Miracle-dz/UniFAR-FTUs huggingface dataset:
Principles of Effective and Robust Innate Immune Response to Viral Infections: A Multiplex Network Analysis

The human innate immune response, particularly the type-I interferon (IFN) response, is highly robust and effective first line of defense against virus invasion. IFN molecules are produced and secreted from infected cells upon virus infection and recognition. They then act as signaling/communication molecules to activate an antiviral response in neighboring cells so that those cells become refractory to infection. Previous experimental studies have identified the detailed molecular mechanisms for the IFN signaling and response. However, the principles underlying how host cells use IFN to communicate with each other to collectively and robustly halt an infection is not understood. Here we take a multiplex network modeling approach to provide a theoretical framework to identify key factors that determine the effectiveness of the IFN response against virus infection of a host. In this approach, we consider the virus spread among host cells and the interferon signaling to protect host cells as a competition process on a two-layer multiplex network. We focused on two types of network topology, i.e., the Erdős-Rényi (ER) network and the Geometric Random (GR) network, which represent the scenarios when infection of cells is mostly well mixed (e.g., in the blood) and when infection is spatially segregated (e.g., in tissues), respectively. We show that in general, the IFN response works effectively to stop viral infection when virus infection spreads spatially (a most likely scenario for initial virus infection of a host at the peripheral tissue). Importantly, we show that the effectiveness of the IFN response is robust against large variations in the distance of IFN diffusion as long as IFNs diffuse faster than viruses and they can effectively induce antiviral responses in susceptible host cells. This suggests that the effectiveness of the IFN response is insensitive to the specific arrangement of host cells in peripheral tissues. Thus, our work provides a quantitative explanation of why the IFN response can serve an effective and robust response in different tissue types to a wide range of viral infections of a host.
Cleavage and Sub-Cellular Redistribution of Nuclear Pore Protein 98 by Coxsackievirus B3 Protease 2A Impairs Cardioprotection

Myocarditis, inflammation of the heart muscle, affects all demographics and is a major cause of sudden and unexpected death in young people. It is most commonly caused by viral infections of the heart, with coxsackievirus B3 (CVB3) being among the most prevalent pathogens. To understand the molecular pathogenesis of CVB3 infection and provide strategies for developing treatments, we examined the role of a key nuclear pore protein 98 (NUP98) in the setting of viral myocarditis. NUP98 was cleaved as early as 2 h post-CVB3 infection. This cleavage was further verified through both the ectopic expression of viral proteases and in vitro using purified recombinant CVB3 proteases (2A and 3C), which demonstrated that CVB3 2A but not 3C is responsible for this cleavage. By immunostaining and confocal imaging, we observed that cleavage resulted in the redistribution of NUP98 to punctate structures in the cytoplasm. Targeted siRNA knockdown of NUP98 during infection further increased viral protein expression and viral titer, and reduced cell viability, suggesting a potential antiviral role of NUP98. Moreover, we discovered that expression levels of neuregulin-1 (NRG1), a cardioprotective gene, and presenilin-1 (PSEN1), a cellular protease processing the tyrosine kinase receptor ERBB4 of NRG1, were reliant upon NUP98 and were downregulated during CVB3 infection. In addition, expression of these NUP98 target genes in myocardium tissue not only occurred at an earlier phase of infection, but also appeared in areas away from the initial inflammatory regions. Collectively, CVB3-induced cleavage of NUP98 and subsequent impairment of the cardioprotective NRG1-ERBB4/PSEN1 signaling cascade may contribute to increased myocardial damage in the context of CVB3-induced myocarditis. To our knowledge, this is the first study to demonstrate the link between NUP98 and the NRG1 signaling pathway in viral myocarditis.
Altered Functional Connectivity Between the Cerebellum and the Cortico-Striato-Thalamo-Cortical Circuit in Obsessive-Compulsive Disorder

Background: Altered resting-state functional connectivity of the cerebellum in obsessive-compulsive disorder (OCD) has been previously reported. However, the previous study investigating cerebellar–cerebral functional connectivity relied on a priori–defined seeds from specific networks. In this study, we aimed to explore the connectivity alterations of the cerebellum in OCD under resting-state conditions with a hypothesis-free approach. Methods: Thirty patients with OCD and 26 healthy controls (HCs) underwent functional magnetic resonance imaging (fMRI) scanning at resting state. Regional cerebral function was evaluated by measuring the fraction of amplitude of low-frequency fluctuation (fALFF). Regions with mean fALFF (mfALFF) alterations were used as seeds in seed correlation analysis (SCA). An independent samples t test was used to compare the differences in mfALFF and functional connection (FC) between the two groups. Pearson correlation analysis was performed to identify the association between functional neural correlates and OCD symptom severity evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Results: Compared with the HC group, the OCD group showed significantly increased mfALFF values in bilateral cerebellar. The results of FC analysis showed weakened connectivity among the left Crus II, lobule VIII, and right striatum and between the right lobule VIII and the right striatum, and cingulate in the OCD group compared with the HC group. Some of the abovementioned results were associated with symptom severity. Conclusions: OCD patients showed abnormal spontaneous cerebellar activity and weakened functional connectivity between the cerebellum and the cortico-striato-thalamo-cortical (CSTC) circuit (striatum and cingulate), suggesting that the cerebellum may play an essential role in the pathophysiology of OCD.
Disrupted Regional Cerebral Blood Flow, Functional Activity and Connectivity in Alzheimer’s Disease: A Combined ASL Perfusion and Resting State fMRI Study

Recent studies have demonstrated a close relationship between regional cerebral blood flow (rCBF) and resting state functional connectivity changes in normal healthy people. However, little is known about the parameter changes in the most vulnerable regions in Alzheimer’s disease (AD). Forty AD patients and 30 healthy controls participated in this study. The data of resting-state perfusion and functional magnetic resonance imaging (fMRI) was collected. By using voxel-wise arterial spin labeling (ASL) perfusion, we identified several regions of altered rCBF in AD patients. Then, by using resting state fMRI analysis, including amplitude low frequency fluctuation (ALFF) and seed-based functional connectivity, we investigated the changes of functional activity and connectivity among the identified rCBF regions. We extracted cognition-related parameters and searched for a sensitive biomarker to differentiate the AD patients from the normal controls (NC). Compared with controls, AD patients showed special disruptions in rCBF, which were mainly located in the left posterior cingulate cortex (PCC), the left and right dorsolateral prefrontal cortex (DLPFC), the left inferior parietal lobule (IPL), the right middle temporal gyrus (MTG), the left middle occipital gyrus (MOG), and the left precuneus (PCu). ALFF was performed based on the seven regions identified by the ASL method, and AD patients presented significantly decreased ALFF in the left PCC, left IPL, right MTG, left MOG, and left PCu and increased ALFF in the bilateral DLPFC. We constituted the network based on the seven regions and found that there was decreased connectivity among the identified regions in the AD patients, which predicted a disruption in the default mode network (DMN), executive control network (ECN) and visual network (VN). Furthermore, these abnormal parameters are closely associated with cognitive performances in AD patients. We combined the rCBF and ALFF value of PCC/PCu as a biomarker to differentiate the two groups and reached a sensitivity of 85.3% and a specificity of 88.5%. Our findings suggested that there was disrupted rCBF, functional activity and connectivity in specific cognition-related regions in Alzheimer’s disease, which can be used as a valuable imaging biomarker for the diagnosis of AD.
The Upregulation of Toll-Like Receptor 3 via Autocrine IFN-β Signaling Drives the Senescence of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Through JAK1

Although mesenchymal stromal cells (MSCs) are among the most promising cell sources for cell-based therapies and regenerative medicine, the decline in their function with age due to cellular senescence limits their therapeutic applications. Unveiling the underlying mechanism of MSC senescence is therefore of substantial interest with regard to advancing MSC-based cell therapies. We here show that the induction of human umbilical cord blood-derived MSC (UCB-MSC) senescence causes the predominant upregulation of Toll-like receptor 3 (TLR3). Subsequent TLR3 activation by polyinosinic-polycytidylic acid triggers the prominent features of senescence. Using a clustered regularly interspaced short palindromic repeats/Cas9 library screening system, we identified Janus kinase 1 (JAK1) as the candidate regulatory factor for TLR3-mediated MSC senescence. A JAK1 deficiency blocked the MSC senescence phenotype upon TLR3 activation and TLR3 induction. Targeting the JAK1 pathway using chemical JAK1 inhibitors also significantly suppressed TLR3-mediated MSC senescence. Importantly, we further observed that UCB-MSC senescence is driven by a senescence-associated secretory phenotype (SASP) and that interferon-β (IFN-β) is a component of TLR3-dependent SASP, whereby its autocrine actions upregulate TLR3 and suppress cell proliferation. A JAK1 depletion significantly interrupted these effects of IFN-β, indicating that JAK1 is a signaling mediator linking IFN-β activity to TLR3 expression and the process of MSC senescence. Collectively, our findings provide new mechanistic insights into UCB-MSC senescence by revealing the role of an autocrine regulatory loop of SASP evoked by TLR3 activation.
Methods for Quantifying Optic Disc Volume and Peripapillary Deflection Volume Using Radial Optical Coherence Tomography Scans and Association With Intracranial Pressure

Purpose: Papilledema and peripapillary deformation of Bruch's membrane (BM) are associated with elevated intracranial pressure (ICP). We have developed a novel methodology to measure these parameters using a radial optical coherence tomography (OCT) scan pattern and apply this to test the hypothesis that ICP is associated with volumetric features of ophthalmic structures. Methods: 6-radial OCT B-scans centered over the optic nerve head were acquired in 17 subjects (30 eyes) before lumbar puncture with measurement of ICP (range: 10–55 cm H2O). Internal limiting membrane (ILM) and BM were segmented. Three definitions of BM were studied to account for imaging artifact affecting peripapillary BM: connecting rater-identified BM margins(traditional), connecting rater-identified BM 1.6 mm on either side of the ONH(estimated), and excluding BM in the central 3.2 mm of the images(excluded). Optic nerve head volume (ONHV), BM displacement volume (BMDV) and cup volume (CV) were calculated by interpolating between B-scans. Ganglion cell complex volume (GCCV) was measured in the macula. Linear generalized estimating equations (GEE) modeled ONVH, BMDV, and CV as a function of ICP and GCCV. Results: Increased ONHV was associated with elevated ICP for traditional (p = 0.006), estimated (p = 0.003) and excluded (p = 0.05) BM definitions. Decreased BMDV was associated with elevated ICP for traditional (p < 0.0005), estimated (p < 0.0005) and excluded (p = 0.001) definitions. Decreased ONHV was independently associated with decreased GCCV (p = 0.001) and decreased ICP (p = 0.031) in multivariable models. CV was neither associated with ICP nor GCCV in univariate or multivariable models. Conclusions: Elevated ICP is associated with ONHV increase and BMDV decrease, calculated from OCT images accounting for image artifact. Ganglion cell atrophy affects the relationship between ICP and ONHV. OCT derived volumetric measures of the posterior eye may have application as biomarkers for elevated ICP.
Targeted Promoter Replacement Reveals That Herpes Simplex Virus Type-1 and 2 Specific VP16 Promoters Direct Distinct Rates of Entry Into the Lytic Program in Sensory Neurons in vivo

Infection and life-long residence in the human nervous system is central to herpes simplex virus (HSV) pathogenesis. Access is gained through innervating axonal projections of sensory neurons. This distinct mode of entry separates the viral genome from tegument proteins, including the potent transactivator of viral IE genes, VP16. This, in turn, promotes a balance between lytic and latent infection which underlies the ability of the virus to invade, disseminate, and set up a large reservoir of latent infections. In the mouse ocular model, TG neurons marked as either “latent” or “lytic” at 48 h postinfection indicated that these programs were selected early and were considered distinct and mutually exclusive. More recently, a temporal analysis of viral program selection revealed a default latent-like state that begins at ~18 h postinfection and in individual neurons, precedes entry into the viral lytic cycle. Studies using refined viral mutants demonstrated that transition out of this latent program depended upon the transactivation function of VP16. Pursuit of the apparent incongruity between the established leaky-late kinetics of VP16 expression with a “preimmediate-early” function led to the discovery of an unrecognized regulatory feature of the HSV-1 VP16 promoter near/downstream of its TATA box. Among three potential sites identified was a putative Egr-1/Sp1 site. Here, we report that a refined mutation of this site, while having no impact on replication in cultured cells or cornea, resulted in ~100-fold reduction in lytic infection in TG in vivo. Notably, the HSV-2 VP16 promoter has 13 direct tandem-repeats upstream of its TATA box forming multiple potential overlapping Egr-1/Sp1 sites. Thus, despite different structures, these promoters might share function in directing the preimmediate-early VP16 protein expression. To test this, the HSV-1 VP16 promoter/5′UTR was replaced by the HSV-2 VP16 promoter/5′UTR in the HSV-1 backbone. Compared to the genomically repaired isolate, the HSV-2 VP16 promoter/5′UTR (1) accelerated the transition into the lytic cycle, and enhanced (2) virulence, and (3) entry into the lytic cycle following a reactivation stressor. These gain-of-function phenotypes support the hypothesis that the VP16 promoter regulates the latent/lytic boundary in neurons and that the HSV-1 and HSV-2 promoter/5′UTRs encode distinct thresholds for this transition.
Exploring the Potential Role of Rosmarinic Acid in Neuronal Differentiation of Human Amnion Epithelial Cells by Microarray Gene Expression Profiling

In the present study, we conducted microarray gene expression profiling to explore the direction of differentiation of human amnion epithelial cells (hAECs) treated with rosmarinic acid (RA). hAECs have several clinical advantages over other types of stem cells, including availability, low immunogenicity, low rejection rate, non-tumorigenicity, and less ethical constraint. On the other hand, RA is a phenolic compound having several health benefits, including neuroprotective and antidepressant-like activities. In this study, hAECs were isolated from discarded term placenta and were treated with 20 μM RA for 7 days. Microarray gene expression profiling was conducted for three biological replicates of RA-treated and untreated control cells on day 0 and day 7. Gene set enrichment analysis, and gene annotation and pathway analysis were conducted using online data mining tools GSEA and DAVID. Gene expression profiling showed that RA treatment biased hAECs toward ectodermal lineage progression, regulated transcription factors involved in neuronal differentiation, regulated neural specific epigenetic modifiers and several extracellular signaling pathways of neural induction, and significantly inhibited Notch signaling pathway. Gene expression profiling of RA-treated hAECs reveals for the first time a potential role of RA in neural induction and neuronal differentiation of hAECs. Having a naturally occurring compound as differentiation inducer as well as a readily available source of stem cells would have great advantages for the cell-based therapies. Findings from our genome-wide analysis could provide a foundation for further in-depth investigation.
The characteristics of osteophyte around lumbar vertebral foramina associated with spinal stenosis

Spinal stenosis most commonly occurs on lumbar vertebrae because of degenerative changes. This research studied the characteristics of osteophyte development in lumbar vertebrae foramina and association of osteophyte development with lumbar spinal stenosis. The total number of all levels of lumbar spines of subjects was 179 from 31 to 90 years of age. The vertebral foramen was divided into six zones. The prevalence and measurements of the length of osteophytes in the vertebral foramina were obtained. The prevalence and length of osteophytes in the posterior body zone were higher than the laminal zone, and higher than the pedicular zone, respectively. In each zone, the highest prevalence of osteophytes was at L5, except for the inferior posterior body zone that the highest prevalence is at L4. The length of osteophyte was also in same direction as the prevalence. The prevalence of osteophytes among six zones of each level were compared, and found, in L1 to L4, the inferior posterior body zone generally had the highest prevalence, except in L5, the superior posterior body zone had the highest prevalence. Moreover, prevalence, as well as length, of osteophytes in lumbar vertebral foramina, of all levels, was positively associated with age. Vertebral osteophytes can develop beginning at 31 years of age. In conclusion, posterior body of L4 and L5 had the highest prevalence of osteophyte formation, thus, these area had the highest probability to cause spinal stenosis.
Disparities in Thyroid Screening and Medication Use in Quebec, Canada

Abstract Background: No studies have examined the frequency of thyroid screening in the Canadian population, and whether thyroid screening and medication use vary by sex, race, income, and preexisting health conditions. Methods: Using data from the 2011, 2012 cycles of the Canadian Community Health Survey, we report rates of thyroid screening among Quebec residents ≥35 (n=7024) and rates of thyroid medication use among Quebec residents ≥35 (n=16,081). We examine variations in medication use and screening by sex, age, race, immigration status, access to a regular doctor, and health conditions that have been linked to thyroid disease. Results: Of the Quebec residents ≥35, 10.3% reported taking thyroid medication and 0.4% reported that the last blood test a physician ordered was to check for a new thyroid condition. Canadian-born residents and those who identified as White reported higher medication use and screening rates, compared to immigrants and those who identified as visible minorities. Racial disparities were especially pronounced, with White Quebec residents reporting three times greater odds of thyroid screening than visible minorities. The strongest predictors of both thyroid medication use and screening were access to a regular doctor. Despite women being eight times more likely to suffer from thyroid disease, women were not significantly more likely to be screened, compared to men (odds ratio=1.38, 95% confidence interval: 0.74–2.60). Discussion: Strategies are needed to decrease disparities in thyroid screening and medication use. Interventions that target health systems (e.g., increasing physician supply), providers (continuing professional education modules about thyroid disease for family physicians), and recipients of care (multilanguage public awareness campaigns and posters at walk-in clinics that describe common symptoms of different thyroid disorders) should be implemented and tested.
Role of Gender in the Prevalence of Myopia among Polish Schoolchildren

Purpose The aim of the paper was to study the role of gender in the progression of myopia among Polish schoolchildren. Materials and Methods 4875 children from elementary schools and high schools were examined (2470 boys, aged 6–16 years, mean age 11.0, SD = 2.6 and 2405 girls, aged 6–16 years, mean age 11.1, SD = 2.6). The examined students were Caucasian and resided in and around Szczecin, Poland. The examination included retinoscopy under cycloplegia. The refractive error readings were reported as spherical equivalent (SE). Myopia was defined as SE of at least −0.5 D. Data analysis was performed using the Mann–Whitney U test and 2-sided Fisher's exact test. p values of less than 0.05 were considered statistically significant. Results It was found that the SE among Polish boys is similar to the SE among Polish girls before the age of 9 years. However, in older children, lower SE values and higher prevalence of myopia were found among girls than boys, both at 9–13 years range (0.45 ± 1.05 vs 0.55 ± 1.23 D, p=0.047 and 8.30% vs 5.71%, p=0.015, respectively) and at 13–16 years range (0.32 ± 1.14 vs 0.54 ± 1.08 D, p=0.0093 and 10.37% vs 5.96%, p=0.0050), respectively. Conclusions Gender is associated with the prevalence of myopia among Polish schoolchildren ranging from 9 to 16 years of age.
Cypermethrin triggers apoptosis, depletes granulosa cells, and induces endometrium thinning in female rats

Objective: To analyze the effects of subchronic Cypermethrin on the ovary and endometrium as well as the involvement of apoptosis in the toxicity of cypermethrin. Methods: A total of 32 female Wistar rats were randomly divided into four groups, with 8 rats in each group. The control group received no treatment, and the other three groups received oral cypermethrin at 10, 15 or 20 mg/kg body weight for 28 days (sub-chronic). The granulosa cells were calculated histopathologically. The apoptotic index was determined by in situ technique. Histopathological examination was performed on the uterus and ovary. Results: There was no significant difference in the number of primary follicular granulosa cells between the treatment groups and the control group (P>0.05). However, the number of secondary and tertiary follicle granulosa cells in the treatment groups was significantly decreased compared to that of the control group (P all<0.05). The apoptotic index of primary follicular granulosa cells increased significantly in the groups treated with cypermethrin compared with the control group (P<0.05). The secondary, tertiary, and endometrial granulosa cell apoptosis index was significantly higher in all treatment groups compared to the control group (P<0.05). The higher the dose of cypermethrin was, the higher the apoptotic index of secondary, tertiary and endometrial granulosa cells was. There was a significant decrease in endometrial thickness in the three treatment groups compared to the control group (P<0.05). Thinning of the endometrial layer was seen in the cypermethrin exposure groups. Conclusions: Exposure to cypermethrin can suppress the number of secondary and tertiary follicular granulosa cells, and trigger thinning of the endometrium through induction of apoptosis.