLN) is a low-molecular-weight protein that copurifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA1). Genomic DNA and cDNA encoding human sarcolipin (SLN) were isolated and characterized and the SLN gene was mapped to chromosome 11q22-q23. Human, rabbit, and mouse cDNAs encode a protein of 31 amino acids. Homology of SLN with phospholamban (PLN) suggests that the first 7 hydrophilic amino acids are cytoplasmic, the next 19 hydrophobic amino acids form a single transmembrane helix, and the last 5 hydrophilic amino acids are lumenal. The cytoplasmic and transmembrane sequences are not well conserved among the three species, but the lumenal sequence is highly conserved. Like SERCA1, SLN is highly expressed in rabbit fast-twitch skeletal muscle, but it is expressed to a lower extent in slow-twitch muscle and to an even lower extent in cardiac muscle, where SERCA2a and PLN are highly expressed. It is expressed in only trace amounts in pancreas and prostate. SLN and PLN genes resemble each other in having two small exons, with their entire coding sequences lying in exon 2 and a large intron separating the two segments. Brody disease is an inherited disorder of skeletal muscle function, characterized by exercise-induced impairment of muscle relaxation. Mutations in the ATP2A1 gene encoding SERCA1 have been associated with the autosomal recessive inheritance of Brody disease in three families, but not with autosomal dominant inheritance of the disease. A search for mutations in the SLN gene in five Brody families, four of which were not linked to ATP2A1, did not reveal any alterations in coding, splice junction or promoter sequences. The homozygous deletion of C438 in the coding sequence of ATP2A1 in Brody disease family 3, leading to a frameshift and truncation following Pro147 in SERCA1, is the fourth ATP2A1 mutation to be associated with autosomal recessive Brody disease
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The impact of mental health recovery narratives on recipients experiencing mental health problems: Qualitative analysis and change model.
BACKGROUND: Mental health recovery narratives are stories of recovery from mental health problems. Narratives may impact in helpful and harmful ways on those who receive them. The objective of this paper is to develop a change model identifying the range of possible impacts and how they occur. METHOD: Semi-structured interviews were conducted with adults with experience of mental health problems and recovery (n = 77). Participants were asked to share a mental health recovery narrative and to describe the impact of other people's recovery narratives on their own recovery. A change model was generated through iterative thematic analysis of transcripts. RESULTS: Change is initiated when a recipient develops a connection to a narrator or to the events descripted in their narrative. Change is mediated by the recipient recognising experiences shared with the narrator, noticing the achievements or difficulties of the narrator, learning how recovery happens, or experiencing emotional release. Helpful outcomes of receiving recovery narratives are connectedness, validation, hope, empowerment, appreciation, reference shift and stigma reduction. Harmful outcomes are a sense of inadequacy, disconnection, pessimism and burden. Impact is positively moderated by the perceived authenticity of the narrative, and can be reduced if the recipient is experiencing a crisis. CONCLUSIONS: Interventions that incorporate the use of recovery narratives, such as peer support, anti-stigma campaigns and bibliotherapy, can use the change model to maximise benefit and minimise harms from narratives. Interventions should incorporate a diverse range of narratives available through different mediums to enable a range of recipients to connect with and benefit from this material. Service providers using recovery narratives should preserve authenticity so as to maximise impact, for example by avoiding excessive editing
Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial
Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (nâ=â15) and Spain (nâ=â1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (nâ=â255) or usual practice (nâ=â254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to â]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840
Metarhizium anisopliae Pathogenesis of Mosquito Larvae: A Verdict of Accidental Death
Metarhizium anisopliae, a fungal pathogen of terrestrial arthropods, kills the aquatic larvae of Aedes aegypti, the vector of dengue and yellow fever. The fungus kills without adhering to the host cuticle. Ingested conidia also fail to germinate and are expelled in fecal pellets. This study investigates the mechanism by which this fungus adapted to terrestrial hosts kills aquatic mosquito larvae. Genes associated with the M. anisopliae early pathogenic response (proteinases Pr1 and Pr2, and adhesins, Mad1 and Mad2) are upregulated in the presence of larvae, but the established infection process observed in terrestrial hosts does not progress and insecticidal destruxins were not detected. Protease inhibitors reduce larval mortality indicating the importance of proteases in the host interaction. The Ae. aegypti immune response to M. anisopliae appears limited, whilst the oxidative stress response gene encoding for thiol peroxidase is upregulated. Cecropin and Hsp70 genes are downregulated as larval death occurs, and insect mortality appears to be linked to autolysis through caspase activity regulated by Hsp70 and inhibited, in infected larvae, by protease inhibitors. Evidence is presented that a traditional host-pathogen response does not occur as the species have not evolved to interact. M. anisopliae retains pre-formed pathogenic determinants which mediate host mortality, but unlike true aquatic fungal pathogens, does not recognise and colonise the larval host
Commissioning of the vacuum system of the KATRIN Main Spectrometer
The KATRIN experiment will probe the neutrino mass by measuring the
beta-electron energy spectrum near the endpoint of tritium beta-decay. An
integral energy analysis will be performed by an electro-static spectrometer
(Main Spectrometer), an ultra-high vacuum vessel with a length of 23.2 m, a
volume of 1240 m^3, and a complex inner electrode system with about 120000
individual parts. The strong magnetic field that guides the beta-electrons is
provided by super-conducting solenoids at both ends of the spectrometer. Its
influence on turbo-molecular pumps and vacuum gauges had to be considered. A
system consisting of 6 turbo-molecular pumps and 3 km of non-evaporable getter
strips has been deployed and was tested during the commissioning of the
spectrometer. In this paper the configuration, the commissioning with bake-out
at 300{\deg}C, and the performance of this system are presented in detail. The
vacuum system has to maintain a pressure in the 10^{-11} mbar range. It is
demonstrated that the performance of the system is already close to these
stringent functional requirements for the KATRIN experiment, which will start
at the end of 2016.Comment: submitted for publication in JINST, 39 pages, 15 figure
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