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YPED: An Integrated Bioinformatics Suite and Database for Mass Spectrometry-based Proteomics Research

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Genomics, Proteomics & Bioinformatics 2015年第1期13卷 25-35页

作者： Christopher M.Colangelo Mark Shifman Kei-Hoi Cheung Kathryn L.Stone Nicholas J.Carriero Erol E.Gulcicek TuKiet T.Lam Terence Wu Robert D.Bjornson Can Bruce Angus C.Nairn Jesse Rinehart Perry L.Miller Kenneth R.Williams W.M.Keck Foundation Biotechnology Resource Laboratory School of Medicine Yale University department of Molecular Biophysics & Biochemistry Yale University yale Center for Medical Informatics School of Medicine Yale University department of Anesthesiology School of Medicine Yale University department of Emergency medicine School of Medicine Yale University VA Connecticut Healthcare System W.M. Keck Foundation Biotechnology Resource Laboratory School of Medicine Yale University department of Computer Science Yale University yale Center for Genome Analysis West Campus Yale University yale West Campus Analytical Core West Campus Yale University yale Bioinformatics Resource School of Medicine Yale University department of Psychiatry School of Medicine Yale University department of Cellular & Molecular Physiology School of Medicine Yale University Systems Biology Institute Yale University

We report a significantly-enhanced bioinformatics suite and database for proteomics research called yale Protein Expression Database（YPED） that is used by investigators at more than 300 institutions worldwide. YPED meets the data management, archival, and analysis needs of a high-throughput mass spectrometry-based proteomics research ranging from a singlelaboratory, group of laboratories within and beyond an institution, to the entire proteomics community. The current version is a significant improvement over the first version in that it contains new modules for liquid chromatography–tandem mass spectrometry（LC–MS/MS） database search results, label and label-free quantitative proteomic analysis, and several scoring outputs for phosphopeptide site localization. In addition, we have added both peptide and protein comparative analysis tools to enable pairwise analysis of distinct peptides/proteins in each sample and of overlapping peptides/proteins between all samples in multiple datasets. We have also implemented a targeted proteomics module for automated multiple reaction monitoring（MRM）/selective reaction monitoring（SRM） assay development. We have linked YPED＇s database search results and both label-based and label-free fold-change analysis to the Skyline Panorama repository for online spectra visualization. In addition, we have built enhanced functionality to curate peptide identifications into an MS/MS peptide spectral library for all of our protein database search identification results.

关键词： Proteomics Database Bioinformatics Mass spectrometry Repository Spectral library

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Blood pressure-related white matter microstructural disintegrity and associated cognitive function impairment in asymptomatic adults

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Stroke & Vascular Neurology 2023年第5期8卷 358-367页

作者： Julián N Acosta Stefan P Haider Cyprien Rivier Audrey C Leasure Kevin N Sheth Guido J Falcone Seyedmehdi Payabvash department of Neurology Yale School of MedicineNew HavenConnecticutUSA department of Radiology and Biomedical Imaging Yale School of MedicineNew HavenConnecticutUSA department of Otorhinolaryngology Ludwig Maximilians University MunichMunchenGermany

Background and objectives We aimed to investigate the white matter(WM)microstructural/cytostructural disintegrity patterns related to higher systolic blood pressure(SBP),and whether they mediate SBP effects on cognitive performance in middle-aged adults.Methods Using the UK Biobank study of community-dwelling volunteers aged 40-69 years,we included participants without a history of stroke,dementia,demyelinating disease or traumatic brain injury.We investigated the association of SBP with MRI diffusion metrics:fractional anisotropy(FA),mean diffusivity(MD),intracellular volume fraction(a measure of neurite density),isotropic(free)water volume fraction(ISOVF)and orientation dispersion across WM tracts.Then,we determined whether WM diffusion metrics mediated the effects of SBP on cognitive function.Results We analysed 31363 participants-mean age of 63.8 years(SD:7.7),and 16523(53%)females.Higher SBP was associated with lower FA and neurite density,but higher MD and ISOVF.Among different WM tracts,diffusion metrics of the internal capsule anterior limb,external capsule,superior and posterior corona radiata were most affected by higher SBP.Among seven cognitive metrics,SBP levels were only associated with‘fluid intelligence’(adjusted p<0.001).In mediation analysis,the averaged FA of external capsule,internal capsule anterior limb and superior cerebellar peduncle mediated 13%,9%and 13%of SBP effects on fluid intelligence,while the averaged MD of external capsule,internal capsule anterior and posterior limbs,and superior corona radiata mediated 5%,7%,7%and 6%of SBP effects on fluid intelligence,respectively.Discussion Among asymptomatic adults,higher SBP is associated with pervasive WM microstructure disintegrity,partially due to reduced neuronal count,which appears to mediate SBP adverse effects on fluid intelligence.Diffusion metrics of select WM tracts,which are most reflective of SBP-related parenchymal damage and cognitive impairment,may serve as imaging biomarkers to assess treatment response in antihypertensive t

关键词： capsule Blood impairment

Elevated phosphorylated ubiquitin level elicits neurodegeneration by aggregating the decline of ubiquitindependent proteasomal degradation

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中国药理学与毒理学杂志 2023年第7期37卷 516-517页

作者： CHEN Cong GAO Tongyao WANG Tong LU Yunbi ZHANG Weiping department of pharmacology School of Medicine Zhejiang University

OBJECTIVE To determine the roles of phosphorylated ubiquitin(pUb) on ubiquitin-dependent proteasomal(UPS) degradation activity, and the roles of pUb on neurodegeneration. METHODS We use PTEN induced kinase 1(PINK1) to phosphorylate ubiquitin. The Ub/S65A cannot be phosphorylated by PINK1, and was used to antagonize the roles of pUb. The Ub/S65E was used to mimic the roles of pUb. The roles of pUb on UPS degradation activity were determined by immunofluorescence, Western blot and TIRF microscope at cellular and protein level. The roles of pUb on neurodegeneration were determined by behavior tests, immunofluorescence,Golgi staining, TEM, Western blot and proteomics sacle in mouse. RESULTS The level of soluble PINK1(sPINK1)and pUb increased in the neurons of aged mouse brain,and in the cells upon the administration of MG132, a proteasome inhibitor. The elevation of sPINK1 and pUb was accompanied by protein aggregation upon aging or the proteasomal inhibition. The pink1 knockout alleviated proteasomal inhibition induced protein aggregation and association of ubiquitinated proteins with proteasome.The over-expression of sPINK1 increased pUb level in hippocampal neuron, which chronically induced protein aggregation, mitochondrial damage and damage the structure of neuronal spines. Such neuronal injury lead to cognitive impairment of mice. The roles of sPINK1 was reversed by co-expression with Ub/S65A, and was mimic by over-expression with Ub/S65E. CONCLUSION The phosphorylation of ubiquitin aggravates UPS degradation, and accelerates neuronal degeneration upon the decline of proteasomal degradation in aging and agerelated neuronal diseases.

关键词： aging neurodegeneration phosphorylated ubiquitin proteasome protein aggregation PTEN induced kinase 1

Selective deletion of the soluble Colony-Stimulating Factor 1 isoform in vivo prevents estrogen-deficiency bone loss in mice

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Bone Research 2017年第4期5卷 367-374页

作者： Gang-Qing Yao Nancy Troiano Christine A Simpson Karl L Insogna department of Internal medicine Yale University School of MedicineNew HavenUSA department of Orthopaedics Yale University School of MedicineNew HavenUSA

Neutralizing CSF1 in vivo completely prevents ovariectomy （OVX）-induced bone loss in mice. There are two isoforms of CSF1, soluble （sCSF1）, and membrane-bound （mCSF1）, but their individual biological functions are unclear. It had been previously reported that mCSF1 knockout （K/O） and wild type （Wt） female mice experience the same degree of bone loss following OVX. In Wt mice the expression of sCSF1 was elevated fourfold in skeletal tissue following OVX while expression of mCSF1 was unchanged. To examine the role of sCSF1 in OVX-induced bone loss, mice were engineered in which sCSF1 was not expressed but expression of mCSF1 was unaffected （sCSF1 K/O）. Isoform-specific reverse transcription PCR confirmed the absence of transcripts for sCSF1 in bone tissue isolated from these animals and no circulating CSF1 was detected by ELISA. Surprisingly, there were no significant differences in bone mineral density （BMD） between sCSF1 K/O mice and Wt controls as assessed by dual-energy X-ray absorptiometry and micro-CT. However, one month after OVX, femoral, spinal and total BMD had declined by 11.2%, 8.9%, and 8.7% respectively in OVX-Wt animals as compared to Sham-OVX. In contrast OVX sCSF1 K/O mice showed changes of ＋0.1%, - 2.4%, and ＋2.3% at the same 3 sites compared to Sham-OVX sCSF1 K/O mice. These data indicate important non-redundant functions for the two isoforms of CSF1 and suggest that sCSF1, but not mCSF1, plays a key role in estrogen-deficiency bone loss.

关键词： CSF Selective deletion of the soluble Colony-Stimulating Factor 1 isoform in vivo prevents estrogen-deficiency bone loss in mice

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Sonic hedgehog signaling:Alternative splicing and pathogenic role in medulloblastoma

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Genes & Diseases 2023年第5期10卷 2013-2028页

作者： Meiyu Qu Qiangqiang He Jiahao Luo Tingyu Shen Ruibo Gao Yana Xu Chengyun Xu Muhammad Qasim Barkat Ling-Hui Zeng Ximei Wu department of pharmacology Zhejiang University City CollegeHangzhouZhejiang 310015China department of pharmacology Zhejiang University School of MedicineHangzhouZhejiang 310058China

Alternative splicing(AS)produces the different mRNA splicing bodies,which are then translated into multiple protein isoforms and participate in various biological functions.With a deeper understanding of alternative splicing through the study of transcriptomes using high-throughput sequencing-based methods,the correlation between aberrant AS and diseases triggered a great concern,especially abnormal AS and cancer.Medulloblastoma(MB)is an intracranial tumor in children.Sonic hedgehog MB(SHH-MB)accounted for approximately 30%of MB,which is associated with the activation of SHH signaling.Growing evidence shows that aberrant AS is closely related to the tumorigenesis of MB.Here,we briefly introduced the AS and its mechanism.Next,we described canonical/noncanonical hedgehog signaling and its correlation with MB.The main description focused on AS of various regulators in canonical hedgehog signaling in MB.In addition,we also described AS of various regulators in noncanonical hedgehog signaling.Meanwhile,activated hedgehog signaling also induces AS in MB.Then,we pointed out that aberrant AS of hedgehog signaling is associated with different MB subgroups.Finally,we summarized the therapeutic applications of targeted AS in cancer treatment.In summary,further understanding of AS in SHH-MB could develop therapeutic targets for splicing factors which may be a novel therapeutic strategy.

关键词： Alternative splicing Exon Hedgehog signaling Medulloblastoma Tumor suppressor

Hydrogen peroxide mediates pro-inflammatory cell-to-cell signaling: a new therapeutic target for inflammation?

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Neural Regeneration Research 2019年第8期14卷 1430-1437页

作者： Dhanushka Gunawardena Ritesh Raju Gerald Münch department of pharmacology School of Medicine Western Sydney University

Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide - like nitric oxide - acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration- dependent manner. The experiment showed concentration-dependent inhib让ion of nitric oxide and tumor necrosis factor-a production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-a production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates ad;acent cells. Like rdtric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-a. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.

关键词： Inflammation glycation redox signaling cytokines anti-inflammatory drugs hydrogen peroxide membrane permeable lipopolysaccharide Interferon-gamma signaling

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Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment

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World Journal of Gastrointestinal Oncology 2017年第1期9卷 21-29页

作者： Keitaro Hayashi Naohiko Anzai department of pharmacology and Toxicology Dokkyo Medical University School of Medicine department of pharmacology Chiba University Graduate School of Medicine

L-type amino acid transporters(LATs) mainly assist the uptake of neutral amino acids into cells. Four LATs(LAT1, LAT2, LAT3 and LAT4) have so far been identified. LAT1(SLC7A5) has been attracting much attention in the field of cancer research since it is commonly up-regulated in various cancers. Basic research has made it increasingly clear that LAT1 plays a predominant role in malignancy. The functional significance of LAT1 in cancer and the potential therapeutic application of the features of LAT1 to cancer management are described in this review.

关键词： LAT1 氨基酸 transporter 分子的目标药氨基酸饥饿反应信号 transduction

Endoscopic treatment of gastroparesis

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World Journal of Gastroenterology 2015年第22期21卷 6842-6849页

作者： Thomas R McCarty Tarun Rustagi department of Internal medicine Yale University School of Medicine Section of Digestive Diseases Department of Internal Medicine Yale University School of Medicine

Gastroparesis has traditionally been a largely medically managed disease with refractory symptoms typically falling under the umbrella of the surgical domain.Surgical options include, but are not limited to, gastrostomy,jejunostomy, pyloromyotomy, or pyloroplasty,and the Food and Drug Administration approvedgastric electrical stimulation implantation. Endoscopic management of gastroparesis most commonly involves intrapyloric botulinum toxin injection; however, there exists a variety of endoscopic approaches on the horizon that have the potential to radically shift standard of care.Endoscopic management of gastroparesis seeks to treat delayed gastric emptying with a less invasive approach compared to the surgical approach. This review will serve to highlight such innovative and potentially transformative, endoscopic interventions available to gastroenterologists in the management of gastroparesis.

关键词： Botulinum Gastrojejunostomy Transpyloric Pyloromyotomy Gastric stimulator Gastric pacemaker Stenting

Assessing the Effectiveness of Strategies in US Birth Cohort Screening for Hepatitis C Infection

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Journal of Clinical and Translational Hepatology 2020年第1期8卷 25-41页

作者： Cynthia J.Tsay Joseph K.Lim department of Internal medicine Yale University School of MedicineNew HavenCTUSA yale Liver Center Section of Digestive DiseasesYale University School of MedicineNew HavenCTUSA

Chronic hepatitis C infection in the USA is a highly morbid condition and current guidelines recommend one-time screening among the birth cohort(1945-1965).Understand-ing strategies to optimize screening can help inform future hepatitis C virus(HCV)screening guidelines.A focused literature search was performed using PubMed and manual abstract review from major hepatology conferences over the past 2 years.The search strategy involved using Medical Subject Headings terms for hepatitis C,screening,birth cohort,baby boomers,and 1945-1965.The review was limited to data from the USA.A total of 327 articles were identified and 36 abstracts were included,with studies published between 2012-2019.Strategies including clinician education,electronic medical record alerts,reflex HCV RNA testing,point-of-care testing,multisite(outpatient,inpatient,emergency department,endoscopy suite)initiatives,direct patient solicitation,and utilization of non-physician providers have increased HCV screening rates.However,broad imple-mentation remains less than optimal.Barriers include lack of patient acceptance to screening and engagement in the HCV care cascade.The Veterans Affairs Healthcare System has achieved higher birth cohort screening rates through an integrated approach requiring high-level engagement by leadership and institutional commitment.Multiple strategies for increasing birth cohort screening have been successful,but overall rates of HCV screening remain low.These strat-egies can inform public health efforts to implement emerging national recommendations for expansion of HCV screening to all U.S.adults age 18 or older.

关键词： Hepatitis C Epidemiology HCV antibody Screening Birth cohort Baby boomers Care cascade Electronic medical records