Yuan Z.,Van Andel Research Institute
Nature Structural and Molecular Biology | Year: 2017
To initiate DNA replication, the origin recognition complex (ORC) and Cdc6 load an Mcm2–7 double hexamer onto DNA. Without ATP hydrolysis, ORC–Cdc6 recruits one Cdt1-bound Mcm2–7 hexamer, thus forming an ORC–Cdc6–Cdt1–Mcm2–7 (OCCM) helicase-loading intermediate. Here we report a 3.9-Å structure of Saccharomyces cerevisiae OCCM on DNA. Flexible Mcm2–7 winged-helix domains (WHDs) engage ORC–Cdc6. A three-domain Cdt1 configuration embraces Mcm2, Mcm4, and Mcm6, thus comprising nearly half of the hexamer. The Cdt1 C-terminal domain extends to the Mcm6 WHD, which binds the Orc4 WHD. DNA passes through the ORC–Cdc6 and Mcm2–7 rings. Origin DNA interaction is mediated by an α-helix within Orc4 and positively charged loops within Orc2 and Cdc6. The Mcm2–7 C-tier AAA+ ring is topologically closed by an Mcm5 loop that embraces Mcm2, but the N-tier-ring Mcm2-Mcm5 interface remains open. This structure suggests a loading mechanism of the first Cdt1-bound Mcm2–7 hexamer by ORC–Cdc6. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
News Article | April 19, 2017
Description: Van Andel Research Institute’s Cryoelectron Microscopy Core harnesses revolutionary technology to visualize some of life’s smallest—yet most vital—components, including genetic material and molecular complexes, like enzymes and proteins. The Core offers researchers across the Institute stunning new insights into the fundamental chemical interactions that promote wellness and cause disease. VARI scientists are using Cryo-EM to understand the proteins that cause Parkinson’s disease, design new cancer drugs and improve current therapies, understand the mechanics of DNA replication, and much more. The centerpiece of VARI’s cryo-EM facility is the Titan Krios transmission electron microscope, the world’s highest-resolution and commercially available cryo-EM. The Institute’s Krios is one of fewer than 100 in the world and offers a visual resolution akin to watching a tennis match from the surface of the moon. The facility also houses a Talos Arctica, often considered the “workhorse” of cryo-EM, and a Tecnai Spirit G2 BioTWIN, which is used for preliminary screening of samples. These multimillion-dollar investments are supported by expert staff and high-performance computing clusters with extensive cloud capabilities.
News Article | May 4, 2017
Although the odds of developing breast cancer are nearly identical for black and white women, black women are 42 percent more likely to die from the disease. This mortality gap - driven by social and environmental, as well as biological factors - continues to persist. A large, multi-institutional study, published on-line May 4, 2017, in JAMA Oncology, was designed to understand this gap by beginning to unravel the germline genetic variations and tumor biological differences between black and white women with breast cancer. This is the first "ancestry-based comprehensive analysis of multiple platforms of genomic and proteomic data of its kind," the authors note. Findings from this study could lead to more personalized risk assessment for women of African heritage and hasten the development of novel approaches designed to diagnose specific subtypes of aggressive breast cancers early and treat them effectively. One new finding is that black women with hormone receptor positive, HER2-negative breast cancer had a higher risk-of-recurrence score than white women. The study also confirmed that black patients were typically diagnosed at a younger age and were more likely to develop aggressive breast-cancer subtypes, including basal-like or triple-negative cancers (tumors lacking estrogen receptors, progesterone receptors and HER2), as well as other aggressive tumor subtypes. "People have long associated breast cancer mortality in black women with poverty, or stress, or lack of access to care, but our results show that much of the increased risk for black women can be attributed to tumor biological differences, which are probably genetically determined," said study author Olufunmilayo Olopade, MD, professor of medicine and human genetics at the University of Chicago. "The good news," she said, "is that as we learn more about these genetic variations, we can combine that information with clinical data to stratify risk and better predict recurrences - especially for highly treatable cancers - and develop interventions to improve treatment outcomes." "This is a great example of how team science and investments in science can accelerate progress in identifying the best therapies for the most aggressive breast cancers," said co-author Charles Perou, PhD, a member of the University of North Carolina Lineberger Comprehensive Cancer Center and professor of genetics, and pathology & laboratory medicine at the UNC School of Medicine. "In the largest dataset to date that has good representation of tumors from black women, we did not find much difference between the somatic mutations driving tumors in black and white women," he added. "Yet black women were more likely to develop aggressive molecular subtypes of breast cancer. Now we provide data showing that differences in germline genetics may be responsible for up to 40 percent of the likelihood of developing one tumor subtype versus another." The study used DNA data collected from 930 women - 154 of predominantly African ancestry and 776 of European ancestry - available through The Cancer Genome Atlas (TCGA), established by the National Cancer Institute and the National Human Genome Research Institute. The researchers combed through the data methodically, looking for racial differences in germline variations (normal DNA), somatic mutations (tumor acquired), subtypes of breast cancers, survival time, as well as gene expression, protein expression and DNA methylation patterns. "Most significantly," explained first author Dezheng Huo, MD, PhD, associate professor of public health sciences at the University of Chicago, "we observed a higher genetic contribution to estrogen-receptor negative breast cancer in blacks." Black women were more likely to get these highly aggressive cancers. This is one of the first studies to connect genetics to this racial difference in tumor subtype frequencies. The study also revealed 142 genes that showed differences in expression levels according to race. One gene, CRYBB2 (Crystallin Beta B2), was consistently higher in tumors from black patients within each breast cancer subtype, as well as in normal tissues, suggesting it may be a race-specific gene. The researchers also found somatic mutations in 13 genes or DNA segments that differed in frequency in tumors from black and white women. One of them, a mutated gene called TP53, was more common in black women (52%) than white women (31%) and was a strong predictor of disease recurrence. "Despite the relatively short follow-up time in the TCGA dataset, we were able to detect a significant racial disparity in patient survival using breast cancer-free interval as the endpoint between patients of African and European ancestries," said co-first author Hai Hu, PhD, vice president for research at the Chan Soon-Shiong Institute of Molecular Medicine at Windber. "Most of the worst outcomes came from basal-like subtype breast cancer patients of African Ancestry." "Black women in all categories, including the most common breast cancers, were likely to have a worse prognosis," Olopade said. "Understanding the basic, underlying genetic differences between black and white women, the higher risk scores and the increased risk of recurrence should lead us to alternative treatment strategies," said Perou. The crucial long-term benefit of this study, according to Olopade, is that "it is a step toward the development of polygenic biomarkers, tools that can help us better understand each patient's prognosis and, as we learn more, play a role in choosing the best treatment." "Genes matter," she added. "This is a foot in the door for precision medicine, for scientifically targeted treatment." "This study now outlines a path for us to personalize breast cancer risk assessment and develop better strategies to empower all women, especially black women, to know their genetics and be more proactive in managing their risk," Perou said. The study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, Susan G. Komen Foundation for the Cure, the American Cancer Society and the U.S. Department of Defense. Also contributing were Toshio Yoshimatsu and Jason Pitt from the University of Chicago; Katherine Hoadley and Melissa Troester of the University of North Carolina at Chapel Hill; Jianfang Liu, Yuanbin Ru, and Lori Sturtz from the Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA; Suhn Rhie of the University of Southern California; Eric Gamazon of Vanderbilt University; Andrew Cherniack from the Broad Institute of MIT and Harvard; Tara Lichtenberg from Nationwide Children's Hospital, Columbus, Ohio; Carl Shelly from the University of Wisconsin; Christopher Benz from the Buck Institute for Research on Aging, Novato, Calif.; Gordon Mill from The MD Anderson Cancer Center; Peter Laird from the Van Andel Research Institute, Grand Rapids, MI; and Craig D. Shriver from the Walter Reed National Military Medical Center, Bethesda, MD. To reach co-author Charles Perou, PhD, of the University of North Carolina Lineberger Comprehensive Cancer Center and professor of genetics, and pathology & laboratory medicine at the UNC School of Medicine, contact Laura Oleniacz, Science Communications Manager, UNC Lineberger Comprehensive Cancer Center, 919-445-4219, firstname.lastname@example.org. To reach co-author Hai Hu, PhD, vice president for research at the Chan Soon-Shiong Institute of Molecular Medicine at Windber contact Natalie Bombatch, Communications & Marketing Manager, Chan Soon-Shiong Institute of Molecular Medicine, Windber, PA, 814-467-3447, email@example.com.
News Article | April 18, 2017
(PRLEAP.COM) April 18, 2017 - One of Grand Rapids newest apartment communities, The Gateway at Belknap, will feature Spartan Net's Ultra High Speed Spartan Fiber Internet service for its residents.Spartan Net announced that 1-Gigabit Internet service has been fully deployed at the new development. The 1,000 Mbps Internet service means faster downloads, less buffering, and an ultra-reliable connection. You can download your favorite 90-minute HD movie in as little as 34 seconds.According to the National Multifamily Housing Council, when considering where to live, renters rank high speed Internet higher than amenities like a pool or a fitness center. The Spartan Fiber Internet service is available at apartment communities throughout Downtown Grand Rapids. Apartments with Grand Rapids fiber Internet service can be found using Spartan Net's apartment fiber locator.The Gateway at Belknap Apartments are located in the Belknap Lookout neighborhood overlooking the Medical Mile, which includes Michigan State University's College of Human Medicine, Spectrum Health's downtown hospital campus, the Van Andel Research Institute and Grand Valley State University's Cook-DeVos Center for Health Sciences.Residents also have access to Spartan Net powered community Wi-Fi which allows connection to any other Spartan Net Wi-Fi location. "They love it," said Richard Laing, Chief Operating Officer of Spartan Net, "It's the best Internet you can get, up to 100 times faster than cable and its here now."The Gateway at Belknap development is located at:513 Clancy Avenue NEGrand Rapids, MI 49503In addition to ultra-fast Internet, residents have access to DIRECTV apartment TV services featuring over 315 channels. Spartan Net is an alternative to the big cable companies with same day local service, free install and no service call fees.To find your fiberhood, visit https://www.spartan-net.com/high-speed-fiber-internet.html About Spartan Net Co.Spartan Net is a Michigan-based, privately owned Internet Service Provider that specializes in Ultra Fast 1-Gigabit Internet and TV solutions for Multi-Family communities of all sizes. Spartan Net understands the unique needs of property owners and goes above and beyond typical apartment Internet service providers.
Van Andel Research Institute and CAS Shanghai Institute of Materia Medica | Date: 2014-09-25
The present invention relates to novel glucocorticoid compounds. The invention also relates to methods of using these compounds, the synthesis of these compounds, and to compositions and formulations comprising the glucocorticoid compounds, and uses thereof.
Van Andel Research Institute and Translational Genomics Research Institute | Date: 2014-12-05
The present invention relates to compounds of Formula III, Formula 111(a), Formula V, Formula V(a), Formula A, Formula A 1, Formula A2, Formula A 3, or a pharmaceutically acceptable salt thereof that are useful as pharmaceutical agents, individually and/or in a combination with a chemotherapeutic agent: PLX-4032 (vemurafenib), or the catalytic mTOR inhibitor AZD8055, to treat a cancer and/or a cancer metastasis, for example a cancer harboring a BRAF protein kinase mutation and/or a HRAS protein mutation. Also, a method of treating and/or preventing malaria in a subject, the method comprising administering a therapeutically effective amount of a compound of Formula A, Formula A 1, Formula A2, Formula A 3, or a pharmaceutically acceptable salt thereof to the subject in need.
Van Andel Research Institute | Date: 2014-03-10
The present invention relates to a method for diagnosing a subject with a malignant pancreatic cyst, the method comprising, obtaining a pancreatic cyst fluid sample from a pancreatic cyst lesion of the subject, detecting the level of MUC5AC, and endorepellin glycoforms present in the pancreatic cyst fluid sample, comparing the levels of MUC5AC and endorepellin glycoforms to a control pancreatic cyst sample level of MUC5AC and endorepellin glycoforms; and diagnosing the pancreatic cyst lesion as malignant if the levels of the MUC5AC and endorepellin glycoforms are differentially expressed compared to the levels of the MUC5AC and endorepellin glycans present in control pancreatic cyst samples.
Van Andel Research Institute | Date: 2013-02-28
The molecular mechanism underlying degenerative joint disease, also known as osteoarthritis (OA), is not fully understood. Disruption of mitogen inducible gene 6 (Mig-6) in mice by homologous recombination (KO mice) led to early onset OA as revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage and the development of bony outgrowths or osteophytes within the joint space. The latter appeared to be derived from proliferation of mesenchymal progenitor cells followed by differentiation into chondrocytes. Because of the striking similarity to human OA, Mig-6 KO mice arc a useful animal model for studying the mechanism of this disease and for testing new drugs or therapies for treating OA. These KO mice also developed epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as lung, gallbladder, and bile duct. Mig-6 is therefore a tumor suppressor gene and is a candidate gene for the frequent Ip36 genetic alterations found in lung cancer. It can be used as a tumor biomarker as well as a target for cancer therapy. Mig-6 is located in human chromosome Ip36, a locus frequently associated with human lung cancer. Mig-6 is a negative regulator of EGF signaling, and like EGF, was induced by HGF/SF in human lung cancer cell lines. Frequently the receptors EGFR and Met were co-expressed, and Mig-6 was induced by both EGF and HGF/SF in a MAPK-dependent fashion. Not all tumor lines express Mig-6 in response to either EGF or HGF/SF. In these cases, missense and nonsense mutations in the Mig-6 coding region were found, as was evidence for Mig-6 transcriptional silencing.
Van Andel Research Institute | Date: 2014-02-20
The present invention relates to Norrin mutant polypeptides that inhibit or reduce angiogenesis in various tissues. Methods for synthesizing recombinant Norrin and Norrin mutant polypeptides are provided. Methods of inhibiting or reducing aberrant angiogenesis comprise contacting a tissue undergoing aberrant angiogenesis with a composition comprising an isolated Norrin C mutant polypeptide.
Van Andel Research Institute and Translational Genomics Research Institute | Date: 2015-11-19
The present invention relates to compounds of formulas III and V that are useful as pharmaceutical agents, particularly as autophagy inhibitors.