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Seeding biosensor cell line that reproduces the Alzheimer tau fold.
Full text linkThe assembly of tau protein into amyloid filaments through templated seeding is believed to underlie the propagation of pathology in neurodegenerative diseases, such as Alzheimer's disease (AD) and other tauopathies. A commonly used model system for studying this process is through the induction of tau filament formation in cultured cells following the addition of tau seeds isolated from the human brain. However, little is known about the structures of seeded filaments; some biosensor cell lines are unable to reproduce the tau filament structures from AD, because they overexpress tau fragments that do not cover the whole of the ordered filament core. Here, we describe a novel tau seeding biosensor model in human embryonic kidney 293T cells that overexpress residues K297-E391 of human 4R tau. The construct contains an N-terminal hemagglutinin tag, which allows the specific detection of the amplified template. The biosensor cells detected filaments seeded by material from sporadic three-repeat (3R) + four-repeat (4R) tauopathies, with little activity by seeds from 3R-only or 4R-only tauopathies. The sensitivity of seed detection from 3R + 4R tauopathies in our system was similar to or higher than for previously reported biosensors. We also structurally characterized the AD-seeded tau filaments by cryo-EM. Most of the cell-derived filaments consisted of two protofilaments with the Alzheimer's fold but with a "head-to-head" interprotofilament packing. Our results establish a sensitive biosensor cell line with specificity toward seeds from 3R + 4R tauopathies
Swift-BAT GUANO Follow-up of Gravitational-wave Triggers in the Third LIGO–Virgo–KAGRA Observing Run
Full text linkWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO–Virgo–KAGRA network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received with low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum-likelihood Non-imaging Transient Reconstruction and Temporal Search pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15–350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10−3 Hz, we compute the GW–BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers
Measurement of the branching fraction of the Λb0→J/ψΛ decay and isospin asymmetry of B → J/ψK decays
Full text linkThis paper describes a measurement of the Λb0→J/ψΛ branching fraction using data collected with the LHCb experiment in proton-proton collisions from 2016 to 2018. The dataset corresponds to an integrated luminosity of 5.4 fb−1. The branching fraction is determined relative to that of B0→J/ψKS0 decays,BΛb0→J/ψΛBB0→J/ψKS0=0.750±0.005±0.022±0.005±0.062,yielding BΛb0→J/ψΛ=3.34±0.02±0.10±0.08±0.28×10−4, where the first uncertainty is statistical, the second systematic, the third due to external inputs on branching fractions and the fourth due to the ratio of Λb0 baryon and B0 meson hadronisation fractions. In addition, the isospin asymmetry between the rates of B0→J/ψKS0 and B+→ J/ψK+ decays is measured to beAI=−0.0135±0.0004±0.0133,where the first uncertainty is statistical and the second systematic
Genetic subtypes associated with multiple sclerosis severity and response to treatment.
Full text linkBACKGROUND: Predicting response to treatment and long-term disability in multiple sclerosis (MS) remains challenging. In other complex diseases, combining genetic risk variants has enabled the detection of relevant clinical endophenotypes associated with important outcomes, but this strategy has never been applied to MS. METHODS: We applied unsupervised hierarchical clustering to genomic risk scores in a prospective Welsh MS cohort (n=1455) and replicated the findings in the postmortem Netherlands Brain Bank (NBB) MS (NBB-MS) cohort (n=272). Disease progression was assessed using survival analysis to determine the time to Expanded Disability Status Scale (EDSS) milestones. RESULTS: Three genomic clusters were identified, each with similar genetic profiles. Baseline demographics did not differ between clusters. Welsh patients in cluster 1 attained EDSS 6 and EDSS 8 significantly later than clusters 2 and 3 (by 6 years, p=3×10-3 and 13 years, p=0.02, respectively). These findings were replicated in the NBB-MS cohort (6-year delay to EDSS 6 for cluster 1 vs 2, p=0.04). Genomic clustering independently predicted disease progression (HRs 1.3-2.0, all p<0.05), beyond established risk factors. Clusters 2 and 3 showed a greater annual increase in T2 lesion load on serial MR imaging (p=0.04). In cluster 2, patients receiving disease-modifying treatments had delayed progression to EDSS 6 (p=3×10-³), while no such benefit was observed in clusters 1 or 3. Cluster 2 patients also had earlier onset of symptoms, including dysphagia (p=0.02) and spasticity (p=8×10-⁴) in the NBB-MS cohort. CONCLUSIONS: Genetic clustering reveals clinically meaningful MS subtypes with distinct prognoses and treatment responses, highlighting its potential role in precision medicine for MS management
Highly excited B, Bs and Bc meson spectroscopy from lattice QCD
No full textExcited state spectra of B, Bs and Bc mesons are computed using lattice QCD. Working with a large basis of carefully constructed, approximately-local qq¯-like operators we determine a rich spectrum of states up to J = 4 in B, Bs and Bc, that can be grouped into patterns matching those of the quark model. In addition, hybrid-like states are identified at approximately 1500 MeV above the ground states in each of B, Bs and Bc, in a multiplet pattern already found in similar computations at a range of quark masses spanning light to bottom. This study is performed using an anisotropic, relativistic Wilson-clover action at a single spatial lattice spacing of as ≈ 0.12 fm and with a light-quark mass corresponding to mπ ≈ 391 MeV. We find good agreement with experimental results where known and discuss prospects for further work in interesting JP quantum numbers
Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID.
No full textLong COVID affects a substantial proportion of survivors of acute infection with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), who suffer a variety of symptoms that limit their quality of life and economic activity. Although the aetiology of long COVID is obscure, it appears to be a chronic inflammatory condition. Complement dysregulation is a prevalent feature of long COVID. Specifically, markers of classical, alternative, and terminal pathway activation are often elevated in patients with this condition. Here, we used a sensitive assay for mannan-binding lectin-associated serine protease-2 (MASP-2)/C1Inh complexes to analyse lectin pathway activation in a previously characterised cohort of patients with long COVID (n = 159) and healthy convalescent individuals with no persistent symptoms after infection with SARS-CoV-2 (n = 76). The data were combined with those from the most predictive complement analytes identified previously to delineate potential biomarkers of long COVID. MASP-2/C1Inh complexes were significantly elevated in patients with long COVID (p = 0.0003). Generalised linear modelling further identified an optimal set of four markers, namely iC3b (alternative pathway), TCC (terminal pathway), MASP-2/C1Inh (lectin pathway), and the complement regulator properdin, which had a receiver operating characteristic predictive power of 0.796 (95% confidence interval = 0.664-0.905). Combinations of the classical pathway markers C4, C1q, and C1s/C1Inh were poorly predictive of long COVID. These findings demonstrate that activation of the lectin complement pathway, which occurs upstream of the alternative and terminal pathways and can be inhibited therapeutically, is a salient feature of long COVID
Data-driven lifting-centered construction site layout planning decision approach with BIM
No full textConstruction site layout planning (CSLP) is essential for optimizing the placement of temporary facilities (TFs), yet it inadequately integrates tower crane characteristics, causing inefficient material transportation and safety risk. Current decision-making relies on labor-intensive data extraction, complex mathematical models, and fragmented workflows incompatible with specialized software. This paper proposes an automated data-driven lifting-centered CSLP decision approach with building information modeling (BIM) and AI to enhance TF placement efficiency. The approach incorporates three stages: automated data extraction from the BIM model with users' promotion, development of data-driven lifting-based multi-objectives CSLP decision engines, and evaluation of generated TFs placement through BIM-based simulations. Validation indicates that over 92 % of AI-generated CSLP outcomes outperform traditional methods (genetic algorithm (GA)). Experiments on a real-world project demonstrate that this approach reduces processing time to 7.93 % of GA and lowers functional costs by 11.60 %. This method assists designers in expediting the CSLP decision-making process with BIM models
A Qualitative meta-analysis of the socioeconomic impacts of offshore wind farms
No full textClimate change and an increased interest in renewable energy have resulted in a burgeoning wind energy sector. However, in the recent past, wind farms have faced resistance in acquiring permits due to concerns about their long-term effects on the local community. To understand the extent of these externalities, this study qualitatively meta-analyses four socio-economic impacts of interest, namely: house prices, tourism, catalytic effects of supply chain clustering, and social change. Geographically, the analysed reports include Europe, Canada and the US, and deductions are made for the EU. In order to bridge the gap of unavailability of primary data on the wind sector, relevant conclusions are drawn from other comparable sectors. Based on a rigorous review of primary qualitative research, this study concludes that offshore wind farms should be located more than 40 km away from the coast to eliminate risks of housing price devaluation and tourist activity reduction, which would directly affect the economic value of the region. In addition, the study found limited evidence to acknowledge the employment benefits in the local economy and social change in the community due to offshore wind farms. Monitoring mechanisms should be set up to prove or disprove the creation of local employment, crime and substance abuse. Furthermore, the study finds that adequate planning and management can ensure better socioeconomic outcomes in the community. Further research is recommended for the specific impact of overhead transmission lines and substations on property values and tourism
The impact of congenital heart disease on the timing of Alzheimer's disease in Down syndrome.
No full textINTRODUCTION: The incidence of Alzheimer's disease (AD) in Down syndrome (DS) exceeds 90%. Approximately 50% of people with DS have congenital heart disease (CHD). Having CHD increases risk for early-onset AD in populations without DS, but it is unclear if CHD influences AD in DS. METHODS: Data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) were used. Participants with CHD (n = 82, mean age = 39.9 ± 8.5 years, 97.6% White race) were age- and sex-matched to participants without CHD (n = 82, mean age = 40.5 ± 8.1 years, 98.8% White race). Cognitive assessments and Centiloid load (CL) (positron emission tomography) were compared by CHD status. RESULTS: People with CHD scored lower for visuospatial ability (β = -3.515, p = 0.022) but had higher CL (29.8 ± 12.8 vs. 39.8 ± 12.8, β = 8.00, p = 0.036) and were projected to hit Aβ positivity at a younger age (37.6 and 42.1 years). DISCUSSION: Presence of CHD may influence AD progression in DS. HIGHLIGHTS: In adults with Down syndrome (DS), those with congenital heart disease (CHD) had higher amyloid beta and reached the threshold for an amyloid positivity at a younger age than those without CHDNo differences in cognition were seen in the age- and sex-matched sample based on CHD status; however, the average age of the sample may be too young to see cognitive changesCHDs may influence the timing of Alzheimer's disease (AD) in adults with DS