Publications by authors named "Julia Wang"

102 Publications

An Autoantigen Profile of Human A549 Lung Cells Reveals Viral and Host Etiologic Molecular Attributes of Autoimmunity in COVID-19.

bioRxiv 2021 Feb 22. Epub 2021 Feb 22.

We aim to establish a comprehensive COVID-19 autoantigen atlas in order to understand autoimmune diseases caused by SARS-CoV-2 infection. Based on the unique affinity between dermatan sulfate and autoantigens, we identified 348 proteins from human lung A549 cells, of which 198 are known targets of autoantibodies. Comparison with current COVID data identified 291 proteins that are altered at protein or transcript level in SARS-CoV-2 infection, with 191 being known autoantigens. These known and putative autoantigens are significantly associated with viral replication and trafficking processes, including gene expression, ribonucleoprotein biogenesis, mRNA metabolism, translation, vesicle and vesicle-mediated transport, and apoptosis. They are also associated with cytoskeleton, platelet degranulation, IL-12 signaling, and smooth muscle contraction. Host proteins that interact with and that are perturbed by viral proteins are a major source of autoantigens. Orf3 induces the largest number of protein alterations, Orf9 affects the mitochondrial ribosome, and they and E, M, N, and Nsp proteins affect protein localization to membrane, immune responses, and apoptosis. Phosphorylation and ubiquitination alterations by viral infection define major molecular changes in autoantigen origination. This study provides a large list of autoantigens as well as new targets for future investigation, e.g., UBA1, UCHL1, USP7, CDK11A, PRKDC, PLD3, PSAT1, RAB1A, SLC2A1, platelet activating factor acetylhydrolase, and mitochondrial ribosomal proteins. This study illustrates how viral infection can modify host cellular proteins extensively, yield diverse autoantigens, and trigger a myriad of autoimmune sequelae.
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http://dx.doi.org/10.1101/2021.02.21.432171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924268PMC
February 2021

An Autoantigen Atlas from Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19.

bioRxiv 2021 Jan 24. Epub 2021 Jan 24.

COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. Using DS affinity, we identified an autoantigenome of 408 proteins from human fetal lung fibroblast HFL11 cells, at least 231 of which are known autoAgs. Comparing with available COVID data, 352 proteins of the autoantigenome have thus far been found to be altered at protein or RNA levels in SARS-Cov-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a strong connection between viral infection and autoimmunity. The vast number of COVID-altered proteins with propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients. The variety of autoAgs related to mRNA metabolism, translation, and vesicles raises concerns about potential adverse effects of mRNA vaccines. The COVID autoantigen atlas we are establishing provides a detailed molecular map for further investigation of autoimmune sequelae of the pandemic.
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http://dx.doi.org/10.1101/2021.01.24.427965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836114PMC
January 2021

Preserving transcriptional stress responses as an anti-aging strategy.

Aging Cell 2021 02 20;20(2):e13297. Epub 2021 Jan 20.

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA.

The progressively increasing frailty, morbidity and mortality of aging organisms coincides with, and may be causally related to, their waning ability to adapt to environmental perturbations. Transcriptional responses to challenges, such as oxidative stress or pathogens, diminish with age. This effect is manifest in the declining function of the stress responsive transcription factor Nrf2. Protective gene expression programs that are controlled by the Drosophila Nrf2 homolog, CncC, support homeostasis and longevity. Age-associated chromatin changes make these genes inaccessible to CncC binding and render them inert to signal-dependent transcriptional activation in old animals. In a previous paper, we have reported that overexpression of the CncC dimerization partner Maf-S counteracts this degenerative effect and preserves organism fitness. Building on this work, we show here that Maf-S overexpression prevents loss of chromatin accessibility and maintains gene responsiveness. Moreover, the same outcome, along with an extension of lifespan, can be achieved by inducing CncC target gene expression pharmacologically throughout adult life. Thus, pharmacological or dietary interventions that can preserve stress responsive gene expression may be feasible anti-aging strategies.
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http://dx.doi.org/10.1111/acel.13297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884037PMC
February 2021

AgRP neurons trigger long-term potentiation and facilitate food seeking.

Transl Psychiatry 2021 01 5;11(1):11. Epub 2021 Jan 5.

Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.

Sufficient feeding is essential for animals' survival, which requires a cognitive capability to facilitate food seeking, but the neurobiological processes regulating food seeking are not fully understood. Here we show that stimulation of agouti-related peptide-expressing (AgRP) neurons triggers a long-term depression (LTD) of spontaneous excitatory post-synaptic current (sEPSC) in adjacent pro-opiomelanocortin (POMC) neurons and in most of their distant synaptic targets, including neurons in the paraventricular nucleus of the thalamus (PVT). The AgRP-induced sEPCS LTD can be enhanced by fasting but blunted by satiety signals, e.g. leptin and insulin. Mice subjected to food-seeking tasks develop similar neural plasticity in AgRP-innervated PVT neurons. Further, ablation of the majority of AgRP neurons, or only a subset of AgRP neurons that project to the PVT, impairs animals' ability to associate spatial and contextual cues with food availability during food seeking. A similar impairment can be also induced by optogenetic inhibition of the AgRP→PVT projections. Together, these results indicate that the AgRP→PVT circuit is necessary for food seeking.
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http://dx.doi.org/10.1038/s41398-020-01161-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791100PMC
January 2021

Control of osteoblast regeneration by a train of Erk activity waves.

Nature 2021 Feb 6;590(7844):129-133. Epub 2021 Jan 6.

Regeneration Next, Duke University, Durham, NC, USA.

Regeneration is a complex chain of events that restores a tissue to its original size and shape. The tissue-wide coordination of cellular dynamics that is needed for proper morphogenesis is challenged by the large dimensions of regenerating body parts. Feedback mechanisms in biochemical pathways can provide effective communication across great distances, but how they might regulate growth during tissue regeneration is unresolved. Here we report that rhythmic travelling waves of Erk activity control the growth of bone in time and space in regenerating zebrafish scales, millimetre-sized discs of protective body armour. We find that waves of Erk activity travel across the osteoblast population as expanding concentric rings that are broadcast from a central source, inducing ring-like patterns of tissue growth. Using a combination of theoretical and experimental analyses, we show that Erk activity propagates as excitable trigger waves that are able to traverse the entire scale in approximately two days and that the frequency of wave generation controls the rate of scale regeneration. Furthermore, the periodic induction of synchronous, tissue-wide activation of Erk in place of travelling waves impairs tissue growth, which indicates that wave-distributed Erk activation is key to regeneration. Our findings reveal trigger waves as a regulatory strategy to coordinate cell behaviour and instruct tissue form during regeneration.
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http://dx.doi.org/10.1038/s41586-020-03085-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864885PMC
February 2021

DEAD-box RNA helicase protein DDX21 as a prognosis marker for early stage colorectal cancer with microsatellite instability.

Sci Rep 2020 12 16;10(1):22085. Epub 2020 Dec 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

DEAD-box RNA helicase DDX21 (also named nucleolar RNA helicase 2) is a nuclear autoantigen with undefined roles in cancer. To explore possible roles of autoimmune recognition in cancer immunity, we examined DDX21 protein expression in colorectal cancer tissue and its association with patient clinical outcomes. Unbiased deep proteomic profiling of two independent colorectal cancer cohorts using mass spectrometry showed that DDX21 protein was significantly upregulated in cancer relative to benign mucosa. We then examined DDX21 protein expression in a validation group of 710 patients, 619 of whom with early stage and 91 with late stage colorectal cancers. DDX21 was detected mostly in the tumor cell nuclei, with high expression in some mitotic cells. High levels of DDX21 protein were found in 28% of stage I, 21% of stage II, 30% of stage III, and 32% of stage IV colorectal cancer cases. DDX21 expression levels correlated with non-mucinous histology in early stage cancers but not with other clinicopathological features such as patient gender, age, tumor location, tumor grade, or mismatch repair status in any cancer stage. Kaplan-Meier analyses revealed that high DDX21 protein levels was associated with longer survival in patients with early stage colorectal cancer, especially longer disease-free survival in patients with microsatellite instability (MSI) cancers, but no such correlations were found for the microsatellite stable subtype or late stage colorectal cancer. Univariate and multivariate analyses also identified high DDX21 protein expression as an independent favorable prognostic marker for early stage MSI colorectal cancer.
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http://dx.doi.org/10.1038/s41598-020-79049-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745018PMC
December 2020

State TANF Time Limit and Work Sanction Stringencies and Long-Term Trajectories of Welfare Use, Labor Supply, and Income.

J Fam Econ Issues 2020 Oct 14:1-47. Epub 2020 Oct 14.

The University of Hong Kong, Pokfulam Road, Hong Kong, China.

While the 1996 welfare reform increased employment and reduced the participation of the Temporary Assistance for Needy Families (TANF) program immediately after its inception, little is known about the extent to which the reform and stringencies of time limit and work sanction policy features have impacted individuals in the long term. This study used the Survey of Income and Program Participation 1996, 2001, and 2004 panels (1996-2007) and a difference-in-difference-in-difference design to follow low-skilled single mothers' trajectories of welfare use, labor supply, and income for 10 years after the welfare reform and compare how these trajectories differ by stringencies of state work sanction and time limit policies. The findings indicate that welfare reform had sustained impacts on reducing welfare use (TANF and the Supplemental Nutrition Assistance Program [SNAP] program) and increasing employment. Stringent work sanction and time limit policies were associated with lower TANF participation rates in the long term, but only short time limit policies were associated with reduced SNAP participation. Neither stringent policy feature increased employment nor income. The differential effects by race were also examined and discussed.
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http://dx.doi.org/10.1007/s10834-020-09714-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556770PMC
October 2020

TPH2 in the Dorsal Raphe Nuclei Regulates Energy Balance in a Sex-Dependent Manner.

Endocrinology 2021 Jan;162(1)

Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas.

AbstractCentral 5-hydroxytryptamine (5-HT), which is primarily synthesized by tryptophan hydroxylase 2 (TPH2) in the dorsal Raphe nuclei (DRN), plays a pivotal role in the regulation of food intake and body weight. However, the physiological functions of TPH2 on energy balance have not been consistently demonstrated. Here we systematically investigated the effects of TPH2 on energy homeostasis in adult male and female mice. We found that the DRN harbors a similar amount of TPH2+ cells in control male and female mice. Adult-onset TPH2 deletion in the DRN promotes hyperphagia and body weight gain only in male mice, but not in female mice. Ablation of TPH2 reduces hypothalamic pro-opiomelanocortin (POMC) neuronal activity robustly in males, but only to a modest degree in females. Deprivation of estrogen by ovariectomy (OVX) causes comparable food intake and weight gain in female control and DRN-specific TPH2 knockout mice. Nevertheless, disruption of TPH2 blunts the anorexigenic effects of exogenous estradiol (E2) and abolishes E2-induced activation of POMC neurons in OVX female mice, indicating that TPH2 is indispensable for E2 to activate POMC neurons and to suppress appetite. Together, our study revealed that TPH2 in the DRN contributes to energy balance regulation in a sexually dimorphic manner.
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http://dx.doi.org/10.1210/endocr/bqaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685027PMC
January 2021

Low doses of the neonicotinoid insecticide imidacloprid induce ROS triggering neurological and metabolic impairments in .

Proc Natl Acad Sci U S A 2020 10 28;117(41):25840-25850. Epub 2020 Sep 28.

School of BioSciences, The University of Melbourne, Parkville, VIC, 3052, Australia;

Declining insect population sizes are provoking grave concern around the world as insects play essential roles in food production and ecosystems. Environmental contamination by intense insecticide usage is consistently proposed as a significant contributor, among other threats. Many studies have demonstrated impacts of low doses of insecticides on insect behavior, but have not elucidated links to insecticidal activity at the molecular and cellular levels. Here, the histological, physiological, and behavioral impacts of imidacloprid are investigated in , an experimental organism exposed to insecticides in the field. We show that oxidative stress is a key factor in the mode of action of this insecticide at low doses. Imidacloprid produces an enduring flux of Ca into neurons and a rapid increase in levels of reactive oxygen species (ROS) in the larval brain. It affects mitochondrial function, energy levels, the lipid environment, and transcriptomic profiles. Use of RNAi to induce ROS production in the brain recapitulates insecticide-induced phenotypes in the metabolic tissues, indicating that a signal from neurons is responsible. Chronic low level exposures in adults lead to mitochondrial dysfunction, severe damage to glial cells, and impaired vision. The potent antioxidant, -acetylcysteine amide (NACA), reduces the severity of a number of the imidacloprid-induced phenotypes, indicating a causal role for oxidative stress. Given that other insecticides are known to generate oxidative stress, this research has wider implications. The systemic impairment of several key biological functions, including vision, reported here would reduce the resilience of insects facing other environmental challenges.
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http://dx.doi.org/10.1073/pnas.2011828117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568275PMC
October 2020

A proteomic repertoire of autoantigens identified from the classic autoantibody clinical test substrate HEp-2 cells.

Clin Proteomics 2020 21;17:35. Epub 2020 Sep 21.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.

Background: Autoantibodies are a hallmark of autoimmune diseases. Autoantibody screening by indirect immunofluorescence staining of HEp-2 cells with patient sera is a current standard in clinical practice. Differential diagnosis of autoimmune disorders is based on commonly recognizable nuclear and cytoplasmic staining patterns. In this study, we attempted to identify as many autoantigens as possible from HEp-2 cells using a unique proteomic DS-affinity enrichment strategy.

Methods: HEp-2 cells were cultured and lysed. Total proteins were extracted from cell lysate and fractionated with DS-Sepharose resins. Proteins were eluted with salt gradients, and fractions with low to high affinity were collected and sequenced by mass spectrometry. Literature text mining was conducted to verify the autoantigenicity of each protein. Protein interaction network and pathway analyses were performed on all identified proteins.

Results: This study identified 107 proteins from fractions with low to high DS-affinity. Of these, 78 are verified autoantigens with previous reports as targets of autoantibodies, whereas 29 might be potential autoantigens yet to be verified. Among the 107 proteins, 82 can be located to nucleus and 15 to the mitotic cell cycle, which may correspond to the dominance of nuclear and mitotic staining patterns in HEp-2 test. There are 55 vesicle-associated proteins and 12 ribonucleoprotein granule proteins, which may contribute to the diverse speckled patterns in HEp-2 stains. There are also 32 proteins related to the cytoskeleton. Protein network analysis indicates that these proteins have significantly more interactions among themselves than would be expected of a random set, with the top 3 networks being mRNA metabolic process regulation, apoptosis, and DNA conformation change.

Conclusions: This study provides a proteomic repertoire of confirmed and potential autoantigens for future studies, and the findings are consistent with a mechanism for autoantigenicity: how self-molecules may form molecular complexes with DS to elicit autoimmunity. Our data contribute to the molecular etiology of autoimmunity and may deepen our understanding of autoimmune diseases.
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http://dx.doi.org/10.1186/s12014-020-09298-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507713PMC
September 2020

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

J Clin Oncol 2020 11 8;38(31):3638-3651. Epub 2020 Sep 8.

INSERM, Laboratory of Integrative Cancer Immunology, Paris, France.

Purpose: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).

Methods: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.

Results: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high low], 0.48; 95% CI, 0.32 to 0.71; = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high low], 0.41; 95% CI, 0.25 to 0.67; .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high low], 0.36; 95% CI, 0.21 to 0.62; .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; = .0011) and high-risk (HR [chemotherapy no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; = .0015) patients, in contrast to the low-Immunoscore group ( > .12).

Conclusion: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
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http://dx.doi.org/10.1200/JCO.19.03205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605397PMC
November 2020

An Investigation Into the Prognostic Significance of High Proteasome PSB7 Protein Expression in Colorectal Cancer.

Front Med (Lausanne) 2020 7;7:401. Epub 2020 Aug 7.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Using unbiased proteomics, we had previously discovered that the catalytic proteasome subunit β type 7 (PSB7) protein is frequently overexpressed in colorectal adenocarcinomas. In this paper, we validate this finding and derive a prognostic significance for PSB7 by examining an expanded, well-annotated clinical cohort of 318 colorectal cancer patients. We found PSB7 protein levels to be similarly increased in both advanced stage primary disease and metastatic lesions. We then examined the prognostic value of PSB7 protein expression. Elevated PSB7 protein as well as mRNA levels showed associations with lower overall survival, particularly in female patients. The prognostic value of elevated PSB7 protein levels was highest for female patients who were older (>60 years of age at diagnosis) or who had received adjuvant chemotherapy. While high PSB7 did not retain its prognostic significance on multivariate analysis, we discuss the potential significance of PSB7 as a biomarker, considering its differential prognostic strength in different colorectal cancer patient groups and given its role as a subunit of the immunoproteasome for antigen presentation.
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http://dx.doi.org/10.3389/fmed.2020.00401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426439PMC
August 2020

A combined FAK, c-MET, and MST1R three-protein panel risk-stratifies colorectal cancer patients.

Transl Oncol 2020 Nov 30;13(11):100836. Epub 2020 Jul 30.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Focal adhesion kinase (FAK) is a key tyrosine kinase downstream of c-MET (or hepatocyte growth factor receptor, HGFR) and MST1R (macrophage-stimulating protein receptor or recepteur d'origine Nantais, RON) membrane receptors. The pathway plays an important role in cancer survival and invasion. In this study, we examined the protein expression of FAK, c-MET, and MST1R levels in a well-annotated cohort of 330 colorectal cancer patients. We found FAK to be overexpressed in colorectal adenocarcinomas (p = 0.0002), and FAK levels correlated positively with phospho-FAK levels (R = 0.81). In comparison, MST1R levels were not significantly different, and c-MET levels were slightly higher in the normal samples. We then developed a combined 3-protein panel of FAK, c-MET, and MST1R expression signatures that can robustly risk-stratify colorectal cancer across all stages into three clusters that differ in progression-free survival. The colorectal cancer subgroup with high FAK, low c-MET, and low MST1R protein levels showed the worst progression-free survival with particularly early progression of disease (p = 0.0053). Combined FAK, c-MET, and MST1R were independently prognostic for progression-free survival in stage II colorectal cancers in a multivariate model. The 3-protein panel provides a potentially clinically attractive method for risk-stratification and adjuvant therapy guidance, especially in stage II disease.
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http://dx.doi.org/10.1016/j.tranon.2020.100836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399195PMC
November 2020

Resilience in the Setting of Adverse Childhood Experiences: A Cross-Sectional Study.

Clin Pediatr (Phila) 2020 Dec 28;59(14):1296-1300. Epub 2020 Jul 28.

Los Angeles County + University of Southern California Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1177/0009922820941633DOI Listing
December 2020

17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling.

Mol Metab 2020 12 23;42:101053. Epub 2020 Jul 23.

USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. Electronic address:

Objective: Estrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17β-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms.

Methods: Wild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF2 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy-D-glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus.

Results: In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF2 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia.

Conclusion: In addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity.
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http://dx.doi.org/10.1016/j.molmet.2020.101053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484552PMC
December 2020

Maspin as a Prognostic Marker for Early Stage Colorectal Cancer With Microsatellite Instability.

Front Oncol 2020 10;10:945. Epub 2020 Jun 10.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Colorectal cancers are among the most common cancers and a leading cause of cancer death. In our pursuit to discover molecular markers for better characterization and precision theranostics of these cancers, we first conducted global deep proteome analyses and identified maspin (serpin B5, peptidase inhibitor 5) as an upregulated protein in tumor tissue. We then validated its expression in a large cohort of 743 patients with colorectal cancers of all stages and found that both cytoplasmic and nuclear expression varied widely between different patients. Comparison with clinicopathological features revealed that maspin expression levels correlate significantly only with mismatch repair (MMR) status but not with other features. To elucidate the prognostic significance of maspin, we analyzed two outcome-annotated cohorts, one of 572 early stage cancer patients and another of 93 late stage cancer patients. Kaplan-Meier survival, univariate, and multivariate analyses revealed that maspin overexpression predicts longer overall and disease-free survival for early stage microsatellite instability (MSI) subtype colorectal cancer, but there is no correlation with survival for patients with early stage cancer of the microsatellite stability (MSS) subtype or late stage cancer. Our study identifies maspin expression as an independent prognostic marker for risk stratification of early stage MSI subtype colorectal cancer and may provide guidance for improved therapeutic management.
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http://dx.doi.org/10.3389/fonc.2020.00945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297950PMC
June 2020

Long-Term (3 Years) Outcomes of Ranolazine Therapy for Refractory Angina Pectoris (from the Ranolazine Refractory Registry).

Am J Cardiol 2020 08 16;129:1-4. Epub 2020 May 16.

The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital, Cincinnati, Ohio. Electronic address:

Ranolazine is approved for patients with chronic stable angina but has not been formally studied in patients with refractory angina pectoris (RAP). Patients with RAP have limited therapeutic options and significant limitations in their quality of life. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness of ranolazine in RAP patients in order to expand treatment options for this challenging patient population. Using an extensive prospective database, we enrolled 158 consecutive patients evaluated in a dedicated RAP clinic. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 12, 24, and 36 months. At 3 years, 95 (60%) patients remained on ranolazine. A ≥2 class improvement in angina was seen in 48% (38 of 80 patients with known Canadian Cardiovascular Society class) of those who remained on ranolazine. Discontinuation due to side effects, ineffectiveness, cost, and progression of disease were the principle reasons for discontinuation, but primarily occurred within the first year. In conclusion, ranolazine is an effective antianginal therapy at 3-year follow-up in patients with RAP and may reduce cardiac readmission.
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http://dx.doi.org/10.1016/j.amjcard.2020.05.020DOI Listing
August 2020

Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance.

Nat Commun 2020 05 1;11(1):2165. Epub 2020 May 1.

Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα) or glucose-excited neurons (GE-ERα). Hypoglycemia activates GI-ERα neurons via the anoctamin 4 channel, and inhibits GE-ERα neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα to mpARH circuit and inhibition of ERα to DRN circuit both increase blood glucose. Thus, our results indicate that ERα neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.
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http://dx.doi.org/10.1038/s41467-020-15982-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195451PMC
May 2020

STAT1 as a potential prognosis marker for poor outcomes of early stage colorectal cancer with microsatellite instability.

PLoS One 2020 10;15(4):e0229252. Epub 2020 Apr 10.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.

Proteomic analyses indicate that STAT1 protein (signal transducer and activator of transcription 1 or transcription factor ISGF-3 components p91/p84) is upregulated in some colorectal cancers. This study examined 736 colorectal cancer patients for the expression of STAT1 protein in tissue specimens, including 614 early stage patients and 122 advanced stage patients. Tissue microarrays were constructed, and STAT1 expression was examined by immunohistochemistry and scored semi-quantitatively. Among all cases, 9% of cases displayed high levels of cytoplasmic expression of STAT1 and 15% of cases had positive nuclear expression. Based on statistical analyses of a cohort of 559 early stage patients with survival data and no neoadjuvant therapy, we found that high levels of cytoplasmic expression of STAT1 correlated with shorter survival time in early stage colorectal cancer, particularly of the microsatellite instability (MSI) subtype. Additional analysis of a 244-case cohort of colorectal cancers from the Cancer Genome Atlas found that STAT1 gene expression correlated positively with PD-L1 (CD274) and PD-1 (PDCD1) but had no correlation with KRAS or BRAF mutation status. STAT1 expression showed no clear correlation with any of the 4 clinical diagnostic markers of mismatch repair, MLH1, MSH2, MSH6, and PMS2, suggesting its potential as an independent outcome marker for MSI cancers. Our findings suggest that STAT1 may be used as a potential prognostic protein marker for stratifying the outcome risk of early stage MSI colorectal cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229252PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147729PMC
July 2020

Measuring the predictability of life outcomes with a scientific mass collaboration.

Authors:
Matthew J Salganik Ian Lundberg Alexander T Kindel Caitlin E Ahearn Khaled Al-Ghoneim Abdullah Almaatouq Drew M Altschul Jennie E Brand Nicole Bohme Carnegie Ryan James Compton Debanjan Datta Thomas Davidson Anna Filippova Connor Gilroy Brian J Goode Eaman Jahani Ridhi Kashyap Antje Kirchner Stephen McKay Allison C Morgan Alex Pentland Kivan Polimis Louis Raes Daniel E Rigobon Claudia V Roberts Diana M Stanescu Yoshihiko Suhara Adaner Usmani Erik H Wang Muna Adem Abdulla Alhajri Bedoor AlShebli Redwane Amin Ryan B Amos Lisa P Argyle Livia Baer-Bositis Moritz Büchi Bo-Ryehn Chung William Eggert Gregory Faletto Zhilin Fan Jeremy Freese Tejomay Gadgil Josh Gagné Yue Gao Andrew Halpern-Manners Sonia P Hashim Sonia Hausen Guanhua He Kimberly Higuera Bernie Hogan Ilana M Horwitz Lisa M Hummel Naman Jain Kun Jin David Jurgens Patrick Kaminski Areg Karapetyan E H Kim Ben Leizman Naijia Liu Malte Möser Andrew E Mack Mayank Mahajan Noah Mandell Helge Marahrens Diana Mercado-Garcia Viola Mocz Katariina Mueller-Gastell Ahmed Musse Qiankun Niu William Nowak Hamidreza Omidvar Andrew Or Karen Ouyang Katy M Pinto Ethan Porter Kristin E Porter Crystal Qian Tamkinat Rauf Anahit Sargsyan Thomas Schaffner Landon Schnabel Bryan Schonfeld Ben Sender Jonathan D Tang Emma Tsurkov Austin van Loon Onur Varol Xiafei Wang Zhi Wang Julia Wang Flora Wang Samantha Weissman Kirstie Whitaker Maria K Wolters Wei Lee Woon James Wu Catherine Wu Kengran Yang Jingwen Yin Bingyu Zhao Chenyun Zhu Jeanne Brooks-Gunn Barbara E Engelhardt Moritz Hardt Dean Knox Karen Levy Arvind Narayanan Brandon M Stewart Duncan J Watts Sara McLanahan

Proc Natl Acad Sci U S A 2020 04 30;117(15):8398-8403. Epub 2020 Mar 30.

Department of Sociology, Princeton University, Princeton, NJ 08544;

How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences.
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http://dx.doi.org/10.1073/pnas.1915006117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165437PMC
April 2020

Prolyl 4-hydroxylase alpha 1 protein expression risk-stratifies early stage colorectal cancer.

Oncotarget 2020 Feb 25;11(8):813-824. Epub 2020 Feb 25.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies. Especially for early stage CRC, prognostic molecular markers are needed to guide therapy. In this study, we first extracted total proteomes from matched pairs of fresh cancer and benign mucosal tissues from 22 CRC patients. Global proteomic profiling with Fourier transform liquid chromatography-mass spectrometry sequencing and label free quantitation uncovered that P4HA1 (prolyl 4-hydroxylase alpha 1) was overexpressed in CRC relative to benign colonic mucosa. We then investigated expression by immunohistochemical staining with P4HA1-specific antibodies using CRC tissue microarrays. Independent validation cohorts of 599 cases of early stage CRC and 91 cases of late stage CRC were examined. Multivariate and univariate survival analyses revealed that high expression of P4HA1 protein was an independent poor prognostic marker for patients with early stage CRC, especially of the microsatellite stable subtype. Our study provides strong support for P4HA1 as a predictive protein marker for precision diagnostics, therapeutic decision-making, and drug development for early stage colorectal cancer and demonstrates the utility of proteomic profiling to identify novel protein biomarkers.
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http://dx.doi.org/10.18632/oncotarget.27491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055541PMC
February 2020

Publisher Correction: Co-opted transposons help perpetuate conserved higher-order chromosomal structures.

Genome Biol 2020 Feb 7;21(1):28. Epub 2020 Feb 7.

The Edison Family Center for Genome Sciences & Systems Biology, Department of Genetics, Washington University, 4515 McKinley Avenue, Campus Box 8510, St. Louis, MO, 63110, USA.

Following publication of the original paper [1], an error was reported in the processing of Fig. 2. The correct Fig. 2 is supplied below and the original article [1] has been corrected. The publishers apologize for the error.
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http://dx.doi.org/10.1186/s13059-020-1944-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006110PMC
February 2020

Co-opted transposons help perpetuate conserved higher-order chromosomal structures.

Genome Biol 2020 01 24;21(1):16. Epub 2020 Jan 24.

The Edison Family Center for Genome Sciences & Systems Biology, Department of Genetics, Washington University, 4515 McKinley Avenue, Campus Box 8510, St. Louis, MO, 63110, USA.

Background: Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed.

Results: Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time.

Conclusions: TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.
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http://dx.doi.org/10.1186/s13059-019-1916-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979391PMC
January 2020

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.

Am J Hum Genet 2019 12 27;105(6):1237-1253. Epub 2019 Nov 27.

Centre Hospitalier Universitaire Saint-Justine Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada. Electronic address:

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904826PMC
December 2019

Using MARRVEL v1.2 for Bioinformatics Analysis of Human Genes and Variant Pathogenicity.

Curr Protoc Bioinformatics 2019 09;67(1):e85

Department of Pediatrics, Jan and Dan Duncan Neurological Research Institute at Texas, Children's Hospital, Houston, Texas.

One of the greatest challenges in the bioinformatic analysis of human sequencing data is identifying which variants are pathogenic. Numerous databases and tools have been generated to address this difficulty. However, these many useful data and tools are broadly dispersed, requiring users to search for their variants of interest through human genetic databases, variant function prediction tools, and model organism databases. To solve this problem, we collected data and observed workflows of human geneticists, clinicians, and model organism researchers to carefully select and display valuable information that facilitates the evaluation of whether a variant is likely to be pathogenic. This program, Model organism Aggregated Resources for Rare Variant ExpLoration (MARRVEL) v1.2, allows users to collect relevant data from 27 public sources for further efficient bioinformatic analysis of the pathogenicity of human variants. © 2019 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpbi.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750039PMC
September 2019

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information.

J Vis Exp 2019 08 15(150). Epub 2019 Aug 15.

Program in Developmental Biology, Baylor College of Medicine; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Department of Molecular and Human Genetics, Baylor College of Medicine; Department of Neuroscience, Baylor College of Medicine;

Through whole-exome/genome sequencing, human geneticists identify rare variants that segregate with disease phenotypes. To assess if a specific variant is pathogenic, one must query many databases to determine whether the gene of interest is linked to a genetic disease, whether the specific variant has been reported before, and what functional data is available in model organism databases that may provide clues about the gene's function in human. MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) is a one-stop data collection tool for human genes and variants and their orthologous genes in seven model organisms including in mouse, rat, zebrafish, fruit fly, nematode worm, fission yeast, and budding yeast. In this Protocol, we provide an overview of what MARRVEL can be used for and discuss how different datasets can be used to assess whether a variant of unknown significance (VUS) in a known disease-causing gene or a variant in a gene of uncertain significance (GUS) may be pathogenic. This protocol will guide a user through searching multiple human databases simultaneously starting with a human gene with or without a variant of interest. We also discuss how to utilize data from OMIM, ExAC/gnomAD, ClinVar, Geno2MP, DGV and DECHIPHER. Moreover, we illustrate how to interpret a list of ortholog candidate genes, expression patterns, and GO terms in model organisms associated with each human gene. Furthermore, we discuss the value protein structural domain annotations provided and explain how to use the multiple species protein alignment feature to assess whether a variant of interest affects an evolutionarily conserved domain or amino acid. Finally, we will discuss three different use-cases of this website. MARRVEL is an easily accessible open access website designed for both clinical and basic researchers and serves as a starting point to design experiments for functional studies.
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http://dx.doi.org/10.3791/59542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401700PMC
August 2019

A comprehensive autoantigen-ome of autoimmune liver diseases identified from dermatan sulfate affinity enrichment of liver tissue proteins.

BMC Immunol 2019 06 26;20(1):21. Epub 2019 Jun 26.

Curandis, New York, USA.

Background: Autoimmune diseases result from aberrant immune attacks by the body itself. It is mysterious how autoantigens, a large cohort of seemingly unconnected molecules expressed in different parts of the body, can induce similar autoimmune responses. We have previously found that dermatan sulfate (DS) can form complexes with molecules of apoptotic cells and stimulate autoreactive CD5+ B cells to produce autoantibodies. Hence, autoantigenic molecules share a unique biochemical property in their affinity to DS. This study sought to further test this uniform principle of autoantigenicity.

Results: Proteomes were extracted from freshly collected mouse livers. They were loaded onto columns packed with DS-Sepharose resins. Proteins were eluted with step gradients of increasing salt strength. Proteins that bound to DS with weak, moderate, or strong affinity were eluted with 0.4, 0.6, and 1.0 M NaCl, respectively. After desalting, trypsin digestion, and gel electrophoresis, proteins were sequenced by mass spectrometry. To validate whether these proteins have been previously identified as autoantigens, an extensive literature search was conducted using the protein name or its alternative names as keywords. Of the 41 proteins identified from the strong DS-affinity fraction, 33 (80%) were verified autoantigens. Of the 46 proteins with moderate DS-affinity, 27 (59%) were verified autoantigens. Of the 125 proteins with weak DS-affinity, 44 (35%) were known autoantigens. Strikingly, these autoantigens fell into the classical autoantibody categories of autoimmune liver diseases: ANA (anti-nuclear autoantibodies), SMA (anti-smooth muscle autoantibodies), AMA (anti-mitochondrial autoantibodies), and LKM (liver-kidney microsomal autoantigens).

Conclusions: This study of DS-affinity enrichment of liver proteins establishes a comprehensive autoantigen-ome for autoimmune liver diseases, yielding 104 verified and 108 potential autoantigens. The liver autoantigen-ome sheds light on the molecular origins of autoimmune liver diseases and further supports the notion of a unifying biochemical principle of autoantigenicity.
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http://dx.doi.org/10.1186/s12865-019-0304-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595630PMC
June 2019

A repertoire of 124 potential autoantigens for autoimmune kidney diseases identified by dermatan sulfate affinity enrichment of kidney tissue proteins.

PLoS One 2019 25;14(6):e0219018. Epub 2019 Jun 25.

Curandis, Scarsdale, New York, United States of America.

Autoantigens are the molecular targets in autoimmune diseases. They are a cohort of seemingly unrelated self-molecules present in different parts of the body, yet they can trigger a similar chain of autoimmune responses such as autoantibody production. We previously reported that dermatan sulfate (DS) can bind self-molecules of dying cells to stimulate autoreactive CD5+ B cells to produce autoantibodies. The formation of autoantigen-DS complexes converts the normally non-antigenic self-molecules to none-self antigens, and thus DS-affinity represents a common underlying biochemical property for autoantigens. This study sought to apply this property to identify potential autoantigens in the kidney. Total proteins were extracted from mouse kidney tissues and loaded onto DS-Sepharose resins. Proteins without affinity were washed off the resins, whereas those with increasing DS-affinity were eluted with step gradients of increasing salt strength. Fractions with strong and moderate DS-affinity were sequenced by mass spectrometry and yielded 25 and 99 proteins, respectively. An extensive literature search was conducted to validate whether these had been previously reported as autoantigens. Of the 124 proteins, 79 were reported autoantigens, and 19 out of 25 of the strong-DS-binding ones were well-known autoantigens. Moreover, these proteins largely fell into the two most common autoantibody categories in autoimmune kidney diseases, including 40 ANA (anti-nuclear autoantibodies) and 25 GBM (glomerular basement membrane) autoantigens. In summary, this study compiles a large repertoire of potential autoantigens for autoimmune kidney diseases. This autoantigen-ome sheds light on the molecular etiology of autoimmunity and further supports our hypothesis DS-autoantigen complexes as a unifying principle of autoantigenicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219018PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592568PMC
February 2020

Psychiatric problems among returned migrants in Mexico: updated findings from the Mexican Migration Project.

Soc Psychiatry Psychiatr Epidemiol 2019 Oct 27;54(10):1285-1294. Epub 2019 Mar 27.

Suzanne Dworak-Peck School of Social Work, University of Southern California, 669 W. 34th St., Los Angeles, CA, 90089-0411, USA.

Purpose: Migration is often a stressful process that can have deleterious effects on health. We study the potential mental health consequences of migration by comparing Mexican migrants to the United States who have since returned to Mexico with Mexicans who have never migrated.

Methods: Data from the Mexican Migration Project were used to compare returned migrants and non-migrants in Mexico for the years 2007-2016 (N = 7716). Random intercept logistic regression models were used to estimate the associations between characteristics of migration and psychiatric problems. Coarsened exact matching was implemented to account for the selection bias inherent to migration.

Results: Relatively healthier Mexicans were more likely to migrate to the United States, regardless of their documentation status. Returned migrants in Mexico who traveled to the United States while undocumented were significantly more likely to report that they experienced psychiatric problems when compared with non-migrant Mexicans, even after adjusting for demographic, socioeconomic, pre-migration health, and community-level factors.

Conclusions: Undocumented return migrants in Mexico are at-risk of developing psychiatric problems, despite evidence that suggests migrants tend to be healthier than non-migrants before they travel to the United States. Mental health services should encompass strategies for migrants on both sides of the border.
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http://dx.doi.org/10.1007/s00127-019-01699-6DOI Listing
October 2019

Acculturative stress, disability, and health treatment utilization among Asian and Latin American immigrants in the United States.

Soc Psychiatry Psychiatr Epidemiol 2019 Oct 20;54(10):1275-1284. Epub 2019 Mar 20.

Suzanne Dworak-Peck School of Social Work, University of Southern California, Los Angeles, USA.

Purpose: Empirical research has largely ignored the potential links between immigration-related stress and disability as well as immigration-related stress and health service utilization despite increasing scholarship on the association between acculturative stress and health. This study examined the associations between acculturative stress, disability, and health treatment utilization among Asian and Latin American immigrants in the United States.

Methods: Data were from the National Latino and Asian American Study (NLAAS), a nationally representative survey of Asians and Latinos living in the United States. The analytic sample contained 2653 immigrants. We utilized multivariable logistic regression and negative binomial regression analyses to examine the associations between acculturative stress and disability domains. We also examined the association between acculturative stress and treatment utilization, as this may have implications for how to best intervene to address any functional disability related to acculturative stress.

Results: Acculturative stress was significantly associated with self-reported disability across five domains: self-care, cognition, mobility, time out of role, and social interaction. Additionally, acculturative stress was significantly associated with a greater frequency of disability domains. Acculturative stress was not significantly associated with utilization of services from mental health or general health sectors, but was significantly and positively associated with utilization of non-health care services. The findings were robust regarding the inclusion of everyday discrimination as well as demographic and socioeconomic covariates.

Conclusions: Acculturative stress may be an important yet overlooked correlate of disability among immigrants in the United States. Non-health care services may provide an effective pathway for intervening for these individuals.
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http://dx.doi.org/10.1007/s00127-019-01691-0DOI Listing
October 2019