SARS-CoV Regulates Immune Function-Related Gene Expressions in Human Monocytic Cells

Background: Severe Acute Respiratory Syndrome (SARS) is characterized by acute respiratory distress (ARDS) and pulmonary fibrosis, and the monocyte/macrophage is the key player in the pathogenesis of SARS.
 
Methods: In this study, we compared the transcriptional profiles of SARS coronavirus (SARS-CoV) infected monocytic cells against that infected by coronavirus 229E (CoV-229E). Total RNA was extracted from infected DC-SIGN transfected monocytes (THP-1-DC-SIGN) at 6 and 24 h after infection and the gene expression was profiled by oligonucleotide-based microarray. 

Results: Analysis of immune-related gene expression profiles showed that 24 h after SARS-CoV infection, (i) IFN-alpha/beta-inducible and cathepsin/proteosome genes were down-regulated; (ii) the hypoxia/hyperoxia-related genes were up-regulated; and (iii) the TLR/TLR-signaling, cytokine/cytokine receptor-related, chemokine/chemokine receptor-related, the lysosome-related, MHC/chaperon-related, and fibrosis-related genes were differentially regulated. 

Conclusion: These results elucidate that monocyte/macrophage dysfunction and dysregulation of fibrosis-related genes are two important pathogenic events of SARS. 
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CR3 and Dectin-1 Collaborate in Macrophage Cytokine Response through Association on Lipid Rafts and Activation of Syk-JNK-AP-1 Pathway

Copyright: © 2015 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Acknowledgments We are grateful to the Second Core Laboratory of Research Core Facility at the National Taiwan University Hospital for confocal microscopy service and providing ultracentrifuge. We thank Dr. William E. Goldman (University of North Carolina, Chapel Hill, NC) for kindly providing WT and ags1-null mutant of H. capsulatum G186A. Funding: This work is supported by research grants 101-2320-B-002-030-MY3 from the Ministry of Science and Technology (http://www.most.gov.tw) and AS-101-TP-B06-3 from Academia Sinica (http://www.sinica.edu.tw) to BAWH. GDB is funded by research grant 102705 from Welcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Immunotherapeutic Approaches of Rheumatoid Arthritis and the Implication on Novel Interventions for Refractoriness

Rheumatoid arthritis is an autoimmune disorder involving the chronic inflammation of affected joints which lead to the distortion and eventually destruction of the articular tissues. Clinically, many therapeutic methods are being used for RA treatment. Non-steroidal anti-inflammatory drugs (NSAIDs), steroid, and disease-modifying anti-rheumatic drugs (DMARDs) are the three main categories of intervention approaches. Among which DMARDs, targeting mainly the release of pro-inflammatory cytokines, demonstrated high efficacy because of its direct drug action that alter the underlying disease mechanisms rather than simply to mediate symptoms relieve. However, the use of DMARDs also accompanying some unwanted adverse side effects, in particular, the development of refractoriness, which hampers the successful rate of treatment. In this chapter, the conventional RA drugs will be reviewed, focusing on the currently used and latest development of DMARDs. Novel methods that could improve RA pathogenesis will also be introduced. Because of the critical role of refractory RA, the progress of the disease to develop resistance to standard drug treatment will also be described. Finally, innovative RA therapeutic methods inspired by researches concerning the pathogenesis and contemporary treatments of RA will be discussed

The Foundation Model Transparency Index

Foundation models have rapidly permeated society, catalyzing a wave of generative AI applications spanning enterprise and consumer-facing contexts. While the societal impact of foundation models is growing, transparency is on the decline, mirroring the opacity that has plagued past digital technologies (e.g. social media). Reversing this trend is essential: transparency is a vital precondition for public accountability, scientific innovation, and effective governance. To assess the transparency of the foundation model ecosystem and help improve transparency over time, we introduce the Foundation Model Transparency Index. The Foundation Model Transparency Index specifies 100 fine-grained indicators that comprehensively codify transparency for foundation models, spanning the upstream resources used to build a foundation model (e.g data, labor, compute), details about the model itself (e.g. size, capabilities, risks), and the downstream use (e.g. distribution channels, usage policies, affected geographies). We score 10 major foundation model developers (e.g. OpenAI, Google, Meta) against the 100 indicators to assess their transparency. To facilitate and standardize assessment, we score developers in relation to their practices for their flagship foundation model (e.g. GPT-4 for OpenAI, PaLM 2 for Google, Llama 2 for Meta). We present 10 top-level findings about the foundation model ecosystem: for example, no developer currently discloses significant information about the downstream impact of its flagship model, such as the number of users, affected market sectors, or how users can seek redress for harm. Overall, the Foundation Model Transparency Index establishes the level of transparency today to drive progress on foundation model governance via industry standards and regulatory intervention.Comment: Authored by the Center for Research on Foundation Models (CRFM) at the Stanford Institute for Human-Centered Artificial Intelligence (HAI). Project page: https://crfm.stanford.edu/fmt

Students of Color and COVID-19: Experiences, Coping Strategies, and Supports

The coronavirus disease of 2019, known as the COVID-19 pandemic, is a disaster event that posed significant physical, social, financial, and mental health risks to college students. Disproportionate experiences of stressors position students of color as a population particularly vulnerable to the negative impacts of COVID-19, thus, the current study assessed the impact of COVID-19 on undergraduate students of color in the United States. Students participated in semi-structured in-depth interviews about their experiences with stressors during the pandemic. Data were analyzed using conventional content analysis and revealed themes including (a) the pandemic’s impact on students; (b) basic needs as college students; (c) strategies used to cope with stressors; and (d) supports desired from institutions and faculty. Findings inform colleges and healthcare providers of the most salient concerns for students of color and the sources found helpful. As such, these findings may guide effective prevention and intervention strategies to minimize the effects of future disasters

A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease.

Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the β-globin (HBB) gene on chromosome 11. However, people with the same genetic mutation display a wide range of clinical phenotypes. Fetal hemoglobin (HbF) expression is an important genetic modifier of SCD complications leading to milder symptoms and improved long-term survival. Therefore, we performed a genome-wide association study (GWAS) using a case-control experimental design in 244 African Americans with SCD to discover genetic factors associated with HbF expression. The case group consisted of subjects with HbF≥8.6% (133 samples) and control group subjects with HbF≤£3.1% (111 samples). Our GWAS results replicated SNPs previously identified in an erythroid-specific enhancer region located in the second intron of theBCL11Agene associated with HbF expression. In addition, we identified SNPs in theSPARC,GJC1,EFTUD2andJAZF1genes as novel candidates associated with HbF levels. To gain insights into mechanisms of globin gene regulation in theHBBlocus, linkage disequilibrium (LD) and haplotype analyses were conducted. We observed strong LD in the low HbF group in contrast to a loss of LD and greater number of haplotypes in the high HbF group. A search of knownHBBlocus regulatory elements identified SNPs 5\u27 of δ-globin located in an HbF silencing region. In particular, SNP rs4910736 created a binding site for a known transcription repressor GFi1 which is a candidate protein for further investigation. Another HbF-associated SNP, rs2855122 in the cAMP response element upstream of Gγ-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated γ-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production

Human Schistosomiasis Resistance to Praziquantel in China: Should We Be Worried?

The efficacy of praziquantel for the treatment of Schistosoma japonicum in humans is reported from a cross-sectional survey conducted in 33 villages in Sichuan Province. Infection prevalence was found to be 5.7% (185 infected of 3,269 tested) in a region where 44–73% prevalence was found 9 years before. Collected miracidia were subjected to an in vitro test of praziquantel susceptibility. An effective concentration of praziquantel associated with 50% of miracidia changing shape was found between 10−8 and 10−7 M and 10−7 and 10−6 M for 10 and 5 minutes of exposure, respectively. After treating infected persons two times with 40-mg/kg doses of praziquantel, only one remained infected. Findings are reported from a 60-household questionnaire on attitudes and behaviors that may be associated with development of drug resistance. The low number of treatment failures and good compliance with treatment despite side effects and repeated annual treatments suggest that, in the near term, praziquantel remains effective in treating human S. japonicum infection in China

Identification of tag single-nucleotide polymorphisms in regions with varying linkage disequilibrium

We compared seven different tagging single-nucleotide polymorphism (SNP) programs in 10 regions with varied amounts of linkage disequilibrium (LD) and physical distance. We used the Collaborative Studies on the Genetics of Alcoholism dataset, part of the Genetic Analysis Workshop 14. We show that in regions with moderate to strong LD these programs are relatively consistent, despite different parameters and methods. In addition, we compared the selected SNPs in a multipoint linkage analysis for one region with strong LD. As the number of selected SNPs increased, the LOD score, mean information content, and type I error also increased

Whole Genome Distribution and Ethnic Differentiation of Copy Number Variation in Caucasian and Asian Populations

Although copy number variation (CNV) has recently received much attention as a form of structure variation within the human genome, knowledge is still inadequate on fundamental CNV characteristics such as occurrence rate, genomic distribution and ethnic differentiation. In the present study, we used the Affymetrix GeneChip® Mapping 500K Array to discover and characterize CNVs in the human genome and to study ethnic differences of CNVs between Caucasians and Asians. Three thousand and nineteen CNVs, including 2381 CNVs in autosomes and 638 CNVs in X chromosome, from 985 Caucasian and 692 Asian individuals were identified, with a mean length of 296 kb. Among these CNVs, 190 had frequencies greater than 1% in at least one ethnic group, and 109 showed significant ethnic differences in frequencies (p<0.01). After merging overlapping CNVs, 1135 copy number variation regions (CNVRs), covering approximately 439 Mb (14.3%) of the human genome, were obtained. Our findings of ethnic differentiation of CNVs, along with the newly constructed CNV genomic map, extend our knowledge on the structural variation in the human genome and may furnish a basis for understanding the genomic differentiation of complex traits across ethnic groups

Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling

SummaryMany signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming