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Cold Spring Harbor Perspectives in Medicine

W Richard McCombie, John D McPherson, Elaine R Mardis
Although DNA and RNA sequencing has a history spanning five decades, large-scale massively parallel sequencing, or next-generation sequencing (NGS), has only been commercially available for about 10 years. Nonetheless, the meteoric increase in sequencing throughput with NGS has dramatically changed our understanding of our genome and ourselves. Sequencing the first human genome as a haploid reference took nearly 10 years but now a full diploid human genome sequence can be accomplished in just a few days. NGS has also reduced the cost of generating sequence data and a plethora of sequence-based methods for probing a genome have emerged using NGS as the readout and have been applied to many species...
November 26, 2018: Cold Spring Harbor Perspectives in Medicine
Samuel Packer, Nicholas Mercado, Anita Haridat
Bioelectronic medicine (BEM) offers exciting opportunities to treat diseases such as movement disorders and refractory inflammatory disease. The many variations of BEM allow for noninvasive aspects of treatment that might eliminate or reduce the need for pharmaceuticals; therefore, the term "electroceuticals" may be suitable. BEM has been effective for movement disorders and improvement of prosthetic devices. Based on this implication, there is an allowance to impact many focus areas that include but are not limited to autoimmune disease, sensory motor conditions, and neurological conditions...
November 26, 2018: Cold Spring Harbor Perspectives in Medicine
W Richard McCombie, John D McPherson
Since the first draft of the human genome was completed, next-generation DNA sequencing technology has dramatically reduced the cost of sequencing a genome. Computational analysis has not advanced as fast as the instruments that generate the data, and storing all the data remains a challenge. Nevertheless, personal genomics has arrived and is already being used in the clinic. Significant privacy issues remain, however, and these are not widely understood. The Genetic Information Non-Discrimination Act (GINA) needs to be extended and the probabilistic nature of genetic predisposition must be better explained to both the public and physicians...
November 26, 2018: Cold Spring Harbor Perspectives in Medicine
Stephan J Sanders
Autism spectrum disorder (ASD) is a common disorder that causes substantial distress. Heritability studies consistently show a strong genetic contribution, raising the hope that identifying ASD-associated genetic variants will offer insights into neurobiology and ultimately therapeutics. Next-generation sequencing (NGS) enabled the identification of disruptive variants throughout protein-coding regions of the genome. Alongside large cohorts and novel statistical methods, these NGS methods revolutionized ASD gene discovery...
November 12, 2018: Cold Spring Harbor Perspectives in Medicine
Elaine R Mardis
The application of next-generation sequencing (NGS) technology to the study of cancer genomes has been transformational. Not only has this technology revealed the genetic and epigenetic underpinnings of disease onset and progression, but also has redefined our clinical diagnosis and treatment paradigms. This rapid translation from discovery to clinical platform has occurred in the context of new pharmaceutical paradigms, enabling the use of NGS for the diagnosis and definition of therapeutic vulnerabilities of cancer...
November 5, 2018: Cold Spring Harbor Perspectives in Medicine
Jonathan B Sellon, Roozbeh Ghaffari, Dennis M Freeman
The tectorial membrane (TM) is widely believed to play a critical role in determining the remarkable sensitivity and frequency selectivity that are hallmarks of mammalian hearing. Recently developed mouse models of human hearing disorders have provided new insights into the molecular, nanomechanical mechanisms that underlie resonance and traveling wave properties of the TM. Herein we review recent experimental and theoretical results detailing TM morphology, local poroelastic and electromechanical interactions, and global spread of excitation via TM traveling waves, with direct implications for cochlear mechanisms...
October 22, 2018: Cold Spring Harbor Perspectives in Medicine
Michael M Shen, Mark A Rubin
No abstract text is available yet for this article.
October 22, 2018: Cold Spring Harbor Perspectives in Medicine
Shawn E Levy, Braden E Boone
More than a decade ago, the term "next-generation" sequencing was coined to describe what was, at the time, revolutionary new methods to sequence RNA and DNA at a faster pace and cheaper cost than could be performed by standard bench-top protocols. Since then, the field of DNA sequencing has evolved at a rapid pace, with new breakthroughs allowing capacity to exponentially increase and cost to dramatically decrease. As genome-scale sequencing has become routine, a paradigm shift is occurring in genomics, which uses the power of high-throughput, rapid sequencing power with large-scale studies...
October 15, 2018: Cold Spring Harbor Perspectives in Medicine
Tobias Dombrowski, Vladan Rankovic, Tobias Moser
When hearing fails, cochlear implants (CIs) provide open speech perception to most of the currently half a million CI users. CIs bypass the defective sensory organ and stimulate the auditory nerve electrically. The major bottleneck of current CIs is the poor coding of spectral information, which results from wide current spread from each electrode contact. As light can be more conveniently confined, optical stimulation of the auditory nerve presents a promising perspective for a fundamental advance of CIs. Moreover, given the improved frequency resolution of optical excitation and its versatility for arbitrary stimulation patterns the approach also bears potential for auditory research...
October 15, 2018: Cold Spring Harbor Perspectives in Medicine
Dolores Bozovic
During the detection of sound, hair bundles perform a crucial step by responding to mechanical deflections and converting them into changes in electrical potential that subsequently lead to the release of neurotransmitter. The sensory hair bundle response is characterized by an essential nonlinearity and an energy-consuming amplification of the incoming sound. The active response has been shown to enhance the hair bundle's sensitivity and frequency selectivity of detection. The biological phenomena shown by the bundle have been extensively studied in vitro, allowing comparisons to behaviors observed in vivo...
October 15, 2018: Cold Spring Harbor Perspectives in Medicine
Lawrence Lustig, Omar Akil
Over 450 million people worldwide suffer from hearing loss, leading to an estimated economic burden of ∼$750 billion. The past decade has seen significant advances in the understanding of the molecular mechanisms that contribute to hearing, and the environmental and genetic factors that can go awry and lead to hearing loss. This in turn has sparked enormous interest in developing gene therapy approaches to treat this disorder. This review documents the most recent advances in cochlear gene therapy to restore hearing loss, and will cover viral vectors and construct designs, potential routes of delivery into the inner ear, and, lastly, the most promising genes of interest...
October 15, 2018: Cold Spring Harbor Perspectives in Medicine
David P Corey, Nurunisa Akyuz, Jeffrey R Holt
The TMC1 channel was identified as a protein essential for hearing in mouse and human, and recognized as one of a family of eight such proteins in mammals. The TMC family is part of a superfamily of seven branches, which includes the TMEM16s. Vertebrate hair cells express both TMC1 and TMC2. They are located at the tips of stereocilia and are required for hair cell mechanotransduction. TMC1 assembles as a dimer and its similarity to the TMEM16s has enabled a predicted tertiary structure with an ion conduction pore in each subunit of the dimer...
October 5, 2018: Cold Spring Harbor Perspectives in Medicine
Michael R Bowl, Sally J Dawson
Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate age-related auditory decline...
October 5, 2018: Cold Spring Harbor Perspectives in Medicine
Jia J Li, Michael M Shen
Stem/progenitor cells play central roles in processes of organogenesis and tissue maintenance, whereas cancer stem cells (CSCs) are thought to drive tumor malignancy. Here, we review recent progress in the identification and analysis of normal prostate stem/progenitor cells as well as putative CSCs in both genetically engineered mouse models as well as in human tissue. We also discuss studies that have investigated the cell type of origin for prostate cancer. In addition, we provide a critical assessment of methodologies used in stem cell analyses and outline directions for future research...
October 5, 2018: Cold Spring Harbor Perspectives in Medicine
Sakhrat Khizroev
To enable patient- and disease-specific diagnostic and treatment at the intracellular level in real time, it is imperative to engineer a perfect way to locally stimulate selected individual neurons, navigate and dispense a cargo of biomolecules into damaged cells or image sites with relatively high efficacy and with adequate spatial and temporal resolutions. Significant progress has been made using biotechnology; especially with the development of bioinformatics, there are endless molecular databases to identify biomolecules to target almost any disease-specific biomarker...
October 5, 2018: Cold Spring Harbor Perspectives in Medicine
Haifeng Ye, Martin Fussenegger
Gene- and cell-based therapies are well recognized as central pillars of next-generation medicine, but controllability remains a critical issue for clinical applications. In this context, optogenetics is opening up exciting new opportunities for precision-guided medicine by using illumination with light of appropriate intensity and wavelength as a trigger signal to achieve pinpoint spatiotemporal control of cellular activities, such as transgene expression. In this review, we highlight recent advances in optogenetics, focusing on devices for biomedical applications...
October 5, 2018: Cold Spring Harbor Perspectives in Medicine
Seward B Rutkove, Benjamin Sanchez
Electrical impedance methods have been used as evaluation tools in biological and medical science for well over 100 years. However, only recently have these techniques been applied specifically to the evaluation of conditions affecting nerve and muscle. This specific application, termed electrical impedance myography (EIM), is finding wide application as it can provide a quantitative index of muscle condition that can assist with diagnosis, track disease progression, and assess the beneficial impact of therapy...
October 5, 2018: Cold Spring Harbor Perspectives in Medicine
Jonathan B Rothbard, Michael P Kurnellas, Shalina S Ousman, Sara Brownell, Jesse J Rothbard, Lawrence Steinman
The α7 nicotinic acetylcholine receptor (α7nAChR) is central to the anti-inflammatory function of the vagus nerve in a physiological mechanism termed the inflammatory reflex. Studies on the inflammatory reflex have been instrumental for the current development of the field of bioelectronic medicine. An independent investigation of the biological role of αB-crystallin (HspB5), the most abundant gene transcript present in active multiple sclerosis lesions in human brains, also led to α7nAChR. Induction of experimental autoimmune encephalomyelitis (EAE) in HspB5-/- mice results in greater paralytic signs, increased levels of proinflammatory cytokines, and T-lymphocyte activation relative to wild-type animals...
September 24, 2018: Cold Spring Harbor Perspectives in Medicine
Sarah A Stanley, Jeffrey M Friedman
The ability to observe the effects of rapidly and reversibly regulating cell activity in targeted cell populations has provided numerous physiologic insights. Over the last decade, a wide range of technologies have emerged for regulating cellular activity using optical, chemical, and, more recently, electromagnetic modalities. Electromagnetic fields can freely penetrate cells and tissue and their energy can be absorbed by metal particles. When released, the absorbed energy can in turn gate endogenous or engineered receptors and ion channels to regulate cell activity...
September 24, 2018: Cold Spring Harbor Perspectives in Medicine
Larry Miller, Aydin Farajidavar, Anil Vegesna
Gastrointestinal (GI) motility disorders are major contributing factors to functional GI diseases that account for >40% of patients seen in gastroenterology clinics and affect >20% of the general population. The autonomic and enteric nervous systems and the muscles within the luminal GI tract have key roles in motility. In health, this complex integrated system works seamlessly to transport liquid, solid, and gas through the GI tract. However, major and minor motility disorders occur when these systems fail...
September 24, 2018: Cold Spring Harbor Perspectives in Medicine
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