Does the Glucocorticoid Stress Response Make Toads More Toxic? An Experimental Study on the Regulation of Bufadienolide Toxin Synthesis.

Chemical defense is a crucial component of fitness in many organisms, yet the physiological regulation of defensive toxin synthesis is poorly understood, especially in vertebrates. Bufadienolides, the main defensive compounds of toads, are toxic to many predators and other natural enemies, and their synthesis can be upregulated by stressors, including predation risk, high conspecific density, and pollutants. Thus, higher toxin content may be the consequence of a general endocrine stress response in toads. Therefore, we hypothesized that bufadienolide synthesis may be stimulated by elevated levels of corticosterone (CORT), the main glucocorticoid hormone of amphibians, or by upstream regulators that stimulate CORT production. To test these alternatives, we treated common toad tadpoles with exogenous CORT (exoCORT) or metyrapone (MTP, a CORT-synthesis inhibitor that stimulates upstream regulators of CORT by negative feedback) in the presence or absence of predation cues for 2 or 6 days, and subsequently measured their CORT release rates and bufadienolide content. We found that CORT release rates were elevated by exoCORT, and to a lesser extent also by MTP, regardless of treatment length. Bufadienolide content was significantly decreased by treatment with exoCORT for 6 days but was unaffected by exposure to exoCORT for 2 days or to MTP for either 6 or 2 days. The presence or absence of predation cues affected neither CORT release rate nor bufadienolide content. Our results suggest that changes in bufadienolide synthesis in response to environmental challenges are not driven by CORT but may rather be regulated by upstream hormones of the stress response.

Lattice QCD Equation of State at Finite Chemical Potential from an Alternative Expansion Scheme.

In this Letter, we introduce a novel scheme for extrapolating the equation of state of QCD to finite chemical potential that features considerably improved convergence properties and allows us to extend its reach to unprecedentedly high baryonic chemical potentials. We present continuum extrapolated lattice results for the new expansion coefficients and show the thermodynamic observables up to µ_{B}/T≤3.5. This novel expansion does not suffer from the shortcomings that characterize the traditional Taylor expansion method, such as difficulties inherent in performing such an expansion with a limited number of coefficients and the poor signal-to-noise ratio that affects Taylor coefficients determined from lattice calculations.

Leading hadronic contribution to the muon magnetic moment from lattice QCD.

The standard model of particle physics describes the vast majority of experiments and observations involving elementary particles. Any deviation from its predictions would be a sign of new, fundamental physics. One long-standing discrepancy concerns the anomalous magnetic moment of the muon, a measure of the magnetic field surrounding that particle. Standard-model predictions1 exhibit disagreement with measurements2 that is tightly scattered around 3.7 standard deviations. Today, theoretical and measurement errors are comparable; however, ongoing and planned experiments aim to reduce the measurement error by a factor of four. Theoretically, the dominant source of error is the leading-order hadronic vacuum polarization (LO-HVP) contribution. For the upcoming measurements, it is essential to evaluate the prediction for this contribution with independent methods and to reduce its uncertainties. The most precise, model-independent determinations so far rely on dispersive techniques, combined with measurements of the cross-section of electron-positron annihilation into hadrons3-6. To eliminate our reliance on these experiments, here we use ab initio quantum chromodynamics (QCD) and quantum electrodynamics simulations to compute the LO-HVP contribution. We reach sufficient precision to discriminate between the measurement of the anomalous magnetic moment of the muon and the predictions of dispersive methods. Our result favours the experimentally measured value over those obtained using the dispersion relation. Moreover, the methods used and developed in this work will enable further increased precision as more powerful computers become available.

[Troponin elevation in acute ischemic stroke-unspecific or acute myocardial infarction? : Diagnostics and clinical implications]. / Troponinerhöhung beim akuten ischämischen Schlaganfall ­ unspezifisch oder Ausdruck eines akuten Myokardinfarkts? : Diagnostik und klinische Implikationen.

Routine determination of troponin levels is recommended for all patients with acute ischemic stroke. In 20-55% of these patients the troponin levels are elevated, which may be caused by ischemic as well as non-ischemic myocardial damage and particularly neurocardiogenic myocardial damage. In patients with acute ischemic stroke, the prevalence of previously unknown coronary heart disease is reported to be up to 27% and is prognostically relevant for these patients; however, relevant coronary stenoses are less frequently detected in stroke patients with troponin elevation compared to patients with non-ST elevation myocardial infarction. The risk of secondary intracerebral hemorrhage due to the necessity for dual platelet aggregation inhibition illustrates the challenging indication for invasive coronary diagnostics and revascularization. Therefore, a diagnostic work-up and interdisciplinary risk evaluation appropriate to the urgency are necessary in order to be able to determine a reasonable treatment approach with timing of the intervention, type and duration of blood thinning. In addition to conventional examination methods, multimodal cardiac imaging is increasingly used for this purpose. This review article aims to provide a pragmatic and clinically oriented approach to diagnostic and therapeutic procedures, taking into account the available evidence.

A multicenter study of transient global amnesia for the better detection of magnetic resonance imaging abnormalities.

BACKGROUND AND PURPOSE: The detection rate of diffusion-weighted (DWI) hyperintense lesions varies widely in patients with transient global amnesia (TGA). The aim was to examine the association of hyperintense lesions on DWI magnetic resonance imaging (MRI) with patient characteristics, precipitating factors, clinical presentation and MRI settings in patients with TGA. METHODS: In this multicenter retrospective observational study, using the standardized diagnosis entry system of electronic health records of four tertiary medical centers in the Kansai district of Japan, TGA patients (n = 261) who underwent brain MRI within 28 days of onset were examined. When the onset time was unavailable, the discovery time was used. RESULTS: Diffusion-weighted hyperintense lesions were observed in 79 patients (30%). There were no significant differences in age, sex, vascular risk factors, precipitating factors or clinical presentation between patients with and without DWI lesions. The detection rate increased linearly 24 h after onset and then reached a plateau of 60%-80% by 84 h. After 84 h, the detection rate decreased rapidly. In a multivariate logistic regression model, MRI examination 24-84 h after onset (odds ratio 7.00, 95% confidence interval 3.50-13.99) and a thin-slice (≤3 mm) DWI sequence (odds ratio 7.59, 95% confidence interval 3.05-18.88) were independent predictors of DWI lesions. CONCLUSIONS: This study suggests that DWI hyperintense lesions in TGA are not associated with patient characteristics and clinical presentation. Brain MRI examination 24-84 h after onset and thin-slice DWI sequences enhance the detection of DWI lesions in TGA patients.

Shedding light on the clinical recognition process of transient global amnesia.

BACKGROUND AND PURPOSE: Diagnostic uncertainty is common in the emergency evaluation of neurological conditions such as acute confusional states, particularly for non-neurologists. We aimed to investigate the clinical recognition process of transient global amnesia (TGA) before arrival at the hospital and in the emergency department (ED). METHODS: In this retrospective observational study, medical records of 365 patients with TGA were analysed concerning mode of arrival, symptoms and suspected diagnosis made by pre-hospital medical care providers and the ED neurologist. RESULTS: More than half of the 248 patients who were evaluated before arrival at the hospital (N = 157, 63.3%) received a diagnosis of suspected stroke, whereas TGA was considered in only 16 patients (6.5%), with recognition of acute amnesia in 150 patients (60.5%) and disturbed orientation in 86 patients (34.7%). Repetitive questions by the patient were noted in 28 patients (11.3%). In contrast, in 355 patients (97.3%), TGA was considered the primary diagnosis by the ED neurologist. Diagnosis in the ED was achieved by documenting ongoing impairment of episodic verbal memory (100.0%), repetitive questions as a prominent ancillary finding (95.5%) and the lack of focal neurological symptoms (100.0%) or by carefully obtaining collateral history suggestive of anterograde memory disturbance (89.9%) and/or repetitive questions (85.7%). CONCLUSION: Recognizing TGA crucially depends on identifying isolated anterograde episodic long-term memory disturbance or its observable effects such as repetitive questions and actions.

What remains after transient global amnesia (TGA)? An ultra-high field 7 T magnetic resonance imaging study of the hippocampus.

BACKGROUND AND PURPOSE: The aim was to study whether ultra-high field 7 T magnetic resonance imaging (MRI) can demonstrate chronic focal defects in the hippocampus corresponding to the former acute diffusion-weighted imaging (DWI) lesions and to assess chronic T2-hyperintense hippocampal lesion load in transient global amnesia (TGA) patients. METHODS: Follow-up of 7 T MRI of the hippocampus was performed in 13 patients with documented hippocampal DWI lesions (detected via 3 T MRI) after acute TGA. The location of the DWI lesions was transformed to 7 T T2 images after data co-registration. Additionally, the T2-hyperintense lesion load was estimated in each patient and compared with that of 13 healthy controls. RESULTS: Magnetic resonance imaging (7 T) was performed after a median of 4 months. No structural abnormality at the site of the previous TGA lesion was observed in any case. None of the controls showed DWI lesions. There was no significant difference between patients and controls concerning the number (P = 0.67) or volume (P = 0.45) of T2-hyperintense hippocampal lesions. CONCLUSIONS: Diffusion-weighted imaging lesions in patients with TGA do not provoke any visible sequelae and do not result in hippocampal cavities. The occurrence of incidental hippocampal T2 lesions after TGA is not more frequent than in controls.

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas.

Microarray, RT-qPCR based arrays and next-generation-sequencing (NGS) are available high-throughput methods for miRNA profiling (miRNome). Analytical and biological performance of these methods were tested in identification of biologically relevant miRNAs in non-functioning pituitary adenomas (NFPA). miRNome of 4 normal pituitary (NP) and 8 NFPA samples was determined by these platforms and expression of 21 individual miRNAs was measured on 30 (20 NFPA and 10 NP) independent samples. Complex bioinformatics was used. 132 and 137 miRNAs were detected by all three platforms in NP and NFPA, respectively, of which 25 were differentially expressed (fold change > 2). The strongest correlation was observed between microarray and TaqMan-array, while the data obtained by NGS were the most discordant despite of various bioinformatics settings. As a technical validation we measured the expression of 21 selected miRNAs by individual RT-qPCR and we were able to validate 35.1%, 76.2% and 71.4% of the miRNAs revealed by SOLiD, TLDA and microarray result, respectively. We performed biological validation using an extended number of samples (20 NFPAs and 8 NPs). Technical and biological validation showed high correlation (p < 0.001; R = 0.96). Pathway and network analysis revealed several common pathways but no pathway showed the same activation score. Using the 25 platform-independent miRNAs developmental pathways were the top functional categories relevant for NFPA genesis. The difference among high-throughput platforms is of great importance and selection of screening method can influence experimental results. Validation by another platform is essential in order to avoid or to minimalize the platform specific errors.

Hadronic Vacuum Polarization Contribution to the Anomalous Magnetic Moments of Leptons from First Principles.

We compute the leading, strong-interaction contribution to the anomalous magnetic moment of the electron, muon, and tau using lattice quantum chromodynamics (QCD) simulations. Calculations include the effects of u, d, s, and c quarks and are performed directly at the physical values of the quark masses and in volumes of linear extent larger than 6 fm. All connected and disconnected Wick contractions are calculated. Continuum limits are carried out using six lattice spacings. We obtain a_{e}^{LO-HVP}=189.3(2.6)(5.6)×10^{-14}, a_{µ}^{LO-HVP}=711.1(7.5)(17.4)×10^{-10} and a_{τ}^{LO-HVP}=341.0(0.8)(3.2)×10^{-8}, where the first error is statistical and the second is systematic.

The effects of different preservation methods on ide (Leuciscus idus) sperm and the longevity of sperm movement.

The present study investigated the effects of chilled storage and cryopreservation on ide sperm motility and fertilizing capacity alongside the longevity of sperm movement. The parameters of motility (progressive motility-pMOT, curvilinear velocity-VCL and straightness-STR) have been recorded during 48 h of chilled storage (4 °C) at 24-h intervals. The longevity of sperm movement was measured following activation for up to 120 s (in a range at 10-120 s) in freshly stripped and thawed sperm. A formerly established cryopreservation method was tested on ide sperm where motility parameters, hatching rate and larval malformation (according to 7 category groups) were investigated. Significant decrement of pMOT has already been observed after 24 h (6 ±â€¯5%) compared to the freshly stripped sperm (49 ±â€¯22%). pMOT and STR showed no significant changes for up to 120 s following activation in fresh sperm, whereas VCL showed significant difference between 10 (51 ±â€¯11 µm/s), 90 (33 ±â€¯3 µm/s) and 120 (31 ±â€¯4 µm/s) seconds as well as between 20 (48 ±â€¯12 µm/s), and 120 s. No negative effect of cryopreservation was recorded on pMOT (fresh: 49 ±â€¯19%, cryopreserved: 22 ±â€¯22%), VCL (fresh: 45 ±â€¯9 µm/s and cryopreserved: 57 ±â€¯5 µm/s), STR (fresh: 81 ±â€¯3% and cryopreserved: 92 ±â€¯1%) hatching rate (fresh: 22 ±â€¯15%, cryopreserved: 33 ±â€¯18%) or larval malformation (fresh: 12 ±â€¯4%, cryopreserved: 12 ±â€¯4%). No significant correlation was found between the three motility parameters and hatching rate. Cryopreservation had no effect on hatching and the prevalence of larval deformity. Furthermore craniofacial and eye deformities were characteristic in the group originating from fertilization with cryopreserved sperm, while edemas (pericardial, yolk) occurred more frequently in the control. The formerly developed cryopreservation protocol (method for cyprinids) was applicable to ide sperm.

Drug Repurposing by Simulating Flow Through Protein-Protein Interaction Networks.

As drug development is extremely expensive, the identification of novel indications for in-market drugs is financially attractive. Multiple algorithms are used to support such drug repurposing, but highly reliable methods combining simulation of intracellular networks and machine learning are currently not available. We developed an algorithm that simulates drug effects on the flow of information through protein-protein interaction networks, and used support vector machine to identify potentially effective drugs in our model disease, psoriasis. Using this method, we screened about 1,500 marketed and investigational substances, identified 51 drugs that were potentially effective, and selected three of them for experimental confirmation. All drugs inhibited tumor necrosis factor alpha-induced nuclear factor kappa B activity in vitro, suggesting they might be effective for treating psoriasis in humans. Additionally, these drugs significantly inhibited imiquimod-induced ear thickening and inflammation in the mouse model of the disease. All results suggest high prediction performance for the algorithm.

Splicing factors differentially expressed in psoriasis alter mRNA maturation of disease-associated EDA+ fibronectin.

The EDA+ fibronectin splicing variant is overexpressed in psoriatic non-lesional epidermis and sensitizes keratinocytes to mitogenic signals. However, regulation of its abundance is only partially understood. In our recent cDNA microarray experiment, we identified three SR-rich splicing factors-splicing factor, arginine/serine-rich 18 (SFRS18), peptidyl-prolyl cis-trans isomerase G (PPIG), and luc-7 like protein 3 (LUC7L3)-which might be implicated in the preactivated states of keratinocytes in psoriatic non-involved skin and could also contribute to the regulation of fibronectin mRNA maturation. In this study, we investigated the role of LUC7L3, PPIG, and SFRS18 in psoriasis and in the mRNA maturation process of fibronectin. Regarding tissue staining experiments, we were able to demonstrate a characteristic distribution of the splicing factors in healthy, psoriatic non-involved and involved epidermis. Moreover, the expression profiles of these SR-rich proteins were found to be very similar in synchronized keratinocytes. Contribution of splicing facwwtors to the EDA+ fibronectin formation was also confirmed: their siRNA silencing leads to altered fibronectin mRNA and protein expression patterns, suggesting the participation in the EDA domain inclusion. Our results indicate that LUC7L3, PPIG, and SFRS18 are not only implicated in EDA+ fibronectin formation, but also that they could possess multiple roles in psoriasis-associated molecular abnormalities.

Critical appraisal of advance directives given by patients with fatal acute stroke: an observational cohort study.

BACKGROUND: Advance directives (AD) imply the promise of determining future medical treatment in case of decisional incapacity. However, clinical practice increasingly indicates that standardized ADs often fail to support patients' autonomy. To date, little data are available about the quality and impact of ADs on end-of-life decisions for incapacitated acute stroke patients. METHODS: We analyzed the ADs of patients with fatal stroke, focusing on: (a) their availability and type, (b) stated circumstances to which the AD should apply, and (c) stated wishes regarding specific treatment options. RESULTS: Between 2011 and 2014, 143 patients died during their hospitalization on our stroke unit. Forty-two of them (29.4%) had a completed and signed, written AD, as reported by their family, but only 35 ADs (24.5%) were available. The circumstances in which the AD should apply were stated by 21/35 (60%) as a "terminal condition that will cause death within a relatively short time" or an ongoing "dying process." A retrospective review found only 16 of 35 ADs (45.7%) described circumstances that, according to the medical file, could have been considered applicable by the treating physicians. A majority of patients objected to cardiopulmonary resuscitation (22/35, 62.9%), mechanical ventilation (19/35, 54.3%), and artificial nutrition (26/35, 74.3%), while almost all (33/35, 94.3%) directed that treatment for alleviation of pain or discomfort should be provided at all times even if it could hasten death. CONCLUSIONS: The prevalence of ADs among patients who die from acute stroke is still low. A major flaw of the ADs in our cohort was their attempt to determine single medical procedures without focusing on a precise description of applicable scenarios. Therefore, less than half of the ADs were considered applicable for severe acute stroke. These findings stress the need to foster educational programs for the general public about advance care planning to facilitate the processing of timely, comprehensive, and individualized end-of-life decision-making.

Factors shaping the composition of the cutaneous microbiota.

From birth, we are constantly exposed to bacteria, fungi and viruses, some of which are capable of transiently or permanently inhabiting our different body parts as our microbiota. The majority of our microbial interactions occur during and after birth, and several different factors, including age, sex, genetic constitution, environmental conditions and lifestyle, have been suggested to shape the composition of this microbial community. Propionibacterium acnes is one of the most dominant lipophilic microbes of the postadolescent, sebum-rich human skin regions. Currently, the role of this bacterium in the pathogenesis of the most common inflammatory skin disease, acne vulgaris, is a topic of intense scientific debate. Recent results suggest that Westernization strongly increases the dominance of the Propionibacterium genus in human skin compared with natural populations living more traditional lifestyles. According to the disappearing microbiota hypothesis proposed by Martin Blaser, such alterations in the composition of our microbiota are the possible consequences of socioeconomic and lifestyle changes occurring after the industrial revolution. Evanescence of species that are important elements of the human ecosystem might lead to the overgrowth and subsequent dominance of others because of the lack of ecological competition. Such changes can disturb the fine-tuned balance of the human body and, accordingly, our microbes developed through a long co-evolutionary process. These processes might lead to the transformation of a seemingly harmless species into an opportunistic pathogen through bacterial dysbiosis. This might have happened in the case of P. acnes in acne pathogenesis.

Calculation of the axion mass based on high-temperature lattice quantum chromodynamics.

Unlike the electroweak sector of the standard model of particle physics, quantum chromodynamics (QCD) is surprisingly symmetric under time reversal. As there is no obvious reason for QCD being so symmetric, this phenomenon poses a theoretical problem, often referred to as the strong CP problem. The most attractive solution for this requires the existence of a new particle, the axion-a promising dark-matter candidate. Here we determine the axion mass using lattice QCD, assuming that these particles are the dominant component of dark matter. The key quantities of the calculation are the equation of state of the Universe and the temperature dependence of the topological susceptibility of QCD, a quantity that is notoriously difficult to calculate, especially in the most relevant high-temperature region (up to several gigaelectronvolts). But by splitting the vacuum into different sectors and re-defining the fermionic determinants, its controlled calculation becomes feasible. Thus, our twofold prediction helps most cosmological calculations to describe the evolution of the early Universe by using the equation of state, and may be decisive for guiding experiments looking for dark-matter axions. In the next couple of years, it should be possible to confirm or rule out post-inflation axions experimentally, depending on whether the axion mass is found to be as predicted here. Alternatively, in a pre-inflation scenario, our calculation determines the universal axionic angle that corresponds to the initial condition of our Universe.

Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis.

BACKGROUND: The term "aseptic meningitis" encompasses cases of meningitis with negative bacterial CSF culture, which predominantly are of viral etiology. While the clinical course is usually benign, complications such as encephalitic involvement resulting in a more severe clinical course may occur. Dysfunction of the blood-brain-barrier (BBB), which is a prerequisite for viral entry into the brain parenchyma, can be approximated using the CSF/serum albumin ratio, readily obtainable in routine CSF analysis. OBJECITVES: Analysis of CSF patterns in patients with aseptic meningitis/meningoencephalitis with a focus on BBB dysfunction as a marker for encephalitic involvement. STUDY DESIGN: Retrospective chart review of patients admitted to our hospital between 2004 and 2016 with a diagnosis of aseptic meningitis/meningoencephalitis. RESULTS: Patients with aseptic meningitis displaying clinical, MR-tomographic or electroencephalographic signs of encephalitic involvement were significantly older than patients without these features (47.4 vs. 35.5 yrs., p=0.002). In patients with meningoencephalitis, CSF analysis revealed a more severe disruption of BBB, approximated by the CSF/serum albumin ratio (p=0.002). Compromised BBB function correlated positively with length of hospitalization (p=0.007), indicative of a more severe clinical course. The number of CSF lymphocytes was found to predict the severity of the BBB disruption, which additionally was more frequently observed when herpesviridae were identified as infectious agents. CONCLUSIONS: We suggest that the CSF/serum albumin ratio as an estimate for BBB function should be attended to in the evaluation of patients with aseptic meningitis. Severe BBB dysfunction, older age and infection with herpesviridae appear to raise the risk for encephalitic involvement.

Up and Down Quark Masses and Corrections to Dashen's Theorem from Lattice QCD and Quenched QED.

In a previous Letter [Borsanyi et al., Phys. Rev. Lett. 111, 252001 (2013)] we determined the isospin mass splittings of the baryon octet from a lattice calculation based on N_{f}=2+1 QCD simulations to which QED effects have been added in a partially quenched setup. Using the same data we determine here the corrections to Dashen's theorem and the individual up and down quark masses. Our ensembles include 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and average up-down quark masses all the way down to their physical value. For the parameter which quantifies violations to Dashen's theorem, we obtain ϵ=0.73(2)(5)(17), where the first error is statistical, the second is systematic, and the third is an estimate of the QED quenching error. For the light quark masses we obtain, m_{u}=2.27(6)(5)(4) and m_{d}=4.67(6)(5)(4) MeV in the modified minimal subtraction scheme at 2 GeV and the isospin breaking ratios m_{u}/m_{d}=0.485(11)(8)(14), R=38.2(1.1)(0.8)(1.4), and Q=23.4(0.4)(0.3)(0.4). Our results exclude the m_{u}=0 solution to the strong CP problem by more than 24 standard deviations.

Lattice Computation of the Nucleon Scalar Quark Contents at the Physical Point.

We present a QCD calculation of the u, d, and s scalar quark contents of nucleons based on 47 lattice ensembles with N_{f}=2+1 dynamical sea quarks, 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and pion masses down to 120 MeV. Using the Feynman-Hellmann theorem, we obtain f_{ud}^{N}=0.0405(40)(35) and f_{s}^{N}=0.113(45)(40), which translates into σ_{πN}=38(3)(3) MeV, σ_{sN}=105(41)(37) MeV, and y_{N}=0.20(8)(8) for the sigma terms and the related ratio, where the first errors are statistical and the second errors are systematic. Using isospin relations, we also compute the individual up and down quark contents of the proton and neutron (results in the main text).