Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of a coupled simulation toolkit for computational radiation biology based on Geant4 and CompuCell3D

Understanding and designing clinical radiation therapy is one of the most important areas of state-of-the-art oncological treatment regimens. Decades of research have gone into developing sophisticated treatment devices and optimization protocols for schedules and dosages. In this paper, we presented a comprehensive computational platform that facilitates building of the sophisticated multi-cell-based model of how radiation affects the biology of living tissue. We designed and implemented a coupled simulation method, including a radiation transport model, and a cell biology model, to simulate the tumor response after irradiation. The radiation transport simulation was implemented through Geant4 which is an open-source Monte Carlo simulation platform that provides many flexibilities for users, as well as low energy DNA damage simulation physics, Geant4-DNA. The cell biology simulation was implemented using CompuCell3D (CC3D) which is a cell biology simulation platform. In order to couple Geant4 solver with CC3D, we developed a ‘bridging’ module, RADCELL, that extracts tumor cellular geometry of the CC3D simulation (including specification of the individual cells) and ported it to the Geant4 for radiation transport simulation. The cell dose and cell DNA damage distribution in multicellular system were obtained using Geant4. The tumor response was simulated using cell-based tissue models based on CC3D, and the cell dose and cell DNA damage information were fed back through RADCELL to CC3D for updating the cell properties. By merging two powerful and widely used modeling platforms, CC3D and Geant4, we delivered a novel tool that can give us the ability to simulate the dynamics of biological tissue in the presence of ionizing radiation, which provides a framework for quantifying the biological consequences of radiation therapy. In this introductory methods paper, we described our modeling platform in detail and showed how it can be applied to study the application of radiotherapy to a vascularized tumor.
On the role of transcription in positioning nucleosomes

Nucleosome positioning is crucial for the genome’s function. Though the role of DNA sequence in positioning nucleosomes is well understood, a unified framework for studying the impact of transcription remains lacking. Using numerical simulations, we investigated the dependence of nucleosome density profiles on transcription level across multiple species. We found that the low nucleosome affinity of yeast, but not mouse, promoters contributes to the formation of phased nucleosomes arrays for inactive genes. For the active genes, a tug-of-war between two types of remodeling enzymes is essential for reproducing their density profiles. In particular, while ISW2 related enzymes are known to position the +1 nucleosome and align it toward the transcription start site (TSS), enzymes such as ISW1 that use a pair of nucleosomes as their substrate can shift the nucleosome array away from the TSS. Competition between these enzymes results in two types of nucleosome density profiles with well- and ill-positioned +1 nucleosome. Finally, we showed that Pol II assisted histone exchange, if occurring at a fast speed, can abolish the impact of remodeling enzymes. By elucidating the role of individual factors, our study reconciles the seemingly conflicting results on the overall impact of transcription in positioning nucleosomes across species.
XAB2 prevents abortive recombinational repair of replication-associated DNA double-strand breaks and its loss is synthetic lethal with RAD52 inhibition

Unrepaired O6-methylguanine lesions induced by the alkylating chemotherapy agent temozolomide lead to replication-associated single-ended DNA double-strand breaks (seDSBs) that are repaired predominantly through RAD51-mediated homologous recombination (HR). Here, we show that loss of the pre-mRNA splicing and DNA repair protein XAB2 leads to increased temozolomide sensitivity in glioblastoma cells, which reflects abortive HR due to Ku retention on resected seDSBs. XAB2-dependent Ku eviction also occurred at seDSBs generated by the topoisomerase I poison campthotecin and operated in parallel to an ATM-dependent pathway previously described. Although Ku retention elicited by loss of XAB2 did not prevent RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased engagement of non-homologous-end-joining in S/G2 and genetic instability. Overexpression of RAD51 or the single-stranded DNA annealing factor RAD52 rescued the XAB2 defects. RAD52 depletion led to severe temozolomide sensitivity, whereas a synthetic lethality interaction was observed between RAD52 and XAB2.
Cognitive Capacity Limits Are Remediated by Practice-Induced Plasticity between the Putamen and Pre-Supplementary Motor Area

Humans show striking limitations in information processing when multitasking, yet can modify these limits with practice. Such limitations have been linked to a frontal-parietal network, but recent models of decision-making implicate a striatal-cortical network. We adjudicated these accounts by investigating the circuitry underpinning multitasking in 100 individuals and the plasticity caused by practice. We observed that multitasking costs, and their practice induced remediation, are best explained by modulations in information transfer between the striatum and the cortical areas that represent stimulus-response mappings. Specifically, our results support the view that multitasking stems at least in part from taxation in information sharing between the putamen and pre-supplementary motor area (pre-SMA). Moreover, we propose that modulations to information transfer between these two regions leads to practice-induced improvements in multitasking. Significance statement Humans show striking limitations in information processing when multitasking, yet can modify these limits with practice. Such limitations have been linked to a frontal-parietal network, but recent models of decision-making implicate a striatal-cortical network. We adjudicated these accounts by investigating the circuitry underpinning multitasking in 100 individuals and the plasticity caused by practice. Our results support the view that multitasking stems at least in part from taxation in information sharing between the putamen and pre-supplementary motor area (pre-SMA). We therefore show that models of cognitive capacity limits must consider how subcortical and cortical structures interface to produce cognitive behaviours, and we propose a novel neurophysiological substrate of multitasking limitations.
MYB5a/NEGAN activates petal anthocyanin pigmentation and shapes the MBW regulatory network in Mimulus luteus var. variegatus

Much of the visual diversity of angiosperms is due to the frequent evolution of novel pigmentation patterns in flowers. The gene network responsible for anthocyanin pigmentation, in particular, has become a model for investigating how genetic changes give rise to phenotypic innovation. In the monkeyflower genus Mimulus, an evolutionarily recent gain of petal lobe anthocyanin pigmentation in M. luteus var. variegatus was previously mapped to genomic region pla2. Here, we use DNA sequence analysis and spatiotemporal patterns of gene expression to identify MYB5a - homologous to the NEGAN transcriptional activator from M. lewisii - as a likely candidate gene within the pla2 region. Transgenic manipulation of gene expression confirms that MYB5a is both necessary and sufficient for petal lobe anthocyanin pigmentation. The deployment of MYB5a/NEGAN to the petal lobe stands in contrast to its more restricted role as a nectar guide anthocyanin activator in other Mimulus species. Transcriptome sequencing of a MYB5a RNAi line reveals the degree to which other regulators of the anthocyanin pathway - including R3 MYB repressors and bHLH and WD40 co-activators - are responsive to the level of expression of MYB5a. Overall, this work reveals that a genetically simple change, which we hypothesize to be a regulatory mutation in cis to MYB5a, has cascading effects on gene expression, not only on the genes downstream of MYB5a but also on all of its known partners in the anthocyanin regulatory network. Graphical abstract. Solid black arrows indicate the direction (though not magnitude) of gene expression change, following RNAi knockdown of MYB5a/NEGAN in M. l. variegatus. The number of black arrows corresponds to the number of gene copies identified in the transcriptome. Grey symbols denote positive and negative regulatory interactions. RTO is an R3 MYB protein that inhibits anthocyanin biosynthesis by sequestering bHLH proteins away from the MBW complex.
Physical and mental health characteristics of adults with subjective cognitive decline: A study of 3,407 people aged 18-81 years from an MTurk-based U.S. national sample

Subjective cognitive decline (SCD), or internal feelings of reduced mental capacity, is of increasing interest in the scientific, clinical, and lay community. Much of the extant literature is focused on SCD as a risk factor for Alzheimer’s disease in older adults, while less attention has been paid to non-cognitive health correlates of SCD across adulthood. Consequently, we investigated physical and mental health correlates of SCD in younger, middle-aged, and older adults. We recruited 3,407 U.S. residents through Amazon’s Mechanical Turk, an online labor market. Participants completed a 90-item self-report survey questionnaire assessing sociodemographic characteristics, physical health, sleep, depression, anxiety, loneliness, wisdom, self-efficacy, and happiness. Overall, 493/1930 (25.5%) of younger adults (18-49) and 278/1032 (26.9%) of older adults (50 or older) endorsed the SCD item. Multivariate analysis of variance and follow-up t-tests revealed worse physical and mental health characteristics in people endorsing SCD compared to those who did not, with effect sizes primarily in the medium to large range. Additionally, age did not moderate relationships between SCD and physical and mental health. Results suggest that SCD is associated with a diverse set of negative health characteristics such as poor sleep and high body mass index, and lower levels of positive factors including happiness and wisdom. Effect sizes of psychological correlates of SCD were as large as (or larger than) those of physical correlates, indicating that mental health and affective symptoms may be critical to consider when evaluating SCD. Overall, findings from this large, national U.S. sample suggest the presence of relationships between SCD and multiple psychological and perceived health factors; our results also show that SCD may be highly prevalent in both younger and older adults, suggesting that it be assessed across the adult lifespan.
An approach for normalization and quality control for NanoString RNA expression data

The NanoString RNA counting assay for formalin-fixed paraffin embedded samples is unique in its sensitivity, technical reproducibility, and robustness for analysis of clinical and archival samples. While commercial normalization methods are provided by NanoString, they are not optimal for all settings, particularly when samples exhibit strong technical or biological variation or where housekeeping genes have variable performance across the cohort. Here, we develop and evaluate a more comprehensive normalization procedure for NanoString data with steps for quality control, selection of housekeeping targets, normalization, and iterative data visualization and biological validation. The approach was evaluated using a large cohort (N = 1,649) from the Carolina Breast Cancer Study, two cohorts of moderate sample size (N = 359 and 130), and a small published dataset (N = 12). The iterative process developed here eliminates technical variation (e.g. from different study phases or sites) more reliably than the three other methods, including NanoString’s commercial package, without diminishing biological variation, especially in long-term longitudinal multi-phase or multi-site cohorts. We also find that probe sets validated for nCounter, such as the PAM50 gene signature, are impervious to batch issues. This work emphasizes that systematic quality control, normalization, and visualization of NanoString nCounter data is an imperative component of study design that influences results in downstream analyses.
Structural analysis of the PTEN:P-Rex2 signalling node reveals how cancer-associated mutations coordinate to hyperactivate Rac1

The PTEN:P-Rex2 complex is one of the most commonly mutated signaling nodes in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cell proliferation. Here, using extensive crosslinking mass spectrometry and functional studies, we provide crucial mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN PDZ-BM tail and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PTEN membrane-binding and PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding and GPCR activation. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. These findings provide a mechanistic framework to understand the dysregulation of the PTEN:P-Rex2 signaling node in metastatic cancer.
MgrA regulates interaction of Staphylococcus aureus with mucin

Background To defend the lungs, mucus adheres to bacterial cells and facilitates their removal by ciliary transport. Our goals were to measure the affinity of mucus for the respiratory pathogen Staphylococcus aureus and identify bacterial genes that regulate this interaction. Methods S. aureus was added to pig tracheas to determine whether it binds mucus or epithelial cells. To quantify its affinity for mucus, we developed a competition assay in microtiter plates. Mucin was added over a dose range as an inhibitor of bacterial attachment. We then examined how transcriptional regulator MgrA and cell wall transpeptidase sortase (SrtA) affect bacterial interaction with mucin. Results In pig tracheas, S. aureus bound mucus strands from submucosal glands more than epithelial cells. In microtiter plate assays, ΔsrtA failed to attach even in the absence of mucin. Mucin blocked wild type S. aureus attachment in a dose-dependent manner. Higher concentrations were needed to inhibit binding of ΔmgrA. Co-deletion of ebh and sraP, which encode surface proteins repressed by MgrA, suppressed the ΔmgrA binding phenotype. No differences between ΔmgrA and wild type were observed when methylcellulose or heparin sulfate were substituted for mucin, indicating specificity. Conclusions Mucin decreases attachment of S. aureus to plastic, consistent with its physiologic role in host defense. S. aureus deficient in MgrA has decreased affinity for mucin. Ebh and SraP, which are normally repressed by MgrA, may function as inhibitors of attachment to mucin. These data show that specific bacterial factors may regulate the interaction of S. aureus with mucus.
The role of auxiliary parameters in evaluating voxel-wise encoding models for 3T and 7T BOLD fMRI data

In neuroimaging, voxel-wise encoding models are a popular tool to predict brain activity elicited by a stimulus. To evaluate the accuracy of these predictions across multiple voxels, one can choose between multiple quality metrics. However, each quality metric requires specifying auxiliary parameters such as the number and selection criteria of voxels, whose influence on model validation is unknown. In this study, we systematically vary these parameters and observe their effects on three common quality metrics of voxel-wise encoding models in two open datasets of 3- and 7-Tesla BOLD fMRI activity elicited by musical stimuli. We show that such auxiliary parameters not only exert substantial influence on model validation, but also differ in how they affect each quality metric. Finally, we give several recommendations for validating voxel-wise encoding models that may limit variability due to different numbers of voxels, voxel selection criteria, and magnetic field strengths.
Eco-evolutionary dynamics of prior selfing rate promotes the coexistence without niche partitioning under reproductive interference

When the two or more plants species share the same pollinators, pollinator-mediated reproductive interference make coexistence difficult. Recent studies suggested prior autonomous selfing mitigate reproductive interference, could enabling coexistence without pollination niche partitioning (pre-emptive selfing hypothesis). However, there are no studies to test whether evolution of prior selfing promote the coexistence, considering eco-evolutionary dynamics of population size, selfing rate and inbreeding depression. To examine conditions that the evolution of prior selfing promote coexistence under mutual reproductive interference especially in the point of view for pollinator availability and dynamics of inbreeding depression, we constructed individual-based model in which two plant species compete against each other in the form of mutual reproductive interference and can evolve prior autonomous selfing rate. We expected that purging of deleterious mutations could cause evolutionary rescue because inferior species could rescue population density through the evolution of prior selfing if the strength of inbreeding depression decreases with an increase of population’s selfing rate. Our simulation demonstrated that the evolution of prior selfing could promote the coexistence while reproductive interference caused competitive exclusion without evolution. We found that lower pollinator availability tended to prefer rapid evolutionary shift to higher prior selfing rate, it neutralizes the negative effect of reproductive interference, and population dynamics exhibit neutral random walk in both species. When the strength of inbreeding depression decreased with an increase in population’s selfing rate, moderate pollinator availability resulted in long-term coexistence in which relative-abundance-dependent selection on the prior selfing rate rescue population density of inferior species intermittently. Synthesis. We showed that the evolution of prior selfing could increase population growth rate of inferior species and consequently enable the long-term coexistence with evolutionary rescue. This is the new mechanisms explaining co-evolutionary coexistence of closely related plant species without niche partitioning and consistent with recent studies reported that closely related mixed-mating species are sympatrically growing even under the mutual reproductive interference.
Channel-wise Aggregation with Self-correction Mechanism for Multi-center Multi-Organ Nuclei Segmentation in Whole Slide Imaging

: In the ﬁeld of computational pathology, there is an essential need for accurate nuclei segmentation methods for performing different studies, such as cancer grading and cancer subtype classiﬁcation. The ambiguous boundary between different cell nuclei and the other objects that have a similar appearance beside the overlapping and clumped nuclei may yield noise in the ground truth masks. To improve the segmentation results of cell nuclei in histopathological images, in this paper, we propose a new technique for aggregating the channel maps of semantic segmentation models. This technique is integrated with a self-correction learning mechanism that can handle noisy ground truth. We show that the proposed nuclei segmentation method gives promising results with images of different organs (e.g., breast, bladder, and colon)collected from medical centers that use devices of different manufacturers and stains. Our method reaches the new state-of-the-art. Mainly, we achieve the AJI score of 0.735 on the Multi-Organ Nuclei Segmentation benchmark, which outperforms the previous closest approaches.
A First-person Database for Detecting Barriers for Pedestrians

Egocentric vision, which relates to the continuous interpretation of images captured by wearable cameras, is increasingly being utilized in several applications to enhance the quality of citizens life, especially for those with visual or motion impairments. The development of sophisticated egocentric computer vision techniques requires automatic analysis of large databases of first-person point of view visual data collected through wearable devices. In this paper, we present our initial findings regarding the use of wearable cameras for enhancing the pedestrians safety while walking in city sidewalks. For this purpose, we create a first-person database that entails annotations on common barriers that may put pedestrians in danger. Furthermore, we derive a framework for collecting visual lifelogging data and define 24 different categories of sidewalk barriers. Our dataset consists of 1796 annotated images covering 1969 instances of barriers. The analysis of the dataset by means of object classification algorithms, depict encouraging results for further study.
Smart Communities: From Sensors to Internet of Things and to a Marketplace of Services

: Our paper was inspired by the recent Society 5.0 initiative of the Japanese Government that seeks to create a sustainable human-centric society by putting to work recent advances in technology: sensor networks, edge computing, IoT ecosystems, AI, Big Data, robotics, to name just a few. The main contribution of this work is a vision of how these technological advances can contribute, directly or indirectly, to making Society 5.0 reality. For this purpose we build on a recently-proposed concept of Marketplace of Services that, in our view, will turn out to be one of the cornerstones of Society 5.0. Instead of referring to Society 5.0 directly, throughout the paper we shall deﬁne a generic Smart Community that implements a subset of the goals of Society 5.0. We show how digital technology in conjunction with the Marketplace of services can contribute to enabling and promoting sustainable Smart Communities. Very much like Society 5.0, our Smart Community can provide a large number of diverse and evolving human-centric services offered as utilities and sold on a metered basis. The services offered by the Smart Community can be synthesized, using the latest technology (e.g. 3D printing, robotics, Big Data analytics, AI, etc.), from a hierarchy of raw resources or other services. The residents of the Smart Community can purchase as much or as little of these services as they ﬁnd suitable to their needs and are billed according to a pay-as-you-go business model.
NMF vs. ICA for Light Source Separation under AC Illumination

: Artiﬁcial light sources powered by an electric grid change their intensities in response to the grid’s alternating current (AC). Their ﬂickers are usually too fast to notice with our naked eyes, but can be captured by using cameras with short exposure time settings. In this paper, we propose a method for light source separation under AC illumination on the basis of Blind Source Separation (BSS). Speciﬁcally, we show that light source separation results in matrix factorization, since the input images of a scene illuminated by multiple AC light sources are represented by the linear combinations of the basis images, each of which is the image of the scene illuminated by only one of the light sources, with the coefﬁcients, each of which is the intensity of the light source. Then, we make use of Non-negative Matrix Factorization (NMF), because both the pixel values of the basis images and the intensities of the light sources are non-negative. We experimentally conﬁrmed that our method using NMF works better than Independent Component Analysis (ICA), and studied the performance of our method under various conditions: varying exposure times and noise levels.