Superconducting diode effect under time-reversal symmetry.

In noncentrosymmetric superconductors, superconducting and normal conductions can interchange on the basis of the current flow direction. This effect is termed a superconducting diode effect (SDE), which is a focal point of recent research. The broken inversion and time-reversal symmetry is believed to be the requirements of SDE, but their intrinsic role has remained elusive. Here, we report strain-controlled SDEs in a layered trigonal superconductor, PbTaSe2. The SDE was found exclusively in a strained device with its absence in an unstrained device despite that it is allowed in unstrained trigonal structure. Moreover, the zero-field or magnetic field-even (magnetic field-odd) SDE is observed when the strain and current are along armchair (zigzag) direction The results unambiguously demonstrate the intrinsic SDE under time-reversal symmetry and the critical role of strain-induced electric polarization.

Giant Modulation of the Second Harmonic Generation by Magnetoelectricity in Two-Dimensional Multiferroic CuCrP2S6.

Multiferroic materials have attracted considerable attention owing to their unique magnetoelectric or magnetooptical properties. The recent discovery of few-layer van der Waals multiferroic crystals provides a new research direction for controlling the multiferroic properties in the atomic layer limit. However, research on few-layer multiferroic crystals is limited and the effect of thickness-dependent symmetries on those properties is less explored. In this study, the symmetries and magnetoelectric responses of van der Waals multiferroic CuCrP2S6 are investigated by optical second harmonic generation (SHG). Structural and magnetic phase transitions are successfully probed by the temperature-dependent SHG signals, revealing significant changes by applying the magnetic field reflecting the magnetoelectric effect. Moreover, it is found that symmetries and resultant magnetoelectric responses can be modulated by the number of layers. These results offer a new principle of controlling the multiferroicity and indicate that 2D van der Waals multiferroic material is a promising building block for functional nanodevices.

Risk factors for oral frailty among community-dwelling pre-frail older adults in Japan: A cross-sectional analysis.

OBJECTIVES: Oral frailty is a well-established risk factor for frailty and plays a significant role in progression to frailty. However, the association between oral frailty and pre-frailty in elderly individuals remains unclear. This cross-sectional study aimed to clarify the characteristics and risk factors of pre-frailty in elderly individuals with oral frailty. METHODS: A total of 377 elderly individuals participated. Oral examinations comprised simple and non-invasive measures of chewing function, self-reported swallowing function, and oral moisture. The frailty screening index was used to assess frailty phenotypes. RESULTS: The overall prevalence of pre-frailty was 63.1%, after excluding 40 frail and 99 robust individuals. The mean age of the pre-frail participants was 76.6 ± 5.8 years; 70.6% were women. 10.5% of the pre-frail elderly participants had oral frailty. In multivariate analysis diabetes mellitus, history of cancer, denture wearing, and malnutrition were independently associated with oral frailty among pre-frail elderly individuals (adjusted odds ratio (OR) 3.8, 95% confidence interval (CI) 1.06-13.54; OR 4.5, CI 1.32-15.36; OR 8.8, CI 1.76-43.78; and OR 3.6, CI 1.30-9.67; respectively). CONCLUSIONS: The prevalence of oral frailty was low among community-dwelling pre-frail elderly individuals. Early interventions involving oral, nutritional, and disease management may prevent or improve oral frailty in pre-frail elderly individuals and may prevent progression to frailty. Further studies are required to elucidate the underlying mechanisms.

Fucosyltransferase 8 (FUT8) and core fucose expression in oxidative stress response.

GlycoMaple is a new tool to predict glycan structures based on the expression levels of 950 genes encoding glycan biosynthesis-related enzymes and proteins using RNA-seq data. The antioxidant response, protecting cells from oxidative stress, has been focused on because its activation may relieve pathological conditions, such as neurodegenerative diseases. Genes involved in the antioxidant response are defined within the GO:0006979 category, including 441 human genes. Fifteen genes overlap between the glycan biosynthesis-related genes defined by GlycoMaple and the antioxidant response genes defined by GO:0006979, one of which is FUT8. 5-Hydroxy-4-phenyl-butenolide (5H4PB) extracted from Chinese aromatic vinegar induces the expression of a series of antioxidant response genes that protect cells from oxidative stress via activation of the nuclear factor erythroid 2-related factor 2-antioxidant response element pathway. Here, we show that FUT8 is upregulated in both our RNA-seq data set of 5H4PB-treated cells and publicly available RNA-seq data set of cells treated with another antioxidant, sulforaphane. Applying our RNA-seq data set to GlycoMaple led to a prediction of an increase in the core fucose of N-glycan that was confirmed by flow cytometry using a fucose-binding lectin. These results suggest that FUT8 and core fucose expression may increase upon the antioxidant response.

The association between atopic dermatitis, cognitive function and school performance in children and young adults.

BACKGROUND: Children with atopic dermatitis (AD) may have disturbed sleep, affected self-esteem and decreased quality of life, likely interfering with performance in school. OBJECTIVES: To examine the association between hospital-managed paediatric AD, school performance and cognitive function. METHODS: In this cross-sectional study we linked data from the Danish national registers and identified three populations between 2001 and 2019. Population 1 comprised children with graduation grades registered from lower secondary school, population 2 comprised adolescents with registration of an upper secondary graduation mean, and population 3 comprised male conscripts with registration of an IQ test score. AD was defined as a hospital diagnostic code (inpatient or outpatient) prior to the exam or conscription date, and was stratified according to severity, activity and atopic comorbidity. Outcomes included graduation mean from lower and upper secondary school, special educational assistance in primary and lower secondary school, and IQ at conscription. RESULTS: In total, 770 611 (12 137 with AD), 394 193 (6261 with AD) and 366 182 (4539 with AD) children and adolescents were included in populations 1 (lower secondary graduation), 2 (upper secondary graduation) and 3 (conscription), respectively. In lower secondary school, children with severe AD had significantly lower overall, written and oral graduation grade means compared with children with mild AD: respectively, difference -0.29 [95% confidence interval (CI) -0.45 to -0.13, P < 0.001], difference -0.26 (95% CI -0.42 to -0.10, P = 0.0016) and difference -0.30 (95% CI -0.49 to -0.11, P = 0.0018). In upper secondary school, adolescents with AD performed similarly to their peers without AD. Young men with AD scored significantly lower IQ test means at conscription examination than male conscripts without AD: difference -0.60 (95% CI -0.87 to -0.32, P < 0.001). CONCLUSIONS: AD, in particular when severe, is associated with lower school performance in childhood and IQ in young men, which can interfere with academic achievements in life. Optimization of treatment of children with AD and specific educational support to children with severe AD could be needed.

A Primer on Deep Learning-Based Cellular Image Classification of Changes in the Spatial Distribution of the Golgi Apparatus After Experimental Manipulation.

The visual classification of cell images according to differences in the spatial patterns of subcellular structure is an important methodology in cell and developmental biology. Experimental perturbation of cell function can induce changes in the spatial distribution of organelles and their associated markers or labels. Here, we demonstrate how to achieve accurate, unbiased, high-throughput image classification using an artificial intelligence (AI) algorithm. We show that a convolutional neural network (CNN) algorithm can classify distinct patterns of Golgi images after drug or siRNA treatments, and we review our methods from cell preparation to image acquisition and CNN analysis.

Vortex dynamics in the two-dimensional BCS-BEC crossover.

The Bardeen-Cooper-Schrieffer (BCS) condensation and Bose-Einstein condensation (BEC) are the two limiting ground states of paired Fermion systems, and the crossover between these two limits has been a source of excitement for both fields of high temperature superconductivity and cold atom superfluidity. For superconductors, ultra-low doping systems like graphene and LixZrNCl successfully approached the crossover starting from the BCS-side. These superconductors offer new opportunities to clarify the nature of charged-particles transport towards the BEC regime. Here we report the study of vortex dynamics within the crossover using their Hall effect as a probe in LixZrNCl. We observed a systematic enhancement of the Hall angle towards the BCS-BEC crossover, which was qualitatively reproduced by the phenomenological time-dependent Ginzburg-Landau (TDGL) theory. LixZrNCl exhibits a band structure free from various electronic instabilities, allowing us to achieve a comprehensive understanding of the vortex Hall effect and thereby propose a global picture of vortex dynamics within the crossover. These results demonstrate that gate-controlled superconductors are ideal platforms towards investigations of unexplored properties in BEC superconductors.

Giant second harmonic transport under time-reversal symmetry in a trigonal superconductor.

Nonreciprocal or even-order nonlinear responses in symmetry-broken systems are powerful probes of emergent properties in quantum materials, including superconductors, magnets, and topological materials. Recently, vortex matter has been recognized as a key ingredient of giant nonlinear responses in superconductors with broken inversion symmetry. However, nonlinear effects have been probed as excess voltage only under broken time-reversal symmetry. In this study, we report second harmonic transport under time-reversal symmetry in the noncentrosymmetric trigonal superconductor PbTaSe2. The magnitude of anomalous nonlinear transport is two orders of magnitude larger than those in the normal state, and the directional dependence of nonlinear signals are fully consistent with crystal symmetry. The enhanced nonlinearity is semiquantitatively explained by the asymmetric Hall effect of vortex-antivortex string pairs in noncentrosymmetric systems. This study enriches the literature on nonlinear phenomena by elucidating quantum transport in noncentrosymmetric superconductors.

Patient characteristics and disease burden of alopecia areata in the Danish Skin Cohort.

PURPOSE: Alopecia areata (AA) is a common disorder of patchy hair loss which carries a substantial psychological burden for patients. The current understanding of AA prevalence, disease course and burden is limited, and further research is needed to improve patient care. This prospective cohort of AA patients within the Danish Skin Cohort was established to provide data that can serve as a tool in future studies of for example, AA epidemiology and disease burden. PARTICIPANTS: A total of 1494 patients with dermatologist-verified AA were included in the cohort. Patients were invited and included through electronic or phone-based questionnaires. Information regarding demographics, biometrics, lifestyle factors, skin type, AA onset and development, health-related quality of life and self-reported severity assessment was collected. FINDINGS TO DATE: The mean (SD) age of AA onset was 32.7 (17.6) years. The mean body mass index and history of cigarette smoking was comparable with the general population. The majority (92.5%) of participants were Caucasian. In total, 72.4% of patients received their diagnosis by a physician within a year after onset of symptoms, and 66.9% reported to still have symptoms of AA within the past year. A total of 12% reported to have a first-degree family member with AA. In total, 31.4% of patients were missing all or nearly all hairs on their scalp, 32.2% had no or barely no eyelashes and 36.2% had no or barely no eyebrow hairs. Overall, most patients (55.7%) did not experience irritated eyes, but 30% reported slight eye irritation and 47.2% reported no damage to finger nails or toenails. FUTURE PLANS: Observational studies regarding comorbidities, psychosocial burden of AA and efficacy of pharmacological interventions will be carried out and additional data will be linked from nationwide registries of routinely collected data. Furthermore, follow-up survey data will be added for longitudinal analyses.

Family burden of hospital-managed pediatric atopic dermatitis: A nationwide registry-based study.

BACKGROUND: Parents of children with atopic dermatitis (AD) report reduced quality of life and higher stress level, which could increase risk of psychiatric and pain disorders, and medication use. METHODS: By use of Danish national registries, we identified family members of all first-born Danish children born between 1 January 1995 and 31 December 2013 with a hospital diagnosis of AD, matched them 1:10 with family members of children without AD, and followed the cohorts over time. RESULTS: Mothers of children with hospital-managed AD had higher risk of filling a prescription for medications for depression, anxiety, pain and sleep problems, and of consulting a psychologist, but most associations disappeared after full adjustment. Siblings had higher risk of receiving a diagnosis for adjustment disorder, and fathers showed increased risk of filling a prescription for pain medication and of divorce, in crude but not adjusted models. CONCLUSIONS: The increased risk of study endpoints seen in mothers of children with hospital-managed AD was not explained by pediatric AD alone. Rather, the total burden in these families including parent and child morbidity and socioeconomic resources seems to explain these observations. The burden in families of children with AD may potentially affect the overall management of their child's AD.

Limitations of Using Questionnaires for Assessing the Prevalence of Psoriasis and Atopic Dermatitis Among Adults.

IMPORTANCE: Questionnaire studies are important for estimating the prevalence of psoriasis and atopic dermatitis; however, validity among the adult population remains an important concern. OBJECTIVE: To examine the test-retest accuracy of questionnaires for measuring psoriasis and atopic dermatitis prevalence in an adult population. DESIGN, SETTING, AND PARTICIPANTS: This nationwide population-based cohort study administered questionnaires on psoriasis and atopic dermatitis to the same 2333 and 2312 randomly selected adults (≥18 years) in Denmark, respectively, at 2 different time points from May 15, 2018, to November 20, 2020. Data were analyzed from January 10 to January 28, 2021. To reduce the risk of participation bias, potential respondents were given information on the research project only after agreeing to participate. EXPOSURES: Participants were asked identical questions on psoriasis and atopic dermatitis in 2018 and in 2020. Responses were linked at the individual-level. MAIN OUTCOMES AND MEASURES: The test-retest reliability (expressed by Cohen κ). RESULTS: The psoriasis questionnaire was completed by 2333 (mean [SD] age, 55.1 [16.2] years; 1338 [57.4%] women) participants in 2018 and in 2020. The atopic dermatitis questionnaire was completed by 2312 (mean [SD] age, 55.0 [16.2] years; 1326 [57.4%] women) participants in 2018 and in 2020. Among participants reporting a history of psoriasis, agreement between individual responses was high (κ = 0.7558); however, among those reporting a history of atopic dermatitis, agreement was low (κ = 0.4395). For psoriasis, prevalence changed from 7.8% to 8.0%; for atopic dermatitis, from 8.2% to 7.6%. Of participants who in 2018 reported dermatologist-diagnosed atopic dermatitis, 36.9% claimed in the 2020 questionnaire that they had never had atopic dermatitis. Analyses revealed substantial agreement for psoriasis responses across all age strata; for atopic dermatitis responses, the κ declined with increasing age, to 0.2613 for participants 65 or older. CONCLUSIONS AND RELEVANCE: This cohort study found considerable agreement between responses over time when participants were asked about a history of psoriasis. When asked about a history of atopic dermatitis, responses over time were inconsistent. This inconsistency suggests that questionnaires on a history of atopic dermatitis will confer considerable risk of bias and misclassification.

Emergent inequality and business cycles in a simple behavioral macroeconomic model.

Standard macroeconomic models assume that households are rational in the sense that they are perfect utility maximizers and explain economic dynamics in terms of shocks that drive the economy away from the steady state. Here we build on a standard macroeconomic model in which a single rational representative household makes a savings decision of how much to consume or invest. In our model, households are myopic boundedly rational heterogeneous agents embedded in a social network. From time to time each household updates its savings rate by copying the savings rate of its neighbor with the highest consumption. If the updating time is short, the economy is stuck in a poverty trap, but for longer updating times economic output approaches its optimal value, and we observe a critical transition to an economy with irregular endogenous oscillations in economic output, resembling a business cycle. In this regime households divide into two groups: poor households with low savings rates and rich households with high savings rates. Thus, inequality and economic dynamics both occur spontaneously as a consequence of imperfect household decision-making. Adding a few "rational" agents with a fixed savings rate equal to the long-term optimum allows us to match business cycle timescales. Our work here supports an alternative program of research that substitutes utility maximization for behaviorally grounded decision-making.

Association of Potent and Very Potent Topical Corticosteroids and the Risk of Osteoporosis and Major Osteoporotic Fractures.

Importance: Systemic and inhaled corticosteroids negatively affect bone remodeling and cause osteoporosis and bone fracture when given continuously or in high doses. However, risk of osteoporosis and major osteoporotic fracture (MOF) after application of topical corticosteroids (TCSs) is largely unexplored. Objective: To examine the association between cumulative exposure to potent and very potent TCSs and risk of osteoporosis and MOF. Design, Setting, and Participants: This nationwide retrospective cohort study included 723 251 Danish adults treated with potent or very potent TCSs from January 1, 2003, to December 31, 2017. Data were obtained from Danish nationwide registries. Filled prescription data were converted in equipotent doses to mometasone furoate (1 mg/g). Data were analyzed from June 1 to August 31, 2019. Exposures: Patients were considered exposed when they had filled prescriptions of cumulative amounts corresponding to the equivalent of at least 500 g of mometasone, using filled prescriptions of 200 to 499 g as the reference group. Main Outcomes and Measures: The co-primary outcomes were a diagnosis of osteoporosis or MOF. Hazard ratios (HRs) adjusted for age, sex, socioeconomic status, medication use, and comorbidity were calculated with 95% CIs using Cox proportional hazards regression models. Results: A total of 723 251 adults treated with the equivalent of at least 200 g of mometasone were included in the analysis (52.8% women; mean [SD] age, 52.8 [19.2] years). Dose-response associations were found between increased use of potent or very potent TCSs and the risk of osteoporosis and MOF. For example, HRs of MOF were 1.01 (95% CI, 0.99-1.03) for exposure to 500 to 999 g, 1.05 (95% CI, 1.02-1.08) for exposure to 1000 to 1999 g, 1.10 (95% CI, 1.07-1.13) for exposure to 2000 to 9999 g, and 1.27 (95% CI, 1.19-1.35) for exposure to at least 10 000 g. A 3% relative risk increase of osteoporosis and MOF was observed per doubling of the cumulative TCS dose (HR, 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for MOF. The lowest exposure needed for 1 additional patient to be harmed (454 person-years) was observed for MOF with exposure of at least 10 000 g. Conclusions and Relevance: These findings demonstrate that use of high cumulative amounts of potent or very potent TCSs was associated with an increased risk of osteoporosis and MOF.

Treatment of adult atopic dermatitis patients according to disease characteristics and demographics.

Little is currently known about possible associations between disease specific characteristics of atopic dermatitis (AD) and use of medical treatments. We explored the use of AD treatments within the past 12 months in Danish adults according to distinct patient characteristics. Patients who had received a diagnosis of AD in a hospital in- or outpatient setting as adults were surveyed and data cross-linked to a national prescription registry. AD severity was measured by the Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD). A total of 3834 patients participated. Use of topical medication in the past 12 months increased with increasing AD severity, whereas no difference was observed for systemic medication use. Positive associations between AD in the face and neck, and use of mild and moderately potent topical corticosteroids were observed, while involvement of palms and chest was associated with use of more potent topical corticosteroids. The mean DLQI, skin pain, and itch severity scores were lower in patients managed only with topical corticosteroids (5.5, 3.2, and 4.3, respectively) compared to patients treated with both oral and topical medication (7.1, 3.8, and 5.0, respectively). Patients with frequent topical corticosteroid use tended to be older (50.7 vs 48.6 years), males (50.0% vs 33.6%), current daily smokers (17.3% vs 13.7%), and having asthma (59.1% vs 43.8%) compared with infrequent users of topical corticosteroids. We found a disconnect between the severity of AD signs and symptoms, and use of AD therapies. In particular, a very modest use of systemic immunosuppressants was seen even among patients with severe AD symptoms. However, the underlying clinical decisions and reasons behind this disconnect is not clear based on the current data.

Nonreciprocal transport in gate-induced polar superconductor SrTiO3.

Polar conductors/superconductors with Rashba-type spin-orbit interaction are potential material platforms for quantum transport and spintronic functionalities. One of their inherent properties is the nonreciprocal transport, where the rightward and leftward currents become inequivalent, reflecting spatial inversion/time-reversal symmetry breaking. Such a rectification effect originating from the polar symmetry has been recently observed at interfaces or bulk Rashba semiconductors, while its mechanism in a polar superconductor remains elusive. Here, we report the nonreciprocal transport in gate-induced two-dimensional superconductor SrTiO3, which is a Rashba superconductor candidate. In addition to the gigantic enhancement of nonreciprocal signals in the superconducting fluctuation region, we found kink and sharp peak structures around critical temperatures, which reflect the crossover behavior from the paraconductivity origin to the vortex origin, based on a microscopic theory. The present result proves that the nonreciprocal transport is a powerful tool for investigating the interfacial/polar superconductors without inversion symmetry, where rich exotic features are theoretically prognosticated.

Association Between Topical Corticosteroid Use and Type 2 Diabetes in Two European Population-Based Adult Cohorts.

OBJECTIVE: Topical corticosteroids (CSs) are commonly used to treat inflammatory skin conditions including eczema and psoriasis. Although topical CS package inserts describe hyperglycemia and glycosuria as adverse drug reactions, it is unclear whether topical CS use in real life is also associated with an increased risk of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Two matched case-control studies and one cohort study were conducted using routinely collected health care data from Denmark and the U.K. A total of 115,218 and 54,944 adults were identified as case subjects with new-onset T2D in the Danish and U.K. case-control study, respectively. For the Danish cohort study, 2,689,473 adults were included. The main exposure was topical CSs, and the outcome was incident T2D. RESULTS: Topical CS was significantly associated with T2D in the Danish (adjusted odds ratio [OR] 1.25 [95% CI 1.23-1.28]) and U.K. (adjusted OR 1.27 [95% CI 1.23-1.31]) case-control studies. Individuals who were exposed to topical CSs had significantly increased risk of incident T2D (adjusted hazard ratio 1.27 [95% CI 1.26-1.29]). We observed significant dose-response relationships between T2D and increasing potency of topical CSs in the two Danish studies. The results were consistent across all sensitivity analyses. CONCLUSIONS: We found a positive association between topical CS prescribing and incident T2D in Danish and U.K. adult populations. Clinicians should be cognizant of possible diabetogenic effects of potent topical CSs.

Chronologic order of appearance of immune-mediated inflammatory diseases relative to diagnosis of psoriasis.

BACKGROUND: Psoriasis is a common inflammatory skin disease associated with several immune-mediated inflammatory diseases (IMIDs); however, little is known of the chronology of disease development. OBJECTIVE: To investigate the chronology of IMIDs relative to psoriasis. METHODS: We utilized routinely collected data from Danish nationwide administrative registries to examine the occurrence of IMIDs in patients with psoriasis (n = 10,923) and general population controls (n = 109,230). RESULTS: Approximately 20% of patients with psoriasis developed ≥1 IMID, with a 5-fold increased risk compared with the general population. Most IMIDs were diagnosed before psoriasis, except for psoriatic arthritis. Psoriasis was significantly associated with having multiple IMIDs (odds ratio 15.2, 95% confidence interval 11.6-20.0). Human leukocyte antigen B27 positivity was significantly more frequent among psoriasis patients. LIMITATIONS: Clinical measurements were unavailable. CONCLUSION: IMIDs occur frequently in patients with psoriasis and most are diagnosed before psoriasis. The observed chronology might represent important mechanisms of disease development.

Prevalence and characteristics of psoriasis in Denmark: findings from the Danish skin cohort.

BACKGROUND: Wide-ranging psoriasis prevalence estimates have been reported, possibly due to methodological differences. OBJECTIVES: To assess the prevalence of psoriasis in Denmark and to validate the use of questionnaire-based data to identify patients with psoriasis. METHODS: We used data from the Danish Skin Cohort, a prospective cohort comprising general population adults, as well as patients with dermatologist-verified psoriasis and atopic dermatitis, respectively. The general population cohort was interviewed to assess the psoriasis prevalence in Denmark, and validation of the questions was performed. RESULTS: From 3490 general population participants, 7.9% (n=275) were found to have self-reported psoriasis. Of these, 221 (prevalence 6.3%) had their disease diagnosed by a physician (the dermatologist-diagnosed prevalence was 4.3%), whereas 54 (prevalence 1.6%) were not diagnosed by a physician. A total of 176 (5%) had active psoriasis within the last 12 months. More than half of patients had at least one disease flare in the last 12 months, and 44.4% of patients with psoriasis had at least one family member with psoriasis, whereas this was only the case for 13.7% of non-psoriasis individuals. Validation of the psoriasis diagnosis yielded a high sensitivity and specificity, with little incremental value of limiting diagnoses to those diagnosed by a physician. CONCLUSION: The lifetime-prevalence of self-reported psoriasis was found to be 7.9%, whereas the 1-year prevalence (ie, currently active psoriasis) was 5.0%. If used appropriately, questionnaire-based data may accurately identify patients with psoriasis.

Native prion protein homodimers are destabilized by oligomeric amyloid ß 1-42 species as shown by single-molecule imaging.

Prion proteins (PrPc) are receptors for amyloid ß 1-42 (Aß1-42) oligomers, but we do not know the impact of Aß1-42 binding to PrPc on the interaction of membrane-bound PrPc with molecules that regulate downstream biological pathways. Stability of the PrPc dimeric complex and subsequent intermolecular interactions with membranous or cytoplasmic molecules are important for physiological functions of PrPc including neuroprotection. The principal aim of this study was to determine whether homodimer lifetime of PrPc is affected by the presence of Aß1-42 oligomers. Single-molecule imaging analysis was carried out by total internal reflection fluorescence microscopy in PrPc-transfected CHO-K1 cells in the absence or presence of characterized Aß1-42 oligomers. The contribution of different Aß1-42 oligomer conformations to Alzheimer's disease pathophysiology and to the associated neurotoxicity is unknown. To be precise, with the oligomeric species used in our study, we biochemically analyzed the molecular weight of oligomers formed from Aß1-42 monomers under our experimental conditions. The lifetime of PrPc homodimers was 210 ms, and in the presence of Aß1-42 oligomers, the lifetime was significantly reduced (to 92 ms). The reduction of PrPc homodimer lifetime by Aß1-42 oligomers may impair PrPc-mediated downstream neuroprotective signaling.

Cortical actin nodes: Their dynamics and recruitment of podosomal proteins as revealed by super-resolution and single-molecule microscopy.

Electron tomography of the plasma membrane (PM) identified several layers of cortical actin meshwork running parallel to the PM cytoplasmic surface throughout the PM. Here, cortical actin structures and dynamics were examined in living cells, using super-resolution microscopy, with (x,y)- and z-resolutions of ~140 and ~400 nm, respectively, and single-molecule imaging. The super-resolution microscopy identified sub-micron-sized actin clusters that appeared identical by both phalloidin post-fixation staining and Lifeact-mGFP expression followed by fixation, and therefore, these actin clusters were named "actin-pl-clusters". In live cells, the actin-pl-clusters visualized by Lifeact-mGFP linked two or more actin filaments in the fine actin meshwork, acting as a node of the meshwork, and dynamically moved on/along the meshwork in a myosin II-dependent manner. Their formation depended on the Arp2/3 activities, suggesting that the movements could involve both the myosin motor activity and actin polymerization-depolymerization. The actin-pl-clusters differ from the actin nodes/asters found previously after latrunculin treatments, since myosin II and filamin A were not colocalized with the actin-pl-clusters, and the actin-pl-clusters were much smaller than the previously reported nodes/asters. The Lifeact linked to a fluorescently-labeled transmembrane peptide from syntaxin4 (Lifeact-TM) expressed in the PM exhibited temporary immobilization in the PM regions on which actin-pl-clusters and stress fibers were projected, showing that ≥66% of actin-pl-clusters and 89% of stress fibers were located in close proximity (within 3.5 nm) to the PM cytoplasmic surface. Podosome-associated cytoplasmic proteins, Tks4, Tks5, cortactin, and N-WASP, were transiently recruited to actin-pl-clusters, and thus, we propose that actin-pl-clusters also represent "actin podosome-like clusters".