Miracle-dz/UniFAR-FTUs huggingface dataset:
APRILE: Exploring the Molecular Mechanisms of Drug Side Effects with Explainable Graph Neural Networks

The majority of people over the age of 65 take two or more medications. While many individual drug side effects are known, polypharmacy side effects due to novel drug combinations poses great risk. Here, we present APRILE: an explainable artificial intelligence (XAI) framework that uses graph neural networks to explore the molecular mechanisms underlying polypharmacy side effects. Given a list of side effects and the pairs of drugs causing them, APRILE identifies a set of proteins (drug targets or non-targets) and associated Gene Ontology (GO) terms as mechanistic ‘explanations’ of associated side effects. Using APRILE, we generate such explanations for 843,318 (learned) and 93,966 (novel) side effect–drug pair events, spanning 861 side effects (472 diseases, 485 symptoms and 9 mental disorders) and 20 disease cate-gories. We show that our two new metrics—pharmacogenomic information utilization and protein-protein interaction information utilization—provide quantitative estimates of mechanism complexity. Explanations were significantly consistent with state of the art disease-gene associations for 232/239 (97%) side effects. Further, APRILE generated new insights into molecular mechanisms of four diverse categories of adverse drug reactions: infection, metabolic diseases, gastrointestinal diseases, and mental disorders, including paradoxical side effects. We demonstrate the viability of discovering polypharmacy side effect mechanisms by training an XAI framework on massive biomedical data. Consequently, it facilitates wider and more reliable use of AI in healthcare.
Promoter architecture links gene duplication with transcriptional divergence

Gene duplication is thought to be a central mechanism in evolution to gain new functions, but gene families vary greatly in their rates of gene duplication and long-term retention. Here, we discover a link between the promoter architecture of vertebrate genes and their rate of duplication: Genes that harbor CpG Islands in their promoters (CGI genes) – nearly 60% of our genes – have rarely duplicated in recent evolutionary times, and most CGI gene duplication events predate the emergence of CGI as a major regulatory element of vertebrate genes. In contrast, CGI-less genes predominate duplications that have occurred since the divergence of vertebrates. Furthermore, CGI-less paralogs are transcriptionally more divergent than CGI paralogs, even when comparing CGI and CGI-less paralogs that have duplicated at similar evolutionary times – suggesting greater capacity of CGI-less promoters to enable divergence in expression. This higher divergence between CGI-less paralogs is also reflected in lower similarity of transcription factors that bind to the promoters of CGI-less paralog pairs in comparison with CGI paralogs. Finally, CGI-less paralogs have a greater tendency to sub- and neo-functionalize, and they transcriptionally diversify faster following duplication. Our results highlight the links between promoter architecture, gene expression plasticity and their impact on gene expansion, and unravel an unappreciated role of CGI elements in shaping genome evolution. Significance statement Gene duplication generates extra gene copies, providing material for evolution of new functions. However, many duplicated genes are eliminated due to functional and regulatory constraints. The evolutionary processes that govern the elimination and persistence of duplicated genes are not well understood. Here, we focus on CpG Islands (CGIs) – important elements that occur in the majority of gene promoters. We show that genes with CGIs in their promoters have duplicated almost exclusively in ancient times, and nearly all recent duplications involve CGI-less genes. Furthermore, duplicated CGI-less genes diverge more in expression and display more distinctive transcription and cis-regulation compared to duplicated CGI-genes. Our results demonstrate how promoter structure influences transcriptional evolvability and, in turn, the retention of new genes.
Enzymatic and structural characterization of HAD5, an essential phosphomannomutase of malaria parasites

The malaria parasite Plasmodium falciparum is responsible for over 200 million infections and 400,000 deaths per year. At multiple stages during its complex life cycle, P. falciparum expresses several essential proteins tethered to its surface by glycosylphosphatidylinositol (GPI) anchors, which are critical for biological processes such as parasite egress and reinvasion of host red blood cells. Targeting this pathway therapeutically has the potential to broadly impact parasite development across several life stages. Here, we characterize an upstream component of GPI anchor biosynthesis, the putative phosphomannomutase (EC 5.4.2.8) of the parasites, HAD5 (PF3D7_1017400). We confirm the phosphomannomutase and phosphoglucomutase activity of purified recombinant HAD5. By regulating expression of HAD5 in transgenic parasites, we demonstrate that HAD5 is required for malaria parasite egress and erythrocyte reinvasion. Finally, we determine the three-dimensional crystal structure of HAD5 and identify a substrate analog that specifically inhibits HAD5, compared to orthologous human phosphomannomutases. These findings demonstrate that the GPI anchor biosynthesis pathway is exceptionally sensitive to inhibition, and that HAD5 has potential as a multi-stage antimalarial target.
A New Likelihood-based Test for Natural Selection

We present a new statistic for testing for neutral evolution from allele frequency data summarised as a site frequency spectrum, which we call the relative likelihood neutrality test or ρ. Classical methods of testing for natural selection, such as Tajima’s D and its relatives, require the null model to have constant population size over time and therefore can confound demographic change with natural selection. ρ can directly incorporate a null hypothesis reflecting general demographic histories. It has a natural Bayesian interpretation as an approximation to the log-probability of the null model, given the data. We use simulations to show that ρ has greater power than Tajima’s D to detect departure from neutrality for a range of scenarios of positive and negative selection. We also show how ρ can be adapted to account for sequencing error. Application to the ACKR1 (FYO) gene in humans supported previous studies inferring positive selection in sub-Saharan populations which were based on inter-population comparisons. However, we did not find the signal of selection to be maximal in the region of the FY*O or Duffy-null allele in these populations. We also applied ρ to investigate in greater detail a region on the 2q11.1 band of the human genome that has previously been identified as showing evidence of selection. This was done for a range of populations: for the European populations we incorporated a demographic history with a bottleneck corresponding to the putative out of Africa event. We were able to localise signals of selection to some specific regions and genes. Overall, we suggest that ρ will be a useful tool for identifying genomic regions that may be subject to natural selection.
Amyloid-β and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer’s disease

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-β and tau pathology in preclinical Alzheimer’s disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-β and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively-unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in approximately 13 years on average. Compared to non-carriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex, and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain’s functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia. SIGNIFICANCE STATEMENT Amyloid-β and tau pathologies in Alzheimer’s disease (AD) are hypothesized to propagate through functional networks. Research is needed to elucidate how AD-related pathologies alter the brain’s functional connections years before symptom-onset to help predict pathology accumulation and dementia risk. Using high-resolution (voxel-level) graph-based network analyses and PET imaging, we showed that greater tau burden was associated with largely dysconnectivity of posterior default-mode network brain regions, and increased connectivity of structures associated with the salience network and others that are critical for integrating information across neural systems in cognitively-unimpaired Presenilin-1 E280A carriers. Findings enlighten how amyloid-β and tau relate to distinct patterns of functional connectivity in regions that underlie memory functioning and are critical for information processing, helping predict disease progression.
Why people adopt smart transportation services: an integrated model of TAM, trust and perceived risk

ABSTRACT Advancements in emerging technologies have brought remarkable socio-technical changes to how people communicate, Smart transportation and urban mobility have become high priority topics for city planners and policymakers as cities seek to become more desirable to citizens. However, few empirical studies have critically examined factors that affect user acceptance of Smart Transportation Services (STS) and their impact. Grounded in perceived risk and trust theory, and the Technology Acceptance Model (TAM), this paper examines the impact of users’ antecedents on the acceptance of smart transportation services. We use structural equation modeling to conduct an empirical analysis of questionnaire data collected from a sample of users in China. Results show that trust and reducing perceived security risk and perceived privacy risk can enhance users’ trust in STS. Our findings provide important practical implications for governments and service providers for improving the acceptance rate of smart transportation services in China.
“Flipgrid netiquette”: unearthing language ideologies in the remote learning era

ABSTRACT Flipgrid as an asynchronous video-mediated online discussion platform has offered a space for teachers and students to interact and show their thinking in remote learning during the COVID-19 pandemic. While Flipgrid discussions can afford educators the chance to build on students’ creative language use, the choices teachers make when designing the discussions can also perpetuate standard language ideologies and purist language norms. This study presents a critical analysis of free and available teaching materials designed to support the use of Flipgrid, highlighting examples that foster or constrain student language choice and body positioning according to socially constructed norms for “Flipgrid netiquette. ”
Visualizing Neuropharmacological Effects of Guanfacine Extended Release in Attention Deficit Hyperactivity Disorder Using Functional Near-Infrared Spectroscopy

Objective: In the current study, we explored the neural substrate for acute effects of guanfacine extended release (GXR) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD), using functional near-infrared spectroscopy (fNIRS). Methods: Following a GXR washout period, 12 AD HD children (6–10 years old) performed a go/no-go task before and 3 h after GXR or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design study. In the primary analysis, fNIRS was used to monitor the right prefrontal cortical hemodynamics of the participants, where our former studies showed consistent dysfunction and osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine hydrochloride (ATX) elicited recovery. We examined the inter-medication contrast, comparing the effect of GXR against the placebo. In the exploratory analysis, we explored neural responses in regions other than the right prefrontal cortex (PFC). Results: In the primary analysis, we observed no significant main effects or interactions of medication type and age in month (two-way mixed ANCOVA, Fs < 0.20, all ps > .05). However, in the post-hoc analysis, we observed significant change in the oxy-Hb signal in the right angular gyrus (AG) for inter-medication (one sample t-test, p < 0.05, uncorrected, Cohen's d = 0.71). Conclusions: These results are different from the neuropharmacological effects of OROS-MPH and ATX, which, in an upregulated manner, reduced right PFC function in ADHD children during inhibitory tasks. This analysis, while limited by its secondary nature, suggested that the improved cognitive performance was associated with activation in the right AG, which might serve as a biological marker to monitor the effect of GXR in the ADHD children.
Fear of Movement/(Re)Injury: An Update to Descriptive Review of the Related Measures

The prevalence of fear of movement (kinesiophobia) in persistent pain ranges from 50 to 70%, and it may hinder the subsequent rehabilitation interventions. Therefore, the evaluation of fear of movement/(re)injury plays a crucial role in making clinical treatment decisions conducive to the promotion of rehabilitation and prognosis. In the decision-making process of pain treatment, the assessment of fear of movement/(re)injury is mainly completed by scale/questionnaire. Scale/questionnaire is the most widely used instrument for measuring fear of movement/(re)injury in the decision-making process of pain treatment. At present, the most commonly used scale/questionnaire are the Tampa Scale for Kinesiophobia (TSK), the Fear-Avoidance Beliefs Questionnaire (FABQ), the Kinesiophobia Causes Scale (KCS), the Athlete Fear-Avoidance Questionnaire (AFAQ), and the Fear-Avoidance Components Scale (FACS). In order to provide necessary tools and references for related research and rehabilitation treatment, this descriptive review is designed as an introduction to the background and content, score system, available language versions, variants of the original questionnaire, and psychometric properties of these scales/questionnaries.
Unmanned Aerial Vehicle for Transmission Line Inspection: Status, Standardization, and Perspectives

As the biggest country in power consumption and generation, China owns the largest scale of transmission line worldwide. The application of unmanned aerial vehicle (UAV) in inspection has been carried out for many years in China because of its strong adaptability and safety compared to the traditional manual way. For the further development of UAV application technology in transmission line inspection, China has accumulated rich experiences and greatly improved line inspection efficiency and formed a relatively complete UAV transmission line inspection standardization system including operation safety management, an equipment configuration method, and functional quality requirements. However, there still exist some obstacles that need to be tackled due to the fact that China’s UAV transmission line inspection standardization and its international promotion have not been thoroughly and comprehensively studied at present. Based on an in-depth analysis of China’s current UAV transmission line inspection standardization system, this study employs SWOT-PEST analysis to insightfully investigate international promotion opportunities/challenges under the current situation, upon which several constructive suggestions are proposed from four aspects of politics, economy, society, and technology. The ultimate purpose is to design feasible schemes to boost the international promotion of China’s UAV transmission line inspection standardization and further development of international UAV inspection technology.
High Expression Levels of CDK1 and CDC20 in Patients With Lung Squamous Cell Carcinoma are Associated With Worse Prognosis

Purpose: Progress related to the early detection and molecular targeted therapy of lung squamous cell carcinoma (LUSC) remains limited. The goal of our study was to identify key candidate indicators of LUSC. Methods: Three microarray datasets (GSE33532, GSE30219 and GSE19188) were applied to find differentially expressed genes (DEGs). Functional enrichment analyses of DEGs were carried out, and their protein-protein interaction (PPI) network was established. Hub genes were chosen from the PPI network according to their degree scores. Then, overall survival (OS) analyses of hub genes were carried out using Kaplan-Meier plotter, and their GSEA analyses were performed. Public databases were used to verify the expression patterns of CDK1 and CDC20. Furthermore, basic experiments were performed to verify our findings. Results: A total of 1,366 DEGs were identified, containing 669 downregulated and 697 upregulated DEGs. These DEGs were primarily enriched in cell cycle, chromosome centromeric region and nuclear division. Seventeen hub genes were selected from PPI network. Survival analyses demonstrated that CDK1 and CDC20 were closely associated with OS. GSEA analyses revealed that cell cycle, DNA replication, and mismatch repair were associated with CDK1 expression, while spliceosome, RNA degradation and cell cycle were correlated with CDC20 expression. Based on The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (THPA) databases, CDK1 and CDC20 were upregulated in LUSC at the mRNA and protein levels. Moreover, basic experiments also supported the obvious upregulation of CDK1 and CDC20 in LUSC. Conclusion: Our study suggests and validates that CDK1 and CDC20 are potential therapeutic targets and prognostic biomarkers of LUSC.
Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1’s subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1’s molecular, cellular, pathophysiological, and biological functions.
Adipose-Derived Stem Cells Based on Electrospun Biomimetic Scaffold Mediated Endothelial Differentiation Facilitating Regeneration and Repair of Abdominal Wall Defects via HIF-1α/VEGF Pathway

Application of synthetic or biological meshes is the main therapy for the repair and reconstruction of abdominal wall defects, a common disease in surgery. Currently, no ideal materials are available, and there is an urgent need to find appropriate ones to satisfy clinical needs. Electrospun scaffolds have drawn attention in soft tissue reconstruction. In this study, we developed a novel method to fabricate a composite electrospun scaffold using a thermoresponsive hydrogel, poly (N-isopropylacrylamide)-block-poly (ethylene glycol), and a biodegradable polymer, polylactic acid (PLA). This scaffold provided not only a high surface area/volume ratio and a three-dimensional fibrous matrix but also high biocompatibility and sufficient mechanical strength, and could simulate the native extracellular matrix and accelerate cell adhesion and proliferation. Furthermore, rat adipose-derived stem cells (ADSCs) were seeded in the composite electrospun scaffold to enhance the defect repair and regeneration by directionally inducing ADSCs into endothelial cells. In addition, we found early vascularization in the process was regulated by the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. In our study, overexpression of HIF-1α/VEGF in ADSCs using a lentivirus system promoted early vascularization in the electrospun scaffolds. Overall, we expect our composite biomimetic scaffold method will be applicable and useful in abdominal wall defect regeneration and repair in the future.