[RETROSPECTIVE] Hepatitis C Virus: 30 Years after Its Discovery
Evidence for the existence of another hepatitis-causing pathogen, other than the known hepatitis A and B viruses, emerged in the mid-1970s. A frustrating search of 15 years was ended by the identification of the hepatitis C virus in 1989 using a recombinant DNA immunoscreening method. This discovery quickly led to blood tests that eliminated posttransfusion hepatitis C and could show the partial efficacy of type 1 interferon-based therapies. Subsequent knowledge of the viral replication cycle then led to the development of effective direct-acting antivirals targeting its serine protease, polymerase, and nonstructural prote...
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Houghton, M. Tags: Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution RETROSPECTIVE Source Type: research

[PERSPECTIVES] The Role of PTEN in Innate and Adaptive Immunity
The lipid and protein phosphatase and tensin homolog (PTEN) controls the differentiation and activation of multiple immune cells. PTEN acts downstream from T- and B-cell receptors, costimulatory molecules, cytokine receptors, integrins, and also growth factor receptors. Loss of PTEN activity in human and mice is associated with cellular and humoral immune dysfunction, lymphoid hyperplasia, and autoimmunity. Although most patients with PTEN hamartoma tumor syndrome (PHTS) have no immunological symptoms, a subclinical immune dysfunction is present in many, and clinical immunodeficiency in few. Comparison of the immune phenot...
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Taylor, H., Laurence, A. D. J., Uhlig, H. H. Tags: The PTEN Family PERSPECTIVES Source Type: research

[TECHNIQUES] Precise Immunodetection of PTEN Protein in Human Neoplasia
PTEN is a major tumor-suppressor protein whose expression and biological activity are frequently diminished in sporadic or inherited cancers. PTEN gene deletion or loss-of-function mutations favor tumor cell growth and are commonly found in clinical practice. In addition, diminished PTEN protein expression is also frequently observed in tumor samples from cancer patients in the absence of PTEN gene alterations. This makes PTEN protein levels a potential biomarker parameter in clinical oncology, which can guide therapeutic decisions. The specific detection of PTEN protein can be achieved by using highly defined anti-PTEN mo...
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Pulido, R., Mingo, J., Gaafar, A., Nunes-Xavier, C. E., Luna, S., Torices, L., Angulo, J. C., Lopez, J. I. Tags: The PTEN Family TECHNIQUES Source Type: research

[TECHNIQUES] Modeling Leukemia with Human Induced Pluripotent Stem Cells
The reprogramming of human somatic cells into induced pluripotent stem cells (iPSCs) a little over a decade ago raised exciting prospects to transform the study and potentially also the therapy of human diseases. iPSC models have now been created for a multitude of hematologic diseases, including malignancies. Here we discuss practical aspects of iPSC modeling of malignant diseases, review recent studies, and discuss the new opportunities that iPSC models offer, as well as their current limitations and prospects for future development. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Papapetrou, E. P. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights TECHNIQUES Source Type: research

[TECHNIQUES] Optogenetic Control of the Peripheral Nervous System
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....
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Chang, R. B. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[TECHNIQUES] Recording and Decoding of Vagal Neural Signals Related to Changes in Physiological Parameters and Biomarkers of Disease
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. The process of acquir...
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Zanos, T. P. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Hair Cell Afferent Synapses: Function and Dysfunction
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. Here we review the current unde...
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Johnson, S. L., Safieddine, S., Mustapha, M., Marcotti, W. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Hair-Bundle Links: Genetics as the Gateway to Function
We describe the structure of these links and review evidence showing CDH23 and PCDH15 are components of the tip, kinocilial, and transient-lateral links, that stereocilin (STRC) and protein tyrosine phosphatase (PTPRQ) are associated with top and shaft connectors, respectively, and that USH2A and ADGRV1 are associated with the ankle links. Whereas tip links are required for mechanoelectrical transduction, all link proteins play key roles in the normal development and/or the maintenance of hair bundle structure and function. Recent crystallographic and single-particle analyses of PCDH15 and CDH23 provide insight as to how t...
Source: Cold Spring Harbor perspectives in medicine - December 2, 2019 Category: Research Authors: Richardson, G. P., Petit, C. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[ERRATUM] Erratum: Bone Tropism in Cancer Metastases
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Wang, H., Zhang, W., Bado, I., Zhang, X. H.- F. Tags: ERRATUM Source Type: research

[TECHNIQUES] Cell Culture Systems of HCV Using JFH-1 and Other Strains
Hepatitis C virus (HCV) infection is seen worldwide and is a significant cause of severe chronic liver diseases. Recently, a large number of direct-acting antivirals (DAAs) have been developed against HCV infection, resulting in significant improvements in treatment efficacy. Rapid progress in HCV research has been largely dependent on the development of HCV culture systems and small animal infection models. In the development of HCV cell culture systems, the discovery of the JFH-1 clone, an HCV strain isolated from a fulminant hepatitis C patient, was a key finding. The JFH-1 strain was the first infectious HCV strain bel...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Wakita, T. Tags: Hepatitis C Viruses: The Story of a Scientific and Therapeutic Revolution TECHNIQUES Source Type: research

[TECHNIQUES] Next-Generation Sequencing Technologies
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 ...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: McCombie, W. R., McPherson, J. D., Mardis, E. R. Tags: Next-Generation Sequencing in Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] PTEN in Autism and Neurodevelopmental Disorders
Phosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes phosphatidylinositol 3-phosphate kinase (PI3K)/AKT signaling. Although there is a strong association of PTEN germline mutations with cancer syndromes, they have also been described in a subset of patients with autism spectrum disorders with macrocephaly characterized by impairments in social interactions and communication, repetitive behavior and, occasionally, epilepsy. To investigate PTEN's role during neurodevelopment and its implication for autism, several conditional Pten knockout mouse models have been generated. These models are v...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Rademacher, S., Eickholt, B. J. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] The Impact of Genetic Variants on PTEN Molecular Functions and Cellular Phenotypes
Phosphatase and tensin homolog (PTEN) is a tumor suppressor that directly regulates a diverse array of cellular phenotypes, including growth, migration, morphology, and genome stability. How a single protein impacts so many important cellular processes remains a fascinating question. This question has been partially resolved by the characterization of a slew of missense variants that alter or eliminate PTEN's various molecular functions, including its enzymatic activity, subcellular localization, and posttranslational modifications. Here, we review what is known about how PTEN variants impact molecular function and, conseq...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Hasle, N., Matreyek, K. A., Fowler, D. M. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] Active Biomechanics of Sensory Hair Bundles
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. The expe...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Bozovic, D. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[TECHNIQUES] Closed-Loop Neuromodulation in Physiological and Translational Research
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 ef...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Zanos, S. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Restoring Movement in Paralysis with a Bioelectronic Neural Bypass Approach: Current State and Future Directions
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. Th...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Bouton, C. E. Tags: Bioelectronic Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Aminoglycoside- and Cisplatin-Induced Ototoxicity: Mechanisms and Otoprotective Strategies
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 treat...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2019 Category: Research Authors: Kros, C. J., Steyger, P. S. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Autism Spectrum Disorder Associated with Germline Heterozygous PTEN Mutations
This review examines our current understanding of autism spectrum disorder (ASD), its prevalence, impact, behavioral treatment, and outcomes. Building on this knowledge, ASD associated with PTEN mutations is introduced and recent human studies of neurobehavioral and neuroimaging findings in patients with PTEN mutations with and without ASD are reviewed. In doing so, we present evidence supporting a model of PTEN loss leading to neurobehavioral deficits, including ASD and intellectual disability. Next, we describe the neurobehavioral spectrum observed across PTEN mutation cases, adding specificity where possible, based on d...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Frazier, T. W. Tags: The PTEN Family PERSPECTIVES Source Type: research

[PERSPECTIVES] PTEN in the Stroma
Although tremendous progress has been made in understanding the functions of Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in tumor cells, only recently have tumor cell-non-autonomous PTEN actions within the tumor microenvironment (TME) been appreciated. While it is accepted that the TME actively communicates with cancer cells to influence disease progression, our understanding of the genes and pathways responsible is still evolving. Given that inactivation of PTEN in the stroma is correlated with worse outcomes in human cancers, determining the unique functions and mechanisms of PTEN regulation in various...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Thies, K. A., Lefler, J. E., Leone, G., Ostrowski, M. C. Tags: The PTEN Family PERSPECTIVES Source Type: research

[TECHNIQUES] Electrical Impedance Methods in Neuromuscular Assessment: An Overview
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. Using noninvasive surface methods, EIM has been studied in a number of conditions ranging from amyotrophic latera...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Rutkove, S. B., Sanchez, B. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[ESSAY] Bioelectronic Medicine--Ethical Concerns
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. There are a wide arr...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Packer, S., Mercado, N., Haridat, A. Tags: Bioelectronic Medicine ESSAY Source Type: research

[PERSPECTIVES] The Tectorial Membrane: Mechanical Properties and Functions
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. (Source...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Sellon, J. B., Ghaffari, R., Freeman, D. M. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Function and Dysfunction of TMC Channels in Inner Ear Hair Cells
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. Cysteine mutagenesis of the pore supports the role of TMC1 and TMC2 as the core ...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Corey, D. P., Akyuz, N., Holt, J. R. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[TECHNIQUES] Single-Cell Applications of Next-Generation Sequencing
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. The goal of this article is to provide a high-level overview of single-cell sequencin...
Source: Cold Spring Harbor perspectives in medicine - October 1, 2019 Category: Research Authors: Anaparthy, N., Ho, Y.-J., Martelotto, L., Hammell, M., Hicks, J. Tags: Next-Generation Sequencing in Medicine TECHNIQUES Source Type: research

[ERRATUM] Erratum: The Tectorial Membrane: Mechanical Properties and Functions
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Sellon, J. B., Ghaffari, R., Freeman, D. M. Tags: ERRATUM Source Type: research

[PERSPECTIVES] The Impact of Next-Generation Sequencing on Cancer Genomics: From Discovery to Clinic
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. This review explores this transformation and identifies cutting-edge applications of NGS that will result ...
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Mardis, E. R. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[TECHNIQUES] Optogenetic Medicine: Synthetic Therapeutic Solutions Precision-Guided by Light
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. We introduce the construction and applications of optogen...
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Ye, H., Fussenegger, M. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[TECHNIQUES] Use of Bioelectronics in the Gastrointestinal Tract
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. Common functional GI motility disorders include dysphagia, gastroesophageal reflux disease, functional dyspepsia...
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Miller, L., Farajidavar, A., Vegesna, A. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Adaptive Immune Responses in Hepatitis A Virus and Hepatitis E Virus Infections
The objective of this review is to summarize our understanding of the relationship between patterns of virus replication, adaptive immune responses, and acute liver injury in HAV and HEV infections. Gaps in knowledge, and recent studies that challenge long-held concepts of how antibodies and T cells contribute to control and pathogenesis of HAV and HEV infections, are highlighted. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Walker, C. M. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] The Epidemiology of Deafness
Hearing loss is the most common sensory deficit worldwide. It affects ~5% of the world population, impacts people of all ages, and exacts a significant personal and societal cost. This review presents epidemiological data on hearing loss. We discuss hereditary hearing loss, complex hearing loss with genetic and environmental factors, and hearing loss that is more clearly related to environment. We also discuss the disparity in hearing loss across the world, with more economically developed countries having overall lower rates of hearing loss compared with developing countries, and the opportunity to improve diagnosis, prev...
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Sheffield, A. M., Smith, R. J. H. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Cochlear Gene Therapy
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, a...
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: Lustig, L., Akil, O. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[ESSAY] Future Promises and Concerns of Ubiquitous Next-Generation Sequencing
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 pub...
Source: Cold Spring Harbor perspectives in medicine - September 3, 2019 Category: Research Authors: McCombie, W. R., McPherson, J. D. Tags: Next-Generation Sequencing in Medicine ESSAY Source Type: research

[TECHNIQUE] Technobiologys Enabler: The Magnetoelectric Nanoparticle
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. Conversely, the technobiology approach that exploi...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Khizroev, S. Tags: Bioelectronic Medicine TECHNIQUE Source Type: research

[PERSPECTIVES] Vagus Nerve Stimulation at the Interface of Brain-Gut Interactions
The vagus nerve, a key component of the cross-communication between the gut and the brain, is a major element of homeostasis sensing the "milieu intérieur" and boosting the nervous and endocrine responses to maintain the gastrointestinal health status. This nerve has anti-inflammatory properties regulating the gut through the activation of the hypothalamic–pituitary–adrenal axis and the release of cortisol and through a vagovagal reflex, which has an anti–tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway. Stimulating this nerve is an interesting tool as a...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Bonaz, B., Sinniger, V., Pellissier, S. Tags: Bioelectronic Medicine PERSPECTIVES Source Type: research

[RETROSPECTIVE] Enterically Transmitted Non-A, Non-B Hepatitis and the Discovery of Hepatitis E Virus
The recognition of hepatitis E as a discreet disease entity in the late 1970s followed the development of serological tests for hepatitis A and the discovery that large waterborne outbreaks of hepatitis in India were not caused by hepatitis A virus (HAV). These "enterically transmitted non-A, non-B hepatitis" outbreaks had distinctive epidemiologic features, including the highest attack rates among young adults, little secondary household transmission of infection, and severe disease in pregnant women. The responsible agent, hepatitis E virus (HEV), was identified several years later in extracts of feces from a s...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Lemon, S. M., Walker, C. M. Tags: Enteric Hepatitis Viruses RETROSPECTIVE Source Type: research

[PERSPECTIVES] Toward the Optical Cochlear Implant
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 ...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Dombrowski, T., Rankovic, V., Moser, T. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Age-Related Hearing Loss
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. However, a prerequisite for design of therapies i...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Bowl, M. R., Dawson, S. J. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Small Animal Models of Hepatitis E Virus Infection
This article reviews the current understanding of small animal models for HEV. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Li, T.-C., Wakita, T. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Next-Generation Sequencing in Autism Spectrum Disorder
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. NGS methods have also contributed substantially to functional genetic data, such as gene expression, ...
Source: Cold Spring Harbor perspectives in medicine - August 1, 2019 Category: Research Authors: Sanders, S. J. Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

[ESSAY] Prostate Cancer Research at the Crossroads
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Shen, M. M., Rubin, M. A. Tags: Prostate Cancer ESSAY Source Type: research

[TECHNIQUES] Empirically Based Guidelines for Selecting Vagus Nerve Stimulation Parameters in Epilepsy and Heart Failure
Vagus nerve stimulation (VNS) is a promising therapy to treat patients with epilepsy and heart failure. Outcomes of preclinical studies and clinical trials indicate that the selection of stimulation parameters has a direct impact on therapeutic efficacy and patient tolerability, suggesting that both the efficacy and tolerability of VNS could potentially be improved with a change in stimulation parameters. In this review, the success of translating stimulation parameters for epilepsy and heart failure from preclinical studies in animal models to human use in the clinic is evaluated on the basis of patient outcomes and stimu...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Musselman, E. D., Pelot, N. A., Grill, W. M. Tags: Bioelectronic Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Small Heat Shock Proteins, Amyloid Fibrils, and Nicotine Stimulate a Common Immune Suppressive Pathway with Implications for Future Therapies
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 p...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Rothbard, J. B., Kurnellas, M. P., Ousman, S. S., Brownell, S., Rothbard, J. J., Steinman, L. Tags: Bioelectronic Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Outer Hair Cells and Electromotility
Outer hair cells (OHCs) of the mammalian cochlea behave like actuators: they feed energy into the cochlear partition and determine the overall mechanics of hearing. They do this by generating voltage-dependent axial forces. The resulting change in the cell length, observed by microscopy, has been termed "electromotility." The mechanism of force generation OHCs can be traced to a specific protein, prestin, a member of a superfamily SLC26 of transporters. This short review will identify some of the more recent findings on prestin. Although the tertiary structure of prestin has yet to be determined, results from the...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Ashmore, J. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Inner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear Function
Connexin 26 and connexin 30 are the prevailing isoforms in the epithelial and connective tissue gap junction systems of the developing and mature cochlea. The most frequently encountered variants of the genes that encode these connexins, which are transcriptionally coregulated, determine complete loss of protein function and are the predominant cause of prelingual hereditary deafness. Reducing connexin 26 expression by Cre/loxP recombination in the inner ear of adult mice results in a decreased endocochlear potential, increased hearing thresholds, and loss of>90% of outer hair cells, indicating that this connexin is ess...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Mammano, F. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research

[PERSPECTIVES] Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis E Virus Genotype 1 and 2 Infections
Infection with genotype 1 or 2 hepatitis E virus (HEV) results primarily from human-to-human transmission through the fecal–oral route in low-resource countries. It presents primarily as "acute viral hepatitis" syndrome, usually a self-limiting illness. A few cases progress to acute liver failure, a serious illness with high fatality. Clinical disease is infrequent among children. Infection during pregnancy is associated with a higher risk of symptomatic disease, severe liver injury, and mortality. Severe disease is also encountered in persons with preexisting chronic liver disease. Some cases have associat...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Aggarwal, R., Goel, A. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment
Hepatitis E virus (HEV) genotype (gt)3 and 4 infections are prevalent in industrialized and high-income countries. Although most HEV gt3 and gt4 infections are clinically silent, acute infection may be symptomatic in some patients. In persons with underlying liver disease and in elderly men, HEV infections may present as acute or acute-on-chronic liver failure. Chronic hepatitis may develop in immunosuppressed individuals, including transplant recipients, human immunodeficiency virus (HIV)-infected patients, and persons with hematologic malignancy undergoing chemotherapy, and may progress to life-threatening liver cirrhosi...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Kamar, N., Pischke, S. Tags: Enteric Hepatitis Viruses PERSPECTIVES Source Type: research

[TECHNIQUES] Next-Generation Sequencing Strategies
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. These new approaches...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2019 Category: Research Authors: Levy, S. E., Boone, B. E. Tags: Next-Generation Sequencing in Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Diabetes Technology: Monitoring, Analytics, and Optimal Control
In conclusion, engineering lessons learned from AP research, and the clinical need for AP systems to prove their safety and efficacy in large-scale clinical trials, are outlined. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Kovatchev, B. Tags: Bioelectronic Medicine PERSPECTIVES Source Type: research

[TECHNIQUE] Bioelectronic Approaches to Control Neuroimmune Interactions in Acute Kidney Injury
Recent studies have shown renal protective effects of bioelectric approaches, including ultrasound treatment, electrical vagus nerve stimulation, and optogenetic brainstem C1 neuron stimulation. The renal protection acquired by all three modalities was lost in splenectomized mice and/or α7 subunit of the nicotinic acetylcholine receptor–deficient mice. C1 neuron-mediated renal protection was blocked by β2-adrenergic receptor antagonist. These findings indicate that all three methods commonly, at least partially, activate the cholinergic anti-inflammatory pathway, a well-studied neuroimmune pathway. In this...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Inoue, T., Tanaka, S., Rosin, D. L., Okusa, M. D. Tags: Bioelectronic Medicine TECHNIQUE Source Type: research

[PERSPECTIVES] Interactions between Macrophages and the Sensory Cells of the Inner Ear
Macrophages are present in most somatic tissues, where they detect and attack invading pathogens. Macrophages also participate in many nonimmune functions, particularly those related to tissue maintenance and injury response. The sensory organs of the inner ear contain resident populations of macrophages, and additional macrophages enter the ear after acoustic trauma or ototoxicity. As expected, such macrophages participate in the clearance of cellular debris. However, otic macrophages can also influence the long-term survival of both hair cells and afferent neurons after injury. The signals that recruit macrophages into t...
Source: Cold Spring Harbor perspectives in medicine - June 3, 2019 Category: Research Authors: Warchol, M. E. Tags: Function and Dysfunction of the Cochlea PERSPECTIVES Source Type: research