Interlayer Coupling Controlled Ordering and Phases in Polar Vortex Superlattices.

The recent discovery of polar topological structures has opened the door for exciting physics and emergent properties. There is, however, little methodology to engineer stability and ordering in these systems, properties of interest for engineering emergent functionalities. Notably, when the surface area is extended to arbitrary thicknesses, the topological polar texture becomes unstable. Here we show that this instability of the phase is due to electrical coupling between successive layers. We demonstrate that this electrical coupling is indicative of an effective screening length in the dielectric, similar to the conductor-ferroelectric interface. Controlling the electrostatics of the superlattice interfaces, the system can be tuned between a pure topological vortex state and a mixed classical-topological phase. This coupling also enables engineering coherency among the vortices, not only tuning the bulk phase diagram but also enabling the emergence of a 3D lattice of polar textures.

STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment-Elevation Myocardial Infarction: A Randomized, Open-Label Trial.

BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.

Crystal, Solution, and Computational Study of the Structure of Ortho-Lithium N,N-Diisopropyl-P,P-Diphenylphosphinothioic Amide.

The first crystal structure of an ortho-lithium phosphinothioic amide complexed with tetramethylethylenediamine 12 is reported. The complex consists of a spirane in which the spiro-lithium is N,N- and C,S-chelated by the diamine and organophosphorus ligands, respectively. The analogous ortho anion 14 obtained by Sn(IV)/Li transmetallation in THF has also been synthesized. Nuclear magnetic resonance study of both anions showed that they exist as monomers in solution and are involved in dynamic processes including the restricted rotation around the P-N bond. 14 is converted at room temperature by nucleophilic cyclization to the dearomatized anion 15, which evolves after a few hours to the benzophosphindole sulfide 16. Density functional theory calculations supported the aggregation state in solution and were used to explore the conformational space of anion 12, the mechanism of ortho-lithiation directed by P(X)-N (X=O, S) groups, and the mechanism of formation of 15.

Inferring the Molecular Basis for Dissolved Organic Matter Photochemical and Optical Properties.

Despite the widespread use of photochemical and optical properties to characterize dissolved organic matter (DOM), a significant gap persists in our understanding of the relationship among these properties. This study infers the molecular basis for the optical and photochemical properties of DOM using a comprehensive framework and known structural moieties within DOM. Utilizing Suwannee River Fulvic Acid (SRFA) as a model DOM, carboxylated aromatics, phenols, and quinones were identified as dominant contributors to the absorbance spectra, and phenols, quinones, aldehydes, and ketones were identified as major contributors to radiative energy pathways. It was estimated that chromophores constitute ∼63% w/w of dissolved organic carbon in SRFA and ∼47% w/w of overall SRFA. Notably, estimations indicate the pool of fluorescent compounds and photosensitizing compounds in SRFA are likely distinct from each other at wavelengths below 400 nm. This perspective offers a practical tool to aid in the identification of probable chemical groups when interpreting optical and photochemical data and challenges the current "black box" thinking. Instead, DOM photochemical and optical properties can be closely estimated by assuming the DOM is composed of a mixture of individual compounds.

Photolysis of Dissolved Organic Matter over Hematite Nanoplatelets.

Solar photoexcitation of chromophoric groups in dissolved organic matter (DOM), when coupled to photoreduction of ubiquitous Fe(III)-oxide nanoparticles, can significantly accelerate DOM degradation in near-surface terrestrial systems, but the mechanisms of these reactions remain elusive. We examined the photolysis of chromophoric soil DOM coated onto hematite nanoplatelets featuring (001) exposed facets using a combination of molecular spectroscopies and density functional theory (DFT) computations. Reactive oxygen species (ROS) probed by electron paramagnetic resonance (EPR) spectroscopy revealed that both singlet oxygen and superoxide are the predominant ROS responsible for DOM degradation. DFT calculations confirmed that Fe(II) on the hematite (001) surface, created by interfacial electron transfer from photoexcited chromophores in DOM, can reduce dioxygen molecules to superoxide radicals (•O2-) through a one-electron transfer process. 1H nuclear magnetic resonance (NMR) and electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) spectroscopies show that the association of DOM with hematite enhances the cleavage of aromatic groups during photodegradation. The findings point to a pivotal role for organic matter at the interface that guides specific ROS generation and the subsequent photodegradation process, as well as the prospect of using ROS signatures as a forensic tool to help interpret more complicated field-relevant systems.

Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.

Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage.

BACKGROUND: Alcohol, a widely abused drug, significantly diminishes life quality, causing chronic diseases and psychiatric issues, with severe health, societal, and economic repercussions. Previously, we demonstrated that non-voluntary alcohol consumption increases the opening of Cx43 hemichannels and Panx1 channels in astrocytes from adolescent rats. However, whether ethanol directly affects astroglial hemichannels and, if so, how this impacts the function and survival of astrocytes remains to be elucidated. RESULTS: Clinically relevant concentrations of ethanol boost the opening of Cx43 hemichannels and Panx1 channels in mouse cortical astrocytes, resulting in the release of ATP and glutamate. The activation of these large-pore channels is dependent on Toll-like receptor 4, P2X7 receptors, IL-1ß and TNF-α signaling, p38 mitogen-activated protein kinase, and inducible nitric oxide (NO) synthase. Notably, the ethanol-induced opening of Cx43 hemichannels and Panx1 channels leads to alterations in cytokine secretion, NO production, gliotransmitter release, and astrocyte reactivity, ultimately impacting survival. CONCLUSION: Our study reveals a new mechanism by which ethanol impairs astrocyte function, involving the sequential stimulation of inflammatory pathways that further increase the opening of Cx43 hemichannels and Panx1 channels. We hypothesize that targeting astroglial hemichannels could be a promising pharmacological approach to preserve astrocyte function and synaptic plasticity during the progression of various alcohol use disorders.

Analytical and clinical validation of Alzheimer's disease blood biomarkers with a focus on plasma p-tau217.

Alzheimer's disease (AD) represents a growing global health challenge, necessitating accurate and reliable diagnostic methodologies for timely intervention and management. Immunoassays, specifically designed to detect biomarkers associated with AD pathology, have emerged as pivotal tools in diagnostic development. Understanding of the established protocols ensures assay sensitivity, specificity, and reproducibility, thereby enhancing the clinical utility of these diagnostic tools. Here, we explore the considerations in immunoassay development, focusing on phosphorylated tau217 assays. Ultimately, a clear understanding of immunoassay development is paramount in advancing the precision and reliability of AD diagnostics, contributing to early detection, improved patient outcomes, and advancements in therapeutic interventions.

Pure Chiral Polar Vortex Phase in PbTiO3/SrTiO3 Superlattices with Tunable Circular Dichroism.

Nontrivial polarization textures have been demonstrated in ferroelectric/dielectric superlattices, where the electrostatic, elastic, and different gradient energies compete in a delicate balance. When PbTiO3/SrTiO3 superlattices are grown on DyScO3, the coexistence of ferroelectric domains and vortex structure is observed for n = 12-20 unit cells. Here, we report an approach to achieve single-phase vortex structures in superlattices by controlling the epitaxial strain using Sr1.04Al0.12Ga0.35Ta0.50O3 substrates. The domain width follows Kittel's law with the thickness of the ferroelectric PbTiO3 layers. A phase transition from vortex to a disordered phase with temperature is characterized by the correlation length. Resonant soft X-ray diffraction circular dichroism at the titanium L-edge reveals enhanced chirality with the thickness of the ferroelectric layer. These results are supported by second-principles simulations, which demonstrate that the integrated helicity increases with n. The stabilization of chiral single-phase polar vortices in ferroelectric/dielectric superlattices can enable novel optoelectronic devices with enhanced ferroelectric-light interaction.

Levels of plasma brain-derived tau and p-tau181 in Alzheimer's disease and rapidly progressive dementias.

INTRODUCTION: Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. METHODS: We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). RESULTS: Plasma BD-tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p-tau181 (r = 0.26, p = 0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p < 0.0001). DISCUSSION: Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.

Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologies.

INTRODUCTION: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy. METHODS: We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients. RESULTS: N-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5). DISCUSSION: Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. HIGHLIGHTS: N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (Aß) co-pathology. N-terminal p-tau181 and p-tau231 in Aß-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.

A novel ultrasensitive assay for plasma p-tau217: Performance in individuals with subjective cognitive decline and early Alzheimer's disease.

INTRODUCTION: Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited. METHODS: We employed a novel p-tau217 immunoassay (University of Gothenburg [UGOT] p-tau217) in four independent cohorts (n = 308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (Barcelonaßeta Brain Research Center's Alzheimer's At-Risk Cohort [ß-AARC]). RESULTS: UGOT p-tau217 showed high accuracy (area under the curve [AUC] = 0.80-0.91) identifying amyloid beta (Aß) pathology, determined either by Aß positron emission tomography or CSF Aß42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aß42/40 ratio (AUC = 0.91). DISCUSSION: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.

Solvent- and functional-group-assisted tautomerism of 3-alkyl substituted 5-(2-pyridyl)-1,2,4-triazoles in DMSO-water.

The tautomerism of a series of 5-alkyl substituted 3-(2-pyridyl)-1,2,4-triazoles in DMSO-d6-containing water has been investigated by 1H, 13C and 15N NMR spectroscopy. The populations of the three possible regioisomers in the tautomeric equilibrium (A [3-alkyl-5-(2-pyridyl)-1H], B [5-alkyl-3-(2-pyridyl)-1H] and C [5-alkyl-3-(2-pyridyl)-4H]) were determined. Isomers A (17-40%) and B (54-79%) are the major components and their ratio is insensitive to the substitution pattern, except for the unsubstituted and the methoxymethyl substituted derivatives. The isomer C (3-5%) has been fully characterised for the first time by NMR spectroscopy. Activation energies of tautomerisation (14.74-16.78 kcal mol-1) were determined by EXSY experiments, which also supported the involvement of water in the tautomerisation. Substituent effects on the 15N chemical shifts are relatively small. The DFT study of the tautomerism in DMSO-water showed that both A/B and B/C interconversions are assisted by the pyridine substituent and catalysed by solvent molecules. The NH-A/NH-B tautomerisation takes place via a relayed quadruple proton transfer mediated by three water molecules in the hydrogen-bonded cyclic substructure of a triazole·4H2O complex. The equilibrium B ⇄ C involves three steps: NH-B transfer to the pyridyl nitrogen mediated by a water molecule in a 1 : 1 cyclic complex, rotamerisation to bring the pyridinium NH close to N4 of the triazole catalysed by complexation to a DMSO molecule and transfer of the NH from the pyridinium donor to the N4 acceptor via a 1 : 1 complex with a bridging water molecule. This mechanism of 1,3-prototropic shift in triazoles is unprecedented in the literature.

Decoupling Optical Response and Photochemical Formation of Singlet Oxygen in Size Isolated Fractions of Ozonated Dissolved Organic Matter.

The complex effects of ozonation on the photophysical and size-based properties of dissolved organic matter (DOM) were investigated using two DOM isolates, Suwannee River Fulvic Acid (SRFA) and Pony Lake Fulvic Acid (PLFA). A size exclusion chromatography system paired with absorbance, fluorescence, and total organic carbon detection was used to determine the fluorescence quantum yield (Φf) as a function of the apparent molecular weight (AMW). Size-based fractions of each isolate were collected and irradiated to measure singlet oxygen (1O2) quantum yield (Φ1O2). Φf decreased with ozonation in low AMW fractions, while increasing in high AMW fractions. Φ1O2 increased with ozone dose in low AMW fractions from ∼2 to ∼7% and ∼3 to ∼11% for PLFA and SRFA, respectively, indicating that these are the most photoreactive fractions of DOM. Decreases in Φf and concomitant increases in Φ1O2 in low AMW fractions indicated that chemical transformations occurred, likely including the conversion of phenols to quinones, particularly in SRFA. Results further suggest that the photoactive and fluorescent fractions of DOM are likely independent pools of chromophores from different AMW fractions. In PLFA, a linear response in Φ1O2, specific UV absorbance at wavelength 254 nm (SUVA254), and Φf with ozonation indicated the equal distribution of ozone-reactive moieties.

Effect of culture conditions at lab-scale on metabolite composition and antibacterial and antibiofilm activities of Dunaliella tertiolecta.

Dunaliella tertiolecta RCC6 was cultivated indoors in glass bubble column photobioreactors operated under batch and semi-continuous regimens and using two different conditions of light and temperature. Biomass was harvested by centrifugation, frozen, and then lyophilized. The soluble material was obtained by sequential extraction of the lyophilized biomass with solvents with a gradient of polarity (hexane, ethyl acetate, and methanol) and its metabolic composition was investigated through nuclear magnetic resonance (NMR) spectroscopy. The effect of light on chlorophyll biosynthesis was clearly shown through the relative intensities of the 1 H NMR signals due to pheophytins. The highest signal intensity was observed for the biomasses obtained at lower light intensity, resulting in a lower light availability per cell. Under high temperature and light conditions, the 1 H NMR spectra of the hexane extracts showed an incipient accumulation of triacylglycerols. In these conditions and under semi-continuous regimen, an enhancement of ß-carotene and sterols production was observed. The antibacterial and antibiofilm activities of the extracts were also tested. Antibacterial activity was not detected, regardless of culture conditions. In contrast, the minimal biofilm inhibitory concentrations (MBICs) against Escherichia coli for the hexane extract obtained under semi-continuous regimen using high temperature and irradiance conditions was promising.

Preanalytical stability of plasma/serum brain-derived tau.

INTRODUCTION: We investigated the effects of matrix type and reagent batch changes on diagnostic performances and longitudinal trajectories of brain-derived tau (BD-tau). METHODS: We evaluated (i) Cohort 1: paired EDTA plasma and serum from Alzheimer biomarker-positive older adults versus controls (n = 26); and (ii) Cohort 2: n = 79 acute ischemic stroke patients with 265 longitudinal samples across four time points. RESULTS: In Cohort 1, plasma and serum BD-tau were strongly correlated (rho = 0.96, p < 0.0001) with similar diagnostic performances (AUCs >99%) and correlations with CSF total-tau (rho = 0.93-0.94, p < 0.0001). However, absolute concentrations were ∼40% higher in plasma versus serum. In Cohort 2, first and repeated BD-tau measurements showed a near-perfect correlation (rho = 0.96, p < 0.0001), with no significant between-batch concentration differences. In longitudinal analyses, substituting ∼10% of the first-run concentrations for the remeasured values showed overlapping estimated trajectories without significant differences at any time point. DISCUSSION: BD-tau has equivalent diagnostic accuracies, but non-interchangeable absolute concentrations, in plasma versus serum. Furthermore, the analytical robustness is unaffected by batch-to-batch reagent variations. HIGHLIGHTS: Brain-derived tau (BD-tau) is a novel blood-based biomarker that quantifies tau protein of CNS origin. Effects of preanalytical handling procedures on the quality and reproducibility of BD-tau measures are unknown. In two cohorts of n = 105 participants, we compared BD-tau concentrations and diagnostic performances in paired plasma and serum samples, and evaluated impacts of batch-to-batch reagent variations. Paired plasma and serum showed equivalent diagnostic performances to separate amyloid-positive AD from amyloid-negative controls, indicating both can be used independently. Repeated measurements and longitudinal trajectories of plasma BD-tau were unaffected by batch-to-batch reagent variation.

Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease.

INTRODUCTION: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS: We measured longitudinal changes in plasma amyloid-beta (Aß)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aß and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. RESULTS: Aß42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non-carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aß-PET and tau-PET positive showed faster plasma pTau181 and GFAP increase compared to PET-negative individuals. DISCUSSION: Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. HIGHLIGHTS: Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E Îµ4 carriers experience faster increase in plasma pTau181 over time than non-carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aß42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden.

Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays.

INTRODUCTION: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. METHODS: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aß42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aß42/p-tau ratio. RESULTS: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aß42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). DISCUSSION: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. HIGHLIGHTS: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.

A New Bioassay for the Detection of Paralytic and Amnesic Biotoxins Based on Motor Behavior Impairments of Zebrafish Larvae.

The global concern about the increase of harmful algal bloom events and the possible impacts on food safety and aquatic ecosystems presents the necessity for the development of more accessible techniques for biotoxin detection for screening purposes. Considering the numerous advantages that zebrafish present as a biological model and particularly as a toxicants sentinel, we designed a sensitive and accessible test to determine the activity of paralytic and amnesic biotoxins using zebrafish larvae immersion. The ZebraBioTox bioassay is based on the automated recording of larval locomotor activity using an IR microbeam locomotion detector, and manual assessment of four complementary responses under a simple stereoscope: survival, periocular edema, body balance, and touch response. This 24 h acute static bioassay was set up in 96-well microplates using 5 dpf zebrafish larvae. For paralytic toxins, a significant decrease in locomotor activity and touch response of the larvae was detected, allowing a detection threshold of 0.1-0.2 µg/mL STXeq. In the case of the amnesic toxin the effect was reversed, detecting hyperactivity with a detection threshold of 10 µg/mL domoic acid. We propose that this assay might be used as a complementary tool for environmental safety monitoring.

Structural Chirality of Polar Skyrmions Probed by Resonant Elastic X-Ray Scattering.

An escalating challenge in condensed-matter research is the characterization of emergent order-parameter nanostructures such as ferroelectric and ferromagnetic skyrmions. Their small length scales coupled with complex, three-dimensional polarization or spin structures makes them demanding to trace out fully. Resonant elastic x-ray scattering (REXS) has emerged as a technique to study chirality in spin textures such as skyrmions and domain walls. It has, however, been used to a considerably lesser extent to study analogous features in ferroelectrics. Here, we present a framework for modeling REXS from an arbitrary arrangement of charge quadrupole moments, which can be applied to nanostructures in materials such as ferroelectrics. With this, we demonstrate how extended reciprocal space scans using REXS with circularly polarized x rays can probe the three-dimensional structure and chirality of polar skyrmions. Measurements, bolstered by quantitative scattering calculations, show that polar skyrmions of mixed chirality coexist, and that REXS allows valuation of relative fractions of right- and left-handed skyrmions. Our quantitative analysis of the structure and chirality of polar skyrmions highlights the capability of REXS for establishing complex topological structures toward future application exploits.