Evolution of Cryptococcal Antigen Testing: What Is New?

Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and microscopy, which have low sensitivity and longer turnaround times, are not widely available, leading to delays in timely antifungal therapy and detrimental patient outcomes. The evolution of cryptococcal antigen (CrAg) testing to develop inexpensive and more sensitive methods to detect cryptococcal antigen is significant. These newer tests employ immunoassays as part of point-of-care platforms, which do not require complex laboratory infrastructure, and they have the potential to detect early disease and reduce time to diagnosis of cryptococcal infection. Advocacy for widely available and efficacious life-saving antifungal treatment should be the only remaining challenge.     

How Much Gravity Is Needed to Establish the Perceptual Upright?

Might the gravity levels found on other planets and on the moon be sufficient to provide an adequate perception of upright for astronauts? Can the amount of gravity required be predicted from the physiological threshold for linear acceleration? The perception of upright is determined not only by gravity but also visual information when available and assumptions about the orientation of the body. Here, we used a human centrifuge to simulate gravity levels from zero to earth gravity along the long-axis of the body and measured observers'' perception of upright using the Oriented Character Recognition Test (OCHART) with and without visual cues arranged to indicate a direction of gravity that differed from the body''s long axis. This procedure allowed us to assess the relative contribution of the added gravity in determining the perceptual upright. Control experiments off the centrifuge allowed us to measure the relative contributions of normal gravity, vision, and body orientation for each participant. We found that the influence of 1 g in determining the perceptual upright did not depend on whether the acceleration was created by lying on the centrifuge or by normal gravity. The 50% threshold for centrifuge-simulated gravity''s ability to influence the perceptual upright was at around 0.15 g, close to the level of moon gravity but much higher than the threshold for detecting linear acceleration along the long axis of the body. This observation may partially explain the instability of moonwalkers but is good news for future missions to Mars.     

Cost-Effectiveness Analysis of Chemical Testing for Decision-Support: How to Include Animal Welfare?

Toxicity testing for regulatory purposes raises the question of test selection for a particular endpoint. Given the public's concern for animal welfare, test selection is a multi-objective decision problem that requires balancing information outcome, animal welfare loss, and monetary testing costs. This paper demonstrates the applicability of cost-effectiveness analysis as a decision-support tool for test selection in a regulatory context such as, for example, the new European chemicals legislation (REACH). We distinguish different decision-making perspectives, in particular the regulator's and chemical industry's perspectives, and we discuss how cost-effectiveness analysis can be applied to test selection from both perspectives. Furthermore, we show how animal welfare goals can be included in cost-effectiveness analyses, and we provide a three-dimensional extension to the standard cost-effectiveness analysis if animal welfare loss cannot be valued in monetary terms. To illustrate how cost-effectiveness analysis works in different settings, we apply our model to a simple case of selecting short-term tests for mutagenicity. We demonstrate that including sufficiently high values for animal welfare induces cost-effective replacements of animal testing. Furthermore, we show that the regulator and chemical companies face different tradeoffs when selecting tests. This may lead to different choices of tests or testing systems.     

What Is the Tree of Life?

A universal Tree of Life (TOL) has long been a goal of molecular phylogeneticists, but reticulation at the level of genes and possibly at the levels of cells and species renders any simple interpretation of such a TOL, especially as applied to prokaryotes, problematic.One of the several ways in which microbiology puts the neo-Darwinian synthesis in jeopardy is by the threatening to “uproot the Tree of Life (TOL)” [1]. Lateral gene transfer (LGT) is much more frequent than most biologists would have imagined up until about 20 years ago, so phylogenetic trees based on sequences of different prokaryotic genes are often different. How to tease out from such conflicting data something that might correspond to a single, universal Tree of Life becomes problematic. Moreover, since many important evolutionary transitions involve lineage fusions at one level or another, the aptness of a tree (a pattern of successive bifurcations) as a summary of life’s history is uncertain [2–4].     

Predicting Falls in Parkinson Disease: What Is the Value of Instrumented Testing in OFF Medication State?

BackgroundFalls are a common complication of advancing Parkinson''s disease (PD). Although numerous risk factors are known, reliable predictors of future falls are still lacking. The objective of this prospective study was to investigate clinical and instrumented tests of balance and gait in both OFF and ON medication states and to verify their utility in the prediction of future falls in PD patients.MethodsForty-five patients with idiopathic PD were examined in defined OFF and ON medication states within one examination day including PD-specific clinical tests, instrumented Timed Up and Go test (iTUG) and computerized dynamic posturography. The same gait and balance tests were performed in 22 control subjects of comparable age and sex. Participants were then followed-up for 6 months using monthly fall diaries and phone calls.ResultsDuring the follow-up period, 27/45 PD patients and 4/22 control subjects fell one or more times. Previous falls, fear of falling, more severe motor impairment in the OFF state, higher PD stage, more pronounced depressive symptoms, higher daily levodopa dose and stride time variability in the OFF state were significant risk factors for future falls in PD patients. Increased stride time variability in the OFF state in combination with faster walking cadence appears to be the most significant predictor of future falls, superior to clinical predictors.ConclusionIncorporating instrumented gait measures into the baseline assessment battery as well as accounting for both OFF and ON medication states might improve future fall prediction in PD patients. However, instrumented testing in the OFF state is not routinely performed in clinical practice and has not been used in the development of fall prevention programs in PD. New assessment methods for daylong monitoring of gait, balance and falls are thus required to more effectively address the risk of falling in PD patients.     

Comparative Study of Chemical Approaches to the Solid-Phase Synthesis of a Tumor-Seeking α-MSH Analogue

The synthesis of a cyclic melanocortin analogue (H-pz-βAla-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH₂), where the Boc-protected derivative of a metal-chelating pyrazolyl ligand (pz) was inserted as N-terminal residue, was addressed by several different Fmoc/tBu and Boc/Bzl solid-phase strategies. On-resin cyclization was achieved immediately following incorporation of Asp, by condensation of the Asp side chain carboxyl with the Lys side chain primary amine after selective and simultaneous removal of side chain protecting groups. The success of the synthesis was highly dependent on the chemical strategy employed, with Boc/Bzl chemistry giving the best results. On the light of our findings, Fmoc/tBu strategies are not advantageous for the solid-phase synthesis of this particular type of lactam-bridged peptides. Last, but not least, the target peptide was recently found to have promising tumor-seeking properties (J Biol Inorg Chem 13:449–459, 2008).     

What Is Needed to Eradicate Lymphatic Filariasis? A Model-Based Assessment on the Impact of Scaling Up Mass Drug Administration Programs

Background

Lymphatic filariasis (LF) is a neglected tropical disease for which more than a billion people in 73 countries are thought to be at-risk. At a global level, the efforts against LF are designed as an elimination program. However, current efforts appear to aim for elimination in some but not all endemic areas. With the 2020 goal of elimination looming, we set out to develop plausible scale-up scenarios to reach global elimination and eradication. We predict the duration of mass drug administration (MDA) necessary to reach local elimination for a variety of transmission archetypes using an existing model of LF transmission, estimate the number of treatments required for each scenario, and consider implications of rapid scale-up.

Methodology

We have defined four scenarios that differ in their geographic coverage and rate of scale-up. For each scenario, country-specific simulations and calculations were performed that took into account the pre-intervention transmission intensity, the different vector genera, drug regimen, achieved level of population coverage, previous progress toward elimination, and potential programmatic delays due to mapping, operations, and administration.

Principal Findings

Our results indicate that eliminating LF by 2020 is unlikely. If MDA programs are drastically scaled up and expanded, the final round of MDA for LF eradication could be delivered in 2028 after 4,159 million treatments. However, if the current rate of scale-up is maintained, the final round of MDA to eradicate LF may not occur until 2050.

Conclusions/Significance

Rapid scale-up of MDA will decrease the amount of time and treatments required to reach LF eradication. It may also propel the program towards success, as the risk of failure is likely to increase with extended program duration.     

What Is the Minimum Number of Residues to Determine the Secondary Structural State?

The failure of protein secondary structural prediction is commonly attributed to the neglect of long-range interactions. The question is, what is the minimum length of subsequence required to determine the central secondary structural state, stabilized only by local interactions? In the present work, the 20 amino acids were classified into eight groups to analyze systematically the relationship between the length and secondary structural state of subsequences in the PDB database. It was found that the fraction of subsequences with a unique central secondary structural state increases with increasing length, and the minimum length of subsequence required to determine the central secondary structural state is about 14–17 residues. The low accuracy of secondary structure prediction does not result from the neglect of long-range interactions, but may result from the limitation of the available protein database size or prediction algorithm.     

Approaches to valuing plant medicines: the economics of culture or the culture of economics?

This paper explores the scope and limitations of the economic valuation of biodiversity. How and why is this a useful exercise, but in what way is its usefulness constrained? These issues are discussed with particular reference to cultural values within the context of medicinal plants and phytopharmaceutical development. It is argued that whilst economic valuation is an extremely important and necessary aid to formulating conservation policy, it probably is not that informative about the motivations of people in their use of certain natural resources. This is especially true for the case of medicinal plants where belief systems about the causes of disease and therefore strategies for healing are important. The paper reviews studies which have attempted to put monetary values on medicinal plants and the option values of pharmaceuticals developed from plants, and discusses the applicability of the various approaches. The implications for conservation policy, and for likely collaboration between social and natural scientists is discussed.     

Widespread and Enzyme-independent N?-Acetylation and N?-Succinylation of Proteins in the Chemical Conditions of the Mitochondrial Matrix

Alterations in mitochondrial protein acetylation are implicated in the pathophysiology of diabetes, the metabolic syndrome, mitochondrial disorders, and cancer. However, a viable mechanism responsible for the widespread acetylation in mitochondria remains unknown. Here, we demonstrate that the physiologic pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to cause dose- and time-dependent, but enzyme-independent acetylation and succinylation of mitochondrial and nonmitochondrial proteins in vitro. These data suggest that protein acylation in mitochondria may be a chemical event facilitated by the alkaline pH and high concentrations of reactive acyl-CoAs present in the mitochondrial matrix. Although these results do not exclude the possibility of enzyme-mediated protein acylation in mitochondria, they demonstrate that such a mechanism may not be required in its unique chemical environment. These findings may have implications for the evolutionary roles that the mitochondria-localized SIRT3 deacetylase and SIRT5 desuccinylase have in the maintenance of metabolic health.     

Time Slices: What Is the Duration of a Percept?

We experience the world as a seamless stream of percepts. However, intriguing illusions and recent experiments suggest that the world is not continuously translated into conscious perception. Instead, perception seems to operate in a discrete manner, just like movies appear continuous although they consist of discrete images. To explain how the temporal resolution of human vision can be fast compared to sluggish conscious perception, we propose a novel conceptual framework in which features of objects, such as their color, are quasi-continuously and unconsciously analyzed with high temporal resolution. Like other features, temporal features, such as duration, are coded as quantitative labels. When unconscious processing is “completed,” all features are simultaneously rendered conscious at discrete moments in time, sometimes even hundreds of milliseconds after stimuli were presented.     

Quantifying Landscape Spatial Pattern: What Is the State of the Art?

Landscape ecology is based on the premise that there are strong links between ecological pattern and ecological function and process. Ecological systems are spatially heterogeneous, exhibiting considerable complexity and variability in time and space. This variability is typically represented by categorical maps or by a collection of samples taken at specific spatial locations (point data). Categorical maps quantize variability by identifying patches that are relatively homogeneous and that exhibit a relatively abrupt transition to adjacent areas. Alternatively, point-data analysis (geostatistics) assumes that the system property is spatially continuous, making fewer assumptions about the nature of spatial structure. Each data model provides capabilities that the other does not, and they should be considered complementary. Although the concept of patches is intuitive and consistent with much of ecological theory, point-data analysis can answer two of the most critical questions in spatial pattern analysis: what is the appropriate scale to conduct the analysis, and what is the nature of the spatial structure? I review the techniques to evaluate categorical maps and spatial point data, and make observations about the interpretation of spatial pattern indices and the appropriate application of the techniques. Pattern analysis techniques are most useful when applied and interpreted in the context of the organism(s) and ecological processes of interest, and at appropriate scales, although some may be useful as coarse-filter indicators of ecosystem function. I suggest several important needs for future research, including continued investigation of scaling issues, development of indices that measure specific components of spatial pattern, and efforts to make point-data analysis more compatible with ecological theory.     

Molecular Probes: What Is the Range of Their Interaction with the Environment?

We performed pressure-tuning hole-burning experiments on a modified cytochrome c protein in a glycerol/buffer glass. The shift and the broadening of the holes were investigated for various frequencies within the inhomogeneous band. On the basis of a simple model, we were able to estimate the interaction range between chromophore and protein. It is ~4.5 Å. The parameters that enter the model are the compressibility, the static mean-square displacement, the inhomogeneous width, and the average spectral shift per pressure. From this result and from our experiments on pressure-induced denaturing, we conclude that water molecules have to be brought very close to the chromophore during the denaturation process.