Miracle-dz/UniFAR-FTUs huggingface dataset:
Crosstalk of the MAP3K1 and EGFR pathways mediates gene-environment interactions that disrupt developmental tissue closure

Aberrant signal transduction pathways can adversely derail developmental processes. One such process is embryonic eyelid closure that requires MAP3K1. Map3k1 knockout mice have defective eyelid closure and an autosomal recessive eye-open at birth phenotype. In utero exposure to dioxin, a persistent environmental toxicant, causes the same eye defect in Map3k1+/- hemizygous but not wild type pups. Here we explore the mechanisms of Map3k1 (gene) and dioxin (environment) interactions (GxE) in the tissue closure defect. We show that, acting through the AHR, dioxin activates EGFR signaling, which in turn depresses MAP3K1-dependent JNK activity. This effect of dioxin is exacerbated by Map3k1 heterozygosity. Therefore, dioxin exposed Map3k1+/- embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out Ahr or Egfr in eyelid epithelium attenuates the open-eye defects in dioxin-treated Map3k1+/- pups, whereas knockout of Jnk1 and S1pr, encoding the S1P receptors upstream of the MAP3K1-JNK pathway, potentiates dioxin toxicity. Our novel findings suggest that dioxin and genes of the AHR, EGFR and S1P-MAP3K1-JNK pathways constitute a multifactorial mechanism underlying tissue closure abnormalities. Summary statement The crosstalk between a global environmental pollutant and the pre-existing genetic conditions is mediated through interactive signaling pathways, resulting in anatomical tissue closure abnormalities in development.
CAR T cell infiltration and cytotoxic killing within the core of 3D breast cancer spheroids under control of antigen sensing in microwell arrays

The success of chimeric antigen receptor (CAR) T cells in blood cancers has intensified efforts to develop CAR T therapies for solid cancers. In the solid tumor microenvironment, CAR T cell trafficking and suppression of cytotoxic killing represent limiting factors for therapeutic efficacy. Here, we present a microwell platform to study CAR T cell interactions with 3D tumor spheroids and determine predictors of anti-tumor CAR T cell function. To precisely control antigen sensing by CAR T cells, we utilized a switchable adaptor CAR system, that instead of directly binding to an antigen of interest, covalently attaches to co-administered antibody adaptors that mediate tumor antigen recognition. Following addition of an anti-HER2 adaptor antibody, primary human CAR T cells exhibited higher infiltration and clustering compared to the no adaptor control. By tracking CAR T cell killing at the individual spheroid level, we showed the suppressive effects of spheroid size and identified the initial CAR T cell : spheroid area ratio as a predictor of cytotoxicity. Spatiotemporal analysis revealed lower CAR T cell numbers and cytotoxicity in the spheroid core compared to the periphery. Finally, increasing CAR T cell seeding density, resulted in higher CAR T cell infiltration and cancer cell elimination in the spheroid core. Our findings provide new quantitative insights into CAR T cell-mediated killing of HER2+ breast tumor cells. Given the miniaturized nature and live imaging capabilities, our microfabricated system holds promise for discovering cell-cell interaction mechanisms that orchestrate antitumor CAR T cell functions and screening cellular immunotherapies in 3D tumor models.
Erosion of X-Chromosome Inactivation in female hiPSCs is heterogeneous and persists during differentiation

During culture, female human pluripotent stem cells (hPSCs), including human induced PSCs (hiPSCs) exhibit a propensity for erosion of X-chromosome inactivation (XCI). This phenomenon is characterized by the loss of XIST RNA expression and reactivation of a subset of X-linked genes from the inactive X chromosome (Xi). XCI erosion, despite its common occurrence, is often overlooked by the stem cell community, hindering a complete understanding of its impact on both fundamental and translational applications of hiPSCs. Investigating erosion dynamics in female hiPSCs, our study reveals that XCI erosion is a frequent yet heterogeneous phenomenon, resulting in the reactivation of several X-linked genes. The likelihood of a gene to erode increases for those located on the short arm of the X chromosome and within H3K27me3-enriched domains. Paradoxically, genes that typically escape XCI are hypersensitive to loss of XIST RNA and XCI erosion. This implies that XIST RNA normally restrains expression levels of these genes on the Xi. Importantly, increased X-linked gene expression upon erosion does not globally impact (hydroxy)methylation levels in hiPSCs or at imprinted regions. By exploring diverse differentiation paradigms, such as trilineage commitment and cardiac differentiation, our study reveals the persistence of abnormal XCI patterns throughout differentiation. This finding has significant implications for fundamental research, translational applications, and clinical use of stem cells. We underscore the importance of raising awareness within the stem cell community regarding XCI erosion and advocate for its inclusion in comprehensive hiPSC quality control.
Empirical Stochastic Modeling of Multipath Polarizations in Indoor Propagation Scenarios

In this contribution, a stochastic modeling approach is proposed for characterizing the polarization status of multipath components (MPCs) in propagation channels. The 2×2 polarization matrix of each MPC is represented by the geometrical parameters of two ellipses, i.e., the ovality, tilt angle, and size of each ellipse, as well as the rotating direction of electric field intensity along the ellipse. The statistics of these parameters including correlation behaviors among them extracted from measurement data constitute the stochastic polarization model for the propagation scenario of interest. Analytical expressions are presented for the transformation from the ellipse parameters to the 2×2 polarization matrix, and vice versa. Comparing with conventional polarization models addressing merely the cross-polarization ratios, the new model provides a more complete description for the per-path polarizations in terms of the power imbalance, tilting, and polarization spread. Furthermore, based on multiple-input multiple-output channel measurement data collected with 100-MHz bandwidth and at the center frequency of 5.25 GHz, stochastic polarization models of the proposed structure are extracted for five indoor scenarios. These models are complementary to the existing geometry-based stochastic channel models for generating realistic polarization matrices for MPCs.
Redefining the role of Hypoxia-inducible factors (HIFs) in oxygen homeostasis

Hypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell’s metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs’ activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs’ function and underscores the need to explicitly consider the cell’s metabolic activity in understanding its responses to changes in oxygen availability.
A Novel Low-Overhead Recovery Approach for Distributed Systems

We have addressed the complex problem of recovery for concurrent failures in distributed computing environment. We have proposed a new approach in which we have effectively dealt with both orphan and lost messages. The proposed checkpointing and recovery approaches enable each process to restart from its recent checkpoint and hence guarantee the least amount of recomputation after recovery. It also means that a process needs to save only its recent local checkpoint. In this regard, we have introduced two new ideas. First, the proposed value of the common checkpointing interval is such that it enables an initiator process to log the minimum number of messages sent by each application process. Second, the determination of the lost messages is always done a priori by an initiator process; besides it is done while the normal distributed application is running. This is quite meaningful because it does not delay the recovery approach in any way.
Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria

Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a novel human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we further expose an altered state of excitability, which we suggest may be connected to metabolic rewiring which is exacerbated by application of 2-dimethyloxoglutrate. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.
RASP: A General Logic Synthesis System for SRAM-Based FPGAs

In this paper, we present a general synthesis system for SRAM-based FPGAs named RASP. RASP consists of a core with a set of synthesis and optimization algorithms for technology independent logic synthesis and technology mapping for generating generic look-up tables (LUTs), together with a set of architecture-specific technology mapping routines to map the generic LUT network to programmable logic blocks (PLBs) for various SRAM-based FPGA architectures. Via a set of design representation converter routines, these architecture-independent and dependent synthesis algorithms are easily linked, and the entire system is seamlessly integrated into the design flow of commercial FPGA design systems. As a result, RASP can produce highly optimized designs for various SRAM-based FPGA architectures, and can be quickly adapted for new SRAM-based FPGA architectures. We compare RASP performance with that of several commercial synthesis systems on the MCNC logic synthesis benchmarks and a video compressor/decompressor. For almost all cases, RASP produces mapping solutions with significantly smaller critical path delay after place and route than current commercial synthesis systems.
COSY communication IP's

The Fsprit/OMI-COSY project defines transaction-levels to set-up the exchange of IP's in separating function from architecture and body-behavior from proprietary interfaces. These transaction-levels are supported by the “COSY COMMUNICATION IPs” that are presented in this paper. They implement onto Systems-On-Chip the extended Kahn Process Network that is defined in COSY for modeling signal processing applications. We present a generic implementation and performance model of these system-level communications and we illustrate specific implementations. They set system communications across software and hardware boundaries, and achieve bus independence through the Virtual Component Interface of the VSI Alliance. Finally, we describe the COSY-VCC flow that supports communication refinement from specification, to performance estimation, to implementation.
HIV integrase compacts viral DNA into biphasic condensates

The human immunodeficiency virus (HIV) infects non-dividing cells and its genome must be compacted to enter the cell nucleus. Here, we show that the viral enzyme integrase (IN) compacts HIV DNA mimetics in vitro. Under physiological conditions, IN-compacted genomes are consistent in size with those found for pre-integration complexes in infected cells. Compaction occurs in two stages: first IN tetramers bridge DNA strands and assemble into “rosette” structures that consist of a nucleo-protein core and extruding bare DNA. In a second stage, the extruding DNA loops condense onto the rosette core to form a disordered and viscoelastic outer layer. Notably, the core complex is susceptible towards IN inhibitors, whereas the diffuse outer layer is not. Together, our data suggest that IN has a structural role in viral DNA compaction and raise the possibility to develop inhibitors that target IN-DNA interactions in disordered condensates.
NeuroDecodeR: A package for neural decoding analyses in R

Neural decoding is a powerful method to analyze neural activity. However, the code needed to run a decoding analysis can be complex, which can present a barrier to using the method. In this paper we introduce a package that makes it easy to perform decoding analyses in the R programing language. We describe how the package is designed in a modular fashion which allows researchers to easily implement a range of different analyses. We also discuss how to format data to be able to use the package, and we give two examples of how to use the package to analyze real data. We believe that this package, combined with the rich data analysis ecosystem in R, will make it significantly easier for researchers to create reproducible decoding analyses, which should help increase the pace of neuroscience discoveries.
Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-β peptide (Aβ) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral β-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Aβ levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Aβ40 to Aβ42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.
Long-Term Transgene Expression and Survival of Transgene-Expressing Grafts Following Lentivirus Transduction of Bone Marrow Side Population Cells

Background. Successful transduction of hematopoietic stem cells is essential if gene therapy is to be used clinically to induce immunologic tolerance. Methods. Hoechst 33342 staining was used to isolate a population of bone marrow cells enriched for stem cells, termed side population (SP) cells. Murine bone marrow SP cells were transduced with HLA-A2.1-expressing VSV-G-pseudotyped lentivirus or retrovirus vectors under identical conditions. Results. After transduction without prestimulating cytokines, which minimizes cell cycling and helps maintain stem cell pluripotency, the HLA-A2.1 gene was found in the DNA of 56% of CFU-GM colonies derived from lentivirus-transduced SP cells, but in only 4% of colonies derived from retrovirus-transduced SP cells. Lentivirus and retrovirus transduction including cytokine prestimulation produced the same degree of integration as that following lentivirus-transduction of non-prestimulated cells. Transplantation of 5,000 lentivirus-transduced SP cells into lethally irradiated mice resulted in long-term expression of the HLA-A2.1 transgene in peripheral blood progeny of bone marrow SP cells and prolonged skin graft survival across this class I MHC barrier until the time of animal sacrifice. Conclusions. Recombinant lentivirus, but not retrovirus vectors, effectively transduced SP cells that were not prestimulated with cytokines and lentivirus-transduced SP cells successfully repopulated lethally irradiated C57BL/6 mice, animals where there is no selective advantage to repopulation with transduced cells. Transplantation of a relatively small number of transduced SP cells led to prolonged transgene mRNA expression and antigen-specific survival of grafts expressing the foreign MHC transgene.
Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non‐antibiotic‐based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4‐MD‐2‐LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)‐6 by Gram‐negative bacteria. In a rabbit model of shigellosis, PAMAM‐DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL‐6 and IL‐8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)‐DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM‐DG potently inhibited Shigella Lipid A‐induced IL‐6 expression. In rabbits, PETIM‐DG prevented Shigella‐induced epithelial gut wall damage, reduced local IL‐6 and IL‐8 expression, and minimized bacterial invasion. There was no change in β‐defensin, IL‐10, interferon‐β, transforming growth factor‐β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.
Lost in translation (and rotation): Rapid extrinsic calibration for 2D and 3D LIDARs

This paper describes a novel method for determining the extrinsic calibration parameters between 2D and 3D LIDAR sensors with respect to a vehicle base frame. To recover the calibration parameters we attempt to optimize the quality of a 3D point cloud produced by the vehicle as it traverses an unknown, unmodified environment. The point cloud quality metric is derived from Rényi Quadratic Entropy and quantifies the compactness of the point distribution using only a single tuning parameter. We also present a fast approximate method to reduce the computational requirements of the entropy evaluation, allowing unsupervised calibration in vast environments with millions of points. The algorithm is analyzed using real world data gathered in many locations, showing robust calibration performance and substantial speed improvements from the approximations.
Reducing human interactions in Web directory searches

Consider a website containing a collection of webpages with data such as in Yahoo or the Open Directory project. Each page is associated with a weight representing the frequency with which that page is accessed by users. In the tree hierarchy representation, accessing each page requires the user to travel along the path leading to it from the root. By enhancing the index tree with additional edges (hotlinks) one may reduce the access cost of the system. In other words, the hotlinks reduce the expected number of steps needed to reach a leaf page from the tree root, assuming that the user knows which hotlinks to take. The hotlink enhancement problem involves finding a set of hotlinks minimizing this cost. This article proposes the first exact algorithm for the hotlink enhancement problem. This algorithm runs in polynomial time for trees with logarithmic depth. Experiments conducted with real data show that significant improvement in the expected number of accesses per search can be achieved in websites using this algorithm. These experiments also suggest that the simple and much faster heuristic proposed previously by Czyzowicz et al. [2003] creates hotlinks that are nearly optimal in the time savings they provide to the user. The version of the hotlink enhancement problem in which the weight distribution on the leaves is unknown is discussed as well. We present a polynomial-time algorithm that is optimal for any tree for any depth.
On the Use of Mutation Faults in Empirical Assessments of Test Case Prioritization Techniques

Regression testing is an important activity in the software life cycle, but it can also be very expensive. To reduce the cost of regression testing, software testers may prioritize their test cases so that those which are more important, by some measure, are run earlier in the regression testing process. One potential goal of test case prioritization techniques is to increase a test suite's rate of fault detection (how quickly, in a run of its test cases, that test suite can detect faults). Previous work has shown that prioritization can improve a test suite's rate of fault detection, but the assessment of prioritization techniques has been limited primarily to hand-seeded faults, largely due to the belief that such faults are more realistic than automatically generated (mutation) faults. A recent empirical study, however, suggests that mutation faults can be representative of real faults and that the use of hand-seeded faults can be problematic for the validity of empirical results focusing on fault detection. We have therefore designed and performed two controlled experiments assessing the ability of prioritization techniques to improve the rate of fault detection of test case prioritization techniques, measured relative to mutation faults. Our results show that prioritization can be effective relative to the faults considered, and they expose ways in which that effectiveness can vary with characteristics of faults and test suites. More importantly, a comparison of our results with those collected using hand-seeded faults reveals several implications for researchers performing empirical studies of test case prioritization techniques in particular and testing techniques in general