Recent developments in our understanding of the interactions between long non-coding RNAs (lncRNAs) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks. Analysis of alternative splicing events across 39 lncRNA knockdown and wildtype RNA-sequencing datasets from three human cell lines-HeLa (cervical cancer), K562 (myeloid leukemia), and U87 (glioblastoma)-resulted in the high-confidence (false discovery rate (fdr) < 0.01) identification of 11,630 skipped exon events and 5895 retained intron events, implicating 759 genes to be impacted at the post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockdown were specific to the cell type. In tandem, the functions annotated to the genes affected by alternative splicing across each lncRNA knockdown also displayed cell-type specificity. To understand the mechanism behind this cell-type-specific alternative splicing pattern, we analyzed RNA-binding protein (RBP)-RNA interaction profiles across the spliced regions in order to observe cell-type-specific alternative splice event RBP binding preference. Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions in a cell-type-specific manner. The cellular functions affected by alternative splicing were also affected in a cell-type-specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs and their downstream functions. We propose that such lncRNA sponges can extensively rewire post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type-specific manner.

Around a quarter of the global adult population have metabolic syndrome (MetS) and therefore increased risk of cardiovascular mortality and diabetes. Docosahexaenoic acid, oat beta-glucan and grape anthocyanins have been shown to be effective in reducing MetS risk factors when administered as isolated compounds, but their effect when administered as bioactive-enriched foods has not been evaluated.

Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated protein that endows its carrier with (lipo-)lactonase-dependent antioxidative features. Low levels of PON1 activity have been observed in association with obesity, a major risk factor for cardiovascular disease (CVD). Considering the well-recognized atheroprotective role of PON1, exogenous/endogenous factors that might modulate its levels/activity are raising great interest. Since adipokines represent a molecular link between obesity and CVD, we here explored the possible impact of these substances on PON1 activity/expression. The levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha, monocyte chemoattractant protein-1, hepatocyte growth factor, resistin, leptin, and adiponectin were measured along with arylesterase, paraoxonase, and lactonase activities of PON1 in 107 postmenopausal women. Moreover, the direct effect of resistin on PON1 expression was evaluated in vitro. Multivariate analysis revealed that only resistin was significantly and inversely correlated with PON1-lactonase activities (r = -0.346, p < 0.001) regardless of confounding factors such as age or HDL-cholesterol. It is worth noting that no statistical link was found between adipokine and arylesterase or paraoxonase, the two promiscuous activities of PON1. Notably, resistin down-regulated PON1 expression occurred in hepatocellular carcinoma cultures. Our study suggests that resistin might be a negative modulator of PON1 expression and anti-oxidative activity.

Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer.

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.

The detection of protein complexes is of great significance for researching mechanisms underlying complex diseases and developing new drugs. Thus, various computational algorithms have been proposed for protein complex detection. However, most of these methods are based on only topological information and are sensitive to the reliability of interactions. As a result, their performance is affected by false-positive interactions in PPINs. Moreover, these methods consider only density and modularity and ignore protein complexes with various densities and modularities.

Little is known about the long-term patterns of body size evolution in Crocodylomorpha, the > 200-million-year-old group that includes living crocodylians and their extinct relatives. Extant crocodylians are mostly large-bodied (3-7 m) predators. However, extinct crocodylomorphs exhibit a wider range of phenotypes, and many of the earliest taxa were much smaller (< 1.2 m). This suggests a pattern of size increase through time that could be caused by multi-lineage evolutionary trends of size increase or by selective extinction of small-bodied species. Here, we characterise patterns of crocodylomorph body size evolution using a model fitting-approach (with cranial measurements serving as proxies). We also estimate body size disparity through time and quantitatively test hypotheses of biotic and abiotic factors as potential drivers of crocodylomorph body size evolution.

This study aimed to investigate the effect of long non-coding RNA nuclear enriched abundant transcript 1 (lnc-NEAT1) on cell proliferation and apoptosis in myocardial ischemia/reperfusion (I/R) injury cells, and explore its target miRNAs.

Nasal bone fracture is the most common type of facial fracture, and the high incidence of severe emergence agitation occurring after closed reduction of the nasal bone fracture can be challenging to manage. The purpose of this trial was to evaluate whether pre-operative administration of dexmedetomidine is effective in reducing the incidence and severity of emergence agitation in adults undergoing closed reduction of nasal bone fractures.

Attention bias modification training (ABMT) and cognitive behavioral therapy (CBT) likely target different aspects of aberrant threat responses in anxiety disorders and may be combined to maximize therapeutic benefit. However, studies investigating the effect of ABMT in the context of CBT have yielded mixed results. Here, we propose an enhanced ABMT to target the attentional bias towards threat, in addition to classic CBT for anxiety disorders in youth. This enhanced ABMT integrates the modified dot-probe task used in previous studies, where a target is always presented at the previous location of the neutral and not the simultaneously presented threatening stimulus, with a visual search, where the targets are always presented distally of threatening distractors. These two training elements (modified dot-probe and visual search) are embedded in an engaging game to foster motivation and adherence. Our goal is to determine the efficacy of the enhanced ABMT in the context of CBT. Further, we aim to replicate two previous findings: (a) aberrant amygdala connectivity being the neurobiological correlate of the attentional bias towards threat at baseline; and (b) amygdala connectivity being a mediator of the ABMT effect. We will also explore moderators of treatment response (age, sex, depressive symptoms and irritability) on a behavioral and neuronal level.

Identifying molecular biomarkers characteristic of ischemic stroke has the potential to aid in distinguishing stroke cases from stroke mimicking symptoms, as well as advancing the understanding of the physiological changes that underlie the body's response to stroke. This study uses machine learning-based analysis of gene co-expression to identify transcription patterns characteristic of patients with acute ischemic stroke.

Imaging examinations, such as ultrasonography, magnetic resonance imaging and computed tomography scans, play key roles in healthcare settings. To assess and improve the quality of imaging diagnosis, we need to manually find and compare the pre-existing reports of imaging and pathology examinations which contain overlapping exam body sites from electrical medical records (EMRs). The process of retrieving those reports is time-consuming. In this paper, we propose a convolutional neural network (CNN) based method which can better utilize semantic information contained in report texts to accelerate the retrieving process.

Alzheimer's disease may compromise several musical competences, though no clear data is available in the scientific literature. Furthermore, music is capable of communicating basic emotions, but little is known about the emotional aspect of music in patients with Alzheimer's disease. We present a systematic investigation of music processing in relation to extra-musical skills, in particular emotional skills in patients with Alzheimer's disease.

Accumulated evidences have demonstrated that long non-coding RNAs (lncRNAs) are dysregulated and correlate with the pathophysiological basis of malignant tumors. The objective of this research is to uncover the possible molecular mechanism of MACC1-AS1 regarding the regulation of pancreatic carcinoma (PC) metastasis.

Kidney Renal Clear Cell Carcinoma (KIRC) accounts for 75% of all renal cancers. Previous study had conflict evidences regarding NR1B2 role in cancer, and its expression and biological role in KIRC remained unclear. Our aims were to characterize the role of NR1B2 in KIRC.

Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos.

Secondary dystroglycanopathies are muscular dystrophies that result from mutations in genes that participate in Dystroglycan glycosylation. Glycosylation of Dystroglycan is essential for muscle fibers to adhere to the muscle extracellular matrix (myomatrix). Although the myomatrix is disrupted in a number of secondary dystroglycanopathies, it is unknown whether improving the myomatrix is beneficial for these conditions. We previously determined that either NAD+ supplementation or overexpression of Paxillin are sufficient to improve muscle structure and the myomatrix in a zebrafish model of primary dystroglycanopathy. Here, we investigate how these modulations affect neuromuscular phenotypes in zebrafish fukutin-related protein (fkrp) morphants modeling FKRP-associated secondary dystroglycanopathy.

The aim of this study was to compare the oncological outcomes and clinical efficacy of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) in patients with pancreatic ductal adenocarcinoma (PDAC).

Pathologically altered tau protein is a common denominator of neurodegenerative disorders including Alzheimer's disease (AD) and other tauopathies. Therefore, promising immunotherapeutic approaches target and eliminate extracellular pathogenic tau species, which are thought to be responsible for seeding and propagation of tau pathology. Tau isoforms in misfolded states can propagate disease pathology in a template-dependent manner, proposed to be mediated by the release and internalization of extracellular tau. Monoclonal antibody DC8E8, binding four highly homologous and independent epitopes in microtubule-binding domain (MTBD) of diseased tau, inhibits tau-tau interaction, discriminates between healthy and pathologically truncated tau and reduces tau pathology in animal model in vivo. Here, we show that DC8E8 antibody acts via extracellular mechanism and does not influence viability and physiological functions of neurons. Importantly, in vitro functional assays showed that DC8E8 recognises pathogenic tau proteins of different size and origin, and potently blocks their entry into neurons. Next, we examined the mechanisms by which mouse antibody DC8E8 and its humanized version AX004 effectively block the neuronal internalization of extracellular AD tau species. We determined a novel mode of action of a therapeutic candidate antibody, which potently inhibits neuronal internalization of AD tau species by masking of epitopes present in MTBD important for interaction with neuron surface Heparan Sulfate Proteoglycans (HSPGs). We show that interference of tau-heparane sulfate interaction with DC8E8 antibody via steric hindrance represents an efficient and important therapeutic approach halting tau propagation.

Gastric ulcer is one of the most prevalent diseases worldwide. In Iranian folk medicine, Achillea wilhelmsii (AW) is used as a treatment for gastric ulcer. Previous reports also mentioned Antiulcerogenic properties for this herbal plant. This study investigated the therapeutic effects of Achillea wilhelmsii C. Koch extract on indomethacin-induced gastric lesion in rats, from both proteomic and metabolomic perspectives.