Differential, Positional-Dependent Transcriptional Response of Antigenic Variation (var) Genes to Biological Stress in Plasmodium falciparum

1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome – expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Turvallinen hoitolaitossiirto : Tarkistuslista päivystyksen henkilökunnalle

Tämän opinnäytetyön tarkoituksena oli tuottaa tarkistuslista Savonlinnan keskussai-raalan päivystyksen hoitohenkilökunnalle turvallisten hoitolaitossiirtojen valmisteluun. Tarkistuslistaa voidaan käyttää myös muissa Itä-Savon sairaanhoitopiirin yksiköissä ja osastoilla. Opinnäytetyön tavoitteena oli parantaa potilasturvallisuutta hoitolaitossiir-roissa luomalla työkalu hoitolaitossiirtojen valmisteluun ja vähentämällä unohduksia. Opinnäytetyömenetelmänä käytettiin tuotekehitysprosessia, mutta tarkistuslistan sisäl-töä selvitettiin myös laadullisella tutkimuksella. Tarkistuslistan sisältö muodostui teo-reettisen viitekehyksen, Savonlinnan keskussairaalan päivystyksen henkilökunnan ja Etelä-Savon Pelastuslaitoksen Savonlinnan ensihoitajien ryhmähaastattelujen poh-jalta. Hahmottelemastamme tarkistuslistasta pyydettiin palautetta Webropol-kyselyllä Savon-linnan keskussairaalan päivystyksen, tehovalvonnan ja kirurgisten osastojen hoito-henkilökunnalta. Lisäksi palautetta tarkistuslistan ulkonäöstä ja sisällöstä pyydettiin työelämäohjaajiltamme. Tarkistuslista viimeisteltiin saadun palautteen perusteella. Tarkistuslistan sisältö tehtiin etenemään hoitolaitossiirron valmistelun vaiheiden mu-kaisesti. Tarkistuslista tehtiin Publisher-ohjelmalla Sosterin ulkoasuohjeiden mukai-sesti ja listan tekijänoikeudet luovutettiin Sosterille. Listaan liitettiin myös ISBAR-taulukko helpottamaan hoitolaitossiirtojen viestintää. Hoitolaitossiirrot ovat aiheena ajankohtainen, sillä tulevien sosiaali- ja terveyspalvelu-jen muutosten myötä siirrot Savonlinnan keskussairaalasta muihin hoitolaitoksiin mahdollisesti lisääntyvät. Tarkistuslistoja ensihoitoon on jo kehitetty, mutta lähettävän yksikön hoitohenkilökunnalle vastaavia tarkistuslistoja ei Sosterin alueelta löytynyt.The purpose of this thesis was to provide a checklist for Savonlinna Central Hospital Emergency Care staff for the preparation of safe patient transfers. The checklist can also be used in other departments in the Eastern Savo Hospital District. The objective of the thesis was to improve patient safety in patient transfers by creating a tool for the preparation of transfers and reducing forgetfulness. The study employed a product development method and qualitative research methods to clarify the contents of the checklist. Theoretical frame of reference and group interviews of Savonlinna Central Hospital emergency staff and paramedics were used to determine the content of the checklist. Feedback for the checklist was asked by a Webropol survey from Savonlinna Central Hospital emergency, ICU and surgical wards staff. Feedback was also asked from the development manager of Eastern Savo Hospital District and emergency ward head nurse concerning the appearance and content of the checklist. The checklist was revised on the basis of the received feedback. The content of the checklist was compiled to proceed according to the phases of the intrahospital transfer preparation. The checklist was designed according to the hospital graphic layout guidelines and the copyright was handed to Eastern Savo Hospital District. An ISBAR table was also included in the list to facilitate communication in intrahospital transfers. The subject is current because the future changes in the social and health services will increase transfers from Savonlinna Central Hospital to other hospitals. A checklist for paramedics has already been developed but not for transfer preparations

Functional Analysis of Spike from SARS-CoV-2 Variants Reveals the Role of Distinct Mutations in Neutralization Potential and Viral Infectivity

Enhanced viral transmission and escape from vaccine–elicited neutralizing antibodies drive worldwide spread of SARS-CoV-2 variants and promote disease progression. However, the impact of specific spike mutations that are carried by different viral variants on viral infectivity and neutralization sensitivity has not been completely defined. Here, we use pseudoviruses to assess the contribution of spike mutations within the Receptor Binding Domain (RBD) and the Furin Cleavage Site (FCS), and appear in circulating viral variants, on viral infectivity and neutralization potential against sera that was drawn from fully vaccinated individuals. Our functional analysis demonstrates that single, P681H, P681R or A701V–FCS mutations do not play a role in viral infectivity and neutralization potential. However, when in conjunction with the RBD–N501Y mutation, viral infectivity is enhanced. Similarly, combining the E484K–RBD mutation to the spike that carries FCS mutations reduces neutralization sensitivity with no effects on viral infectivity. Employing a similar approach onto the spike from Delta or Lota SARS-CoV-2 variants further reveals that specific RBD mutations affect neutralization sensitivity or viral infectivity differently. Our results validate the efficacy of the Pfizer third dose vaccine against Delta and Lota SARS-CoV-2 variants, and outline the significance of distinct RBD mutations in promoting viral infectivity and neutralization sensitivity to post–vaccination sera

The Risk of Rectal Temperature Measurement in Neutropenia

Background: Avoiding rectal thermometry is recommended in patients with neutropenic fever. Permeability of the anal mucosa may result in a higher risk of bacteremia in these patients. Still, this recommendation is based on only a few studies. Methods: This retrospective study included all individuals admitted to our emergency department during 2014–2017 with afebrile (body temperature <38.3°C) neutropenia (neutrophil count <500 cells/microL) who were over the age of 18. Patients were stratified by the presence or absence of a rectal temperature measurement. The primary outcome was bacteremia during the first five days of index hospitalization; the secondary outcome was in-hospital mortality. Results: The study included 40 patients with rectal temperature measurements and 407 patients whose temperatures were only measured orally. Among patients with oral temperature measurements, 10.6% had bacteremia, compared to 5.1% among patients who had rectal temperature measurements. Rectal temperature measurement was not associated with bacteremia, neither in non-matched (odds ratio [OR] 0.36, 95% confidence interval [CI] 0.07–1.77) nor in matched cohort analyses (OR 0.37, 95% CI 0.04–3.29). In-hospital mortality was also similar between the groups. Conclusions: Patients with neutropenia who had their temperature taken using a rectal thermometer did not experience a higher frequency of events of documented bacteremia or increased in-hospital mortality

Remanent Polarization and Strong Photoluminescence Modulation by an External Electric Field in Epitaxial CsPbBr3Nanowires

Metal halide perovskites (MHPs) have unique characteristics and hold great potential for next-generation optoelectronic technologies. Recently, the importance of lattice strain in MHPs has been gaining recognition as a significant optimization parameter for device performance. While the effect of strain on the fundamental properties of MHPs has been at the center of interest, its combined effect with an external electric field has been largely overlooked. Here we perform an electric-field-dependent photoluminescence study on heteroepitaxially strained surface-guided CsPbBr3 nanowires. We reveal an unexpected strong linear dependence of the photoluminescence intensity on the alternating field amplitude, stemming from an induced internal dipole. Using low-frequency polarized-Raman spectroscopy, we reveal structural modifications in the nanowires under an external field, associated with the observed polarity. These results reflect the important interplay between strain and an external field in MHPs and offer opportunities for the design of MHP-based optoelectronic nanodevices

Analysis of expression of exported non-<i>var</i> genes upon exposure to 10 µM tBHP in NF-54 parasites.

<p>Stress induction, cDNA production and qPCR analysis were performed as described in the legend to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006991#pone-0006991-g001" target="_blank">Fig. 1</a>. Error bars represent mean of triplicates ± SEM.</p

Analysis of expression of <i>var</i> and non-<i>var</i> exported genes upon exposure to oxidative stress in genetically modified parasites.

<p>A. The relative change in expression of the <i>ups A, B, and C var</i> subtypes upon exposure to 10 µM <i>t</i>BHP in Δ<i>pfsir2</i> parasites in relation to unexposed Δ<i>pfsir2</i> parasites. B. Analysis of expression of exported non-<i>var</i> genes upon exposure to oxidative stress in Δ<i>pfsir2</i> parasites. C. Analysis of expression of h<i>dhfr</i> – the gene under control of an <i>upsC</i> element in the 3D7/upsC transgenic line – upon exposure to 10 µM tBHP. Stress induction, cDNA production and qPCR analysis were performed as described in the legend to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006991#pone-0006991-g001" target="_blank">Fig. 1</a>. Error bars represent mean of triplicates ± SEM.</p