[PERSPECTIVES] Drug-Evoked Synaptic Plasticity of Excitatory Transmission in the Ventral Tegmental Area
Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive, and addiction develops. Here, we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements, as well as the expression mechanism of t...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Bellone, C., Loureiro, M., Lüscher, C. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] Neural Substrates and Circuits of Drug Addiction
Drug addiction is a chronic relapsing disorder, and a significant amount of research has been devoted to understand the factors that contribute to the development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide an overview of various theories of addiction to drugs of abuse and the neurobiology involved in elements of the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the role of the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the contr...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Feltenstein, M. W., See, R. E., Fuchs, R. A. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] The Epidemiology, Virology, and Pathogenicity of Human Infections with Avian Influenza Viruses
Influenza is a global challenge, and future pandemics of influenza are inevitable. One of the lessons learned from past pandemics is that all pandemic influenza viruses characterized to date possess viral genes originating from avian influenza viruses (AIVs). During the past decades, a wide range of AIVs have overcome the species barrier and infected humans with different clinical manifestations ranging from mild illness to severe disease and even death. Understanding the mechanisms of infection in the context of clinical outcomes, the mechanism of interspecies transmission, and the molecular determinants that confer inter...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Wang, D., Zhu, W., Yang, L., Shu, Y. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[RETROSPECTIVE] Influenza Reverse Genetics--Historical Perspective
The generation of wild-type, mutant, and reassortant influenza viruses from viral cDNAs (reverse genetics) is now a basic molecular virology technique in many influenza virus laboratories. Here, I describe the original RNA polymerase I reverse genetics system and the modifications that have been developed in past years. Together, these technologies have made possible many advances in basic and applied influenza virology that would not have been otherwise attainable, including the revival and study of extinct influenza viruses, the rapid characterization of emerging influenza viruses, the generation of conventional influenz...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Neumann, G. Tags: Influenza: The Cutting Edge RETROSPECTIVE Source Type: research

[PERSPECTIVES] Influenza Therapeutics in Clinical Practice--Challenges and Recent Advances
In the last few years, several new direct-acting influenza antivirals have been licensed, and others have advanced in clinical development. The increasing diversity of antiviral classes should allow an adequate public health response should a resistant virus to one agent or class widely circulate. One new antiviral, baloxavir marboxil, has been approved in the United States for treatment of influenza in those at high risk of developing influenza-related complications. Except for intravenous zanamivir in European Union countries, no antivirals have been licensed specifically for the indication of severe influenza or hospita...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Beigel, J. H., Hayden, F. G. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Advances in Small-Cell Lung Cancer (SCLC) Translational Research
Over the past several years, we have witnessed a resurgence of interest in the biology and therapeutic vulnerabilities of small-cell lung cancer (SCLC). This has been driven in part through the development of a more extensive array of representative models of disease, including a diverse variety of genetically engineered mouse models and human tumor xenografts. Herein, we review recent progress in SCLC model development, and consider some of the particularly active avenues of translational research in SCLC, including interrogation of intratumoral heterogeneity, insights into the cell of origin and oncogenic drivers, mechan...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Drapkin, B. J., Rudin, C. M. Tags: Lung Cancer: Disease Biology and Its Potential for Clinical Translation PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Somatic Mutations in Acute Myeloid Leukemia Pathogenesis
Acute myeloid leukemia (AML) is characterized by attenuation of lineage differentiation trajectories that results in impaired hematopoiesis and enhanced self-renewal. To date, sequencing studies have provided a rich landscape of information on the somatic mutations that contribute to AML pathogenesis. These studies show that most AML genomes harbor relatively fewer mutations, which are acquired in a stepwise manner. Our understanding of the genetic basis of leukemogenesis informs a broader understanding of what initiates and maintains the AML clone and informs the development of prognostic models and mechanism-based therap...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Kishtagari, A., Levine, R. L. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] Mouse Models in the Study of Mature B-Cell Malignancies
Over the past two decades, genomic analyses of several B-cell lymphoma entities have identified a large number of genes that are recurrently mutated, suggesting that their aberrant function promotes lymphomagenesis. For many of those genes, the specific role in normal B-cell development is unknown; moreover, whether and how their deregulated activity contributes to lymphoma initiation and/or maintenance is often difficult to determine. Genetically engineered mouse models that faithfully mimic lymphoma-associated genetic alterations represent valuable tools for elucidating the pathogenic roles of candidate oncogenes and tum...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2021 Category: Research Authors: Pasqualucci, L., Klein, U. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] Neonatal Opioid Withdrawal Syndrome (NOWS): A Transgenerational Echo of the Opioid Crisis
The incidence of neonatal opioid withdrawal syndrome (NOWS) has increased substantially in the setting of the opioid epidemic, a major public health problem in the United States. At present, NOWS has commonly used assessment and treatment protocols, but new protocols have questioned old practices. However, because of limited access to opioid use disorder (OUD) treatment and socioeconomic factors, many pregnant (and postpartum) women with OUD do not receive treatment. The pathophysiology of NOWS is not completely understood, although limited research studies have been conducted in humans and animals to better understand its...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Weller, A. E., Crist, R. C., Reiner, B. C., Doyle, G. A., Berrettini, W. H. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction
Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which glutamate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expre...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Heinsbroek, J. A., De Vries, T. J., Peters, J. Tags: Addiction PERSPECTIVES Source Type: research

[TECHNIQUES] Integrating Family-Based and Mendelian Randomization Designs
Most Mendelian randomization (MR) studies published in the literature to date have involved analyses of unrelated, putatively independent sets of individuals. However, estimates obtained from these sorts of studies are subject to a range of biases including dynastic effects, assortative mating, residual population stratification, and horizontal pleiotropy. The inclusion of related individuals in MR studies can help control for and, in some cases, estimate the effect of these biases on causal parameters. In this review, we discuss these biases, how they can affect MR studies, and describe three sorts of family-based study d...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Hwang, L.-D., Davies, N. M., Warrington, N. M., Evans, D. M. Tags: Combining Human Genetics and Causal Inference to Understand Human Disease and Development TECHNIQUES Source Type: research

[TECHNIQUES] Family-Based Designs that Disentangle Inherited Factors from Pre- and Postnatal Environmental Exposures: In Vitro Fertilization, Discordant Sibling Pairs, Maternal versus Paternal Comparisons, and Adoption Designs
Identifying environmental risk and protective exposures that have causal effects on health is an important scientific goal. Many environmental exposures are nonrandomly allocated and influenced by dispositional factors including inherited ones. We review family-based designs that can separate the influence of environmental exposures from inherited influences shared between parent and offspring. We focus on prenatal exposures. We highlight that the family-based designs that can separate the prenatal environment from inherited confounds are different to those that are able to pull apart later-life environmental exposures fro...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Thapar, A., Rice, F. Tags: Combining Human Genetics and Causal Inference to Understand Human Disease and Development TECHNIQUES Source Type: research

[PERSPECTIVES] Swine Influenza A Viruses and the Tangled Relationship with Humans
Influenza A viruses (IAVs) are the causative agents of one of the most important viral respiratory diseases in pigs and humans. Human and swine IAV are prone to interspecies transmission, leading to regular incursions from human to pig and vice versa. This bidirectional transmission of IAV has heavily influenced the evolutionary history of IAV in both species. Transmission of distinct human seasonal lineages to pigs, followed by sustained within-host transmission and rapid adaptation and evolution, represent a considerable challenge for pig health and production. Consequently, although only subtypes of H1N1, H1N2, and H3N2...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Anderson, T. K., Chang, J., Arendsee, Z. W., Venkatesh, D., Souza, C. K., Kimble, J. B., Lewis, N. S., Davis, C. T., Vincent, A. L. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Immunity to Influenza Infection in Humans
This review discusses the human immune responses to influenza infection with some insights from studies using animal models, such as experimental infection of mice. Recent technological advances in the study of human immune responses have greatly added to our knowledge of the infection and immune responses, and therefore much of the focus is on recent studies that have moved the field forward. We consider the complexity of the adaptive response generated by many sequential encounters through infection and vaccination. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Topham, D. J., DeDiego, M. L., Nogales, A., Sangster, M. Y., Sant, A. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Antibody Responses in Hepatitis C Infection
Antibody responses in hepatitis C virus (HCV) have been a rather mysterious research topic for many investigators working in the field. Chronic HCV infection is often associated with dysregulation of immune functions particularly in B cells, leading to abnormal lymphoproliferation or the production of autoantibodies that exacerbate inflammation and extrahepatic diseases. When considering the antiviral function of antibody, it was difficult to endorse its role in HCV protection, whereas T-cell response has been shown unequivocally critical for natural recovery. Recent breakthroughs in the study of HCV and antigen-specific a...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Law, M. Tags: Hepatitis C Virus: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[RETROSPECTIVE] A History of Cancer Research: Carcinogens and Mutagens
Observations of the incidence of tumors among chimney sweeps in the eighteenth century and later experiments with coal tars provided early evidence that carcinogens in the environment can promote cancer. Subsequent studies of individuals exposed to radiation, work on fly genetics, and the discovery that DNA was the genetic material led to the idea that these carcinogens act by inducing mutations in DNA that change the behavior of cells and ultimately cause cancer. In this excerpt from his forthcoming book, Joe Lipsick looks back at how the concepts of mutagenesis and carcinogenesis emerged, how these converged with develop...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Lipsick, J. Tags: RETROSPECTIVE Source Type: research

[PERSPECTIVES] Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells
Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2021 Category: Research Authors: Shingleton, J., Wang, J., Baloh, C., Dave, T., Davis, N., Happ, L., Jadi, O., Kositsky, R., Li, X., Love, C., Panea, R., Qin, Q., Reddy, A., Singhi, N., Smith, E., Thakkar, D., Dave, S. S. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[TECHNIQUES] Polygenic Mendelian Randomization
This article reviews the concepts and assumptions underlying the commonly used polygenic MR methods. Using a polygenic score as an instrument is equivalent to a weighted mean of individual SNP results, and the other fundamental averages, median and mode, may also be used to estimate causal effects. Outlier detection is useful for identifying pleiotropic SNPs to be excluded from analysis. Bayesian approaches are available to incorporate prior beliefs about pleiotropy. These methods each entail different assumptions, and together provide a set of sensitivity analyses to help triangulate evidence about causality. (Source: Col...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Dudbridge, F. Tags: Combining Human Genetics and Causal Inference to Understand Human Disease and Development TECHNIQUES Source Type: research

[PERSPECTIVES] Opioid-Induced Molecular and Cellular Plasticity of Ventral Tegmental Area Dopamine Neurons
Opioid drugs are highly valued as potent analgesics; however, there are significant risks associated with long-term use because of their abuse liability. Opioids cause changes in ventral tegmental area (VTA) gene expression and cell activity that have been linked to addiction-related behaviors in rodent models. Here, we focus on VTA dopamine (DA) neurons and review the cellular, structural, and synaptic plasticity changes induced by acute and chronic opioid exposure. We also discuss many avenues for future research including determination of whether opioid neuroadaptations are specific for subpopulations of VTA DA neurons....
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Doyle, M. A., Mazei-Robison, M. S. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of the Central Amygdala in Alcohol Dependence
Alcohol dependence is a chronically relapsing disorder characterized by compulsive drug-seeking and drug-taking, loss of control in limiting intake, and the emergence of a withdrawal syndrome in the absence of the drug. Accumulating evidence suggests an important role for synaptic transmission in the central nucleus of the amygdala (CeA) in mediating alcohol-related behaviors and neuroadaptive mechanisms associated with alcohol dependence. Acute alcohol facilitates -aminobutyric acid (GABA)ergic transmission in the CeA via both pre- and postsynaptic mechanisms, and chronic alcohol increases baseline GABAergic transmission....
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Roberto, M., Kirson, D., Khom, S. Tags: Addiction PERSPECTIVES Source Type: research

[TECHNIQUES] Multivariable Mendelian Randomization and Mediation
Mendelian randomization (MR) is the use of genetic variants associated with an exposure to estimate the causal effect of that exposure on an outcome. Mediation analysis is the method of decomposing the effects of an exposure on an outcome, which act directly, and those that act via mediating variables. These effects are decomposed through the use of multivariable analysis to estimate the causal effects between three types of variables: exposures, mediators, and an outcome. Multivariable MR (MVMR) is a recent extension to MR that uses genetic variants associated with multiple, potentially related exposures to estimate the e...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Sanderson, E. Tags: Combining Human Genetics and Causal Inference to Understand Human Disease and Development TECHNIQUES Source Type: research

[PERSPECTIVES] Pathobiological Origins and Evolutionary History of Highly Pathogenic Avian Influenza Viruses
High-pathogenicity avian influenza (HPAI) viruses have arisen from low-pathogenicity avian influenza (LPAI) viruses via changes in the hemagglutinin proteolytic cleavage site, which include mutation of multiple nonbasic to basic amino acids, duplication of basic amino acids, or recombination with insertion of cellular or viral amino acids. Between 1959 and 2019, a total of 42 natural, independent H5 (n = 15) and H7 (n = 27) LPAI to HPAI virus conversion events have occurred in Europe (n = 16), North America (n = 9), Oceania (n = 7), Asia (n = 5), Africa (n = 4), and South America (n = 1). Thirty-eight of these HPAI outbrea...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Lee, D.-H., Criado, M. F., Swayne, D. E. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Bat-Borne Influenza A Viruses: An Awakening
Influenza A viruses (IAVs) originating from aquatic waterfowl recurrently cross interspecies barriers, which is greatly facilitated by utilizing cell surface–exposed monosaccharide sialic acids located on vertebrate cells as a universal host cell receptor. These glycan structures are first bound by the viral hemagglutinin (HA) for cell entry and then cleaved by the viral neuraminidase (NA) for particle release. In contrast, viruses of the recently identified bat-borne IAV subtypes H17N10 and H18N11 encode HA and NA homologs unable to interact with sialic acid residues despite a high degree of structural homology with...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Ciminski, K., Schwemmle, M. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Innate Immunity in Hepatitis C Virus Infection
Activation and viral control of the innate immune response are hallmarks of hepatitis C virus (HCV) infection and are major determinants of spontaneous clearance or progression to chronic infection and liver disease. In this review, we provide a contemporary overview of how HCV is sensed by the host cell to trigger innate immune activation and the mechanisms deployed by the virus to evade this response. Type I and III interferons (IFNs) are crucial mediators of antiviral innate immunity against HCV, and we specifically highlight the importance of IFN- host genetics for the outcome of HCV infection. Last, we focus on the pr...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Schwerk, J., Negash, A., Savan, R., Gale, M. Tags: Hepatitis C Virus: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Chronic Lymphocytic Leukemia
Patients with chronic lymphocytic leukemia can be divided into three categories: those who are minimally affected by the problem, often never requiring therapy; those that initially follow an indolent course but subsequently progress and require therapy; and those that from the point of diagnosis exhibit an aggressive disease necessitating treatment. Likewise, such patients pass through three phases: development of the disease, diagnosis, and need for therapy. Finally, the leukemic clones of all patients appear to require continuous input from the exterior, most often through membrane receptors, to allow them to survive an...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2021 Category: Research Authors: Chiorazzi, N., Chen, S.-S., Rai, K. R. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking and Addiction
Cannabis sativa, like all known drugs of abuse, leads to increased dopamine activation within the mesolimbic pathway. Consequent dopamine release within terminal regions of the striatum is a powerful mediator of reward and reinforcement and patterned dopamine release is critical for associative learning processes that are fundamentally involved in addiction. The endocannabinoid system modulates dopamine release at multiple sites, and the receptors, endogenous ligands, and synthetic and metabolic enzymes of the endocannabinoid system may provide key targets for pharmacotherapies to treat disorders of motivation including ad...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Peters, K. Z., Oleson, E. B., Cheer, J. F. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] Medications Development for Treatment of Opioid Use Disorder
This review describes methods for preclinical evaluation of candidate medications to treat opioid use disorder (OUD). The review is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effectiveness, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and effects of candidate medications. Effects of opioid medications and vaccines on opioid choice in nondependent and opioid-dependent subjects are reviewed...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Townsend, E. A., Negus, S. S., Banks, M. L. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] Canine and Feline Influenza
Influenza virus infections of carnivores—primarily in dogs and in large and small cats—have been repeatedly observed to be caused by a number of direct spillovers of avian viruses or in infections by human or swine viruses. In addition, there have also been prolonged epizootics of an H3N8 equine influenza virus in dogs starting around 1999, of an H3N2 avian influenza virus in domestic dog populations in Asia and in the United States that started around 2004, and an outbreak of an avian H7N2 influenza virus among cats in an animal shelter in the United States in 2016. The impact of influenza viruses in domestica...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Wasik, B. R., Voorhees, I. E. H., Parrish, C. R. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] The Two Sides of the Same Coin--Influenza Virus and Intracellular Signal Transduction
Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling inside the cell, primarily induced by pathogen-associated molecular patterns (PAMPs) that provoke safeguard mechanisms to defend from the invader. In the constant arms race between pathogen and cellular defense, viruses not only have evolved mechanisms to suppress or misuse supposedly antiviral signaling processes for their own benefit but also actively induce signaling to promote replication. This creates viral dependencies that may be exploited for novel strat...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Ludwig, S., Hrincius, E. R., Boergeling, Y. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] Influenza in Children
Influenza poses a significant disease burden on children worldwide, with high rates of hospitalization and substantial morbidity and mortality. Although the clinical presentation of influenza in children has similarities to that seen in adults, there are unique aspects to how children present with infection that are important to recognize. In addition, children play a significant role in viral transmission within communities. Growing evidence supports the idea that early influenza infection can uniquely establish lasting immunologic memory, making an understanding of how viral immunity develops in this population critical ...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Nayak, J., Hoy, G., Gordon, A. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[PERSPECTIVES] T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy
Approximately 70% of acute hepatitis C virus (HCV) infections become chronic, indicating that the virus is exceptionally well adapted to persist in humans with otherwise normal immune function. Robust, lifelong replication of this small RNA virus does not require a generalized failure of immunity. HCV effectively subverts innate and adaptive host defenses while leaving immunity against other viruses intact. Here, the role of CD4+ and CD8+ T-cell responses in control of HCV infection and their failure to prevent virus persistence in most individuals are reviewed. Two issues of practical importance remain priorities in an er...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Smith, S., Honegger, J. R., Walker, C. Tags: Hepatitis C Virus: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] HCV Assembly and Egress via Modifications in Host Lipid Metabolic Systems
Hepatitis C virus (HCV) proliferates by hijacking the host lipid machinery. In vitro replication systems revealed many aspects of the virus life cycle; in particular, viral utilization of host lipid metabolism during HCV proliferation. HCV interacts with lipid droplets (LDs) before starting the process of virus capsid formation at the lipid-rich endoplasmic reticulum (ER) membrane compartment. HCV buds into the ER via lipoprotein assembly and secretion. Exchangeable apolipoproteins, represented by apolipoprotein E (apoE), play pivotal roles in enhancing HCV-specific infectivity. HCV virions are likely to interact with othe...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Shimotohno, K. Tags: Hepatitis C Virus: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[TECHNIQUE] Mouse Models of Myeloid Malignancies
Mouse models of human myeloid malignancies support the detailed and focused investigation of selected driver mutations and represent powerful tools in the study of these diseases. Carefully developed murine models can closely recapitulate human myeloid malignancies in vivo, enabling the interrogation of a number of aspects of these diseases including their preclinical course, interactions with the microenvironment, effects of pharmacological agents, and the role of non-cell-autonomous factors, as well as the synergy between co-occurring mutations. Importantly, advances in gene-editing technologies, particularly CRISPR&ndas...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2021 Category: Research Authors: Basheer, F., Vassiliou, G. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights TECHNIQUE Source Type: research

[PERSPECTIVES] Growth Factors and Alcohol Use Disorder
Neurotrophic growth factors were originally characterized for their support in neuronal differentiation, outgrowth, and survival during development. However, it has been acknowledged that they also play a vital role in the adult brain. Abnormalities in growth factors have been implicated in a variety of neurological and psychiatric disorders, including alcohol use disorder (AUD). This work focuses on the interaction between alcohol and growth factors. We review literature suggesting that several growth factors play a unique role in the regulation of alcohol consumption, and that breakdown in these growth factor systems is ...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Liran, M., Rahamim, N., Ron, D., Barak, S. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] Psychostimulant-Induced Adaptations in Nucleus Accumbens Glutamatergic Transmission
Carrying different aspects of emotional and motivational signals, glutamatergic synaptic projections from multiple limbic and paralimbic brain regions converge to the nucleus accumbens (NAc), in which these arousing signals are processed and prioritized for behavioral output. In animal models of drug addiction, some key drug-induced alterations at NAc glutamatergic synapses underlie important cellular and circuit mechanisms that promote subsequent drug taking, seeking, and relapse. With the focus of cocaine, we review changes at NAc glutamatergic synapses that occur after different drug procedures and abstinence durations,...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Wright, W. J., Dong, Y. Tags: Addiction PERSPECTIVES Source Type: research

[PERSPECTIVES] Influenza in High-Risk Hosts--Lessons Learned from Animal Models
Factoring significantly into the global burden of influenza disease are high-risk populations that suffer the bulk of infections. Classically, the very young, very old, and pregnant women have been identified as high-risk populations; however, recent research has uncovered several other conditions that contribute to severe infection. By using varied animal models, researchers have identified molecular mechanisms underpinning the increased likelihood for infection due to obesity and malnourishment, as well as insight into the role sex hormones play in antiviral immunity in males, in females, and across the life span. Additi...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Honce, R., Wohlgemuth, N., Meliopoulos, V. A., Short, K. R., Schultz-Cherry, S. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[TECHNIQUE] Experimental Approaches to Identify Host Factors Important for Influenza Virus
An ever-expanding toolkit of experimental methods provides the means to discover and characterize host factors important for influenza virus. Here, we describe common methods for investigating genetic relationships and physical interactions between virus and host. A comprehensive knowledge of host:virus interactions is key to understanding how influenza virus exploits the host cell and to potentially identify vulnerabilities that may be manipulated to prevent or treat disease. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Schaack, G. A., Mehle, A. Tags: Influenza: The Cutting Edge TECHNIQUE Source Type: research

[PERSPECTIVES] Genetic Risk Assessment in Psychiatry
Most psychiatric disorders of pediatric and adult onset are caused by a complex interplay of genetic and environmental risk factors. Risk assessment in genetic counseling is correspondingly complicated. Outside of neurodevelopmental conditions, genetic and genomic testing has not achieved clinical utility. Genetic counselors most often base risk assessment on the client's medical and family history and empiric recurrence risk data. In rare cases significant familial risk may arise from variants of large effect. New approaches such as polygenic risk scores have the potential to inform diagnosis and management of affected in...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Peay, H. L. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Impact of Emerging Technologies in Prenatal Genetic Counseling
For decades, prenatal testing has been offered to evaluate pregnancies for genetic conditions. In recent years, the number of testing options and range of testing capabilities has dramatically increased. Because of the risks associated with invasive diagnostic testing, research has focused on the detection of genetic conditions through screening technologies such as cell-free DNA. Screening for aneuploidy, copy number variants, and monogenic disorders is clinically available using a sample of maternal blood, but limited data exist on the accuracy of some of these testing options. Additional research is needed to examine th...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Stevens, B. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Normal Hematopoiesis Is a Balancing Act of Self-Renewal and Regeneration
The hematopoietic system is highly organized to maintain its functional integrity and to meet lifelong organismal demands. Hematopoietic stem cells (HSCs) must balance self-renewal with differentiation and the regeneration of the blood system. It is a complex balancing act between these competing HSC functions. Although highly quiescent at steady state, HSCs become activated in response to inflammatory cytokines and regenerative challenges. This activation phase leads to many intrinsic stresses such as replicative, metabolic, and oxidative stress, which can cause functional decline, impaired self-renewal, and exhaustion of...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Olson, O. C., Kang, Y.-A., Passegue, E. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] Epigenetic Mechanisms in Leukemias and Lymphomas
Although we are just beginning to understand the mechanisms that regulate the epigenome, aberrant epigenetic programming has already emerged as a hallmark of hematologic malignancies including acute myeloid leukemia (AML) and B-cell lymphomas. Although these diseases arise from the hematopoietic system, the epigenetic mechanisms that drive these malignancies are quite different. Yet, in all of these tumors, somatic mutations in transcription factors and epigenetic modifiers are the most commonly mutated set of genes and result in multilayered disruption of the epigenome. Myeloid and lymphoid neoplasms generally manifest ep...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2020 Category: Research Authors: Duy, C., Beguelin, W., Melnick, A. Tags: Leukemia and Lymphoma: Molecular and Therapeutic Insights PERSPECTIVES Source Type: research

[PERSPECTIVES] The Evolution and Ecology of Resistance in Cancer Therapy
Despite the continuous deployment of new treatment strategies and agents over many decades, most disseminated cancers remain fatal. Cancer cells, through their access to the vast information of the human genome, have a remarkable capacity to deploy adaptive strategies for even the most effective treatments. We note there are two critical steps in the clinical manifestation of treatment resistance. The first, which is widely investigated, requires molecular machinery necessary to eliminate the cytotoxic effect of the treatment. However, the emergence of a resistant phenotype is not in itself clinically significant. That is,...
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Gatenby, R. A., Brown, J. S. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[RETRACTION] Retraction: The Evolution and Ecology of Resistance in Cancer Therapy
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Gatenby, R., Brown, J. Tags: RETRACTION Source Type: research

[TECHNIQUES] Synthetic Virology: Building Viruses to Better Understand Them
Generally comprised of less than a dozen components, RNA viruses can be viewed as well-designed genetic circuits optimized to replicate and spread within a given host. Understanding the molecular design that enables this activity not only allows one to disrupt these circuits to study their biology, but it provides a reprogramming framework to achieve novel outputs. Recent advances have enabled a "learning by building" approach to better understand virus biology and create valuable tools. Below is a summary of how modifying the preexisting genetic framework of influenza A virus has been used to track viral movemen...
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: tenOever, B. R. Tags: Influenza: The Cutting Edge TECHNIQUES Source Type: research

[PERSPECTIVES] The Structure, Function, and Pathobiology of the Influenza A and B Virus Ion Channels
Influenza A virus AM2 protein is an integral membrane protein that is an ion channel (also known as a viroporin). The channel has 24 extracellular residues, 19 residues that span the membrane once and acts as both the channel pore and also the membrane anchoring domain, and a 54-residue cytoplasmic tail. The M2 protein has four identical chains linked via two disulfide bonds that form a four-helix bundle that is 107–108 more permeable to protons than Na+ ions. The M2 channel is activated by low pH, His residue 37 is the pH sensor, and Trp residue 41 is the channel gate. The channel is blocked by the antiviral drug am...
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Lamb, R. A. Tags: Influenza: The Cutting Edge PERSPECTIVES Source Type: research

[TECHNIQUES] Cellular Plasticity during Metastasis: New Insights Provided by Intravital Microscopy
Metastasis is a highly dynamic process during which cancer and microenvironmental cells undergo a cascade of events required for efficient dissemination throughout the body. During the metastatic cascade, tumor cells can change their state and behavior, a phenomenon commonly defined as cellular plasticity. To monitor cellular plasticity during metastasis, high-resolution intravital microscopy (IVM) techniques have been developed and allow us to visualize individual cells by repeated imaging in animal models. In this review, we summarize the latest technological advancements in the field of IVM and how they have been applie...
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Margarido, A. S., Bornes, L., Vennin, C., van Rheenen, J. Tags: Metastasis: Mechanism to Therapy TECHNIQUES Source Type: research

[PERSPECTIVES] Premetastasis
Sterile inflammation within primary tumor tissues can spread to distant organs that are devoid of tumor cells. This happens in a manner dependent on tumor-led secretome, before the actual metastasis occurs. The premetastatic microenvironment is established in this way and is at least partly regulated by hijacking the host innate immune system. The biological manifestation of premetastasis include increased vascular permeability, cell mobilization via the blood stream, degradation of the extracellular matrix, immunosuppression, and host antineoplastic activities. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Maru, Y. Tags: Metastasis: Mechanism to Therapy PERSPECTIVES Source Type: research

[PERSPECTIVES] Interferon-Free Hepatitis C Virus Therapy
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with ~71 million chronically infected individuals worldwide. Treatment of patients with HCV-related liver disease has advanced considerably thanks to the development of new direct-acting antiviral drugs that are now administered as highly potent, safe, and well-tolerated combinations with a high barrier to resistance. International organizations, such as the European Association for the Study of the Liver, the American Association for the Study of Liver Diseases jointly with the Infectious Diseases Society of America, or the World Health Organizat...
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Pawlotsky, J.-M. Tags: Hepatitis C Virus: The Story of a Scientific and Therapeutic Revolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Birds of a Feather? Genetic Counseling, Genetic Testing, and Humanism
Humanism is a philosophy that emphasizes rational, scientific, and empiric analysis of the world we live in to improve the physical, social, and psychological life of humanity. Although individual genetic counselors may or may not identify as humanists, genetic counseling and genetic testing are primarily humanistic endeavors because they are situated in the context of humanistic medicine in the westernized world. Humanistic goals are also implicit and explicit in the profession and practice of genetic counselors. This review examines the relationship between humanism and genetic counseling, highlighting situations in whic...
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Resta, R. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetic Counseling and Assisted Reproductive Technologies
Despite the ever-increasing number of patients undergoing fertility treatments and the expanded use of genetic testing in this context, there has been limited focus in the literature on the involvement of genetics professionals in the assisted reproductive technology (ART) setting. Here we discuss the importance of genetic counseling within reproductive medicine. We review how genetic testing of embryos is performed, the process of gamete donation, the challenges associated with genetic testing, and the complexities of genetic test result interpretation. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - November 2, 2020 Category: Research Authors: Lilienthal, D., Cahr, M. Tags: Genetic Counseling: Clinical Practice and Ethical Considerations PERSPECTIVES Source Type: research