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[PERSPECTIVES] Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras
RAS genes are mutated in 5%–40% of a spectrum of myeloid and lymphoid cancers with NRAS affected 2–3 times more often than KRAS. Genomic analysis indicates that RAS mutations generally occur as secondary events in leukemogenesis, but are integral to the disease phenotype. The tractable nature of the hematopoietic system has facilitated generating accurate mouse models of hematologic malignancies characterized by hyperactive Ras signaling. These strains provide robust platforms for addressing how oncogenic Ras expression perturbs proliferation, differentiation, and self-renewal programs in stem and progenitor ce...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Wandler, A., Shannon, K. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[PERSPECTIVES] Bone Remodeling and the Microbiome
Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the microbiome. The gastrointestinal tract harbors the greatest numbers of these microorganisms, which regulate human nutrition, metabolism, and immune system function. Moreover, the intestinal microbiota contains pro- and anti-inflammatory products that modulate immune responses and may play a role in maintaining gut barrier function. Therefore, the community composition of the microbiota has profound effects on the immune status of the host and impacts the development and/or progressi...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Pacifici, R. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Preclinical and Coclinical Studies in Prostate Cancer
Men who develop metastatic castration-resistant prostate cancer (mCRPC) will invariably succumb to their disease. Thus there remains a pressing need for preclinical testing of new drugs and drug combinations for late-stage prostate cancer (PCa). Insights from the mCRPC genomic landscape have revealed that, in addition to sustained androgen receptor (AR) signaling, there are other actionable molecular alterations and distinct molecular subclasses of PCa; however, the rate at which this knowledge translates into patient care via current preclinical testing is painfully slow and inefficient. Here, we will highlight the issues...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Chen, M., Pandolfi, P. P. Tags: Prostate Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] Effects of Exercise on Vascular Function, Structure, and Health in Humans
Physical activity has profound impacts on the vasculature in humans. Acute exercise induces immediate changes in artery function, whereas repeated episodic bouts of exercise induce chronic functional adaptation and, ultimately, structural arterial remodeling. The nature of these changes in function and structure are dependent on the characteristics of the training load and may be modulated by other factors such as exercise-induced inflammation and oxidative stress. The clinical implications of these physiological adaptations are profound. Exercise impacts on the development of atherosclerosis and on the incidence of primar...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Green, D. J., Smith, K. J. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] On the Run for Hippocampal Plasticity
Accumulating research in rodents and humans indicates that exercise benefits brain function and may prevent or delay onset of neurodegenerative conditions. In particular, exercise modifies the structure and function of the hippocampus, a brain area important for learning and memory. This review addresses the central and peripheral mechanisms underlying the beneficial effects of exercise on the hippocampus. We focus on running-induced changes in adult hippocampal neurogenesis, neural circuitry, neurotrophins, synaptic plasticity, neurotransmitters, and vasculature. The role of peripheral factors in hippocampal plasticity is...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Cooper, C., Moon, H. Y., van Praag, H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Effector T Cells in Multiple Sclerosis
Multiple sclerosis (MS) has long been considered a CD4 T-cell disease, primarily because of the findings that the strongest genetic risk for MS is the major histocompatibility complex (MHC) class II locus, and that T cells play a central role in directing the immune response. The importance that the T helper (Th)1 cytokine, interferon (IFN-), and the Th17 cytokine, interleukin (IL)-17, play in MS pathogenesis is indicated by recent clinical trial data by the enhanced presence of Th1/Th17 cells in central nervous system (CNS) tissue, cerebrospinal fluid (CSF), and blood, and by research on animal models of MS, such as exper...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Kaskow, B. J., Baecher-Allan, C. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[TECHNIQUE] Phylogenetic Quantification of Intratumor Heterogeneity
We describe how multiple samples can guide tree inference through accurate phasing of germline variants and copy-number profiles. We show their relevance in detecting clonal expansions and deriving summary statistics quantifying the overall degree of ITH, and discuss how the relationship of metastatic clades might give us insight into the dominant mode of cancer progression. We further outline how multisample studies might help us better understand selective processes acting on cancer genomes and help to detect neutral evolution and mutator phenotypes. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Watkins, T. B. K., Schwarz, R. F. Tags: Cancer Evolution TECHNIQUE Source Type: research

[PERSPECTIVES] The Genetics of C9orf72 Expansions
Repeat expansions in the promoter region of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and related disorders of the ALS/frontotemporal lobar degeneration (FTLD) spectrum. Remarkable clinical heterogeneity among patients with a repeat expansion has been observed, and genetic anticipation over different generations has been suggested. Genetic factors modifying the clinical phenotype have been proposed, including genetic variation in other known disease genes, the genomic context of the C9orf72 repeat, and expanded repeat size, which has been estimated between 45 and several thousand unit...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Gijselinck, I., Cruts, M., Van Broeckhoven, C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Disease Mechanisms of C9ORF72 Repeat Expansions
G4C2 repeat expansions within the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense G4C2 and antisense G2C4 repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased C9ORF72 mRNA and protein expression. Consequently, there is ample opportunity for the C9ORF72 mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in be...
Source: Cold Spring Harbor perspectives in medicine - April 2, 2018 Category: Research Authors: Gendron, T. F., Petrucelli, L. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] The Evolution and Ecology of Resistance in Cancer Therapy
Despite 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 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 deployment of a mechanism of resistance that usually involves increased expression of molecular machinery necessary to eliminate the cytotoxic effect of treatment. However, the emergence ...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Gatenby, R., Brown, J. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] The Heart and Great Vessels
This article gives a general overview of this work as it pertains to the development of great vessels, myocardium, and heart valves. In each area, we focus on currently studied methods, limitations, and areas for future study. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Onwuka, E., King, N., Heuer, E., Breuer, C. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Targeting Ras with Macromolecules
Activating Ras mutations are associated with ~30% of all human cancers and the four Ras isoforms are highly attractive targets for anticancer drug discovery. However, Ras proteins are challenging targets for conventional drug discovery because they function through intracellular protein–protein interactions and their surfaces lack major pockets for small molecules to bind. Over the past few years, researchers have explored a variety of approaches and modalities, with the aim of specifically targeting oncogenic Ras mutants for anticancer treatment. This perspective will provide an overview of the efforts on developing...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Pei, D., Chen, K., Liao, H. Tags: Ras and Cancer in the 21st Century PERSPECTIVES Source Type: research

[TECHNIQUE] Anatomic and Molecular Imaging in Prostate Cancer
Prostate cancer is characterized by a complex set of heterogeneous disease states. This review aims to describe how imaging has been studied within each specific state. As physicians transition into an era of precision medicine, multiparametric magnetic resonance imaging (mpMRI) is proving to be a powerful tool leading the way for a paradigm shift in the diagnosis and management of localized prostate cancer. With further research and development, molecular imaging modalities will likely change the way we approach recurrent and metastatic disease. Given the range of possible oncological progression patterns, a thorough unde...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Miller, E. T., Salmasi, A., Reiter, R. E. Tags: Prostate Cancer TECHNIQUE Source Type: research

[PERSPECTIVES] Exosomes as Mediators of the Systemic Adaptations to Endurance Exercise
Habitual endurance exercise training is associated with multisystemic metabolic adaptations that lower the risk of inactivity-associated disorders such as obesity and type 2 diabetes mellitus (T2DM). Identification of complex systemic signaling networks responsible for these benefits are of great interest because of their therapeutic potential in metabolic diseases; however, specific signals that modulate the multisystemic benefits of exercise in multiple tissues and organs are only recently being discovered. Accumulated evidence suggests that muscle and other tissues have an endocrine function and release peptides and nuc...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Safdar, A., Tarnopolsky, M. A. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Effects of Exercise and Aging on Skeletal Muscle
A substantial loss of muscle mass and strength (sarcopenia), a decreased regenerative capacity, and a compromised physical performance are hallmarks of aging skeletal muscle. These changes are typically accompanied by impaired muscle metabolism, including mitochondrial dysfunction and insulin resistance. A challenge in the field of muscle aging is to dissociate the effects of chronological aging per se on muscle characteristics from the secondary influence of lifestyle and disease processes. Remarkably, physical activity and exercise are well-established countermeasures against muscle aging, and have been shown to attenuat...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Distefano, G., Goodpaster, B. H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Multiple Sclerosis Pathology
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesions in the gray and white matter and to diffuse neurodegeneration in the entire brain. In this review, the spectrum of MS lesions and their relation to the inflammatory process is described. Pathology suggests that inflammation drives tissue injury at all stages of the disease. Focal inflammatory infiltrates in the meninges and the perivascular spaces appear to produce soluble factors, which induce demyelination or neurodegeneration either directly or indirectly through microglia activa...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Lassmann, H. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] TDP-43 Prions
The most common neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, are all protein-misfolding diseases and are characterized by the presence of disease-specific protein aggregates in affected neuronal cells. Recent studies have shown that, like tau and α-synuclein, TAR-DNA binding protein of 43 kDa (TDP-43) can form aggregates in vitro in a seed-dependent, self-templating, prion-like manner. Insoluble TDP-43 prepared from the brains of patients has been classified into several strains, which can be transferred from cell to cell in vitro, suggesting the involve...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Nonaka, T., Hasegawa, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Cell Biology and Pathophysiology of {alpha}-Synuclein
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson’s disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated. In this perspective, we review the structural characteristics of α-synuclei...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2018 Category: Research Authors: Burre, J., Sharma, M., Südhof, T. C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[RETROSPECTIVE] From Ras to Rap and Back, a Journey of 35 Years
Our laboratory has studied Ras and Ras-like proteins since the discovery of the Ras oncogene 35 years ago. In this review, I will give an account of what we have done in these 35 years and indicate the main papers that have guided our research. Our efforts started with the early analysis of mutant Ras in human tumors followed by deciphering of the role of Ras in signal transduction pathways. In an attempt to interfere in Ras signaling we turned to Rap proteins. These proteins are the closest relatives of Ras and were initially identified as Ras antagonists. However, our studies revealed that the Rap signaling network prima...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Bos, J. L. Tags: Ras and Cancer in the 21st Century RETROSPECTIVE Source Type: research

[PERSPECTIVES] Control of Muscle Metabolism by the Mediator Complex
Exercise represents an energetic challenge to whole-body homeostasis. In skeletal muscle, exercise activates a variety of signaling pathways that culminate in the nucleus to regulate genes involved in metabolism and contractility; however, much remains to be learned about the transcriptional effectors of exercise. Mediator is a multiprotein complex that links signal-dependent transcription factors and other transcriptional regulators with the basal transcriptional machinery, thereby serving as a transcriptional "hub." In this article, we discuss recent studies highlighting the role of Mediator subunits in metabol...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Amoasii, L., Olson, E. N., Bassel-Duby, R. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+ Handling
The contractile function of skeletal muscle declines during intense or prolonged physical exercise, that is, fatigue develops. Skeletal muscle fibers fatigue acutely during highly intense exercise when they have to rely on anaerobic metabolism. Early stages of fatigue involve impaired myofibrillar function, whereas decreased Ca2+ release from the sarcoplasmic reticulum (SR) becomes more important in later stages. SR Ca2+ release can also become reduced with more prolonged, lower intensity exercise, and it is then related to glycogen depletion. Increased reactive oxygen/nitrogen species can cause long-lasting impairments in...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Cheng, A. J., Place, N., Westerblad, H. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[TECHNIQUES] Observing Clonal Dynamics across Spatiotemporal Axes: A Prelude to Quantitative Fitness Models for Cancer
The ability to accurately model evolutionary dynamics in cancer would allow for prediction of progression and response to therapy. As a prelude to quantitative understanding of evolutionary dynamics, researchers must gather observations of in vivo tumor evolution. High-throughput genome sequencing now provides the means to profile the mutational content of evolving tumor clones from patient biopsies. Together with the development of models of tumor evolution, reconstructing evolutionary histories of individual tumors generates hypotheses about the dynamics of evolution that produced the observed clones. In this review, we ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: McPherson, A. W., Chan, F. C., Shah, S. P. Tags: Cancer Evolution TECHNIQUES Source Type: research

[PERSPECTIVES] Microglial Phenotypes and Functions in Multiple Sclerosis
Microglia are the resident immune cells that constantly survey the central nervous system. They can adapt to their environment and respond to injury or insult by altering their morphology, phenotype, and functions. It has long been debated whether microglial activation is detrimental or beneficial in multiple sclerosis (MS). Recently, the two opposing yet connected roles of microglial activation have been described with the aid of novel microglial markers, RNA profiling, and in vivo models. In this review, microglial phenotypes and functions in the context of MS will be discussed with evidence from both human pathological ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: OLoughlin, E., Madore, C., Lassmann, H., Butovsky, O. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Historical Perspective and Future Direction of Blood Vessel Developments
Over the past 40 years, remarkable advances have been made in our understanding of successful blood vessel regeneration, starting with the failures of early tissue-engineered vascular grafts designed using isolated components or molecules, such as collagen gels. The vascular tissue engineers are today better educated and have steered ongoing research developments toward clinical developments of more complete vascular grafts that replicate the multitude of specialized arterial aspects required for function. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Dimitrievska, S., Niklason, L. E. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[TECHNIQUES] Three-Dimensional Bioprinting Strategies for Tissue Engineering
Over the past decades, many approaches have been developed to fabricate biomimetic extracellular matrices of desired properties for engineering functional tissues. However, the inability of these techniques to precisely control the spatial architecture has posed a significant challenge in producing complex tissues. 3D bioprinting technology has emerged as a potential solution by bringing unprecedented freedom and versatility in depositing biological materials and cells in a well-controlled manner in the 3D volumes, therefore achieving precision engineering of functional tissues. In this article, we review the application o...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Zhang, Y. S., Oklu, R., Dokmeci, M. R., Khademhosseini, A. Tags: Tissue Engineering and Regenerative Medicine TECHNIQUES Source Type: research

[PERSPECTIVES] Prion-Like Characteristics of Polyglutamine-Containing Proteins
Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by the conversion of prion protein (PrP) into a self-replicating conformation that spreads via templated conversion of natively folded PrP molecules within or between cells. Recent studies provide compelling evidence that prion-like behavior is a general property of most protein aggregates associated with neurodegenerative diseases. Many of these disorders are associated with spontaneous protein aggregation, but genetic mutations can increase the aggregation propensity of specific proteins, including expansion of polyglutamine (polyQ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Pearce, M. M. P., Kopito, R. R. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Chronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation?
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. There is often a long latency period between an individual’s exposure to repetitive brain trauma and the clinical symptoms of CTE. The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebr...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2018 Category: Research Authors: Kriegel, J., Papadopoulos, Z., McKee, A. C. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Regulation of Bone Metabolism by Sex Steroids
Osteoporosis is a significant public health problem, and a major cause of the disease is estrogen deficiency following menopause in women. In addition, considerable evidence now shows that estrogen is also a major regulator of bone metabolism in men. Since the original description of the effects of estrogen deficiency on bone by Fuller Albright more than 70 years ago, there has been enormous progress in understanding the mechanisms of estrogen and testosterone action on bone using human and mouse models. Although we understand more about the effects of estrogen on bone as compared with testosterone, both sex steroids do pl...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Khosla, S., Monroe, D. G. Tags: Bone: A Regulator of Physiology PERSPECTIVES Source Type: research

[PERSPECTIVES] Theoretical and Biological Evaluation of the Link between Low Exercise Capacity and Disease Risk
Large-scale epidemiological studies show that low exercise capacity is the highest risk factor for all-cause morbidity and mortality relative to other conditions including diabetes, hypertension, and obesity. This led us to formulate the energy transfer hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As a test of this hypothesis, we predicted that two-way selective breeding of genetically heterogeneous rats for low and high intrinsic treadmill running capacity (a surrogate for energy transfer) would also produce rats that differ fo...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Koch, L. G., Britton, S. L. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] The Interleukin (IL)-23/T helper (Th)17 Axis in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
T helper (Th)17 cells are responsible for host defense against fungi and certain extracellular bacteria but have also been reported to play a role in a variety of autoimmune diseases. Th17 cells respond to environmental cues, are very plastic, and might also be involved in tissue homeostasis and regeneration. The imprinting of pathogenic properties in Th17 cells in autoimmunity seems highly dependent on interleukin (IL)-23. Since Th17 cells were first described in experimental autoimmune encephalomyelitis, they have been suggested to also promote tissue damage in multiple sclerosis (MS). Indeed, some studies linked Th17 ce...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Hiltensperger, M., Korn, T. Tags: Multiple Sclerosis PERSPECTIVES Source Type: research

[PERSPECTIVES] The "Achilles' Heel" of Cancer and Its Implications for the Development of Novel Immunotherapeutic Strategies
Over the last century, scientists have embraced the idea of mobilizing antitumor immune responses in patients with cancer. In the last decade, we have seen the rebirth of cancer immunotherapy and its validation in a series of high profile clinical trials following the discovery of several immune-regulatory receptors. Recent studies point toward the tumor mutational load and resulting neoantigen burden as being crucial to tumor cell recognition by the immune system, highlighting a potentially targetable Achilles' heel in cancer. In this review, we explore the key mechanisms that underpin the recognition of cancerous cells b...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Joshi, K., Chain, B. M., Peggs, K. S., Quezada, S. A. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[PERSPECTIVES] Craniofacial Tissue Engineering
The craniofacial complex is composed of fundamental components such as blood vessels and nerves, and also a variety of specialized tissues such as craniofacial bones, cartilages, muscles, ligaments, and the highly specialized and unique organs, the teeth. Together, these structures provide many functions including speech, mastication, and aesthetics of the craniofacial complex. Craniofacial defects not only influence the structure and function of the jaws and face, but may also result in deleterious psychosocial issues, emphasizing the need for rapid and effective, precise, and aesthetic reconstruction of craniofacial tiss...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Zhang, W., Yelick, P. C. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Modern Vector Control
The rapid spread of mosquito resistance to currently available insecticides, and the current lack of an efficacious malaria vaccine are among many challenges that affect large-scale efforts for malaria control. As goals of malaria elimination and eradication are put forth, new vector-control paradigms and tools and/or further optimization of current vector-control products are required to meet public health demands. Vector control remains the most effective measure to prevent malaria transmission and present gains against malaria mortality and morbidity may be maintained as long as vector-intervention strategies are sustai...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Lobo, N. F., Achee, N. L., Greico, J., Collins, F. H. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Malaria Pathogenesis
In the mosquito–human life cycle, the six species of malaria parasites infecting humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 106 organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Milner, D. A. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Therapeutic Strategies for Restoring Tau Homeostasis
Normal tau homeostasis is achieved when the synthesis, processing, and degradation of the protein is balanced. Together, the pathways that regulate tau homeostasis ensure that the protein is at the proper levels and that its posttranslational modifications and subcellular localization are appropriately controlled. These pathways include the enzymes responsible for posttranslational modifications, those systems that regulate mRNA splicing, and the molecular chaperones that control tau turnover and its binding to microtubules. In tauopathies, this delicate balance is disturbed. Tau becomes abnormally modified by posttranslat...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Young, Z. T., Mok, S. A., Gestwicki, J. E. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission
More than 30 proteins form amyloid in humans, most of them outside of the brain. Deposition of amyloid in extracerebral tissues is very common and seems inevitable for an aging person. Most deposits are localized, small, and probably without consequence, but in some instances, they are associated with diseases such as type 2 diabetes. Other extracerebral amyloidoses are systemic, with life-threatening effects on the heart, kidneys, and other organs. Here, we review how amyloid may spread through seeding and whether transmission of amyloid diseases may occur between humans. We also discuss whether cross-seeding is important...
Source: Cold Spring Harbor perspectives in medicine - January 2, 2018 Category: Research Authors: Westermark, G. T., Fändrich, M., Lundmark, K., Westermark, P. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of MicroRNAs in the Cardiac Response to Exercise
Noncoding microRNAs (miRNAs) have emerged as central regulators of cardiac biology, modulating cardiac development and the response to pathological stress in disease. Although less well developed, emerging evidence suggests miRNAs are likely also important in the heart’s response to the physiological stress of exercise. Given the well-recognized cardiovascular benefits of exercise, elucidating the contribution of miRNAs to this response has the potential not only to reveal novel aspects of cardiovascular biology but also to identify new targets for therapeutic intervention that may complement those discovered through...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Liu, X., Platt, C., Rosenzweig, A. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Evolution of Premalignant Disease
We describe the hurdles of prognosticating cancer risk in premalignant disease by making reference to the underlying continuous and multivariate natures of genotypes and phenotypes and the particular challenge inherent in defining a cell lineage as "cancerized." (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Curtius, K., Wright, N. A., Graham, T. A. Tags: Cancer Evolution PERSPECTIVES Source Type: research

[TECHNIQUE] Honing Cell and Tissue Culture Conditions for Bone and Cartilage Tissue Engineering
An avenue of tremendous interest and need in health care encompasses the regeneration of bone and cartilage. Over the years, numerous tissue engineering strategies have contributed substantial progress toward the realization of clinically relevant therapies. Cell and tissue culture protocols, however, show many variations that make experimental results among different publications challenging to compare. This collection surveys prevalent cell sources, soluble factors, culture medium formulations, environmental factors, and genetic modification approaches in the literature. The intent of consolidating this information is to...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Lam, J., Lee, E. J., Clark, E. C., Mikos, A. G. Tags: Tissue Engineering and Regenerative Medicine TECHNIQUE Source Type: research

[PERSPECTIVES] Anopheline Reproductive Biology: Impacts on Vectorial Capacity and Potential Avenues for Malaria Control
Vectorial capacity is a mathematical approximation of the efficiency of vector-borne disease transmission, measured as the number of new infections disseminated per case per day by an insect vector. Multiple elements of mosquito biology govern their vectorial capacity, including survival, population densities, feeding preferences, and vector competence. Intriguingly, biological pathways essential to mosquito reproductive fitness directly or indirectly influence a number of these elements. Here, we explore this complex interaction, focusing on how the interplay between mating and blood feeding in female Anopheles not only s...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Mitchell, S. N., Catteruccia, F. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Determinants of Malaria Transmission at the Population Level
Transmission of malaria from man to mosquito defines the human infectious reservoir of malaria. At the population level this is influenced by a variety of human, parasite, and mosquito vector factors some or all of which may vary depending on the epidemiological setting. Here, we review our current state of knowledge related to human infectiousness to mosquitoes and how current malaria control strategies might be adapted to focus on reducing this. While much progress has been made in malaria control, we argue that an improved understanding of human infectivity will allow more effective use of current control tools and make...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Bousema, T., Drakeley, C. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Fused in Sarcoma Neuropathology in Neurodegenerative Disease
Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms. (Source...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Mackenzie, I. R. A., Neumann, M. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Structural and Chemical Biology of Presenilin Complexes
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the , , site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several confor...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2017 Category: Research Authors: Johnson, D. S., Li, Y.-M., Pettersson, M., St George-Hyslop, P. H. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations
Exercise stimulates the release of proteins with autocrine, paracrine, or endocrine functions produced in skeletal muscle, termed myokines. Based on the current state of knowledge, the major physiological function of myokines is to protect the functionality and to enhance the exercise capacity of skeletal muscle. Myokines control adaptive processes in skeletal muscle by acting as paracrine regulators of fuel oxidation, hypertrophy, angiogenesis, inflammatory processes, and regulation of the extracellular matrix. Endocrine functions attributed to myokines are involved in body weight regulation, low-grade inflammation, insul...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Hoffmann, C., Weigert, C. Tags: The Biology of Exercise PERSPECTIVES Source Type: research

[PERSPECTIVES] Experimental Models of Inherited PrP Prion Diseases
The inherited prion protein (PrP) prion disorders, which include familial Creutzfeldt–Jakob disease, Gerstmann–Stra╠łussler–Scheinker disease, and fatal familial insomnia, constitute ~10%–15% of all PrP prion disease cases in humans. Attempts to generate animal models of these disorders using transgenic mice expressing mutant PrP have produced variable results. Although many lines of mice develop spontaneous signs of neurological illness with accompanying prion disease–specific neuropathological changes, others do not. Furthermore, demonstrating the presence of protease-resistant PrP species a...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Watts, J. C., Prusiner, S. B. Tags: Prion Diseases PERSPECTIVES Source Type: research

[PERSPECTIVES] Current and Future Prospects for Preventing Malaria Transmission via the Use of Insecticides
Malaria vectors have developed resistance to all classes of insecticides that are used to target the adult mosquito to prevent parasite transmission. The number of resistant mosquito populations has increased dramatically in recent years, most likely as a result of the scale-up of vector control activities, and the intensity of this resistance is increasing rapidly and compromising the performance of vector control tools. Bednets and indoor residual spray formulations containing alternative active ingredients have shown promise in field trials but are still several years away from implementation. As existing insecticides b...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Ranson, H. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia
Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associ...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Krivtsov, A. V., Hoshii, T., Armstrong, S. A. Tags: Chromatin Deregulation in Cancer PERSPECTIVES Source Type: research

[PERSPECTIVES] The Self-Assembling Process and Applications in Tissue Engineering
Tissue engineering strives to create neotissues capable of restoring function. Scaffold-free technologies have emerged that can recapitulate native tissue function without the use of an exogenous scaffold. This review will survey, in particular, the self-assembling and self-organization processes as scaffold-free techniques. Characteristics and benefits of each process are described, and key examples of tissues created using these scaffold-free processes are examined to provide guidance for future tissue-engineering developments. We aim to explore the potential of self-assembly and self-organization scaffold-free approache...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Lee, J. K., Link, J. M., Hu, J. C. Y., Athanasiou, K. A. Tags: Tissue Engineering and Regenerative Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Host Cell Tropism and Adaptation of Blood-Stage Malaria Parasites: Challenges for Malaria Elimination
Plasmodium falciparum and Plasmodium vivax account for most of the mortality and morbidity associated with malaria in humans. Research and control efforts have focused on infections caused by P. falciparum and P. vivax, but have neglected other malaria parasite species that infect humans. Additionally, many related malaria parasite species infect nonhuman primates (NHPs), and have the potential for transmission to humans. For malaria elimination, the varied and specific challenges of all of these Plasmodium species will need to be considered. Recent advances in molecular genetics and genomics have increased our knowledge o...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Lim, C., Dankwa, S., Paul, A. S., Duraisingh, M. T. Tags: Malaria: Biology in the Era of Eradication PERSPECTIVES Source Type: research

[PERSPECTIVES] Biological Spectrum of Amyotrophic Lateral Sclerosis Prions
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, the...
Source: Cold Spring Harbor perspectives in medicine - November 1, 2017 Category: Research Authors: Polymenidou, M., Cleveland, D. W. Tags: Prion Diseases PERSPECTIVES Source Type: research