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The time instant-the first-passage time (FPT)-when a diffusive particle (e.g., a ligand such as oxygen or a signalling protein) for the first time reaches an immobile target located on the surface of a bounded three-dimensional domain (e.g., a hemoglobin molecule or the cellular nucleus) is a decisive characteristic time-scale in diverse biophysical and biochemical processes, as well as in intermediate stages of various inter- and intra-cellular signal transduction pathways. Adam and Delbruck put forth the reduction-of-dimensionality concept, according to which a ligand first binds non-specifically to any point of the surface on which the target is placed and then diffuses along this surface until it locates the target. In this work, we analyse the efficiency of such a scenario and confront it with the efficiency of a direct search process, in which the target is approached directly from the bulk and not aided by surface diffusion. We consider two situations: (i) a single ligand is launched from a fixed or a random position and searches for the target, and (ii) the case of 'amplified' signals when N ligands start either from the same point or from random positions, and the search terminates when the fastest of them arrives to the target. For such settings, we go beyond the conventional analyses, which compare only the mean values of the corresponding FPTs. Instead, we calculate the full probability density function of FPTs for both scenarios and study its integral characteristic-the 'survival' probability of a target up to time t. On this basis, we examine how the efficiencies of both scenarios are controlled by a variety of parameters and single out realistic conditions in which the reduction-of-dimensionality scenario outperforms the direct search.
Marine sedimentary archives are routinely used to reconstruct past environmental changes. In many cases, bioturbation and sedimentary mixing affect the proxy time-series and the age-depth relationship. While idealized models of bioturbation exist, they usually assume homogeneous mixing, thus that a single sample is representative for the sediment layer it is sampled from.
However, it is largely unknown to which extent this assumption holds for sediments used for paleoclimate reconstructions.
To shed light on
1) the age-depth relationship and its full uncertainty,
2) the magnitude of mixing processes affecting the downcore proxy variations, and
3) the representativity of the discrete sample for the sediment layer, we designed and performed a case study on South China Sea sediment material which was collected using a box corer and which covers the last glacial cycle.
Using the radiocarbon content of foraminiferal tests as a tracer of time, we characterize the spatial age-heterogeneity of sediments in a three-dimensional setup. In total, 118 radiocarbon measurements were performed on defined small- and large-volume bulk samples ( similar to 200 specimens each) to investigate the horizontal heterogeneity of the sediment. Additionally, replicated measurements on small numbers of specimens (10 x 5 specimens) were performed to assess the heterogeneity within a sample volume. Visual assessment of X-ray images and a quantitative assessment of the mixing strength show typical mixing from bioturbation corresponding to around 10 cm mixing depth.
Notably, our 3D radiocarbon distribution reveals that the horizontal heterogeneity (up to 1,250 years), contributing to the age uncertainty, is several times larger than the typically assumed radiocarbon based age-model error (single errors up to 250 years). Furthermore, the assumption of a perfectly bioturbated layer with no mixing underneath is not met.
Our analysis further demonstrates that the age-heterogeneity might be a function of sample size; smaller samples might contain single features from the incomplete mixing and are thus less representative than larger samples.
We provide suggestions for future studies, optimal sampling strategies for quantitative paleoclimate reconstructions and realistic uncertainty in age models, as well as discuss possible implications for the interpretation of paleoclimate records.
In this study we present a novel method for the automatic detection of minerals and elements using hyperspectral transmittance imaging microscopy measurements of complete thin sections (HyperTIM).
This is accomplished by using a hyperspectral camera system that operates in the visible and near-infrared (VNIR) range with a specifically designed sample holder, scanning setup, and a microscope lens.
We utilize this method on a monazite ore thin section from Steenkampskraal (South Africa), which we analyzed for the rare earth element (REE)-bearing mineral monazite ((Ce,Nd,La)PO4), with high concentrations of Nd. The transmittance analyses with the hyperspectral VNIR camera can be used to identify REE minerals and Nd in thin sections.
We propose a three-point band depth index, the Nd feature depth index (NdFD), and its related product the Nd band depth index (NdBDI), which enables automatic mineral detection and classification for the Nd-bearing monazites in thin sections. In combination with the average concentration of the relative Nd content, it permits a destruction-free, total concentration calculation for Nd across the entire thin section.
Background
Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes.
It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes.
We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops.
Methods
Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years).
Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression.
Results
In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints).
Conclusions
Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.
Food preferences are crucial for diet-related decisions, which substantially impact individual health and global climate. However, the persistence of unfavorable food preferences is a significant obstacle to changing eating behavior.
Here we explored the effects of posthypnotic suggestions (PHS) on food-related decisions by measuring food choices, subjective ratings, and indifference points. In Session 1, demographic data and hypnotic susceptibility of participants were assessed. In Session 2, following hypnosis induction, PHS aiming to increase the desirability of healthy food was delivered.
Afterward, a task set was administrated twice, once when PHS was activated and once deactivated. The order of PHS activation was counterbalanced across participants. The task set included a liking-rating task for 170 pictures of different food items, followed by an online supermarket where participants were instructed to select enough food for a fictitious week of quarantining from the same item pool. After 1 week, Session 3 repeated Session 2 without hypnosis induction in order to assess the persistence of PHS.
The crucial dependent measures were food choices, subjective ratings, and the indifference points as a function of time and PHS condition.
Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling.
Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations.
In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions.
In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.
LegacyPollen 1.0
(2022)
Here we describe the LegacyPollen 1.0, a dataset of 2831 fossil pollen records with metadata, a harmonized taxonomy, and standardized chronologies.
A total of 1032 records originate from North America, 1075 from Europe, 488 from Asia, 150 from Latin America, 54 from Africa, and 32 from the Indo-Pacific.
The pollen data cover the late Quaternary (mostly the Holocene). The original 10 110 pollen taxa names (including variations in the notations) were harmonized to 1002 terrestrial taxa (including Cyperaceae), with woody taxa and major herbaceous taxa harmonized to genus level and other herbaceous taxa to family level.
The dataset is valuable for synthesis studies of, for example, taxa areal changes, vegetation dynamics, human impacts (e.g., deforestation), and climate change at global or continental scales.
The harmonized pollen and metadata as well as the harmonization table are available from PANGAEA (https://doi.org/10.1594/PANGAEA.929773; Herzschuh et al., 2021). R code for the harmonization is provided at Zenodo (https://doi.org/10.5281/zenodo.5910972; Herzschuh et al., 2022) so that datasets at a customized harmonization level can be easily established.
Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes.
Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described.
However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients.
Eleven myasthenia gravis patients (age: 70.64 +/- 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 +/- 8.98; 11 males). Most of the patients (n = 10, 0.91%) received cholinesterase inhibitors.
Structural brain changes were determined by applying voxel-based morphometry using high-resolution T-1-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels.
Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, P = 0.034, d = 1.466), verbal episodic memory (P = 0.003, d = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, P = 0.003, d = 1.200).
Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (P = 0.001, d = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions.
Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.
Klaus et al. compared myasthenia gravis patients to matched healthy control subjects and identified functional alterations in memory functions as well as structural alterations in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus.
We argue for a perspective on bilingual heritage speakers as native speakers of both their languages and present results from a large-scale, cross-linguistic study that took such a perspective and approached bilinguals and monolinguals on equal grounds.
We targeted comparable language use in bilingual and monolingual speakers, crucially covering broader repertoires than just formal language. A main database was the open-access RUEG corpus, which covers comparable informal vs. formal and spoken vs. written productions by adolescent and adult bilinguals with heritage-Greek, -Russian, and -Turkish in Germany and the United States and with heritage-German in the United States, and matching data from monolinguals in Germany, the United States, Greece, Russia, and Turkey. Our main results lie in three areas.
(1) We found non-canonical patterns not only in bilingual, but also in monolingual speakers, including patterns that have so far been considered absent from native grammars, in domains of morphology, syntax, intonation, and pragmatics.
(2) We found a degree of lexical and morphosyntactic inter-speaker variability in monolinguals that was sometimes higher than that of bilinguals, further challenging the model of the streamlined native speaker.
(3) In majority language use, non-canonical patterns were dominant in spoken and/or informal registers, and this was true for monolinguals and bilinguals. In some cases, bilingual speakers were leading quantitatively. In heritage settings where the language was not part of formal schooling, we found tendencies of register leveling, presumably due to the fact that speakers had limited access to formal registers of the heritage language.
Our findings thus indicate possible quantitative differences and different register distributions rather than distinct grammatical patterns in bilingual and monolingual speakers. This supports the integration of heritage speakers into the native-speaker continuum. Approaching heritage speakers from this perspective helps us to better understand the empirical data and can shed light on language variation and change in native grammars.
Furthermore, our findings for monolinguals lead us to reconsider the state-of-the art on majority languages, given recurring evidence for non-canonical patterns that deviate from what has been assumed in the literature so far, and might have been attributed to bilingualism had we not included informal and spoken registers in monolinguals and bilinguals alike.
The present study proposes and tests pathways by which racial discrimination might be positively related to bullying victimization among Black and White adolescents. Data were derived from the 2016 National Survey of Children's Health, a national survey that provides data on children's physical and mental health and their families. Data were collected from households with one or more children between June 2016 to February 2017.
A letter was sent to randomly selected households, who were invited to participate in the survey. The caregivers consisted of 66.9% females and 33.1% males for the White sample, whose mean age was 47.51 (SD = 7.26), and 76.8% females and 23.2% males for the Black sample, whose mean age was 47.61 (SD = 9.71).
In terms of the adolescents, 49.0% were females among the White sample, whose mean age was 14.73 (SD = 1.69). For Black adolescents, 47.9% were females and the mean age was 14.67(SD = 1.66).
Measures for the study included bullying perpetration, racial discrimination, academic disengagement, and socio-demographic variables of the parent and child.
Analyses included descriptive statistics, bivariate correlations, and structural path analyses.
For adolescents in both racial groups, racial discrimination appears to be positively associated with depression, which was positively associated with bullying perpetration. For White adolescents, racial discrimination was positively associated with academic disengagement, which was also positively associated with bullying perpetration. For Black adolescents, although racial discrimination was not significantly associated with academic disengagement, academic disengagement was positively associated with bullying perpetration.
High annotation costs are a substantial bottleneck in applying deep learning architectures to clinically relevant use cases, substantiating the need for algorithms to learn from unlabeled data.
In this work, we propose employing self-supervised methods. To that end, we trained with three self-supervised algorithms on a large corpus of unlabeled dental images, which contained 38K bitewing radiographs (BWRs). We then applied the learned neural network representations on tooth-level dental caries classification, for which we utilized labels extracted from electronic health records (EHRs). Finally, a holdout test-set was established, which consisted of 343 BWRs and was annotated by three dental professionals and approved by a senior dentist.
This test-set was used to evaluate the fine-tuned caries classification models. Our experimental results demonstrate the obtained gains by pretraining models using self-supervised algorithms. These include improved caries classification performance (6 p.p. increase in sensitivity) and, most importantly, improved label-efficiency.
In other words, the resulting models can be fine-tuned using few labels (annotations).
Our results show that using as few as 18 annotations can produce >= 45% sensitivity, which is comparable to human-level diagnostic performance.
This study shows that self-supervision can provide gains in medical image analysis, particularly when obtaining labels is costly and expensive.
From victims to activists
(2022)
Stimulus data and experimental design for a self-paced reading study on emoji-word substitutions
(2022)
This data paper presents the experimental design and stimuli from an online self-paced reading study on the processing of emojis substituting lexically ambiguous nouns. We recorded reading times for the target ambiguous nouns and for emojis depicting either the intended target referent or a contextually inappropriate homophonous noun. Furthermore, we recorded comprehension accuracy, demographics and a self-assessment of the participants' emoji usage frequency. The data includes all stimuli used, the raw data, the full JavaScript code for the online experiment, as well as Python and R code for the data analysis. We believe that our dataset may give important insights related to the comprehension mechanisms involved in the cognitive processing of emojis. For interpretation and discussion of the experiment, please see the original article entitled "The processing of emoji-word substitutions: A self-paced-reading study".
Landslides in deglaciated and deglaciating mountains represent a major hazard, but their distribution at the spatial scale of entire mountain belts has rarely been studied. Traditional models of landslide distribution assume that landslides are concentrated in the steepest, wettest, and most tectonically active parts of the orogens, where glaciers reached their greatest thickness.
However, based on mapping large landslides (>0.9 km(2)) over an unprecedentedly large area of Southern Patagonia (similar to 305,000 km(2)), we show that the distribution of landslides can have the opposite trend.
We show that the largest landslides within the limits of the former Patagonian Ice Sheet (PIS) cluster along its eastern margins occupying lower, tectonically less active, and arid part of the Patagonian Andes. In contrast to the heavily glaciated, highest elevations of the mountain range, the peripheral regions have been glaciated only episodically, leaving a larger volume of unstable sedimentary and volcanic rocks that are subject to ongoing slope instability.
Incorporation of noncanonical amino acids (ncAAs) with bioorthogonal reactive groups by amber suppression allows the generation of synthetic proteins with desired novel properties. Such modified molecules are in high demand for basic research and therapeutic applications such as cancer treatment and in vivo imaging. The positioning of the ncAA-responsive codon within the protein's coding sequence is critical in order to maintain protein function, achieve high yields of ncAA-containing protein, and allow effective conjugation. Cell-free ncAA incorporation is of particular interest due to the open nature of cell-free systems and their concurrent ease of manipulation. In this study, we report a straightforward workflow to inquire ncAA positions in regard to incorporation efficiency and protein functionality in a Chinese hamster ovary (CHO) cell-free system. As a model, the well-established orthogonal translation components Escherichia coli tyrosyl-tRNA synthetase (TyrRS) and tRNATyr(CUA) were used to site-specifically incorporate the ncAA p-azido-l-phenylalanine (AzF) in response to UAG codons. A total of seven ncAA sites within an anti-epidermal growth factor receptor (EGFR) single-chain variable fragment (scFv) N-terminally fused to the red fluorescent protein mRFP1 and C-terminally fused to the green fluorescent protein sfGFP were investigated for ncAA incorporation efficiency and impact on antigen binding. The characterized cell-free dual fluorescence reporter system allows screening for ncAA incorporation sites with high incorporation efficiency that maintain protein activity. It is parallelizable, scalable, and easy to operate. We propose that the established CHO-based cell-free dual fluorescence reporter system can be of particular interest for the development of antibody-drug conjugates (ADCs).
The benefits of counting butterflies: recommendations for a successful citizen science project
(2022)
Citizen science (CS) projects, being popular across many fields of science, have recently also become a popular tool to collect biodiversity data. Although the benefits of such projects for science and policy making are well understood, relatively little is known about the benefits participants get from these projects as well as their personal backgrounds and motivations. Furthermore, very little is known about their expectations. We here examine these aspects, with the citizen science project "German Butterfly Monitoring" as an example. A questionnaire was sent to all participants of the project and the responses to the questionnaire indicated the following: center dot Most transect walkers do not have a professional background in this field, though they do have a high educational level, and are close to retirement, with a high number of females; center dot An important motivation to join the project is to preserve the natural environment and to contribute to scientific knowledge; center dot Participants benefit by enhancing their knowledge about butterflies and especially their ability to identify different species (taxonomic knowledge); center dot Participants do not have specific expectations regarding the project beyond proper management and coordination, but have an intrinsic sense of working for a greater good. The willingness to join a project is higher if the project contributes to the solution of a problem discussed in the media (here, insect decline). Based on our findings from the analysis of the questionnaire we can derive a set of recommendations for establishing a successful CS project. These include the importance of good communication, e.g., by explaining what the (scientific) purpose of the project is and what problems are to be solved with the help of the data collected in the project. The motivation to join a CS project is mostly intrinsic and CS is a good tool to engage people during difficult times such as the COVID-19 pandemic, giving participants the feeling of doing something useful.
In this paper, we employ an experimental paradigm using insights from the psychology of reasoning to investigate the question whether certain modals generate and draw attention to alternatives. The article extends and builds on the methodology and findings of Mascarenhas & Picat (2019). Based on experimental results, they argue that the English epistemic modal might raises alternatives. We apply the same methodology to the English modal allowed to to test different hypotheses regarding the involvement of alternatives in deontic modality. We find commonalities and differences between the two modals we tested. We discuss theoretical consequences for existing semantic analyses of these modals, and argue that reasoning tasks can serve as a diagnostic tool to discover which natural language expressions involve alternatives.
So far, various studies have aimed at decomposing the integrated terrestrial water storage variations observed by satellite gravimetry (GRACE, GRACE-FO) with the help of large-scale hydrological models. While the results of the storage decomposition depend on model structure, little attention has been given to the impact of the way that vegetation is represented in these models. Although vegetation structure and activity represent the crucial link between water, carbon, and energy cycles, their representation in large-scale hydrological models remains a major source of uncertainty. At the same time, the increasing availability and quality of Earth-observation-based vegetation data provide valuable information with good prospects for improving model simulations and gaining better insights into the role of vegetation within the global water cycle. In this study, we use observation-based vegetation information such as vegetation indices and rooting depths for spatializing the parameters of a simple global hydrological model to define infiltration, root water uptake, and transpiration processes. The parameters are further constrained by considering observations of terrestrial water storage anomalies (TWS), soil moisture, evapotranspiration (ET) and gridded runoff ( Q) estimates in a multi-criteria calibration approach. We assess the implications of including varying vegetation characteristics on the simulation results, with a particular focus on the partitioning between water storage components. To isolate the effect of vegetation, we compare a model experiment in which vegetation parameters vary in space and time to a baseline experiment in which all parameters are calibrated as static, globally uniform values. Both experiments show good overall performance, but explicitly including varying vegetation data leads to even better performance and more physically plausible parameter values. The largest improvements regarding TWS and ET are seen in supply-limited (semi-arid) regions and in the tropics, whereas Q simulations improve mainly in northern latitudes. While the total fluxes and storages are similar, accounting for vegetation substantially changes the contributions of different soil water storage components to the TWS variations. This suggests an important role of the representation of vegetation in hydrological models for interpreting TWS variations. Our simulations further indicate a major effect of deeper moisture storages and groundwater-soil moisture-vegetation interactions as a key to understanding TWS variations. We highlight the need for further observations to identify the adequate model structure rather than only model parameters for a reasonable representation and interpretation of vegetation-water interactions.
We study the first-arrival (first-hitting) dynamics and efficiency of a one-dimensional random search model performing asymmetric Levy flights by leveraging the Fokker-Planck equation with a delta-sink and an asymmetric space-fractional derivative operator with stable index alpha and asymmetry (skewness) parameter beta.
We find exact analytical results for the probability density of first-arrival times and the search efficiency, and we analyse their behaviour within the limits of short and long times.
We find that when the starting point of the searcher is to the right of the target, random search by Brownian motion is more efficient than Levy flights with beta <= 0 (with a rightward bias) for short initial distances, while for beta>0 (with a leftward bias) Levy flights with alpha -> 1 are more efficient.
When increasing the initial distance of the searcher to the target, Levy flight search (except for alpha=1 with beta=0) is more efficient than the Brownian search. Moreover, the asymmetry in jumps leads to essentially higher efficiency of the Levy search compared to symmetric Levy flights at both short and long distances, and the effect is more pronounced for stable indices alpha close to unity.