julilili42/papers huggingface dataset:
Prediction of Individual Disease Progression Including Parameter Uncertainty in Rare Neurodegenerative Diseases: The Example of Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS)
2024-04-30

Abstract The aim of this study was to develop a model to predict individual subject disease trajectories including parameter uncertainty and accounting for missing data in rare neurological diseases, showcased by the ultra-rare disease Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). We modelled the change in SARA (Scale for Assessment and Rating of Ataxia) score versus Time Since Onset of symptoms using non-linear mixed effect models for a population of 173 patients with ARSACS included in the prospective real-world multicenter Autosomal Recessive Cerebellar Ataxia (ARCA) registry. We used the Multivariate Imputation Chained Equation (MICE) algorithm to impute missing covariates, and a covariate selection procedure with a pooled p-value to account for the multiply imputed data sets. We then investigated the impact of covariates and population parameter uncertainty on the prediction of the individual trajectories up to 5 years after their last visit. A four-parameter logistic function was selected. Men were estimated to have a 25% lower SARA score at disease onset and a moderately higher maximum SARA score, and time to progression (T50) was estimated to be 35% lower in patients with age of onset over 15 years. The population disease progression rate started slowly at 0.1 points per year peaking to a maximum of 0.8 points per year (at 36.8 years since onset of symptoms). The prediction intervals for SARA scores 5 years after the last visit were large (median 7.4 points, Q1-Q3: 6.4–8.5); their size was mostly driven by individual parameter uncertainty and individual disease progression rate at that time. Graphical Abstract
Intensity Score of Vessel Wall Contrast Enhancement in MRI Allows Prediction of Disease Progression in Moyamoya Angiopathy
2024-04-30

BACKGROUND AND OBJECTIVES: The underlying pathophysiological cause of moyamoya angiopathy (MMA) is still unclear. High-resolution vessel wall imaging has become a useful tool. The aim was to study vessel wall contrast-enhancement (VW-CE) as an imaging marker to predict disease progression in MMA. METHODS: Patients with MMA, who had undergone serial contrast-enhanced high-resolution MRI with concomitant and follow-up digital subtraction angiography, were analyzed retrospectively. VW-CE was semiquantified by measurement of the signal intensity of the vessel wall in in contrast-enhanced high-resolution MRI. A comparative quotient with the contrast-intensity of the pituitary stalk was calculated and graded accordingly from grade 1 to 5. VW-CE status was correlated with disease status, stroke, cerebrovascular reactivity in CO2-triggered blood-oxygen level-dependent MRI, angiographic disease progression, revascularization surgery, and follow-up imaging. RESULTS: Forty eight patients met the inclusion criteria. N = 56 MRI and digital subtraction angiography time-intervals were evaluated for 12 vessel sections per hemisphere each (N = 1344). N = 38 (79%) patients showed VW-CE and N = 10 (21%) did not. VW-CE was only observed in the terminal internal carotid artery and the proximal circle of Willis (N = 96/1344). Notably, patients with VW-CE significantly more often presented with acute infarction in the concomitant MRI. The incidence of angiographically proven disease progression was significantly associated with the incidence of VW-CE, and time to disease progression was earlier in higher grades of VW-CE compared with lower grades. CONCLUSION: VW-CE is a semiquantifiable marker for disease activity in patients with MMA and associated with disease progression and increased risk of stroke. VW-CE analysis can be routinely performed in patients with MMA to estimate the risk for disease progression and stroke.
Ghrelin is associated with an elevated mood after an overnight fast in depression
2024-04-30

Our results reveal potentially mood-enhancing effects of ghrelin in fasting individuals that exceed associations with metabolic state ratings. These associations with circulating neuropeptides might help explain anti-depressive effects of fasting interventions and could complement conventional treatments in patients with melancholic MDD.
P66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion byBorrelia burgdorferi
2024-04-30

Summary Paragraph Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic “don’t eat me” signaling axis between CD47 (ligand) and SIRPα (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRPα. Expression of the gene encoding the protein is required for bacteria to bind SIRPα or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRPα. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.
Practice Design and Coaching to Support Learning in Elite Youth Soccer Players: Recommendations From International Coaches, Coach Educators, and Researchers
2024-04-30

Providing optimal learning support is a major challenge within talent development settings. To accomplish this challenge, practitioners’ decisions, and actions should be informed by a blend of practical experiences and academic knowledge. This study explored experts’ recommendations on how to facilitate learning in elite adolescent soccer players during practice. Special focus was dedicated to why certain practice and coaching approaches were recommended to better understand experts’ justifications. Eighteen semistructured interviews were conducted with international experts representing three complementary groups of expertise (i.e., six of each soccer coaches ; coach educators/developers ; and researchers in talent development, motor learning, or coaching pedagogy). By employing a reflexive thematic analysis three themes were constructed: (I) differentiating overarching learning goals to address players’ individual needs, (II) designing purposeful training sessions with the game in mind, and (III) coaching interventions to support player learning within a group environment. Overall, the experts recommended the complementary use of different practice and coaching strategies to address individual learning needs. While some strategies may be associated with conflicting theoretical paradigms and established pedagogical approaches, the findings inform a purposeful integration of those different approaches in practical work. Therefore, participants’ recommendations can be discussed by integrating interdisciplinary theoretical perspectives.
CuBe: a geminivirus-based copper-regulated expression system suitable for post-harvest activation
2024-04-30

ABSTRACT The growing demand for sustainable platforms for biomolecule manufacturing has fueled the development of plant-based production systems. Agroinfiltration, the current industry standard, offers several advantages but faces limitations for large-scale production due to high operational costs and batch-to-batch variability. Alternatively, here, we describe the CuBe system, a novel bean yellow dwarf virus (BeYDV)-derived conditional replicative expression platform stably transformed in Nicotiana benthamiana and activated by copper sulfate (CuSO 4 ), an inexpensive and widely used agricultural input. The CuBe system utilizes a synthetic circuit of four genetic modules integrated into the plant genome: (i) a replicative vector harboring the gene of interest (GOI) flanked by cis-acting elements for geminiviral replication and novelly arranged to enable transgene transcription exclusively upon formation of the circular replicon, (ii) copper-inducible Rep/RepA proteins essential for replicon formation, (iii) the yeast-derived CUP2-Gal4 copper-responsive transcriptional activator for Rep/RepA expression, and (iv) a copper-inducible Flp recombinase to minimize basal Rep/RepA expression. Copper sulfate application triggers the activation of the system, leading to the formation of extrachromosomal replicons, expression of the GOI, and accumulation of the desired recombinant protein. We demonstrate the functionality of the CuBe system in N. benthamiana plants expressing high levels of eGFP and an anti-SARS-CoV-2 antibody upon copper treatment. Notably, the system is also functional with post-harvest copper application, a strategy with potential advantages for large-scale biomanufacturing. This work presents the CuBe system as a promising alternative to agroinfiltration for cost-effective and scalable production of recombinant proteins in plants.
Disparate occurrences of a chalicotheriine and a schizotheriine chalicothere (Mammalia, Chalicotheriidae) at the Late Miocene hominid locality Hammerschmiede (Germany)
2024-04-30

Abstract Chalicotheres are enigmatic perissodactyls that had large claws instead of hooves. The present study concerns the material of Chalicotheriidae from the Late Miocene hominid locality of Hammerschmiede in Germany. The HAM 5 fossil site (11.62 Ma) consists of six isolated dental and postcranial chalicothere elements. Based on the morphology and dimensions of the dentition, the material can be assigned to the chalicotheriine Anisodon sp. This genus is the most common representative of Chalicotheriidae in Central Europe during the Middle Miocene but becomes much rarer during the Late Miocene. The HAM 4 fossil site (11.44 Ma) has yielded a patella belonging to a schizotheriine and a skull fragment that could possibly also belong to a schizotheriine. Thus, the schizotheriine and the chalicotheriine occur in different horizons in Hammerschmiede. Both taxa probably had a rather similar diet but different locomotion, and their disparate occurrences are most plausibly associated with environmental differences among the two fossiliferous levels.
Inferior Frontal Sulcal Hyperintensities on Brain MRI Are Associated with Amyloid Positivity beyond Age—Results from the Multicentre Observational DELCODE Study
2024-04-30

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer’s disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05–3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57–2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00–1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26–0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age.
Automated Measurement and Three-Dimensional Fitting of Corneal Ulcerations and Erosions via AI-Based Image Analysis
2024-04-30

The developed algorithm is capable of reliably providing exact values for corneal lesion sizes. Additionally, three-dimensional modeling of the corneal surface is essential for an accurate measurement of lesion sizes. Besides telemedicine applications, this approach harbors great potential for clinical trials where exact quantitative and observer-independent measurements are essential.
Shock to Thrill: Linking Sensation and Information Seeking
2024-04-30

Sensation-seeking (SS) is characterised by a proclivity for intense experiences and disregard for potential aversive consequences. While SS is implicated as a vulnerability factor in various mental disorders, the underlying mechanisms remain elusive. Recent approaches propose an alternative perspective, suggesting that SS may be linked to highly explorative, and therefore risky, behaviours driven by a preference for informative environments. To probe this hypothesis, we reanalysed a dataset where participants chose to self-administer or avoid mild electric stimulation (MES) in an economic decision-making task. Contrary to previous interpretations associating higher sensation-seeking with the positive economic value of experiencing MES, Bayesian models of learning reveal an alternative account: sensation-seekers are more attuned to information about stimuli-shock contingencies. Specifically, high sensation-seeking individuals are less avoidant of information about the possibility of a shock, supporting the idea that sensation-seeking is linked to a preference for informative environments.
Testing two-step models of negative quantification using a novel machine learning analysis of EEG
2024-04-30

The sentences “<i>More than half</i> of the students passed the exam” and “<i>Fewer than half</i> of the students failed the exam” describe the same set of situations, and yet the former results in shorter reaction times in verification tasks. The two-step model explains this result by postulating that negative quantifiers contain hidden negation, which involves an extra processing stage. To test this theory, we applied a novel EEG analysis technique focused on detecting cognitive stages (HsMM-MVPA) to data from a picture-sentence verification task. We estimated the number of processing stages during reading and verification of quantified sentences (e.g. “<i>Fewer than half</i> of the dots are blue”) that followed the presentation of pictures containing coloured geometric shapes. We did not find evidence for an extra step during the verification of sentences with <i>fewer than half</i>. We provide an alternative interpretation of our results in line with an expectation-based pragmatic account.
Acid Resistance of Metakaolin-Based Geopolymers and Geopolymeric Mortars Reinforced with Coconut Fibers
2024-05-01

This paper investigates the durability of geopolymers and geopolymeric mortars made with metakaolin and alkaline activators, with and without a coconut fiber addition, after immersion for seven days into solutions of citric acid (1%, 2.5%, 5%, and 10%); hydrochloric acid (1%, 2.5%, 5%, and 10%); and sulfuric acid (1%, 2.5%, 5%, and 10%). The study focuses on mass changes, uniaxial compressive strength, flexural strength, and ultrasound pulse velocity measurements. X-ray diffraction and scanning electron microscopy are used to analyze the degradation products and microstructural changes. The aim is to assess the effect of acid exposure on the strength and stability of geopolymer materials and identify any protective effects of coconut fiber reinforcement. The samples are immersed in acid solutions of varying concentrations, and their mechanical properties are measured. The presence of coconut fibers slightly modifies the physical properties and the compressive strength, improving the mechanical flexural strength. Geopolymer and geopolymeric mortar materials experienced a weak decrease in strength when exposed to solutions of citric acid and a significant one when exposed to solutions of hydrochloric and sulfuric acids, attributed to depolymerization of the aluminosilicate binders. Brick waste geopolymeric mortars reinforced with coconut fibers showed the best performance in acid solutions with respect to geopolymers and quartz-rich sand geopolymeric mortars, suggesting a more stable cross-linked aluminosilicate geopolymer structure in this material.
Predicting and evaluating seasonal water turbidity in Lake Balkhash, Kazakhstan, using remote sensing and GIS
2024-05-01

Lake Balkhash is Asia’s third-largest lake and an endorheic basin. The lake and its contributing tributaries provide essential water and ecosystem services to the surrounding population, particularly in the Kazakh region. With approximately 2.5 million people living in the areas such as Almaty oblast, Zhetisu oblast, several districts of Karagandy oblast, and Abay province, monitoring and maintaining the lake’s health and water quality is essential for the sustainable management of water resources. The hydrology of Lake Balkhash has been significantly impacted in recent decades by a warming climate, landuse landcover changes, and water-consuming economic activities, the latter of which are driven by population growth and expansion. Turbidity—the measurement of water clarity—serves as a major indicator of water health. Here, we analyze spatial and temporal variability in turbidity across Lake Balkhash by mapping the normalized difference turbidity index (NDTI) based on Landsat data for 1991–2022. We consider major exploratory variables such as precipitation, near-surface temperature, wind speed and direction, water level, and landuse landcover (LULC) within the catchment. We find an overall decrease in turbidity over interannual and seasonal timescales. We observe significant negative correlations between NDTI, near-surface temperature, and water level at both scales but no clear relationship between turbidity and precipitation or wind variables. Among the LULC variables, grassland and bareland near Lake Balkhash showed a positive correlation with NDTI but have spatially decreased over time. Conversely, shrubland and wetland exhibit a negative correlation with NDTI; however, this has spatially increased with time. Our results highlight the significant impact of rising temperatures, anthropogenically influenced water levels, and the LULC variables on turbidity. The turbidity dynamics, in turn, influence the circulation, oxidation, and overall health of Lake Balkhash’s water. Therefore, the study emphasizes that the warming climate and alterations in the lake’s hydrology have a considerable impact on water quality. This suggests that monitoring water health alone may not suffice to mitigate the impacts of climate change and human activities. However, a more comprehensive approach is needed to sustainably manage and conserve dryland water resources.
Motor Intentions Decoded from fMRI Signals
2024-05-01

Motor intention is a high-level brain function related to planning for movement. Although studies have shown that motor intentions can be decoded from brain signals before movement execution, it was unclear whether intentions relating to mental imagery of movement could be decoded. Here, we investigated whether differences in spatial and temporal patterns of brain activation were elicited by intentions to perform different types of motor imagery and whether the patterns could be used by a multivariate pattern classifier to detect such differential intentions. The results showed that it is possible to decode intentions before the onset of different types of motor imagery from functional MR signals obtained from fronto-parietal brain regions, such as the premotor cortex and posterior parietal cortex, while controlling for eye movements and for muscular activity of the hands. These results highlight the critical role played by the aforementioned brain regions in covert motor intentions. Moreover, they have substantial implications for rehabilitating patients with motor disabilities.
A physiologically‐based pharmacokinetic precision dosing approach to manage dasatinib drug–drug interactions
2024-05-01

Abstract Dasatinib, a second‐generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH‐sensitive solubility, dasatinib is susceptible to enzyme‐mediated drug–drug interactions (DDIs) with CYP3A4 perpetrators and pH‐dependent DDIs with acid‐reducing agents. This work aimed to develop a whole‐body physiologically‐based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme‐mediated and pH‐dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration–time curve from the first to the last timepoint of measurement (AUC last ) and maximum plasma concentration ( C max ) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUC last and C max ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%–80% for strong and 0%–70% for moderate CYP3A4 inhibitors and a 2.3–3.1‐fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient‐related factors, such as elevated gastric pH.