Accurate and reliable forecasts of seasonal epidemics of infectious disease can assist in the design of countermeasures and increase public awareness and preparedness. This article describes two main ...contributions we made recently toward this goal: a novel approach to probabilistic modeling of surveillance time series based on "delta densities", and an optimization scheme for combining output from multiple forecasting methods into an adaptively weighted ensemble. Delta densities describe the probability distribution of the change between one observation and the next, conditioned on available data; chaining together nonparametric estimates of these distributions yields a model for an entire trajectory. Corresponding distributional forecasts cover more observed events than alternatives that treat the whole season as a unit, and improve upon multiple evaluation metrics when extracting key targets of interest to public health officials. Adaptively weighted ensembles integrate the results of multiple forecasting methods, such as delta density, using weights that can change from situation to situation. We treat selection of optimal weightings across forecasting methods as a separate estimation task, and describe an estimation procedure based on optimizing cross-validation performance. We consider some details of the data generation process, including data revisions and holiday effects, both in the construction of these forecasting methods and when performing retrospective evaluation. The delta density method and an adaptively weighted ensemble of other forecasting methods each improve significantly on the next best ensemble component when applied separately, and achieve even better cross-validated performance when used in conjunction. We submitted real-time forecasts based on these contributions as part of CDC's 2015/2016 FluSight Collaborative Comparison. Among the fourteen submissions that season, this system was ranked by CDC as the most accurate.
Does nuclear superiority offer states political or military benefits? And do those benefits accrue beyond acquiring a secure second-strike capability? International relations theory has long held ...that nuclear superiority does not confer significant advantages, a conclusion supported by much of the qualitative literature on bargaining and crisis interactions between nuclear-armed states. New work by scholars using statistical methods to analyze data on nuclear crises, interstate disputes, and compellent threats has sought to answer these questions, producing conflicting results. Despite the contributions of these recent works, this line of research has assumed that warhead counts are an appropriate measure of nuclear capabilities and that states possess accurate information about the material balance. Instead, states use multiple quantitative and qualitative characteristics to evaluate the nuclear balance, and they often have inaccurate or incomplete information about the
size, composition, and configuration of other states' nuclear forces. Using new data, replications of two prominent recent works show that results are sensitive to how the nuclear balance is operationalized. Drawing on archival and interview data from the United States and the Soviet Union during the Cold War, findings show how states and leaders often understand and respond to the nuclear balance in inconsistent, asymmetric, and subjective ways.
Late embryogenesis abundant (LEA) proteins are hydrophilic, mostly intrinsically disordered proteins, which play major roles in desiccation tolerance. In Arabidopsis thaliana, 51 genes encoding LEA ...proteins clustered into nine families have been inventoried. To increase our understanding of the yet enigmatic functions of these gene families, we report the subcellular location of each protein. Experimental data highlight the limits of in silico predictions for analysis of subcellular localization. Thirty-six LEA proteins localized to the cytosol, with most being able to diffuse into the nucleus. Three proteins were exclusively localized in plastids or mitochondria, while two others were found dually targeted to these organelles. Targeting cleavage sites could be determined for five of these proteins. Three proteins were found to be endoplasmic reticulum (ER) residents, two were vacuolar, and two were secreted. A single protein was identified in pexophagosomes. While most LEA protein families have a unique subcellular localization, members of the LEA_ 4 family are widely distributed (cytosol, mitochondria, plastid, ER, and pexophagosome) but share the presence of the class A α-helix motif. They are thus expected to establish interactions with various cellular membranes under stress conditions. The broad subcellular distribution of LEA proteins highlights the requirement for each cellular compartment to be provided with protective mechanisms to cope with desiccation or cold stress.
Seed germination is a vital developmental transition for production of progeny by sexual reproduction in spermatophytes. Quiescent cells in nondormant dry embryos are reawakened first by imbibition ...and then by perception of germination triggers. Reanimated tissues enter into a germination program requiring energy for expansion growth. However, germination requires that embryonic tissues develop to support the more energy-demanding processes of cell division and organogenesis of the new seedling. Reactivation of mitochondria to supply the required energy is thus a key process underpinning germination and seedling survival. Using live imaging, we investigated reactivation of mitochondrial bioenergetics and dynamics using Arabidopsis thaliana as a model. Bioenergetic reactivation, visualized by presence of a membrane potential, is immediate upon rehydration. However, reactivation of mitochondrial dynamics only occurs after transfer to germination conditions. Reactivation of mitochondrial bioenergetics is followed by dramatic reorganization of the chondriome (all mitochondrial in a cell, collectively) involving massive fusion and membrane biogenesis to form a perinuclear tubuloreticular structure enabling mixing of previously discrete mitochondrial DNA nucleoids. The end of germination coincides with fragmentation of the chondriome, doubling of mitochondrial number, and heterogeneous redistribution of nucleoids among the mitochondria, generating a population of mitochondria tailored to seedling growth.
Experts increasingly highlight the dangers of nuclear-conventional entanglement, particularly in the U.S.-China context. This article develops a framework for assessing entanglement and its risks. ...Applying that framework to China, it finds that Beijing's missiles are not as entangled as is sometimes feared, but ongoing trends may increase future entanglement. It also presents evidence that, counter to the prevailing wisdom, Chinese entanglement has not emerged as a strategic policy choice but, rather, as the byproduct of more parochial organizational dynamics. Strategic signaling and perception management will be key to controlling escalation risks stemming from nuclear-conventional entanglement in China.
Seasonal influenza epidemics cause consistent, considerable, widespread loss annually in terms of economic burden, morbidity, and mortality. With access to accurate and reliable forecasts of a ...current or upcoming influenza epidemic's behavior, policy makers can design and implement more effective countermeasures. This past year, the Centers for Disease Control and Prevention hosted the "Predict the Influenza Season Challenge", with the task of predicting key epidemiological measures for the 2013-2014 U.S. influenza season with the help of digital surveillance data. We developed a framework for in-season forecasts of epidemics using a semiparametric Empirical Bayes framework, and applied it to predict the weekly percentage of outpatient doctors visits for influenza-like illness, and the season onset, duration, peak time, and peak height, with and without using Google Flu Trends data. Previous work on epidemic modeling has focused on developing mechanistic models of disease behavior and applying time series tools to explain historical data. However, tailoring these models to certain types of surveillance data can be challenging, and overly complex models with many parameters can compromise forecasting ability. Our approach instead produces possibilities for the epidemic curve of the season of interest using modified versions of data from previous seasons, allowing for reasonable variations in the timing, pace, and intensity of the seasonal epidemics, as well as noise in observations. Since the framework does not make strict domain-specific assumptions, it can easily be applied to some other diseases with seasonal epidemics. This method produces a complete posterior distribution over epidemic curves, rather than, for example, solely point predictions of forecasting targets. We report prospective influenza-like-illness forecasts made for the 2013-2014 U.S. influenza season, and compare the framework's cross-validated prediction error on historical data to that of a variety of simpler baseline predictors.
Key points
Mice are commonly housed at room temperatures below their thermoneutral zone meaning they are exposed to chronic thermal stress.
Endurance exercise induces browning and mitochondrial ...biogenesis in white adipose tissue of rodents, but there are conflicting reports of this phenomenon in humans.
We hypothesized that the ambient room temperature at which mice are housed could partially explain these discrepant reports between humans and rodents.
We housed mice at room temperature or thermoneutrality and studied their physiological responses to acute and chronic exercise. We found that thermoneutral housing altered running behaviour and glucose homeostasis, and further, that exercise‐induced markers of mitochondrial biogenesis and the browning of white adipose tissue were reduced in mice housed at thermoneutrality.
Mice are often housed at temperatures below their thermoneutral zone resulting in compensatory increases in thermogenesis. Despite this, many studies report housing mice at room temperature (RT), likely for the convenience of the researchers studying them. As such, the conflicting reports between humans and rodents regarding the ability of exercise to increase mitochondrial and thermogenic markers in white adipose tissue may be explained by the often‐overlooked variable, housing temperature. To test this hypothesis, we housed male C57BL/6 mice at RT (22°C) or thermoneutrality (TN) (29°C) with or without access to a voluntary running wheel for 6 weeks or subjected them to an acute exhaustive bout of treadmill running. We examined the gene expression and protein content of select mitochondrial and thermogenic markers in skeletal muscle, epididymal white adipose tissue (eWAT), inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). We also assessed adipocyte morphology and indices of glucose homeostasis. Housing temperature influenced glucose tolerance and insulin action in vivo, yet the beneficial effects of exercise, both acute and chronic, remained intact in eWAT, BAT and skeletal muscle irrespective of housing temperature. Housing mice at TN led to an attenuation of some of the effects of exercise on iWAT. Collectively, we present data characterizing the acute and chronic metabolic adaptations to exercise at different housing temperatures and demonstrate, for the first time, that temperature influences the ability of exercise to increase markers of mitochondrial biogenesis and the browning of white adipose tissue.
Key points
Mice are commonly housed at room temperatures below their thermoneutral zone meaning they are exposed to chronic thermal stress.
Endurance exercise induces browning and mitochondrial biogenesis in white adipose tissue of rodents, but there are conflicting reports of this phenomenon in humans.
We hypothesized that the ambient room temperature at which mice are housed could partially explain these discrepant reports between humans and rodents.
We housed mice at room temperature or thermoneutrality and studied their physiological responses to acute and chronic exercise. We found that thermoneutral housing altered running behaviour and glucose homeostasis, and further, that exercise‐induced markers of mitochondrial biogenesis and the browning of white adipose tissue were reduced in mice housed at thermoneutrality.
Mitochondria are involved in many fundamental processes underpinning plant growth, development and death. Owing to their multiple roles, as the sites of the tricarboxylic acid cycle and oxidative ...phosphorylation, as harbourers of their own genomes and as sensors of cell redox status, amongst others, mitochondria are in a unique position to act as sentinels of cell physiology. The plant chondriome is typically organized as a population of physically discrete organelles, but visualization of mitochondria in living tissues has shown that the mitochondrial population is highly interactive. Mitochondria are highly motile and movement on the cytoskeleton ensures that the physically discrete organelles come into contact with one another, which allows transient fusion, followed by division of the mitochondrial membranes. This article serves to review our current knowledge of mitochondrial fusion and division, and link this to recent discoveries regarding a putative mitochondrial 'health-check' and repair process, whereby non-repairable dysfunctional mitochondria can be removed from the chondriome. It is proposed that the unequal distribution of the multipartite plant mitochondrial genome between discrete organelles provides the driver for transient mitochondrial fusion that, in turn, is dependent on mitochondrial motility, and that both fusion and motility are necessary to maintain a healthy functional chondriome.
Infectious diseases impose considerable burden on society, despite significant advances in technology and medicine over the past century. Advanced warning can be helpful in mitigating and preparing ...for an impending or ongoing epidemic. Historically, such a capability has lagged for many reasons, including in particular the uncertainty in the current state of the system and in the understanding of the processes that drive epidemic trajectories. Presently we have access to data, models, and computational resources that enable the development of epidemiological forecasting systems. Indeed, several recent challenges hosted by the U.S. government have fostered an open and collaborative environment for the development of these technologies. The primary focus of these challenges has been to develop statistical and computational methods for epidemiological forecasting, but here we consider a serious alternative based on collective human judgment. We created the web-based "Epicast" forecasting system which collects and aggregates epidemic predictions made in real-time by human participants, and with these forecasts we ask two questions: how accurate is human judgment, and how do these forecasts compare to their more computational, data-driven alternatives? To address the former, we assess by a variety of metrics how accurately humans are able to predict influenza and chikungunya trajectories. As for the latter, we show that real-time, combined human predictions of the 2014-2015 and 2015-2016 U.S. flu seasons are often more accurate than the same predictions made by several statistical systems, especially for short-term targets. We conclude that there is valuable predictive power in collective human judgment, and we discuss the benefits and drawbacks of this approach.
Abstract
The world population is aging, leading to increased rates of neurodegenerative disorders. Exercise has countless health benefits and has consistently been shown to improve brain health and ...cognitive function. The purpose of this review is to provide an overview of exercise-induced adaptations in the brain with a focus on crosstalk between peripheral tissues and the brain. We highlight recent investigations into exercise-induced circulating factors, or exerkines, including irisin, cathepsin B, GPLD1, and ketones and the mechanisms mediating their effects in the brain.
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