Large magnetic gap at the Dirac point in Bi2Te3/MnBi2Te4 heterostructures.

Magnetically doped topological insulators enable the quantum anomalous Hall effect (QAHE), which provides quantized edge states for lossless charge-transport applications1-8. The edge states are hosted by a magnetic energy gap at the Dirac point2, but hitherto all attempts to observe this gap directly have been unsuccessful. Observing the gap is considered to be essential to overcoming the limitations of the QAHE, which so far occurs only at temperatures that are one to two orders of magnitude below the ferromagnetic Curie temperature, TC (ref. 8). Here we use low-temperature photoelectron spectroscopy to unambiguously reveal the magnetic gap of Mn-doped Bi2Te3, which displays ferromagnetic out-of-plane spin texture and opens up only below TC. Surprisingly, our analysis reveals large gap sizes at 1 kelvin of up to 90 millielectronvolts, which is five times larger than theoretically predicted9. Using multiscale analysis we show that this enhancement is due to a remarkable structure modification induced by Mn doping: instead of a disordered impurity system, a self-organized alternating sequence of MnBi2Te4 septuple and Bi2Te3 quintuple layers is formed. This enhances the wavefunction overlap and size of the magnetic gap10. Mn-doped Bi2Se3 (ref. 11) and Mn-doped Sb2Te3 form similar heterostructures, but for Bi2Se3 only a nonmagnetic gap is formed and the magnetization is in the surface plane. This is explained by the smaller spin-orbit interaction by comparison with Mn-doped Bi2Te3. Our findings provide insights that will be crucial in pushing lossless transport in topological insulators towards room-temperature applications.

Is sleep bruxism in obstructive sleep apnea only an oral health related problem?

BACKGROUND: The etiology of sleep bruxism in obstructive sleep apnea (OSA) patients is not yet fully clarified. This prospective clinical study aimed to investigate the connection between probable sleep bruxism, electromyographic muscle tone, and respiratory sleep patterns recorded during polysomnography. METHODS: 106 patients with OSA (74 males, 31 females, mean age: 56.1 ± 11.4 years) were divided into two groups (sleep bruxism: SB; no sleep bruxism: NSB). Probable SB were based on the AASM criteria: self-report of clenching/grinding, orofacial symptoms upon awakening, abnormal tooth wear and hypertrophy of the masseter muscle. Both groups underwent clinical examination for painful muscle symptoms aligned with Temporomandibular Disorders Diagnostic Criteria (DC/TMD), such as myalgia, myofascial pain, and headache attributed to temporomandibular disorder. Additionally, non-complaint positive muscle palpation and orofacial-related limitations (Jaw Functional Limited Scale-20: JFLS-20) were assessed. A one-night polysomnography with electromyographic masseter muscle tone (EMG) measurement was performed. Descriptive data, inter-group comparisons and multivariate logistic regression were calculated. RESULTS: OSA patients had a 37.1% prevalence of SB. EMG muscle tone (N1-N3, REM; P = 0.001) and the number of hypopneas (P = 0.042) were significantly higher in the sleep bruxism group. While measures like apnea-hypopnea-index (AHI), respiratory-disturbance-index (RDI), apnea index (AI), hypopnea-index (HI), number of arousals, and heart rate (1/min) were elevated in sleep bruxers, the differences were not statistically significant. There was no difference in sleep efficiency (SE; P = 0.403). Non-complaint masseter muscle palpation (61.5%; P = 0.015) and myalgia (41%; P = 0.010) were significant higher in SB patients. Multivariate logistic regression showed a significant contribution of EMG muscle tone and JFLS-20 to bruxism risk. CONCLUSION: Increased EMG muscle tone and orofacial limitations can predict sleep bruxism in OSA patients. Besides, SB patients suffer more from sleep disorder breathing. Thus, sleep bruxism seems to be not only an oral health related problem in obstructive apnea. Consequently, interdisciplinary interventions are crucial for effectively treating these patients. TRIAL REGISTRATION: The study was approved by the Ethics Committee of Philipps-University Marburg (reg. no. 13/22-2022) and registered at the "German Clinical Trial Register, DRKS" (DRKS0002959).

Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics.

Intramembrane proteolysis - cleavage of proteins within the plane of a membrane - is a widespread phenomenon that can contribute to the functional activation of substrates and is involved in several diseases. Although different families of intramembrane proteases have been discovered and characterized, we currently do not know how these enzymes discriminate between substrates and non-substrates, how site-specific cleavage is achieved, or which factors determine the rate of proteolysis. Focusing on γ-secretase and rhomboid proteases, we argue that answers to these questions may emerge from connecting experimental readouts, such as reaction kinetics and the determination of cleavage sites, to the structures and the conformational dynamics of substrates and enzymes.

Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits.

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.

In a positron-emission tomography (PET) study with the ß-amyloid (Aß) tracer [(18)F]-florbetaben, we previously showed that Aß deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aß42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aß-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aß-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aß were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aß42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aß-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

Quality Requirements for the early Fetal Ultrasound Assessment at 11-13+6 Weeks of Gestation (DEGUM Levels II and III).

The early fetal ultrasound assessment at 11 - 13(+6) weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 - 13(+6) weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 - 13(+6) weeks of gestation.

Neural effects of cognitive-behavioural therapy on dysfunctional attitudes in depression.

BACKGROUND: Dysfunctional attitudes are a feature of depression that has been correlated with receptor binding abnormalities in limbic and cortical regions. We sought to investigate the functional neuroanatomy of dysfunctional attitudes in major depressive disorder (MDD) and the effects of treatment with cognitive-behavioural therapy (CBT). METHOD: Participants were 16 patients with unipolar depression in an acute depressive episode (mean age 40.0 years) and 16 matched healthy controls (mean age 39.9 years). Patients were medication free and received a course of treatment with CBT. All participants underwent functional magnetic resonance imaging (fMRI) scans at baseline and at week 16, prior to the initiation of therapy and following the course of CBT for patients. During each fMRI scan, participants indicated their attributions to statements from a modified Dysfunctional Attitudes Scale (mDAS-48). RESULTS: MDD patients in an acute depressive episode endorsed a greater number of extreme responses to DAS statements, which normalized following CBT treatment. Extreme attributions were associated with greater activation in the left hippocampal region, inferior parietal lobe and precuneus in MDD patients as compared with healthy controls as a main effect of group. An interaction effect was found in the left parahippocampal region, which showed less attenuation in MDD patients at the follow-up scan relative to healthy controls. CONCLUSIONS: Attenuation of activity in the parahippocampal region may be indicative of an improvement in dysfunctional thinking following CBT treatment in depression, while persistent engagement of regions involved in attentional processing and memory retrieval with extreme attributions reflects a trait feature of depression.

Chronic γ-secretase inhibition reduces amyloid plaque-associated instability of pre- and postsynaptic structures.

The loss of synapses is a strong histological correlate of the cognitive decline in Alzheimer's disease (AD). Amyloid ß-peptide (Aß), a cleavage product of the amyloid precursor protein (APP), exerts detrimental effects on synapses, a process thought to be causally related to the cognitive deficits in AD. Here, we used in vivo two-photon microscopy to characterize the dynamics of axonal boutons and dendritic spines in APP/Presenilin 1 (APP(swe)/PS1(L166P))-green fluorescent protein (GFP) transgenic mice. Time-lapse imaging over 4 weeks revealed a pronounced, concerted instability of pre- and postsynaptic structures within the vicinity of amyloid plaques. Treatment with a novel sulfonamide-type γ-secretase inhibitor (GSI) attenuated the formation and growth of new plaques and, most importantly, led to a normalization of the enhanced dynamics of synaptic structures close to plaques. GSI treatment did neither affect spines and boutons distant from plaques in amyloid precursor protein/presenilin 1-GFP (APPPS1-GFP) nor those in GFP-control mice, suggesting no obvious neuropathological side effects of the drug.

[Management of postpartum hemorrhage (PPH): algorithm of the interdisciplinary D-A-CH consensus group PPH (Germany - Austria - Switzerland)]. / Management der postpartalen Blutung (PPH): Algorithmus der Interdisziplinären D-A-CH-Konsensusgruppe PPH (Deutschland - Österreich - Schweiz).

Postpartum hemorrhage (PPH) is one of the main causes of maternal deaths even in industrialized countries. It represents an emergency situation which necessitates a rapid decision and in particular an exact diagnosis and root cause analysis in order to initiate the correct therapeutic measures in an interdisciplinary cooperation. In addition to established guidelines, the benefits of standardized therapy algorithms have been demonstrated. A therapy algorithm for the obstetric emergency of postpartum hemorrhage in the German language is not yet available. The establishment of an international (Germany, Austria and Switzerland D-A-CH) "treatment algorithm for postpartum hemorrhage" was an interdisciplinary project based on the guidelines of the corresponding specialist societies (anesthesia and intensive care medicine and obstetrics) in the three countries as well as comparable international algorithms for therapy of PPH.The obstetrics and anesthesiology personnel must possess sufficient expertise for emergency situations despite lower case numbers. The rarity of occurrence for individual patients and the life-threatening situation necessitate a structured approach according to predetermined treatment algorithms. This can then be carried out according to the established algorithm. Furthermore, this algorithm presents the opportunity to train for emergency situations in an interdisciplinary team.

Childhood-onset psoriasis: association with future cardiovascular and metabolic comorbidities.

BACKGROUND: Psoriasis is associated with higher prevalences of cardiovascular and metabolic comorbidities in adults but the relationship of age at onset and those prevalences is unknown. OBJECTIVE: To evaluate whether the childhood onset of psoriasis (COP) is correlated with the frequency of cardiovascular and metabolic comorbidities in adulthood. METHODS: This noninterventional, cross-sectional, multicentre study of adults with psoriasis was conducted in 29 dermatology centres in France. Data on sex, age at onset of psoriasis and its clinical characteristics, and cardiovascular risk factors, including weight, body mass index, waist circumference, dyslipidaemia, diabetes, hypertension, smoking, and personal/familial major adverse cardiovascular events (MACE) were systematically recorded. RESULTS: Two thousand two hundred and one patients with psoriasis (male: 56%; mean age: 49 years; 25% with COP) were included consecutively in the study. Univariate analysis showed that COP was associated with lower frequencies of obesity, high waist circumference, diabetes, dyslipidaemia, hypertension, familial cardiovascular disease, MACE and metabolic syndrome, but more frequent active smoking. Multivariate analysis retained age as being associated with frequency of cardiovascular and metabolic comorbidities, and sex with smoking, but not age at the onset of psoriasis. Psoriasis severity was associated with higher frequencies of obesity and psoriatic arthritis. CONCLUSION: Our results showed that COP does not seem to be an additional risk factor for higher frequencies of cardiovascular and metabolic comorbidities during adulthood.

Remineralisation capability of silver diamine fluoride in artificial enamel lesions on smooth surfaces using quantitative light-induced fluorescence measurements in-vitro.

Enamel demineralisation can develop on smooth surfaces as an undesirable side effect during orthodontic treatment with fixed appliances. This study aimed to evaluate the ability of 38% silver diamine fluoride in remineralisation (as estimated by fluorescence gain) of artificial initial lesions in smooth surfaces of human enamel. The smooth surfaces of 50 human tooth samples were artificially demineralised and 45 samples were allocated randomly into three groups receiving a single treatment with a varnish: group I: Riva Star (silver diamine fluoride, SDF), group II: Bifluorid 12 (NaF, CaF2), and group III: Cervitec F (CHX, CPC, NH4F). Five samples were assigned as a negative control group without treatment. All samples were exposed to pH-cycling for 28 days. Fluorescence behavior was measured using Quantitative light-induced fluorescence before and after demineralisation and up to four weeks on a weekly basis. Analysis of variance (ANOVA) with Tukey-Kramer post-hoc tests and repeated measures ANOVA were used for statistical evaluation (α = 0.05). After demineralisation, all samples showed mean ΔF of - 16.22% ± 4.35, without significance differences between the fluorescence behaviour of the samples (p = 0.251). After 28 days group comparison showed a statistically significant difference (p = 0.034) for ΔF values: the lowest fluorescence values were found in group I (SDF, mean ΔF - 16.47 ± 6.08) with a significant difference compared to group III (Cervitec F, mean ΔF - 11.71 ± 4.83). In group II (Bifluorid 12) mean ΔF value was - 15.55 ± 2.15) without statistically significant differences to groups I and III. The fluorescence behaviour of SDF varnish on smooth surfaces with artificial initial enamel lesions was significantly lower compared to Cervitec F varnish after short time use.

Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch.

Mutations in the presenilin-1 (PS1) gene are associated with Alzheimer's disease and cause increased secretion of the neurotoxic amyloid-beta peptide (Abeta). Critical intramembraneous aspartates at residues 257 and 385 are required for the function of PS1 protein. Here we investigate the biological function of a naturally occurring PS1 splice variant (PS1 Deltaexon 8), which lacks the critical aspartate 257. Cell lines that stably express PS1 Deltaexon 8 or a PS1 protein in which aspartate residue 257 is mutated secrete significant levels of Abeta, whereas Abeta generation is severely reduced in cells transfected with PS1 containing a mutation of aspartate 385. In contrast, endoproteolytic processing of Notch is almost completely inhibited in cell lines expressing any of the PS1 variants that lack one of the critical aspartates. These data indicate that PS1 may differentially facilitate gamma-secretase-mediated generation of Abeta and endoproteolysis of Notch.

Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases.

Endoproteolysis of beta-amyloid precursor protein (betaAPP) and Notch requires conserved aspartate residues in presenilins 1 and 2 (PS1 and PS2). Although PS1 and PS2 have therefore been proposed to be aspartyl proteases, no homology to other aspartyl proteases has been found. Here we identify homology between the presenilin active site and polytopic aspartyl proteases of bacterial origin, thus supporting the hypothesis that presenilins are novel aspartyl proteases.

Experimental investigation of geologically produced antineutrinos with KamLAND.

The detection of electron antineutrinos produced by natural radioactivity in the Earth could yield important geophysical information. The Kamioka liquid scintillator antineutrino detector (KamLAND) has the sensitivity to detect electron antineutrinos produced by the decay of 238U and 232Th within the Earth. Earth composition models suggest that the radiogenic power from these isotope decays is 16 TW, approximately half of the total measured heat dissipation rate from the Earth. Here we present results from a search for geoneutrinos with KamLAND. Assuming a Th/U mass concentration ratio of 3.9, the 90 per cent confidence interval for the total number of geoneutrinos detected is 4.5 to 54.2. This result is consistent with the central value of 19 predicted by geophysical models. Although our present data have limited statistical power, they nevertheless provide by direct means an upper limit (60 TW) for the radiogenic power of U and Th in the Earth, a quantity that is currently poorly constrained.

Posttraumatic stress disorder in children and adolescents: a review of psychopharmacological treatment.

UNLABELLED: PTSD in children and adolescents differs from the adult disease. Therapeutic approaches involve both psychotherapy and psychopharmacotherapy. OBJECTIVES: The current paper aims at reviewing studies on psychopharmacological treatment of childhood and adolescent PTSD. Additionally, developmental frameworks for PTSD diagnosis and research along with an experimental model of quenching and kindling in the context of stress exposure are presented. We conducted an extensive literature search of reviews on psychopharmacotherapy as well as studies on psychopharmacological treatment for PTSD among children and adolescents. We used the database PubMed and focused on the time period of the last 10 years up to January 2009. Pertinent earlier papers were also included.There are a limited number of studies specifically assessing the psychopharmacological treatment of PTSD in children and adolescents. The vast majority of them lack verification in RCTs. Only the use of imipramine, divalproex sodium and sertraline were already evaluated in RCTs. Future studies should take into account developmental approaches to the diagnosis and treatment of PTSD in children and adolescents. In this context, different underlying neurobiological patterns, which are reflected in distinct clinical symptomatology, require a precise investigation and a symptom-orientated psychopharmacological approach.

Impact of self-assembling peptides in remineralisation of artificial early enamel lesions adjacent to orthodontic brackets.

Enamel demineralisation can occur as a side effect during orthodontic treatment with fixed appliances. This study aimed to evaluate the efficacy of the self-assembling peptide P11-4 for remineralisation combined with fluorides, compared to application of fluoride varnish alone. De- and remineralisation was assessed by Quantitative light-induced fluorescence (QLF). Orthodontic brackets were bonded on 108 human enamel samples and white spot lesions were created. The samples were allocated randomly into three groups: Group I received no treatment, group II had a single application of fluoride varnish (22,600 ppm), and group III was treated with P11-4 following a single application of fluoride varnish. Quantitative light-induced fluorescence (QLF) measurements were performed at baseline, after demineralisation and after storage in remineralisation solution for 7 and 30 days. Non-parametric tests (Kruskal-Wallis test and Friedman test) were used for further analysis. After demineralisation, all samples showed a median ΔF -9.38% ± 2.79. After 30 days median ΔF values were as followed: group I = -9.04% ± 2.51, group II = -7.89 ± 2.07, group III = -6.08% ± 2.79). The median ΔF values differed significantly between all groups at all investigation times (p < 0.00001). Application of P11-4 with fluoride varnish was superior to the use of fluorides alone for remineralisation of enamel adjacent to brackets.

Fetal weight estimation by 2D and 3D ultrasound: comparison of six formulas.

PURPOSE: To evaluate and compare the accuracy of different formulas to estimate fetal weight using 2D and 3D ultrasound. MATERIALS AND METHODS: We performed a prospective study on unselected singleton pregnancies. All scanned fetuses delivered within 7 days in absence of structural and chromosomal abnormalities were included. The fetal weight was calculated using the 3D Schild, Chang, Liang and 2D Hansmann, Merz and Hadlock formulas. Absolute and mean deviations of estimated fetal weight were calculated. RESULTS: Of 249 scanned fetuses 200 that fulfilled the criteria were included. Birth weights ranged between 535 and 5020 g. The highest correlation between estimated fetal and birth weight was achieved by applying Schild's equation, and the absolute percentage error was 5.6%. The corresponding values for 2D Hansmann, Merz and four-parametric Hadlock formulas were 7.5%, 7.9%, and 9.2%, respectively, while these were 13.1% and 30.7% for Liang's and Chang's 3D equations. Using the Schild formula, a deviation from birth weight below 10 % was achieved in 80 % of fetuses, with Hansmann's in 73.5% and with Merz in 72.5%, while this parameter was much lower in the remaining equations. CONCLUSION: The best option with the highest accuracy for sonographic fetal weight estimation was the 3D Schild equation followed by the 2D Hansmann and Merz formulas. Published data of the accuracy could be reproduced with the exception of the "Asian" 3D equations in our European population. The limited improvement in weight agreement using the 3D technique compared to the 2D technique may be outweighed by the time consumption.

Randomised in situ clinical trial investigating self-assembling peptide matrix P11-4 in the prevention of artificial caries lesions.

The aim was to investigate the ability of self-assembling Peptide P11-4 Matrix (SAPM) to remineralize artificial initial caries lesions compared to the use of fluoride varnish. Volunteers were recruited for this randomised, cross-over in situ trial. Bovine specimens, half including orthodontic brackets, were recessed on the buccal aspects of mandibular appliances. Specimens included internal sound enamel control, a demineralised control and a part exposed during the in situ phase. Each phase lasted four weeks, followed by a one-week washout. Treatment groups were: A: negative control, no treatment,B: positive control, 22,600 ppm fluoride varnish,C: test group, 1,000 ppm SAPM. Laser fluorescence values (LF) were measured before/after demineralisation, and after the in situ period. Micro-CT analysis was used to assess mineral changes within the specimens after the in situ phase. In specimens without brackets, ΔLF values after in situ phase were: A: +5.28, B: +0.85, C: -2.89. Corresponding ΔLF for specimens with brackets were: A: +5.77, B: +1.30, C: -3.15. LF-values between groups significantly differed from each other (p < 0.0001) after the in situ phase. Micro-CT analysis yielded no significant difference among groups for specimens without brackets. For specimens with brackets, the test group showed significantly more remineralisation than the negative (p = 0.01) and positive control (p = 0.003). Within the limitations of the study, SAPM showed prevention of caries and remineralisation of enamel around orthodontic brackets.