One-fourth of all deaths in industrialized countries result from coronary heart disease. A century of research has revealed the essential causative agent: cholesterol-carrying low-density lipoprotein ...(LDL). LDL is controlled by specific receptors (LDLRs) in liver that remove it from blood. Mutations that eliminate LDLRs raise LDL and cause heart attacks in childhood, whereas mutations that raise LDLRs reduce LDL and diminish heart attacks. If we are to eliminate coronary disease, lowering LDL should be the primary goal. Effective means to achieve this goal are currently available. The key questions are: who to treat, when to treat, and how long to treat.
Nobel laureates Joe Goldstein and Mike Brown revisit a century of cholesterol research and discuss the causative role of cholesterol-carrying LDL in coronary heart disease. As effective means to decrease LDL levels are currently available, the key questions become who to treat, when to treat, and how long to treat.
Epidemiologic studies, including prospective birth cohort investigations, have implicated maternal immune activation in the etiology of neuropsychiatric disorders. Maternal infectious pathogens and ...inflammation are plausible risk factors for these outcomes and have been associated with schizophrenia, autism spectrum disorder, and bipolar disorder. Concurrent with epidemiologic research are animal models of prenatal immune activation, which have documented behavioral, neurochemical, neuroanatomic, and neurophysiologic disruptions that mirror phenotypes observed in these neuropsychiatric disorders. Epidemiologic studies of maternal immune activation offer the advantage of directly evaluating human populations but are limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between maternal immune activation and neuropsychiatric phenotypes. Incorporating these risk factors in reverse translational animal models of maternal immune activation has yielded a wealth of data supporting the predictive potential of epidemiologic studies. To further enhance the translatability between epidemiology and basic science, the authors propose a complementary approach that includes deconstructing neuropsychiatric outcomes of maternal immune activation into key pathophysiologically defined phenotypes that are identifiable in humans and animals and that evaluate the interspecies concordance regarding interactions between maternal immune activation and genetic and epigenetic factors, including processes involving intergenerational disease transmission. AJP AT 175: Remembering Our Past As We Envision Our Future October 1857: The Pathology of Insanity J.C. Bucknill: "In the brain the state of inflammation itself either very quickly ceases or very soon causes death; but when it does cease it leaves behind it consequences which are frequently the causes of insanity, and the conditions of cerebral atrophy." (Am J Psychiatry 1857; 14:172-193 ).
Resistance to insecticides and herbicides has cost billions of U.S. dollars in the agricultural sector and could result in millions of lives lost to insect-vectored diseases. We mostly continue to ...use pesticides as if resistance is a temporary issue that will be addressed by commercialization of new pesticides with novel modes of action. However, current evidence suggests that insect and weed evolution may outstrip our ability to replace outmoded chemicals and other control mechanisms. To avoid this outcome, we must address the mix of ecological, genetic, economic, and sociopolitical factors that prevent implementation of sustainable pest management practices. We offer an ambitious proposition.
Since the days of silent films, music has been integral to the
cinematic experience, serving, variously, to allay audiences' fears
of the dark and to heighten a film's emotional impact. Yet viewers
...are often unaware of its presence. In this bold, insightful book,
film and music scholar and critic Royal S. Brown invites readers
not only to "hear" the film score, but to understand it in relation
to what they "see." Unlike earlier books, which offered historical,
technical, and sociopolitical analyses, Overtones and
Undertones draws on film, music, and narrative theory to
provide the first comprehensive aesthetics of film music. Focusing
on how the film/score interaction influences our response to
cinematic situations, Brown traces the history of film music from
its beginnings, covering both American and European cinema. At the
heart of his book are close readings of several of the best
film/score interactions, including Psycho, Laura, The Sea Hawk,
Double Indemnity, and Pierrot le Fou. In revealing
interviews with Bernard Herrmann, Miklós Rósza, Henry Mancini, and
others, Brown also allows the composers to speak for themselves. A
complete discography and bibliography conclude the volume.
In the last twenty years, our understanding of the rules and mechanisms for the outward light-driven proton transport (and underlying proton transfers) by microbial rhodopsins has been changing ...dramatically. It transitioned from a very detailed atomic-level understanding of proton transport by bacteriorhodopsin, the prototypical proton pump, to a confounding variety of sequence motifs, mechanisms, directions, and modes of transport in its newly found homologs. In this review, we will summarize and discuss experimental data obtained on new microbial rhodopsin variants, highlighting their contribution to the refinement and generalization of the ideas crystallized in the previous century. In particular, we will focus on the proton transport (and transfers) vectoriality and their structural determinants, which, in many cases, remain unidentified.
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•Modes and mechanisms of proton transport by microbial rhodopsins are reviewed.•The detailed proton transport model by bacteriorhodopsin is enriched by new data.•Outward and inward proton pumping mechanisms are contrasted.
Scap is a polytopic membrane protein that functions as a molecular machine to control the cholesterol content of membranes in mammalian cells. In the 21 years since our laboratory discovered Scap, we ...have learned how it binds sterol regulatory element-binding proteins (SREBPs) and transports them from the endoplasmic reticulum (ER) to the Golgi for proteolytic processing. Proteolysis releases the SREBP transcription factor domains, which enter the nucleus to promote cholesterol synthesis and uptake. When cholesterol in ER membranes exceeds a threshold, the sterol binds to Scap, triggering several conformational changes that prevent the Scap-SREBP complex from leaving the ER. As a result, SREBPs are no longer processed, cholesterol synthesis and uptake are repressed, and cholesterol homeostasis is restored. This review focuses on the four domains of Scap that undergo concerted conformational changes in response to cholesterol binding. The data provide a molecular mechanism for the control of lipids in cell membranes.
All of life is a game, and evolution by natural selection is no exception. The evolutionary game theory developed in this 2005 book provides the tools necessary for understanding many of nature's ...mysteries, including co-evolution, speciation, extinction and the major biological questions regarding fit of form and function, diversity, procession, and the distribution and abundance of life. Mathematics for the evolutionary game are developed based on Darwin's postulates leading to the concept of a fitness generating function (G-function). G-function is a tool that simplifies notation and plays an important role developing Darwinian dynamics that drive natural selection. Natural selection may result in special outcomes such as the evolutionarily stable strategy (ESS). An ESS maximum principle is formulated and its graphical representation as an adaptive landscape illuminates concepts such as adaptation, Fisher's Fundamental Theorem of Natural Selection, and the nature of life's evolutionary game.
To maintain optimal fitness, a cell must balance the risk of inadequate energy reserve for response to a potentially fatal perturbation against the long-term cost of maintaining high concentrations ...of ATP to meet occasional spikes in demand. Here we apply a game theoretic approach to address the dynamics of energy production and expenditure in eukaryotic cells. Conventionally, glucose metabolism is viewed as a function of oxygen concentrations in which the more efficient oxidation of glucose to CO2 and H2O produces all or nearly all ATP except under hypoxic conditions when less efficient (2 ATP/ glucose vs. about 36ATP/glucose) anaerobic metabolism of glucose to lactic acid provides an emergency backup. We propose an alternative in which energy production is governed by the complex temporal and spatial dynamics of intracellular ATP demand. In the short term, a cell must provide energy for constant baseline needs but also maintain capacity to rapidly respond to fluxes in demand particularly due to external perturbations on the cell membrane. Similarly, longer-term dynamics require a trade-off between the cost of maintaining high metabolic capacity to meet uncommon spikes in demand versus the risk of unsuccessfully responding to threats or opportunities. Here we develop a model and computationally explore the cell's optimal mix of glycolytic and oxidative capacity. We find the Warburg effect, high glycolytic metabolism even under normoxic conditions, is represents a metabolic strategy that allow cancer cells to optimally meet energy demands posed by stochastic or fluctuating tumor environments.
Accumulating evidence suggests that prenatal exposure to infection contributes to the etiology of schizophrenia. This line of investigation has been advanced by birth cohort studies that utilize ...prospectively acquired data from serologic assays for infectious and immune biomarkers. These investigations have provided further support for this hypothesis and permitted the investigation of new infectious pathogens in relation to schizophrenia risk. Prenatal infections that have been associated with schizophrenia include rubella, influenza, and toxoplasmosis. Maternal cytokines, including interleukin-8, are also significantly increased in pregnancies giving rise to schizophrenia cases. Although replication of these findings is required, this body of work may ultimately have important implications for the prevention of schizophrenia, the elaboration of pathogenic mechanisms in this disorder, and investigations of gene-environment interactions.
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