MUTATION LOAD AND THE SURVIVAL OF SMALL POPULATIONS

Previous attempts to model the joint action of selection and mutation in finite populations have treated population size as being independent of the mutation load. However, the accumulation of deleterious mutations is expected to cause a gradual reduction in population size. Consequently, in small populations random genetic drift will progressively overpower selection making it easier to fix future mutations. This synergistic interaction, which we refer to as a mutational melt-down, ultimately leads to population extinction. For many conditions, the coefficient of variation of extinction time is less than 0.1, and for species that reproduce by binary fission, the expected extinction time is quite insensitive to population carrying capacity. These results are consistent with observations that many cultures of ciliated protozoans and vertebrate fibroblasts have characteristic extinction times. The model also predicts that clonal lineages are unlikely to survive more than 10⁴ to 10⁵ generations, which is consistent with existing data on parthenogenetic animals. Contrary to the usual view that Muller's ratchet does more damage when selection is weak, we show that the mean extinction time declines as mutations become more deleterious. Although very small sexual populations, such as self-fertilized lines, are subject to mutational meltdowns, recombination effectively eliminates the process when the effective population size exceeds a dozen or so. The concept of the effective mutation load is developed, and several procedures for estimating it are described. It is shown that this load can be reduced substantially when mutational effects are highly variable.     

Design and analysis of experiments on random drift and inbreeding depression

While the genetic consequences of inbreeding and small population size are of fundamental importance in many areas of biology, empirical research on these phenomena has proceeded in the absence of a well-developed statistical methodology. The usual approach is to compare observed means and variances with the expectations of Wright's neutral, additive genetic model for quantitative characters. If the observations deviate from the expectations more than can be accounted for by sampling variance of the parameter estimates, the null hypothesis is routinely rejected in favor of alternatives invoking evolutionary forces such as selection or nonadditive gene action. This is a biased procedure because it treats sequential samples from the same populations as independent, and because it ignores the fact that the expectations of the neutral additive genetic model will rarely be realized when only a finite number of lines are studied. Even when genes are perfectly additive and neutral, the variation among the properties of founder populations, the random development of linkage disequilibrium within lines, and the variance in inbreeding between lines reduce the likelihood that Wright's expectations will be realized in any particular set of lines. Under most experimental designs, these sources of variation are much too large to be ignored. Formulas are presented for the variance-covariance structure of the realized within- and between-line variance under the neutral additive genetic model. These results are then used to develop statistical tests for detecting the operation of selection and/or inbreeding depression in small populations. A number of recommendations are made for the optimal design of experiments on drift and inbreeding, and a method is suggested for the correction of data for general environmental effects. In general, it appears that we can best understand the response of populations to inbreeding and finite population size by studying a very large number (>100) of self-fertilizing or full-sib mated lines in parallel with one or more stable control populations.     

A randomized controlled trial of qigong for fibromyalgia

Introduction

Fibromyalgia is difficult to treat and requires the use of multiple approaches. This study is a randomized controlled trial of qigong compared with a wait-list control group in fibromyalgia.

Methods

One hundred participants were randomly assigned to immediate or delayed practice groups, with the delayed group receiving training at the end of the control period. Qigong training (level 1 Chaoyi Fanhuan Qigong, CFQ), given over three half-days, was followed by weekly review/practice sessions for eight weeks; participants were also asked to practice at home for 45 to 60 minutes per day for this interval. Outcomes were pain, impact, sleep, physical function and mental function, and these were recorded at baseline, eight weeks, four months and six months. Immediate and delayed practice groups were analyzed individually compared to the control group, and as a combination group.

Results

In both the immediate and delayed treatment groups, CFQ demonstrated significant improvements in pain, impact, sleep, physical function and mental function when compared to the wait-list/usual care control group at eight weeks, with benefits extending beyond this time. Analysis of combined data indicated significant changes for all measures at all times for six months, with only one exception. Post-hoc analysis based on self-reported practice times indicated greater benefit with the per protocol group compared to minimal practice.

Conclusions

This study demonstrates that CFQ, a particular form of qigong, provides long-term benefits in several core domains in fibromyalgia. CFQ may be a useful adjuvant self-care treatment for fibromyalgia.

Trial registration

clinicaltrials.gov NCT00938834.     

Mortality,Morbidity and Health-Seeking Behaviour during the Ebola Epidemic 2014–2015 in Monrovia Results from a Mobile Phone Survey

Between March 2014 and July 2015 at least 10,500 Ebola cases including more than 4,800 deaths occurred in Liberia, the majority in Monrovia. However, official numbers may have underestimated the size of the outbreak. Closure of health facilities and mistrust in existing structures may have additionally impacted on all-cause morbidity and mortality. To quantify mortality and morbidity and describe health-seeking behaviour in Monrovia, Médecins sans Frontières (MSF) conducted a mobile phone survey from December 2014 to March 2015. We drew a random sample of households in Monrovia and conducted structured mobile phone interviews, covering morbidity, mortality and health-seeking behaviour from 14 May 2014 until the day of the survey. We defined an Ebola-related death as any death meeting the Liberian Ebola case definition. We calculated all-cause and Ebola-specific mortality rates. The sample consisted of 6,813 household members in 905 households. We estimated a crude mortality rate (CMR) of 0.33/10,000 persons/day (95%CI:0.25–0.43) and an Ebola-specific mortality rate of 0.06/10,000 persons/day (95%-CI:0.03–0.11). During the recall period, 17 Ebola cases were reported including those who died. In the 30 days prior to the survey 277 household members were reported sick; malaria accounted for 54% (150/277). Of the sick household members, 43% (122/276) did not visit any health care facility. The mobile phone-based survey was found to be a feasible and acceptable alternative method when data collection in the community is impossible. CMR was estimated well below the emergency threshold of 1/10,000 persons/day. Non-Ebola-related mortality in Monrovia was not higher than previous national estimates of mortality for Liberia. However, excess mortality directly resulting from Ebola did occur in the population. Importantly, the small proportion of sick household members presenting to official health facilities when sick might pose a challenge for future outbreak detection and mitigation. Substantial reported health-seeking behaviour outside of health facilities may also suggest the need for adapted health messaging and improved access to health care.     

MUTATIONAL MELTDOWNS IN SEXUAL POPULATIONS

Although it is widely acknowledged that the gradual accumulation of mildly deleterious mutations is an important source of extinction for asexual populations, it is generally assumed that this process is of little relevance to sexual species. Here we present results, based on computer simulations and supported by analytical approximations, that indicate that mutation accumulation in small, random-mating monoecious populations can lead to mean extinction times less than a few hundred to a few thousand generations. Unlike the situation in obligate asexuals in which the mean time to extinction (t?_e) increases more slowly than linearly with the population carrying capacity (K), t?_e increases approximately exponentially with K in outcrossing sexual populations. The mean time to extinction for obligately selfing populations is shown to be equivalent to that for asexual populations of the same size, but with half the mutation rate and twice the mutational effect; this suggests that obligate selfing, like obligate asexuality, is inviable as a long-term reproductive strategy. Under all mating systems, the mean time to extinction increases relatively slowly with the logarithm of fecundity, and mutations with intermediate effects (similar to those observed empirically) cause the greatest risk of extinction. Because our analyses ignore sources of demographic and environmental stochasticity, which have synergistic effects that exacerbate the accumulation of deleterious mutations, our results should yield liberal upper bounds to the mean time to extinction caused by mutational degradation. Thus, deleterious mutation accumulation cannot be ruled out generally as a significant source of extinction vulnerability in small sexual populations or as a selective force influencing mating-system evolution.     

Regulation by glucocorticoids of rat-liver phenylalanine hydroxylase in vivo

Phenylalanine hydroxylase, a liver-associated enzyme, is induced markedly by glucocorticoids in two permanent rat-hepatoma cell lines. In order to gain evidence that this phenomenon also occurs in vivo, we examined the effect of adrenalectomy and/or hormone supplementation on the levels of phenylalanine hydroxylase in the livers of adult rats: glucocorticoid administration increases, and adrenal ablation reduces, the activity of the hepatic enzyme, and the diminution occurring in the latter instance is entirely prevented by concurrent hormone replacement. These results thus corroborate earlier findings from a single experiment and are consistent with the hypothesis that adrenal corticosteroid hormones participate in modulating phenylalanine-hydroxylase levels within the diploid hepatocyte.     

4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner

4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal. Here we have shown that treatment of tumor-bearing mice with agonistic 4-1BB-specific Abs can lead to T cell-mediated tumor rejection. In vivo mAb depletion experiments demonstrated that this rejection requires CD8(+) cells but not CD4(+) or NK cells. Both IFN-gamma- and CD40-mediated signals were also required, because no benefit was observed on treatment with 4-1BB mAb in mice in which the genes for these molecules had been knocked out. Interestingly, 4-1BB-mediated stimulation of immune responses in CD40L(-/-) mice is effective (although at a reduced level), and may suggest the existence of an alternative ligand for CD40. Additional experiments in IL-15(-/-) mice indicate that IL-15 is not required for either the generation of the primary tumor-specific immune response or the maintenance of the memory immune response. In contrast, the presence of CD4 cells during the primary immune response appears to play a significant role in the maintenance of effective antitumor memory. Finally, in mice in which the number of dendritic cells had been expanded by Fms-like tyrosine kinase3 ligand treatment, the antitumor effects of 4-1BB ligation were enhanced.     

Relationships between mutans streptococci and perceived treatment need of primary root-caries lesions.

A total of 447 primary root-caries lesions from 169 dental patients was studied to determine the relationships between mutans streptococci and the perceived treatment need of primary root-caries lesions. Samples of this altered dentine for microbiological culture were obtained. Lesions were classified into 5 treatment categories; soft and restore, leathery and restore, leathery and debride of caries, leathery and treat chemotherapeutically, and hard, to receive no treatment. The total numbers of mutans streptococci decreased significantly with decreased treatment need. The percentage of mutans streptococci from lesions requiring no treatment was significantly less than from lesions requiring treatment. The frequency of isolation of mutans streptococci was significantly greater from lesions requiring more treatment. Significantly more lesions containing > 10² mutans streptococci were distributed in the groups with a greater perceived treatment need or with larger dimensions occlusogingivally and/or mesio-distally or bucco-lingually or with a closer proximity to the gingival margin.     

Evidence for independence of circadian characters and extent of photoresponsiveness in the Djungarian hamster, Phodopus sungorus.

Djungarian hamsters (Phodopus sungorus) exposed to a short-day photoperiod generally respond with a syndrome of physiological and behavioral changes, such as body weight loss and molt to a white pelage. The extent of the short-day-induced responses differs among individuals. Furthermore, some hamsters show no photoresponse. In this study, we sought to determine whether variation in the photoresponse would be associated with circadian function: whether phase angle or free-running period (tau) would differ between responsive and nonresponsive hamsters; and whether changes in these circadian characters would correlate with the extent of weight loss and molt (and the timing of molt onset) in photoresponsive hamsters. Adult hamsters were kept in a short-day photoperiod (9 hr light, 15 hr dark) for 14 weeks, during which time body weight and molt were measured biweekly. Hamsters were then transferred to cages equipped with running wheels; we measured the phase angle of activity onset under a short-day photoperiod and tau in constant dark. Hamsters exhibiting a short-day-induced molt had a significantly shorter tau and a less negative phase angle than nonmolting animals. Hamsters that exhibited weight loss also had a significantly less negative phase angle, but no difference in tau. No significant Pearson's or Spearman's correlation coefficients were found between extent (or timing) of the photoresponse and the circadian characters in responsive hamsters. Although these results indicate that threshold for photoresponsiveness is related to circadian function, the extent (and timing) of the photoresponse may not be.