Diagnostic accuracy of the primary care screener for affective disorder (PC-SAD) in primary care

Background: Depression goes often unrecognised and untreated in non-psychiatric medical settings. Screening has recently gained acceptance as a first step towards improving depression recognition and management. The Primary Care Screener for Affective Disorders (PC-SAD) is a self-administered questionnaire to screen for Major Depressive Disorder (MDD) and Dysthymic Disorder (Dys) which has a sophisticated scoring algorithm that confers several advantages. This study tested its performance against a ‘gold standard’ diagnostic interview in primary care. Methods: A total of 416 adults attending 13 urban general internal medicine primary care practices completed the PC-SAD. Of 409 who returned a valid PC-SAD, all those scoring positive (N=151) and a random sample (N=106) of those scoring negative were selected for a 3-month telephone follow-up assessment including the administration of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) by a psychiatrist who was masked to PC-SAD results. Results: Most selected patients (N=212) took part in the follow-up assessment. After adjustment for partial verification bias the sensitivity, specificity, positive and negative predictive value for MDD were 90%, 83%, 51%, and 98%. For Dys, the corresponding figures were 78%, 79%, 8%, and 88%. Conclusions: While some study limitations suggest caution in interpreting our results, this study corroborated the diagnostic validity of the PC-SAD, although the low PPV may limit its usefulness with regard to Dys. Given its good psychometric properties and the short average administration time, the PC-SAD might be the screening instrument of choice in settings where the technology for computer automated scoring is available

Deactylase inhibition in myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are clonal haemopoietic progenitor cell disorders characterized by the proliferation of one or more of the haemopoietic lineages (myeloid, erythroid and/or megakaryocytic). The MPNs include eight haematological disorders: chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis (SM), chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), chronic neutrophilic leukemia (CNL), and unclassifiable MPN (MPN, U). Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors (TKIs) for BCR-ABL1+ CML and JAK2 inhibitors for PV, ET and PMF. Histone deacetylase inhibitors (HDACi) are a novel class of drugs capable of altering the acetylation status of both histone and non-histone proteins, thereby affecting a repertoire of cellular functions in neoplastic cells including proliferation, differentiation, immune responses, angiogenesis and survival. Preliminary studies indicate that HDACi when used in combination with tyrosine kinase or JAK2 inhibitors may overcome resistance to the latter agents and enhance the pro-apoptotic effects on MPN cells. This review provides a review of pre-clinical and clinical studies that have explored the use of HDACi as potential therapeutics for MPNs

Towards methodological adventure in cost overrun research : linking process and product

The continued adoption of singular paradigms in the study of construction phenomena has elicited dialectical debates in scholarly literature. Calls have been made for more adventurous research methods, beyond the positivist versus interpretivist philosophical divide traditionally embraced by the industry. This study analyses the extensive scholarly debates, advancing and advocating philosophical positions to understand construction phenomena, and further narrows down the argument to within the specific domain of cost overrun research. A systematic and chronological literature review of the methodological/philosophical underpinnings of 41 papers was carried out. The papers were selected by following a staged exclusion criterion. The study outcome reveals that similar dialectical debates and methodological conservatism are still evident, with the predominance of mono-paradigm studies in the bulk of the empirical literature. Most of the empirical literature either provides interpretivist theoretical explanations from qualitative data or positivistically analyses quantitative data to provide technical explanations. To this end, mixed paradigm examples are spotlighted, demonstrating the relevance of linking process and product via methodological adventure in cost overrun research. Transcending the paradigmic divide is necessary to develop a more useful and contextually anchored view of practice, essential to mitigate and provide a holistic understanding of what drives cost overruns in public projects

MicroRNA degradation by a conserved target RNA regulates animal behavior

International audiencemicroRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3′ UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3′ trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavio

Regulation of microRNA biogenesis and turnover by animals and their viruses

Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes

Exploring the coupled ocean and atmosphere system with a data science approach applied to observations from the Antarctic Circumnavigation Expedition

The Southern Ocean is a critical component of Earth’s climate system, but its remoteness makes it challenging to develop a holistic understanding of its processes from the small scale to the large scale. As a result, our knowledge of this vast region remains largely incomplete. The Antarctic Circumnavigation Expedi�tion (ACE, austral summer 2016/2017) surveyed a large number of variables describing the state of the ocean and the atmosphere, the freshwater cycle, atmospheric chemistry, and ocean biogeochemistry and microbiology. This circumpolar cruise included visits to 12 remote islands, the marginal ice zone, and the Antarctic coast. Here, we use 111 of the observed variables to study the latitudinal gradients, seasonality, shorter-term variations, geographic setting of environmental processes, and interactions between them over the duration of 90 d. To re�duce the dimensionality and complexity of the dataset and make the relations between variables interpretable we applied an unsupervised machine learning method, the sparse principal component analysis (sPCA), which describes environmental processes through 14 latent variables. To derive a robust statistical perspective on these processes and to estimate the uncertainty in the sPCA decomposition, we have developed a bootstrap approach. Our results provide a proof of concept that sPCA with uncertainty analysis is able to identify temporal patterns from diurnal to seasonal cycles, as well as geographical gradients and “hotspots” of interaction between envi�ronmental compartments. While confirming many well known processes, our analysis provides novel insights into the Southern Ocean water cycle (freshwater fluxes), trace gases (interplay between seasonality, sources, and sinks), and microbial communities (nutrient limitation and island mass effects at the largest scale ever reported). More specifically, we identify the important role of the oceanic circulations, frontal zones, and islands in shap�ing the nutrient availability that controls biological community composition and productivity; the fact that sea ice controls sea water salinity, dampens the wave field, and is associated with increased phytoplankton growth and net community productivity possibly due to iron fertilisation and reduced light limitation; and the clear regional patterns of aerosol characteristics that have emerged, stressing the role of the sea state, atmospheric chemical processing, and source processes near hotspots for the availability of cloud condensation nuclei and hence cloud formation. A set of key variables and their combinations, such as the difference between the air and sea surface temperature, atmospheric pressure, sea surface height, geostrophic currents, upper-ocean layer light intensity, surface wind speed and relative humidity played an important role in our analysis, highlighting the necessity for Earth system models to represent them adequately. In conclusion, our study highlights the use of sPCA to identify key ocean–atmosphere interactions across physical, chemical, and biological processes and their associated spatio-temporal scales. It thereby fills an important gap between simple correlation analyses and complex Earth system models. The sPCA processing code is available as open-access from the following link: https://renkulab.io/gitlab/ACE-ASAID/spca-decomposition (last access: 29 March 2021). As we show here, it can be used for an exploration of environmental data that is less prone to cognitive biases (and confirmation biases in particular) compared to traditional regression analysis that might be affected by the underlying research question

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity

Overview of the Alaskan Layered Pollution and Chemical Analysis (ALPACA) Field Experiment

The Alaskan Layered Pollution And Chemical Analysis (ALPACA) field experiment was a collaborative study designed to improve understanding of pollution sources and chemical processes during winter (cold climate and low-photochemical activity), to investigate indoor pollution, and to study dispersion of pollution as affected by frequent temperature inversions. A number of the research goals were motivated by questions raised by residents of Fairbanks, Alaska, where the study was held. This paper describes the measurement strategies and the conditions encountered during the January and February 2022 field experiment, and reports early examples of how the measurements addressed research goals, particularly those of interest to the residents. Outdoor air measurements showed high concentrations of particulate matter and pollutant gases including volatile organic carbon species. During pollution events, low winds and extremely stable atmospheric conditions trapped pollution below 73 m, an extremely shallow vertical scale. Tethered-balloon-based measurements intercepted plumes aloft, which were associated with power plant point sources through transport modeling. Because cold climate residents spend much of their time indoors, the study included an indoor air quality component, where measurements were made inside and outside a house to study infiltration and indoor sources. In the absence of indoor activities such as cooking and/or heating with a pellet stove, indoor particulate matter concentrations were lower than outdoors; however, cooking and pellet stove burns often caused higher indoor particulate matter concentrations than outdoors. The mass-normalized particulate matter oxidative potential, a health-relevant property measured here by the reactivity with dithiothreiol, of indoor particles varied by source, with cooking particles having less oxidative potential per mass than pellet stove particles

Uridylation and adenylation of RNAs

The posttranscriptional addition of nontemplated nucleotides to the 3′ ends of RNA molecules can have a significant impact on their stability and biological function. It has been recently discovered that nontemplated addition of uridine or adenosine to the 3′ ends of RNAs occurs in different organisms ranging from algae to humans, and on different kinds of RNAs, such as histone mRNAs, mRNA fragments, U6 snRNA, mature small RNAs and their precursors etc. These modifications may lead to different outcomes, such as increasing RNA decay, promoting or inhibiting RNA processing, or changing RNA activity. Growing pieces of evidence have revealed that such modifications can be RNA sequence-specific and subjected to temporal or spatial regulation in development. RNA tailing and its outcomes have been associated with human diseases such as cancer. Here, we review recent developments in RNA uridylation and adenylation and discuss the future prospects in this research area