Miracle-dz/UniFAR-FTUs huggingface dataset:
Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord

Abstract Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.
Analysis of the signalling mechanisms involved in cell wall integrity maintenance in A. thaliana

3 ABBREVIATIONS . 4 ACKNOWLEDGMENTS . 5 COLLABORATIONS . 7 TABLE OF CONTENTS . 8 TABLE OF FIGURES . 11 CHAPTER 1 GENERAL INTRODUCTION . 14 1.1 THE PLANT CELL WALL . 14 1.1.1 PLANT CELL WALL STRUCTURE . 14 1.1.2 SYNTHESIS OF THE PLANT CELL WALL . 18 1.1.3 USEFULNESS OF A. THALIANA FOR STUDY OF THE PLANT CELL WALL . 21 1.1.4 THE PLANT CELL WALL EXISTS AS A CONTINUUM WITH THE PLASMA MEMBRANE . 23 1.1. 5 PLASTICITY OF THE PLANT CELL WALL . 25 1.2 CELL WALL INTEGRITY SIGNALLING IN YEAST . 27 1.3 CANDIDATE PLANT CELL WALL INTEGRITY SIGNALLING MECHANISMS . 30 1.3. 1 PLANT CELL WALL DERIVED SIGNALLING MOLECULES . 30 1.3. 2 RECEPTOR LIKE KINASES INVOLVEMENT IN CWI SENSING AND SIGNALLING . 32 1.3. 3 CARANANTHUS ROSEUS RLK-LIKE FAMILY (CRRLK) . 33 1.3. 4 WALL ASSOCIATED KINASES (WAKS) . 33 1.3. 5 PROLINE RICH EXTENSIN-LIKE RECEPTOR KINASES (PERKS) . 35 1.3. 6 LEGUMINOUS L-TYPE LECTIN RLKS (LECRKS) . 36 1.3. 7 MECHANO–SENSITIVE CHANNELS.36 1.4 AIMS . 41 CHAPTER 2 GENERAL MATERIALS AND METHODS . 42 2.1 A. THALIANA GROWTH CONDITIONS . 42 2.2 LIGNIN STAINING . 42 2.3 JA / SA / ABA QUANTIFICATION . 43 2.4 ROOT GROWTH INHIBITION (RGI) ASSAY . 44 2.5 RNA EXTRACTION . 45 2.6 CDNA SYNTHESIS . 45 2.7 QUANTITATIVE REAL TIME PCR (QRT-PCR) . 45 2.8 EVANS BLUE QUANTIFICATION OF CELL DEATH . 45 CHAPTER 3 ISOXABEN AS A TOOL FOR STUDYING CELL WALL DAMAGE . 47 3.
Intrinsic features of Zika Virus non-structural proteins NS2A and NS4A in the regulation of viral replication

Zika virus (ZIKV) is a mosquito-borne flavivirus and can cause neurodevelopmental disorders in fetus. As a neurotropic virus, ZIKV persistently infects neural tissues during pregnancy but the viral pathogenesis remains largely unknown. ZIKV has a positive-sense and single-stranded RNA genome, which encodes 7 non-structural (NS) proteins, participating in viral replication and dysregulation of host immunity. Like those in many other viruses, NS proteins are considered to be products evolutionarily beneficiary to viruses and some are virulence factors. However, we found that some NS proteins encoded by ZIKV genome appeared to function against the viral replication. In this report we showed that exogenously expressed ZIKV NS2A and NS4A inhibited ZIKV infection by inhibiting viral RNA replication in microglial cells and astrocytes. To understand how viral NS proteins suppressed viral replication, we analyzed the transcriptome of the microglial cells and astrocytes and found that expression of NS4A induced the upregulation of ISGs, including MX1/2, OAS1/2/3, IFITM1, IFIT1, IFI6, IFI27, ISG15 or BST2 through activating the ISGF3 signaling pathway. Upregulation of these ISGs seemed to be related to the inhibition of ZIKV replication, since the anti-ZIKV function of NS4A was partially attenuated when the cells were treated with Abrocitinib, an inhibitor of the ISGF3 signaling pathway, or were knocked down with STAT2. Aborting the protein expression of NS4A, but not its nucleic acid, eliminated the antiviral activity of NS4A effectively. Dynamic expression of viral NS proteins was examined in ZIKV-infected microglial cells and astrocytes, which showed comparatively NS4A occurred later than other NS proteins during the infection. We hypothesize that NS4A may possess intrinsic features to serve as a unique type of pathogen associated molecular pattern (PAMP), detectable by the cells to induce an innate immune response, or function with other mechanisms, to restrict the viral replication to a certain level as a negative feedback, which may help ZIKV maintain its persistent infection in fetal neural tissues.
Safety and efficacy of a feed additive consisting of butylated hydroxytoluene (BHT) for all animal species (Lanxess Deutschland GmbH)

Abstract Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of butylated hydroxytoluene (BHT) as a feed additive for all animal species. The additive BHT is considered safe for chickens for fattening and weaned piglets at the maximum proposed concentration of 150 mg/kg complete feed. This conclusion is extended to chickens reared for laying and extrapolated to pigs for fattening. In the absence of data, no conclusion on the safety for the other target species could be drawn. The exposure of the consumer to BHT from tissues and products of animals fed the additive ranged from 1% to 3% of the acceptable daily intake (ADI). The FEEDAP Panel concluded that the use of BHT as a feed additive at the proposed conditions of use is of no concern for the safety of the consumers. Exposure of the user to BHT via inhalation is likely; however, the Panel is not in the position to conclude on the potential inhalation toxicity of the additive. BHT is a skin and eye irritant, no conclusions can be drawn on the potential of the additive to be a skin sensitiser. In the absence of data, the FEEDAP Panel cannot conclude on the safety of BHT for the environment. The additive BHT is considered an efficacious antioxidant in feedingstuffs for all animal species.
Sexuality and relationship experiences of women with spinal cord injury: reflections from an Indian context

Abstract Spinal cord injury (SCI) is one of the most devastating physical disabilities. It leads to varying degrees of loss in sensations and mobility below the level of injury and causes loss in autonomic functions, such as bladder/bowel control, and sexual impairments. Research, mostly conducted in the developed western nations, reveals that coming to terms with one’s sexuality after SCI is most crucial for early reintegration in the society and quality of life for persons with SCI. Thus, experts advocate that the sexual rehabilitation of persons with SCI is an integral component of comprehensive rehabilitation. In the Indian context, however, the sexuality of persons with SCI, particularly women, has been largely overlooked by the disability rights movement, and discourses on gender, sexuality and rehabilitation. This article is based on an in-depth study of the experiences of sexuality and intimate relationships of 24 women with SCI in India. It demonstrates that sexuality and intimate relationships are integral aspects of health and well-being for women. But there are wide gaps in the sexual rehabilitation and support needs for women with SCI in India, making their sexual adjustment extremely challenging. By analysing women’s journeys of sexual adjustment and rediscovery of sexual pleasure that echo their voices as sexual beings, this article argues for the development of evidence-based and gender-sensitive sexual rehabilitation services for women with SCI in India.
Signaling repurposable drug combinations against COVID-19 by developing the heterogeneous deep herb-graph method

BACKGROUND Coronavirus disease 2019 (COVID-19) has spurred a boom in uncovering repurposable existing drugs. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication. MOTIVATION Current works of drug repurposing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are mostly limited to only focusing on chemical medicines, analysis of single drug targeting single SARS-CoV-2 protein, one-size-fits-all strategy using the same treatment (same drug) for different infected stages of SARS-CoV-2. To dilute these issues, we initially set the research focusing on herbal medicines. We then proposed a heterogeneous graph embedding method to signaled candidate repurposing herbs for each SARS-CoV-2 protein, and employed the variational graph convolutional network approach to recommend the precision herb combinations as the potential candidate treatments against the specific infected stage. METHOD We initially employed the virtual screening method to construct the 'Herb-Compound' and 'Compound-Protein' docking graph based on 480 herbal medicines, 12,735 associated chemical compounds and 24 SARS-CoV-2 proteins. Sequentially, the 'Herb-Compound-Protein' heterogeneous network was constructed by means of the metapath-based embedding approach. We then proposed the heterogeneous-information-network-based graph embedding method to generate the candidate ranking lists of herbs that target structural, nonstructural and accessory SARS-CoV-2 proteins, individually. To obtain precision synthetic effective treatments forvarious COVID-19 infected stages, we employed the variational graph convolutional network method to generate candidate herb combinations as the recommended therapeutic therapies. RESULTS There were 24 ranking lists, each containing top-10 herbs, targeting 24 SARS-CoV-2 proteins correspondingly, and 20 herb combinations were generated as the candidate-specific treatment to target the four infected stages. The code and supplementary materials are freely available at https://github.com/fanyang-AI/TCM-COVID19.
A multi-scale and multi-domain heart sound feature-based machine learning model for ACC/AHA heart failure stage classification

Objective. Heart sounds can reflect detrimental changes in cardiac mechanical activity that are common pathological characteristics of chronic heart failure (CHF). The ACC/AHA heart failure (HF) stage classification is essential for clinical decision-making and the management of CHF. Herein, a machine learning model that makes use of multi-scale and multi-domain heart sound features was proposed to provide an objective aid for ACC/AHA HF stage classification. Approach. A dataset containing phonocardiogram (PCG) signals from 275 subjects was obtained from two medical institutions and used in this study. Complementary ensemble empirical mode decomposition and tunable-Q wavelet transform were used to construct self-adaptive sub-sequences and multi-level sub-band signals for PCG signals. Time-domain, frequency-domain and nonlinear feature extraction were then applied to the original PCG signal, heart sound sub-sequences and sub-band signals to construct multi-scale and multi-domain heart sound features. The features selected via the least absolute shrinkage and selection operator were fed into a machine learning classifier for ACC/AHA HF stage classification. Finally, mainstream machine learning classifiers, including least-squares support vector machine (LS-SVM), deep belief network (DBN) and random forest (RF), were compared to determine the optimal model. Main results. The results showed that the LS-SVM, which utilized a combination of multi-scale and multi-domain features, achieved better classification performance than the DBN and RF using multi-scale or/and multi-domain features alone or together, with average sensitivity, specificity, and accuracy of 0.821, 0.955 and 0.820 on the testing set, respectively. Significance. PCG signal analysis provides efficient measurement information regarding CHF severity and is a promising noninvasive method for ACC/AHA HF stage classification.
Role of Kinesiotherapy in the Prevention of Heterotopic Ossification

Objective The role of kinesiotherapy in heterotopic ossification remains unclear. The goal of this study was to revisit the literature on the preventive role of kinesiotherapy against heterotopic ossification formation and maturation. Design A systematic review was performed in MEDLINE, OVID, Scopus, and Cochrane databases. Results A high-quality clinical trial is missing from the literature. Of 9617 studies primarily identified, nine studies offered the proper data and were included. They infer that satisfactory results on neurogenic heterotopic ossification prevention were achieved with passive exercises, including continuous passive motion, that were initiated early and at a painless range of motion. On the contrary, for elbow posttraumatic heterotopic ossification and major joints burn-associated heterotopic ossification, active range of motion is indicated as early as possible. Conclusions Because of the very low quality of the studies included in this review, firm conclusions cannot be drawn about the effectiveness of kinesiotherapy. Nevertheless, it is recommended that controlled passive range of motion exercises (especially continuous passive motion) be applied early and pain-free especially in the neurogenic heterotopic ossification patients while active range of motion in painless limits is beneficial in the heterotopic ossification prevention of traumatic elbows or burn joints.
Adipose tissue‐derived mesenchymal stem cells' acellular product extracellular vesicles as a potential therapy for Crohn's disease

The breakdown of gastrointestinal tract immune homeostasis leads to Crohn's disease (CD). Mesenchymal stem cells (MSCs) have demonstrated clinical efficacy in treating CD in clinical trials, but there is little known about the mechanism of healing. Considering the critical roles of macrophage polarization in CD and immunomodulatory properties of MSCs, we sought to decipher the interaction between adipose‐derived MSCs and macrophages, including their cytokine production, regulation of differentiation, and pro‐/anti‐inflammatory function. RNA extraction and next generation sequencing was performed in adipose tissue from healthy control patients' mesentery (n = 3) and CD mesentery (n = 3). Infiltrated macrophage activation in the CD mesentery was tested, MSCs and extracellular vesicles (EVs) were isolated to compare the regulation of macrophage differentiation, cytokines production, and self‐renewal capacities in vitro. CD patients' mesentery has increased M1 macrophage polarization and elevated activation. MSCs and their derived EVs, isolated from inflamed Crohn's mesentery, leads to a rapid differentiation of monocytes to a M1‐like polarized phenotype. Conversely, MSCs and their derived EVs from healthy, non‐Crohn's patients results in monocyte polarization into a M2 phenotype; this is seen regardless of the adipose source of MSCs (subcutaneous fat, omentum, normal mesentery). EVs derived from MSCs have the ability to regulate macrophage differentiation. Healthy MSCs and their associated EVs have the ability to drive monocytes to a M2 subset, effectively reversing an inflammatory phenotype. This mechanism supports why MSCs may be an effective therapeutic in CD and highlights EVs as a novel therapeutic for further exploration.
Exploring the Impact of Fuel Data Acquisition Technology on the USMC Expeditionary Energy Command and Control System

Abstract : Marine Corps commanders have inadequate tools for energy awareness on the battlefield. The purpose of this study is to explore how vehicle telematics could impact operational reach through improving awareness of fuel stocks from hours to near-real time. The research uses an exploratory sequential mixed methods design to establish how current practices may change with the introduction of telematics. The first-phase qualitative findings suggest that the tactical fuel supply chain is inherently unstable due to information delays and information processing distortion. The second phase tests the hypothesis that telematics has a positive effect on operational reach. This is accomplished through a supply chain simulation that compares the current process against a reengineered solution with telematics. Between the two models, the reengineered supply chain produced the opportunity for higher tempo, more agile combat units, and increased system stability. While these are desirable effects, operational reach was reduced by 7% as fuel was more available to combat units. In addition to fuel-saving initiatives that telematics may inform, there may be long-term benefits that warrant the full integration of fuel telematics throughout the military supply chain.
Periodontal disease affects oral cancer progression in a surrogate animal model for tobacco exposure

For decades, the link between poor oral hygiene and the increased prevalence of oral cancer has been suggested. Most recently, emerging evidence has suggested that chronic inflammatory diseases from the oral cavity (e.g., periodontal disease), to some extent, play a role in the development of oral squamous cell carcinoma (OSCC). The present study aimed to explore the direct impact of biofilm-induced periodontitis in the carcinogenesis process using a tobacco surrogate animal model for oral cancer. A total of 42 Wistar rats were distributed into four experimental groups: Control group, periodontitis (Perio) group, 4-nitroquinoline 1-oxide (4-NQO) group and 4NQO/Perio group. Periodontitis was stimulated by placing a ligature subgingivally, while oral carcinogenesis was induced by systemic administration of 4NQO in the drinking water for 20 weeks. It was observed that the Perio, 4NQO and 4NQO/Perio groups presented with significantly higher alveolar bone loss compared with that in the control group. Furthermore, all groups receiving 4NQO developed lesions on the dorsal surface of the tongue; however, the 4NQO/Perio group presented larger lesions compared with the 4NQO group. There was also a modest overall increase in the number of epithelial dysplasia and OSCC lesions in the 4NQO/Perio group. Notably, abnormal focal activation of cellular differentiation (cytokeratin 10-positive cells) that extended near the basal cell layer of the mucosa was observed in rats receiving 4NQO alone, but was absent in rats receiving 4NQO and presenting with periodontal disease. Altogether, the presence of periodontitis combined with 4NQO administration augmented tumor size in the current rat model and tampered with the protective mechanisms of the cellular differentiation of epithelial cells.
AMP activated kinase negatively regulates hepatic Fetuin-A via p38 MAPK-C/EBPβ/E3 Ubiquitin Ligase Signaling pathway

Fetuin-A (Fet-A) is a liver-secreted phosphorylated protein, known to impair insulin signaling, which has been shown to be associated with obesity, insulin resistance, and incident diabetes. Fet-A interacts with the insulin-stimulated insulin receptor (IR) and inhibits IR tyrosine kinase activity and glucose uptake. It has been shown that high glucose increases Fet-A expression through the ERK1/2 signaling pathway. However, factors that downregulate Fet-A expression and their potential mechanisms are unclear. We examined the effect of AMP-activated protein kinase (AMPK) on high-glucose induced Fet-A expression in HepG2 cells, Hep3B cells and primary rat hepatocytes. High glucose increased Fet-A and phosphorylated (Ser312) fetuin-A (pFet-A) expression, which are known to impair insulin signaling. AICAR-induced AMPK activation significantly down-regulated high glucose-induced Fet-A expression and secretion of pFet-A while treatment with Compound C (AMPK inhibitor), SB202190 (p38 MAPK inhibitor) or p38 MAPK siRNA transfection prevented AICAR-induced downregulation of Fet-A expression. In addition, activation of p38 MAPK, by anisomycin, decreased the hepatic expression of Fet-A. Further, we our studies have shown that short-term effect of AICAR-treatment on Fet-A expression was mediated by proteosomal degradation, and long-term treatment of AICAR was associated with decrease in hepatic expression of C/EBP beta, an important transcription factor involved in the regulation of Fet-A. Taken together, our studies implicate a critical role for AMPK-p38 MAPK-C/EBPb-ubiquitin-proteosomal axis in the regulation of the expression of hepatic Fet-A.
Considering similarity and the rating conversion of neighbors on neural collaborative filtering

One of the most popular recommender system techniques is collaborative filtering (CF). Nowadays, many researchers apply a neural network with CF, but few focus on the neighbors’ concept of CF. This work needs to consider two major issues: the similarity levels between the neighbors and the target user and the user’s rating pattern conversion. Because different neighbors have a different influence on the target user and different users usually have a different rating pattern, the ratings directly utilized by the neighbor’s preference pattern may be incorrect for the target user. Under two main issues, we try to accomplish three main ideas of CF’s prediction: the similarity between users’ levels, the neighbor’s rating, and the rating conversion. Thus, we propose three main modules, the rating conversion module, the similarity module, and the prediction module, to solve the two issues mentioned above. The rating conversion module projects the neighbor’s rating into the target user’s aspect. The similarity module uses the users’ attentions to compute similarity levels between users. Finally, these similarity levels and the converted ratings are integrated to perform the prediction. The proposed method is compared with the current CF with friends and latent factor model using two types of datasets: real-world and synthetic datasets. We evaluate N neighbors and all neighbors on real-world datasets to prove the number of neighbor is important. Moreover, the performance of the rating conversion module is also evaluated. The proposed method simulates the full rating datasets and the partial rating dataset to compare the effectiveness of using different types of distribution and dataset size. The experimental results demonstrate that the proposed method effectively outperformed the baselines using ranking evaluation and prediction accuracy on real-world and synthetic datasets. Besides, The effectiveness of using different the number of neighbors depends on the quality of neighbors.