Optical detection of radio waves through a nanomechanical transducer.

Low-loss transmission and sensitive recovery of weak radio-frequency and microwave signals is a ubiquitous challenge, crucial in radio astronomy, medical imaging, navigation, and classical and quantum communication. Efficient up-conversion of radio-frequency signals to an optical carrier would enable their transmission through optical fibres instead of through copper wires, drastically reducing losses, and would give access to the set of established quantum optical techniques that are routinely used in quantum-limited signal detection. Research in cavity optomechanics has shown that nanomechanical oscillators can couple strongly to either microwave or optical fields. Here we demonstrate a room-temperature optoelectromechanical transducer with both these functionalities, following a recent proposal using a high-quality nanomembrane. A voltage bias of less than 10 V is sufficient to induce strong coupling between the voltage fluctuations in a radio-frequency resonance circuit and the membrane's displacement, which is simultaneously coupled to light reflected off its surface. The radio-frequency signals are detected as an optical phase shift with quantum-limited sensitivity. The corresponding half-wave voltage is in the microvolt range, orders of magnitude less than that of standard optical modulators. The noise of the transducer--beyond the measured 800 pV Hz-1/2 Johnson noise of the resonant circuit--consists of the quantum noise of light and thermal fluctuations of the membrane, dominating the noise floor in potential applications in radio astronomy and nuclear magnetic imaging. Each of these contributions is inferred to be 60 pV Hz-1/2 when balanced by choosing an electromechanical cooperativity of ~150 with an optical power of 1 mW. The noise temperature of the membrane is divided by the cooperativity. For the highest observed cooperativity of 6,800, this leads to a projected noise temperature of 40 mK and a sensitivity limit of 5 pV Hz-1/2. Our approach to all-optical, ultralow-noise detection of classical electronic signals sets the stage for coherent up-conversion of low-frequency quantum signals to the optical domain.

Children with atopic dermatitis may have unacknowledged contact allergies contributing to their skin symptoms.

BACKGROUND: Whether children with atopic dermatitis have an altered risk of contact allergy than children without atopic dermatitis is frequently debated and studies have been conflicting. Theoretically, the impaired skin barrier in atopic dermatitis (AD) facilitates the penetration of potential allergens and several authors have highlighted the risk of underestimating and overlooking contact allergy in children with atopic dermatitis. OBJECTIVE: To determine the prevalence of contact allergy in Danish children with atopic dermatitis and explore the problem of unacknowledged allergies maintaining or aggravating the skin symptoms. METHODS: In a cross-sectional study, 100 children and adolescents aged 5-17 years with a diagnosis of atopic dermatitis were patch tested with a paediatric series of 31 allergens. RESULTS: Thirty per cent of the children had at least one positive patch test reaction, and 17% had at least one contact allergy that was relevant to the current skin symptoms. The risk of contact allergy was significantly correlated to the severity of atopic dermatitis. Metals and components of topical skincare products were the most frequent sensitizers. CONCLUSION: Patch testing is relevant as a screening tool in the management of children with atopic dermatitis as they may have unacknowledged contact allergies contributing to or maintaining their skin symptoms. Children with atopic dermatitis seem to be at greater risk of sensitization to certain allergens including metals and components of skincare products.

Physiological reactions to long-term fishing in the Barents Sea.

Background: Fishing in distant waters for months may induce physiological stress. Aims: To assess the physiological stress reactions in fishermen working for 2-3 months continuously in 6-h shifts on trawlers in the Barents Sea. Methods: The crew of five trawlers fishing in the Barents Sea from January to April 2004 were invited to participate. In the week before and 5-7 days after the trip, the following measures were collected: salivary cortisol four times a day, 24-h urinary cortisol, blood pressure, heart rate, serum cholesterol, serum high-density lipoprotein (HDL-cholesterol), HbA1c (glycosylated haemoglobin) and weight. In addition, 24-h urinary cortisol, blood pressure and heart rate were measured three times. A questionnaire on health, social conditions and work environment was obtained after the trip. Results: In total, 136 men agreed to participate. Full data were obtained for 96 fishermen (70%). A significant decrease in salivary and urinary cortisol was found during the trip. Adjustment for age, body mass index, smoking, shift work schedule and time of day for sample collection did not change this finding. Systolic and diastolic blood pressure declined significantly and remained significantly lower after the trip compared to before the trip. Serum cholesterol/HDL ratio declined significantly, whereas triglycerides, HbA1c and weight were unchanged. Conclusions: Working up to 3 months on 6-h shifts, 84 h a week, with moderate physical activity, even in artificial light and cold weather on a ship, did not result in increased physiological stress.

Contact allergy in children with atopic dermatitis: a systematic review.

The importance of contact allergy in children with atopic dermatitis is frequently debated. Previously, patients with atopic dermatitis were believed to have a reduced ability to produce a type IV immunological response. However, this belief has been challenged and authors have highlighted the risk of underestimating and overlooking allergic contact dermatitis in children with atopic dermatitis. Several studies have been published aiming to shed light on this important question but results are contradictory. To provide an overview of the existing knowledge, we systematically reviewed studies that report frequencies of positive patch test reactions in children with atopic dermatitis. We identified 436 manuscripts of which 31 met the inclusion criteria. Although the literature is conflicting, it is evident that contact allergy is a common problem in children with atopic dermatitis.

Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease.

BACKGROUND: Finding early and dynamic biomarkers in Huntington's disease is a key to understanding the early pathology of Huntington's disease and potentially to tracking disease progression. This would benefit the future evaluation of potential neuroprotective and disease-modifying therapies, as well as aid in identifying an optimal time point for initiating a potential therapeutic intervention. METHODS: This explorative proteomics study evaluated cerebrospinal fluid from 94 Huntington's disease gene-expansion carriers (39 premanifest and 55 manifest) and 27 Huntington's disease gene-expansion negative individuals using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry. Differences in peak intensity from SELDI-TOF spectra were evaluated. RESULTS: Levels of 10 peaks were statistically significantly different between manifest gene-expansion carriers and controls. One of them identified as ubiquitin was shown to be dependent on the Unified Huntington Disease Rating Scale Total Functional Capacity, a pseudo-measure of disease severity (P = 0.001), and the Symbol Digit Modalities Test (0.04) in manifest and CAG-age product score (P = 0.019) in all gene-expansion carriers. CONCLUSIONS AND RELEVANCE: Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG-age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset.

Application of the PredictAD decision support tool to a Danish cohort of patients with Alzheimer's disease and other dementias.

BACKGROUND: The diagnosis of Alzheimer's disease (AD) is based on an ever-increasing body of data and knowledge making it a complex task. The PredictAD tool integrates heterogeneous patient data using an interactive user interface to provide decision support. The aim of this project was to investigate the performance of the tool in distinguishing AD from non-AD dementia using a realistic clinical dataset. METHODS: We retrieved clinical data from a group of patients diagnosed with AD (n = 72), vascular dementia (VaD, n = 30), frontotemporal dementia (FTD, n = 25) or dementia with Lewy bodies (DLB, n = 14) at the Copenhagen Memory Clinic at Rigshospitalet. Three classification methods were applied to the data in order to differentiate between AD and a group of non-AD dementias. The methods were the PredictAD tool's Disease State Index (DSI), the naïve Bayesian classifier and the random forest. RESULTS: The DSI performed best for this realistic dataset with an accuracy of 76.6% compared to the accuracies for the naïve Bayesian classifier and random forest of 67.4 and 66.7%, respectively. Furthermore, the DSI differentiated between the four diagnostic groups with a p value of <0.0001. CONCLUSION: In this dataset, the DSI method used by the PredictAD tool showed a superior performance for the differentiation between patients with AD and those with other dementias. However, the methods need to be refined further in order to optimize the differential diagnosis between AD, FTD, VaD and DLB.

Serum Tau-A and Tau-C Levels and Their Association with Cognitive Impairment and Dementia Progression in a Memory Clinic Derived Cohort.

BACKGROUND: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia. OBJECTIVES: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD- ß-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia. DESIGN: Cross-sectional and a substudy using a retrospective cohort design. SETTING: Memory clinic derived subjects contributing to the Danish Dementia Biobank. PARTICIPANTS: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer's dementia (n=52). MEASUREMENTS: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C. RESULTS: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 - 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 - 7.05) when compared to those in the lowest quartile. CONCLUSIONS: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation.

Software tool for improved prediction of Alzheimer's disease.

BACKGROUND: Diagnostic criteria of Alzheimer's disease (AD) emphasize the integration of clinical data and biomarkers. In practice, collection and analysis of patient data vary greatly across different countries and clinics. OBJECTIVE: The goal was to develop a versatile and objective clinical decision support system that could reduce diagnostic errors and highlight early predictors of AD. METHODS: Novel data analysis methods were developed to derive composite disease indicators from heterogeneous patient data. Visualizations that communicate these findings were designed to help the interpretation. The methods were implemented with a software tool that is aimed for daily clinical practice. RESULTS: With the tool, clinicians can analyze available patients as a whole, study them statistically against previously diagnosed cases, and characterize the patients with respect to having AD. The tool is able to work with virtually any patient measurement data, as long as they are stored in electronic format or manually entered into the system. For a subset of patients from the test cohort, the tool was able to predict conversion to AD at an accuracy of 93.6%. CONCLUSION: The software tool developed in this study provides objective information for early detection and prediction of AD based on interpretable visualizations of patient data.

The role of phosphoinositides in membrane transport.

Phosphoinositides serve as intrinsic membrane signals that regulate intracellular membrane trafficking. Recently, phosphoinositides have been found to direct the localization and activity of effector proteins containing consensus sequence motifs such as FYVE, PH and ENTH domains. In addition, recent results show that regulated synthesis and turnover of phosphoinositides by membrane-associated phosphoinoside kinases and phosphatases spatially restrict the location of effectors critical for cellular transport processes, such as clathrin-mediated endocytosis, autophagy, phagocytosis, macropinocytosis and biosynthetic trafficking.

Phosphoinositides and phagocytosis.

Phosphoinositide 3 kinases (PI3Ks)*Abbreviation used in this paper: PI3K, phosphoinositide 3 kinase. are known as regulators of phagocytosis. Recent results demonstrate that class I and III PI3Ks act consecutively in phagosome formation and maturation, and that their respective products, phosphatidylinositol 3,4,5-trisphosphate (PI[3,4,5]P(3)) and phosphatidylinositol 3-phosphate (PI[3]P), accumulate transiently at different stages. Phagosomes containing Mycobacterium tuberculosis do not acquire the PI(3)P-binding protein EEA1, which is required for phagosome maturation. This suggests a possible mechanism of how this microorganism evades degradation in phagolysosomes.

Magnetic resonance imaging with optical preamplification and detection.

Magnetic resonance (MR) imaging relies on conventional electronics that is increasingly challenged by the push for stronger magnetic fields and higher channel count. These problems can be avoided by utilizing optical technologies. As a replacement for the standard low-noise preamplifier, we have implemented a new transduction principle that upconverts an MR signal to the optical domain and imaged a phantom in a clinical 3 T scanner with signal-to-noise comparable to classical induction detection.

Publisher Correction: A short isoform of ATG7 fails to lipidate LC3/GABARAP.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

A short isoform of ATG7 fails to lipidate LC3/GABARAP.

Autophagy is a degradation pathway important for cellular homeostasis. The E1-like enzyme ATG7 is a key component of the autophagy machinery, with the main function of mediating the lipidation of LC3/GABARAP during autophagosome formation. By analysing mRNA-sequencing data we found that in addition to the full-length ATG7 isoform, various tissues express a shorter isoform lacking an exon of 27 amino acids in the C-terminal part of the protein, termed ATG7(2). We further show that ATG7(2) does not bind LC3B and fails to mediate the lipidation of members of the LC3/GABARAP family. We have thus identified an isoform of ATG7 that is unable to carry out the best characterized function of the protein during the autophagic response. This short isoform will have to be taken into consideration when further studying the role of ATG7.

A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer's disease versus normal aging and frontotemporal dementia.

BACKGROUND: An early and accurate diagnosis of Alzheimer's disease (AD) is important in order to initiate symptomatic treatment with currently approved drugs and will be of even greater importance with the advent of disease-modifying compounds. METHODS: Protein profiles of human cerebrospinal fluid samples from patients with AD (n = 85), frontotemporal dementia (n = 20), and healthy controls (n = 32) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to verify previously discovered biomarkers. RESULTS: We verified 15 protein biomarkers that were able to differentiate between AD and controls, and 7 of these 15 markers also differentiated AD from FTD. CONCLUSION: A panel of cerebrospinal fluid protein markers was verified by a proteomics technology which may potentially improve the accuracy of the AD diagnosis.

The leucine-based motif DDQxxLI is recognized both for internalization and basolateral sorting of invariant chain in MDCK cells.

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) contains signals for transport to endocytic compartments where the class II molecules bind antigenic peptides for presentation to CD4+ T cells. Two leucine-based signals in the Ii cytoplasmic tail can be independently recognized for endosomal sorting of Ii, and we have recently shown that each signal is sufficient for basolateral sorting and internalization of Ii in polarized Madine Darby Canine Kidney (MDCK) II cells. The recognition motif for endosomal sorting is complex and consists of two critical leucine-like residues as well as surrounding amino acids. Here, we have analyzed the importance of residues surrounding the membrane-distal leucine-based signal in basolateral sorting and internalization of Ii in MDCK II cells. We find that the DDQxxLI motif is involved in both sorting events indicating the presence of similar signal recognition components both at the TGN and at the plasma membrane. The identical motif is required for endosomal localization and internalization of Ii also in simian COS cells and the human HeLa and M1 cells.

Syntaxin-16, a putative Golgi t-SNARE.

Members of the syntaxin family of integral membrane proteins have recently been implicated as vesicle receptors on target membranes, coresponsible for the specificity of intracellular membrane traffic. So far, only a small number of different mammalian syntaxins have been identified. Here we report the cloning of three new human syntaxin cDNAs, presumably originating from alternative splicing of the same transcript. Syntaxin-16A and syntaxin-16B are identical, except that the latter contains an insertion of 21 amino acid residues. Syntaxin-16C is a truncated version of syntaxin-16A, lacking the C-terminal coiled-coil and hydrophobic regions characteristic for syntaxins. Database searches identified putative yeast, plant and nematode homologues of syntaxin-16, indicating that this protein is conserved through evolution, and syntaxin-16 belongs to a new subgroup of syntaxins. Epitope-tagged syntaxin-16A and syntaxin-16B were found to colocalize with the Golgi marker beta-COP, while syntaxin-16C was found in the cytosol. Syntaxin-16A associates posttranslationally with microsomes, and appears to be transported to the Golgi via the endoplasmic reticulum. The three syntaxin-16 forms may have differential roles in intracellular trafficking.

Acyl-coenzyme A organizes laterally in membranes and is recognized specifically by acyl-coenzyme A binding protein.

Long chain acyl-coenzyme A (acyl-CoA) is a biochemically important amphiphilic molecule that is known to partition strongly into membranes by insertion of the acyl chain. At present, microscopically resolved evidence is lacking on how acyl-CoA influences and organizes laterally in membranes. By atomic force microscopy (AFM) imaging of membranes exposed to acyl-CoA in microM concentrations, it is shown that aggregate formation takes place within the membrane upon long-time exposure. It is known that acyl-CoA is bound by acyl-CoA binding protein (ACBP) with high affinity and specificity and that ACBP may bind and desorb membrane-bound acyl-CoA via a partly unknown mechanism. Following incubation with acyl-CoA, it is shown that ACBP is able to reverse the formation of acyl-CoA aggregates and to associate peripherally with acyl-CoA on the membrane surface. Our microscopic results point to the role of ACBP as an intermembrane transporter of acyl-CoA and demonstrate the ability of AFM to reveal the remodelling of membranes by surfactants and proteins.