[PERSPECTIVES] The Function of TrophomiRs and Other MicroRNAs in the Human Placenta
In eutherian organisms, the placenta interfaces the fetal and maternal environments. Located at the placental villous surface, in direct contact with maternal blood, is the trophoblast layer, which mediates the crucial maternal–fetal exchange of gases, nutrients, and waste products, produces hormones that support the pregnancy, and provides immunologic defense. Discovery of microRNAs (miRNAs) and their role in development, differentiation, and homeostatic resilience has increased our understanding of genomic and epigenomic networks that regulate placental function. Moreover, unique miRNA species, which are expressed ...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Sadovsky, Y., Mouillet, J.-F., Ouyang, Y., Bayer, A., Coyne, C. B. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Glutamatergic Mechanisms Associated with Seizures and Epilepsy
Epilepsy is broadly characterized by aberrant neuronal excitability. Glutamate is the predominant excitatory neurotransmitter in the adult mammalian brain; thus, much of past epilepsy research has attempted to understand the role of glutamate in seizures and epilepsy. Seizures induce elevations in extracellular glutamate, which then contribute to excitotoxic damage. Chronic seizures can alter neuronal and glial expression of glutamate receptors and uptake transporters, further contributing to epileptogenesis. Evidence points to a shared glutamate pathology for epilepsy and other central nervous system (CNS) disorders, incl...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Barker-Haliski, M., White, H. S. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Immune Response in Hepatitis B Virus Infection
Hepatitis B virus (HBV) can replicate within hepatocytes without causing direct cell damage. The host immune response is, therefore, not only essential to control the spread of virus infection, but it is also responsible for the inflammatory events causing liver pathologies. In this review, we discuss how HBV deals with host immunity and how we can harness it to achieve virus control and suppress liver damage. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Tan, A., Koh, S., Bertoletti, A. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis B Virus and Hepatitis D Virus Entry, Species Specificity, and Tissue Tropism
Entry of hepatitis B (HBV) and hepatitis D viruses (HDV) into a host cell represents the initial step of infection. This process requires multiple steps, including the low-affinity attachment of the virus to the cell surface, followed by high-affinity attachment to specific receptor(s), and subsequent endocytosis-mediated internalization. Within the viral envelope, the preS1 region is involved in receptor binding. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as an entry receptor of HBV and HDV by affinity purification using a preS1 peptide. NTCP is mainly or exclusively expressed in t...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Watashi, K., Wakita, T. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[RETROSPECTIVE] Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm
Modern tuberculosis (TB) chemotherapy is widely viewed as a crowning triumph of anti-infectives research. However, only one new TB drug has entered clinical practice in the past 40 years while drug resistance threatens to further destabilize the pandemic. Here, we review a brief history of TB drug development, focusing on the evolution of mechanism(s)-of-action studies and key conceptual barriers to rational, mechanism-based drugs. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Chakraborty, S., Rhee, K. Y. Tags: Tuberculosis RETROSPECTIVE Source Type: research

[PERSPECTIVES] The Mycobacterial Cell Wall--Peptidoglycan and Arabinogalactan
The mycobacterial bacillus is encompassed by a remarkably elaborate cell wall structure. The mycolyl-arabinogalactan-peptidoglycan (mAGP) complex is essential for the viability of Mycobacterium tuberculosis and maintains a robust basal structure supporting the upper "myco-membrane." M. tuberculosis peptidoglycan, although appearing to be unexceptional at first glance, contains a number of unique molecular subtleties that become particularly important as the TB-bacilli enters into nonreplicative growth during dormancy. Arabinogalactan, a highly branched polysaccharide, serves to connect peptidoglycan with the oute...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Alderwick, L. J., Harrison, J., Lloyd, G. S., Birch, H. L. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Inherent Anticipation in the Pharmaceutical and Biotechnology Industries
Pharmaceutical and biotech research often involves discovering new properties of, or new methods to use, existing compositions. The doctrine of inherent anticipation, however, prevents the issuance and/or validity of a patent for discoveries deemed to have been implicitly disclosed in the prior art. This can be a barrier to patent rights in these technologies. Inherent anticipation therefore creates uncertainty for patent protection in the pharmaceutical and biotech sciences. Despite this uncertainty, Federal Circuit jurisprudence provides guidance on the boundaries of the inherent anticipation doctrine. In view of the cas...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Goldman, M., Evans, G., Zappia, A. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Introduction to Intellectual Property: A U.S. Perspective
This review introduces patents and trade secrets, the two mechanisms that U.S. law provides inventors to protect their inventions. These mechanisms are mutually exclusive: One demands disclosure and the other calls for concealment. Many biotechnology innovators opt for patents, which grant legal, time-limited monopolies to eligible inventions. To obtain a patent in the United States, an invention must be useful to the public and made or altered by the hand of man. It must then clear the hurdles of novelty and nonobviousness. If an invention can do that, obtaining a patent becomes a matter of form: Who qualifies as an inven...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Murphy, A., Stramiello, M., Lewis, S., Irving, T. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Thermally Dimorphic Human Fungal Pathogens--Polyphyletic Pathogens with a Convergent Pathogenicity Trait
Fungi are adept at changing their cell shape and developmental program in response to signals in their surroundings. Here we focus on a group of evolutionarily related fungal pathogens of humans known as the thermally dimorphic fungi. These organisms grow in a hyphal form in the environment but shift their morphology drastically within a mammalian host. Temperature is one of the main host signals that initiates their conversion to the "host" form and is sufficient in the laboratory to trigger establishment of this host-adapted developmental program. Here we discuss the major human pathogens in this group, which a...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Sil, A., Andrianopoulos, A. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Black Molds and Melanized Yeasts Pathogenic to Humans
A review is given of melanized fungi involved in human infection, including species forming budding cells and strictly filamentous representatives. Classically, they are known as "phaeoid" or "dematiaceous" fungi, and, today, agents are recognized to belong to seven orders of fungi, of which the Chaetothyriales and Pleosporales are the most important. Infections range from cutaneous or pulmonary colonization to systemic or disseminated invasion. Subcutaneous involvement, either primary or after dissemination, may lead to host tissue proliferation of dermis or epidermis. Particularly in the Chaetothyrial...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Chowdhary, A., Perfect, J., de Hoog, G. S. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis
Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the ...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Bush, R. A., Wei, L. L., Sieving, P. A. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] Differential Gene Expression in Age-Related Macular Degeneration
Gene expression is the first step in ascribing function between an associated gene and disease. Understanding how variation in a gene influences expression, particularly in tissues affected by the disease, may help elucidate what influences the phenotypic outcome of that disease. Previous studies of the genetics of age-related macular degeneration (AMD) have identified several risk factors, but have not yet bridged the gap between gene association and identifying a specific mechanism or function that is involved in the pathogenesis of AMD. Advances in genomic technologies, such as RNA sequencing (RNA-seq), single cell RNA-...
Source: Cold Spring Harbor perspectives in medicine - August 3, 2015 Category: Research Authors: Morgan, D. J., DeAngelis, M. M. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] Human Endometrial Transcriptomics: Implications for Embryonic Implantation
Human endometrium has been extensively investigated in the search for markers capable of predicting its receptive status. The completion of the Human Genome Project has triggered a rapid development of new fields in molecular biology, the "transcriptomics" being a major turning point in the knowledge acquisition of endometrial receptivity. Based on this, a customized Endometrial Receptivity Array (ERA) has been developed, which is capable of identifying the genomic signature of receptivity. This diagnostic tool showed that the window of implantation (WOI) is displaced in one out of four patients with implantation...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Gomez, E., Ruiz-Alonso, M., Miravet, J., Simon, C. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Initiation, Propagation, and Termination of Partial (Focal) Seizures
The neurophysiological patterns that correlate with partial (focal) seizures are well defined in humans by standard electroencephalogram (EEG) and presurgical depth electrode recordings. Seizure patterns with similar features are reproduced in animal models of partial seizures and epilepsy. However, the network determinants that support interictal spikes, as well as the initiation, progression, and termination of seizures, are still elusive. Recent findings show that inhibitory networks are prominently involved at the onset of these seizures, and that extracellular changes in potassium contribute to initiate and sustain se...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: de Curtis, M., Avoli, M. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis D Virus: Introduction and Epidemiology
Hepatitis D is caused by the hepatitis D virus (HDV), a unique RNA pathogen that requires the hepatitis B surface antigen (HBsAg) to infect. Hepatitis D is transmitted by the parenteral route. The main susceptible group is patients with chronic HBsAg infection who become superinfected with the virus. Hepatitis D occurs throughout the globe, but control of hepatitis B virus (HBV) in the last two decades has consistently diminished the circulation of HDV in industrialized countries. However, hepatitis D remains a medical issue for injecting drug users (IDUs), as well as immigrants from endemic HDV areas, who are reintroducin...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Rizzetto, M. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepadnavirus Genome Replication and Persistence
Hallmarks of the hepadnavirus replication cycle are the formation of covalently closed circular DNA (cccDNA) and the reverse transcription of a pregenomic RNA (pgRNA) in core particles leading to synthesis of the relaxed circular DNA (rcDNA) genome. cccDNA, the template for viral RNA transcription, is the basis for the persistence of these viruses in infected hepatocytes. In this review, we summarize the current state of knowledge on the mechanisms of hepadnavirus reverse transcription and the biochemical and structural properties of the viral reverse transcriptase (RT). We highlight important gaps in knowledge regarding c...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Hu, J., Seeger, C. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetic Approaches to Facilitate Antibacterial Drug Development
Very few chemically novel agents have been approved for antibacterial chemotherapies during the last 50 yr. Yet new antibacterial drugs are needed to reduce the impact on global health of an increasing number of drug-resistant infections, including highly drug-resistant forms of tuberculosis. This review discusses how genetic approaches can be used to study the mechanism of action of whole-cell screening hits and facilitate target-driven strategies for antimicrobial drug development. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Schnappinger, D. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Regulatory Agencies and Intellectual Property: Part II
Patent law and antitrust law have traditionally been areas of the law involving at least some inherent tension. Champions of antitrust argue that the patent "monopoly" must be strictly limited as an exception to the general legal principle that competition should be unfettered. Patent lawyers argue that patents are the result of an exercise of congressional authority, enshrined in the Constitution, reflecting the policy decision by the Founders that granting a limited exclusionary right was justified by the public benefits derived from full disclosure of the patented invention. In the modern era these competing v...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Noonan, K. E. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Regulatory Agencies and Intellectual Property: Part I
The patent and regulatory regimes of different agencies of the federal government are not always in agreement, and although the concept of the "unified executive" holds that the executive branch speaks with one voice, that is not always the case.1 Some agencies, like the Food and Drug Administration, tend toward cooperation with government patent policies, whereas others, notably the Federal Trade Commission, are often at odds with the Patent Office, the patent system, or both. These skirmishes, when they arise, eventually come before federal courts and ultimately the Supreme Court, where balancing the differing ...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Noonan, K. E. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Mechanisms of Antifungal Drug Resistance
Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Can...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Cowen, L. E., Sanglard, D., Howard, S. J., Rogers, P. D., Perlin, D. S. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Fungal Pathogens: Survival and Replication within Macrophages
This article will discuss five of the most important human fungal pathogens (Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Coccidiodes immitis, and Histoplasma capsulatum) and consider the strategies and virulence factors adopted by each to survive and replicate within macrophages. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Gilbert, A. S., Wheeler, R. T., May, R. C. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Tuberculosis and HIV Coinfection
Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) constitute the main burden of infectious disease in resource-limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact ...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Bruchfeld, J., Correia-Neves, M., Kallenius, G. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Gene Therapies for Neovascular Age-Related Macular Degeneration
Pathological neovascularization is a key component of the neovascular form (also known as the wet form) of age-related macular degeneration (AMD) and proliferative diabetic retinopathy. Several preclinical studies have shown that antiangiogenesis strategies are effective for treating neovascular AMD in animal models. Vascular endothelial growth factor (VEGF) is one of the main inducers of ocular neovascularization, and several clinical trials have shown the benefits of neutralizing VEGF in patients with neovascular AMD or diabetic macular edema. In this review, we summarize several preclinical and early-stage clinical tria...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Pechan, P., Wadsworth, S., Scaria, A. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetics of Primary Inherited Disorders of the Optic Nerve: Clinical Applications
Inherited disorders of the optic nerve significantly impact vision in children and adults. The optic nerve disorders most commonly encountered clinically are glaucoma and primary optic neuropathy including Leber’s hereditary optic neuropathy (LHON) and autosomal dominant or Kjer’s optic atrophy. Current knowledge of the genetics of optic neuropathy and glaucoma makes it possible to test for mutations in disease-causing genes allowing for presymptomatic testing and risk assessment, and recent advances have revealed important disease mechanisms that may suggest potential therapeutic targets. In this perspective, ...
Source: Cold Spring Harbor perspectives in medicine - July 1, 2015 Category: Research Authors: Allen, K. F., Gaier, E. D., Wiggs, J. L. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] Treatment Principles for Candida and Cryptococcus
The yeasts Candida and Cryptococcus spp. are important human opportunistic pathogens. Candida spp. rely on skin or mucosal breach to cause bloodstream infection, whereas Cryptococcus spp. exploit depressed cell-mediated immunity characteristic of advanced HIV infection. The treatment for both organisms relies on the administration of rapidly fungicidal agents. In candidaemia, source control is important, with removal of prosthetic material and drainage of collections, as well as hunting for and tailoring therapy to disseminated sites of infection, particularly the eyes and heart. For cryptococcal meningitis, restoration of...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Whitney, L. C., Bicanic, T. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] The Perinatal Microbiome and Pregnancy: Moving Beyond the Vaginal Microbiome
The human microbiome, the collective genome of the microbial community that is on and within us, has recently been mapped. The initial characterization of healthy subjects has provided investigators with a reference population for interrogating the microbiome in metabolic, intestinal, and reproductive health and disease states. Although it is known that bacteria can colonize the vagina, recent metagenomic studies have shown that the vaginal microbiome varies among reproductive age women. Similarly, the richness and diversity of intestinal microbiota also naturally fluctuate among gravidae in both human and nonhuman primate...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Prince, A. L., Chu, D. M., Seferovic, M. D., Antony, K. M., Ma, J., Aagaard, K. M. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Seizures and Epilepsy: An Overview for Neuroscientists
This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Stafstrom, C. E., Carmant, L. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Management of Chronic Hepatitis B in Patients from Special Populations
Here we review the management of chronic hepatitis B (CHB) in four special categories of patients: CHB in pregnancy, in patients on immunosuppressive treatments, in patients undergoing liver transplantation, and in patients coinfected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV). (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Lai, C.-L., Yuen, M.-F. Tags: Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] The Chimpanzee Model for Hepatitis B Virus Infection
Even before the discovery of hepatitis B virus (HBV), it was known that chimpanzees (Pan troglodytes) are susceptible to human hepatitis viruses. The chimpanzee is the only primate animal model for HBV infections. Much like HBV-infected human patients, chimpanzees can develop acute and chronic HBV infections and consequent hepatitis. Chimpanzees also develop a cellular immune response similar to that observed in humans. For these reasons, the chimpanzee has proven to be an invaluable model for investigations on HBV-driven disease pathogenesis and also the testing of novel antiviral therapies and prophylactic approaches. (S...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Wieland, S. F. Tags: Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets
The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse ...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Mdluli, K., Kaneko, T., Upton, A. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Baseball Bats and Chocolate Chip Cookies: The Judicial Treatment of DNA in the Myriad Genetics Litigation
In June 2013, the U.S. Supreme Court rendered a controversial ruling that naturally occurring DNA segments are "products of nature" and therefore not patentable subject matter. At this intersection between science and law, in litigation of crucial importance to patients, science, and multibillion-dollar biotech enterprises, the appellate judges sidestepped genetics and engaged in a war of metaphors from diamonds to chocolate chip cookies. This case is not an outlier. Apprehensive judges and juries in both Canada and the United States find many convenient excuses to avoid coming to grips with the underlying scienc...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Binnie, I., Park-Thompson, V. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Canada's Patented Medicines (Notice of Compliance) Proceedings and Intellectual Property
This article provides information on the requirements for listing a patent on the Patent Register and an overview of how the Patent Medicines (Notice of Compliance) Regulations affect the drug approval process. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Bian, H., McCourt, C. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Innate Defense against Fungal Pathogens
Human fungal infections have been on the rise in recent years and proved increasingly difficult to treat as a result of the lack of diagnostics, effective antifungal therapies, and vaccines. Most pathogenic fungi do not cause disease unless there is a disturbance in immune homeostasis, which can be caused by modern medical interventions, disease-induced immunosuppression, and naturally occurring human mutations. The innate immune system is well equipped to recognize and destroy pathogenic fungi through specialized cells expressing a broad range of pattern recognition receptors (PRRs). This review will outline the cells and...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Drummond, R. A., Gaffen, S. L., Hise, A. G., Brown, G. D. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Imaging in Tuberculosis
Despite many advances in both diagnosis and treatment, tuberculosis still remains one of commonest causes of morbidity and mortality from any infectious cause in the world. Although the overall incidence and mortality rate for tuberculosis has decreased over the years, timely and accurate diagnosis of tuberculosis is essential for the health of the patient as well as the public. For the diagnosis of tuberculosis, a high degree of clinical suspicion is required, and this becomes much more important in high-risk populations. Tuberculosis may masquerade as any disease; therefore, tissue and microbiological assessment is somet...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Bomanji, J. B., Gupta, N., Gulati, P., Das, C. J. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Gene Therapy for the Retinal Degeneration of Usher Syndrome Caused by Mutations in MYO7A
Usher syndrome is a deaf-blindness disorder. One of the subtypes, Usher 1B, is caused by loss of function of the gene encoding the unconventional myosin, MYO7A. A variety of different viral-based delivery approaches have been tested for retinal gene therapy to prevent the blindness of Usher 1B, and a clinical trial based on one of these approaches has begun. This review evaluates the different approaches. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Lopes, V. S., Williams, D. S. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] Genetic Modifiers and Oligogenic Inheritance
Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance and expressivity of causal alleles has been modest, in part because of the methodological challenges in identifying genetic modifiers. Nonetheless, the progressive discovery of modifier alleles has improved both our interpretative ability and our analytical tools to dissect such phenomena. In this review, we analyze the genetic properties and behaviors of modifiers as derived from studies in patient populations and model organisms and we highlight conceptu...
Source: Cold Spring Harbor perspectives in medicine - June 1, 2015 Category: Research Authors: Kousi, M., Katsanis, N. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] The Human Placental Methylome
This review provides an overview of the unique features of DNA methylation in the human placenta. We discuss the importance of understanding placental development, structure, and function in the interpretation of DNA methylation data. Examples are given of how DNA methylation is important in regulating placental-specific gene expression, including monoallelic expression and X-chromosome inactivation in the placenta. We also discuss studies of global DNA methylation changes in the context of placental pathology and environmental exposures. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Robinson, W. P., Price, E. M. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Malformations of Cortical Development and Epilepsy
Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagno...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Barkovich, A. J., Dobyns, W. B., Guerrini, R. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis B Virus Genotypes and Variants
In conclusion, HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Lin, C.-L., Kao, J.-H. Tags: Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis B Virus Epidemiology
The epidemiology of hepatitis B virus (HBV) infection is geographically diverse, with population prevalence, age and mode of acquisition, and likelihood of progression to chronic infection mutually interdependent. The burden of chronic HBV infection is increasingly being recognized, with cirrhosis and liver cancer attributable to HBV continuing to increase. The outcomes of chronic HBV infection are affected by a range of factors, including viral genotype, the presence of coinfections with other blood-borne viruses, and the impact of other causes of liver disease. The increased recognition of HBV infection as a leading caus...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: MacLachlan, J. H., Cowie, B. C. Tags: Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] The Impact of Myriad and Mayo: Will Advancements in the Biological Sciences Be Spurred or Disincentivized? (Or Was Biotech Patenting Not Complicated Enough?)
For years, purified and isolated naturally occurring biological substances of great medical importance—including genes—have been the subject of U.S. patents. Similarly, methods in which the detection of a biological substance (e.g., in a blood sample) dictates subsequent actions, as in disease diagnostics and treatment, have long enjoyed patent protection. However, two recent Supreme Court cases, Association for Molecular Pathology v. Myriad Genetics, Inc. (133 S. Ct. 2107) (2013) and Mayo Collaborative Services v. Prometheus Laboratories, Inc. (132 S. Ct. 1289) (2012), have shaken up the status quo of biotech ...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Gordon, J. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Patentability of Genes: A European Union Perspective
Unlike the position in the United States following the recent Supreme Court decision in Myriad, in the European Union naturally occurring genetic sequences, whether of human or other origin, remain patent-eligible. Here the basis for such eligibility in legislation and in case law is explained. The utility of a sequence must be disclosed as a condition of eligibility, and requirements outlined in European Patent Office (EPO) and U.K. case law are discussed. A claimed sequence must also satisfy requirements of novelty and inventive step, the latter being considered primarily using the tests of "obvious to try" and...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Cole, P. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] The Human Mycobiome
Fungi are fundamental to the human microbiome, the collection of microbes distributed across and within the body, and the microbiome has been shown, in total, to modify fundamental human physiology, including energy acquisition, vitamin-cofactor availability, xenobiotic metabolism, immune development and function, and even neurological development and behavior. Here, a comprehensive review of current knowledge about the mycobiome, the collective of fungi within the microbiome, highlights methods for its study, diversity between body sites, and dynamics during human development, health, and disease. Early-stage studies show...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Seed, P. C. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Antifungal Pharmacokinetics and Pharmacodynamics
Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studie...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Lepak, A. J., Andes, D. R. Tags: Human Fungal Pathogens PERSPECTIVES Source Type: research

[PERSPECTIVES] Animal Models of Tuberculosis: Guinea Pigs
The progression of the disease that follows infection of guinea pigs with Mycobacterium tuberculosis displays many features of human tuberculosis (TB), and the guinea pig model of TB has been used for more than 100 years as a research tool to understand and describe disease mechanisms. Changes in the bacterial burden and pathology following infection can be readily monitored and used to evaluate the impact of TB interventions. Demonstration of the protective efficacy of vaccines in the low-dose aerosol guinea pig model is an important component of the preclinical data package for novel vaccines in development, and there is...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Clark, S., Hall, Y., Williams, A. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Tuberculosis Treatment and Drug Regimens
Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial for maintaining adequate blood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosis strains are mainly favored by the inadequate medical management of the patients. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosis drugs (bedaquiline and delamanid) have been recently approved by the health authorities, but t...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Sotgiu, G., Centis, R., D'ambrosio, L., Migliori, G. B. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Gene Therapy of ABCA4-Associated Diseases
The ATP-binding cassette (ABC) transporter gene, ABCA4 (ABCR), was characterized in 1997 as the causal gene for autosomal recessive Stargardt disease (STGD1). Shortly thereafter several other phenotypes were associated with mutations in ABCA4, which now have collectively emerged as the most frequent cause of retinal degeneration phenotypes of Mendelian inheritance. ABCA4 functions as an important transporter (or "flippase") of vitamin A derivatives in the visual cycle. Several ways to alleviate the effects of the defective ABCA4 protein, which cause accumulation of 11-cis and all-trans-retinal in photoreceptors a...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Auricchio, A., Trapani, I., Allikmets, R. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] Stem Cells as Tools for Studying the Genetics of Inherited Retinal Degenerations
The ability to provide early clinical intervention for inherited disorders is heavily dependent on knowledge of a patient’s disease-causing mutations and the resultant pathophysiologic mechanism(s). Without knowing a patient’s disease-causing gene, and how gene mutations alter the health and functionality of affected cells, it would be difficult to develop and deliver patient-specific molecular or small molecule therapies. Many believe that the field of stem cell biology holds the keys to the future development of disease-, patient-, and cell-specific therapies. In the case of the eye, which is susceptible to a...
Source: Cold Spring Harbor perspectives in medicine - May 1, 2015 Category: Research Authors: Wiley, L. A., Burnight, E. R., Mullins, R. F., Stone, E. M., Tucker, B. A. Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

[PERSPECTIVES] The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease
Numerous recent studies have shown the power of cell-free fetal RNA, obtained from amniotic fluid supernatant, to report on the development of the living fetus in real time. Examination of these transcripts on a genome-wide basis has led to new insights into the prenatal pathophysiology of multiple genetic, developmental, and environmental diseases. Each studied condition presents a unique, characteristic fetal transcriptome, which points to specific disrupted molecular pathways. These studies have also improved our knowledge of the normal development of the human fetus, revealing gestational age-related dynamic gene expre...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2015 Category: Research Authors: Zwemer, L. M., Bianchi, D. W. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development
Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as "mTORopathies." Mutations in mTOR regulatory genes (e.g., TSC1, TSC2, AKT3, DEPDC5) have been associated with several focal MCD highly associated with epilepsy such as tuberous sclerosis complex (TSC), hemimegalencephaly (HME; brain malformation associated with dramatic enlargement of one brain hemisphere), and cortical dysplasia. mTOR plays important roles in the regulation of cell divi...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2015 Category: Research Authors: Crino, P. B. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research