Review
Abstract
Human cytomegalovirus (CMV), one of the eight herpesviruses that commonly infect humans, is best known for its propensity to cause disease in immunocompromised patients, especially transplant recipients, patients with advanced AIDS, and congenitally infected newborns. Advances in molecular virology coupled with improvements in diagnostic methods and treatment options have vastly improved our understanding of and ability to manage CMV, but many uncertainties remain, including the mechanisms of persistence and pathogenesis and its hypothesized roles in a variety of human illnesses. Here we review recent advances that are reshaping our view and approach to this fascinating virus.
Authors
Michael Boeckh, Adam P. Geballe
Abstract
Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets — both those that have been tried in the clinic with limited success and those currently under clinical development — that knowledge of these pathways gives us.
Authors
Seth A. Wander, Bryan T. Hennessy, Joyce M. Slingerland
Abstract
Food allergies affect up to 6% of young children and 3%–4% of adults. They encompass a range of disorders that may be IgE and/or non-IgE mediated, including anaphylaxis, pollen food syndrome, food-protein–induced enterocolitis syndrome, food-induced proctocolitis, eosinophilic gastroenteropathies, and atopic dermatitis. Many complex host factors and properties of foods are involved in the development of food allergy. With recent advances in the understanding of how these factors interact, the development of several novel diagnostic and therapeutic strategies is underway and showing promise.
Authors
Julie Wang, Hugh A. Sampson
Abstract
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that results from expansion of the polyglutamine repeat in the huntingtin (HTT) gene. There are currently no effective treatments for this devastating disease. Given its monogenic nature, disease modification therapies for HD should be theoretically feasible. Currently, pharmacological therapies aimed at disease modification by altering levels of HTT protein are in late-stage preclinical development. Here, we review current efforts to develop new treatments for HD based on our current understanding of HTT function and the main pathological mechanisms. We emphasize the need to enhance translational efforts and highlight the importance of aligning the clinical and basic research communities to validate existing hypotheses in clinical studies. Human and animal therapeutic trials are presented with an emphasis on cellular and molecular mechanisms relevant to disease progression.
Authors
Ignacio Munoz-Sanjuan, Gillian P. Bates
Abstract
Recent studies have focused on understanding the neural mechanisms underlying the emergence of clinical signs and symptoms in early stage Huntington disease (HD). Although cell-based assays have focused on cell autonomous effects of mutant huntingtin, animal HD models have revealed alterations in the function of neuronal networks, particularly those linking the cerebral cortex and striatum. These findings are complemented by metabolic imaging studies of disease progression in premanifest subjects. Quantifying metabolic progression at the systems level may identify network biomarkers to aid in the objective assessment of new disease-modifying therapies and identify new regions that merit mechanistic study in HD models.
Authors
David Eidelberg, D. James Surmeier
Abstract
Huntington disease is an autosomal dominant neurodegenerative disorder caused by a toxic expansion in the CAG repeat region of the huntingtin gene. Oligonucleotide approaches based on RNAi and antisense oligonucleotides provide promising new therapeutic strategies for direct intervention through reduced production of the causative mutant protein. Allele-specific and simultaneous mutant and wild-type allele–lowering strategies are being pursued with local delivery to the brain, each with relative merits. Delivery remains a key challenge for translational success, especially with chronic therapy. The potential of disease-modifying oligonucleotide approaches for Huntington disease will be revealed as they progress into clinical trials.
Authors
Dinah W.Y. Sah, Neil Aronin
Abstract
Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations.
Authors
Fanny Mochel, Ronald G. Haller
Abstract
Influenza A viruses cause recurrent, seasonal epidemics and occasional global pandemics with devastating levels of morbidity and mortality. The ability of influenza A viruses to adapt to various hosts and undergo reassortment events ensures constant generation of new strains with unpredictable degrees of pathogenicity, transmissibility, and pandemic potential. Currently, the combination of factors that drives the emergence of pandemic influenza is unclear, making it impossible to foresee the details of a future outbreak. Identification and characterization of influenza A virus virulence determinants may provide insight into genotypic signatures of pathogenicity as well as a more thorough understanding of the factors that give rise to pandemics.
Authors
Donna M. Tscherne, Adolfo García-Sastre
Abstract
Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.
Authors
Peter D. Crompton, Susan K. Pierce, Louis H. Miller
Abstract
The somatic sensory system responds to stimuli of distinct modalities, including touch, pain, itch, and temperature sensitivity. In the past century, great progress has been made in understanding the coding of these sensory modalities. From this work, two major features have emerged. First, there are specific neuronal circuits or labeled lines transmitting specific sensory information from the skin to the brain. Second, the generation of specific sensations often involves crosstalk among distinct labeled lines. These features suggest that population coding is the mechanism underlying somatic sensation.
Authors
Qiufu Ma
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