Dissection of Bitcoin's multiscale bubble history from January 2012 to February 2018.

We present a detailed bubble analysis of the Bitcoin to US Dollar price dynamics from January 2012 to February 2018. We introduce a robust automatic peak detection method that classifies price time series into periods of uninterrupted market growth (drawups) and regimes of uninterrupted market decrease (drawdowns). In combination with the Lagrange Regularization Method for detecting the beginning of a new market regime, we identify three major peaks and 10 additional smaller peaks, that have punctuated the dynamics of Bitcoin price during the analysed time period. We explain this classification of long and short bubbles by a number of quantitative metrics and graphs to understand the main socio-economic drivers behind the ascent of Bitcoin over this period. Then, a detailed analysis of the growing risks associated with the three long bubbles using the Log-Periodic Power-Law Singularity (LPPLS) model is based on the LPPLS Confidence Indicators, defined as the fraction of qualified fits of the LPPLS model over multiple time windows. Furthermore, for various fictitious 'present' times t 2 before the crashes, we employ a clustering method to group the predicted critical times t c of the LPPLS fits over different time scales, where t c is the most probable time for the ending of the bubble. Each cluster is proposed as a plausible scenario for the subsequent Bitcoin price evolution. We present these predictions for the three long bubbles and the four short bubbles that our time scale of analysis was able to resolve. Overall, our predictive scheme provides useful information to warn of an imminent crash risk.

Improved method for MR microscopy of brain tissue cultured with the interface method combined with Lenz lenses.

MR in microscopy can non-invasively image the morphology of living tissue, which is of particular interest in studying the mammalian brain. Many studies use live animals for basic research on brain functions, disease pathogenesis, and drug development. However, in vitro systems are on the rise, due to advantages such as the absence of a blood-brain barrier, predictable pharmacokinetics, and reduced ethical restrictions. Hence, they present an inexpensive and adequate technique to answer scientific questions and to perform drug screenings. Some publications report the use of acute brain slices for MR microscopy studies, but these only permit single measurements over several hours. Repetitive MR measurements in longitudinal studies demand an MR-compatible setup which allows cultivation for several days or weeks, and hence properly functioning in vitro systems. Organotypic hippocampal slice cultures (OHSC) are a well-established and robust in vitro system which still exhibits most histological hallmarks of the hippocampal network in vivo. An MR compatible incubation platform is introduced in which OHSC are cultivated according to the interface method following Stoppini et al. In this cultivation method a tissue slice is placed onto a membrane with nutrition medium underneath and a gas atmosphere above, where the air-tissue interface perpendicular to the B0 field induces strong artefacts. We introduce a handling protocol that suppresses these artefacts and increases signal quality significantly to acquire high resolution images of tissue slices. An additional challenge is the lack of available of MR microscopy equipment suitable for small animal scanners. A Lenz lens with an attached capacitor can dramatically increase the SNR in these cases, and wirelessly bring the detection system in close proximity to the sample without compromising the OHSC system through the introduction of wired detectors. The resultant signal gain is demonstrated by imaging a PFA-fixed brain slice with a 72 mm diameter volume coil without a Lenz lens, and with a broadband and a self-resonant Lenz lens. In our setting, the self-resonant Lenz lens increases the SNR 10-fold over using the volume coil only.

Differential methylation of insulin-like growth factor 2 in offspring of physically active pregnant women.

Several studies have suggested that maternal lifestyle during pregnancy may influence long-term health of offspring by altering the offspring epigenome. Whether maternal leisure-time physical activity (LTPA) during pregnancy might have this effect is unknown. The purpose of this study was to determine the relationship between maternal LTPA during pregnancy and offspring DNA methylation. Participants were recruited from the Archive for Research on Child Health study. At enrollment, participants' demographic information and self-reported LTPA during pregnancy were determined. High active participants (averaged 637.5 min per week of LTPA; n=14) were matched by age and race to low active participants (averaged 59.5 min per week LTPA; n=28). Blood spots were obtained at birth. Pyrosequencing was used to determine methylation levels of long interspersed nucleotide elements (LINE-1) (global methylation) and peroxisome proliferator-activated receptor-gamma (PPARγ), peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α), insulin-like growth factor 2 (IGF2), pyruvate dehydrogenase kinase, isozyme 4 (PDK4) and transcription factor 7-like 2 (TCF7L2). We found no differences between offspring of high active and low active groups for LINE-1 methylation. The only differences in candidate gene methylation between groups were at two CpG sites in the P2 promoter of IGF2; the offspring of low active group had significantly higher DNA methylation (74.70±2.25% methylation for low active v. 72.83±2.85% methylation for high active; P=0.045). Our results suggest no effect of maternal LTPA on offspring global and candidate gene methylation, with the exception of IGF2. IGF2 has been previously associated with regulation of physical activity, suggesting a possible role of maternal LTPA on regulation of offspring physical activity.

Ion mass and energy selective hyperthermal ion-beam assisted deposition setup.

For the synthesis of high-quality thin films, ion-beam assisted deposition (IBAD) is a frequently used technique providing precise control over several substantial film properties. IBAD typically relies on the use of a broad-beam ion source. Such ion sources suffer from the limitation that they deliver a blend of ions with different ion masses, each of them possessing a certain distribution of kinetic energy. In this paper, a compact experimental setup is presented that enables the separate control of ion mass and ion kinetic energy in the region of hyperthermal energies (few 1 eV - few 100 eV). This ion energy region is of increasing interest not only for ion-assisted film growth but also for the wide field of preparative mass spectrometry. The setup consists of a constricted glow-discharge plasma beam source and a tailor-made, compact quadrupole system equipped with entry and exit ion optics. It is demonstrated that the separation of monoatomic and polyatomic nitrogen ions (N+ and N2+) is accomplished. For both ion species, the kinetic energy is shown to be selectable in the region of hyperthermal energies. At the sample position, ion current densities are found to be in the order of 1 µA/cm2 and the full width at half maximum of the ion beam profile is in the order of 10 mm. Thus, the requirements for homogeneous deposition processes in sufficiently short periods of time are fulfilled. Finally, employing the described setup, for the first time in practice epitaxial GaN films were deposited. This opens up the opportunity to fundamentally study the influence of the simultaneous irradiation with hyperthermal ions on the thin film growth in IBAD processes and to increase the flexibility of the technique.

Hypersensitivity pneumonitis and antigen identification--An alternate approach.

OBJECTIVES: Identification of the causal antigen for patients with hypersensitivity pneumonitis (HP) is challenging in a standard clinical setting. The purpose of this pilot study was to determine whether it was possible to evaluate the home/workplace of patients, and identify the causal antigen. METHODS: Using a case-control study design we compared the presence of antibody to antigen collected in the environment of individuals with HP and controls consisting of family members/co-workers. Based on patient interviews, homes/workplaces were evaluated and suspected sources of antigen collected for use in immunoassays. RESULTS: Nineteen individuals with HP participated with 15 classified as having fibrotic disease. Up to 54 bulk samples were collected from each patient's environment, with multiple isolates (antigens) cultured from each. Of the seven individuals who tested positive to one or more environmental samples, three had a positive response to more than 1 antigen from the environmental sample (range 1-9). Twelve individuals tested positive to antigen(s) on a standard panel, with only one overlapping with the antigen from the home/workplace sample. A significant association existed between results of interviews/site evaluations, and ability to collect antigen eliciting a positive response (p < 0.001). CONCLUSION: Antigen identification was successful for patients with 'active' disease. Antigens for which patients test positive on standard panels may not be present in their environment. One benefit to patient-centered testing is the ability to develop recommendations specific to their environment. As most individuals tested positive for >1 antigen, further investigation is warranted to determine the actual antigen responsible for disease.

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

Teratoma formation of human embryonic stem cells in three-dimensional perfusion culture bioreactors.

Teratoma formation in mice is today the most stringent test for pluripotency that is available for human pluripotent cells, as chimera formation and tetraploid complementation cannot be performed with human cells. The teratoma assay could also be applied for assessing the safety of human pluripotent cell-derived cell populations intended for therapeutic applications. In our study we examined the spontaneous differentiation behaviour of human embryonic stem cells (hESCs) in a perfused 3D multi-compartment bioreactor system and compared it with differentiation of hESCs and human induced pluripotent cells (hiPSCs) cultured in vitro as embryoid bodies and in vivo in an experimental mouse model of teratoma formation. Results from biochemical, histological/immunohistological and ultrastuctural analyses revealed that hESCs cultured in bioreactors formed tissue-like structures containing derivatives of all three germ layers. Comparison with embryoid bodies and the teratomas revealed a high degree of similarity of the tissues formed in the bioreactor to these in the teratomas at the histological as well as transcriptional level, as detected by comparative whole-genome RNA expression profiling. The 3D culture system represents a novel in vitro model that permits stable long-term cultivation, spontaneous multi-lineage differentiation and tissue formation of pluripotent cells that is comparable to in vivo differentiation. Such a model is of interest, e.g. for the development of novel cell differentiation strategies. In addition, the 3D in vitro model could be used for teratoma studies and pluripotency assays in a fully defined, controlled environment, alternatively to in vivo mouse models.

Extracellular serine proteases from Stenotrophomonas maltophilia: Screening, isolation and heterologous expression in E. coli.

A large strain collection comprising antagonistic bacteria was screened for novel detergent proteases. Several strains displayed protease activity on agar plates containing skim milk but were inactive in liquid media. Encapsulation of cells in alginate beads induced protease production. Stenotrophomonas maltophilia emerged as best performer under washing conditions. For identification of wash-active proteases, four extracellular serine proteases called StmPr1, StmPr2, StmPr3 and StmPr4 were cloned. StmPr2 and StmPr4 were sufficiently overexpressed in E. coli. Expression of StmPr1 and StmPr3 resulted in unprocessed, insoluble protein. Truncation of most of the C-terminal domain which has been identified by enzyme modeling succeeded in expression of soluble, active StmPr1 but failed in case of StmPr3. From laundry application tests StmPr2 turned out to be a highly wash-active protease at 45°C. Specific activity of StmPr2 determined with suc-L-Ala-L-Ala-L-Pro-l-Phe-p-nitroanilide as the substrate was 17±2U/mg. In addition we determined the kinetic parameters and cleavage preferences of protease StmPr2.

Phase transformation behaviour of hydroxyapatite foams subject to heat treatment.

This study examined the relationship between sintering and phase transformation behaviour in hydroxyapatite (HA). Pellets and replicated foams were sintered at five different temperatures ranging from 1350 degrees C to 1550 degrees C. Hydroxyapatite remained as the major phase in all the samples studied. In the pellets, sintering took place prior to the phase transformation which occurs primarily at the surface. This created damage that extended into the interior of the pellet above 1400 degrees C. In contrast, the foams transformed at lower temperatures due to the higher surface area. This did not create damage in the foam. The differences in the foams and the pellets are discussed in terms of sintering and phase transformation behaviour.

FOXP3 expression in hepatitis C virus-specific CD4+ T cells during acute hepatitis C.

BACKGROUND & AIMS: Down-regulation of hepatitis C virus (HCV)-specific CD4(+) T-cell responses is a hallmark of chronic viral persistence in acute hepatitis C. FOXP3(+)CD25(+)CD4(+) regulatory T cells can modulate HCV-specific immune responses in vitro, but the role of virus-specific regulatory T cells in the pathogenesis of chronic viral persistence is unknown. METHODS: Two novel HLA-DR15 tetramers were synthesized to study the kinetics and phenotype of FOXP3(+)-expressing HCV-specific CD4(+) T cells from 10 patients with acute hepatitis C and 15 patients with chronic hepatitis C. RESULTS: In acute hepatitis C, generally only a low percentage of HCV-specific CD4(+) T cells expressed FOXP3(+) (mean of 2.5% in patients with self-limited acute hepatitis C vs 2.4% in patients with evolving chronic hepatitis C). Although distinct but short-lived increases in virus-specific FOXP3(+)CD4(+) T cells occurred in 3 patients (30%, 26%, and 7% of tet(+) CD4(+) T cells, respectively), these did not correlate with the evolution of chronic hepatitis C. HCV-specific FOXP3(+)CD4(+) T cells displayed a distinct phenotype, with only 10% expressing CD25 and 40% being CD127low. Interestingly, this phenotype of FOXP3(+)CD4(+) T cells was already expanded in bulk CD4(+) T cells in patients with chronic hepatitis C. CONCLUSIONS: Although short-lived increases in HCV-specific FOXP3(+)CD4(+) T cells occur during the course of acute hepatitis C, we could not demonstrate an association of HCV-specific regulatory T cells and persistent viremia.

Myocardial wall thickening from gated Magnetic Resonance images using Laplace's equation.

The aim of our work is to present a robust 3D automated method for measuring regional myocardial thickening using cardiac magnetic resonance imaging (MRI) based on Laplace's equation. Multiple slices of the myocardium in short-axis orientation at end-diastolic and end-systolic phases were considered for this analysis. Automatically assigned 3D epicardial and endocardial boundaries were fitted to short-axis and long axis slices corrected for breathold related misregistration, and final boundaries were edited by a cardiologist if required. Myocardial thickness was quantified at the two cardiac phases by computing the distances between the myocardial boundaries over the entire volume using Laplace's equation. The distance between the surfaces was found by computing normalized gradients that form a vector field. The vector fields represent tangent vectors along field lines connecting both boundaries. 3D thickening measurements were transformed into polar map representation and 17-segment model (American Heart Association) regional thickening values were derived. The thickening results were then compared with standard 17-segment 6-point visual scoring of wall motion/wall thickening (0=normal; 5=greatest abnormality) performed by a consensus of two experienced imaging cardiologists. Preliminary results on eight subjects indicated a strong negative correlation (r=-0.8, p<0.0001) between the average thickening obtained using Laplace and the summed segmental visual scores. Additionally, quantitative ejection fraction measurements also correlated well with average thickening scores (r=0.72, p<0.0001). For segmental analysis, we obtained an overall correlation of -0.55 (p<0.0001) with higher agreement along the mid and apical regions (r=-0.6). In conclusion 3D Laplace transform can be used to quantify myocardial thickening in 3D.

Development of a European human embryonic stem cell registry.

The number of human embryonic stem cell (hESC) lines that are available and that are subsequently being used in numerous research projects is increasing steadily. However, there is little coordination of hESC line derivation, and comparative information on the characteristics and quality of these cells is sparse. Obtaining consistent information on hESCs is hampered further by legislative fragmentation, particularly in Europe. Recognizing these obstacles, the European Commission has set up a Human Embryonic Stem Cell Registry (hESCreg) to make hESCs and their characterizing information accessible and to ensure that the results of research become more quickly available to the public. The primary objectives of hESCreg are to provide freely accessible information on existing hESC lines, their derivation, molecular characteristics, use and quality. Successful research with listed hESC lines will be used to evaluate clinical potential and thus directly influence policy decisions. The developing integration with other initiatives, such as characterization projects, registries and cell banks, is expected to lead to a common and internationally accepted central reference. The hESCreg provides a first step in this direction and might grow into an internationally funded and administered project.

Acute hepatitis C: current status and remaining challenges.

The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. In some patients, the infection resolves spontaneously, whereas in others it develops into chronic disease. However, because acute hepatitis C is often asymptomatic, detection and diagnosis are usually difficult. What is more, there are no established treatment guidelines, leaving physicians to make several challenging decisions, such as whether to treat, when to treat and what treatment regimen to use. Pegylated interferon alfa monotherapy is most commonly used to treat patients with acute hepatitis C; the role of ribavirin has yet to be established. In this review, we discuss the epidemiology of acute hepatitis C, its risk factors and routes of transmission and current treatment practices. We also discuss data from published clinical studies and focus on unresolved issues for which additional studies are needed in order to establish standardized treatment guidelines for the management of acute hepatitis C.

Hot topics in liver transplantation: organ allocation--extended criteria donor--living donor liver transplantation.

Liver transplantation has become the mainstay for the treatment of end-stage liver disease, hepatocellular cancer and some metabolic disorders. Its main drawback, though, is the disparity between the number of donors and the patients needing a liver graft. In this review we will discuss the recent changes regarding organ allocation, extended donor criteria, living donor liver transplantation and potential room for improvement. The gap between the number of donors and patients needing a liver graft forced the transplant community to introduce an objective model such as the modified model for end-stage liver disease (MELD) in order to obtain a transparent and fair organ allocation system. The use of extended criteria donor livers such as organs from older donors or steatotic grafts is one possibility to reduce the gap between patients on the waiting list and available donors. Finally, living donor liver transplantation has become a standard procedure in specialized centers as another possibility to reduce the donor shortage. Recent data clearly indicate that center experience is of major importance in achieving good results. Great progress has been made in recent years. However, further research is needed to improve results in the future.

Culture of subconfluent human fibroblasts and keratinocytes using biodegradable transfer membranes.

This study aims to assess the suitability of biodegradable membranes as transfer matrix materials for the culture of subconfluent fibroblasts and keratinocytes. The materials investigated were based on collagen, chitosan and enzyme-digestible cellulose. The proliferation and growth behaviour of human keratinocytes and dermal fibroblasts were analysed and morphology and distribution determined. Cultured fibroblasts exhibited no significant differences in proliferation for the different membrane types, whereas keratinocytes revealed significantly higher proliferation on collagen membranes compared with membranes based on cellulose and chitosan. Co-cultured fibroblasts and keratinocytes from the same donor on collagen membranes showed more homogenous cell distribution, but they segregated in heterologous co-cultures; this effect must be further investigated. Thus, collagen and collagen-coated chitosan membranes are suitable for the subconfluent transfer of human fibroblasts and keratinocytes.

Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.

BACKGROUND: CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. METHODOLOGY/PRINCIPAL FINDINGS: Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. CONCLUSIONS/SIGNIFICANCE: During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.

[2-COM: presentation of an instrument facilitating communication between physicians and carers in daily practice]. / 2-COM: présentation d'un instrument permettant de faciliter la communication entre médecin et soignants en pratique quotidienne.

Communication between the patient and the professional carer lies at the heart of all decisions regarding diagnosis and treatment. However, patients and doctors often have divergent views on care needs; 2-COM (for 2-communication) is a simple patient-completed self-report instrument designed in order to facilitate patient-professional carer communication. Aims - To present 2-COM and to examine whether providing patients with an opportunity to identify and discuss their needs would improve communication and induce changes in care. Methods - The 2-COM is a simple list of 20 common problems, or areas of perceived need, that might be experienced by patients with severe mental illness. The list includes problems with housing, relationships, money, lack of activities, psychological distress, sexuality, symptoms and treatment side effects; 2-COM has shown adequate test-retest reliability and is well accepted by patients as a valued aid to communication with their doctor; 134 patients in a clinical diagnosis of schizophrenia or schizoaffective disorder were recruited at seven European centres: Maastricht, Oviedo, Gijon, Hamburg, Copenhagen, Milan and Nice. The assessment took place over 3 out patient clinic visits; at visit 1, the clinician recorded a list of all current interventions, including medication and non-medical treatments, together with demographic information and an assessment of current level of functioning, using the Global Assessment of Functioning scale. Prior to the second visit, patients were randomised to receive either 2-COM or "standard care" - a routine appointment without 2-COM. Immediately after the interview, all patients, whether they had completed 2-COM or not, completed a confidential questionnaire in which they could indicate the perceived quality of communication. Similarly, clinicians completed a repeat of the list of all current interventions, together with an assessment of any changes to the treatment plan implemented after the interview with the patient. Four to six weeks after clinic visit 2, patients attended the clinic for a third, "routine" clinical interview. Both patients and clinicians then completed the same set of post-interview assessments as at visit 2. The 2-COM induced a stable improvement of patient-reported quality of patient-doctor communication (B=0.33, P=0.031), and induced changes in management immediately after the intervention. Treatment change was more likely in patients with more reported needs at the 2-COM and needs most likely to induce treatment changes. In conclusion, the study showed that 2-COM is a useful instrument to expose and subsequently bridge, patient-professional carer discordance on patient needs.