The free plasma amyloid Aß1-42/Aß1-40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aß1-42/Aß1-40 ratio. The BALTAZAR study.

BACKGROUND AND PURPOSE: Blood-based biomarkers are a non-invasive solution to predict the risk of conversion of mild cognitive impairment (MCI) to dementia. The utility of free plasma amyloid peptides (not bound to plasma proteins and/or cells) as an early indicator of conversion to dementia is still debated, as the results of studies have been contradictory. In this context, we investigated whether plasma levels of the free amyloid peptides Aß1-42 and Aß1-40 and the free plasma Aß1-42/Aß1-40 ratio are associated with the conversion of MCI to dementia, in particular AD, over three years of follow-up in a subgroup of the BALTAZAR cohort. We also compared their predictive value to that of total plasma Aß1-42 and Aß1-40 levels and the total plasma Aß1-42/Aß1-40 ratio. METHODS: The plasma Aß1-42 and Aß1-40 peptide assay was performed using the INNO-BIA kit (Fujirebio Europe). Free amyloid levels (defined by the amyloid fraction directly accessible to antibodies of the assay) were obtained with the undiluted plasma, whereas total amyloid levels were obtained after the dilution of plasma (1/3) with a denaturing buffer. Free and total Aß1-42 and Aß1-40 levels were measured at inclusion for a subgroup of participants (N = 106) with mild cognitive impairment (MCI) from the BALTAZAR study (a large-scale longitudinal multicenter cohort with a three-year follow-up). Associations between conversion and the free/total plasma Aß1-42 and Aß1-40 levels and Aß1-42/Aß1-40 ratio were analyzed using logistic and Cox Proportional Hazards models. Demographic, clinical, cognitive (MMSE, ADL and IADL), APOE, and MRI characteristics (relative hippocampal volume) were compared using non-parametric (Mann-Whitney) or parametric (Student) tests for quantitative variables and Chi-square or Fisher exact tests for qualitative variables. RESULTS: The risk of conversion to dementia was lower for patients in the highest quartile of free plasma Aß1-42/Aß1-40 (≥ 25.8%) than those in the three lower quartiles: hazard ratio = 0.36 (95% confidence interval [0.15-0.87]), after adjustment for age, sex, education, and APOE ε4 (p-value = 0.022). This was comparable to the risk of conversion in the highest quartile of total plasma Aß1-42/Aß1-40: hazard ratio = 0.37 (95% confidence interval [0.16-0.89], p-value = 0.027). However, while patients in the highest quartile of total plasma Aß1-42/Aß1-40 showed higher MMSE scores and a higher hippocampal volume than patients in the three lowest quartiles of total plasma Aß1-42/Aß1-40, as well as normal CSF biomarker levels, the patients in the highest quartile of free plasma Aß1-42/Aß1-40 did not show any significant differences in MMSE scores, hippocampal volume, or CSF biomarker levels relative to the three lowest quartiles of free plasma Aß1-42/Aß1-40. CONCLUSION: The free plasma Aß1-42/Aß1-40 ratio is associated with a risk of conversion from MCI to dementia within three years, with performance comparable to that of the total plasma Aß1-42/Aß1-40 ratio. Threshold levels of the free and total plasma Aß1-42/Aß1-40 ratio could be determined, with a 60% lower risk of conversion for patients above the threshold than those below.

Strong coupling between a microwave photon and a singlet-triplet qubit.

Combining superconducting resonators and quantum dots has triggered tremendous progress in quantum information, however, attempts at coupling a resonator to even charge parity spin qubits have resulted only in weak spin-photon coupling. Here, we integrate a zincblende InAs nanowire double quantum dot with strong spin-orbit interaction in a magnetic-field resilient, high-quality resonator. The quantum confinement in the nanowire is achieved using deterministically grown wurtzite tunnel barriers. Our experiments on even charge parity states and at large magnetic fields, allow us to identify the relevant spin states and to measure the spin decoherence rates and spin-photon coupling strengths. We find an anti-crossing between the resonator mode in the single photon limit and a singlet-triplet qubit with a spin-photon coupling strength of g/2π = 139 ± 4 MHz. This coherent coupling exceeds the resonator decay rate κ/2π = 19.8 ± 0.2 MHz and the qubit dephasing rate γ/2π = 116 ± 7 MHz, putting our system in the strong coupling regime.

Generation of induced pluripotent stem cell lines IRMBi003-A and IRMBi003-B from a healthy donor to model Alzheimer's disease.

Induced Pluripotent Stem Cell (iPSC) lines derived from healthy individuals are helpful and essential tools for disease modelling. Here, we described the reprogramming of skin fibroblasts obtained from a healthy 59-year-old individual without Alzheimer's disease. The generated iPSC lines have a normal karyotype, expressed pluripotency markers, and demonstrated the ability to differentiate into the three germ layers. The iPSC lines will be used as controls to study Alzheimer's disease mechanisms.

Establishment of induced pluripotent stem cells IRMBi005-A from a patient with sporadic Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder and the most common form of dementia worldwide. Sporadic Alzheimer's disease (sAD) cases are the main forms, over 95% of AD cases, but still poorly understood. Thereby there is a crucial need to develop in vitro models for studying this multifactorial disorder. Here, we report the reprogramming of skin fibroblasts from a 57-years-old male donor. The new generated iPSC cell line has a normal karyotype and, is pluripotent since it demonstrates the ability to differentiate in vitro into the three germ layers. This iPSC line will be used to understand pathological mechanisms of sAD.

Overview of the blood biomarkers in Alzheimer's disease: Promises and challenges.

The increasing number of people with advanced Alzheimer's disease (AD) represents a significant psychological and financial cost to the world population. Accurate detection of the earliest phase of preclinical AD is of major importance for the success of preventive and therapeutic strategies (Cullen et al., 2021). Advances in analytical techniques have been essential for the development of sensitive, specific and reliable diagnostic tests for AD biomarkers in biological fluids (cerebrospinal fluid and blood). Blood biomarkers hold promising potential for early and minimally invasive detection of AD, but also for differential diagnosis of dementia and for monitoring the course of the disease. The aim of this review is to provide an overview of current blood biomarkers of AD, from tau proteins and amyloid peptides to biomarkers of neuronal degeneration and inflammation, reactive and metabolic factors. We thus discuss the informative value of currently candidate blood biomarkers and their potential to be integrated into clinical practice for the management of AD in the near future.

700,000 years of tropical Andean glaciation.

Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores1; these interhemispheric connections may have existed during previous glacial cycles.

Integrated bioelectronic proton-gated logic elements utilizing nanoscale patterned Nafion.

A central endeavour in bioelectronics is the development of logic elements to transduce and process ionic to electronic signals. Motivated by this challenge, we report fully monolithic, nanoscale logic elements featuring n- and p-type nanowires as electronic channels that are proton-gated by electron-beam patterned Nafion. We demonstrate inverter circuits with state-of-the-art ion-to-electron transduction performance giving DC gain exceeding 5 and frequency response up to 2 kHz. A key innovation facilitating the logic integration is a new electron-beam process for patterning Nafion with linewidths down to 125 nm. This process delivers feature sizes compatible with low voltage, fast switching elements. This expands the scope for Nafion as a versatile patternable high-proton-conductivity element for bioelectronics and other applications requiring nanoengineered protonic membranes and electrodes.

Effect of manual and digital contact tracing on COVID-19 outbreaks: a study on empirical contact data.

Non-pharmaceutical interventions are crucial to mitigate the COVID-19 pandemic and contain re-emergence phenomena. Targeted measures such as case isolation and contact tracing can alleviate the societal cost of lock-downs by containing the spread where and when it occurs. To assess the relative and combined impact of manual contact tracing (MCT) and digital (app-based) contact tracing, we feed a compartmental model for COVID-19 with high-resolution datasets describing contacts between individuals in several contexts. We show that the benefit (epidemic size reduction) is generically linear in the fraction of contacts recalled during MCT and quadratic in the app adoption, with no threshold effect. The cost (number of quarantines) versus benefit curve has a characteristic parabolic shape, independent of the type of tracing, with a potentially high benefit and low cost if app adoption and MCT efficiency are high enough. Benefits are higher and the cost lower if the epidemic reproductive number is lower, showing the importance of combining tracing with additional mitigation measures. The observed phenomenology is qualitatively robust across datasets and parameters. We moreover obtain analytically similar results on simplified models.

Digital proximity tracing on empirical contact networks for pandemic control.

Digital contact tracing is a relevant tool to control infectious disease outbreaks, including the COVID-19 epidemic. Early work evaluating digital contact tracing omitted important features and heterogeneities of real-world contact patterns influencing contagion dynamics. We fill this gap with a modeling framework informed by empirical high-resolution contact data to analyze the impact of digital contact tracing in the COVID-19 pandemic. We investigate how well contact tracing apps, coupled with the quarantine of identified contacts, can mitigate the spread in real environments. We find that restrictive policies are more effective in containing the epidemic but come at the cost of unnecessary large-scale quarantines. Policy evaluation through their efficiency and cost results in optimized solutions which only consider contacts longer than 15-20 minutes and closer than 2-3 meters to be at risk. Our results show that isolation and tracing can help control re-emerging outbreaks when some conditions are met: (i) a reduction of the reproductive number through masks and physical distance; (ii) a low-delay isolation of infected individuals; (iii) a high compliance. Finally, we observe the inefficacy of a less privacy-preserving tracing involving second order contacts. Our results may inform digital contact tracing efforts currently being implemented across several countries worldwide.

Growth, lifetime, directional movement and myosin-dependent motility of mutant keratin granules in cultured cells.

Intermediate filament polypeptides (IFPs) are prominent components of cytoplasmic aggregates, which are pathognomonic for multiple diseases. Recent observations in cultured cells suggest that they are dynamic and subject to regulated turnover. The emerging concept is that multiple factors contribute to motility and turnover of IFP-containing aggregates. To understand their relative contribution, quantitative tools are needed. The current study addresses this need using epithelial cells producing mutant keratin IFPs that have been identified as the cause of the hereditary blister-forming skin disease epidermolysis bullosa simplex. Digital image analysis of individual granules allowed mapping of their complete life cycle, with information on multiple characteristics at any given time-point. The deduced signet features revealed rapid granule fusion and directed transport from the periphery towards the cell centre, and a limited, ~ 30 min lifetime with a slow, continuous growth phase followed by fast disassembly. As paradigmatic proof-of-principle, we demonstrate that inhibition of myosin II selectively reduces granule movement, linking keratin granule motility to retrograde cortical acto-myosin flow. The newly developed methods and established parameters will help in the characterization of known and the identification of novel regulators of IFP-containing aggregates.

Prehospital management of patients with suspected acute coronary syndrome : Real world experience reflecting current guidelines.

BACKGROUND: In case of suspected acute coronary syndrome (ACS), international guidelines recommend to obtain a 12-lead ECG as soon as possible after first medical contact, to administrate platelet aggregation inhibitors and antithrombins, and to transfer the patient as quickly as possible to an emergency department. METHODS: A German emergency care service database was retrospectively analysed from 2014 to 2016. Data were tested for normal distribution and the Mann-Whitney test was used for statistical analysis. Results are presented as medians (IQR). RESULTS: A total of 1424 patients with suspected ACS were included in the present analysis. A 12-lead ECG was documented in 96% of patients (n = 1369). The prehospital incidence of ST-segment elevation myocardial infarction (STEMI) was 18% (n = 250). In 981 patients (69%), acetylsalicylic acid (ASA), unfractionated heparin (UFH), or ASA and UFH was given. Time in prehospital care differed significantly between non-STEMI (NSTEMI) ACS (37 [IQR 30, 44] min) and STEMI patients (33 [IQR 26, 40] min, n = 1395, p < 0.0001). Most of NSTEMI ACS and STEMI patients were brought to the emergency care unit, while 30% of STEMI patients were directly handed over to a cardiac catheterization laboratory. CONCLUSIONS: Prehospital ECG helps to identify patients with STEMI, which occurs in 18% of suspected ACS. Patients without ST-elevations suffered from longer prehospital care times. Thus, it is tempting to speculate that ST-elevations in patients prompt prehospital medical teams to act more efficiently while the absence of ST-elevations even in patients with suspected ACS might cause unintended delays. Moreover, this analysis suggests the need for further efforts to make the cardiac catheterization laboratory the standard hand-over location for all STEMI patients.

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders.

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

Extract and the quassinoid ailanthone from Ailanthus altissima inhibit nematode reproduction by damaging germ cells and rachis in the model organism Caenorhabditis elegans.

Bark and leaves of Ailanthus altissima (Mill.) Swingle are widely used in European folk medicine to treat intestinal worm infections. The study aimed to rationalize a potential anthelmintic effect of A. altissima extract against the model organism Caenorhabditis elegans. A methanol-water (7:3, v/v) extract of the primary stem bark was tested on L4 larvae of C. elegans for induction of mortality and influence on reproduction. Bioactivity-guided fractionation was performed by chromatography on MCI-gel, preparative HPLC on RP18 stationary phase and fast-centrifugal-partition-chromatography. Structural elucidation of isolated quassinoids was performed by NMR and HR-ESI-MS. The sterilizing effect on C. elegans was investigated by light microscopy and atomic force microscopy of ultra-sections. Different GFP-tagged reporter strains were used to identify involved signaling pathways. A. altissima extract (1 mg/mL) irreversibly inhibited the reproduction of C. elegans L4 larvae. This effect was dependent on the larval stage since L3 larvae and adults were less affected. Bioactivity-guided fractionation revealed the quassinoid ailanthone 1 as the major active compound (IC50 2.47 µM). The extract caused severe damages to germ cells and rachis, which led to none or only poorly developed oocytes. These damages led to activation of the transcription factor DAF-16, which plays a major role in the nematode's response to stress. A regulation via the respective DAF-2/insulin-like signaling pathway was not observed. The current findings support the traditional use of A. altissma in phytotherapy to treat helminth infections and provide a base for standardization of the herbal material.

Keratin 6a mutations lead to impaired mitochondrial quality control.

BACKGROUND: Epidermal differentiation is a multilevel process in which keratinocytes need to lose their organelles, including their mitochondria, by autophagy. Disturbed autophagy leads to thickening of the epidermis as seen in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17. OBJECTIVES: To ask if mitophagy, the selective degradation of mitochondria by autophagy, is disturbed in PC and, if so, at which stage. METHODS: Immortalized keratinocytes derived from patients with PC were used in fluorescence-based and biochemical assays to dissect the different steps of mitophagy. RESULTS: PC keratinocytes accumulated old mitochondria and displayed disturbed clearance of mitochondria after mitochondrial uncoupling. However, early mitophagy steps and autophagosome formation were not affected. We observed that autolysosomes accumulate in PC and are not sufficiently recycled. CONCLUSIONS: We propose an influence of keratins on autolysosomal degradation and recycling. What's already known about this topic? Terminal epidermal differentiation is a multistep process that includes the elimination of cellular components by autophagy. Autophagy-impaired keratinocytes have been shown to result in thickening of epidermal layers. Hyperkeratosis also occurs in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17. What does this study add? Keratins contribute to mitochondrial quality control as well as maintenance of mitochondria-endoplasmic reticulum contact sites. Keratins influence autolysosomal maturation or reformation. What is the translational message? Overaged mitochondria and autolysosomes accumulate in PC. Mutations in keratin 6a lead to severely impaired mitophagy, which might contribute to PC pathogenesis.

Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The prognostic value of serum neurofilament light chain (sNfL), a biomarker of neurodegeneration, compared to other prognostic factors of amyotrophic lateral sclerosis (ALS) at the time of diagnosis, remains unclear. METHODS: Sera from ALS patients were prospectively collected at the first diagnostic visit in our centre. sNfL levels were determined by single molecule array in 207 ALS patients and in 21 healthy controls. The prognostic value of sNfL was compared with that of other known clinical prognostic factors using a Cox regression model and multivariate analysis. RESULTS: Serum neurofilament light chain levels were higher in ALS patients than in controls (P < 0.0001). Seven parameters were predictive of death in ALS: older age, bulbar onset, higher ALS Functional Rating Scale revised (ALSFRS-R) score, greater weight loss, lower maximal inspiratory pressure, forced vital capacity and higher sNfL levels. A Cox regression model showed that sNfL (P < 0.0001), weight loss (P = 0.040) and site at onset (P = 0.048) were independent predictive factors of death. In a sub-cohort restricted to 139 patients with complete spirometry data, sNfL level (P < 0.005) and forced vital capacity (P = 0.022) were independent factors predictive of death. In a subgroup of 142 patients in whom ALSFRS-R score was available at several time points, sNfL levels positively correlated with ALSFRS-R rate of decline (r = 0.571, P < 10-12 ). CONCLUSIONS: Higher sNfL concentration is a strong and independent prognostic factor of death in ALS as early as the time of diagnosis.

Electrical control of spins and giant g-factors in ring-like coupled quantum dots.

Emerging theoretical concepts for quantum technologies have driven a continuous search for structures where a quantum state, such as spin, can be manipulated efficiently. Central to many concepts is the ability to control a system by electric and magnetic fields, relying on strong spin-orbit interaction and a large g-factor. Here, we present a mechanism for spin and orbital manipulation using small electric and magnetic fields. By hybridizing specific quantum dot states at two points inside InAs nanowires, nearly perfect quantum rings form. Large and highly anisotropic effective g-factors are observed, explained by a strong orbital contribution. Importantly, we find that the orbital contributions can be efficiently quenched by simply detuning the individual quantum dot levels with an electric field. In this way, we demonstrate not only control of the effective g-factor from 80 to almost 0 for the same charge state, but also electrostatic change of the ground state spin.

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.

BACKGROUND: In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES: This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS: Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS: Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION: This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.

Diagnosis associated with Tau higher than 1200 pg/mL: Insights from the clinical and laboratory practice.

CONTEXT: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling. PATIENTS AND METHODS: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aß 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis. RESULTS: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aß1-42 and Aß1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aß1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aß1-42 concentrations <550 pg/mL or pTau>60 pg/mL. CONCLUSION: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.