Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic ...approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs.
The world's population will reach 10.4 billion in 2067, with 81% residing in Africa or Asia. Arable land available for food production will decrease to 0.15 ha per person. Temperature will increase ...in tropical and temperate zones, especially in the Northern Hemisphere, and this will push growing seasons and dairy farming away from arid areas and into more northern latitudes. Dairy consumption will increase because it provides essential nutrients more efficiently than many other agricultural systems. Dairy farming will become modernized in developing countries and milk production per cow will increase, doubling in countries with advanced dairying systems. Profitability of dairy farms will be the key to their sustainability. Genetic improvements will include emphasis on the coding genome and associated noncoding epigenome of cattle, and on microbiomes of dairy cattle and farmsteads. Farm sizes will increase and there will be greater lateral integration of housing and management of dairy cattle of different ages and production stages. Integrated sensors, robotics, and automation will replace much of the manual labor on farms. Managing the epigenome and microbiome will become part of routine herd management. Innovations in dairy facilities will improve the health of cows and permit expression of natural behaviors. Herds will be viewed as superorganisms, and studies of herds as observational units will lead to improvements in productivity, health, and well-being of dairy cattle, and improve the agroecology and sustainability of dairy farms. Dairy farmers in 2067 will meet the world's needs for essential nutrients by adopting technologies and practices that provide improved cow health and longevity, profitable dairy farms, and sustainable agriculture.
We report the results of a search for neutrinoless double-beta decay in a 9.8 kg yr exposure of Te-130 using a bolometric detector array, CUORE-0. The characteristic detector energy resolution and ...background level in the region of interest are 5.1 +/- 0.3 keV FWHM and 0.058 +/- 0.004(stat) +/- 0.002(syst)counts/(keV kg yr), respectively. The median 90% C.L. lower-limit half-life sensitivity of the experiment is 2.9 x 10(24) yr and surpasses the sensitivity of previous searches. We find no evidence for neutrinoless double-beta decay of Te-130 and place a Bayesian lower bound on the decay half-life, T-1/2(0 nu) > 2.7 x 10(24) yr at 90% C.L. Combining CUORE-0 data with the 19.75 kg yr exposure of Te-130 from the Cuoricino experiment we obtain T-1/2(0 nu) > 4.0 x 10(24) yr at 90% C.L. (Bayesian), the most stringent limit to date on this half-life. Using a range of nuclear matrix element estimates we interpret this as a limit on the effective Majorana neutrino mass, m beta beta < 270-760 meV.
The molecular basis underlying fetal programming in response to maternal nutrition remains unclear. Herein, we investigated the regulatory relationships between genes in fetal cerebrum, liver, and ...muscle tissues to shed light on the putative mechanisms that underlie the effects of early maternal nutrient restriction on bovine developmental programming. To this end, cerebrum, liver, and muscle gene expression were measured with RNA-Seq in 14 fetuses collected on day 50 of gestation from dams fed a diet initiated at breeding to either achieve 60% (RES, n = 7) or 100% (CON, n = 7) of energy requirements. To build a tissue-to-tissue gene network, we prioritized tissue-specific genes, transcription factors, and differentially expressed genes. Furthermore, we built condition-specific networks to identify differentially co-expressed or connected genes. Nutrient restriction led to differential tissue regulation between the treatments. Myogenic factors differentially regulated by ZBTB33 and ZNF131 may negatively affect myogenesis. Additionally, nutrient-sensing pathways, such as mTOR and PI3K/Akt, were affected by gene expression changes in response to nutrient restriction. By unveiling the network properties, we identified major regulators driving gene expression. However, further research is still needed to determine the impact of early maternal nutrition and strategic supplementation on pre- and post-natal performance.
Developmental programming, which proposes that “insults” or “stressors” during intrauterine or postnatal development can have not only immediate but also long-term consequences for healthy and ...productivity, has emerged as a major biological principle, and based on studies in many animal species also seems to be a universal phenomenon. In eutherians, the placenta appears to be programmed during its development, which has consequences for fetal growth and development throughout pregnancy, and likewise has long-term consequences for postnatal development, leading to programming of organ function of the offspring even into adulthood. This review summarizes our current understanding of the placenta’s role in developmental programming, the mechanisms involved, and the challenges remaining.
We describe in detail the methods used to obtain the lower bound on the lifetime of neutrinoless double-beta (0 nu beta beta) decay in Te-130 and the associated limit on the effective Majorana mass ...of the neutrino using the CUORE-0 detector. CUORE-0 is a bolometric detector array located at the Laboratori Nazionali del Gran Sasso that was designed to validate the background reduction techniques developed for CUORE, a next-generation experiment scheduled to come online in 2016. CUORE-0 is also a competitive 0 nu beta beta decay search in its own right and functions as a platform to further develop the analysis tools and procedures to be used in CUORE. These include data collection, event selection and processing, as well as an evaluation of signal efficiency. In particular, we describe the amplitude evaluation, thermal gain stabilization, energy calibration methods, and the analysis event selection used to create our final 0 nu beta beta search spectrum. We define our high level analysis procedures, with emphasis on the new insights gained and challenges encountered. We outline in detail our fitting methods near the hypothesized 0 nu beta beta decay peak and catalog the main sources of systematic uncertainty. Finally, we derive the 0 nu beta beta decay half-life limits previously reported for CUORE-0, T-1/2(0 nu) > 2.7 x 10(24) yr, and in combination with the Cuoricino limit, T-1/2(0 nu) > 4.0 x 10(24) yr.
Models represent our primary method for integration of small-scale, process-level phenomena into a comprehensive description of forest-stand or ecosystem function. They also represent a key method ...for testing hypotheses about the response of forest ecosystems to multiple changing environmental conditions. This paper describes the evaluation of 13 stand-level models varying in their spatial, mechanistic, and temporal complexity for their ability to capture intra- and interannual components of the water and carbon cycle for an upland, oak-dominated forest of eastern Tennessee. Comparisons between model simulations and observations were conducted for hourly, daily, and annual time steps. Data for the comparisons were obtained from a wide range of methods including: eddy covariance, sapflow, chamber-based soil respiration, biometric estimates of stand-level net primary production and growth, and soil water content by time or frequency domain reflectometry. Response surfaces of carbon and water flux as a function of environmental drivers, and a variety of goodness-of-fit statistics (bias, absolute bias, and model efficiency) were used to judge model performance. A single model did not consistently perform the best at all time steps or for all variables considered. Intermodel comparisons showed good agreement for water cycle fluxes, but considerable disagreement among models for predicted carbon fluxes. The mean of all model outputs, however, was nearly always the best fit to the observations. Not surprisingly, models missing key forest components or processes, such as roots or modeled soil water content, were unable to provide accurate predictions of ecosystem responses to short-term drought phenomenon. Nevertheless, an inability to correctly capture short-term physiological processes under drought was not necessarily an indicator of poor annual water and carbon budget simulations. This is possible because droughts in the subject ecosystem were of short duration and therefore had a small cumulative impact. Models using hourly time steps and detailed mechanistic processes, and having a realistic spatial representation of the forest ecosystem provided the best predictions of observed data. Predictive ability of all models deteriorated under drought conditions, suggesting that further work is needed to evaluate and improve ecosystem model performance under unusual conditions, such as drought, that are a common focus of environmental change discussions.
Milk and dairy products provide highly sustainable concentrations of essential amino acids and other required nutrients for humans; however, amount of milk currently produced per dairy cow globally ...is inadequate to meet future needs. Higher performing dairy cows and herds produce more milk with less environmental impact per kg than lower performing cows and herds. In 2018, 15.4% of the world’s dairy cows produced 45.4% of the world’s dairy cow milk, reflecting the global contribution of high-performing cows and herds. In high-performing herds, genomic evaluations are utilized for multiple trait selection, welfare is monitored by remote sensing, rations are formulated at micronutrient levels, health care is focused on prevention and reproduction is managed with precision. Higher performing herds require more inputs and generate more waste products per cow, thus innovations in environmental management on such farms are essential for lowering environmental impacts. Our focus is to provide perspectives on technologies and practices that contribute most to sustainable production of milk from high-performing dairy cows and herds.
We utilize empirically derived estimates of landscape resistance to assess current landscape connectivity of American marten (
Martes americana
) in the northern Rocky Mountains, USA, and project how ...a warming climate may affect landscape resistance and population connectivity in the future. We evaluate the influences of five potential future temperature scenarios involving different degrees of warming. We use resistant kernel dispersal models to assess population connectivity based on full occupancy of suitable habitat in each of these hypothetical future resistance layers. We use the CDPOP model to simulate gene exchange among individual martens in each of these hypothetical future climates. We evaluate: (1) changes in the extent, connectivity and pattern of marten habitat, (2) changes in allelic richness and expected heterozygosity, and (3) changes in the range of significant positive genetic correlation within the northern Idaho marten population under each future scenario. We found that even moderate warming scenarios resulted in very large reductions in population connectivity. Calculation of genetic correlograms for each scenario indicates that climate driven changes in landscape connectivity results in decreasing range of genetic correlation, indicating more isolated and smaller genetic neighborhoods. These, in turn, resulted in substantial loss of allelic richness and reductions in expected heterozygosity. In the U.S. northern Rocky Mountains, climate change may extensively fragment marten populations to a degree that strongly reduces genetic diversity. Our results demonstrate that for species, such as the American marten, whose population connectivity is highly tied to climatic gradients, expected climate change can result in profound changes in the extent, pattern, connectivity and gene flow of populations.
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