Correcting the Bias in Estimation of Genetic Variances Contributed by Individual QTL

In addition to locating chromosomal positions of quantitative trait loci (QTL), estimating the sizes of identified QTL is also an important component in QTL mapping. The size of a QTL is usually measured by the proportion of the phenotypic variance contributed by the QTL. However, the genetic variance may be overestimated in a small line crossing experiment. In this study, we investigate this bias and develop a simple method to correct the bias. The bias correction, however, requires the error of the estimated genetic effect, which is not trivial if the genetic effect is estimated using the Expectation and Maximization (EM) algorithm. Therefore, we also develop a simple method to estimate the standard error of the estimated genetic effect, which is subsequently used to correct the bias in the variance estimate.     

The single chlorophyll a molecule in the cytochrome b6f complex: unusual optical properties protect the complex against singlet oxygen

The cytochrome b(6)f complex of oxygenic photosynthesis mediates electron transfer between the reaction centers of photosystems I and II and facilitates coupled proton translocation across the membrane. High-resolution x-ray crystallographic structures (Kurisu et al., 2003; Stroebel et al., 2003) of the cytochrome b(6)f complex unambiguously show that a Chl a molecule is an intrinsic component of the cytochrome b(6)f complex. Although the functional role of this Chl a is presently unclear (Kuhlbrandt, 2003), an excited Chl a molecule is known to produce toxic singlet oxygen as the result of energy transfer from the excited triplet state of the Chl a to oxygen molecules. To prevent singlet oxygen formation in light-harvesting complexes, a carotenoid is typically positioned within approximately 4 A of the Chl a molecule, effectively quenching the triplet excited state of the Chl a. However, in the cytochrome b(6)f complex, the beta-carotene is too far (> or =14 Angstroms) from the Chl a for effective quenching of the Chl a triplet excited state. In this study, we propose that in this complex, the protection is at least partly realized through special arrangement of the local protein structure, which shortens the singlet excited state lifetime of the Chl a by a factor of 20-25 and thus significantly reduces the formation of the Chl a triplet state. Based on optical ultrafast absorption difference experiments and structure-based calculations, it is proposed that the Chl a singlet excited state lifetime is shortened due to electron exchange transfer with the nearby tyrosine residue. To our knowledge, this kind of protection mechanism against singlet oxygen has not yet been reported for any other chlorophyll-containing protein complex. It is also reported that the Chl a molecule in the cytochrome b(6)f complex does not change orientation in its excited state.     

Measuring the fit of sequence data to phylogenetic model: allowing for missing data

It is fundamentally important to assess the fit of data to model in phylogenetic and evolutionary studies. Phylogenetic methods using molecular sequences typically start with a multiple alignment. It is possible to measure the fit of data to model expectations of data, for example, via the likelihood-ratio (G) test or the X(2) test, if all sites in all sequences have an unambiguous residue. However, nearly all alignments of interest contain sites (columns of the alignment) with missing data, that is, ambiguous nucleotides, gaps, or unsequenced regions, which must presently be removed before using the above tests. Unfortunately, this is often either undesirable or impractical, as it will discard much of the data. Here, we show how iterative ML estimators may directly estimate the site-pattern probabilities for columns with missing data, given only standard i.i.d. assumptions. The optimization may use an EM or Newton algorithm, or any other hill-climbing approach. The resulting optimal likelihood under the unconstrained or multinomial model may be compared directly with the likelihood of the data coming from the model (a G statistic). Alternatively the modified observed and the expected frequencies of site patterns may be compared using a X(2) test. The distribution of such statistics is best assessed using appropriate simulations. The new method is applicable to models using codons or paired sites. The methods are also useful with Hadamard conjugations (spectral analysis) and are illustrated with these and with ML evolutionary models that allow site-rate variability.     

Approval policies for modifications to machine learning‐based software as a medical device: A study of bio‐creep

Successful deployment of machine learning algorithms in healthcare requires careful assessments of their performance and safety. To date, the FDA approves locked algorithms prior to marketing and requires future updates to undergo separate premarket reviews. However, this negates a key feature of machine learning—the ability to learn from a growing dataset and improve over time. This paper frames the design of an approval policy, which we refer to as an automatic algorithmic change protocol (aACP), as an online hypothesis testing problem. As this process has obvious analogy with noninferiority testing of new drugs, we investigate how repeated testing and adoption of modifications might lead to gradual deterioration in prediction accuracy, also known as “biocreep” in the drug development literature. We consider simple policies that one might consider but do not necessarily offer any error‐rate guarantees, as well as policies that do provide error‐rate control. For the latter, we define two online error‐rates appropriate for this context: bad approval count (BAC) and bad approval and benchmark ratios (BABR). We control these rates in the simple setting of a constant population and data source using policies aACP‐BAC and aACP‐BABR, which combine alpha‐investing, group‐sequential, and gate‐keeping methods. In simulation studies, bio‐creep regularly occurred when using policies with no error‐rate guarantees, whereas aACP‐BAC and aACP‐BABR controlled the rate of bio‐creep without substantially impacting our ability to approve beneficial modifications.     

Mark–recapture of Cerambyx welensii in dehesa woodlands: dispersal behaviour,population density,and mass trapping efficiency with low trap densities

The longhorn beetle, Cerambyx welensii Küster (Coleoptera: Cerambycidae), is an emerging pest involved in oak decline episodes in dehesa open woodlands. Larvae are xylophagous and cause considerable physiological, mechanical, and structural damages to trees. Chemical and biological control are currently unsatisfactory. Recent research has shown that mass trapping with a high density of baited traps (40 traps ha^?1) could be useful to manage C. welensii populations, although such a trap density was too high to be cost‐effective. In this 2‐year study (2010–2011) we investigated with mark–recapture methods in a large plot (1) the flight dispersal behaviour, (2) the adult population density, and (3) the efficiency of mass trapping at two low trap densities (one or four traps ha^?1). Results indicated that many adults were sedentary (60%) but flying adults displayed a strong propensity to move, both sexes dispersing on average more than 200 m and one male and one female flying at least 540 and 349 m, respectively. Recapture rates were high (0.26–0.35) and population density was estimated to be 6–22 adults ha^?1 with maximum likelihood models. Trapping efficiency ranged 48–61% with no significant effect of trap density or year. We conclude that results were not satisfactory enough to recommend mass trapping with low trap densities as control method for C. welensii and that more research is still required on the technical, ecological, and behavioural factors affecting control efficiency.     

Role of reactive oxygen species and NADPH-oxidase in the development of rat cerebellum

Experimental evidence suggests that reactive oxygen species (ROS) could participate in the regulation of some physiological conditions. In the nervous system, ROS have been suggested to act as signaling molecules involved in several developmental processes including cell differentiation, proliferation and programmed of cell death. Although ROS can be generated by several sources, it has been suggested that NADPH oxidase (NOX) could be critical in the production of ROS acting as a signal in some of these events. It has been reported that ROS production by NOX enzymes participate in neuronal maturation and differentiation during brain development. In the present study, we found that during rat cerebellar development there was a differential ROS generation at different ages and areas of the cerebellum. We also found a differential expression of NOX homologues during rat cerebellar development. When we treated developing rats with an antioxidant or with apocynin, an inhibitor of NOX, we found a marked decrease of the ROS levels in all the cerebellar layers at all the ages tested. Both treatments also induced a significant change in the cerebellar foliation as well as an alteration in motor behavior. These results suggest that both ROS and NOX have a critical role during cerebellar development.     

Pike and salmon as sister taxa: Detailed intraclade resolution and divergence time estimation of Esociformes + Salmoniformes based on whole mitochondrial genome sequences

The increasing number of taxa and loci in molecular phylogenetic studies of basal euteleosts has brought stability in a controversial area. A key emerging aspect to these studies is a sister Esociformes (pike) and Salmoniformes (salmon) relationship. We evaluate mitochondrial genome support for a sister Esociformes and Salmoniformes hypothesis by surveying many potential outgroups for these taxa, employing multiple phylogenetic approaches, and utilizing a thorough sampling scheme. Secondly, we conduct a simultaneous divergence time estimation and phylogenetic inference in a Bayesian framework with fossil calibrations focusing on relationships within Esociformes + Salmoniformes. Our dataset supports a sister relationship between Esociformes and Salmoniformes; however the nearest relatives of Esociformes + Salmoniformes are inconsistent among analyses. Within the order Esociformes, we advocate for a single family, Esocidae. Subfamily relationships within Salmonidae are poorly supported as Salmoninae sister to Thymallinae + Coregoninae.     

Population genetic structure of the Plasmodium vivax circumsporozoite protein (Pvcsp) in Sri Lanka

Molecular methods elucidate evolutionary and ecological processes in parasites, where interaction between hosts and parasites enlighten the evolution of parasite lifestyles and host defenses. Population genetics of Plasmodium vivax parasites accurately describe transmission dynamics of the parasites and evaluation of malaria control measures. As a first generation vaccine candidate against malaria, the Circumsporozoite Protein (CSP) has demonstrated significant potential in P. falciparum. Extensive polymorphism hinders the development of a potent malaria vaccine. Hence, the genetic diversity of Pvcsp was investigated for the first time in 60 Sri Lankan clinical isolates by obtaining the nucleotide sequence of the central repeat (CR) domain and examining the polymorphism of the peptide repeat motifs (PRMs), the genetic diversity indices and phylogenetic relationships. PCR amplicons determined size polymorphism of 610, 700 and 710 bp in Pvcsp of Sri Lanka where all amino acid sequences obtained were of the VK210 variant, consisting variable repeats of 4 different PRMs. The two most abundant PRMs of the CR domain, GDRADGQPA and GDRAAGQPA consisted ~ 2-4 repeats, while GNRAAGQPA was unique to the island. Though, different nucleotide sequences termed repeat allotypes (RATs) were observed for each PRM, these were synonymous contributing to a less polymorphic CR domain. The genetic diversity of Pvcsp in Sri Lanka was due to the number of repetitive peptide repeat motifs, point mutations, and intragenic recombination. The 19 amino acid haplotypes defined were exclusive to Sri Lanka, whereas the 194 Pvcsp sequences of global isolates generated 57 more distinct a.a. haplotypes of the VK210 variant. Strikingly, the CR domain of both VK210 and VK247 variants was under purifying selection interpreting the scarcity of CSP non-synonymous polymorphisms. Insights to the distribution of RATs in the CR region with geographic clustering of the P. vivax VK210 variant were revealed. The cladogram reiterated this unique geographic clustering of local (VK210) and global isolates (VK210 and VK247), which was further validated by the elevated fixation index values of the VK210 variant.