The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ...ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.
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•Ultra-deep rRNA-depleted RNA sequencing of 144 localized prostate tumors•Fusion gene profiles differentiate localized from metastatic disease•Widespread RNA circularization events define clinically distinct tumor subtypes•Functional screening reveals pervasive circular isoform-specific essentiality
RNA circularization is a pervasive feature of prostate cancer, with hundreds of circRNAs promoting cell proliferation through functions distinct from their parental linear RNA.
Objectives
To understand the development of iron deficiency in obesity and its long‐term impact on the profile of anemia in spontaneously obese nonhuman primates.
Methods
The study included 69 adult ...male nonhuman primates, (NHPs, Macaca mulatta, rhesus monkeys), ranging from normal to obese, and type 2 diabetes (T2D) as defined for humans.
Results
Iron deficiency was present in 31.9% and mild anemia in 13% of the rhesus monkey in the colony. Serum iron levels were significantly lower in obese (p < .01) and T2D (p < .01)) compared with normal NHP. Obese NHPs also had significantly higher hemoglobin (p < .05), and red blood cell count (p < .05) than normal weight NHPs, thus not related to anemia.
Conclusions
Iron deficiency with increased hemoglobin and red blood cells was significantly associated with increased adiposity, insulin resistance, and diabetes. Iron deficiency does not cause and is not related to anemia in obese and T2D NHPs.
Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct ...etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management.
Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis.
After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA
DS
-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091).
Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal.
ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigate the plasma environment of comet 67P/Churyumov‐Gerasimenko, the target of the European Space Agency's Rosetta mission. Rosetta will rendezvous with the comet in 2014 at almost 3.5 AU ...and follow it all the way to and past perihelion at 1.3 AU. During its journey towards the inner solar system the comet's environment will significantly change. The interaction of the solar wind with a well developed neutral coma leads to the formation of an upstream bow shock and, closer to the comet, the inner shock separating the solar wind, with cometary pick‐up ions mass‐loaded, from the inner cometary ions which are dragged outward through abundant collisions and charge exchange with the expanding neutral gas. As a consequence the interplanetary magnetic field is prevented from penetrating the innermost region of the comet, the so‐called magnetic cavity. We use our magnetohydrodynamics model BATSRUS (Block‐Adaptive‐Tree‐Solarwind‐Roe‐Upwind‐Scheme) to simulate the solar wind – comet interaction. The model includes photoionization, ion‐electron recombination, and charge exchange. Under certain conditions our model predicts an unstable plasma flow at the inner shock. We show that the plasma shear flow around the magnetic cavity can lead to Kelvin‐Helmholtz instabilities. We investigate the onset of this phenomenon with change of heliocentric distance and furthermore show that a previously stable magnetic cavity boundary can become unstable when the neutral gas is predominately released from the dayside of the comet.
Key Points
MHD model of a comet's plasma‐solar wind interaction
Peculiar plasma flows at the magnetic cavity boundary associated to jets
Kelvin‐Helmholtz instabilities predicted to occur under certain conditions
Fatty acids are well-established biomarkers used to characterize trophic ecology, food-web linkages, and the ecological niche of many different taxa. Most often, fatty acids that are examined include ...only those previously identified as “dietary” or “extended dietary” biomarkers. Fatty acids considered as nondietary biomarkers, however, represent numerous fatty acids that can be extracted. Some studies may include nondietary fatty acids (i.e., combined with dietary fatty acids), but do not specifically assess them, whereas in other studies, these data are discarded. In this study, we explored whether nondietary biomarker fatty acids can provide worthwhile information by assessing their ability to discriminate intraspecific diversity within and between lakes. Nondietary fatty acids used as biomarkers delineated variation among regions, among locations within a lake, and among ecotypes within a species. Physiological differences that arise from differences in energy processing can be adaptive and linked to habitat use by a species’ ecotype and likely explains why nondietary fatty acid biomarkers can be a relevant tool to delineate intraspecific diversity. Little is known about the nondietary-mediated differences in fatty acid composition, but our results showed that nondietary fatty acid biomarkers can be useful tool in identifying variation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The pathology of allergic diseases involves type 2 immune cells, such as Th2, ILC2, and basophils exerting their effect by production of IL‐4, IL‐5, and IL‐13. However, surface receptors ...that are specifically expressed on type 2 immune cells are less well documented. The aim of this investigation was to identify surface markers associated with type 2 inflammation.
Methods
Naïve human CD4+ T cells were short‐term activated in the presence or absence of IL‐4 and analyzed for expression of >300 cell‐surface proteins. Ex vivo‐isolated peripheral blood mononuclear cells (PBMCs) from peanut‐allergic (PA) and nonallergic subjects were stimulated (14–16 h) with peanut extract to detect peanut‐specific CD4+CD154+ T cells. Biopsies were obtained for transcriptomic analysis from healthy controls and patients with extrinsic or intrinsic atopic dermatitis (AD) and psoriasis.
Results
Expression analysis of >300 surface proteins enabled identification of IL‐4‐upregulated surface proteins, such as CD90, CD108, CD109, and CD200R (CD200R1). Additional analysis of in vitro‐differentiated Th0, Th1, and Th2 cultures identified CD200R as upregulated on Th2 cells. From ex vivo‐isolated PBMCs, we found high expression of CD200R on Th2 and ILC2 cells and basophils. In PA subjects, the peanut‐specific Th2 (CD154+CRTh2+) cells expressed more CD200R than the non‐allergen‐specific Th2 (CD154−CRTh2+) cells. Moreover, costaining of CD161 and CD200R identified peanut‐specific highly differentiated IL‐4+IL‐5+ Th2 cells. Finally, transcriptomic analysis revealed upregulation of CD200R in lesional skin from subjects with an extrinsic AD phenotype compared to healthy skin.
Conclusion
These results indicate that CD200R expression strongly correlates with Th2 pathology; though, the mechanism is as yet elusive.
Subglacial till can deform when overriding ice exerts shear traction at the ice--till interface. This deformation leaves a strain signature in the till, aligning grains in the direction of ice flow ...and producing a range of diagnostic microstructures. Constraining the conditions that produce these kinematic indicators is key to interpreting the myriad of features found in basal till deposits. Here, we used a cryogenic ring shear device with transparent sample chamber walls to slip a ring of temperate ice over a till bed from which we examined the strain signature in the till. We used cameras mounted to the side of the ring shear and bead strings inserted in the till to estimate the strain distribution within the till layer. Following the completion of the experiment, we extracted and analyzed anisotropy of magnetic susceptibility (AMS) samples and created thin sections of the till bed for microstructure analysis. We then compared the AMS and microstructures with the observed strain history to examine the relationship between kinematic indicators and strain in a setting where shear traction is supplied by ice. We found that AMS fabrics show a high degree of clustering in regions of high strain near the ice--till interface. In the uppermost zone of till, k.sub.1 eigenvector azimuths are generally aligned with ice flow, and S.sub.1 eigenvalues are high. However, S.sub.1 eigenvalues and the alignment of the k.sub.1 eigenvector with ice flow decrease nonlinearly with distance from the ice--till interface. There is a high occurrence of microshears in the zone of increased deformation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background After heart valve surgery, knowledge on long-term self-reported health status and readmission is lacking. Thus, the optimal strategy for out-patient management after surgery ...remains unclear. Methods Using a nationwide survey with linkage to Danish registers with one year follow-up, we included all adults 6–12 months after heart valve surgery irrespective of valve procedure, during Jan–June 2011 (n = 867). Participants completed a questionnaire regarding health-status (n = 742), and answers were compared with age- and sex-matched healthy controls. Readmission rates and mortality were investigated. Results After valve surgery, the self-reported health was lower (Short Form-36 (SF-36) Physical Component Scale (PCS): 44.5 vs. 50.6 and Mental Component Scale (MCS): 51.9 vs. 55.0, p < 0.0001) and more were physically sedentary compared with healthy controls (11.1% vs. 15.2%). Clinical signs of anxiety and depression were present in 13.6% and 13.8%, respectively (Hospital Anxiety and Depression Scale score ≥ 8). Twelve months following discharge, 483 persons (56%) were readmitted. Readmission was associated with lower self-reported health (SF-36 PCS: 46.5 vs. 43.9, and MCS 52.2 vs. 50.7). Higher age (hazard ratio (95% CI): 1.3 (1.0–1.6)), male sex (1.2 (1.0–1.5)), mitral valve surgery (1.3 (1.0–1.6)), and infective endocarditis after surgery (1.8 (1.1–3.0), p: 0.01) predicted readmission, whereas higher age (2.3 (1.0–5.4)), higher comorbidity score (3.2 (1.8–6.0)), and infective endocarditis after surgery (3.2 (1.2–8.9)) predicted mortality. Conclusions 6–12 months after heart valve surgery the readmission rate is high and the self-reported health status is low. Readmission is associated with low self-reported health. Therefore, targeted follow-up strategies post-surgery are needed.
Background: Allergy to hazelnuts is a common example of birch pollen related food allergy. Symptoms upon ingestion are often confined to the mouth and throat, but severe systemic reactions have been ...described in some patients. The aim of the study was to evaluate the reduction in allergenicity by roasting of the nuts.
Methods: Double‐blind, placebo‐controlled food challenges (DBPCFC) with roasted hazelnuts (140°C, 40 min) were performed in 17 birch pollen allergic patients with DBPCFC‐confirmed food allergy to raw hazelnuts. The effect of roasting was further evaluated by skin prick test (SPT), histamine release (HR), measurement of specific IgE, and IgE‐inhibition experiments.
Results: In 5/17 patients the DBPCFC with the roasted nuts were positive. The symptoms were generally mild and included OAS (oral allergy syndrome) in all patients. Roasting of the nuts significantly reduced the allergenic activity evaluated by SPT, HR, specific IgE, and IgE‐inhibition. Immunoblotting experiments with recombinant hazelnut allergens showed sensitization against Cor a 1.04 in 16/17 patients and against Cor a 2 in 7/17 patients. None of the patients were sensitized to Cor a 8. Challenge‐positive patients did not differ from the rest in IgE‐binding pattern.
Conclusions: All the applied methods indicated that roasting of hazelnuts reduces the allergenicity, but since 5/17 birch pollen allergic patients were DBPCFC‐positive to the roasted nuts, ingestion of roasted hazelnuts or products containing roasted hazelnuts can not be considered safe for a number of hazelnut allergic consumers. For patients with a history of severe allergic symptoms upon ingestion of hazelnuts, thorough and conscientious food labelling of hazelnuts and hazelnut residues is essential.
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