Linear and nonlinear mixed-effects models for censored HIV viral loads using normal/independent distributions

HIV RNA viral load measures are often subjected to some upper and lower detection limits depending on the quantification assays. Hence, the responses are either left or right censored. Linear (and nonlinear) mixed-effects models (with modifications to accommodate censoring) are routinely used to analyze this type of data and are based on normality assumptions for the random terms. However, those analyses might not provide robust inference when the normality assumptions are questionable. In this article, we develop a Bayesian framework for censored linear (and nonlinear) models replacing the Gaussian assumptions for the random terms with normal/independent (NI) distributions. The NI is an attractive class of symmetric heavy-tailed densities that includes the normal, Student's-t, slash, and the contaminated normal distributions as special cases. The marginal likelihood is tractable (using approximations for nonlinear models) and can be used to develop Bayesian case-deletion influence diagnostics based on the Kullback-Leibler divergence. The newly developed procedures are illustrated with two HIV AIDS studies on viral loads that were initially analyzed using normal (censored) mixed-effects models, as well as simulations.     

Inbreeding reveals stronger net selection on Drosophila melanogaster males: implications for mutation load and the fitness of sexual females

Stronger selection on males has the potential to lower the deleterious mutation load of females, reducing the cost of sex. However, few studies have directly quantified the strength of selection for both sexes. As the magnitude of inbreeding depression (ID) is related to the strength of selection, we measured the cost of inbreeding for both males and females in a laboratory population of Drosophila melanogaster. Using a novel technique for inbreeding, we found significant ID for both juvenile viability and adult fitness in both sexes. The genetic variation responsible for this depression in fitness appeared to be recessive for adult fitness (h=0.11) and partially additive for juvenile viability (h=0.29). ID was identical across the sexes in terms of juvenile viability but was significantly more deleterious for males than females as adults, even though female X-chromosome homogamety should predispose them to a higher inbreeding load. We estimated the strength of selection on adult males to be 1.24 greater than on adult females, and this appears to be a consequence of selection arising from competition for mates. Combined with the generally positive intersexual genetic correlation for inbred lines, our results suggest that the mutation load of sexual females could be meaningfully reduced by stronger selection acting on males.     

Seasonal differences in energy requirements of Garden Warblers Sylvia borin migrating across the Sahara desert

The Sahara desert acts as an ecological barrier for billions of passerine birds on their way to and from their African wintering areas. The Garden Warbler Sylvia borin is one of the most common migrants involved. We used body mass of this species from Greece in autumn and spring to simulate the desert crossing and to assess how body mass relates to fuel requirement. The flight range estimates were adjusted to the seasonal extent of the desert, 2200 km in autumn and about 2800 km in spring. In autumn, with an average fuel load of about 100% of body mass without fuel, birds were not able to cross the desert in still air, but northerly winds prevail during September and with the average wind assistance only one in 14 was predicted to fail to make the crossing. Body mass data from spring, after the desert crossing, was used to estimate departure body mass from south of the desert. The average wind assistance in spring is close to zero and departure body mass of the average bird arriving at Antikythira, a small Greek island, under such conditions was estimated to be 34.6 g, which corresponded to a fuel load of 116%. Calculations based on 1% body mass loss per hour of flight showed slightly larger body mass loss than that calculated from flight range estimates. The results suggest that passerine birds about to cross the eastern part of the Sahara desert need to attain a larger fuel load in spring than in autumn.     

The Ca sensor S100A1 modulates neuroinflammation,histopathology and Akt activity in the PSAPP Alzheimer's disease mouse model

The contribution of the Ca²⁺ sensor S100A1 to in vivo Alzheimer's disease (AD) pathobiology has not been elucidated although S100A1 regulates numerous cellular processes linked to AD. This study uses genetic ablation to ascertain the effects of S100A1 on neuroinflammation, beta-amyloid (Aβ) plaque deposition and Akt activity in the PSAPP AD mouse model. PSAPP/S100A1^−/− mice exhibited decreases in astrocytosis (GFAP burden), microgliosis (Iba1 burden) and plaque load/number when compared to PSAPP/S100A1^+/+ mice at six and twelve months of age. The presence of detectable S100A1 staining in human AD specimens is consistent with a detrimental gain of S100A1 function in AD. S100A1 ablation also reduced plaque associated and increased non-plaque associated PO₄-Akt and PO₄-GSK3β staining. S100A1·Akt complexes were undetectable in PC12 cells and AD brain tissue suggesting that S100A1 indirectly modulates Akt activity. In contrast, S100A1·RyR (ryanodine receptor) complexes were present in human/mouse AD brain and exhibited Ca²⁺-dependent formation in neuronal cells. This is the first direct demonstration of an S100A1· target protein complex in tissue/cells and identifies the RyR as a primary S100A1 target protein in the brain. Collectively, these data suggest that S100A1 inhibition may be a novel strategy for normalizing aberrant Ca²⁺ signaling in AD.     

Maximum realised lifetime parasitism and occurrence of time limitation in Gonatocerus ashmeadi (Hymenoptera: Mymaridae) foraging in citrus orchards

The relationship between body size (hind tibia length), <12 h egg load, wing wear and parasitoid age was used to estimate realised lifetime parasitism of recently dead Gonatocerus ashmeadi collected in a citrus orchard. Under prevailing field conditions and methodology assumptions, it was estimated that female G. ashmeadi lived on average for 183 ± 17 degree-days, parasitised a total of 87 ± 9 Homalodisca vitripennis eggs, and died with 34 ± 5 eggs remaining in the ovaries. Only 17% of dead G. ashmeadi died with no mature eggs suggesting that 83% of G. ashmeadi were not egg limited at time of death. Estimates of realised lifetime parasitism for female G. ashmeadi under prevailing field conditions in July and August in a southern California citrus orchard indicated that time of year had a significant effect on reproductive output. Additionally, live G. ashmeadi captured daily during June through August 2006 had body size, egg load and wing wear recorded to detect possible monthly changes in parasitoid age and egg load. Foraging G. ashmeadi captured alive in June were older and oviposited more eggs in the field compared with August. Only 0.5% of live G. ashmeadi were captured with no mature eggs in their ovaries indicating that the vast majority of live G. ashmeadi were not egg limited.     

Parasite load and MHC diversity in undisturbed and agriculturally modified habitats of the ornate dragon lizard

Major histocompatibility complex (MHC) gene polymorphism is thought to be driven by host–parasite co‐evolution, but the evidence for an association between the selective pressure from parasites and the number of MHC alleles segregating in a population is scarce and inconsistent. Here, we characterized MHC class I polymorphism in a lizard whose habitat preferences (rock outcrops) lead to the formation of well‐defined and stable populations. We investigated the association between the load of ticks, which were used as a proxy for the load of pathogens they transmit, and MHC class I polymorphism across populations in two types of habitat: undisturbed reserves and agricultural land. We hypothesized that the association would be positive across undisturbed reserve populations, but across fragmented agricultural land populations, the relationship would be distorted by the loss of MHC variation due to drift. After controlling for habitat, MHC diversity was not associated with tick number, and the habitats did not differ in this respect. Neither did we detect a difference between habitats in the relationship between MHC and neutral diversity, which was positive across all populations. However, there was extensive variation in the number of MHC alleles per individual, and we found that tick number was positively associated with the average number of alleles carried by lizards across reserve populations, but not across populations from disturbed agricultural land. Our results thus indicate that local differences in selection from parasites may contribute to MHC copy number variation within species, but habitat degradation can distort this relationship.     

Research on the Interstitial Fluid Load Support Characteristics and Start-Up Friction Mechanisms of PVA-HA-Silk Composite Hydrogel

Hydrogel has been extensively studied as an articular cartilage repair and replacement material. PVA-HA-Silk composite hydrogel was prepared by freezing-thawing method in this paper. Mechanical properties were determined by experiments and the friction coefficient of PVA-HA-Silk composite hydrogel against steel ball was verified using micro-tribometer. Finite Element Method （FEM） was used to study the lubrication mechanism of PVA-HA-Silk composite hydrogel and the relation between the interstitial fluid load support and the start-up friction resistance. The results show that the elastic modulus and the permeability are 2.07 MPa and 10^-15m^4N^-1s^-1, respectively, and the start-up friction coefficients of PVA-HA-Silk composite hydrogel are in the range of 0.154）.2 at different contact loads, contact time and sliding speeds. The start-up friction resistance of PVA-HA-Silk composite hydrogel increases with the contact load and contact time. With the increase in sliding speed, the start-up friction resistance of PVA-HA-Silk composite hydrogel decreases. There is an inverse relation between the start-up friction resistance and the interstitial fluid load support. The change of fluid flow with the increase in sliding displacement has an important effect on the interstitial fluid load support and friction resistance. The interstitial fluid load support decreases with the increase in contact load and contact time, while the interstitial fluid load support reinforces with the increase in sliding speed. Moreover, PVA-HA-Silk composite hydrogel has mechanical properties of recovery and self-lubricating.     

The role of the interactome in the maintenance of deleterious variability in human populations

Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.     

Weakened purifying selection leads to elevated mutation load under environmental sex determination

In many gonochoristic taxa, sex is influenced by developmental environment, a system that can lead to temporal fluctuations in offspring sex ratio. Demographic models suggest that only short‐lived species with environmental sex determination (ESD) are negatively impacted by sex‐ratio fluctuations, yet these models fail to account for the potential mutation load associated with reductions in genetically effective population sizes. In this study, we developed a series of individual‐based simulation models that explore the fixation rates of mildly deleterious alleles under different sex‐determining systems and examine the impacts of variation in lifespan and offspring sex ratio. Populations with ESD exhibited increases in fixation rates in both short‐ and long‐lived populations, but substantial increases were limited to populations characterized by a combination of high sex‐ratio variation and short lifespan. Fixation rates were negatively associated with effective population size, indicating that purifying selection operates less efficiently under ESD relative to genotypic sex determination. Reductions in effective population size could be attributed to both intragenerational forces (unequal sex ratio) and intergenerational forces (variable census population sizes). Levels of temporal sex‐ratio variation calculated from wild populations of ESD species were capable of yielding large increases in fixation rates, although this relationship was strongly mediated by lifespan. Our results may help to explain the limited phylogenetic distribution of ESD in short‐lived taxa.     

Effect of mental fatigue on induced tremor in human knee extensors

In this study, the effects of mental fatigue on mechanically induced tremor at both a low (3–6 Hz) and high (8–12 Hz) frequency were investigated. The two distinct tremor frequencies were evoked using two springs of different stiffness, during 20 s sustained contractions of the knee extensor muscles at 30% maximum voluntary contraction (MVC) before and after 100 min of a mental fatigue task, in 12 healthy (29 ± 3.7 years) participants. Mental fatigue resulted in a 6.9% decrease in MVC and in a 9.4% decrease in the amplitude of the agonist muscle EMG during sustained 30% MVC contractions in the induced high frequency only. Following the mental fatigue task, the coefficient of variation and standard deviation of the force signal decreased at 8–12 Hz induced tremor by 31.7% and 35.2% respectively, but not at 3–6 Hz induced tremor. Similarly, the maximum value and area underneath the peak in the power spectrum of the force signal decreased by 55.5% and 53.1% respectively in the 8–12 Hz range only. In conclusion, mental fatigue decreased mechanically induced 8–12 Hz tremor and had no effect on induced 3–6 Hz tremor. We suggest that the reduction could be attributed to the decreased activation of the agonist muscles.