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Thermodynamic stability as well as structural, electronic, and elastic properties of boron-deficient AlB _2 -type tantalum diborides, which is designated as $\alpha-$ TaB $_{2-x}$ , due to the presence of vacancies at its boron sublattice are studied via first-principles calculations. The results reveal that $\alpha-$ TaB $_{2-x}$ , where 0.167 $\lesssim\,x\,\lesssim$ 0.25, is thermodynamically stable even at absolute zero. On the other hand, the shear and Young’s moduli as well as the hardness of stable $\alpha-$ TaB $_{2-x}$ are predicted to be superior as compared to those of $\alpha-$ TaB _2 . The changes in the relative stability and also the elastic properties of $\alpha-$ TaB $_{2-x}$ with respect to those of $\alpha-$ TaB _2 can be explained by the competitive effect between the decrease in the number of electrons filling in the antibonding states of $\alpha-$ TaB _2 and the increase in the number of broken bonds around the vacancies, both induced by the increase in the concentration of boron vacancies. A good agreement between our calculated lattice parameters, elastic moduli and hardness of $\alpha-$ TaB $_{2-x}$ and the experimentally measured data of as-synthesized AlB _2 -type tantalum diborides with the claimed composition of TaB $_{\thicksim2}$ , available in the literature, suggests that, instead of being a line compound with a stoichiometric composition of TaB _2 , AlB _2 -type tantalum diboride is readily boron-deficient, and its stable composition in equilibrium may be ranging at least from TaB $_{\thicksim1.833}$ to TaB $_{\thicksim1.75}$ . Furthermore, the substitution of vacancies for boron atoms in $\alpha-$ TaB _2 is responsible for destabilization of WB _2 -type tantalum diboride and orthorhombic Ta _2 B _3 , predicted in the previous theoretical studies to be thermodynamically stable in the Ta−B system, and it thus enables the interpretation of why the two compounds have never been realized in actual experiments.

The aim of the study was to analyse the impact of renal transplantation on body composition (Body Cell Mass) in adult kidney transplant recipients.Body Cell Mass (BCM) was calculated from total body potassium (TBK), determined from K-40 in a whole body counter. Patients were measured before transplantation and 3 months, 1 year and 2 years after transplantation. Patients were encouraged to take part in physical exercise, but supervised physical training was not included in the study Out of 50 included patients, 44 have had a kidney transplant (9 F, 35 M). Mean age at transplantation was 49 (23-72) years. Before transplantation, mean BW was 80 (SD 13) kg and mean BMI 25,6 (SD 4) kg/m2. Mean TBK was 3162 (SD 690) mmol, corresponding to 90 % of predicted value. In the 1 year follow up, no significant changes in TBK (n=42) were found, nor in patients examined 2-3 years after transplantation (n=35). To examine whether post transplantation improvement of BCM will appear later, as has been seen in Liver Transplant recipients, patients were invited to a follow up measurement. So far, 11 patients have repeated the measurement 6 (4½-7½) years after transplantation. TBK improvements of >10% were seen in 4 patients, decreases of >10% in 2 patients, and changes of a lower magnitude in remaining patients. In conclusion, no increase in Body Cell Mass was seen in this unselected group of kidney transplant recipients during the first 2-3 years after transplantation. Pro catabolic events and low physical activity may explain this lack ofimprovement.

Understanding the coupling of clouds to large-scale circulation is one of the grand challenges for the global climate research community. In this context, realistically modelling the vertical structure of cloud radiative heating (CRH) and/or cooling in Earth system models is a key premise to understand this coupling. Here, we evaluate CRH in two versions of the European Community Earth System Model (EC-Earth) using retrievals derived from the combined radar and lidar data from the CloudSat and Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) satellites. One model version is also used with two different horizontal resolutions. Our study evaluates large-scale intraseasonal variability in the vertical structure of CRH and cloud properties and investigates the changes in CRH during different phases of the El Niño–Southern Oscillation (ENSO), a process that dominates the interannual climate variability in the tropics. EC-Earth generally captures both the intraseasonal and meridional pattern of variability in CRH over the convectively active and stratocumulus regions and the CRH during the positive and negative phases of ENSO. However, two key differences between model simulations and satellite retrievals emerge. First, the magnitude of CRH, in the upper troposphere, over the convectively active zones is up to twice as large in the models compared to the satellite data. Further dissection of net CRH into its shortwave and longwave components reveals noticeable differences in their vertical structure. The shortwave component of the radiative heating is overestimated by all model versions in the lowermost troposphere and underestimated in the middle troposphere. These over- and underestimates of shortwave heating are partly compensated by an overestimate of longwave cooling in the lowermost troposphere and heating in the middle troposphere. The biases in CRH can be traced back to disagreement in cloud amount and cloud water content. There is no noticeable improvement of CRH by increasing the horizontal resolution in the model alone. Our findings highlight the importance of evaluating models with satellite observations that resolve the vertical structure of clouds and cloud properties.

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukemia.

Abstract Background Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear. Methods Utilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/− mouse model was used to detect entero-endocrine cell hyperplasia with IHC. Results Analyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/− mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease. Conclusions Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.

Background The cardiovagal function can be assessed by quantification of respiratory sinus arrhythmia (RSA) during a deep breathing test. However, population studies of RSA and coronary atherosclerosis are lacking. This population‐based study examined the relationship between RSA during deep breathing and coronary atherosclerosis, assessed by coronary artery calcium score (CACS). Methods and Results SCAPIS (Swedish Cardiopulmonary Bioimage Study) randomly invited men and women aged 50 to 64 years from the general population. CACS was obtained from computed tomography scanning, and deep breathing tests were performed in 4654 individuals. Expiration–inspiration differences (E‐Is) of heart rates were calculated, and reduced RSA was defined as E‐I in the lowest decile of the population. The relationship between reduced RSA and CACS (CACS≥100 or CACS≥300) was calculated using multivariable‐adjusted logistic regression. The proportion of CACS≥100 was 24% in the lowest decile of E‐I and 12% in individuals with E‐I above the lowest decile (P

Antisecretory factor (AF) is a protein which regulates fluid transport in the intestine and other organs. Extensive malting of wheat releases certain chemicals which induce AF and inhibit enterotoxic diarrhoea. The aim of this study was to identify AF-inducing substances in wheat malt. The active fractions of the malt leachate contained guaiacol, ferulic acid, and vanillic acid. These three 2-methyl-catechols gave >50% inhibition of cholera toxin-induced secretion in the gut. In contrast, fully methylated catechol had the opposite action; that is, they were secretory rather than antisecretory. Guaiacol and ferulic acid were further shown to induce AF in blood. Since the 2-methoxyphenol structure is present in substances binding to the vanilloid receptor, TRPV1, the specific blocker of this receptor—capsazepine—was tested. This substance exerted >50% inhibition of cholera secretion. Thus 2-methyl-catechols in wheat malt induce AF, and probably exert their effect via the TRPV1 receptor.

Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) receptor upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K+ stimuli. Furthermore, an in vivo toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ETB receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ETB receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed ex vivo on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ETB receptor upregulation. Cremophor EL has an additional positive effect, preventing functional ETB receptor upregulation, making it suitable as a drug delivery system.

Split fluorescent proteins have wide applicability as biosensors for protein-protein interactions, genetically encoded tags for protein detection and localization, as well as fusion partners in super-resolution microscopy. We have here established and validated a novel platform for functional analysis of leave-one-out split fluorescent proteins (LOO-FPs) in high throughput and with rapid turnover. We have screened more than 12,000 variants of the beta-strand split fragment using high-density peptide microarrays for binding and functional complementation in Green Fluorescent Protein. We studied the effect of peptide length and the effect of different linkers to the solid support. We further mapped the effect of all possible amino acid substitutions on each position as well as in the context of some single and double amino acid substitutions. As all peptides were tested in 12 duplicates, the analysis rests on a firm statistical basis allowing for confirmation of the robustness and precision of the method. Based on experiments in solution, we conclude that under the given conditions, the signal intensity on the peptide microarray faithfully reflects the binding affinity between the split fragments. With this, we are able to identify a peptide with 9-fold higher affinity than the starting peptide.

The composition of the diet affects many processes in the body, including body weight and endocrine system. We have previously shown that dietary fat also affects the immune system. Mice fed high fat diet rich in polyunsaturated fatty acids survive S. aureus infection to a much greater extent than mice fed high fat diet rich in saturated fatty acids. Here we present data regarding the dietary effects on protein expression in spleen from mice fed three different diets, I) low fat/chow diet (LFD, n = 4), II) high fat diet rich in saturated fatty acids (HFD-S, n = 4) and III) high fat diet rich in polyunsaturated fatty acids (HFD-P, n = 4). We performed mass spectrophotometry based quantitative proteomics analysis of isolated spleen by implementing the isobaric tags for relative and absolute quantification (iTRAQ) approach. Mass spectrometry data were analyzed using Proteome Discoverer 2.4 software using the search engine mascot against Mus musculus in SwissProt. 924 proteins are identified in all sets (n = 4) for different dietary effects taken for statistical analysis using Qlucore Omics Explorer software. Only 20 proteins were found to be differentially expressed with a cut-off value of false discovery rate < 0.1 (q-value) when comparing HFD-S and HFD-P but no differentially expressed proteins were found when LFD was compared with HFD-P or HFD-S. The identified proteins and statistical analysis comparing HFD-S and HFD-P diets are available as a supplementary file S1. We identified a subset of proteins that showed an inverse expression pattern between two high fat diets. These differentially expressed proteins were further classified by gene ontology for their role in biological processes and molecular functions. Mass spectrometry raw data are also available via ProteomeXchange with identifier PXD020365.

This manuscript is a companion paper to Ulleryd M.U. et al., “Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells” Atherosclerosis, 2019 [1]. Data shown here include RNA sequencing data from whole aorta of ApoE-/- mice fed high fat diet and treated with the alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonist AZ6983 for 8 weeks using subcutaneously implanted osmotic minipumps. Here we present the top gene networks affected by treatment with AZ6983, as well as the up- and down-regulated genes in aorta after treatment. Further, a URL link to the RNA sequencing datasets submitted to GEO is included.

[This corrects the article DOI: 10.1371/journal.pone.0138111.].

Aviation is a highly inter-connected system. This means that a problem in one area may cause effects in other countries or parts of the Air Transport System (ATS). Examples range from local air traffic disruptions to the 2010 volcanic ash crisis. Agility, like resilience, refers to the ability to cope with dynamics and complexity in a flexible manner, by adjusting and adapting performance and the organization of work to fit changing demands. The aim of this work is to help ATS organizations with increasing their agility in the face of crises and challenges. To this end, this article presents the Agile Response Capability (ARC) guidance material. ARC was developed from a literature study and a number of case studies that combined past event analysis, interviews, focus groups, workshops, questionnaires, and exercise observation methodologies. ARC aims to help aviation organizations to set up, run, and evaluate exercises promoting agility to handle disturbances and crises, and to enable structured pro-active and retrospective analysis of scenarios and actual events. The elements and steps of the ARC approach are illustrated and exemplified with data from three case studies. The ARC methodology facilitates more agile and resilient ways of responding to the fundamental and novel surprises that have become almost commonplace in the past decade, and are likely to continue to do so.

Testosterone deficiency is associated with autoimmunity and increased B cell numbers, but the underlying mechanism is unclear. Here the authors show that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels.

Abstract Background The multifaceted control of gene expression requires tight coordination of regulatory mechanisms at transcriptional and post-transcriptional level. Here, we studied the interdependence of transcription initiation, splicing and polyadenylation events on single mRNA molecules by full-length mRNA sequencing. Results In MCF-7 breast cancer cells, we find 2700 genes with interdependent alternative transcription initiation, splicing and polyadenylation events, both in proximal and distant parts of mRNA molecules, including examples of coupling between transcription start sites and polyadenylation sites. The analysis of three human primary tissues (brain, heart and liver) reveals similar patterns of interdependency between transcription initiation and mRNA processing events. We predict thousands of novel open reading frames from full-length mRNA sequences and obtained evidence for their translation by shotgun proteomics. The mapping database rescues 358 previously unassigned peptides and improves the assignment of others. By recognizing sample-specific amino-acid changes and novel splicing patterns, full-length mRNA sequencing improves proteogenomics analysis of MCF-7 cells. Conclusions Our findings demonstrate that our understanding of transcriptome complexity is far from complete and provides a basis to reveal largely unresolved mechanisms that coordinate transcription initiation and mRNA processing.

This article tries to be funny in a very serious way, following Virginia Woolf’s call in Three Guineas that, in the face of man-made disasters, we may have to make fools of ourselves in relation to common sense. Apocalypses, such as the Anthropocene, climate change, and mass extinction require—like the Second World War that Woolf refused to simplify—a tentative search for knowledge, not controlling and predictable methods in the search for a solution. The article is based on how Jacques Derrida’s discussion with Immanuel Kant regarding how truth should sound before the apocalypse over the years has increasingly come to describe contemporary doxa, within which there is only room for mystagogues, who inaugurate followers in the “real truth” behind “fake news”, or scientisticists, who believe that facts and truth are the same thing. When Derrida shows how these two positions depend on each other, sharing the modern belief that knowledge is associated with development, boundaries and control, he also shows how this narrows knowledge down to the predictable, and, thus, makes it complicit with the mistaken efforts of control responsible for today’s challenges. Against this background, the article analyzes works by the artist, Eva Löfdahl, and links them with questions concerning connections between truth, knowledge, art, and science.

Abstract Background Caveolae are membrane invaginations measuring 50–100 nm. These organelles, composed of caveolin and cavin proteins, are important for cellular signaling and survival. Caveolae play incompletely defined roles in human kidneys. Induction of caveolin-1/CAV1 in diseased tubules has been described previously, but the responsible mechanism remains to be defined. Methods Healthy and atrophying human kidneys were stained for caveolar proteins, (caveolin 1–3 and cavin 1–4) and examined by electron microscopy. Induction of caveolar proteins was studied in isolated proximal tubules and primary renal epithelial cells. These cells were challenged with hypoxia or H2O2. Primary tubular cells were also subjected to viral overexpression of megakaryoblastic leukemia 1 (MKL1) and MKL1 inhibition by the MKL1 inhibitor CCG-1423. Putative coregulators of MKL1 activity were investigated by Western blotting for suppressor of cancer cell invasion (SCAI) and filamin A (FLNA). Finally, correlative bioinformatic studies of mRNA expression of caveolar proteins and MKL1 were performed. Results In healthy kidneys, caveolar proteins were expressed by the parietal epithelial cells (PECs) of Bowman’s capsule, endothelial cells and vascular smooth muscle. Electron microscopy confirmed caveolae in the PECs. No expression was seen in proximal tubules. In contrast, caveolar proteins were expressed in proximal tubules undergoing atrophy. Caveolar proteins were also induced in cultures of primary epithelial tubular cells. Expression was not enhanced by hypoxia or free radical stress (H2O2), but proved sensitive to inhibition of MKL1. Viral overexpression of MKL1 induced caveolin-1/CAV1, caveolin-2/CAV2 and SDPR/CAVIN2. In kidney tissue, the mRNA level of MKL1 correlated with the mRNA levels for caveolin-1/CAV1, caveolin-2/CAV2 and the archetypal MKL1 target tenascin C (TNC), as did the MKL1 coactivator FLNA. Costaining for TNC as readout for MKL1 activity demonstrated overlap with caveolin-1/CAV1 expression in PECs as well as in atrophic segments of proximal tubules. Conclusions Our findings support the view that MKL1 contributes to the expression of caveolar proteins in healthy kidneys and orchestrates the induction of tubular caveolar proteins in renal injury.

Comprehensive transcriptome studies of cancers often rely on corresponding normal tissue samples to serve as a transcriptional reference. In this study, we performed in-depth analyses of normal kidney tissue transcriptomes from the TCGA and demonstrate that the histological variability in cellularity, inherent in the kidney architecture, lead to considerable transcriptional differences between samples. This should be considered when comparing expression profiles of normal and cancerous kidney tissues. We exploited these differences to define renal-cell-specific gene signatures and used these as a framework to analyze renal cell carcinoma (RCC) ontogeny. Chromophobe RCCs express FOXI1-driven genes that define collecting duct intercalated cells, whereas HNF-regulated genes, specific for proximal tubule cells, are an integral part of clear cell and papillary RCC transcriptomes. These networks may be used as a framework for understanding the interplay between genomic changes in RCC subtypes and the lineage-defining regulatory machinery of their non-neoplastic counterparts.

Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca2+ channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1) receptors, has previously been shown to be a factor in the pathology of SAH. The aim of the study was to compare intrathecal and subcutaneous treatment regimens of nimodipine and intrathecal treatment regimens of U0126, a MEK1/2 inhibitor, in a single injection experimental rat SAH model with post 48 h endpoints consisting of wire myography of cerebral arteries, flow cytometry of cerebral arterial tissue and behavioural evaluation. Following ET-1 concentration-response curves, U0126 exposed arteries had a significantly lower ET-1max than vehicle arteries. Arteries from both the intrathecal- and subcutaneous nimodipine treated animals had significantly higher ET-1max contractions than the U0126 arteries. Furthermore, Ca2+ concentration response curves (precontracted with ET-1 and in the presence of nimodipine) showed that nimodipine treatment could result in larger nimodipine insensitive contractions compared to U0126. Flow cytometry showed decreased protein expression of the ETB receptor in U0126 treated cerebral vascular smooth muscle cells compared to vehicle. Only U0126 treatment lowered ET-1max contractions and ETB receptor levels, as well as decreased the contractions involving nimodipine-insensitive Ca2+ channels, when compared to both intrathecal and subcutaneous nimodipine treatment. This indicate that targeting gene expression might be a better strategy than blocking specific receptors or ion channels in future treatments of SAH.