In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular ...understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The World Health Organization's (WHO’s) Health Promoting Schools (HPS) framework is an holistic, settings‐based approach to promoting health and educational attainment in school. The ...effectiveness of this approach has not been previously rigorously reviewed.
Objectives
To assess the effectiveness of the Health Promoting Schools (HPS) framework in improving the health and well‐being of students and their academic achievement.
Search methods
We searched the following electronic databases in January 2011 and again in March and April 2013: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, Campbell Library, ASSIA, BiblioMap, CAB s, IBSS, Social Science Citation Index, Sociological s, TRoPHI, Global Health Database, SIGLE, Australian Education Index, British Education Index, Education Resources Information Centre, Database of Education Research, Dissertation Express, Index to Theses in Great Britain and Ireland, ClinicalTrials.gov, Current controlled trials, and WHO International Clinical Trials Registry Platform. We also searched relevant websites, handsearched reference lists, and used citation tracking to identify other relevant articles.
Selection criteria
We included cluster‐randomised controlled trials where randomisation took place at the level of school, district or other geographical area. Participants were children and young people aged four to 18 years, attending schools or colleges. In this review, we define HPS interventions as comprising the following three elements: input to the curriculum; changes to the school’s ethos or environment or both; and engagement with families or communities, or both. We compared this intervention against schools that implemented either no intervention or continued with their usual practice, or any programme that included just one or two of the above mentioned HPS elements.
Data collection and analysis
At least two review authors identified relevant trials, extracted data, and assessed risk of bias in the trials. We grouped different types of interventions according to the health topic targeted or the approach used, or both. Where data permitted, we performed random‐effects meta‐analyses to provide a summary of results across studies.
Main results
We included 67 eligible cluster trials, randomising 1443 schools or districts. This is made up of 1345 schools and 98 districts. The studies tackled a range of health issues: physical activity (4), nutrition (12), physical activity and nutrition combined (18), bullying (7), tobacco (5), alcohol (2), sexual health (2), violence (2), mental health (2), hand‐washing (2), multiple risk behaviours (7), cycle‐helmet use (1), eating disorders (1), sun protection (1), and oral health (1). The quality of evidence overall was low to moderate as determined by the GRADE approach. 'Risk of bias' assessments identified methodological limitations, including heavy reliance on self‐reported data and high attrition rates for some studies. In addition, there was a lack of long‐term follow‐up data for most studies.
We found positive effects for some interventions for: body mass index (BMI), physical activity, physical fitness, fruit and vegetable intake, tobacco use, and being bullied. Intervention effects were generally small but have the potential to produce public health benefits at the population level. We found little evidence of effectiveness for standardised body mass index (zBMI) and no evidence of effectiveness for fat intake, alcohol use, drug use, mental health, violence and bullying others; however, only a small number of studies focused on these latter outcomes. It was not possible to meta‐analyse data on other health outcomes due to lack of data. Few studies provided details on adverse events or outcomes related to the interventions. In addition, few studies included any academic, attendance or school‐related outcomes. We therefore cannot draw any clear conclusions as to the effectiveness of this approach for improving academic achievement.
Authors' conclusions
The results of this review provide evidence for the effectiveness of some interventions based on the HPS framework for improving certain health outcomes but not others. More well‐designed research is required to establish the effectiveness of this approach for other health topics and academic achievement.
In Paris, France, December 2015, the Conference of the Parties (COP) to the United Nations Framework Convention on Climate Change (UNFCCC) invited the Intergovernmental Panel on Climate Change (IPCC) ...to provide a special report in 2018 on the impacts of global warming of 1.5 °C above pre-industrial levels and related global greenhouse gas emission pathways. In Nairobi, Kenya, April 2016, the IPCC panel accepted the invitation. Here we describe the response devised within the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) to provide tailored, cross-sectorally consistent impact projections to broaden the scientific basis for the report. The simulation protocol is designed to allow for (1) separation of the impacts of historical warming starting from pre-industrial conditions from impacts of other drivers such as historical land-use changes (based on pre-industrial and historical impact model simulations); (2) quantification of the impacts of additional warming up to 1.5 °C, including a potential overshoot and long-term impacts up to 2299, and comparison to higher levels of global mean temperature change (based on the low-emissions Representative Concentration Pathway RCP2.6 and a no-mitigation pathway RCP6.0) with socio-economic conditions fixed at 2005 levels; and (3) assessment of the climate effects based on the same climate scenarios while accounting for simultaneous changes in socio-economic conditions following the middle-of-the-road Shared Socioeconomic Pathway (SSP2, Fricko et al., 2016) and in particular differential bioenergy requirements associated with the transformation of the energy system to comply with RCP2.6 compared to RCP6.0. With the aim of providing the scientific basis for an aggregation of impacts across sectors and analysis of cross-sectoral interactions that may dampen or amplify sectoral impacts, the protocol is designed to facilitate consistent impact projections from a range of impact models across different sectors (global and regional hydrology, lakes, global crops, global vegetation, regional forests, global and regional marine ecosystems and fisheries, global and regional coastal infrastructure, energy supply and demand, temperature-related mortality, and global terrestrial biodiversity).
SARS-CoV-2 produces two long viral protein precursors from one open reading frame using a highly conserved RNA pseudoknot that enhances programmed -1 ribosomal frameshifting. The 1.3 Å-resolution ...X-ray structure of the pseudoknot reveals three coaxially stacked helices buttressed by idiosyncratic base triples from loop residues. This structure represents a frameshift-stimulating state that must be deformed by the ribosome and exhibits base-triple-adjacent pockets that could be targeted by future small-molecule therapeutics.
Sarcomas are a rare group of mesenchymal cancers comprising over 70 different histological subtypes. For the majority of these diseases, the molecular understanding of the basis of their initiation ...and progression remains unclear. As such, limited clinical progress in prognosis or therapeutic regimens have been made over the past few decades. Proteomics techniques are being increasingly utilised in the field of sarcoma research. Proteomic research efforts have thus far focused on histological subtype characterisation for the improvement of biological understanding, as well as for the identification of candidate diagnostic, predictive, and prognostic biomarkers for use in clinic. However, the field itself is in its infancy, and none of these proteomic research findings have been translated into the clinic. In this review, we provide a brief overview of the proteomic strategies that have been employed in sarcoma research. We evaluate key proteomic studies concerning several rare and ultra-rare sarcoma subtypes including, gastrointestinal stromal tumours, osteosarcoma, liposarcoma, leiomyosarcoma, malignant rhabdoid tumours, Ewing sarcoma, myxofibrosarcoma, and alveolar soft part sarcoma. Consequently, we illustrate how routine implementation of proteomics within sarcoma research, integration of proteomics with other molecular profiling data, and incorporation of proteomics into clinical trial studies has the potential to propel the biological and clinical understanding of this group of complex rare cancers moving forward.
Background and Aims
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are common and increasing in prevalence. We examined prevalence and predictors of functional impairment ...in biopsy-proven ALD and NAFLD. Change in function over 3 years was explored.
Methods
Validated functional, cognitive, autonomic, and fatigue symptom assessment tools were completed by patients who had attended our liver clinic.
Results
Totals of 224 NAFLD and 107 ALD patients returned the assessment tools. NAFLD and ALD demonstrated comparable functional difficulties, which were significantly worse than controls (
p
< 0.001) with the proportion of participants experiencing difficulty significantly higher
x
2
8.93(3), (
p
= 0.01). No significant functional difficulty was demonstrated between those participants who were pre-cirrhotic or cirrhotic. Independent associations were present between difficulty with function in ALD and higher burden of autonomic and cognitive symptoms (
p
= 0.02) and in NAFLD-increased cognitive difficulty (
p
< 0.0001), age (
p
= 0.001), fatigue (
p
= 0.01), lower albumin (
p
= 0.02), and bilirubin (
p
= 0.04). PHAQ scores increased 21 % 2008–2011 {(3.2/15.6) 15.6 (0–93.8) to 18.75 (0–90.6)}. Functional difficulty of participants alive 15.6 (0–96.9) was significantly less compared to those who died 40.6 (0–100) (
p
= 0.02).
Conclusions
NAFLD and ALD patients experience significant functional impairment affecting activities of daily living that persists over time. This has implications for the management of liver disease and service provision.
Urban development has major impacts on connectivity among wildlife populations and is thus likely an important factor shaping pathogen transmission in wildlife. However, most investigations of ...wildlife diseases in urban areas focus on prevalence and infection risk rather than potential effects of urbanization on transmission itself. Feline immunodeficiency virus (FIV) is a directly transmitted retrovirus that infects many felid species and can be used as a model for studying pathogen transmission at landscape scales. We investigated phylogenetic relationships among FIV isolates sampled from five bobcat (Lynx rufus) populations in coastal southern California that appear isolated due to major highways and dense urban development. Divergence dates among FIV phylogenetic lineages in several cases reflected historical urban growth and construction of major highways. We found strong FIV phylogeographic structure among three host populations north‐west of Los Angeles, largely coincident with host genetic structure. In contrast, relatively little FIV phylogeographic structure existed among two genetically distinct host populations south‐east of Los Angeles. Rates of FIV transfer among host populations did not vary significantly, with the lack of phylogenetic structure south‐east of Los Angeles unlikely to reflect frequent contemporary transmission among populations. Our results indicate that major barriers to host gene flow can also act as barriers to pathogen spread, suggesting potentially reduced susceptibility of fragmented populations to novel directly transmitted pathogens. Infrequent exchange of FIV among host populations suggests that populations would best be managed as distinct units in the event of a severe disease outbreak. Phylogeographic inference of pathogen transmission is useful for estimating the ability of geographic barriers to constrain disease spread and can provide insights into contemporary and historical drivers of host population connectivity.
Magnetic anisotropy allows magnets to maintain their direction of magnetization over time. Using a scanning tunneling microscope to observe spin excitations, we determined the orientation and ...strength of the anisotropies of individual iron and manganese atoms on a thin layer of copper nitride. The relative intensities of the inelastic tunneling processes are consistent with dipolar interactions, as seen for inelastic neutron scattering. First-principles calculations indicate that the magnetic atoms become incorporated into a polar covalent surface molecular network in the copper nitride. These structures, which provide atom-by-atom accessibility via local probes, have the potential for engineering anisotropies large enough to produce stable magnetization at low temperatures for a single atomic spin.
Abstract
RNAs begin to fold and function during transcription. Riboswitches undergo cotranscriptional switching in the context of transcription elongation, RNA folding, and ligand binding. To ...investigate how these processes jointly modulate the function of the folate stress-sensing
Fusobacterium ulcerans
ZTP riboswitch, we apply a single-molecule vectorial folding (VF) assay in which an engineered superhelicase Rep-X sequentially releases fluorescently labeled riboswitch RNA from a heteroduplex in a 5′-to-3′ direction, at ~60 nt s
−1
comparable to the speed of bacterial RNA polymerase (RNAP). We demonstrate that the ZTP riboswitch is kinetically controlled and that its activation is favored by slower unwinding, strategic pausing between but not before key folding elements, or a weakened transcription terminator. Real-time single-molecule monitoring captures folding riboswitches in multiple states, including an intermediate responsible for delayed terminator formation. These results show how individual nascent RNAs occupy distinct channels within the folding landscape that controls the fate of the riboswitch.
Reaching the magnetic anisotropy limit of a 3d metal atom Rau, Ileana G.; Baumann, Susanne; Rusponi, Stefano ...
Science (American Association for the Advancement of Science),
05/2014, Letnik:
344, Številka:
6187
Journal Article
Recenzirano
Designing systems with large magnetic anisotropy is critical to realize nanoscopic magnets. Thus far, the magnetic anisotropy energy per atom in single-molecule magnets and ferromagnetic films ...remains typically one to two orders of magnitude below the theoretical limit imposed by the atomic spin-orbit interaction. We realized the maximum magnetic anisotropy for a 3d transition metal atom by coordinating a single Co atom to the O site of an MgO(100) surface. Scanning tunneling spectroscopy reveals a record-high zero-field splitting of 58 millielectron volts as well as slow relaxation of the Co atom's magnetization. This striking behavior originates from the dominating axial ligand field at the O adsorption site, which leads to out-of-plane uniaxial anisotropy while preserving the gas-phase orbital moment of Co, as observed with x-ray magnetic circular dichroism.
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