Miracle-dz/UniFAR-FTUs huggingface dataset:
Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid reduced efficacy of therapy are explored including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase and the isopropyl group at position 7 increased substantially the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piper-azin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses including suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.
Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture

Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these processes is mammalian hair follicle development, initiated by the formation of an epithelial invagination - termed placode – that coincides with the emergence of a designated hair follicle stem cell population. The mechanisms directing the deformation of the epithelium, cell state transitions, and physical compartmentalization of the placode are unknown. Here, we identify a key role for coordinated mechanical forces stemming from contractile, proliferative, and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which in collaboration with polarized epithelial myosin activity promote elongation and local tissue thickening. These mechanical stresses further enhance and compartmentalize Sox9 expression to promote stem cell positioning. Subsequently, proteolytic remodeling locally softens the basement membrane to facilitate release of pressure on the placode, enabling localized cell divisions, tissue fluidification, and epithelial invagination into the underlying mesenchyme. Together, our experiments and modeling identify dynamic cell shape transformations and tissue-scale mechanical co-operation as key factors for orchestrating organ formation.
Assignment Problem Generalization

A classical assignment problem takes a significant part in models and methods of combinatory (discrete) optimization. The problem belongs to so-called Boolean optimization problems where the unknowns possess values equal to 0 or 1. Solution of an assignment problem can be obtained by method of potentials as it consists in a partial case of transportation problem – the volumes of demand and supply for each manufacturer and consumer are equal to one. With account taken of a high level of degeneracy in the primary reference plan of an assignment problem mathematic model, solution thereof based on the method of potentials contains many trivial steps hampering the solution process convergence. The Hungarian method is rapidly converging and adapted to problems of this class.
Performance Predictors for Conversational Fashion Recommendation

In Conversational Recommendation Systems (CRS), a user can provide natural language feedback on suggested items, which the recommender uses to produce improved suggestions. Therefore, the success of a user’s conversation with the CRS is determined by how well the system is able to interpret the user’s feedback and the quality of the recommendations. Knowing whether a conversation is likely to be successful may allow the CRS to adjust accordingly - for instance, changing its retrieval strategy, or asking a clarifying question. Existing work on Query Performance Prediction (QPP) has examined a number of predictors that indicate the effectiveness of a search engine’s ranking in response to a query. Inspired by existing work in QPP, we propose a framework for Conversational Performance Prediction (CPP) that aims to predict conversation failures by considering the recommendation ranking at different turns of a conversation, either one turn at a time, or by considering multiple consecutive turns. In this regard, we adapt post-retrieval predictors to address the multi-turn nature of the CRS task. We conduct our analysis on Shoes and FashionIQ Shirts & Dresses datasets. In particular, as a ground truth, we measure conversation difficulty by the effectiveness of the ranking at a given turn of the conversation. Overall, we find some promiseinscore-basedretrievalpredictorsforCPP,obtainingmediumstrengthcorrelationswithconversationdifficulty-for instance,observingaSpearman’s 𝜌 of 0.423 on the Shoes dataset, which is comparable to correlations observed for standard QPP predictors on adhoc search tasks.
The inner gaseous accretion disk around a Herbig Be star revealed by near- and mid-infrared spectro-interferometry

Abstract Herbig Ae/Be stars are pre-main-sequence stars of intermediate mass, which are still accreting material from their environment, probably via a disk composed of gas and dust. Here we present a recent study of the geometry of the inner (AU-scale) circumstellar region around the Herbig Be star MWC 147 using long-baseline interferometry. By combining for the first time near- and mid-infrared spectro-interferometry on a Herbig star, our VLTI/AMBER and VLTI/MIDI data constrain not only the geometry of the brightness distribution, but also the radial temperature distribution in the disk. The emission from MWC 147 is clearly resolved and has a characteristic physical size of ∼1.3 AU and ∼9 AU at 2.2 μm and 11 μm respectively. This increase in apparent size towards longer wavelengths is much steeper than predicted by analytic disk models assuming power-law radial temperature distributions. For a detailed modeling of the interferometric data and the spectral energy distribution of MWC 147, we employ 2-D frequency-dependent radiation transfer simulations. This analysis shows that passive irradiated Keplerian dust disks can easily fit the SED, but predict much lower visibilities than observed, so these models can clearly be ruled out. Models of a Keplerian disk with emission from an optically thick inner gaseous accretion disk (inside the dust sublimation zone), however, yield a good fit of the SED and simultaneously reproduce the observed near- and mid-infrared visibilities. We conclude that the near-infrared continuum emission from MWC 147 is dominated by accretion luminosity emerging from an optically thick inner gaseous disk, while the mid-infrared emission also contains strong contributions from the passive irradiated dust disk.
Combining IGA and KG for Serendipitous Learning Contents Recommendation

Although there have been few attempts to propose serendipity-oriented recommender systems in the field of education, such systems appear to lack of the essential ability to support learners’ agency, which is learners’ feeling of ownership and control over their own learning. In this paper, we propose an Interactive Evolutionary Computation driven recommender system that enables learners to take control and responsibility of their own learning while recommending learning resources that are novel and unexpected, yet still relevant to learners’ interests. The proposed system specifically employs Interactive Genetic Algorithm (IGA) and Knowledge Graphs (KG) for dynamic recommendation of learning contents related to the history of scientific discoveries. We conducted both numerical simulations that confirmed the effectiveness of the learning contents optimization algorithm and an experimental evaluation which hinted at the meaningfulness of the proposed approach towards inducing serendipity within learners.
On fermion mass hierarchy from flavor-dependent Yukawas

We discuss the fermion masses in a string-inspired scalar extension of the standard model in four stacks of intersecting D-branes with a flavor-dependent symmetry. A complex scalar field S is required to generate all fermion Yukawa couplings. The latter are successively suppressed and their magnitudes weight the scales of fermion masses and offer a partial solution to the hierarchy problem. Using the known data, we estimate the relevant scales for the model.
Pediatric radius torus fractures in x-rays—how computer vision could render lateral projections obsolete

It is an indisputable dogma in extremity radiography to acquire x-ray studies in at least two complementary projections, which is also true for distal radius fractures in children. However, there is cautious hope that computer vision could enable breaking with this tradition in minor injuries, clinically lacking malalignment. We trained three different state-of-the-art convolutional neural networks (CNNs) on a dataset of 2,474 images: 1,237 images were posteroanterior (PA) pediatric wrist radiographs containing isolated distal radius torus fractures, and 1,237 images were normal controls without fractures. The task was to classify images into fractured and non-fractured. In total, 200 previously unseen images (100 per class) served as test set. CNN predictions reached area under the curves (AUCs) up to 98% [95% confidence interval (CI) 96.6%–99.5%], consistently exceeding human expert ratings (mean AUC 93.5%, 95% CI 89.9%–97.2%). Following training on larger data sets CNNs might be able to effectively rule out the presence of a distal radius fracture, enabling to consider foregoing the yet inevitable lateral projection in children. Built into the radiography workflow, such an algorithm could contribute to radiation hygiene and patient comfort.
Automatic target recognition using kinematic priors

Traditional automatic target recognition (ATR) systems discriminate based upon target size, target shape, or both. In this paper, an ATR algorithm is proposed that exploits aircraft-class specific kinematics to assess the tracked target's likelihood. Prior information on kinematics includes the physical parameters of the aircraft, allowable input forces to a pilot, and pilot behavior in the aircraft. It is shown that the computation of the likelihood of observed events is intractable. A suboptimal approximation to the likelihood can be computed using a hypothesis reduction method based on the generalized pseudo-Bayesian (GPB) class of algorithms. A bound on the L/sub 1/ distance of a suboptimal approximate density from the true density is derived. <<ETX>>
River temperature analysis with a new way of using Independant Component Analysis

In the context of global warming, river management is essential to maintain favourable water temperature ranges for aquatic species. Therefore, understanding the main factors influencing the water temperature becomes a key part in the management process. In this paper, we used Independent Component Analysis (ICA) to identify these main factors and improve water temperature forecasting. The study is caried out on two rivers in Normandy (France) with quite different characteristics. Each river was equipped with several temperature sensors which series range from 2011 to 2021. The ICA analysis of the data series reveals that the thermal regime of these two rivers is mainly controlled by seasonal and daily climatic factors. The Sélune regime also turns out to be influenced by the presence of a dam, dismantled during the monitoring of the river. The temperature of the Odon appears to be clearly controlled by seasonal lightening conditions in connection with the presence of the riparian vegetation. Complementary, an innovative approach called “successive ICA” is used to reconstruct the natural thermal regime of the Sélune without the presence of the dam. Emphasis is therefore placed here on the interest of ICA in hydrology as en elementary method for extracting the main influencing factors and quantifying their importance on the thermal regime of a river. It also allows to remove the influence of a particular factor and reconstruct time series better suited for temperature forecasting. The method used here is not specific to temperature time series and can be applied to any region even with different hydrological characteristics.
Genetic evidence of aberrant striatal synaptic maturation and secretory pathway alteration in a dystonia mouse model

Animal models of DYT-TOR1A dystonia consistently demonstrate abnormalities of striatal cholinergic function, but the molecular pathways underlying this pathophysiology are unclear. To probe these molecular pathways in a genetic model of DYT-TOR1A, we performed laser microdissection in juvenile mice to isolate striatal cholinergic interneurons and non-cholinergic striatal tissue largely comprising spiny projection neurons during maturation. Both cholinergic and GABAergic enriched samples demonstrated a defined set of gene expression changes consistent with a role of torsinA in the secretory pathway. GABAergic enriched striatum samples also showed alteration to genes regulating synaptic transmission and an upregulation of activity dependent immediate early genes. Reconstruction of Golgi-Cox stained striatal spiny projection neurons from adult mice demonstrated significantly increased spiny density, suggesting that torsinA null striatal neurons have increased excitability during striatal maturation and long lasting increases in afferent input. These findings are consistent with a developmental role for torsinA in the secretory pathway and link torsinA loss of function with functional and structural changes of striatal cholinergic and GABAergic neurons. These transcriptomic datasets are freely available as a resource for future studies of torsinA loss of function-mediated striatal dysfunction.
Measuring embodiment: A review of methods for prosthetic devices

The development of neural interfaces to provide improved control and somatosensory feedback from prosthetic limbs has initiated a new ability to probe the various dimensions of embodiment. Scientists in the field of neuroprosthetics require dependable measures of ownership, body representation, and agency to quantify the sense of embodiment felt by patients for their prosthetic limbs. These measures are critical to perform generalizable experiments and compare the utility of the new technologies being developed. Here, we review outcome measures used in the literature to evaluate the senses of ownership, body-representation, and agency. We categorize these existing measures based on the fundamental psychometric property measured and whether it is a behavioral or physiological measure. We present arguments for the efficacy and pitfalls of each measure to guide better experimental designs and future outcome measure development. The purpose of this review is to aid prosthesis researchers and technology developers in understanding the concept of embodiment and selecting metrics to assess embodiment in their research. Advances in the ability to measure the embodiment of prosthetic devices have far-reaching implications in the improvement of prosthetic limbs as well as promoting a broader understanding of ourselves as embodied agents.
Impact of mindfulness on irrigation water consumption

As two irreversible trends—population growth and climate change advance further, demand for water conservation will increase. Since irrigation is the major source of use (and waste) of freshwater, the professionals in this field will be under pressure to find innovative ways to increase physical irrigation efficiency. Irrigation water management promotes the delivery of water in a quantity that meets the needs of the crop while avoiding runoff and prolonged soil saturation. Water and energy can be conserved by improving application precision and decreasing unused applications. The adoption of water conservation technologies do not always increase the physical irrigation efficiency. Paradoxically, in many cases it may also increase water withdrawal. However, there are non-economic reasons because of which farmers invest their time and effort to reduce wastage of water. Higher irrigation efficiency is likely to depend on behavioral characteristics of the farmer. This research looks at whether mindfulness is one of the characteristics that influences water conservation. It also looks at the mechanism of this effect and the mediating role of environmental concern. It is found that mindfulness has a direct effect as also an indirect effect (through environmental concern) on increase in physical irrigation efficiency. The estimated effect of mindfulness through environmental concern is about two-thirds of the total effect, the remaining one-third of the effect coming directly from mindfulness.
Yao medicine Amydrium hainanense suppresses hepatic fibrosis by repressing hepatic stellate cell activation via STAT3 signaling

Ethnopharmacological relevance: Hepatic fibrosis (HF) occurs in response to chronic liver injury and may easily develop into irreversible liver cirrhosis or even liver cancer. Amydrium hainanense water extract (AHWE) is a water-soluble component extracted from the Yao medicine Amydrium hainanense (H.Li, Y.Shiao & S.L.Tseng) H.Li, which is commonly used for treating inflammatory diseases in folk. Previous evidence suggested that AHWE significantly inhibited hepatic stellate cell activation. However, little is known regarding the therapeutic effect of AHWE in HF and its underlying action mechanism. Objective: Investigation of the therapeutic effect of AHWE in HF and its underlying mechanism. Methods: The therapeutic effect of AHWE was tested in vivo using an HF mouse model via an intraperitoneal injection of carbon tetrachloride (CCl4). Histological evaluation of liver injury and fibrosis were tested by H&E staining and Masson’s trichrome staining. Serum levels of ALT, AST, collagen type I (Col I), and hydroxyproline (HYP) were measured. The mRNA expression of liver fibrotic and inflammatory genes were tested, and the protein levels of alpha smooth muscle actin (α-SMA) and signal transducers and activators of transcription 3 (STAT3) were analyzed. The in vitro experiments were conducted using HSC-T6 and RAW264.7 cell lines. Results: Treatment with AHWE significantly reversed histopathological liver damage and liver function abnormalities in CCl4 mouse model. Also, the serum levels of ALT, AST, Col I, and HYP in CCl4-induced HF mice were improved in AHWE treatment. Further, AHWE showed a remarkable inhibitory effect on the expression of fibrosis markers (Acta2, Col1a1, and Col3a1) and inflammatory factors (Stat3, Tnfa, Il6, and Il1b) induced by CCl4. The results of in vitro experiments were consistent with those obtained in vivo. In addition, it is shown that STAT3 signaling was involved in the anti-fibrotic effects of AHWE as evidenced by STAT3 overexpression. Conclusion: The present study proposed a novel ethnomedicine for HF and suggested the underlying role of STAT3 signaling pathway regulation in this anti-fibrotic effect of the proposed medicine. These findings would serve as solid scientific evidence in support of the development of AHWE as a novel alternative or complementary therapy for HF prevention and treatment.
Neuroanatomical and psychological considerations in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is associated with a variety of structural and psychological alterations. Recently, there has been renewed interest in using brain tissue resected during epilepsy surgery, in particular ‘non-epileptic’ brain samples with normal histology that can be found alongside epileptic tissue in the same epileptic patients — with the aim being to study the normal human brain organization using a variety of methods. An important limitation is that different medical characteristics of the patients may modify the brain tissue. Thus, to better determine how ‘normal’ the resected tissue is, it is fundamental to know certain clinical, anatomical and psychological characteristics of the patients. Unfortunately, this information is frequently not fully available for the patient from which the resected tissue has been obtained — or is not fully appreciated by the neuroscientists analyzing the brain samples, who are not necessarily experts in epilepsy. In order to present the full picture of TLE in a way that would be accessible to multiple communities (e.g., basic researchers in neuroscience, neurologists, neurosurgeons and psychologists), we have reviewed 34 TLE patients, who were selected due to the availability of detailed clinical, anatomical, and psychological information for each of the patients. Our aim was to convey the full complexity of the disorder, its putative anatomical substrates, and the wide range of individual variability, with a view toward: (1) emphasizing the importance of considering critical patient information when using brain samples for basic research and (2) gaining a better understanding of normal and abnormal brain functioning. In agreement with a large number of previous reports, this study (1) reinforces the notion of substantial individual variability among epileptic patients, and (2) highlights the common but overlooked psychopathological alterations that occur even in patients who become “seizure-free” after surgery. The first point is based on pre- and post-surgical comparisons of patients with hippocampal sclerosis and patients with normal-looking hippocampus in neuropsychological evaluations. The second emerges from our extensive battery of personality and projective tests, in a two-way comparison of these two types of patients with regard to pre- and post-surgical performance.
Spatial genetic patterns in African wild dogs reveal signs of effective dispersal across southern Africa

Across much of Africa, decades of civil war, land reforms, and persecution by humans have decimated wildlife populations. African wild dogs (Lycaon pictus) have declined dramatically during the past decades, but have shown recent natural recolonisation of some areas. In Angola, they were rediscovered after almost five decades when no surveys were being conducted, and they have recolonised areas in southern Zimbabwe and northern South Africa. Wild dogs were also reintroduced to Mozambique, where only few individuals remained. Against this backdrop, understanding genetic structure and effective dispersal between fragmented populations is essential to ensure the best conservation approaches for the long-term survival of the species. Our study investigated population genetic diversity, differentiation and gene flow of wild dogs across southern Africa, to include areas where they have recently been rediscovered, reestablished or reintroduced. Our results point to four weakly differentiated genetic clusters, representing the lowveld of Zimbabwe/Limpopo, Kruger NP, Angola/KAZA-TFCA, and the managed metapopulation, counterbalanced by moderate levels of effective dispersal on a southern African scale. Our results suggest that if the human footprint and impact can be significantly minimized, natural dispersal of wild dogs could lead to the demographic recovery of the species in southern Africa.