julilili42/papers huggingface dataset:
Genetic Semantic Dementia? Twins’ Data and Review of Autosomal Dominant Cases
2024-10-18

Abstract Background Amongst different subtypes of frontotemporal dementia (FTD), semantic dementia (SD, also known as the semantic variant of primary progressive aphasia, svPPA), is the least likely to have a genetic basis. Methods Our study had two aims: (i) to describe two SD cases and detailed assessments of their unaffected monozygotic (MZ) twins, and (ii) to review cases with FTD-associated mutations or known family history classified as SD/svPPA either in the Genetic Frontotemporal dementia Initiative (GENFI) or in the published literature. Results The two affected twins displayed characteristic features of SD, both in neuroimaging and cognition, whereas their MZ twins exhibited no abnormalities in either regard, even up to 15 years of follow-up for one affected twin. Only five cases out of more than 1300 people in GENFI were classified as svPPA, with a genetic mutation. The systematic review revealed 29 cases with sufficient clinical and language details regarding ‘genetic’ SD/svPPA. A comparison of these five GENFI and 29 literature cases to the patterns observed in a large number of sporadic cases revealed critical differences in presentation. Conclusions Both parts of our study suggest that true SD/svPPA is unlikely to have an autosomal dominant genetic aetiology and that, while mutation carriers may resemble SD/svPPA in some respects, they may not meet current clinical diagnostic criteria for this condition. What is already known on this topic : Approximately 30% of all frontotemporal dementia cases are associated with an autosomal dominant pattern of inheritance but the reported prevalence of mutation in semantic dementia/semantic variant of primary progressive aphasia (SD/svPPA) is very low. What this study adds : From (a) outlining the discordance for SD/svPPA in two pairs of monozygotic twins and (b) comparing the clinical and cognitive profiles of people who had been classified as SD/svPPA with an FTD-associated genetic mutation versus sporadic SD/svPPA, we conclude that true SD/svPPA is unlikely to have an autosomal dominant genetic aetiology. How this study might affect research, practice or policy : Our study highlights gaps in the understanding of environmental and epigenetic influences on sporadic SD/svPPA and a need for further unbiased genotyping and phenotyping of SD/svPPA and “SD-like” syndromes. Open access: For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Lactate production from lactose-rich wastewater: A comparative study on reactor configurations to maximize conversion rates and efficiencies
2024-10-18

ABSTRACT About 90% of global lactate production is derived from bacterial fermentation of sugars via pure cultures of homofermentative bacteria in batch mode. Acid whey, which is a wastewater from the yogurt industry with lactose and galactose as the main sugars, can be used as an alternative substrate for the commercial production of lactate. Operating open cultures of microbial consortia ( i.e ., reactor microbiomes) reduces the costs of lactate production by circumventing sterilization, while continuous operation achieves higher productivity at shorter production times. Homofermentation can be achieved by maintaining acidic and thermophilic conditions, while product formation in continuous systems can be increased with biomass retention strategies. To find the best reactor configuration for lactate production from acid whey, we operated three different reactor configurations: (1) an upflow anaerobic sludge blanket (UASB) reactor; (2) an anaerobic filter reactor (AFR); and (3) an anaerobic continuously stirred tank reactor (CSTR) with a hollow-fiber membrane module. We operated at different hydraulic retention times (HRTs) to find the optimum parameters to maximize the lactose and galactose-into-lactate (LG-into-LA) conversion efficiency. We did not use an inoculum but enriched the endogenous D-lactate-producing Lactobacillus spp. that later dominated the reactor microbiomes (&gt; 90% relative abundance). Undissociated lactic acid concentrations of more than 60 mmol C L -1 inhibited the microbiomes. We alleviated the inhibition effect by shortening the HRT to 0.6 days and using diluted acid-whey substrate (1.67-fold dilution) to achieve almost complete conversion of the acid-whey sugars to lactate. At the 0.6-day HRT commencement, the AFR and CSTR performed better than the UASB reactor due to their better cell retention abilities. During the period between Day 365-384, we experienced an error in the pH control of the CSTR system during which the pH value dropped to 4.3. After this pH-error period, the LG-into-LA conversion efficiency for the CSTR considerably improved and surpassed the AFR. We achieved the highest lactate conversion rate of 1256 ± 46.3 mmol C L -1 d -1 (1.57 ± 0.06 g L -1 h -1 ) at a LG-into-LA conversion efficiency of 82.2 ± 3.4% (in mmol C), with a yield of 0.85 ± 0.02 mmol C mmol C -1 (product per consumed substrate) for the CSTR.
From Simulations to Inference: Using Machine Learning to Tune Patient-Specific Finite-Element Models of the Middle Ear Towards Objective Diagnosis
2024-10-18

Abstract Computational models, particularly finite-element (FE) models, are essential for interpreting experimental data and predicting system behavior, especially when direct measurements are limited. A major challenge in tuning these models is the large number of parameters involved. Traditional methods, such as one-by-one sensitivity analyses, are time-consuming, subjective, and often return only a single set of parameter values, focusing on reproducing averaged data rather than capturing the full variability of experimental measurements. In this study, we applied simulation-based inference (SBI) using neural posterior estimation (NPE) to tune an FE model of the human middle ear. The training dataset consisted of 10,000 FE simulations of stapes velocity, ear-canal (EC) input impedance, and absorbance, paired with seven FE parameter values randomly sampled within plausible ranges. The neural network learned the association between parameters and simulation outcomes, returning the probability distribution of parameter values that can reproduce experimental data. Our approach successfully identified parameter sets that reproduced three experimental datasets simultaneously. By accounting for experimental noise and variability during training, the method provided a probability distribution of parameters, representing all valid combinations that could fit the data, rather than tuning to averaged values. The network demonstrated robustness to noise and exhibited an efficient learning curve due to the large training dataset. SBI offers an objective alternative to laborious sensitivity analyses, providing probability distributions for each parameter and uncovering interactions between them. This method can be applied to any biological FE model, and we demonstrated its effectiveness using a middle-ear model. Importantly, it holds promise for objective differential diagnosis of conductive hearing loss by providing insight into the mechanical properties of the middle ear.
Comprehensive Coverage of Glycolysis and Pentose Phosphate Metabolic Pathways by Isomer-Selective Accurate Targeted Hydrophilic Interaction Liquid Chromatography-Tandem Mass Spectrometry Assay
2024-10-19

The accurate liquid chromatography-tandem mass spectrometry analysis of phosphorylated isomers from glycolysis and pentose phosphate pathways is a challenging analytical problem in metabolomics due to extraction problems from the biological matrix, adherence to stainless steel surfaces leading to tailing in LC, and incomplete separation of hexose and pentose phosphate isomers. In this study, we present a targeted HILIC-ESI-MS/MS method based on a BEH amide fully porous 1.7 μm particle column with an inert surface coating of column hardware and multiple reaction monitoring (MRM) acquisition fully covering the glycolysis and pentose phosphate pathway metabolites. To minimize contact of the phosphorylated analytes with stainless steel surfaces, a μ-ESI-MS probe with a hybrid electrode made of PEEKsil was employed. Optimized HILIC gradient elution conditions with 100 mM ammonium formate (pH 11) provided the separation of hexose monophosphate and pentose phosphate isomers. To ensure good retention time repeatability in HILIC, perfluoroalkoxy alkane bottles were used for the mobile phase (with sd over 60 runs between 0.01 and 0.02 min). For the quantitative assay, the U-<sup>13</sup>C-labeled cell extract was spiked prior to extraction by metal oxide-based affinity chromatography (MOAC) with TiO<sub>2</sub> beads. The concentrations of the 24 targets were quantified in HeLa and human embryonic kidney (HEK293) cells. Erastin-induced ferroptosis in HEK293 cells was accompanied by enhanced levels of fructose-1,6-bis-phosphate, 2- and 3-phosphoglycerate, and 2,3-bis-phosphoglycerate.
The mode of toxic action of ionic liquids: Narrowing down possibilities using high-throughput, in vitro cell-based bioassays
2024-10-20

Growing concerns about the environmental impact of ionic liquids (ILs) have spurred research into their (eco)toxic effects, but studies on their mode of toxic action (MOA) still remain limited. However, understanding the MOA and identifying structural features responsible for enhanced toxicity is crucial for characterising the hazard and designing safer alternatives. Therefore, 45 ILs, with systematically varied chemical structures, were tested for cytotoxicity and two specific endpoints in reporter gene assays targeting the Nrf2-ARE mediated oxidative stress response (AREc32) and aryl hydrocarbon receptor activation (AhR-CALUX). While none of the ILs activated the reporter genes, cytotoxicity was high and markedly different between cell lines. Seven and 25 ILs proved more cytotoxic than predicted by baseline toxicity model in the AREc32 and the AhR-CALUX assays, respectively. The length of the side chain and headgroup structures of ILs altered the MOA of ILs. Cellular metabolism of the ILs, investigated by LC-MS/MS, showed side-chain oxidation of the long-chain quaternary ammonium compounds in AhR-CALUX cells and, to a lower extent, in AREc32 cells, however, this transformation could not explain the high cytotoxicity. Effect data for 72 ILs for ten endpoints retrieved from the Tox21 database identified the inhibition of aromatase activity and of mitochondrial membrane potential as potential MOAs. However, in vitro fluorimetric assays for these endpoints demonstrated that effects were activated in a non-specific manner, probably through cytotoxicity. Although many of the ILs tested induced cytotoxicity at concentrations lower than baseline toxicity, the specific MOAs responsible could not be identified. Alternatively, we suggest that the descriptors currently used may fail to define the affinity of ILs for cells. Testing of the affinity of ILs for a diverse range of biomolecules is needed to accurately describe their interactions with cells.
Revealing the range of maximum likelihood estimates in the admixture model
2024-10-20

Abstract Many ancestry inference tools, including STRUCTURE and ADMIXTURE, rely on the admixture model to infer both, allele frequencies p and individual admixture proportions q for a collection of individuals relative to a set of hypothetical ancestral populations. We show that under realistic conditions the likelihood in the admixture model is typically flat in some direction around a maximum likelihood estimate . In particular, the maximum likelihood estimator is non-unique and there is a complete spectrum of possible estimates. Common inference tools typically identify only a few points within this spectrum. We provide an algorithm which computes the set of equally likely , when starting from . It is analytic for K = 2 ancestral populations and numeric for K &gt; 2. We apply our algorithm to data from the 1000 genomes project, and show that inter-European estimators of q can come with a large set of equally likely possibilities. In general, markers with large allele frequency differences between populations in combination with individuals with concentrated admixture proportions lead to small areas with a flat likelihood. Our findings imply that care must be taken when interpreting results from STRUCTURE and ADMIXTURE if populations are not separated well enough.
Constraining the properties of the thermonuclear burst oscillation source XTE J1814−338 through pulse profile modelling
2024-10-21

ABSTRACT Pulse profile modelling (PPM) is a comprehensive relativistic ray-tracing technique employed to determine the properties of neutron stars. In this study, we apply this technique to the Type I X-ray burster and accretion-powered millisecond pulsar XTE J1814−338, extracting its fundamental properties using PPM of its thermonuclear burst oscillations. Using data from its 2003 outburst, and a single uniform temperature hotspot model, we infer XTE J1814−338 to be located at a distance of kpc, with a mass of M and an equatorial radius of km. Our results also offer insight into the time evolution of the hotspot but point to some potential shortcomings of the single uniform temperature hotspot model. We explore the implications of this result, including what we can learn about thermonuclear burst oscillation mechanisms and the importance of modelling the accretion contribution to the emission during the burst.
First observation of single photons in a CRESST detector and new dark matter exclusion limits
2024-10-21

The main goal of the CRESST-III experiment is the direct detection of dark matter particles via their scattering off target nuclei in cryogenic detectors. In this work we present the results of a silicon-on-sapphire (SOS) detector with a mass of 0.6 g and an energy threshold of <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" display="inline"><a:mrow><a:mo stretchy="false">(</a:mo><a:mn>6.7</a:mn><a:mo>±</a:mo><a:mn>0.2</a:mn><a:mo stretchy="false">)</a:mo><a:mtext> </a:mtext><a:mtext> </a:mtext><a:mi>eV</a:mi></a:mrow></a:math> with a baseline energy resolution of <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" display="inline"><e:mrow><e:mo stretchy="false">(</e:mo><e:mn>1.0</e:mn><e:mo>±</e:mo><e:mn>0.2</e:mn><e:mo stretchy="false">)</e:mo><e:mtext> </e:mtext><e:mtext> </e:mtext><e:mi>eV</e:mi></e:mrow></e:math>. This allowed for a calibration via the detection of single luminescence photons in the eV-range, which could be observed in CRESST for the first time. We present new exclusion limits on the spin-independent and spin-dependent dark matter-nucleon cross section that extend to dark matter particle masses of less than <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" display="inline"><i:mrow><i:mn>100</i:mn><i:mtext> </i:mtext><i:mtext> </i:mtext><i:mi>MeV</i:mi><i:mo>/</i:mo><i:msup><i:mrow><i:mi mathvariant="normal">c</i:mi></i:mrow><i:mrow><i:mn>2</i:mn></i:mrow></i:msup></i:mrow></i:math>. Published by the American Physical Society 2024
Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease
2024-10-21

BACKGROUND: Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. METHODS: AVD progression and its consequences for cardiac function were examined in a murine wire injury–induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by liquid chromatography-mass spectrometry. Calcification of human valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by liquid chromatography-mass spectrometry. RESULTS: Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. CONCLUSIONS: Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.
Receptor usage of Syncytin-1: ASCT2, but not ASCT1, is a functional receptor and effector of cell fusion in the human placenta
2024-10-21

Syncytin-1, a human fusogenic protein of retroviral origin, is crucial for placental syncytiotrophoblast formation. To mediate cell-to-cell fusion, Syncytin-1 requires specific interaction with its cognate receptor. Two trimeric transmembrane proteins, Alanine, Serine, Cysteine Transporters 1 and 2 (ASCT1 and ASCT2), were suggested and widely accepted as Syncytin-1 cellular receptors. To quantitatively assess the individual contributions of human ASCT1 and ASCT2 to the fusogenic activity of Syncytin-1, we developed a model system where the ASCT1 and ASCT2 double knockout was rescued by ectopic expression of either ASCT1 or ASCT2. We demonstrated that ASCT2 was required for Syncytin-1 binding, cellular entry, and cell-to-cell fusion, while ASCT1 was not involved in this receptor interaction. We experimentally validated the ASCT1–ASCT2 heterotrimers as a possible explanation for the previous misidentification of ASCT1 as a receptor for Syncytin-1. This redefinition of receptor specificity is important for proper understanding of Syncytin-1 function in normal and pathological pregnancy.
Investigating the dynamic history of a promontory ice rise using radar data
2024-10-21

Abstract Ice rises hold valuable records revealing the ice dynamics and climatic history of Antarctic coastal areas from the Last Glacial Maximum to today. This history is often reconstructed from isochrone radar stratigraphy and simulations focusing on Raymond arch evolution beneath the divides. However, this relies on complex ice-flow models where many parameters are unconstrained by observations. Our study explores quad-polarimetric, phase-coherent radar data to enhance understanding near ice divides and domes, using Hammarryggen Ice Rise (HIR) as a case study. Analysing a 5 km profile intersecting the dome, we derive vertical strain rates and ice-fabric properties. These align with ice core data near the summit, increasing confidence in tracing signatures from the dome to the flanks. The Raymond effect is evident, correlating with surface strain rates and radar stratigraphy. Stability is inferred over millennia for the saddle connecting HIR to the mainland, but dome ice-fabric appears relatively young compared to 2D model predictions. In a broader context, quad-polarimetric measurements provide valuable insights into ice-flow models, particularly for anisotropic rheology. Including quad-polarimetric data advances our ability to reconstruct past ice flow dynamics and climatic history in ice rises.
The Journey to a FAIR CORE DATA SET for Diabetes Research in Germany
2024-10-21

Abstract The German Center for Diabetes Research (DZD) established a core data set (CDS) of clinical parameters relevant for diabetes research in 2021. The CDS is central to the design of current and future DZD studies. Here, we describe the process and outcomes of FAIRifying the initial version of the CDS. We first did a baseline evaluation of the FAIRness using the FAIR Data Maturity Model. The FAIRification process and the results of this assessment led us to convert the CDS into the recommended format for spreadsheets, annotating the parameters with standardized medical codes, licensing the data set, enriching the data set with metadata, and indexing the metadata. The FAIRified version of the CDS is more suitable for data sharing in diabetes research across DZD sites and beyond. It contributes to the reusability of health research studies.
Beyond buzzwords: fostering interdisciplinary and collaborative global health research in Germany and beyond
2024-10-21

Despite achievements, challenges persist. Wider support, especially from universities and research institutions, is necessary to make global health research an attractive career path and to reduce bureaucratic barriers for collaborators in LMICs. Sustained, longer-term federal funding mechanisms will also be essential for ongoing progress.