Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice

Wu, Nan,Kim, Kang Ho,Zhou, Ying,Lee, Jae Man,Kettner, Nicole M.,Mamrosh, Jennifer L.,Choi, Sungwoo,Fu, Loning,Moore, David D. The Endocrine Society 2016 Molecular endocrinology Vol.30 No.9

Dietary supplementation of L-arginine and conjugated linoleic acid reduces retroperitoneal fat mass and increases lean body mass in rats.

Nall, Jennifer L,Wu, Guoyao,Kim, Kyoung Hoon,Choi, Chang Weon,Smith, Stephen B Wistar Institute of Anatomy and Biology 2009 The Journal of nutrition Vol.139 No.7

<P>We hypothesized that l-arginine and conjugated linoleic acid (CLA) would have additive effects in decreasing adiposity. Sprague Dawley rats were assigned to the following dietary groups (n = 6/group; 5 wk total): 1) control (2.55% l-alanine plus 1.5% canola oil); 2) arginine (1.25% l-arginine plus 1.5% canola oil); 3) CLA (2.55% l-alanine plus 1.5% CLA); and 4) arginine plus CLA (1.25% l-arginine plus 1.5% CLA). Supplemental amino acids were provided in drinking water and CLA was incorporated into the food pellets. Daily weight gain, food intake, arginine intake, and final body and eviscerated body weights were greater in rats fed supplemental CLA then in rats fed canola oil. The retroperitoneal adipose tissue:body weight ratio was less in rats fed supplemental CLA than in rats fed canola oil, but epididymal adipose tissue, liver, and soleus and extensor digitorum longus muscle weights were unaffected by arginine or CLA. CLA decreased epididymal adipose tissue concentrations of palmitoleic, oleic, and cis-vaccenic acid. CLA and arginine increased palmitate oxidation to CO(2) in epididymal adipose tissue in vitro relative to control rats. Glucose and palmitate incorporation into total lipids in epididymal adipose tissue was lower in rats fed supplemental arginine than in alanine-fed rats. Arginine increased plasma glycerol relative to alanine-fed rats and CLA and arginine independently decreased most serum essential amino acids and alanine, glutamate, glutamine, and ornithine. We conclude that CLA and arginine modulated adipose tissue metabolism by separate, but not additive, effects. Also, CLA and arginine may have depressed muscle protein turnover.</P>

Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility

Zhao, Jian,Wu, Hui,Khosravi, Melanie,Cui, Huijuan,Qian, Xiaoxia,Kelly, Jennifer A.,Kaufman, Kenneth M.,Langefeld, Carl D.,Williams, Adrienne H.,Comeau, Mary E.,Ziegler, Julie T.,Marion, Miranda C.,Adl Public Library of Science 2011 PLoS genetics Vol.7 No.5

<▼1><P>Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the <I>CFH</I>-<I>CFHRs</I> region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic <I>CFH</I> SNP (rs6677604, in intron 11, <I>P</I><SUB>meta</SUB> = 6.6×10<SUP>−8</SUP>, OR = 1.18) and an intergenic SNP between <I>CFHR1</I> and <I>CFHR4</I> (rs16840639, <I>P</I><SUB>meta</SUB> = 2.9×10<SUP>−7</SUP>, OR = 1.17) rather than to previously identified disease-associated <I>CFH</I> exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of <I>CFH</I> to downstream of <I>CFHR1</I>. Within this block, the deletion of <I>CFHR3</I> and <I>CFHR1</I> (<I>CFHR3-1</I>Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of <I>CFHR3-1</I>Δ (<I>P</I><SUB>meta</SUB> = 3.2×10<SUP>−7</SUP>, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (<I>P</I><SUB>meta</SUB> = 3.5×10<SUP>−4</SUP>, OR = 1.14). These results suggested that the <I>CFHR3-1</I>Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of <I>CFH</I>, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼1><▼2><P><B>Author Summary</B></P><P>Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing <I>CFH</I> and <I>CFHRs</I> with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of <I>CFHR3</I> and <I>CFHR1</I> genes but not previously identified disease-associated exonic variants of <I>CFH</I>. This study provides the first evidence for consistent association between <I>CFH/CFHRs</I> and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼2>

Ipsilateral Malignant Axillary Lymphadenopathy and Contralateral Reactive Lymph Nodes in a COVID-19 Vaccine Recipient With Breast Cancer

Mehmet Emin Adin,Jennifer Wu,Edvin Isuf,Edison Tsui,Darko Pucar 한국유방암학회 2022 Journal of breast cancer Vol.25 No.2

Vaccine-related axillary nodal enlargement is a common benign condition that many mRNA vaccine receivers experience. However, a false attribution of axillary swelling to vaccination may result in delay in cancer care and potential disease progression, particularly in breast cancer patients presenting with ipsilateral axillary lymphadenopathy. We report the case of a 41-year-old pre-menopausal female who presented with suspicious axillary nodal enlargement and a right breast lump (triple-negative invasive ductal carcinoma) after recent administration of the second dose of Moderna mRNA coronavirus disease 2019 (COVID-19) vaccine. On imaging, bilateral axillary lymph nodes were detected. The ipsilateral rightsided node was proven to be metastatic, whereas contralateral nodes were related to a recent mRNA COVID-19 vaccination. Right-sided lymph node had intense uptake (maximum standardized uptake value [SUVmax] = 5), while the contralateral reactive nodes were mildly avid (SUVmax = 2.6). On magnetic resonance imaging, the right-sided node revealed asymmetric cortical thickening and marked cortical enhancement as opposed to normalappearing left-sided nodes.

The 14-3-3 Gene Function of Cryptococcus neoformans Is Required for its Growth and Virulence

( Jingbo Li ),( Yun C. Chang ),( Chun Hua Wu ),( Jennifer Liu ),( Kyung J. Kwon Chung ),( Sheng He Huang ),( Hiro Shimada ),( Rob Fante ),( Xiaowei Fu ),( Ambrose Jong ) 한국미생물 · 생명공학회 2016 Journal of microbiology and biotechnology Vol.26 No.5

Cryptococcus neoformans is a life-threatening pathogenic yeast that causes devastating meningoencephalitis. The mechanism of cryptococcal brain invasion is largely unknown, and recent studies suggest that its extracellular microvesicles may be involved in the invasion process. The 14-3-3 protein is abundant in the extracellular microvesicles of C. neoformans, and the 14-3-3-GFP fusion has been used as the microvesicle’s marker. However, the physiological role of 14-3-3 has not been explored. In this report, we have found that C. neoformans contains a single 14-3-3 gene that apparently is an essential gene. To explore the functions of 14-3-3, we substituted the promoter region of the 14-3-3 with the copper-controllable promoter CTR4. The CTR4 regulatory strain showed an enlarged cell size, drastic changes in morphology, and a decrease in the thickness of the capsule under copper-enriched conditions. Furthermore, the mutant cells produced a lower amount of total proteins in their extracellular microvesicles and reduced adhesion to human brain microvascular endothelial cells in vitro. Proteomic analyses of the protein components under 14-3-3-overexpressed and -suppressed conditions revealed that the 14-3-3 function(s) might be associated with the microvesicle biogenesis. Our results support that 14-3-3 has diverse pertinent roles in both physiology and pathogenesis in C. neoformans. Its gene functions are closely relevant to the pathogenesis of this fungus.

A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Lu, Yingchang,Beeghly-Fadiel, Alicia,Wu, Lang,Guo, Xingyi,Li, Bingshan,Schildkraut, Joellen M.,Im, Hae Kyung,Chen, Yian A.,Permuth, Jennifer B.,Reid, Brett M.,Teer, Jamie K.,Moysich, Kirsten B.,Andrul American Association for Cancer Research 2018 Cancer Research Vol.78 No.18

Deubiquitination and Stabilization of PD-L1 by CSN5

Lim, Seung-Oe,Li, Chia-Wei,Xia, Weiya,Cha, Jong-Ho,Chan, Li-Chuan,Wu, Yun,Chang, Shih-Shin,Lin, Wan-Chi,Hsu, Jung-Mao,Hsu, Yi-Hsin,Kim, Taewan,Chang, Wei-Chao,Hsu, Jennifer L.,Yamaguchi, Hirohito,Ding Elsevier 2016 Cancer cell Vol.30 No.6

<P><B>Summary</B></P> <P>Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation </LI> <LI> Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization </LI> <LI> CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination </LI> <LI> Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

Zhao, Jian,Giles, Brendan M,Taylor, Rhonda L,Yette, Gabriel A,Lough, Kara M,Ng, Han Leng,Abraham, Lawrence J,Wu, Hui,Kelly, Jennifer A,Glenn, Stuart B,Adler, Adam J,Williams, Adrienne H,Comeau, Mary E H. K. Lewis 2016 Annals of the rheumatic diseases Vol.75 No.1

<P><B>Objectives</B></P><P>Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (<I>CR2/CD21</I>) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.</P><P><B>Methods</B></P><P>Genotyped and imputed genetic variants spanning <I>CR2</I> were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.</P><P><B>Results</B></P><P>The strongest association signal was detected at rs1876453 in intron 1 of <I>CR2</I> (p<SUB>meta</SUB>=4.2×10<SUP>−4</SUP>, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control p<SUB>meta</SUB>=7.6×10<SUP>−7</SUP>, OR 0.71; case-only p<SUB>meta</SUB>=1.9×10<SUP>−4</SUP>, OR 0.75). Although allele-specific effects on B cell <I>CR2</I> mRNA or protein levels were not identified, levels of complement receptor 1 (<I>CR1/CD35)</I> mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.</P><P><B>Conclusions</B></P><P>These data suggest that rs1876453 in <I>CR2</I> has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.</P>