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Aims: The aim of this study was to clarify whether worsening of independence in activities of daily living (ADL) and also difficulties in ADL are triggered by hospitalization in older patients with heart failure (HF) and whether difficulties in ADL can predict readmission for HF regardless of independence in ADL in these patients., Methods and Results: We enrolled 241 HF patients in the present multi-institutional, prospective, observational study. The patients were divided according to age into the non-older patient group (<75 years, n = 137) and the older patient group (≥75 years, n = 104). The Katz index and the Performance Measure for Activities of Daily Living-8 (PMADL-8) were used to evaluate independence and difficulties in ADL, respectively. The endpoint of this study was rehospitalization for HF. Independence as indicated by the Katz index at discharge was significantly lower than that before admission only in the older patient group, and the value of the PMADL-8 at discharge was significantly higher than that before admission (P < 0.001). In all patients, after adjusting for the Katz index and other variables, PMADL-8 score was a significant predictor of rehospitalization for HF (hazard ratio 1.50; 95% confidence interval 1.07-2.13; P = 0.021)., Conclusions: Worsening of both independence and difficulties in ADL was triggered by hospitalization in older HF patients, and difficulties in ADL were relevant factors for risk of rehospitalization regardless of independence in ADL. These findings indicate the importance of preventing not only decreased independence but also increased difficulties in ADL during and after hospitalization., Competing Interests: Conflict of interest: The authors certify that there are no conflicts of interest with any financial organizations regarding the material discussed in this manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Lower leg strength at hospital discharge is strongly associated with poor prognosis in older patients with acute decompensated heart failure (ADHF). Improving leg strength is important in acute-phase cardiac rehabilitation (CR)., Aims: This study aimed to clarify whether a change in leg strength occurs during hospitalization of older ADHF patients receiving CR and whether it affects leg strength at discharge., Methods and Results: We enrolled 247 ADHF patients who underwent CR during hospitalization. They were divided into the non-older patient group (&lt;75 years; n = 142) and older patient group (≥75 years; n = 105). Quadriceps isometric strength (QIS), body mass-corrected QIS (%BM QIS), and change in QIS during hospitalization (QIS ratio) were evaluated in all patients. Physical function in the stable phase was measured by the Performance Measure for Activities of Daily Living-8 (PMADL-8). The QIS value increased during hospitalization in the non-older patient group (30.0 ± 11.1 vs. 31.6 ± 10.9 kgf, P &lt; 0.001) but did not increase in the older patient group (19.1 ± 6.3 vs. 19.5 ± 6.1 kgf, P = 0.275). Multiple regression analysis revealed that PMADL-8 significantly predicted %BM QIS at discharge in the non-older patient group (β = -0.254, P = 0.004), whereas in the older patient group, QIS ratio and PMADL-8 significantly predicted %BM QIS at discharge (β = 0.264, P = 0.008 for QIS ratio and β = -0.307, P = 0.003 for PMADL-8)., Conclusions: Leg strength was not improved in older ADHF patients during hospitalization even if they received CR, and this affected leg strength at discharge, suggesting that careful skeletal muscle intervention should be provided during hospitalization, and patients need to continue exercise after discharge., Competing Interests: Conflicts of interest: The authors declare that there is no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

For more than 100 years, house mice (Mus musculus) have been used as a key animal model in biomedical research. House mice are genetically diverse, yet their genetic background at the global level has not been fully understood. Previous studies have suggested that they originated in South Asia and diverged into three major subspecies, almost simultaneously, approximately 110,000-500,000 years ago; however, they have spread across the world with the migration of modern humans in prehistoric and historic times (∼10,000 years ago to the present day) and have undergone secondary contact, which has complicated the genetic landscape of wild house mice. In this study, we sequenced the whole-genome sequences of 98 wild house mice collected from Eurasia, particularly East Asia, Southeast Asia, and South Asia. Although wild house mice were found to consist of three major genetic groups corresponding to the three major subspecies, individuals representing admixtures between subspecies were more prevalent in East Asia than has been previously recognized. Furthermore, several samples exhibited an incongruent pattern of genealogies between mitochondrial and autosomal genomes. Using samples that likely retained the original genetic components of subspecies with the least admixture, we estimated the pattern and timing of divergence among the subspecies. The estimated divergence time of the three subspecies was 187,000-226,000 years ago. These results will help us to understand the genetic diversity of wild mice on a global scale, and the findings will be particularly useful in future biomedical and evolutionary studies involving laboratory mice established from such wild mice., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Previous studies of the brown bear (Ursus arctos) on Hokkaido Island, Japan, have detected three geographically distinct subpopulations representing different mitochondrial lineages and shown that gene flow between subpopulations has occurred due to male-biased dispersal. In this study, we determined whole-genomic sequences for six Hokkaido brown bears and analyzed these data along with previously published genomic sequences of 17 brown bears from other parts of the world. We found that the Hokkaido population is genetically distinct from the other populations, keeping genetic diversity higher than the endangered populations in western Europe but lower than most populations on the continents. A reconstruction of historical demography showed no increase in population size for the Hokkaido population during the Eemian interglacial period (130,000-114,000 years ago). In a phylogenetic analysis of the autosomal data, the Hokkaido population formed a clade distinct from North American and European populations, showing that it has maintained genetic diversity independently from continental populations following geographical isolation on the island. This autosomal genetic similarity contrasts with the geographically separate mitochondrial lineages on Hokkaido and indicates the occurrence of male-driven gene flow between subpopulations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The role of sex-specific demography in hybridization and admixture of genetically diverged species and populations is essential to understand the origins of the genomic diversity of sexually reproducing organisms. In order to infer how sex-linked loci have been differentiated undergoing frequent hybridization and admixture, we examined 17 whole-genome sequences of seven species representing the genus Macaca, which shows frequent inter-specific hybridization and predominantly female philopatry. We found that hybridization and admixture were prevalent within these species. For three cases of suggested hybrid origin of species/subspecies, Macaca arctoides, Macaca fascicularis ssp. aurea, and Chinese Macaca mulatta, we examined the level of admixture of X chromosomes, which is less affected by male-biased migration than that of autosomes. In one case, we found that Macaca cyclopis and Macaca fuscata was genetically closer to Chinese M. mulatta than to the Indian M. mulatta, and the admixture level of Chinese M. mulatta and M. fuscata/cyclopis was more pronounced on the X chromosome than on autosomes. Since the mitochondrial genomes of Chinese M. mulatta, M. cyclopis, and M. fuscata were found to cluster together, and the mitochondrial genome of Indian M. mulatta is more distantly related, the observed pattern of genetic differentiation on X-chromosomal loci is consistent with the nuclear swamping hypothesis, in which strong, continuous male-biased introgression from the ancestral Chinese M. mulatta population to a population related to M. fuscata and M. cyclopis generated incongruencies between the genealogies of the mitochondrial and nuclear genomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Spring leaf phenology strongly influences plant productivity in temperate deciduous forests. Many studies have detected earlier budburst and leaf maturation in smaller trees within species, and have discussed the adaptive significance of increasing carbon gain before canopy closure in small trees. However, some previous studies have found the opposite pattern, and the physiological and environmental bases for this discrepancy are incompletely understood. We investigated the spring leaf phenology of 11 deciduous species in a cool-temperate forest in Japan for 2 years with different amounts of snowfall, and also gathered data on the day of budburst from multiple studies to assess whether and how the timing of budburst is related to tree size, phylogeny, temperature and annual snowfall of study sites. We found that differences in the timing of budburst and leaf maturation between saplings (<1 m height) and short trees (1-10 m height) are larger than those between short trees and tall trees (>10 m height), resulting in non-linear relationships between timing and height in most species. Cumulative degree-days to the day of budburst were smaller in saplings than in tall trees, probably because saplings are selected to outcompete the other individuals/species to become established. Moreover, phylogenetic relatedness did not explain the difference in spring leaf phenology between saplings and tall trees in the literature survey. In addition, our literature survey showed that budburst occurred earlier in saplings of most species in sites with less snowfall, whereas budburst occurred earlier in tall trees at sites with heavy snowfall. These results suggest that the opposite patterns found in some studies may be due to (i) differences in the target size, as saplings show larger phenological discrepancies than short and tall trees, and (ii) the microclimate experienced by the tree, as sites with heavy snow show delayed sapling phenology., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cis - and trans -regulatory mutations are important contributors to transcriptome evolution. Quantifying their relative contributions to intraspecific variation in gene expression is essential for understanding the population genetic processes that underlie evolutionary changes in gene expression. Here, we have examined this issue by quantifying genome-wide, allele-specific expression (ASE) variation using a crossing scheme that produces F 1 hybrids between 18 different Drosophila melanogaster strains sampled from the Drosophila Genetic Reference Panel and a reference strain from another population. Head and body samples from F 1 adult females were subjected to RNA sequencing and the subsequent ASE quantification. Cis - and trans -regulatory effects on expression variation were estimated from these data. A higher proportion of genes showed significant cis -regulatory variation (∼28%) than those that showed significant trans -regulatory variation (∼9%). The sizes of cis -regulatory effects on expression variation were 1.98 and 1.88 times larger than trans -regulatory effects in heads and bodies, respectively. A generalized linear model analysis revealed that both cis - and trans -regulated expression variation was strongly associated with nonsynonymous nucleotide diversity and tissue specificity. Interestingly, trans -regulated variation showed a negative correlation with local recombination rate. Also, our analysis on proximal transposable element (TE) insertions suggested that they affect transcription levels of ovary-expressed genes more pronouncedly than genes not expressed in the ovary, possibly due to defense mechanisms against TE mobility in the germline. Collectively, our detailed quantification of ASE variations from a natural population has revealed a number of new relationships between genomic factors and the effects of cis - and trans -regulatory factors on expression variation., (Copyright © 2017 by the Genetics Society of America.)

Joint quantification of genetic and epigenetic effects on gene expression is important for understanding the establishment of complex gene regulation systems in living organisms. In particular, genomic imprinting and maternal effects play important roles in the developmental process of mammals and flowering plants. However, the influence of these effects on gene expression are difficult to quantify because they act simultaneously with cis -regulatory mutations. Here we propose a simple method to decompose cis -regulatory ( i.e. , allelic genotype), genomic imprinting [ i.e. , parent-of-origin (PO)], and maternal [ i.e. , maternal genotype (MG)] effects on allele-specific gene expression using RNA-seq data obtained from reciprocal crosses. We evaluated the efficiency of method using a simulated dataset and applied the method to whole-body Drosophila and mouse trophoblast stem cell (TSC) and liver RNA-seq data. Consistent with previous studies, we found little evidence of PO and MG effects in adult Drosophila samples. In contrast, we identified dozens and hundreds of mouse genes with significant PO and MG effects, respectively. Interestingly, a similar number of genes with significant PO effect were detect in mouse TSCs and livers, whereas more genes with significant MG effect were observed in livers. Further application of this method will clarify how these three effects influence gene expression levels in different tissues and developmental stages, and provide novel insight into the evolution of gene expression regulation., (Copyright © 2017 Takada et al.)

Background: Chronic pruritus (CP) is present in approximately one-third of all dermatological patients. Diagnostics and treatment are challenging and impair patients' quality of life., Objectives: To analyse therapeutic needs in terms of the importance of treatment goals in a large sample of patients with CP., Methods: Routine data of 2747 patients with CP were analysed with descriptive methods and significance tests (univariate and multivariate variance analyses). The importance of 27 need items was measured using the Patient Needs Questionnaire of the Patient Benefit Index., Results: The most important needs were to find a clear diagnosis and treatment, to no longer experience itching and to have confidence in the therapy, which were quite or very important to > 90% of the patients. The least important goals concerned a normal working or sex life. Nine needs related mostly to disease and psychological symptoms, and some social needs differed in importance between sexes (P ≤ 0·05). Patients with pruritus on inflamed skin or with chronic scratch lesions judged more than half of all needs as more important than did patients with pruritus on noninflamed skin (P ≤ 0·05). In the multivariate model, age, pruritus intensity and quality of life had a significant effect on the importance of therapeutic needs besides sex and pruritus classification., Conclusions: Patients with CP present high levels of various therapeutic needs with differences by sex and clinical phenotype. The most important needs can be addressed through medical activities such as appropriate itch medication and a trustful doctor-patient relationship., (© 2016 British Association of Dermatologists.)

Cynomolgus macaques (Macaca fascicularis) were introduced to the island of Mauritius by humans around the 16th century. The unique demographic history of the Mauritian cynomolgus macaques provides the opportunity to not only examine the genetic background of well-established nonhuman primates for biomedical research but also understand the effect of an extreme population bottleneck on the pattern of polymorphisms in genomes. We sequenced the whole genomes of six Mauritian cynomolgus macaques and obtained an average of 20-fold coverage of the genome sequences for each individual. The overall level of nucleotide diversity was 23% smaller than that of the Malaysian cynomolgus macaques, and a reduction of low-frequency polymorphisms was observed. In addition, we also confirmed that the Mauritian cynomolgus macaques were genetically closer to a representative of the Malaysian population than to a representative of the Indochinese population. Excess of nonsynonymous polymorphisms in low frequency, which has been observed in many other species, was not very strong in the Mauritian samples, and the proportion of heterozygous nonsynonymous polymorphisms relative to synonymous polymorphisms is higher within individuals in Mauritian than Malaysian cynomolgus macaques. Those patterns indicate that the extreme population bottleneck made purifying selection overwhelmed by the power of genetic drift in the population. Finally, we estimated the number of founding individuals by using the genome-wide site frequency spectrum of the six samples. Assuming a simple demographic scenario with a single bottleneck followed by exponential growth, the estimated number of founders (∼20 individuals) is largely consistent with previous estimates., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Continuous cell lines that originate from mammalian tissues serve as not only invaluable tools for life sciences, but also important animal cell substrates for the production of various types of biological pharmaceuticals. Vero cells are susceptible to various types of microbes and toxins and have widely contributed to not only microbiology, but also the production of vaccines for human use. We here showed the genome landscape of a Vero cell line, in which 25,877 putative protein-coding genes were identified in the 2.97-Gb genome sequence. A homozygous ∼9-Mb deletion on chromosome 12 caused the loss of the type I interferon gene cluster and cyclin-dependent kinase inhibitor genes in Vero cells. In addition, an ∼59-Mb loss of heterozygosity around this deleted region suggested that the homozygosity of the deletion was established by a large-scale conversion. Moreover, a genomic analysis of Vero cells revealed a female Chlorocebus sabaeus origin and proviral variations of the endogenous simian type D retrovirus. These results revealed the genomic basis for the non-tumourigenic permanent Vero cell lineage susceptible to various pathogens and will be useful for generating new sub-lines and developing new tools in the quality control of Vero cells., (© The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Macaques are the most widely distributed nonhuman primates and used as animal models in biomedical research. The availability of full-genome sequences from them would be essential to both biomedical and primate evolutionary studies. Previous studies have reported whole-genome sequences from rhesus macaque (Macaca mulatta) and cynomolgus macaque (M. fascicularis, CE), both of which belong to the fascicularis group. Here, we present a 37-fold coverage genome sequence of the Tibetan macaque (M. thibetana; TM). TM is an endemic species to China belonging to the sinica group. On the basis of mapping to the rhesus macaque genome, we identified approximately 11.9 million single-nucleotide variants), of which 3.9 million were TM specific, as assessed by comparison two Chinese rhesus macaques (CR) and two CE genomes. Some genes carried TM-specific homozygous nonsynonymous variants (TSHNVs), which were scored as deleterious in human by both PolyPhen-2 and SIFT (Sorting Tolerant From Intolerant) and were enriched in the eye disease genes. In total, 273 immune response and disease-related genes carried at least one TSHNV. The heterozygosity rates of two CRs (0.002617 and 0.002612) and two CEs (0.003004 and 0.003179) were approximately three times higher than that of TM (0.000898). Polymerase chain reaction resequencing of 18 TM individuals showed that 29 TSHNVs exhibited high allele frequencies, thus confirming their low heterozygosity. Genome-wide genetic divergence analysis demonstrated that TM was more closely related to CR than to CE. We further detected unusual low divergence regions between TM and CR. In addition, after applying statistical criteria to detect putative introgression regions (PIRs) in the TM genome, up to 239,620 kb PIRs (8.84% of the genome) were identified. Given that TM and CR have overlapping geographical distributions, had the same refuge during the Middle Pleistocene, and show similar mating behaviors, it is highly likely that there was an ancient introgression event between them. Moreover, demographic inferences revealed that TM exhibited a similar demographic history as other macaques until 0.5 Ma, but then it maintained a lower effective population size until present time. Our study has provided new insight into the macaque evolutionary history, confirming hybridization events between macaque species groups based on genome-wide data., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

PR/SET domain containing 9 (Prdm9) mediates histone modifications such as H3K4me3 and marks hotspots of meiotic recombination. In many mammalian species, the Prdm9 gene is highly polymorphic. Prdm9 polymorphism is assumed to play two critical roles in evolution: to diversify the spectrum of meiotic recombination hotspots and to cause male hybrid sterility, leading to reproductive isolation and speciation. Nevertheless, information about Prdm9 sequences in natural populations is very limited. In this study, we conducted a comprehensive population survey on Prdm9 polymorphism in the house mouse, Mus musculus. Overall M. musculus Prdm9 displays an extraordinarily high level of polymorphism, particularly in regions encoding zinc finger repeats, which recognize recombination hotspots. Prdm9 alleles specific to various M. musculus subspecies dominate in subspecies territories. Moreover, introgression into other subspecies territories was found for highly divergent Prdm9 alleles associated with t-haplotype. The results of our phylogeographical analysis suggest that the requirement for hotspot diversity depends on geographical range and time span in mouse evolution, and that Prdm9 polymorphism has not been maintained by a simple balanced selection in the population of each subspecies., (© The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

The ratio of genetic diversity on X chromosomes relative to autosomes in organisms with XX/XY sex chromosomes could provide fundamental insight into the process of genome evolution. Here we report this ratio for 24 cynomolgus monkeys (Macaca fascicularis) originating in Indonesia, Malaysia, and the Philippines. The average X/A diversity ratios in these samples was 0.34 and 0.20 in the Indonesian-Malaysian and Philippine populations, respectively, considerably lower than the null expectation of 0.75. A Philippine population supposed to derive from an ancestral population by founding events showed a significantly lower ratio than the parental population, suggesting a demographic effect for the reduction. Taking sex-specific mutation rate bias and demographic effect into account, expected X/A diversity ratios generated by computer simulations roughly agreed with the observed data in the intergenic regions. In contrast, silent sites in genic regions on X chromosomes showed strong reduction in genetic diversity and the observed X/A diversity ratio in the genic regions cannot be explained by mutation rate bias and demography, indicating that natural selection also reduces the level of polymorphism near genes. Whole-genome analysis of a female cynomolgus monkey also supported the notion of stronger reduction of genetic diversity near genes on the X chromosome.

Background: Although sex and gender are increasingly perceived as important factors in medicine, there is only very little knowledge on these issues in patients with chronic pruritus (CP)., Objectives: The aim of this retrospective study was to compare multiple parameters of CP in a large representative group of patients and to assess any sex and gender differences., Methods: Patients (n = 1037, 54·8% women) with CP (> 6 weeks' duration) were analysed concerning gender differences in multiple parameters, including quality of life, CP-underlying diseases, co-morbidities and clinics. We used McNemar tests for dependent variables, and χ(2) tests and t-tests for independent variables, to evaluate gender-specific differences., Results: Men were significantly older (P < 0·001) than women and had significantly more often cardiovascular (P < 0·001) and urogenital (P < 0·0001) co-morbidities, a higher number of co-medications (P = 0·041), and more often dermatological and systemic diseases leading to CP. Women had more neuropathic and psychosomatic diseases underlying the CP. They significantly more often showed a worsening of the CP by emotional (P = 0·002) and psychosomatic factors (P = 0·046). Women reported more often on localized itching occurring in attacks, with stinging, warmth and painful qualities (P < 0·05). Women significantly more often showed chronic scratch lesions and prurigo nodularis (P = 0·001), in contrast to men who significantly more frequently had CP on noninflamed skin (P = 0·004). In addition, women obtained higher visual analogue scale scores (P = 0·031) and reported a higher impact on quality of life (P = 0·033) than men., Conclusions: There are gender-specific differences not only in the quality, localization and triggering of CP but also in the underlying disease and scratching behaviour. These facts must be taken into account in the medical care of patients with CP and when conducting any kind of clinical research on itch. Further research is needed to achieve a gender-specific and gender-adapted diagnostics and treatment of CP., (© 2013 The Authors BJD © 2013 British Association of Dermatologists.)

Aims: In several clinical and pre-clinical studies, application of ranolazine (RAN) led to suppression of atrial fibrillation (AF). The aim of the present study was to investigate whether RAN can suppress AF in an experimental rabbit whole heart model, in which acute haemodynamic changes trigger AF. Ranolazine was compared with flecainide and sotalol as established antiarrhythmic agents., Methods and Results: In 60 Langendorff-perfused, isolated rabbit hearts, AF episodes were evoked by burst pacing with a fixed number of stimuli at baseline and following acute atrial stretch. Data were obtained in the absence and presence of acute dilatation of the left atrium (20 mmHg) at baseline and after drug application (RAN 10 µM, n = 10; flecainide 2 µM, n = 10; sotalol 50 µM, n = 10). Application of sotalol, but not RAN or flecainide increased the atrial action potential duration at 90% repolarization (aAPD90); however, both RAN (+8 ms) and flecainide (+13 ms) increased interatrial conduction time. All three drugs caused a significant increase in atrial effective refractory period (aERP) and, thus, an increase in atrial post-repolarization refractoriness (aPRR: +11 ms each, P < 0.05). Acute dilatation of the left atrium reduced aAPD90 and aERP. The described drug effects were preserved in the setting of acute atrial dilatation. Acute atrial dilatation significantly increased the incidence of AF. Ranolazine and flecainide, but not sotalol, decreased the number of responses., Conclusion: Ranolazine-related sodium channel block is preserved upon acute atrial stretch. Ranolazine suppresses stretch-induced AF by increasing interatrial conduction time and aPRR. These results shed further evidence on the potential role of RAN in the prevention of AF. This might also apply to clinical conditions that are associated with haemodynamic or mechanical disorders, leading to acute dilatation of the atria.

The "nearly neutral" theory of molecular evolution proposes that many features of genomes arise from the interaction of three weak evolutionary forces: mutation, genetic drift, and natural selection acting at its limit of efficacy. Such forces generally have little impact on allele frequencies within populations from generation to generation but can have substantial effects on long-term evolution. The evolutionary dynamics of weakly selected mutations are highly sensitive to population size, and near neutrality was initially proposed as an adjustment to the neutral theory to account for general patterns in available protein and DNA variation data. Here, we review the motivation for the nearly neutral theory, discuss the structure of the model and its predictions, and evaluate current empirical support for interactions among weak evolutionary forces in protein evolution. Near neutrality may be a prevalent mode of evolution across a range of functional categories of mutations and taxa. However, multiple evolutionary mechanisms (including adaptive evolution, linked selection, changes in fitness-effect distributions, and weak selection) can often explain the same patterns of genome variation. Strong parameter sensitivity remains a limitation of the nearly neutral model, and we discuss concave fitness functions as a plausible underlying basis for weak selection.

Accelerated rates of mitochondrial protein evolution have been proposed to reflect Darwinian coadaptation for efficient energy production for mammalian flight and brain activity. However, several features of mammalian mtDNA (absence of recombination, small effective population size, and high mutation rate) promote genome degradation through the accumulation of weakly deleterious mutations. Here, we present evidence for "compensatory" adaptive substitutions in nuclear DNA- (nDNA) encoded mitochondrial proteins to prevent fitness decline in primate mitochondrial protein complexes. We show that high mutation rate and small effective population size, key features of primate mitochondrial genomes, can accelerate compensatory adaptive evolution in nDNA-encoded genes. We combine phylogenetic information and the 3D structure of the cytochrome c oxidase (COX) complex to test for accelerated compensatory changes among interacting sites. Physical interactions among mtDNA- and nDNA-encoded components are critical in COX evolution; amino acids in close physical proximity in the 3D structure show a strong tendency for correlated evolution among lineages. Only nuclear-encoded components of COX show evidence for positive selection and adaptive nDNA-encoded changes tend to follow mtDNA-encoded amino acid changes at nearby sites in the 3D structure. This bias in the temporal order of substitutions supports compensatory weak selection as a major factor in accelerated primate COX evolution.

Population genetics of species living in marginal habitats could be particularly informative about the genetics of adaptation, but such analyses have not been readily feasible until recently. Sonneratia alba, a mangrove species widely distributed in the Indo-West Pacific, provides a very suitable system for the study of local adaptation. In this study, we analyzed DNA variation by pooling 71 genes from 85-100 individuals for DNA sequencing. For each of the two nearby S. alba populations, we obtained ~2,500 × coverage on the Illumina GA platform and for the Sanya population, an additional 5,400 × coverage on the AB SOLiD platform. For the Sanya sample, although each sequencing method called many putative single nucleotide polymorphisms, the two sets of calls did not overlap, suggesting platform-dependent errors. Conventional sequencing corroborated that each population is monomorphic. The two populations differ by 54 bp of 79,000 sites, but 90% of the variants are found in 10% of the genes. Strong local adaptation and high migration may help to explain the extensive monomorphism shared by the two populations in the presence of a small number of highly differentiated loci.

Aims: exercise may dramatically change the extent of functional mitral regurgitation (MR) and left ventricular (LV) geometry in patients with chronic heart failure (CHF). We hypothesized that dynamic changes in MR and LV geometry would affect exercise capacity., Methods and Results: this study included 30 CHF patients with functional MR who underwent symptom-limited bicycle exercise stress echocardiography and cardiopulmonary exercise testing for quantitative assessment of MR (effective regurgitant orifice; ERO), and pulmonary artery systolic pressure (PASP). LV sphericity index was obtained from real-time three-dimensional echocardiograms. The patients were stratified into exercised-induced MR (EMR; n = 10, an increase in ERO by ≥13 mm(2)) or non-EMR (NEMR; n = 20, an increase in ERO by <13 mm(2)) group. At rest, no differences in LV volume and function, ERO, and PASP were found between the two groups. At peak exercise, PASP and sphericity index were significantly greater (all P < 0.01) in the EMR group. The EMR group revealed lower peak oxygen uptake (peak VO(2); P = 0.018) and greater minute ventilation/carbon dioxide production slope (VE/VCO(2) slope; P = 0.042) than the NEMR group. Peak VO(2) negatively correlated with changes in ERO (r = -0.628) and LV sphericity index (r = -0.437); meanwhile, VE/VCO(2) slope was well correlated with these changes (r = 0.414 and 0.364, respectively). A multivariate analysis identified that the change in ERO was the strongest predictor of peak VO(2) (P = 0.001)., Conclusion: dynamic changes in MR and LV geometry contributed to the limitation of exercise capacity in patients with CHF.

Aims: Left ventricular (LV) shape and LV dyssynchrony are two cofactors associated with functional mitral regurgitation (MR) in patients with heart failure. Both can be accurately examined by real-time three-dimensional echocardiography (3DE). We examined the relationship between dynamic MR and exercise-induced changes in LV shape and synchronicity using 3DE., Methods and Results: Fifty patients with systolic LV dysfunction underwent 2D and 3D quantitative assessment of LV function, shape, and synchronicity at rest and during symptom-limited exercise test. According to the magnitude of change in MR, patients were divided into EMR group (15 patients, 30%), if the degree of MR increased during test, and NEMR group. During exercise, the changes in LV volumes and ejection fraction were similar in both groups, whereas changes in mitral valvular deformation parameters, in LV sphericity index, and in the extent of LV dyssynchrony were more pronounced in the EMR group. At rest, only the 3D sphericity index could distinguish the two groups. By stepwise multiple regression model, dynamic changes in the systolic dyssynchrony index, sphericity index, and coaptation distance were associated with dynamic MR (r(2) = 0.45, P = 0.012)., Conclusion: Dynamic MR during exercise is related to the 3D changes in LV shape and in LV synchronicity.

There is a mounting evidence for the correlation between the gene expression pattern and sequence divergence. However, little is known about the relationship between the gene expression pattern and polymorphism. We compiled the gene expression, polymorphism, and divergence data from the public databases of the human genome. The ratios of nonsynonymous (A) to synonymous (S) substitutions in polymorphism and divergence in the human genome were strongly influenced by the expression pattern and breadth of genes and showed strong correlations. Among the tissues we analyzed, the brain-expressed genes have the smallest and the liver-expressed genes have the largest proportion of amino acid changes both in polymorphism and divergence. The analysis implies that negative selection is the primary factor affecting expression-dependent gene evolution and the prevalent but nonuniform distribution of slightly deleterious mutations in the genome. Although the genes under relaxed negative selection evolved faster than the other genes, these genes are even more liable to slightly deleterious mutations in the population. On the other hand, nonneutral mutations in the highly conservative genes, such as brain-expressed and housekeeping genes, are largely deleterious and eliminated before they enter the population.

Nucleotide sequence polymorphisms affecting gene expression occur in the regulatory region of genes (in cis) and elsewhere in the genome (in trans). Further study is required to weigh the relative importance of cis- and trans-acting mutations in mediating gene expression differences within and between species. Here, microarray hybridization experiments were used to isolate 363 gene expression differences between the female fly head transcriptomes of 2 Drosophila melanogaster strains. One strain (French) represented the cosmopolitan M mating race and the other strain (ZS30) represented the Z mating race derived from Zimbabwe, Africa. From chromosomal substitution strains engineered from the 2 strains, we inferred that the expression differences between M and Z alleles largely could be attributed to the genotype of the chromosomes where the differentially expressed genes were located, that is, cis-regulatory polymorphisms prominently influence gene expression differences between M and Z. The effects of trans-regulatory polymorphisms were apparent yet difficult to quantify. Results have implications for models of gene regulatory evolution as well as experimental studies trying to identify the nucleotide sequence polymorphisms underlying gene expression differences between Drosophila strains.

Retrotransposable element-1 (RTE-1) is a class of long interspersed nucleotide elements that contain in its open reading frame an apurinic/apyrimidinic endonuclease domain (AP-END) and a reverse transcriptase domain. Ruminants have a clade-specific RTE-1 (BovB/RTE). The bovine bcnt gene (bucentaur or craniofacial developmental protein 1) has a duplicated paralog (bcntp97) in tandem that recruited an AP-END of BovB/RTE as a coding exon (RTE exon). We obtained sequence of the bcnt region from several animals and showed that other ruminants also have the bcntp97 with a conserved RTE exon while camels and pigs do not. Genomic Southern analysis showed that camels and pigs have multiple bcnt-related sequences but not BovB/RTE which bovines and lesser mouse deer have abundantly. These results indicate that the bcnt gene duplication followed by the creation of bcntp97 including recruitment of the RTE exon occurred in the ancestral ruminant about 55 MYA. The indication of time frame is supported by a phylogenetic analysis. Taken together with a result of differential tissue expression of the two bcnt paralogs, we conclude that bcntp97 was created concurrently with the early radiation of BovB/RTE in an ancestral ruminant and then acquired a novel function.

The substitution rate and structural divergence in the 5'-untranslated region (UTR) were investigated by using human and cynomolgus monkey cDNA sequences. Due to the weaker functional constraint in the UTR than in the coding sequence, the divergence between humans and macaques would provide a good estimate of the nucleotide substitution rate and structural divergence in the 5'UTR. We found that the substitution rate in the 5'UTR (K5UTR) averaged approximately 10%-20% lower than the synonymous substitution rate (Ks). However, both the K5UTR and nonsynonymous substitution rate (Ka) were significantly higher in the testicular cDNAs than in the brain cDNAs, whereas the Ks did not differ. Further, an in silico analysis revealed that 27% (169/622) of macaque testicular cDNAs had an altered exon-intron structure in the 5'UTR compared with the human cDNAs. The fraction of cDNAs with an exon alteration was significantly higher in the testicular cDNAs than in the brain cDNAs. We confirmed by using reverse transcriptase-polymerase chain reaction that about one-third (6/16) of in silico "macaque-specific" exons in the 5'UTR were actually macaque specific in the testis. The results imply that positive selection increased K5UTR and structural alteration rate of a certain fraction of genes as well as Ka. We found that both positive and negative selection can act on the 5'UTR sequences.

The strictly allopatric model of speciation makes definable predictions on the pattern of divergence, one of which is the uniformity in the divergence time across genomic regions. Using 345 coding and 143 intergenic sequences from the African great apes, we were able to reject the null hypothesis that the divergence time in the coding sequences (CDSs) and intergenic sequences (IGSs) is the same between human and chimpanzee. The conclusion is further supported by the analysis of whole-genome sequences between these species. The difference suggests a prolonged period of genetic exchange during the formation of these two species. Because the analysis should be generally applicable, collecting DNA sequence data from many genomic regions between closely related species should help to settle the debate over the prevalence of the allopatric mode of speciation.

Ruminant Bcnt protein with a molecular mass of 97 kDa (designated p97Bcnt) includes a region derived from the endonuclease domain of a retrotransposable element RTE-1. Human and mouse Bcnt proteins lack the corresponding region but have a highly conserved 82-amino acid region at the C-terminus that is not present in p97Bcnt. By screening a bovine BAC library, we found two more bcnt-related genes: human-type bcnt (h-type bcnt) and its processed pseudogene. Whereas the pseudogene is localized on chromosome 26, both bcntp97 and the h-type bcnt genes are found on bovine chromosome 18, a synteny region of human chromosome 16 on which human BCNT is localized. Complete nucleotide sequencing of the BAC clone reveals that the bcntp97 and h-type bcnt genes are located just 6 kb apart in a tandem manner. The two h-type bcnt and bcntp97genes are active at both the transcriptional level and the protein level. H-type bovine Bcnt is more like human BCNT than p97Bcnt, when compared at their N-terminal regions. However, phylogenetic analysis using the N-terminal region of the bcnt gene family revealed that the duplication of bovine genes occurred within the bovine lineage with significantly accelerated substitution in bcntp97. This acceleration was not ascribed definitely to positive selection. After duplication, one of the bovine bcnt genes recruited the endonuclease domain of an intronic RTE-1 repeat accompanied by the accelerated substitution at the 5'-ORF, resulting in creation of a novel type of Bcnt protein in bovine.

To investigate crown development patterns, branch architecture, branch-level light interception, and leaf and branch dynamics were studied in saplings of a plagiotropically branching tree species, Polyalthia jenkinsii Hk. f. & Thoms. (Annonaceae) in a Malaysian rain forest. Lengths of branches and parts of the branches lacking leaves ('bare' branches) were smaller in upper branches than in lower branches within crowns, whereas lengths of 'leafy' parts and the number of leaves per branch were larger in intermediate than in upper and lower branches. Maximum diffuse light absorption (DLA) of individual leaves was not related to sapling height or branch position within crowns, whereas minimum DLA was lower in tall saplings. Accordingly, branch-level light interception was higher in intermediate than in upper and lower branches. The leaf production rate was higher and leaf loss rate was smaller in upper than in intermediate and lower branches. Moreover, the branch production rate of new first-order branches was larger in the upper crowns. Thus, leaf and branch dynamics do not correspond to branch-level light interception in the different canopy zones. As a result of architectural constraints, branches at different vertical positions experience predictable light microenvironments in plagiotropic species. Accordingly, this pattern of carbon allocation among branches might be particularly important for growth and crown development in plagiotropic species., (Copyright 2003 Annals of Botany Company)

Allometry of shoot extension units (hereafter termed "current shoots") was analyzed in a Malaysian canopy species, Elateriospermum tapos Bl. (Euphorbiaceae). Changes in current shoot allometry with increasing tree height were related to growth and maintenance of tree crowns. Total biomass, biomass allocation ratio of non-photosynthetic to photosynthetic organs, and wood density of current shoots were unrelated to tree height. However, shoot structure changed with tree height. Compared with short trees, tall trees produced current shoots of the same mass but with thicker and shorter stems. Current shoots with thin and long stems enhanced height growth in short trees, whereas in tall trees, thick and short current shoots may reduce mechanical and hydraulic stresses. Furthermore, compared with short trees, tall trees produced current shoots with more leaves of lower dry mass, smaller area, and smaller specific leaf area (SLA). Short trees adapted to low light flux density by reducing mutual shading with large leaves having a large SLA. In contrast, tall trees reduced mutual shading within a shoot by producing more small leaves in distal than in proximal parts of the shoot stem. The production of a large number of small leaves promoted light penetration into the dense crowns of tall trees. All of these characteristics suggest that the change in current shoot structure with increasing tree height is adaptive in E. tapos, enabling short trees to maximize height growth and tall trees to maximize light capture.