Effects of residual smoothing on the posterior of the fixed effects in disease-mapping models

Disease-mapping models for areal data often have fixed effects to measure the effect of spatially varying covariates and random effects with a conditionally autoregressive (CAR) prior to account for spatial clustering. In such spatial regressions, the objective may be to estimate the fixed effects while accounting for the spatial correlation. But adding the CAR random effects can cause large changes in the posterior mean and variance of fixed effects compared to the nonspatial regression model. This article explores the impact of adding spatial random effects on fixed effect estimates and posterior variance. Diagnostics are proposed to measure posterior variance inflation from collinearity between the fixed effect covariates and the CAR random effects and to measure each region's influence on the change in the fixed effect's estimates by adding the CAR random effects. A new model that alleviates the collinearity between the fixed effect covariates and the CAR random effects is developed and extensions of these methods to point-referenced data models are discussed.     

Determination of intrinsic hydrophilicity/hydrophobicity of amino acid side chains in peptides in the absence of nearest-neighbor or conformational effects

Understanding the hydrophilicity/hydrophobicity of amino acid side chains in peptides/proteins is one the most important aspects of biology. Though many hydrophilicity/hydrophobicity scales have been generated, an "intrinsic" scale has yet to be achieved. "Intrinsic" implies the maximum possible hydrophilicity/hydrophobicity of side chains in the absence of nearest-neighbor or conformational effects that would decrease the full expression of the side-chain hydrophilicity/hydrophobicity when the side chain is in a polypeptide chain. Such a scale is the fundamental starting point for determining the parameters that affect side-chain hydrophobicity and for quantifying such effects in peptides and proteins. A 10-residue peptide sequence, Ac-X-G-A-K-G-A-G-V-G-L-amide, was designed to enable the determination of the intrinsic values, where position X was substituted by all 20 naturally occurring amino acids and norvaline, norleucine, and ornithine. The coefficients were determined by reversed-phase high-performance liquid chromatography using six different mobile phase conditions involving different pH values (2, 5, and 7), ion-pairing reagents, and the presence and absence of different salts. The results show that the intrinsic hydrophilicity/hydrophobicity of amino acid side chains in peptides (proteins) is independent of pH, buffer conditions, or whether C(8) or C(18) reversed-phase columns were used for 17 side chains (Gly, Ala, Cys, Pro, Val, nVal, Leu, nLeu, Ile, Met, Tyr, Phe, Trp, Ser, Thr, Asn, and Gln) and dependent on pH and buffer conditions, including the type of salt or ion-pairing reagent for potentially charged side chains (Orn, Lys, His, Arg, Asp, and Glu).     

Hepatic guanylate cyclase activity is decreased in a model of cirrhosis: a quantitative cytochemistry study

The production of nitric oxide (NO) in liver disease and its role in vascular control has been a subject of much interest in recent years. However, the activity of guanylate cyclase (GC), the enzyme activated by NO has received little attention with regard to liver disease. In this study we have utilised a quantitative cytochemical technique to examine the activity of GC on a per cell basis in a rat model of cirrhosis. Our results show a significant reduction in GC activity, indicating that vascular regulation is likely to be substantially affected irrespective of NO generation in this disease model.     

Annual Variation in Ecology and Reproduction of Wild Simakobu (Simias concolor)

Seasonal breeding in primates is related to the degree of environmental seasonality, particularly the availability and predictability of food. Southeast Asian species in general show moderate birth seasonality due to either low environmental seasonality or unpredictable fluctuations of mast-fruiting food resources. One Southeast Asian primate, the simakobu (Simias concolor), however, has been reported to be a strict seasonal breeder with births occurring in June and July only. It is unclear whether these observations are characteristic of the species or result from a sampling bias. To address this question, we documented the annual distribution of 11 births in eight groups of simakobu over two consecutive years at Pungut, an undisturbed site on Siberut Island, Indonesia. We assessed annual variation in ecology and reproduction via rainfall, temperature, food availability, feeding time, physical condition, conceptions, and births. Mean monthly temperature was nearly constant (26.3–27.1?°C), and monthly precipitation always high (219–432?mm). Although simakobu foods were abundant year-round, there were two fruit-feeding peaks in June and September. In contrast to previous reports, we documented births in 7?mo. Most births occurred in October (45?%), the wettest month of the year, and most conceptions in March and April, following a peak in unripe fruit availability. Although sample sizes are very small, females seemed to conceive when their physical condition was best, suggesting that simakobu time conceptions flexibly to the recovery of energy reserves. Across study sites, births occurred in 10 calendar months, indicating that simakobu reproduction is not strictly seasonal.     

Dynamics and memory of heterochromatin in living cells

Posttranslational histone modifications are important for gene regulation, yet the mode of propagation and the contribution to heritable gene expression states remains controversial. To address these questions, we developed a chromatin in vivo assay (CiA) system employing chemically induced proximity to initiate and terminate chromatin modifications in living cells. We selectively recruited HP1α to induce H3K9me3-dependent gene silencing and describe the kinetics and extent of chromatin modifications at the Oct4 locus in fibroblasts and pluripotent cells. H3K9me3 propagated symmetrically and continuously at average rates of ~0.18 nucleosomes/hr to produce domains of up to 10 kb. After removal of the HP1α stimulus, heterochromatic domains were heritably transmitted, undiminished through multiple cell generations. Our data enabled quantitative modeling of reaction kinetics, which revealed that dynamic competition between histone marking and turnover, determines the boundaries and stability of H3K9me3 domains. This framework predicts the steady-state dynamics and spatial features of the majority of euchromatic H3K9me3 domains over the genome.     

Caregiver burden in amyotrophic lateral sclerosis is more dependent on patients’ behavioral changes than physical disability: a comparative study

Background

Behavioral changes in patients with amyotrophic lateral sclerosis (ALS) mirror those found in frontotemporal dementia (FTD). Considering the high rate of neuropsychiatric symptoms found in ALS patients, this paper examines whether caregiver burden is associated with behavioral changes over and above the physical disability of patients with ALS, and if the presence of caregivers’ depression, anxiety and stress also impacts on caregiver burden.

Methods

140 caregivers of patients with ALS participated in a postal survey investigating patients’ neuropsychiatric symptoms (Cambridge Behaviour Inventory Revised CBI-R), motor function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised - ALSFRS-R), caregiver burden (Zarit Burden Interview), and caregiver mood (Depression, Anxiety and Stress Scale- DASS21). Seventy four percent of them were caregivers of patients with limb onset and 25.7% were caregivers of patients with bulbar onset.

Results

Moderate to severe behavioral changes were reported in 10-40% of patients with ALS. The levels of depression, anxiety and stress in the caregivers reached 20%. Burden was high in 48% of the caregivers. The strongest predictor of high caregiver burden was ALS patients’ abnormal behavior rather than physical disability, with an odds ratio of 1.4, followed by caregivers’ stress.

Conclusions

Our study has identified that behavioral changes (e.g. disinhibition, impulsivity) and caregiver stress have greater impact on caregiver burden than level and pattern of physical disability.

     

Watch and learn: seeing is better than doing when acquiring consecutive motor tasks

During motor adaptation learning, consecutive physical practice of two different tasks compromises the retention of the first. However, there is evidence that observational practice, while still effectively aiding acquisition, will not lead to interference and hence prove to be a better practice method. Observers and Actors practised in a clockwise (Task A) followed by a counterclockwise (Task B) visually rotated environment, and retention was immediately assessed. An Observe-all and Act-all group were compared to two groups who both physically practised Task A, but then only observed (ObsB) or did not see or practice Task B (NoB). The two observer groups and the NoB control group better retained Task A than Actors, although importantly only the observer groups learnt Task B. RT data and explicit awareness of the rotation suggested that the observers had acquired their respective tasks in a more strategic manner than Actor and Control groups. We conclude that observational practice benefits learning of multiple tasks more than physical practice due to the lack of updating of implicit, internal models for aiming in the former.     

Grey and White Matter Changes across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Continuum

There is increasing evidence that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10), ALS-FTD (n = 10) and behavioural variant FTD (bvFTD; n = 15) as well as controls (n = 18), underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum.