Miracle-dz/UniFAR-FTUs huggingface dataset:
Modeling and Predicting Tumor Response in Radioligand Therapy

The aim of this work was to develop a theranostic method that allows prediction of prostate-specific membrane antigen (PSMA)–positive tumor volume after radioligand therapy (RLT) based on a pretherapeutic PET/CT measurement and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling at the example of RLT using 177Lu-labeled PSMA for imaging and therapy (PSMA I&T). Methods: A recently developed PBPK model for 177Lu-PSMA I&T RLT was extended to account for tumor (exponential) growth and reduction due to irradiation (linear quadratic model). Data from 13 patients with metastatic castration-resistant prostate cancer were retrospectively analyzed. Pharmacokinetic/pharmacodynamic parameters were simultaneously fitted in a Bayesian framework to PET/CT activity concentrations, planar scintigraphy data, and tumor volumes before and after (6 wk) therapy. The method was validated using the leave-one-out Jackknife method. The tumor volume after therapy was predicted on the basis of pretherapy PET/CT imaging and PBPK/PD modeling. Results: The relative deviation of the predicted and measured tumor volume for PSMA-positive tumor cells (6 wk after therapy) was 1% ± 40%, excluding 1 patient (prostate-specific antigen–negative) from the population. The radiosensitivity for the prostate-specific antigen–positive patients was determined to be 0.0172 ± 0.0084 Gy−1. Conclusion: To our knowledge, the proposed method is the first attempt to solely use PET/CT and modeling methods to predict the PSMA-positive tumor volume after RLT. Internal validation shows that this is feasible with an acceptable accuracy. Improvement of the method and external validation of the model is ongoing.
Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

Background/Aims: Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. Current evidence has revealed the key roles of long non-coding RNAs (IncRNAs) in multiple cancers, including CRC. In this study we identified the lncRNA SH3PXD2A-AS1 as a novel molecule associated with CRC progression by analyzing the publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to examine the expression levels of SH3PXD2A-AS1 in CRC tissue samples and CRC cell lines. Cell viability examination, colony-formation experiments, ethynyl deoxyuridine (Edu) assays and flow cytometry were performed to investigate the roles of SH3PXD2A-AS1 in CRC proliferation, cell cycle regulation, and apoptosis. Transwell assays were used to explore the effects of SH3PXD2A-AS1 on CRC cells migration and invasion. A nude mice model was used to assess the effects of SH3PXD2A-AS1 on tumorigenesis in vivo. Subcellular fractionation, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays were conducted to detect the molecular mechanisms of SH3PXD2A-ASl-mediated gene expression. Rescue assays were used to determine whether P57 and Kruppel-like factor 2 (KLF2) were involved in SH3PXD2A-ASl-dependent CRC proliferation. Results: We firstly found that SH3PXD2A-AS1 was significantly upregulated in CRC tissues and cell lines, and overexpression of SH3PXD2A-AS1 was correlated with tumor size, TNM stage, and lymph node metastasis in patients with CRC. Furthermore, SH3PXD2A-AS1 knockdown inhibited CRC cells proliferation, migration and invasion in vitro, and suppressed tumorigenesis in vivo. Mechanistic studies indicated that SH3PXD2A-AS1 could epiqenetically repress P57 and KLF2 expression through interaction with EZH2. Rescue experiments suggested that SH3PXD2A-ASl-mediated oncogenesis was impaired by overexpression of P57 or KLF2. Interestingly, the expression of SH3PXD2A-AS1 was inversely correlated with the expression of P57 and KLF2 in CRC tissue samples. Conclusion: Our research presents the first evidence that SH3PXD2A-AS1 acts as an oncogene in CRC, and may be a promising diagnostic or therapeutic target in patients with CRC.
Big data and the global economy

Peculiarities of the global economy development are analyzed in this paper. The imbalance between financial and real sectors of global economy is a typical feature of its modern development. The method of analysis is also expressed in this paper. The analysis of the global economy development in context of the growing gap between the real and financial sectors is based on the system of leading indicators. Index of stability of the global economy in context of the growing gap between real and financial sectors is suggested. The index of stability allows to indicate the crisis periods. The structure of statistical data for the analysis of the global economy development allows to define the structure of the database.
Effect of Substrates on the Properties of ZnO Thin Films Grown by Pulsed Laser Deposition

Polycrystalline zinc oxide (ZnO) thin films have been deposited at 450°C onto glass and silicon substrates by pulsed laser deposition technique (PLD). The used source was a KrF excimer laser (248 nm, 25 ns, 5 Hz, 2 J/cm2). The effects of glass and silicon substrates on structural and optical properties of ZnO films have been investigated. X-ray diffraction patterns showed that ZnO films are polycrystalline with a hexagonal wurtzite—type structure with a strong (103) orientation and have a good crystallinity on monocrystalline Si(100) substrate. The thickness and compositional depth profile were studied by Rutherford Backscattering spectrometry (RBS). The average transmittance of ZnO films deposited on glass substrate in the visible range is 70%.
The HLA-G Genetic Contribution to Bipolar Disorder: A Trans-Ethnic Replication

ABSTRACT Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection. Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC. Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development.
Numerical modeling of two-photon focal modulation microscopy with a sinusoidal phase filter

Abstract. A spatiotemporal phase modulator (STPM) is theoretically investigated using the vectorial diffraction theory. The STPM is equivalent to a time-dependent phase-only pupil filter that alternates between a homogeneous filter and a stripe-shaped filter with a sinusoidal phase distribution. It is found that two-photon focal modulation microscopy (TPFMM) using this STPM can significantly suppress the background contribution from out-of-focus ballistic excitation and achieve almost the same resolution as two-photon microscopy. The modulation depth is also evaluated and a compromise exists between the signal-to-background ratio and signal-to-noise ratio. The theoretical investigations provide important insights into future implementations of TPFMM and its potential to further extend the penetration depth of nonlinear microscopy in imaging multiple-scattering biological tissues.
New algorithms for sparse representation of discrete signals based on ℓp-ℓ2 optimization

This paper investigates a nonconvex relaxation of the popular ℓ<inf>1</inf>-ℓ<inf>2</inf> formulation for finding sparse representation of discrete signals in overcomplete dictionary. The specific nonconvex problem we propose to solve is an ℓ<inf>p</inf>-ℓ<inf>2</inf> problem with 0 < p < 1. Our algorithms are built on a recent algorithm, known as the monotone fast iterative shrinkage/thresholding algorithm, where a key step of soft shrinkage is replaced by a global solver for the minimization of a 1-D nonconvex ℓ<inf>p</inf> problem. Two efficient techniques for solving the 1-D ℓ<inf>p</inf> problem in question are proposed. Simulation studies are presented to evaluate the performance of the proposed algorithms with various values of p and compare with the well known basis pursuit (BP) algorithm with p = 1.
Mastering dependencies in multi-language software applications

In software development, developers use source-code restructurings or refactorings to preserve or improve a source-code’s maintainability, that is, the source-code’s capability to be adopted to new requirements. For that purpose, a refactoring modifies the source-code’s structure without modifying the behavior implemented by the sourcecode. Practitioners and researchers formulated a number of refactorings for different programming languages and programming paradigms. Usually, software developers use more than a single programming language to implement a software application. For instance, software developers embed SQL statements in the source-code of a general-purpose language to create, read, modify, and delete datasets in a database. The practice of using more than one programming language is called polyglot programming. The result of polyglot programming is a Multi-Language Software Application (MLSA) in which source-code of many languages interact. Though polyglot programming is common in software development, refactorings are defined for source-code of a single programming language or programming paradigm. However, by restructuring source code of a single language the interaction in an MLSA can break. We give examples how refactoring can break a database application comprising the object-oriented, the functional, and the relational paradigm. We also discuss why a general approach to automated refactorings for MLSAs, so called multi-language refactorings, are hard to realize. Our goal is to provide sufficient support for software developers who refactor an MLSA. For that purpose, we introduce an approach that takes the challenges in refactoring MLSAs into account. We present implementations of our approach for two programmingparadigm pairs: the object-oriented and relational paradigm and the object-oriented and functional paradigm. Finally, we report the results of an evaluation of one of our tools. The evaluation studied the effect of our tool on the development performance of 79 participants who are asked to fix an MLSA with broken language interaction.
Complement system's role in cancer and its therapeutic potential in ovarian cancer

Cancer immunotherapy is a strong candidate for the long‐awaited new edition to standard cancer therapies. For an effective immunotherapy, it is imperative to delineate the players of antitumour immune response. As an important innate immune system effector mechanism, complement is highly likely to play a substantial role in cancer immunity. Studies suggest that there may be two different “states of complement” that show opposing effects on cancer cells; a complement profile that has antitumour effects with low expression of membrane‐bound complement regulator proteins (mCRPs), lytic membrane attack complex (MAC) concentration and moderate C5a concentration, and a complement profile that has protumour effects with high expression of mCRPs, sublytic MAC and high concentrations of C5a. One of the cancers that urgently require innovative therapeutic approaches is ovarian cancer, and complement has a potential to be a good target for this purpose. A combinatorial approach where the complement cascade is fine‐tuned by inhibiting some of its activities while promoting the others can prove to be a fruitful approach. Herein, we will briefly discuss the cancer‐immune system interaction and then present a discussion of complement system's role in tumour immunity and its therapeutic potential for ovarian cancer immunotherapy.
Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development

Chondrocyte hypertrophy is the terminal step in chondrocyte differentiation and is crucial for endochondral bone formation. How signaling pathways regulate chondrocyte hypertrophic differentiation remains incompletely understood. In this study, using a Tbx18:Cre (Tbx18Cre/+) gene-deletion approach, we selectively deleted the gene for the signaling protein SMAD family member 4 (Smad4f/f) in the limbs of mice. We found that the Smad4-deficient mice develop a prominent shortened limb, with decreased expression of chondrocyte differentiation markers, including Col2a1 and Acan, in the humerus at mid-to-late gestation. The most striking defects in these mice were the absence of stylopod elements and failure of chondrocyte hypertrophy in the humerus. Moreover, expression levels of the chondrocyte hypertrophy–related markers Col10a1 and Panx3 were significantly decreased. Of note, we also observed that the expression of runt-related transcription factor 2 (Runx2), a critical mediator of chondrocyte hypertrophy, was also down-regulated in Smad4-deficient limbs. To determine how the skeletal defects arose in the mouse mutants, we performed RNA-Seq with ChIP-Seq analyses and found that Smad4 directly binds to regulatory elements in the Runx2 promoter. Our results suggest a new mechanism whereby Smad4 controls chondrocyte hypertrophy by up-regulating Runx2 expression during skeletal development. The regulatory mechanism involving Smad4-mediated Runx2 activation uncovered here provides critical insights into bone development and pathogenesis of chondrodysplasia.
One "Ruler" for All Languages: Multi-Lingual Dialogue Evaluation with Adversarial Multi-Task Learning

Automatic evaluating the performance of Open-domain dialogue system is a challenging problem. Recent work in neural network-based metrics has shown promising opportunities for automatic dialogue evaluation. However, existing methods mainly focus on monolingual evaluation, in which the trained metric is not flexible enough to transfer across different languages. To address this issue, we propose an adversarial multi-task neural metric (ADVMT) for multi-lingual dialogue evaluation, with shared feature extraction across languages. We evaluate the proposed model in two different languages. Experiments show that the adversarial multi-task neural metric achieves a high correlation with human annotation, which yields better performance than monolingual ones and various existing metrics.
The Disordered C-Terminus of Yeast Hsf1 Contains a Cryptic Low-Complexity Amyloidogenic Region

Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap. It could be that the same principle applies for disordered protein regions. In this context, we show here that a predicted low-complexity interacting region in the disordered C-terminus of the stress response master regulator heat shock factor 1 (Hsf1) protein corresponds to a cryptic amyloid region able to self-assemble into fibrillary structures resembling those found in neurodegenerative disorders.
Loneliness of University Students and Its Relationship with Serf-concealment,Serf-disclosure,Coping Style and Perceived Social Support

Objective:To investigate the impact of self-concealment,self-disclosure,coping style and per- ceived social support on university students'loneliness.Methods:Loneliness and related factors were assessed among 482 university students using scales including UCLA Loneliness Scale,Self-concealment Scale(SCS),Self-disclosure Index(SDI),Simplified Coping Style Questionnaire(SCSQ)and Perceived Social Support Scale(PSSS). Results: The level of university students'loneliness was not high(36.5±7.4);males experienced more loneliness than fe- males(37.4±7.5/35.4±7.3,F=8.25,P0.01);There was no significant grades differences(P0.05). Regression analysis showed that SCS,SCSQ and PSSS predicted UCLA effectively(β=0.207,-0.218,0.157, -0.380). The testing of mediating effect indicated that SCS had direct and indirect impact on UCLA through nega- tive coping style and PSSS;SDI had only indirect impact on UCLA through positive coping style and PSSS.Conclusion:SCS,SDI,SCSQ and PSSS are important factors influencing UCLA,and the intervention of univer- sity students'loneliness should focus on these variables.
Recurrent bridgehead effects accelerate global alien ant spread

Significance Because of the globalization of trade and travel, worldwide invasion rates are high. A potential driver of the global acceleration of new invasions is the so-called bridgehead effect, in which initial invasive populations serve as the source of additional invasions via secondary introductions. However, the frequency and overall importance of secondary introductions remain largely unknown. Using a remarkable dataset, spanning nearly 100 years (1914–2013), of ant interceptions at air and maritime ports in the United States and New Zealand, we found that most ant introductions arise via secondary transport via intermediate regions. Our analyses also reveal positive feedback between the introduction and establishment stages of the invasion process via secondary introductions acting as a critical driver of increasing global invasion rates. Biological invasions are a major threat to biological diversity, agriculture, and human health. To predict and prevent new invasions, it is crucial to develop a better understanding of the drivers of the invasion process. The analysis of 4,533 border interception events revealed that at least 51 different alien ant species were intercepted at US ports over a period of 70 years (1914–1984), and 45 alien species were intercepted entering New Zealand over a period of 68 years (1955–2013). Most of the interceptions did not originate from species’ native ranges but instead came from invaded areas. In the United States, 75.7% of the interceptions came from a country where the intercepted ant species had been previously introduced. In New Zealand, this value was even higher, at 87.8%. There was an overrepresentation of interceptions from nearby locations (Latin America for species intercepted in the United States and Oceania for species intercepted in New Zealand). The probability of a species’ successful establishment in both the United States and New Zealand was positively related to the number of interceptions of the species in these countries. Moreover, species that have spread to more continents are also more likely to be intercepted and to make secondary introductions. This creates a positive feedback loop between the introduction and establishment stages of the invasion process, in which initial establishments promote secondary introductions. Overall, these results reveal that secondary introductions act as a critical driver of increasing global rates of invasions.
Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factors

Significance In this study, we demonstrate a platform for reprogramming somatic cells with high efficiency in the absence of exogenous reprogramming factors. Sustained laterally confined growth of cells on micropatterned substrates results in sequential changes to the nucleus and chromatin with each cell division, leading to the progressive erasure of lineage specific characteristics and incorporation of pluripotency. After 10 days of confined growth, the cells exhibit stemness and have multilineage differentiation potential. Our observation highlights a previously unknown role of mechanical constraints in nuclear reprogramming. Our method provides a unique approach to greatly improve stem cell technologies for developing patient specific disease models and regenerative medicine. Cells in tissues undergo transdifferentiation programs when stimulated by specific mechanical and biochemical signals. While seminal studies have demonstrated that exogenous biochemical factors can reprogram somatic cells into pluripotent stem cells, the critical roles played by mechanical signals in such reprogramming process have not been well documented. In this paper, we show that laterally confined growth of fibroblasts on micropatterned substrates induces nuclear reprogramming with high efficiency in the absence of any exogenous reprogramming factors. We provide compelling evidence on the induction of stem cell-like properties using alkaline phosphatase assays and expression of pluripotent markers. Early onset of reprogramming was accompanied with enhanced nuclear dynamics and changes in chromosome intermingling degrees, potentially facilitating rewiring of the genome. Time-lapse analysis of promoter occupancy by immunoprecipitation of H3K9Ac chromatin fragments revealed that epithelial, proliferative, and reprogramming gene promoters were progressively acetylated, while mesenchymal promoters were deacetylated by 10 days. Consistently, RNA sequencing analysis showed a systematic progression from mesenchymal to stem cell transcriptome, highlighting pathways involving mechanisms underlying nuclear reprogramming. We then demonstrated that these mechanically reprogrammed cells could be maintained as stem cells and can be redifferentiated into multiple lineages with high efficiency. Importantly, we also demonstrate the induction of cancer stemness properties in MCF7 cells grown in such laterally confined conditions. Collectively, our results highlight an important generic property of somatic cells that, when grown in laterally confined conditions, acquire stemness. Such mechanical reprogramming of somatic cells demonstrated here has important implications in tissue regeneration and disease models.