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Visual Question Answering (VQA) is the problem of automatically answering a natural language question about a given image or video. Standard Arabic is the sixth most spoken language around the world. However, to the best of our knowledge, there are neither research attempts nor datasets for VQA in Arabic. In this paper, we generate the first Visual Arabic Question Answering (VAQA) dataset, which is fully automatically generated. The dataset consists of almost 138k Image-Question-Answer (IQA) triplets and is specialized in yes/no questions about real-world images. A novel database schema and an IQA ground-truth generation algorithm are specially designed to facilitate automatic VAQA dataset creation. We propose the first Arabic-VQA system, where the VQA task is formulated as a binary classification problem. The proposed system consists of five modules, namely visual features extraction, question pre-processing, textual features extraction, feature fusion, and answer prediction. Since it is the first research for VQA in Arabic, we investigate several approaches in the question channel, to identify the most effective approaches for Arabic question pre-processing and representation. For this purpose, 24 Arabic-VQA models are developed, where two question-tokenization approaches, three word-embedding algorithms, and four LSTM networks with different architectures are investigated. A comprehensive performance comparison is conducted between all these Arabic-VQA models on the VAQA dataset. Experiments indicate that the performance of all Arabic-VQA models ranges from 80.8 to 84.9%, while utilizing Arabic-specified question pre-processing approaches of considering the special case of separating the question tool "Image missing" and embedding the question words using fine-tuned Word2Vec models from AraVec2.0 have significantly improved the performance. The best-performing model is which treats the question tool "Image missing" as a separate token, embeds the question words using AraVec2.0 Skip-Gram model, and extracts the textual feature using one-layer unidirectional LSTM. Further, our best Arabic-VQA model is compared with related VQA models developed on other popular VQA datasets in a different natural language, considering their performance only on yes/no questions according to the scope of this paper, showing a very comparable performance.

In some shape-memory single crystals the stress–strain (σ~ε) curves, belonging to stress induced martensitic transformations from austenite to martensite at fixed temperature, instead of being the usual slightly increasing function or horizontal, have an overall negative slope with sudden stress drops in it. We discuss this phenomenon by using a local equilibrium thermodynamic approach and analysing the sign of the second derivative of the difference of the Gibbs free energy. We show that, considering also the possible nucleation and growth of two martensite structural modifications/variants, the stress–strain loops can be unstable. This means that the overall slope of the uploading branch of the stress–strain curve can be negative for smooth transformation if the second martensite, which is more stable with larger transformation strain, is the final product. We also show that local stress-drops on the stress–strain curve can appear if the nucleation of the second martensite is difficult, and the presence of such local stress-drops alone can also result in an overall negative slope of the stress–strain curves. It is illustrated that the increase of the temperature of the thermal recovery during burst-like transition is a measure of the change of the nucleation energy: the more stable martensite has larger nucleation energy.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

Gain-of-function mutations in the protein-tyrosine phosphatase SHP2 are the most frequently occurring mutations in sporadic juvenile myelomonocytic leukemia (JMML) and JMML-like myeloproliferative neoplasm (MPN) associated with Noonan syndrome (NS). Hematopoietic stem and progenitor cells (HSPCs) are the disease propagating cells of JMML. Here, we explored transcriptomes of HSPCs with SHP2 mutations derived from JMML patients and a novel NS zebrafish model. In addition to major NS traits, CRISPR/Cas9 knock-in Shp2Juvenile myelomonocytic leukaemia is a childhood blood cancer. It is more common in children with a genetic condition called Noonan Syndrome, which causes problems with development in many parts of the body. The most frequent cause is a mutation in a protein called Src homology region 2 domain-containing phosphatase-2, or SHP2 for short. Juvenile myelomonocytic leukaemia starts in the stem cells that normally become blood cells. In children with Noonan Syndrome, these cells show signs of problems before leukaemia begins. Recreating Noonan Syndrome in an animal could shed light on how this childhood cancer develops, but doing this is not straightforward. One option is to use zebrafish, a species of fish in which the embryos are transparent, allowing scientists to watch their blood cells developing under a microscope. They also share many genes with humans, including SHP2. Solman et al. genetically modified zebrafish so they would carry one of the most common mutations seen in children with Noonan Syndrome in the SHP2 protein. The fish had many of the typical features of the condition, including problems producing blood cells. Single cell analysis of the stem cells that become these blood cells showed that, in the mutated fish, these cells had abnormally high levels of activity in genes involved in inflammation. Treating the fish with an anti-inflammatory drug, dexamethasone, reversed the problem. When Solman et al. investigated stem cells from human patients with juvenile myelomonocytic leukaemia, they found the same high levels of activity in inflammatory genes. The current treatment for juvenile myelomonocytic leukaemia is a stem cell transplant, which is only successful in around half of cases. Finding a way to prevent the cancer from developing altogether could save lives. This new line of zebrafish allows researchers to study Noonan Syndrome in more detail, and to test new treatments. A next step could be to find out whether anti-inflammatory drugs have the same effects in mammals as they do in fish.

Contains fulltext : 281498.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cohesinopathies is a term that refers to/covers rare genetic diseases caused by mutations in the cohesin complex proteins. The cohesin complex is a multiprotein complex that facilitates different aspects of cell division, gene transcription, DNA damage repair, and chromosome architecture. Shugoshin proteins prevent the cohesin complex from premature dissociation from chromatids during cell division. Patients with a homozygous missense mutation in SGO1, which encodes for Shugoshin1, have problems with normal pacing of the heart and gut. RESULTS: To study the role of shugoshin during embryo development, we mutated the zebrafish sgo1 gene. Homozygous sgo1 mutant embryos display various phenotypes related to different organs, including a reduced heart rate accompanied by reduced cardiac function. In addition, sgo1 mutants are vision-impaired as a consequence of structurally defective and partially non-functional photoreceptor cells. Furthermore, the sgo1 mutants display reduced food intake and early lethality. CONCLUSION: We have generated a zebrafish model of Sgo1 that showed its importance during organ development and function.

Cardiomyopathies are a group of heterogeneous diseases that affect the muscles of the heart, leading to early morbidity and mortality in young and adults. Genetic forms of cardiomyopathy are caused predominantly by mutations in structural components of the cardiomyocyte sarcomeres, the contractile units of the heart, which includes cardiac Troponin T (TnT). Here, we generated mutations with CRISPR/Cas9 technology in the zebrafish tnnt2a gene, encoding cardiac TnT, at a mutational “hotspot” site to establish a zebrafish model for genetic cardiomyopathies. We found that a heterozygous tnnt2a mutation deleting Arginine at position 94 and Lysine at position 95 of TnT causes progressive cardiac structural changes resulting in heart failure. The cardiac remodeling is presented by an enlarged atrium, decreased ventricle size, increased myocardial stress as well as increased fibrosis. As early as five days post fertilization, larvae carrying the TnT RK94del mutation display diastolic dysfunction and impaired calcium dynamics related to increased Ca2+ sensitivity. In conclusion, adult zebrafish with a heterozygous TnT-RK94del mutation develop cardiomyopathy as seen in patients with TnT mutations and therefore represent a promising model to study disease mechanisms and to screen for putative therapeutic compounds.

There are many systems producing crackling noise (avalanches) in materials. Temporal shapes of avalanches, U(t) (U is the detected voltage signal, t is the time), have self-similar behaviour and the normalized U(t) function (e.g., dividing both the values of U and t by S1/2, where S is the avalanche area), averaged for fixed S, should be the same, independently of the type of materials or avalanche mechanisms. However, there are experimental evidences that the temporal shapes of avalanches do not scale completely in a universal way. The self-similarity also leads to universal power-law-scaling relations, e.g., between the energy, E, and the peak amplitude, Am, or between S and Am. There are well-known enigmas, where the above exponents in acoustic emission measurements are rather close to 2 and 1, respectively, instead of E~Am3 and S~Am2, obtained from the mean field theory, MFT. We show, using a theoretically predicted averaged function for the fixed avalanche area, U(t)=atexp(−bt2) (where a and b are non-universal, material-dependent constants), that the scaling exponents can be different from the MFT values. Normalizing U by Am and t by tm (the time belonging to the Am: rise time), we obtain tm~Am1−φ (the MFT values can be obtained only if φ would be zero). Here, φ is expected to be material-independent and to be the same for the same mechanism. Using experimental results on martensitic transformations in two different shape-memory single-crystals, φ = 0.8 ± 0.1 was obtained (φ is the same for both alloys). Thus, dividing U by Am as well as t by Am1−φ (~tm) leads to the same common, normalized temporal shape for different, fixed values of S. This normalization can also be used in general for other experimental results (not only for acoustic emission), which provide information about jerky noises in materials.

The heterozygous phospholamban (PLN) p.Arg14del (R14del) mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. The PLN R14del mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding PLN R14del induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we addressed these issues using a knock-in PLN R14del zebrafish model. Hearts from adult zebrafish with the R14del mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography revealed contractile pulsus alternans before overt structural changes occurred, which correlated at the cellular level with action potential duration (APD) alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts. We found that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular APD alternans, while it improves cardiac relaxation. Thus, we present novel insight into the pathophysiology of PLN R14del cardiomyopathy and identify istaroxime as a potential novel drug for its treatment.

Pheochromocytomas and paragangliomas (PPGLs) caused by mutations in the B-subunit of the succinate dehydrogenase (SDHB) have the highest metastatic rate among PPGLs, and effective systemic therapy is lacking. To unravel underlying pathogenic mechanisms, and to evaluate therapeutic strategies, suitable in vivo models are needed. The available systemic Sdhb knock-out mice cannot model the human PPGL phenotype: heterozygous Sdhb mice lack a disease phenotype, and homozygous Sdhb mice are embryonically lethal. Using CRISPR/cas9 technology, we introduced a protein-truncating germline lesion into the zebrafish sdhb gene. Heterozygous sdhb mutants were viable and displayed no obvious morphological or developmental defects. Homozygous sdhb larvae were viable, but exhibited a decreased lifespan. Morphological analysis revealed incompletely or non-inflated swim bladders in homozygous sdhb mutants at day 6. Although no differences in number and ultrastructure of the mitochondria were observed. Clear defects in energy metabolism and swimming behavior were observed in homozygous sdhb mutant larvae. Functional and metabolomic analyses revealed decreased mitochondrial complex 2 activity and significant succinate accumulation in the homozygous sdhb mutant larvae, mimicking the metabolic effects observed in SDHB-associated PPGLs. This is the first study to present a vertebrate animal model that mimics metabolic effects of SDHB-associated PPGLs. This model will be useful in unraveling pathomechanisms behind SDHB-associated PPGLs. We can now study the metabolic effects of sdhb disruption during different developmental stages and develop screening assays to identify novel therapeutic targets in vivo. Besides oncological syndromes, our model might also be useful for pediatric mitochondrial disease caused by loss of the SDHB gene.

The CXCR3‐CXCL11 chemokine‐signaling axis plays an essential role in infection and inflammation by orchestrating leukocyte trafficking in human and animal models, including zebrafish. Atypical chemokine receptors (ACKRs) play a fundamental regulatory function in signaling networks by shaping chemokine gradients through their ligand scavenging function, while being unable to signal in the classic G‐protein‐dependent manner. Two copies of the CXCR3 gene in zebrafish, cxcr3.2 and cxcr3.3, are expressed on macrophages and share a highly conserved ligand‐binding site. However, Cxcr3.3 has structural characteristics of ACKRs indicative of a ligand‐scavenging role. In contrast, we previously showed that Cxcr3.2 is an active CXCR3 receptor because it is required for macrophage motility and recruitment to sites of mycobacterial infection. In this study, we generated a cxcr3.3 CRISPR‐mutant to functionally dissect the antagonistic interplay among the cxcr3 paralogs in the immune response. We observed that cxcr3.3 mutants are more susceptible to mycobacterial infection, whereas cxcr3.2 mutants are more resistant. Furthermore, macrophages in the cxcr3.3 mutant are more motile, show higher activation status, and are recruited more efficiently to sites of infection or injury. Our results suggest that Cxcr3.3 is an ACKR that regulates the activity of Cxcr3.2 by scavenging common ligands and that silencing the scavenging function of Cxcr3.3 results in an exacerbated Cxcr3.2 signaling. In human, splice variants of CXCR3 have antagonistic functions and CXCR3 ligands also interact with ACKRs. Therefore, in zebrafish, an analogous regulatory mechanism appears to have evolved after the cxcr3 gene duplication event, through diversification of conventional and atypical receptor variants.

The CXCR3-CXCL11 chemokine-signaling axis plays an essential role in infection and inflammation by orchestrating leukocyte trafficking in human and animal models, including zebrafish. Atypical chemokine receptors (ACKRs) play a fundamental regulatory function in signaling networks by shaping chemokine gradients through their ligand scavenging function, while being unable to signal in the classic G-protein-dependent manner. Two copies of the CXCR3 gene in zebrafish, cxcr3.2 and cxcr3.3, are expressed on macrophages and share a highly conserved ligand-binding site. However, Cxcr3.3 has structural characteristics of ACKRs indicative of a ligand-scavenging role. In contrast, we previously showed that Cxcr3.2 is an active CXCR3 receptor since it is required for macrophage motility and recruitment to sites of mycobacterial infection. In this study, we generated a cxcr3.3 CRISPR-mutant to functionally dissect the antagonistic interplay between the cxcr3 paralogs in the immune response. We observed that cxcr3.3 mutants are more susceptible to mycobacterial infection, while cxcr3.2 mutants are more resistant. Furthermore, macrophages in the cxcr3.3 mutant are more motile, show higher activation status, and are recruited more efficiently to sites of infection or injury. Our results suggest that Cxcr3.3 is an ACKR that regulates the activity of Cxcr3.2 by scavenging common ligands and that silencing the scavenging function of Cxcr3.3 results in an exacerbated Cxcr3.2 signaling. In human, splice variants of CXCR3 have antagonistic functions and CXCR3 ligands also interact with ACKRs. Therefore, in zebrafish, an analogous regulatory mechanism appears to have evolved after the cxcr3 gene duplication event, through diversification of conventional and atypical receptor variants.Summary sentenceCXCR3 paralogue with structural characteristics of atypical chemokine receptors regulates the activity of a conventional receptor involved in macrophage motility by scavenging shared ligands.

Cofactor of BRCA1 (COBRA1) is one of the four subunits that make up the negative elongation factor (NELF) complex that is involved in the stalling of RNA polymerase II early during transcription elongation. As such, it regulates the expression of a substantial number of genes involved in cell cycle control, cellular metabolism and DNA repair. With no DNA binding domain, its capacity to modulate gene expression occurs via its ability to interact with different transcription factors. In the field of cancer, its role is not yet fully understood. In this study, we demonstrate the frequent overexpression of COBRA1 along with the remaining NELF subunits in hepatocellular carcinoma (HCC) tissues relative to non-cancerous liver tissues. To elucidate its biological significance in HCC, RNA interference was utilized to silence COBRA1 expression in the HCC cell line, HepG2. Interestingly, COBRA1 knockdown resulted in a significant decrease in cell proliferation and migration, accompanied by a concomitant reduction in the expression of the proliferation marker, Ki-67. Survivin, a proto-oncogene that is commonly upregulated in almost all human malignancies including HCC, was also significantly downregulated following COBRA1 silencing. This suggests that it might be one of the mechanisms by which COBRA1 mediates its role in HCC. Taken together, our data findings collectively highlight an important role for COBRA1 in supporting HCC proliferation and migration.

Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function., ABCC9 encodes the SUR2 subunit of KATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of KATP channel function.

Contraction of muscle reflects its physiological state. Methods to quantify contraction are often complex, expensive and tailored to specific models or recording conditions, or require specialist knowledge for data extraction. Here we describe an automated, open-source software tool (MUSCLEMOTION) adaptable for use with standard laboratory and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes and pharmacological responses. MUSCLEMOTION allowed rapid and easy measurement of contractility in (i) single cardiomyocytes from primary adult heart and human pluripotent stem cells, (ii) multicellular 2D-cardiomyocyte cultures, 3D engineered heart tissues and cardiac organoids/microtissues in vitro and (iii) intact hearts of zebrafish and humans in vivo. Good correlation was found with conventional measures of contraction in each system. Thus, using a single method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell- and animal models and human echocardiograms.

Rationale: There are several methods to measure cardiomyocyte and muscle contraction, but these require customized hardware, expensive apparatus, and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming, and only specialist researchers can quantify data. Objective: Here, we describe and validate an automated, open-source software tool (MUSCLEMOTION) adaptable for use with standard laboratory and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes, and pharmacological responses. Methods and Results: MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in (1) 1-dimensional in vitro models, such as isolated adult and human pluripotent stem cell-derived cardiomyocytes; (2) 2-dimensional in vitro models, such as beating cardiomyocyte monolayers or small clusters of human pluripotent stem cell-derived cardiomyocytes; (3) 3-dimensional multicellular in vitro or in vivo contractile tissues, such as cardiac “organoids,” engineered heart tissues, and zebrafish and human hearts. MUSCLEMOTION was effective under different recording conditions (bright-field microscopy with simultaneous patch-clamp recording, phase contrast microscopy, and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement, such as optical flow, post deflection, edge-detection systems, or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. Conclusions: Using a single open-source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell, animal, and human models.

Effective undergraduate teaching has always been a challenge. In 1987 Chickering & Gamson published the seven principles for good practice in undergraduate education, which was highly used and recommended by most practitioners, yet teaching basic science was still difficult. It is not easy to convey that in science negative results are as important as positive results. In fact, sometimes interpretation and troubleshooting are more important than the experiment itself. In order to make the students feel the importance of science and the importance of every experiment they are doing, the laboratory component of the course was designed as a small project through which they were taught important lessons. Every time an experiment failed, we (instructors) pointed out how it could serve the purpose of the project and how each result, whether positive or negative, leads us to another step and a better understanding of the project's goal. Other than the technical aspects of designing the course, we made sure that there's a strong bond between every student and us without compromising discipline, as it is the way to success and great achievements. Everyone had a talent and a skill that needed to be sculptured to unleash the great scientist –we believe- was in him or her. Our goal was to create an image and to set an example of how a scientist should be; manners, attitude, discipline and perseverance. By the end of the semester, the students were able to interpret, troubleshoot and report the results they collected throughout the whole semester in consolidated reports that mimicked published research papers. More importantly, they learned how to be scientists and they enjoyed learning science.