julilili42/papers huggingface dataset:
Advancing Cancer Therapy Predictions with Patient-Derived Organoid Models of Metastatic Breast Cancer
2023-07-13

The poor outcome of metastasized breast cancer (BC) stresses the need for reliable personalized oncology and the significance of models recapitulating the heterogeneous nature of BC. Here, we cultured metastatic tumor cells derived from advanced BC patients with malignant ascites (MA) or malignant pleural effusion (MPE) using organoid technology. We identified the characteristics of tumor organoids by applying immunohistochemistry and mutation analysis. Tumor organoids preserved their expression patterns and hotspot mutations when compared to their original metastatic counterpart and are consequently a well-suited in vitro model for metastasized BC. We treated the tumor organoids to implement a reliable application for drug screenings of metastasized cells. Drug assays revealed that responses are not always in accord with expression patterns, pathway activation, and hotspot mutations. The discrepancy between characterization and functional testing underlines the relevance of linking IHC stainings and mutational analysis of metastasized BC with in vitro drug assays. Our metastatic BC organoids recapitulate the characteristics of their original sample derived from MA and MPE and serve as an invaluable tool that can be utilized in a preclinical setting for guiding therapy decisions.
Adult lifespan trajectories of neuromagnetic signals and interrelations with cortical thickness
2023-07-13

Oscillatory power and phase synchronization map neuronal dynamics and are commonly studied to differentiate the healthy and diseased brain. Yet, little is known about the course and spatial variability of these features from early adulthood into old age. Leveraging magnetoencephalography (MEG) resting-state data in a cross-sectional adult sample (n = 350), we probed lifespan differences (18-88 years) in connectivity and power and interaction effects with sex. Building upon recent attempts to link brain structure and function, we tested the spatial correspondence between age effects on cortical thickness and those on functional networks. We further probed a direct structure-function relationship at the level of the study sample. We found MEG frequency-specific patterns with age and divergence between sexes in low frequencies. Connectivity and power exhibited distinct linear trajectories or turning points at midlife that might reflect different physiological processes. In the delta and beta bands, these age effects corresponded to those on cortical thickness, pointing to co-variation between the modalities across the lifespan. Structure-function coupling was frequency-dependent and observed in unimodal or multimodal regions. Altogether, we provide a comprehensive overview of the topographic functional profile of adulthood that can form a basis for neurocognitive and clinical investigations. This study further sheds new light on how the brain's structural architecture relates to fast oscillatory activity.
An extinct deep-snouted Alligator species from the Quaternary of Thailand and comments on the evolution of crushing dentition in alligatorids
2023-07-13

Abstract Fossil Alligator remains from Asia are critical for tracing the enigmatic evolutionary origin of the Chinese alligator, Alligator sinensis , the only living representative of Alligatoridae outside the New World. The Asian fossil record is extremely scarce and it remains unknown whether A. sinensis is an anagenetic lineage or alternatively, extinct divergent species were once present. We provide a detailed comparative description of a morphologically highly distinct Alligator skull from the Quaternary of Thailand. Several autapomorphic characters warrant the designation of a new species. Alligator munensis sp. nov. shares obvious derived features with A. sinensis but autapomorphies imply a cladogenetic split, possibly driven by the uplift of the southeastern Tibetan plateau. The presence of enlarged posterior alveoli in Alligator munensis is most consistent with a reversal to the alligatorine ancestral condition of having crushing dentition, a morphology strikingly absent among living alligatorids. Crushing dentition has been previously considered to indicate an ecological specialisation in early alligatorines that was subsequently lost in Alligator spp . However, we argue that there is yet no evidence for crushing dentition reflecting an adaptation for a narrower niche, while opportunistic feeding, including seasonal utilisation of hard-shelled preys, is a reasonable alternative interpretation of its function.
Modest Effects of Osteoclast‐Specific ERα Deletion after Skeletal Maturity
2023-07-13

ABSTRACT Estrogen regulates bone mass in women and men, but the underlying cellular mechanisms of estrogen action on bone remain unclear. Although both estrogen receptor (ER)α and ERβ are expressed in bone cells, ERα is the dominant receptor for skeletal estrogen action. Previous studies using either global or cell‐specific ERα deletion provided important insights, but each of these approaches had limitations. Specifically, either high circulating sex steroid levels in global ERα knockout mice or the effects of deletion of ERα during growth and development in constitutive cell‐specific knockout mice have made it difficult to clearly define the role of ERα in specific cell types in the adult skeleton. We recently generated and characterized mice with tamoxifen‐inducible ERα deletion in osteocytes driven by the 8‐kb Dmp1 promoter (ERαΔOcy mice), revealing detrimental effects of osteocyte‐specific ERα deletion on trabecular bone volume (−20.1%) and bone formation rate (−18.9%) in female, but not male, mice. Here, we developed and characterized analogous mice with inducible ERα deletion in osteoclasts using the Cathepsin K promoter (ERαΔOcl mice). In a study design identical to that with the previously described ERαΔOcy mice, adult female, but not male, ERαΔOcl mice showed a borderline (−10.2%, p = 0.084) reduction in trabecular bone volume, no change in osteoclast numbers, but a significant increase in serum CTx levels, consistent with increased osteoclast activity. These findings in ERαΔOcl mice differ from previous studies of constitutive osteoclast‐specific ERα deletion, which led to clear deficits in trabecular bone and increased osteoclast numbers. Collectively, these data indicate that in adult mice, estrogen action in the osteocyte is likely more important than via the osteoclast and that ERα deletion in osteoclasts from conception onward has more dramatic skeletal effects than inducible osteoclastic ERα deletion in adult mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Using Computational Models to Understand the Role and Nature of Valuation Bias in Mixed Gambles
2023-07-13

It is a well-known observation that people tend to dislike risky situations that could potentially lead to a loss, a phenomenon that is called loss aversion. This is often explained using valuation bias, i.e., the subjective value of losses is larger than the subjective value of gains of equal magnitude. However, recent studies using the drift-diffusion model have shown that a pre-valuation bias towards rejection is also a primary determinant of loss-averse behavior. It has large contributions to model fits, predicts a key relationship between rejection rates and response times, and explains the most individual heterogeneity in the rejection rates of participants. We analyzed data from three previously published experiments using the drift-diffusion model and found that these findings generalize to them. However, we found that valuation bias plays the most important role in predicting how likely a person is to accept a given gamble. Our findings also showed that a person's loss aversion parameter, which captures their propensity to avoid losses is closely related to valuation bias. These results combined highlight the importance of valuation bias in understanding people's choice patterns. Finally, using the leaky, competing accumulator model, we show strong mimicking between valuation bias and an attentional bias wherein people pay more attention to losses as compared to gains. This finding suggests that behaviors that seem to arise due to valuation bias may arise due to such an attentional bias.
Collective nouns are conceptually plural: Evidence from the grammatical SNARC effect.
2023-07-13

To develop theories of how comprehenders extract the message from a linguistic stream, it is critical to understand how they conceptually represent referents. The experiments reported here focus on singular collective nouns (e.g., <i>committee, team</i>), which introduce a single group into the discourse and test whether they nonetheless are conceptually plural (i.e., construed as consisting of multiple entities) by using the spatial-numerical association of response codes (SNARC) paradigm (Dehaene & Changeux, 1993). In this paradigm, participants are typically faster to respond to smaller numbers or numerical stimuli when making a response on their left and faster to respond to larger numbers or numerical stimuli when making a response on their right. In three experiments, participants saw German words on a computer screen and decided whether each one described a single entity or something that could be subdivided into multiple entities (Experiment 1) or whether they would use "ist" or "sind" ("is" or "are") in combination with the word if it were the subject of a sentence (Experiments 2 and 3). The mapping of responses to participants' left and right hands was counterbalanced. Experiment 1 failed to show a grammatical SNARC effect. Experiments 2 and 3 showed a grammatical SNARC effect that extended to collective noun phrases. The results of these experiments suggest that collective noun phrases are instantiated as conceptually plural in comprehenders' minds. We discuss the differential task effects and the implications of these data on theories of language comprehension. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Margaret MacDonald's scientific common- sense philosophy
2023-07-13

Margaret MacDonald (1907-1956) was a central figure in the history of early analytic philosophy in Britain due to both her editorial work as well as her own writings.While her later work on aesthetics and political philosophy has lately received attention, her early writings in the 1930s present a coherent and, for its time, strikingly original blend of common-sense and scientific philosophy.In these papers, MacDonald tackles central problems of philosophy of her day: verification, the problem of induction, and the relationship between philosophical and scientific method.MacDonald's philosophy of science starts from the principle that we should carefully analyze the elements of scientific practice (particularly its temporal features) and the ways that scientists describe that practice.That is, she applies the techniques of ordinary language philosophy on actual scientific language.MacDonald shows how "scientific common-sense" is inconsistent with both of the dominant schools of philosophy of her day.Bringing MacDonald back into the story of analytic philosophy corrects the impression that in early analytic philosophy, there are fundamental dichotomies between the style of Moore and Wittgenstein, on the one hand, and the Vienna Circle on the other.
Emergence of Hydrodynamic Spatial Long-Range Correlations in Nonequilibrium Many-Body Systems
2023-07-14

At large scales of space and time, the nonequilibrium dynamics of local observables in extensive many-body systems is well described by hydrodynamics. At the Euler scale, one assumes that each mesoscopic region independently reaches a state of maximal entropy under the constraints given by the available conservation laws. Away from phase transitions, maximal entropy states show exponential correlation decay, and independence of fluid cells might be assumed to subsist during the course of time evolution. We show that this picture is incorrect: under ballistic scaling, regions separated by macroscopic distances "develop long-range correlations as time passes." These correlations take a universal form that only depends on the Euler hydrodynamics of the model. They are rooted in the large-scale motion of interacting fluid modes and are the dominant long-range correlations developing in time from long-wavelength, entropy-maximized states. They require "the presence of interaction" and "at least two different fluid modes" and are of a fundamentally different nature from well-known long-range correlations occurring from diffusive spreading or from quasiparticle excitations produced in far-from-equilibrium quenches. We provide a universal theoretical framework to exactly evaluate them, an adaptation of the macroscopic fluctuation theory to the Euler scale. We verify our exact predictions in the hard-rod gas, by comparing with numerical simulations and finding excellent agreement.
Massless Dirac perturbations in a consistent model of loop quantum gravity black hole: quasinormal modes and particle emission rates
2023-07-14

Abstract We consider perturbations of the massless Dirac field in the background of a black hole solution found by Bodendorfer, Mele, and Münch (BMM), using a polymerization technique that furnishes contributions inspired by loop quantum gravity (LQG) Theory. Using the sixth order WKB method, we analyzed its quasinormal modes for several modes, multipole numbers and the two classes of BMM black holes. We also considered the potential that governs these perturbations to analyze the bound on the greybody factor (GF) due the emission rates of particles. As results, we found that the LQG parameters are responsible for raising the potential and the real and imaginary parts of the quasinormal frequencies and decrease the bound on the GF for the two classes of black holes (with more prominent effects for the de-amplification case, which is compatible with previous analyses done for other fields).
Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel
2023-07-14

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Simultaneous Detection of Different Antibody Classes in a Multiplexed Serological Test
2023-07-14

To monitor the progression of infectious diseases, it is useful to assess immunoreactivity against various antigenic determinants, and measure different antibody isotypes because they appear at different stages of the host immune response. With Lyme borreliosis, the pathogenic agent can be one of the multiple members of the Borrelia species. Therefore, correct sample classification requires evaluating the immunoreactivity against different antigens of different Borrelia species. Additionally, anti-pathogen IgG and IgM responses can have different elicitation time courses during disease progression. Here we demonstrate the development of a two-reporter multiplex immunoassay that has utility in identifying Borrelia-specific immune response in human serum samples by simultaneously evaluating both IgG and IgM immunoreactivity against different bacterial antigens in the same reaction well. This dual-reporter approach retains the analytical performance of single-reporter methods while conserving time and resources and reducing sample size requirements. This assay allows essentially double the serological information to be generated from a blood sample in half the time.
The Lipid Phosphate Phosphatase Wunen Promotes Eggshell Formation and Is Essential for Fertility in Drosophila
2023-07-14

The eggshell that surrounds insect eggs acts as a barrier, protecting against biotic factors and desiccation. The eggshell is a multi-layered structure which is synthesised by the somatic follicle cells that surround the developing oocyte. Although the temporal order of expression of the protein eggshell components goes someway to explaining how the different layers are built up, but how the precise three-dimensional structure is achieved and how lipid components responsible for desiccation resistance are incorporated are poorly understood. In this paper, we demonstrate that wunen, which encodes a lipid phosphate phosphatase, is necessary for fertility in Drosophila females. Compared to sibling controls, females null for wunen lay fewer eggs which subsequently collapse such that no larvae emerge. We show that this is due to a requirement for wunen in the ovarian follicle cells which is needed to produce an ordered and functional eggshell. Knockdown of a septate junction component also results in collapsed eggs, supporting the idea that similar to its role in embryonic tracheal development, Wunen in follicle cells also promotes septate junction function.
Lost in translation: the pitfalls of Ensembl gene annotations between human genome assemblies and their impact on diagnostics
2023-07-14

For discrepant genes, the inaccurate label of 'non-protein-coding' has relevant ramifications on clinical genetics. Accurate collation of these genes allows for manual curation in clinically relevant scenarios.
SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission
2023-07-15

Abstract SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3− uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes ‘slit-like’ lateral ventricles and corpus callosum abnormalities. Slc4a10 −/− mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10−/− mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10−/− mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10−/− mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.
Comparison of Live and Remote Video Ratings of the Scale for Assessment and Rating of Ataxia
2023-07-15

Abstract Background Video recordings of neurological examinations are often used in clinical trials. The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale for ataxic patients. Despite several advantages of video ratings, correlation between live ratings and remote video‐ratings has not been systematically investigated. Objective To compare live and remote video assessment of SARA. Methods Full SARA examinations of 69 patients with cerebellar ataxia were recorded on video. Live rating from site investigators were compared with remote video rating of three experienced ataxia clinicians using Bland–Altman analysis. Results Live and remote video ratings showed a high level of agreement for the complete score (bias = 0.09, with standard deviation = 2.00) and all single SARA items (bias &lt;0.20 for all items). Conclusion Remote video ratings of SARA are a reliable means to assess severity of ataxia.
Mirroring Mediterraneanization: Pottery production at Archaic Monte Iato, Western Sicily (6th to 5th century BCE)
2023-07-15

With a total of 162 samples, one of the most extensive NAA sample series from one single inland settlement in Archaic Sicily is now available to address long debated issues about the impact of the so called 'Greek Colonization' on local pottery production. In a previous series, a wide range of wares manufactured on site could be determined, ranging from traditional style incised and stamped vessels via matt painted ceramics of regional style to Greek style pottery. The second series presented here was intended to extend and deepen the results obtained and to investigate the variability of the potter's responses to new challenges and demands in the course of Monte Iato's changing indigenous society. These responses were found to present even greater variance than expected before, fitting the overall picture of the site's increasing integration into Mediterranean networks.