Miracle-dz/UniFAR-FTUs huggingface dataset:
The Importance of Semantic Network Brain Regions in Integrating Prior Knowledge with an Ongoing Dialogue

Abstract To understand a dialogue, we need to know the topics that are being discussed. This enables us to integrate our knowledge of what was said previously to interpret the current dialogue. This study involved a large-scale behavioral experiment conducted online and a separate fMRI experiment, both testing human participants. In both, we selectively manipulated knowledge about the narrative content of dialogues presented in short videos. The clips were scenes from situation comedies that were split into two parts. The speech in the part 1 clips could either be presented normally or spectrally rotated to render it unintelligible. The part 2 clips that concluded the scenes were always presented normally. The behavioral experiment showed that knowledge of the preceding narrative boosted memory for the part 2 clips as well as increased the intersubject semantic similarity of recalled descriptions of the dialogues. The fMRI experiment replicated the finding that prior knowledge improved memory for the conclusions of the dialogues. Furthermore, prior knowledge strengthened temporal intersubject correlations in brain regions including the left angular gyrus and inferior frontal gyrus. Together, these findings show that (1) prior knowledge constrains the interpretation of a dialogue to be more similar across individuals; and (2), consistent with this, the activation of brain regions involved in semantic control processing is also more similar between individuals who share the same prior knowledge. Processing in these regions likely supports the activation and integration of prior knowledge, which helps people to better understand and remember dialogues as they unfold.
Epithelial-to-mesenchymal transition proceeds through directional destabilization of multidimensional attractor

How a cell changes from one stable phenotype to another one is a fundamental problem in developmental and cell biology. Epithelial-to-mesenchymal transition (EMT) is a phenotypic transition process extensively studied recently but mechanistic details remain elusive. Through time-lapse imaging we recorded single cell trajectories of human A549/Vim-RFP cells undergoing EMT induced by different concentrations of TGF-β in a multi-dimensional cell feature space. The trajectories cluster into two distinct groups, indicating that the transition dynamics proceeds through parallel paths. We then reconstructed the reaction coordinates and corresponding pseudo-potentials from the trajectories. The potentials reveal a plausible mechanism for the emergence of the two paths as the original stable epithelial attractor collides with two saddle points sequentially with increased TGF-β concentration, and relaxes to a new one. Functionally the directional saddle-node bifurcation ensures a CPT proceeds towards a specific cell type, as a mechanistic realization of the canalization idea proposed by Waddington.
Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching

The common null polymorphism (R577X) in the ACTN3 gene is present in over 1.5 billion people worldwide and results in the absence of the protein α-actinin-3 from the Z-discs of fast-twitch skeletal muscle fibres. We have previously reported that this polymorphism is a modifier of dystrophin deficient Duchenne Muscular Dystrophy. To investigate the mechanism underlying this we use a double knockout (dk)Actn3KO/mdx (dKO) mouse model which lacks both dystrophin and sarcomere α-actinin-3. We used dKO mice and mdx dystrophic mice at 12 months (aged) to investigate the correlation between morphological changes to the fast-twitch dKO EDL and the reduction in force deficit produced by an in vitro eccentric contraction protocol. In the aged dKO mouse we found a marked reduction in fibre branching complexity that correlated with protection from eccentric contraction induced force deficit. Complex branches in the aged dKO EDL fibres (28%) were substantially reduced compared to aged mdx EDL fibres (68%) and this correlates with a graded force loss over three eccentric contractions for dKO muscles (∼35% after first contraction, ∼66% overall) compared to an abrupt drop in mdx upon the first eccentric contraction (∼73% after first contraction, ∼89% after three contractions). In dKO protection from eccentric contraction damage was linked with a doubling of SERCA1 pump density the EDL. We propose that the increased oxidative metabolism of fast-twitch glycolytic fibres characteristic of the null polymorphism (R577X) and increase in SR Ca2+ pump proteins reduces muscle fibre branching and decreases susceptibility to eccentric injury in the dystrophinopathies.
The kinesin KIF4 mediates HBV/HDV entry through regulation of surface NTCP localization and can be targeted by RXR agonists in vitro

Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family Member 4 (KIF4) plays an important role in HBV/HDV infection. We intended to explore host factors impacting the HBV life cycle that can be therapeutically addressed using siRNA library transfection and HBV/NLuc (HBV/NL) reporter virus infection in HepG2-hNTCP C4 cells. KIF4 silencing resulted in a 3-fold reduction in luciferase activity following HBV/NL infection and suppressed both wild-type HBV and HDV infection. Transient KIF4 depletion reduced surface and raised intracellular NTCP (HBV/HDV entry receptor) levels, according to both cellular fractionation and immunofluorescence analysis (IF). Overexpression of wild-type KIF4 but not ATPase-null KIF4 regains the surface localization of NTCP in these cells. Furthermore, immunofluorescence (IF) revealed KIF4 and NTCP colocalization across microtubule filaments, and a co-immunoprecipitation study showed that KIF4 physically binds to NTCP. KIF4 expression is regulated by FOXM1. Interestingly, we discovered that RXR agonists (Bexarotene, and Alitretinoin) down-regulated KIF4 expression via FOXM1-mediated suppression, resulting in a substantial decrease in HBV-Pre-S1 protein attachment to HepG2-hNTCP cell surface and subsequent suppression of HBV infection in HepG2-hNTCP and primary human hepatocytes (PXB) (Bexarotene, IC50 1.89 ± 0.98 μM). Overall, our findings show that human KIF4 is a critical regulator of NTCP surface transport and localization, which is required for NTCP to function as a receptor for HBV/HDV entry. Furthermore, small molecules that suppress or alleviate KIF4 expression would be potential antiviral candidates that target HBV and HDV entry phases. Author Summary Understanding HBV/HDV entry machinery and the mechanism by which NTCP (HBV/HDV entry receptor) surface expression is regulated is crucial to develop antiviral entry inhibitors. We found that NTCP surface transport is mainly controlled by the motor kinesin KIF4. Surprisingly, KIF4 was negatively regulated by RXR receptors through FOXM1-mediated suppression This study not only mechanistically correlated the role of RXR receptors in regulating HBV/HDV entry but also suggested a novel approach to develop therapeutic rexinoids for preventing HBV and/or HDV infections in important clinical situations, such as in patients undergoing liver transplantation or those who are at a high risk of HBV infection and unresponsive to HBV vaccination.
FGF signalling is involved in cumulus migration in the common house spider Parasteatoda tepidariorum

Cell migration is a fundamental component during the development of most multicellular organisms. In spiders, the collective migration of a signalling centre, known as the cumulus, is required to set the dorsoventral body axis of the embryo. Here, we show that FGF signalling plays an important role during cumulus migration in the spider Parasteatoda tepidariorum. Spider embryos with reduced FGF signalling lack cumulus migration and display dorsoventral patterning defects. Our study reveals that cumulus expression of several FGF signalling components is regulated by the transcription factor Ets4. In conjunction with a previous study, we show that the expression of fgf8 in the germ-disc is regulated via the Hedgehog signalling pathway. We also demonstrate that FGF signalling influences the BMP signalling pathway activity in the region around cumulus cells. Finally, we show that FGF signalling might also influence cumulus migration in basally branching spiders and we propose a hypothetical model in which fgf8 acts a chemo-attractant to guide cumulus cells towards the future dorsal pole of the spider embryo.
Structural basis of ATP-dependent high-fidelity epigenome maintenance

Epigenetic evolution occurs over million-year timescales in Cryptococcus neoformans and is mediated by DNMT5, the first maintenance-type cytosine methyltransferase identified in the fungal or protist kingdoms. DNMT5 requires ATP and displays exquisite hemimethyl-DNA specificity. To understand these novel properties, we solved cryo-EM structures of CnDNMT5 in three states. These studies reveal an elaborate allosteric cascade in which hemimethylated DNA first activates the SNF2 ATPase domain by a large rigid body rotation while the target cytosine partially flips out the DNA duplex. ATP binding then triggers a striking structural reconfiguration of the methyltransferase catalytic pocket that enables cofactor binding, completion of base-flipping, and catalysis. Unmethylated DNA binding fails to open cofactor pocket and subsequent ATP binding triggers its ejection to ensure fidelity. This chaperone-like, enzyme-remodeling role of the SNF2 domain illuminates how energy can be used to enable faithful epigenetic memory. Highlights Structures of DNMT5 reveal mechanism of ATP-dependent DNA methylation Hemimethylated CpG recognition triggers partial base flipping of the target cytosine Hemimethylated DNA induces rigid body rotation to activate the SNF2 ATPase domain MTase catalytic pocket is remodeled by the SNF2 ATPase to achieve specificity
CellDepot: A unified repository for scRNA-seq data and visual exploration

CellDepot serves as an integrated web application to assist users in exploring single-cell RNA-seq (scRNA-seq) datasets and comparing the datasets among various studies through a user-friendly interface with advanced visualization and analytical tools. To begin with, it provides an efficient data management system that users can upload single cell datasets and query the database by multiple attributes such as species and cell types. In addition, the advanced query function incorporated in MySQL database system and its conditional filtering, allows users to quickly query and compare the expression of gene(s) across the datasets of interest. Moreover, by embedding the cellxgene VIP tool, CellDepot enables fast exploration of individual dataset in the manner of interactivity and scalability to gain more refined insights such as cell composition, gene expression profiles, and differentially expressed genes among cell types. In summary, the web portal allows large scale single cell data sharing, analysis and visualization for supporting decision-making, and encouraging scientists to contribute to the single-cell community in a tractable and collaborative way. Finally, CellDepot is released as open-source software to motivate crowd contribution, broad adoption, and local deployment for private data.
The European Prevention of Alzheimer’s Dementia (EPAD) MRI Dataset and Processing Workflow

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer’s Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features — i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features — Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) — were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.
An Approach to Measuring Protein Turnover in Human Induced Pluripotent Stem Cell Organoids by Mass Spectrometry

Patient-derived organoids from induced pluripotent stem cells have emerged as a model for studying human diseases beyond conventional two-dimensional (2D) cell culture. Briefly, these three-dimensional organoids are highly complex, capable of self-organizing, recapitulate cellular architecture, and have the potential to model diseases in complex organs, such as the brain. For example, the hallmark of Parkinson’s disease - proteostatic dysfunction leading to the selective death of neurons in the substantia nigra - present a subtle distinction in cell type specificity that is simply lost in 2D cell culture models. As such, the development of robust methods to study global proteostasis and protein turnover in organoids will remain a critical need as organoid models evolve. To solve this problem, we have designed a workflow to extract proteins from organoids and measure global protein turnover using mass spectrometry and stable isotope labeling using amino acids in cell culture (SILAC). This allowed us to measure the turnover rates of 844 proteins and compare protein turnover to previously reported data in primary cell cultures and in vivo models. Taken together, this method will facilitate the study of proteostasis in organoid models of human disease and will provide an analytical and statistical framework to measure protein turnover in organoids of all cell types.
The Prognostic Value of Calcium in Post-Cardiovascular Surgery Patients in the Intensive Care Unit

Background: Present researches exploring the prognostic value of calcium concentration are undermined by sample size and study design. Our study investigated the association of both total calcium (tCa) and ionized Ca (iCa) to short- and long-term mortality and other outcomes in post-cardiovascular surgery (PCS) patients admitted to intensive care unit (ICU) from two large public data sets. Methods: The Medical Information Mart for Intensive Care III (MIMIC-III) database and the eICU Collaborative Research Database (eICU) were inspected to identify PCS patients. The primary outcome was 28-day mortality. Multivariate regression was used to elucidate the relationship between calcium concentration and outcomes. The propensity score estimation was performed to validate our findings. Results: A total of 6122 and 914 patients were included from the MIMIC III and eICU data sets, respectively. The groups with the most patients were the mild hypo-iCa and hypo-tCa groups. The mild hypo-iCa group showed significant association with worse short-term and long-term prognosis, less use of ventilation, longer ICU and hospital stay, and more incidence of 7-day acute kidney injury. Conclusions: The mild hypo-iCa (0.9–1.15 mmol/L) within the first day of admission to the ICU could serve as an independent prognosis factor for PCS patients.
Yttrium-90 TOF-PET-Based EUD Predicts Response Post Liver Radioembolizations Using Recommended Manufacturer FDG Reconstruction Parameters

Purpose Explaining why 90Y TOF-PET based equivalent uniform dose (EUD) using recommended manufacturer FDG reconstruction parameters has been shown to predict response. Methods The hot rods insert of a Jaszczak deluxe phantom was partially filled with a 2.65 GBq 90Y - 300ml DTPA water solution resulting in a 100 Gy mean absorbed dose in the 6 sectors. A two bed 20min/position acquisition was performed on a 550ps- and on a 320ps- TOF-PET/CT and reconstructed with recommended manufacturer FDG reconstruction parameters, without and with additional filtering. The whole procedure was repeated on both PET after adding 300ml of water (50Gy setup). The phantom was acquired again after decay by a factor of 10 (5Gy setup), but with 200min per bed position. For comparison, the phantom was also acquired with 18F activity corresponding to a clinical FDG whole body acquisition. Results The 100Gy-setup provided a hot rod sectors image almost as good as the 18F phantom. However, despite acquisition time compensation, the 5Gy-setup provides much lower quality imaging. TOF-PET based sectors EUDs for the three large rod sectors agreed with the actual EUDs computed with a radiosensitivity of 0.021Gy-1 well in the range observed in external beam radiotherapy (EBRT), i.e. 0.01-0.04Gy-1. This agreement explains the reunification of the dose-response relationships of the glass and resin spheres in HCC using the TOF-PET based EUD. Additional filtering reduced the EUDs agreement quality. Conclusions Recommended manufacturer FDG reconstruction parameters are suitable in TOF-PET post 90Y liver radioembolization for accurate tumour EUD computation. The present results rule out the use of low specific activity phantom studies to optimize reconstruction parameters.
Single-cell transcriptomics reveals the identity and regulators of human mast cell progenitors

Mast cell accumulation is a hallmark of a number of diseases including allergic asthma and systemic mastocytosis. IgE-mediated crosslinking of the FcεRI receptors causes mast cell activation and contributes to disease pathogenesis. The mast cell lineage is one of the least studied among the hematopoietic cell lineages and there are still controversies about the identity of the mast cell progenitor, i.e., whether FcεRI expression appears during the hematopoietic progenitor stage or in maturing mast cells. Here, we used single-cell transcriptomics to reveal a temporal association between the appearance of FcεRI and the mast cell gene signature in CD34+ hematopoietic progenitors. In agreement with these data, the FcεRI+ hematopoietic progenitors formed morphologically, phenotypically and functionally mature mast cells in long-term culture assays. Single-cell transcriptomics analysis further revealed the expression patterns of prospective cytokine receptors regulating mast cell progenitor development. Culture assays showed that IL-3 and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust FcεRI downregulation. Taken together, we have demonstrated that FcεRI appears during the hematopoietic progenitor stage of mast cell differentiation and that external stimuli may regulate the FcεRI expression. Thus, the results resolve the controversy regarding the appearance of FcεRI during mast cell development. One-sentence summary Single-cell analysis of human hematopoiesis uncovers the stage at which FcεRI appears during mast cell differentiation and reveals disparate effects of IL-3, IL-5 and IL-33 on mast cell progenitor proliferation, survival, and suppression of FcεRI expression.
Distance estimation from monocular cues in an ethological visuomotor task

In natural contexts, sensory processing and motor output are closely coupled, which is reflected in the fact that many brain areas contain both sensory and movement signals. However, standard reductionist paradigms decouple sensory decisions from their natural motor consequences, and head-fixation prevents the natural sensory consequences of self-motion. In particular, movement through the environment provides a number of depth cues beyond stereo vision that are poorly understood. To study the integration of visual processing and motor output in a naturalistic task, we investigated distance estimation in freely moving mice. We found that mice use vision to accurately jump across a variable gap, thus directly coupling a visual computation to its corresponding ethological motor output. Monocular eyelid suture did not affect gap jumping success, thus mice can use cues that do not depend on binocular disparity and stereo vision. Under monocular conditions, mice altered their head positioning and performed more vertical head movements, consistent with a shift from using stereopsis to other monocular cues, such as motion or position parallax. Finally, optogenetic suppression of primary visual cortex impaired task performance under both binocular and monocular conditions when optical fiber placement was localized to binocular or monocular zone V1, respectively. Together, these results show that mice can use monocular cues, relying on visual cortex, to accurately judge distance. Furthermore, this behavioral paradigm provides a foundation for studying how neural circuits convert sensory information into ethological motor output.
Associations Between Binocular Depth Perception and Performance Gains in Laparoscopic Skill Acquisition

The ability to perceive differences in depth is important in many daily life situations. It is also of relevance in laparoscopic surgical procedures that require the extrapolation of three-dimensional visual information from two-dimensional planar images. Besides visual-motor coordination, laparoscopic skills and binocular depth perception are demanding visual tasks for which learning is important. This study explored potential relations between binocular depth perception and individual variations in performance gains during laparoscopic skill acquisition in medical students naïve of such procedures. Individual differences in perceptual learning of binocular depth discrimination when performing a random dot stereogram (RDS) task were measured as variations in the slope changes of the logistic disparity psychometric curves from the first to the last blocks of the experiment. The results showed that not only did the individuals differ in their depth discrimination; the extent with which this performance changed across blocks also differed substantially between individuals. Of note, individual differences in perceptual learning of depth discrimination are associated with performance gains from laparoscopic skill training, both with respect to movement speed and an efficiency score that considered both speed and precision. These results indicate that learning-related benefits for enhancing demanding visual processes are, in part, shared between these two tasks. Future studies that include a broader selection of task-varying monocular and binocular cues as well as visual-motor coordination are needed to further investigate potential mechanistic relations between depth perceptual learning and laparoscopic skill acquisition. A deeper understanding of these mechanisms would be important for applied research that aims at designing behavioral interventions for enhancing technology-assisted laparoscopic skills.