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Cold Spring Harbor Perspectives in Medicine

Rui B Chang
The peripheral nervous system (PNS) is highly complicated and heterogenous. Conventional neuromodulatory approaches have revealed numerous essential biological functions of the PNS and provided excellent tools to treat a large variety of human diseases. Yet growing evidence indicated the importance of cell-type-specific neuromodulation in the PNS in not only biological research using animal models but also potential human therapies. Optogenetics is a recently developed neuromodulatory approach combining optics and genetics that can effectively stimulate or silence neuronal activity with high spatial and temporal precision...
February 11, 2019: Cold Spring Harbor Perspectives in Medicine
Chad E Bouton
Bioelectronic medicine is a rapidly growing field that explores targeted neuromodulation in new treatment options addressing both disease and injury. New bioelectronic methods are being developed to monitor and modulate neural activity directly. The therapeutic benefit of these approaches has been validated in recent clinical studies in various conditions, including paralysis. By using decoding and modulation strategies together, it is possible to restore lost function to those living with paralysis and other debilitating conditions by interpreting and rerouting signals around the affected portion of the nervous system...
February 11, 2019: Cold Spring Harbor Perspectives in Medicine
Theodoros P Zanos
Our bodies have built-in neural reflexes that continuously monitor organ function and maintain physiological homeostasis. Whereas the field of bioelectronic medicine has mainly focused on the stimulation of neural circuits to treat various conditions, recent studies have started to investigate the possibility of leveraging the sensory arm of these reflexes to diagnose disease states. To accomplish this, neural signals emanating from the body's built-in biosensors and propagating through peripheral nerves must be recorded and decoded to identify the presence or levels of relevant biomarkers of disease...
January 22, 2019: Cold Spring Harbor Perspectives in Medicine
Guy P Richardson, Christine Petit
Up to five distinct cell-surface specializations interconnect the stereocilia and the kinocilium of the mature hair bundle in some species: kinocilial links, tip links, top connectors, shaft connectors, and ankle links. In developing hair bundles, transient lateral links are prominent. Mutations in genes encoding proteins associated with these links cause Usher deafness/blindness syndrome or nonsyndromic (isolated) forms of human hereditary deafness, and mice with constitutive or conditional alleles of these genes have provided considerable insight into the molecular composition and function of the different links...
January 7, 2019: Cold Spring Harbor Perspectives in Medicine
Mireille Montcouquiol, Matthew W Kelley
Within the mammalian cochlea, sensory hair cells and supporting cells are aligned in curvilinear rows that extend along the length of the tonotopic axis. In addition, all of the cells within the epithelium are uniformly polarized across the orthogonal neural-abneural axis. Finally, each hair cell is intrinsically polarized as revealed by the presence of an asymmetrically shaped and apically localized stereociliary bundle. It has been known for some time that many of the developmental processes that regulate these patterning events are mediated, to some extent, by the core planar cell polarity (PCP) pathway...
January 7, 2019: Cold Spring Harbor Perspectives in Medicine
Stuart L Johnson, Saaid Safieddine, Mirna Mustapha, Walter Marcotti
To provide a meaningful representation of the auditory landscape, mammalian cochlear hair cells are optimized to detect sounds over an incredibly broad range of frequencies and intensities with unparalleled accuracy. This ability is largely conferred by specialized ribbon synapses that continuously transmit acoustic information with high fidelity and sub-millisecond precision to the afferent dendrites of the spiral ganglion neurons. To achieve this extraordinary task, ribbon synapses employ a unique combination of molecules and mechanisms that are tailored to sounds of different frequencies...
January 7, 2019: Cold Spring Harbor Perspectives in Medicine
David C Kohrman, Guoqiang Wan, Luis Cassinotti, Gabriel Corfas
Hidden hearing loss (HHL), a recently described auditory disorder, has been proposed to affect auditory neural processing and hearing acuity in subjects with normal audiometric thresholds, particularly in noisy environments. In contrast to central auditory processing disorders, HHL is caused by defects in the cochlea, the peripheral auditory organ. Noise exposure, aging, ototoxic drugs, and peripheral neuropathies are some of the known risk factors for HHL. Our knowledge of the causes and mechanisms of HHL are based primarily on animal models...
January 7, 2019: Cold Spring Harbor Perspectives in Medicine
Naishitha Anaparthy, Yu-Jui Ho, Luciano Martelotto, Molly Hammell, James Hicks
The single cell is considered the basic unit of biology, and the pursuit of understanding how heterogeneous populations of cells can functionally coexist in tissues, organisms, microbial ecosystems, and even cancer, makes them the subject of intense study. Next-generation sequencing (NGS) of RNA and DNA has opened a new frontier of (single)-cell biology. Hundreds to millions of cells now can be assayed in parallel, providing the molecular profile of each cell in its milieu inexpensively and in a manner that can be analyzed mathematically...
January 7, 2019: Cold Spring Harbor Perspectives in Medicine
Corné J Kros, Peter S Steyger
Ototoxicity refers to damage of inner ear structures (i.e., the cochlea and vestibule) and their function (hearing and balance) following exposure to specific in-hospital medications (i.e., aminoglycoside antibiotics, platinum-based drugs), as well as a variety of environmental or occupational exposures (e.g., metals and solvents). This review provides a narrative derived from relevant papers describing factors contributing to (or increasing the risk of) aminoglycoside and cisplatin-induced ototoxicity. We also review current strategies to protect against ototoxicity induced by these indispensable pharmacotherapeutic treatments for life-threatening infections and solid tumors...
December 17, 2018: Cold Spring Harbor Perspectives in Medicine
Stavros Zanos
Neuromodulation, the focused delivery of energy to neural tissue to affect neural or physiological processes, is a common method to study the physiology of the nervous system. It is also successfully used as treatment for disorders in which the nervous system is affected or implicated. Typically, neurostimulation is delivered in open-loop mode (i.e., according to a predetermined schedule and independently of the state of the organ or physiological system whose function is sought to be modulated). However, the physiology of the nervous system or the modulated organ can be dynamic, and the same stimulus may have different effects depending on the underlying state...
December 17, 2018: 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
Bruce L Innis, Julia A Lynch
Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in Escherichia coli Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries where the disease burden is highest...
November 1, 2018: Cold Spring Harbor Perspectives in Medicine
David P Labbé, Myles Brown
Prostate cancer development involves corruption of the normal prostate transcriptional network, following deregulated expression or mutation of key transcription factors. Here, we provide an overview of the transcription factors that are important in normal prostate homeostasis (NKX3-1, p63, androgen receptor [AR]), primary prostate cancer (ETS family members, c-MYC), castration-resistant prostate cancer (AR, FOXA1), and AR-independent castration-resistant neuroendocrine prostate cancer (RB1, p53, N-MYC). We use functional (in vitro and in vivo) as well as clinical data to discuss evidence that unveils their roles in the initiation and progression of prostate cancer, with an emphasis on results of chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq)...
November 1, 2018: Cold Spring Harbor Perspectives in Medicine
Harry R Dalton, Jacques Izopet
Following the introduction of robust serological and molecular tools, our understanding of the epidemiology of zoonotic hepatitis E virus (HEV) has improved considerably in recent years. Current thinking suggests that consumption of pork meat products is the key route of infection in humans, but it is certainly not the only one. Other routes of infection include environmental spread, contaminated water, and via the human blood supply. The epidemiology of HEV genotype (gt)3 and gt4 is complex, as there are several sources and routes of infection, and it is likely that these vary between and within countries and over time...
November 1, 2018: Cold Spring Harbor Perspectives in Medicine
Sarah G Hymowitz, Shiva Malek
Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors...
November 1, 2018: Cold Spring Harbor Perspectives in Medicine
Ian Ahearn, Mo Zhou, Mark R Philips
The three human RAS genes encode four proteins that play central roles in oncogenesis by acting as binary molecular switches that regulate signaling pathways for growth and differentiation. Each is subject to a set of posttranslational modifications (PTMs) that modify their activity or are required for membrane targeting. The enzymes that catalyze the various PTMs are potential targets for anti-RAS drug discovery. The PTMs of RAS proteins are the focus of this review.
November 1, 2018: Cold Spring Harbor Perspectives in Medicine
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