Research Project No. 15, Predicting Individual Tree Height of Planted Loblolly and Slash Pines in East Texas, Update: 1987

Updated equations to estimate individual total tree height of loblolly pine ( Pinus taeda L. ) and slash pine ( Pinus elliottii Engelm. ) trees planted on non-old-fields in East Texas are presented. The new revised equations were developed using data from initial measurement and first remeasurement of the East Texas Pine Plantation Research Project Permanent plots ( 1982-1987)

YGR198w (YPP1) targets A30P α-synuclein to the vacuole for degradation

Using a genetic screen we discovered that YGR198w (named YPP1), which is an essential Saccharomyces cerevisiae gene of unknown function, suppresses the toxicity of an α-synuclein (α-syn) mutant (A30P) that is associated with early onset Parkinson's disease. Here, we show that YPP1 suppresses lethality of A30P, but not of wild-type α-syn or the A53T mutant. The Ypp1 protein, when overexpressed, drives each of the three α-syns into vesicles that bud off the plasma membrane, but only A30P-containing vesicles traffick to and merge with the vacuole, where A30P is proteolytically degraded. We show that Ypp1p binds to A30P but not the other two α-syns; that YPP1 interacts with genes involved in endocytosis/actin dynamics (SLA1, SLA2, and END3), protein sorting (class E vps), and vesicle-vacuole fusion (MON1 and CCZ1) to dispose of A30P; and that YPP1 also participates in pheromone-triggered receptor-mediated endocytosis. Our data reveal that YPP1 mediates the trafficking of A30P to the vacuole via the endocytic pathway

Characterization of cleavage events in the multifunctional cilium adhesin Mhp684 (P146) reveals a mechanism by which mycoplasma hyopneumoniae regulates surface topography

Mycoplasma hyopneumoniae causes enormous economic losses to swine production worldwide by colonizing the ciliated epithelium in the porcine respiratory tract, resulting in widespread damage to the mucociliary escalator, prolonged inflammation, reduced weight gain, and secondary infections. Protein Mhp684 (P146) comprises 1,317 amino acids, and while the N-terminal 400 residues display significant sequence identity to the archetype cilium adhesin P97, the remainder of the molecule is novel and displays unusual motifs. Proteome analysis shows that P146 preprotein is endogenously cleaved into three major fragments identified here as P50P146, P40P146, and P85P146 that reside on the cell surface. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) identified a semitryptic peptide that delineated a major cleavage site in Mhp684. Cleavage occurred at the phenylalanine residue within sequence 672ATEF2QQ677, consistent with a cleavage motif resembling S/T-X-F2XD/E recently identified in Mhp683 and other P97/P102 family members. Biotinylated surface proteins recovered by avidin chromatography and separated by two-dimensional gel electrophoresis (2-D GE) showed that more-extensive endoproteolytic cleavage of P146 occurs. Recombinant fragments F1P146-F3P146 that mimic P50P146, P40P146, and P85P146 were constructed and shown to bind porcine epithelial cilia and biotinylated heparin with physiologically relevant affinity. Recombinant versions of F3P146 generated from M. hyopneumoniae strain J and 232 sequences strongly bind porcine plasminogen, and the removal of their respective C-terminal lysine and arginine residues significantly reduces this interaction. These data reveal that P146 is an extensively processed, multifunctional adhesin of M. hyopneumoniae. Extensive cleavage coupled with variable cleavage efficiency provides a mechanism by which M. hyopneumoniae regulates protein topography

Realist synthesis : illustrating the method for implementation research

BackgroundRealist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question \u27what interventions and strategies are effective in enabling evidence-informed healthcare?\u27 The strengths and challenges of conducting realist review are also considered. MethodsThe realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses. ResultsBased on key terms and concepts related to various interventions to promote evidenceinformed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area. ConclusionsRealist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review. <br /

Novel suppressors of α-synuclein toxicity identified using yeast

The mechanism by which the Parkinson’s disease-related protein α-synuclein (α-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from α-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing α-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes—ENT3, IDP3, JEM1, ARG2 and HSP82—ranked highest in their ability to block α-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of α-syn as judged by growth defects compared with wild-type cells expressing α-syn, which indicates that these genes protect cells from α-syn. Strikingly, four of the five genes are specific for α-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that α-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes α-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of α-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans

Evaluation of a multi-disciplinary back pain rehabilitation programme—individual and group perspectives

To evaluate the impact of a multi-disciplinary back pain rehabilitation programme using a combination of individual and group change data. A total of 261 consecutive patients attending an assessment session for the back pain rehabilitation programme completed the SF-36 health survey questionnaire. The patients were requested to complete the questionnaires again at programme completion and at the 6-month follow-up. The Reliable Change Index was used to define 'clinical significance' in terms of the assessment of individual change. Half of those patients considered to be suitable for the programme subsequently completed it. In group terms, non-completers scored lower than completers on all SF-36 scales. Statistically significant improvements were evident for those completing the programme (all scales at P < 0.000), with improvement maintained at follow-up. In individual terms, 'clinical significance' was exceeded most frequently in the Physical Functioning and Role Physical scales. Whilst some participants lost previous improvements between completion and follow-up, others improved over this same time period. The majority of those completing the programme showed improvement in at least one scale. Adding assessment of individual change to traditional group change measures provides greater insight into the impact a rehabilitation programme has upon participants' quality of life. Whilst the programme is clearly effective for those who complete it, work is required to limit post-programme deterioration and improve uptak

Perceptual and conceptual processing of visual objects across the adult lifespan

Abstract: Making sense of the external world is vital for multiple domains of cognition, and so it is crucial that object recognition is maintained across the lifespan. We investigated age differences in perceptual and conceptual processing of visual objects in a population-derived sample of 85 healthy adults (24–87 years old) by relating measures of object processing to cognition across the lifespan. Magnetoencephalography (MEG) was recorded during a picture naming task to provide a direct measure of neural activity, that is not confounded by age-related vascular changes. Multiple linear regression was used to estimate neural responsivity for each individual, namely the capacity to represent visual or semantic information relating to the pictures. We find that the capacity to represent semantic information is linked to higher naming accuracy, a measure of task-specific performance. In mature adults, the capacity to represent semantic information also correlated with higher levels of fluid intelligence, reflecting domain-general performance. In contrast, the latency of visual processing did not relate to measures of cognition. These results indicate that neural responsivity measures relate to naming accuracy and fluid intelligence. We propose that maintaining neural responsivity in older age confers benefits in task-related and domain-general cognitive processes, supporting the brain maintenance view of healthy cognitive ageing

Distinct components of cardiovascular health are linked with age-related differences in cognitive abilities

Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n = 708, age 18–88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging

Poorer White Matter Microstructure Predicts Slower and More Variable Reaction Time Performance: Evidence for a Neural Noise Hypothesis in a Large Lifespan Cohort

Most prior research has focused on characterizing averages in cognition, brain characteristics, or behavior, and attempting to predict differences in these averages among individuals. However, this overwhelming focus on mean levels may leave us with an incomplete picture of what drives individual differences in behavioral phenotypes by ignoring the variability of behavior around an individual's mean. In particular, enhanced white matter (WM) structural microstructure has been hypothesized to support consistent behavioral performance by decreasing Gaussian noise in signal transfer. Conversely, lower indices of WM microstructure are associated with greater within-subject variance in the ability to deploy performance-related resources, especially in clinical populations. We tested a mechanistic account of the “neural noise” hypothesis in a large adult lifespan cohort (Cambridge Centre for Ageing and Neuroscience) with over 2500 adults (ages 18-102; 1508 female; 1173 male; 2681 behavioral sessions; 708 MRI scans) using WM fractional anisotropy to predict mean levels and variability in reaction time performance on a simple behavioral task using a dynamic structural equation model. By modeling robust and reliable individual differences in within-person variability, we found support for a neural noise hypothesis (Kail, 1997), with lower fractional anisotropy predicted individual differences in separable components of behavioral performance estimated using dynamic structural equation model, including slower mean responses and increased variability. These effects remained when including age, suggesting consistent effects of WM microstructure across the adult lifespan unique from concurrent effects of aging. Crucially, we show that variability can be reliably separated from mean performance using advanced modeling tools, enabling tests of distinct hypotheses for each component of performance

Ageing increases reliance on sensorimotor prediction through structural and functional differences in frontostriatal circuits

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group.The control of voluntary movement changes markedly with age. A critical component of motor control is the integration of sensory information with predictions of the consequences of action, arising from internal models of movement. This leads to sensorimotor attenuation – a reduction in the perceived intensity of sensations from self-generated compared to external actions. Here we show that sensorimotor attenuation occurs in 98% of adults in a population-based cohort (n=325; 18-88 years; the Cambridge Centre for Ageing and Neuroscience). Importantly, attenuation increases with age, in proportion to reduced sensory sensitivity. This effect is associated with differences in the structure and functional connectivity of the pre-supplementary motor area (pre-SMA), assessed with magnetic resonance imaging. The results suggest that ageing alters the balance between the sensorium and predictive models, mediated by the pre-SMA and its connectivity in frontostriatal circuits. This shift may contribute to the motor and cognitive changes observed with age.Cam-CAN research was supported by the Biotechnology and Biological Sciences Research Council (BB/H008217/1). JBR and NW were supported by the James S. McDonnell Foundation 21st Century Science Initiative, Scholar Award in Understanding Human Cognition. JBR was also supported by Wellcome Trust [103838] and the Medical Research Council [MC-A060-5PQ30]. DMW was supported by the Wellcome Trust [097803], Human Frontier Science Program and the Royal Society Noreen Murray Professorship in Neurobiology. RNH was supported by the Medical Research Council [MC-A060-5PR10]. RAK was supported by a Sir Henry Wellcome Trust Postdoctoral Fellowship [107392]. LG was funded by a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO)