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Jan A.M. Smeitink

Bio: Jan A.M. Smeitink is an academic researcher from Radboud University Nijmegen. The author has contributed to research in topics: Mitochondrion & Mitochondrial disease. The author has an hindex of 90, co-authored 415 publications receiving 28842 citations. Previous affiliations of Jan A.M. Smeitink include Aarhus University & University of Bari.


Papers
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Journal ArticleDOI
TL;DR: The data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity by the 677(C-->T) mutation, and can be an additional genetic risk factor for N TDs.
Abstract: Summary Recently, we showed that homozygosity for the common 677(C→T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A→C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an Mbo II recognition site and has an allele frequency of .33. This 1298(A→C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P P P n = 86) of the NTD patients compared with 20% ( n = 403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9–4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C→T) mutation, and can be an additional genetic risk factor for NTDs.

1,598 citations

Journal ArticleDOI
01 Oct 1998-AIDS
TL;DR: Although the introduction of protease inhibitors has changed management of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy.
Abstract: After zidovudine (ZDV), a 3′-azido analogue of thymi-dine, was found to be an effective antiretroviral drugagainst HIV [1,2], other nucleoside analogues inhibit-ing reverse transcriptase (RT) soon followed: didano-sine (ddI), zalcitabine (ddC), lamivudine (3TC),stavudine (D4T), and recently abacavir (1592U89)[3–7]. These drugs have demonstrated efficacy inreduction of morbidity and mortality, especially incombination therapy [8–10]. A special feature of someof these drugs is the protection against AIDS dementiacomplex, which appears to be related to good penetra-tion of the blood–brain barrier [11–13]. Although theintroduction of protease inhibitors has changed themanagement of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy [9,10].More than 10 years of experience with NRTI therapyhas revealed important adverse effects ranging frommild (myopathy) to fatal in some cases (pancreatitis,liver failure and lactic acidosis). Behind most of theseside-effects there appears to be a common mechanism:a decreased mitochondrial energy-generating capacity.In this review we will summarize the literature inwhich this mechanism is analysed and will emphasizethe importance of acquired mitochondrial dysfunctionthat will accumulate during long-term treatment withantiretroviral nucleoside analogues.

888 citations

Journal ArticleDOI
TL;DR: It is postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in theDevelopment of multiple symmetrical lipomatosis.

787 citations

Journal ArticleDOI
TL;DR: The mitochondrial oxidative phosphorylation system is the final biochemical pathway in the production of ATP and improvements in this arena have profited from progress in various genome projects, as well as improvements in the ability to create relevant animal models.
Abstract: The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway in the production of ATP. The OXPHOS system consists of five multiprotein complexes, the individual subunits of which are encoded either by the mitochondrial or by the nuclear genome. Defects in the OXPHOS system result in devastating, mainly multisystem, diseases, and recent years have seen the description of the underlying genetic mutations in mitochondrial and nuclear genes. Advances in this arena have profited from progress in various genome projects, as well as improvements in our ability to create relevant animal models.

675 citations

Journal ArticleDOI
TL;DR: Survivity, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies of infantile Pompe's disease.
Abstract: Objective. Infantile Pompe’s disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. Methods. A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected. Results. The course of Pompe’s disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe’s disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major developmental milestones are generally not achieved. For the Dutch patient group, growth deviates significantly from normal despite start of nasogastric tube feeding. Levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, or creatine kinase-myocardial band isoenzyme are typically elevated, although aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase increase significantly with age. The patients have fully deleterious mutations. Acid α-glucosidase activity is severely deficient. Conclusions. Survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies of infantile Pompe’s disease. Mutation analysis and measurement of the α-glucosidase activity should be part of the enrollment program.

470 citations


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TL;DR: These Guidelines were developed by the Panel* on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation.
Abstract: SUMMARY The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for the clinical management of HIV-infected adults and adolescents. This report recommends that care should be supervised by an expert, and makes recommendations for laboratory monitoring including plasma HIV RNA, CD4 cell counts and HIV drug resistance testing. The report also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special considerations are provided for adolescents and pregnant women. As with treatment of other chronic conditions, therapeutic decisions require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Antiretroviral regimens are complex, have major side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance due to non-adherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic

4,321 citations

Journal ArticleDOI
David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M. White1, Matthew J. O’Meara2, Veronica V. Rezelj3, Jeffrey Z. Guo, Danielle L. Swaney, Tia A. Tummino4, Ruth Hüttenhain, Robyn M. Kaake, Alicia L. Richards, Beril Tutuncuoglu, Helene Foussard, Jyoti Batra, Kelsey M. Haas, Maya Modak, Minkyu Kim, Paige Haas, Benjamin J. Polacco, Hannes Braberg, Jacqueline M. Fabius, Manon Eckhardt, Margaret Soucheray, Melanie J. Bennett, Merve Cakir, Michael McGregor, Qiongyu Li, Bjoern Meyer3, Ferdinand Roesch3, Thomas Vallet3, Alice Mac Kain3, Lisa Miorin1, Elena Moreno1, Zun Zar Chi Naing, Yuan Zhou, Shiming Peng4, Ying Shi, Ziyang Zhang, Wenqi Shen, Ilsa T Kirby, James E. Melnyk, John S. Chorba, Kevin Lou, Shizhong Dai, Inigo Barrio-Hernandez5, Danish Memon5, Claudia Hernandez-Armenta5, Jiankun Lyu4, Christopher J.P. Mathy, Tina Perica4, Kala Bharath Pilla4, Sai J. Ganesan4, Daniel J. Saltzberg4, Rakesh Ramachandran4, Xi Liu4, Sara Brin Rosenthal6, Lorenzo Calviello4, Srivats Venkataramanan4, Jose Liboy-Lugo4, Yizhu Lin4, Xi Ping Huang7, Yongfeng Liu7, Stephanie A. Wankowicz, Markus Bohn4, Maliheh Safari4, Fatima S. Ugur, Cassandra Koh3, Nastaran Sadat Savar3, Quang Dinh Tran3, Djoshkun Shengjuler3, Sabrina J. Fletcher3, Michael C. O’Neal, Yiming Cai, Jason C.J. Chang, David J. Broadhurst, Saker Klippsten, Phillip P. Sharp4, Nicole A. Wenzell4, Duygu Kuzuoğlu-Öztürk4, Hao-Yuan Wang4, Raphael Trenker4, Janet M. Young8, Devin A. Cavero4, Devin A. Cavero9, Joseph Hiatt9, Joseph Hiatt4, Theodore L. Roth, Ujjwal Rathore9, Ujjwal Rathore4, Advait Subramanian4, Julia Noack4, Mathieu Hubert3, Robert M. Stroud4, Alan D. Frankel4, Oren S. Rosenberg, Kliment A. Verba4, David A. Agard4, Melanie Ott, Michael Emerman8, Natalia Jura, Mark von Zastrow, Eric Verdin4, Eric Verdin10, Alan Ashworth4, Olivier Schwartz3, Christophe d'Enfert3, Shaeri Mukherjee4, Matthew P. Jacobson4, Harmit S. Malik8, Danica Galonić Fujimori, Trey Ideker6, Charles S. Craik, Stephen N. Floor4, James S. Fraser4, John D. Gross4, Andrej Sali, Bryan L. Roth7, Davide Ruggero, Jack Taunton4, Tanja Kortemme, Pedro Beltrao5, Marco Vignuzzi3, Adolfo García-Sastre, Kevan M. Shokat, Brian K. Shoichet4, Nevan J. Krogan 
30 Apr 2020-Nature
TL;DR: A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
Abstract: A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

3,319 citations

Journal Article
TL;DR: This volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of the instrument and its ancillary tools are simply and well presented.
Abstract: I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

3,197 citations