scholarly journals APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

2020 ◽  
Author(s):  
Miles Berger ◽  
Mary Cooter ◽  
Alexander S. Roesler ◽  
Stacey Chung ◽  
John Park ◽  
...  
Keyword(s):  
Copy Number ◽  
Disease Risk ◽  
Clinical Status ◽  
Future Studies ◽  
Complement Proteins ◽  
Protein Levels ◽  
Proteomic Data ◽  
False Discovery ◽  
Significant Expression ◽  
Lower Expression

AbstractBackgroundAPOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.ObjectivesTo characterize CSF proteomic changes as a function of APOE4 copy number.MethodsWe analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons.ResultsIn the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (q<0.05 for each). In the second model (controlling for age, sex, and AD clinical status), increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.ConclusionsIncreasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

scholarly journals APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid

2020 ◽  
pp. 1-20
Author(s):  
Miles Berger ◽  
Mary Cooter ◽  
Alexander S. Roesler ◽  
Stacey Chung ◽  
John Park ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Copy Number ◽  
Linear Models ◽  
Disease Risk ◽  
Clinical Status ◽  
Future Studies ◽  
Protein Levels ◽  
Proteomic Data ◽  
False Discovery ◽  
The One

Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q <  0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q <  0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

scholarly journals 551. Convalescent plasma early in disease course improves survival in COVID-19

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S341-S342
Author(s):  
Varidhi Nauriyal ◽  
Anita Shallal ◽  
Amit T Vahia ◽  
Linoj Samuel ◽  
Robert Tibbetts ◽  
...  
Keyword(s):  
Scale Score ◽  
Medical Records ◽  
Clinical Status ◽  
Ordinal Scale ◽  
Optimal Timing ◽  
Care Hospital ◽  
Future Studies ◽  
Patient Gender ◽  
Significant Difference ◽  
Pcr Test

Abstract Background Convalescent plasma (CP) has been described as a potential therapy for coronavirus disease 2019 (COVID-19). Given paucity of data, we sought to describe characteristics of CP recipients in survivors and non-survivors. Methods We conducted retrospective review of electronic medical records which included any patient with a positive SARS-CoV-2 PCR test who received CP at an 890-bed quaternary care hospital in Southeast Michigan between March-May 2020. Data collected included: demographics, co-morbidities, mSOFA score on admission, laboratory values, and treatment. Outcomes assessed included inflammatory markers and clinical status based on an 8-point ordinal scalea. These values were recorded on admission, the date of CP (day 1), day 3, 7, and day 30 post-CP. Patient outcomes were stratified by ordinal scale score and compared using Mann-Whitney U tests to examine differences in clinical characteristics: scale of 1–4 (“meaningful survivor”), 5–7 (“survivor”), and 8 (“non-survivor”). Results Results of our study are summarized in Table 1 and 2. Non-survivors were older than survivors (62 vs 71 years; p=0.026). There was no statistically significant difference between patient gender, race, number of days from positive PCR test to CP, treatments, and co-morbidities. There was a trend toward higher mSOFA score on admission in non-survivors (p=0.056). A lower ordinal scale score on the date of receiving CP was significantly associated with meaningful survivorship (6 vs 7, p=0.005). Comparisons of Characteristics Based on Ordinal Scale at Day 30 Comparisons of Outcomes Based on Ordinal Scale at Day 30 Conclusion Patients who have a lower ordinal scale score on the date of CP administration are most likely to have meaningful survivorship at day 30. Future studies should evaluate optimal timing and outcomes for CP therapy in COVID-19. Disclosures All Authors: No reported disclosures

scholarly journals Inflammation in children with cystic fibrosis: contribution of bacterial production of long-chain fatty acids

2021 ◽  
Author(s):  
Erin Felton ◽  
Aszia Burrell ◽  
Hollis Chaney ◽  
Iman Sami ◽  
Anastassios C. Koumbourlis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Fatty Acid ◽  
Antibiotic Treatment ◽  
Bacterial Production ◽  
Clinical Status ◽  
Achromobacter Xylosoxidans ◽  
List Type ◽  
Future Studies ◽  
Long Chain

Abstract Background Cystic fibrosis (CF) affects >70,000 people worldwide, yet the microbiologic trigger for pulmonary exacerbations (PExs) remains unknown. The objective of this study was to identify changes in bacterial metabolic pathways associated with clinical status. Methods Respiratory samples were collected at hospital admission for PEx, end of intravenous (IV) antibiotic treatment, and follow-up from 27 hospitalized children with CF. Bacterial DNA was extracted and shotgun DNA sequencing was performed. MetaPhlAn2 and HUMAnN2 were used to evaluate bacterial taxonomic and pathway relative abundance, while DESeq2 was used to evaluate differential abundance based on clinical status. Results The mean age of study participants was 10 years; 85% received combination IV antibiotic therapy (beta-lactam plus a second agent). Long-chain fatty acid (LCFA) biosynthesis pathways were upregulated in follow-up samples compared to end of treatment: gondoate (p = 0.012), oleate (p = 0.048), palmitoleate (p = 0.043), and pathways of fatty acid elongation (p = 0.012). Achromobacter xylosoxidans and Escherichia sp. were also more prevalent in follow-up compared to PEx (p < 0.001). Conclusions LCFAs may be associated with persistent infection of opportunistic pathogens. Future studies should more closely investigate the role of LCFA production by lung bacteria in the transition from baseline wellness to PEx in persons with CF. Impact Increased levels of LCFAs are found after IV antibiotic treatment in persons with CF. LCFAs have previously been associated with increased lung inflammation in asthma. This is the first report of LCFAs in the airway of persons with CF. This research provides support that bacterial production of LCFAs may be a contributor to inflammation in persons with CF. Future studies should evaluate LCFAs as predictors of future PExs.

scholarly journals Associations Between Genetically Predicted Protein Levels and COVID-19 Severity

2020 ◽  
Vol 223 (1) ◽  
pp. 19-22
Author(s):  
Jingjing Zhu ◽  
Chong Wu ◽  
Lang Wu
Keyword(s):  
False Discovery Rate ◽  
Drug Repurposing ◽  
Bonferroni Correction ◽  
Host Genetics ◽  
Protein Levels ◽  
False Discovery

Abstract It is critical to identify potential causal targets for SARS-CoV-2, which may guide drug repurposing options. We assessed the associations between genetically predicted protein levels and COVID-19 severity. Leveraging data from the COVID-19 Host Genetics Initiative comparing 6492 hospitalized COVID-19 patients and 1 012 809 controls, we identified 18 proteins with genetically predicted levels to be associated with COVID-19 severity at a false discovery rate of &lt;0.05, including 12 that showed an association even after Bonferroni correction. Of the 18 proteins, 6 showed positive associations and 12 showed inverse associations. In conclusion, we identified 18 candidate proteins for COVID-19 severity.

scholarly journals cn.FARMS: a latent variable model to detect copy number variations in microarray data with a low false discovery rate

2011 ◽  
Vol 39 (12) ◽  
pp. e79-e79 ◽  
Author(s):  
D.-A. Clevert ◽  
A. Mitterecker ◽  
A. Mayr ◽  
G. Klambauer ◽  
M. Tuefferd ◽  
...  
Keyword(s):  
False Discovery Rate ◽  
Microarray Data ◽  
Copy Number ◽  
Latent Variable ◽  
Copy Number Variations ◽  
Latent Variable Model ◽  
Variable Model ◽  
False Discovery

scholarly journals Bayesian copy number detection and association in large-scale studies

2020 ◽  
Author(s):  
Stephen Cristiano ◽  
David McKean ◽  
Jacob Carey ◽  
Paige Bracci ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Copy Number ◽  
Large Scale ◽  
Disease Risk ◽  
Copy Number Variants ◽  
Regulatory Elements ◽  
Cancer Case ◽  
Tumor Supressor ◽  
Increase Risk ◽  
Control Study

AbstractGermline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

scholarly journals Characterization of Formononetin Sulfonation in SULT1A3 Overexpressing HKE293 Cells: Involvement of Multidrug Resistance-Associated Protein 4 in Excretion of Sulfate

2021 ◽  
Vol 11 ◽  
Author(s):  
Fanye Liu ◽  
Shuhua Pei ◽  
Wenqi Li ◽  
Xiao Wang ◽  
Chao Liang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Specific Inhibitor ◽  
Cancer Resistance ◽  
Traditional Chinese Herbal Medicine ◽  
Protein Levels ◽  
293 Cells ◽  
Expression Activity ◽  
Sulfate Formation ◽  
Significant Expression ◽  
Excretion Rates

Formononetin is one of the main active compounds of traditional Chinese herbal medicine Astragalus membranaceus. However, disposition of formononetin via sulfonation pathway remains undefined. Here, expression-activity correlation was performed to identify the contributing of SULT1A3 to formononetin metabolism. Then the sulfonation of formononetin and excretion of its sulfate were investigated in SULT1A3 overexpressing human embryonic kidney 293 cells (or HKE-SULT1A3 cells) with significant expression of breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). As a result, formononetin sulfonation was significantly correlated with SULT1A3 protein levels (r = 0.728; p &lt; 0.05) in a bank of individual human intestine S9 fractions (n = 9). HEK-SULT1A3 cells catalyzed formononetin formation of a monosulfate metabolite. Sulfate formation of formononetin in HEK-SULT1A3 cell lysate followed the Michaelis-Menten kinetics (Vmax = 13.94 pmol/min/mg and Km = 6.17 μM). Reduced activity of MRP4 by MK-571 caused significant decrease in the excretion rate (79.1%–94.6%) and efflux clearance (85.3%–98.0%) of formononetin sulfate, whereas the BCRP specific inhibitor Ko143 had no effect. Furthermore, silencing of MRP4 led to obvious decrease in sulfate excretion rates (&gt;32.8%) and efflux clearance (&gt;50.6%). It was worth noting that the fraction of dose metabolized (fmet), an indicator of the extent of drug sulfonation, was also decreased (maximal 26.7%) with the knockdown of MRP4. In conclusion, SULT1A3 was of great significance in determining sulfonation of formononetin. HEK-SULT1A3 cells catalyzed formononetin formation of a monosulfate. MRP4 mainly contributed to cellular excretion of formononetin sulfate and further mediated the intracellular sulfonation of formononetin.

False discovery rates and copy number variation

Biometrika ◽  
2011 ◽  
Vol 98 (2) ◽  
pp. 251-271 ◽  
Author(s):  
Bradley Efron ◽  
Nancy R. Zhang
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
False Discovery Rates ◽  
False Discovery ◽  
Number Variation ◽  
Discovery Rates

Post-transcriptional Cosuppression of Ty1 Retrotransposition

Genetics ◽  
2003 ◽  
Vol 165 (1) ◽  
pp. 83-99
Author(s):  
David J Garfinkel ◽  
Katherine Nyswaner ◽  
Jun Wang ◽  
Jae-Yong Cho
Keyword(s):  
Gene Silencing ◽  
Reverse Transcription ◽  
Copy Number ◽  
Transcript Level ◽  
Gag Protein ◽  
Protein Levels ◽  
Copy Number Control ◽  
Gal1 Promoter ◽  
Pgk1 Promoter ◽  
Ty1 Retrotransposition

Abstract To determine whether homology-dependent gene silencing or cosuppression mechanisms underlie copy number control (CNC) of Ty1 retrotransposition, we introduced an active Ty1 element into a naïve strain. Single Ty1 element retrotransposition was elevated in a Ty1-less background, but decreased dramatically when additional elements were present. Transcription from the suppressing Ty1 elements enhanced CNC but translation or reverse transcription was not required. Ty1 CNC occurred with a transcriptionally active Ty2 element, but not with Ty3 or Ty5 elements. CNC also occurred when the suppressing Ty1 elements were transcriptionally silenced, fused to the constitutive PGK1 promoter, or contained a minimal segment of mostly TYA1-gag sequence. Ty1 transcription of a multicopy element expressed from the GAL1 promoter abolished CNC, even when the suppressing element was defective for transposition. Although Ty1 RNA and TyA1-gag protein levels increased with the copy number of expressible elements, a given element's transcript level varied less than twofold regardless of whether the suppressing elements were transcriptionally active or repressed. Furthermore, a decrease in the synthesis of Ty1 cDNA is strongly associated with Ty1 CNC. Together our results suggest that Ty1 cosuppression can occur post-transcriptionally, either prior to or during reverse transcription.

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