Lincoln-proposed schedule modifications covering 8-month period for installation and test of first direction center

Includes: introduction; schedule requirements; related schedules; and status of the direction center on 1 March 1957.Memorandum proposing to reduce by 14 weeks that time requirement scheduled by the ADES Engineering-Installation Phasing Subcommittees for the first SAGE installation, test, and program checking period

Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation

ChatGPT sits the DFPH exam: large language model performance and potential to support public health learning

Background Artificial intelligence-based large language models, like ChatGPT, have been rapidly assessed for both risks and potential in health-related assessment and learning. However, their applications in public health professional exams have not yet been studied. We evaluated the performance of ChatGPT in part of the Faculty of Public Health’s Diplomat exam (DFPH). Methods ChatGPT was provided with a bank of 119 publicly available DFPH question parts from past papers. Its performance was assessed by two active DFPH examiners. The degree of insight and level of understanding apparently displayed by ChatGPT was also assessed. Results ChatGPT passed 3 of 4 papers, surpassing the current pass rate. It performed best on questions relating to research methods. Its answers had a high floor. Examiners identified ChatGPT answers with 73.6% accuracy and human answers with 28.6% accuracy. ChatGPT provided a mean of 3.6 unique insights per question and appeared to demonstrate a required level of learning on 71.4% of occasions. Conclusions Large language models have rapidly increasing potential as a learning tool in public health education. However, their factual fallibility and the difficulty of distinguishing their responses from that of humans pose potential threats to teaching and learning

Evolving thermal thresholds explain the distribution of temperature sex reversal in an Australian dragon lizard

Aim: Species with temperature-dependent sex determination (TSD) are particularly vulnerable to climate change because a resultant skew in population sex ratio can have severe demographic consequences and increase vulnerability to local extinction. The Australian central bearded dragon (Pogona vitticeps) has a thermosensitive ZZ male/ZW female system of genetic sex determination (GSD). High incubation temperatures cause reversal of the ZZ genotype to a viable female phenotype. Nest temperatures in the wild are predicted to vary on a scale likely to produce heterogeneity in the occurrence of sex reversal, and so we predict that sex reversal will correlate positively with inferred incubation conditions. Location: Mainland Australia. Methods: Wild-caught specimens of P. vitticeps vouchered in museum collections and collected during targeted field trips were genotypically and phenotypically sexed to determine the distribution of sex reversal across the species range. To determine whether environmental conditions or genetic structure can explain this distribution, we infer the incubation conditions experienced by each individual and apply a multi-model inference approach to determine which conditions associate with sex reversal. Further, we conduct reduced representation sequencing on a subset of specimens to characterize the population structure of this broadly distributed species. Results: Here we show that sex reversal in this widespread Australian dragon lizard is spatially restricted to the eastern part of the species range. Neither climatic variables during the inferred incubation period nor geographic population genetic structure explain this disjunct distribution of sex reversal. The main source of genetic variation arose from isolation by distance across the species range. Main conclusions: We propose that local genetic adaptation in the temperature threshold for sex reversal can counteract the sex-reversing influence of high incubation temperatures in P. vitticeps. Our study demonstrates that complex evolutionary processes need to be incorporated into modelling biological responses to future climate scenarios

MSWEP V2 global 3-hourly 0.1° precipitation : methodology and quantitative assessment

We present Multi-Source Weighted-Ensemble Precipitation, version 2 (MSWEP V2), a gridded precipitation P dataset spanning 1979-2017. MSWEP V2 is unique in several aspects: i) full global coverage (all land and oceans); ii) high spatial (0.1 degrees) and temporal (3 hourly) resolution; iii) optimal merging of P estimates based on gauges [WorldClim, Global Historical Climatology Network-Daily (GHCN-D), Global Summary of the Day (GSOD), Global Precipitation Climatology Centre (GPCC), and others], satellites [Climate Prediction Center morphing technique (CMORPH), Gridded Satellite (GridSat), Global Satellite Mapping of Precipitation (GSMaP), and Tropical Rainfall Measuring Mission (TRMM) Multisatellite Precipitation Analysis (TMPA) 3B42RT)], and reanalyses [European Centre for Medium-Range Weather Forecasts (ECMWF) interim reanalysis (ERA-Interim) and Japanese 55-year Reanalysis (JRA-55)]; iv) distributional bias corrections, mainly to improve the P frequency; v) correction of systematic terrestrial P biases using river discharge Q observations from 13,762 stations across the globe; vi) incorporation of daily observations from 76,747 gauges worldwide; and vii) correction for regional differences in gauge reporting times. MSWEP V2 compares substantially better with Stage IV gauge-radar P data than other state-of-the-art P datasets for the United States, demonstrating the effectiveness of the MSWEP V2 methodology. Global comparisons suggest that MSWEP V2 exhibits more realistic spatial patterns in mean, magnitude, and frequency. Long-term mean P estimates for the global, land, and ocean domains based on MSWEP V2 are 955, 781, and 1,025 mm yr(-1), respectively. Other P datasets consistently underestimate P amounts in mountainous regions. Using MSWEP V2, P was estimated to occur 15.5%, 12.3%, and 16.9% of the time on average for the global, land, and ocean domains, respectively. MSWEP V2 provides unique opportunities to explore spatiotemporal variations in P, improve our understanding of hydrological processes and their parameterization, and enhance hydrological model performance

Materialising architecture for social care: brick walls and compromises in design for later life.

This article reports on an ethnography of architectural projects for later life social care in the UK. Informed by recent debates in material studies and ‘materialities of care’ we offer an analysis of a care home project that is sensitive to architectural materials that are not normally associated with care and wellbeing. Although the care home design project we focus on in this article was never built, we found that design discussions relating to both a curved brick wall and bricks more generally were significant to its architectural ‘making’. The curved wall and the bricks were used by the architects to encode quality and values of care into their design. This was explicit in the design narrative that was core to a successful tender submitted by a consortium comprising architects, developers, contractors, and a care provider to a local authority who commissioned the care home. However, as the project developed, initial consensus for the design features fractured. Using a materialised analysis, we document the tussles generated by the curved wall and the bricks and argue that mundane building materials can be important to, and yet marginalised within, the relations inherent within an ‘architectural care assemblage.’ During the design process we saw how decisions about materials are contentious and they act as a catalyst of negotiations that compromise ‘materialities of care.

No influence of oxygen levels on pathogenesis and virus shedding in Salmonid alphavirus (SAV)-challenged Atlantic salmon (Salmo salar L.)

<p>Abstract</p> <p>Background</p> <p>For more than three decades, diseases caused by salmonid alphaviruses (SAV) have become a major problem of increasing economic importance in the European fish-farming industry. However, experimental infection trials with SAV result in low or no mortality i.e very different from most field outbreaks of pancreas disease (PD). This probably reflects the difficulties in reproducing complex biotic and abiotic field conditions in the laboratory. In this study we looked at the relationship between SAV-infection in salmon and sub-lethal environmental hypoxia as a result of reduced flow-through in tank systems.</p> <p>Results</p> <p>The experiment demonstrated that constant reduced oxygen levels (60-65% oxygen saturation: 6.5-7.0 mg/L) did not significantly increase the severity or the progress of pancreas disease (PD). These conclusions are based upon assessments of a semi-quantitative histopathological lesion score system, morbidities/mortalities, and levels of SAV RNA in tissues and water (measured by 1 MDS electropositive virus filters and downstream real-time RT-PCR). Furthermore, we demonstrate that the fish population shed detectable levels of the virus into the surrounding water during viraemia; 4-13 days after i.p. infection, and prior to appearance of severe lesions in heart (21-35 dpi). After this period, viral RNA from SAV could not be detected in water samples although still present in tissues (gills and hearts) at lasting low levels. Lesions could be seen in exocrine pancreas at 7-21 days post infection, but no muscle lesions were seen.</p> <p>Conclusions</p> <p>In our study, experimentally induced hypoxia failed to explain the discrepancy between the severities reported from field outbreaks of SAV-disease and experimental infections. Reduction of oxygen levels to constant suboptimal levels had no effect on the severity of lesions caused by SAV-infection or the progress of the disease. Furthermore, we present a modified VIRADEL method which can be used to detect virus in water and to supplement experimental infection trials with information related to viral shedding. By using this method, we were able to demonstrate for the first time that shedding of SAV from the fish population into the surrounding water coincides with viraemia.</p

LAB/NTAL Facilitates Fungal/PAMP-induced IL-12 and IFN-γ Production by Repressing β-Catenin Activation in Dendritic Cells.

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2−/− mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted inLat2−/− DCs. Accordingly, Lat2−/− DCs directed reduced Th1 polarization in vitro and Lat2−/−mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. // METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. // RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). // CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. // CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883

Stres na radu i zdravlje medicinskih sestara u jedinicama intenzivne njege u Srbiji

The aim of this study was to identify and analyse professional stressors, evaluate the level of stress in nurses in Intensive Care Units (ICU), and assess the correlation between the perception of stress and psychological and somatic symptoms or diseases shown by nurses. The research, designed as a crosssectional study, was carried out in the Intensive Care Units (ICU), in health centres in Serbia. The sample population encompassed 1000 nurses. Expanded Nursing Stress Scale (ENSS) was used as the research instrument. ENSS revealed a valid metric characteristic within our sample population. Nurses from ICUs rated situations involving physical and psychological working environments as the most stressful ones, whereas situations related to social working environment were described as less stressful; however, the differences in the perception of stressfulness of these environments were minor. Socio-demographic determinants of the participants (age, marital status and education level) significantly affected the perception of stress at work. Significant differences in the perception of stressfulness of particular stress factors were observed among nurses with respect to psychological and somatic symptoms (such as headache, insomnia, fatigue, despair, lower back pain, mood swings etc.) and certain diseases (such as hypertension, myocardial infarction, stroke, diabetes mellitus etc). In view of permanent escalation of professional stressors, creating a supportive working environment is essential for positive health outcomes, prevention of job-related diseases and better protection of already ill nurses.Cilj je ovoga rada bio identifi cirati i analizirati profesionalne stresore, procijeniti razinu stresa kod medicinskih sestara u jedinicama intenzivne njege te procijeniti korelaciju između percepcije stresa i prisutnosti psiholoških i somatskih simptoma ili bolesti kod medicinskih sestara. Istraživanje je provedeno u obliku studije presjeka u Jedinicama intenzivne njege u zdravstvenim centrima u Srbiji. Uzorak se sastojao od 1000 medicinskih sestara-tehničara. Za procjenu i analizu profesionalnih stresora korišten je upitnik Expanded Nursing Stress Scale (ENSS), koji je pokazao validne metrijske karakteristike na našoj ispitanoj populaciji. Medicinske sestre u Jedinicama intenzivne njege ocijenile su situacije iz fizičkoga i psihološkoga radnog okruženja kao izrazito opterećujuće, a situacije iz socijalnoga radnog okruženja kao manje opterećujuće. Razlika u percepciji stresogenosti navedenih radnih okruženja nije bila statistički značajna. Sociodemografske determinante ispitanika (dob, bračno stanje i stupanj obrazovanja) značajno utječu na percepciju stresa na radnom mjestu. Utvrđena je statistički značajna razlika u opažanju stresogenosti pojedinih stresnih situacija na radnom mjestu između medicinskih sestara u odnosu na postojanje psihosomatskih simptoma (kao što su glavobolja, nesanica, umor, očaj, bol u leđima, česte promjene raspoloženja) ili određenih bolesti (kao što su povišena hipertenzija, infarkt miokarda, cerebrovaskularni inzult, šećerna bolest). Zbog sve izraženije prisutnosti profesionalnih stresora nužno je poduzeti određene strateške mjere kod medicinskih sestara u Jedinicama intenzivne njege. Strateške mjere podrazumijevaju unaprjeđenje psihosocijalne radne klime, što bi unaprijedilo njihovo zdravlje i spriječilo nastanak bolesti u svezi s radom, ali i omogućilo bolju zaštitu već oboljelim medicinskim sestrama