Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping

BACKGROUND: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. METHODS: Additional genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-III-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. RESULTS: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). CONCLUSIONS: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.     

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy

We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.     

Malignant Rhabdoid Tumor of the Floor of Mouth: First Reported Case in the Oral Cavity of an Adult

Malignant rhabdoid tumors (MRTs) are exceedingly rare lesions. To our knowledge, only 2 cases have been reported in the oral cavity, with both examples occurring in infants. The current case is the third reported case of MRT of the oral cavity and the first reported case to occur in an adult at this location. The following report describes the clinical, histologic and immunohistochemical features of this tumor.     

A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years

The study of human evolution has been revolutionized by inferences from ancient DNA analyses. Key to these studies is the reliable estimation of the age of ancient specimens. High-resolution age estimates can often be obtained using radiocarbon dating, and, while precise and powerful, this method has some biases, making it of interest to directly use genetic data to infer a date for samples that have been sequenced. Here, we report a genetic method that uses the recombination clock. The idea is that an ancient genome has evolved less than the genomes of present-day individuals and thus has experienced fewer recombination events since the common ancestor. To implement this idea, we take advantage of the insight that all non-Africans have a common heritage of Neanderthal gene flow into their ancestors. Thus, we can estimate the date since Neanderthal admixture for present-day and ancient samples simultaneously and use the difference as a direct estimate of the ancient specimen’s age. We apply our method to date five Upper Paleolithic Eurasian genomes with radiocarbon dates between 12,000 and 45,000 y ago and show an excellent correlation of the genetic and ¹⁴C dates. By considering the slope of the correlation between the genetic dates, which are in units of generations, and the ¹⁴C dates, which are in units of years, we infer that the mean generation interval in humans over this period has been 26–30 y. Extensions of this methodology that use older shared events may be applicable for dating beyond the radiocarbon frontier.Ancient DNA analyses have transformed research into human evolutionary history, making it possible to directly observe genetic variation patterns that existed in the past, instead of having to infer them retrospectively (1). To interpret findings from an ancient specimen, it is important to have an accurate estimate of its age. The current gold standard is radiocarbon dating, which is applicable for estimating dates for samples up to 50,000 y old (2). This method is based on the principle that, when a living organism dies, the existing ¹⁴C starts decaying to ¹⁴N with a half-life of ∼5,730 y (3). By measuring the ratio of ¹⁴C to ¹²C in the sample and assuming that the starting ratio of carbon isotopes is the same everywhere in the biosphere, the age of the sample is inferred. A complication is that carbon isotope ratios vary among carbon reservoirs (e.g., marine, freshwater, atmosphere) and over time. Thus, ¹⁴C dates must be converted to calendar years using calibration curves based on other sources, including annual tree rings (dendrochronology) or uranium-series dating of coral (2). Such calibrations, however, may not fully capture the variation in atmospheric carbon. In addition, contamination of a sample by modern carbon, introduced during burial or by handling afterwards, can make a sample seem younger than it actually is (2). The problem is particularly acute for samples that antedate 30,000 y ago because they retain very little original ¹⁴C.Here, we describe a genetic approach for dating ancient samples, applicable in cases where DNA sequence data are available, as is becoming increasingly common (1). This method relies on the insight that an ancient genome has experienced fewer generations of evolution compared with the genomes of its living (i.e., extant) relatives. Because recombination occurs at an approximately constant rate per generation, the accumulated number of recombination events provides a molecular clock for the time elapsed or, in the case of an ancient sample, the number of missing generations since it ceased to evolve. This idea is referred to as “branch shortening” and estimates of missing evolution can be translated into absolute time in years by using an estimate of the mean age of reproduction (generation interval) or an independent calibration point such as human–ape divergence time.Branch shortening has been used in studies of population history, for inferring mutation rates, and for establishing time scales for phylogenic trees in humans and other species (4, 5). It was first applied for dating ancient samples on a genome-wide scale by Meyer et al. (6), who used the mutation clock (instead of the recombination clock as proposed here) to estimate the age of the Denisova finger bone, which is probably older than 50,000 y, and has not been successfully radiocarbon dated (6). Specifically, the authors compared the divergence between the Denisova and extant humans and calibrated the branch shortening relative to human–chimpanzee (HC) divergence time. The use of ape divergence time for calibration, however, relies on estimates of mutation rate that are uncertain (7). In particular, recent pedigree studies have yielded a yearly mutation rate that is approximately twofold lower than the one obtained from phylogenetic methods (7). In addition, comparison with HC divergence relies on branch-shortening estimates that are small relative to the total divergence of millions of years, so that even very low error rates in allele detection can bias estimates. These issues lead to substantial uncertainty in estimated age of the ancient samples, making this approach impractical for dating specimens that are tens of thousands of years old, a time period that encompasses the vast majority of ancient human samples sequenced to date.Given the challenges associated with the use of the mutation clock, here we explore the possibility of using a molecular clock based on the accumulation of crossover events (the recombination clock), which is measured with high precision in humans (8). In addition, instead of using a distant outgroup, such as chimpanzees, we rely on a more recent shared event that has affected both extant and ancient modern humans and is therefore a more reliable fixed point on which to base the dating. Previous studies have documented that most non-Africans derive 1–4% ancestry from Neanderthals from an admixture event that occurred ∼37,000–86,000 y before present (yBP) (9, 10), with some analyses proposing a second event (around the same time) into the ancestors of East Asians (11, 12). Because the vast majority of ancient samples sequenced to date were discovered in Eurasia (with estimated ages of ∼2,000–45,000 yBP), postdate the Neanderthal admixture, and show evidence of Neanderthal ancestry, we used the Neanderthal gene flow as the shared event.The idea of our method is to estimate the date of Neanderthal gene flow separately for the extant and ancient genomes. Because the ancient sample is closer in time to the shared Neanderthal admixture event, we expect that the inferred dates of Neanderthal admixture will be more recent in ancient genomes (by an amount that is directly determined by the sample’s age) compared with the dates in the extant genomes. The difference in the dates thus provides an estimate of the amount of missing evolution: that is, the age of the ancient sample. An illustration of the idea is shown in SI Appendix, Fig. S1. An assumption in our approach is that the Neanderthal admixture into the ancestors of modern humans occurred approximately at the same time and that the same interbreeding events contributed to the ancestry of all of the non-African samples being compared. Deviations from this model could lead to incorrect age estimates. Our method is not applicable for dating genomes that do not have substantial Neanderthal ancestry, such as sub-Saharan African genomes.To date the Neanderthal admixture event, we used the insight that gene flow between genetically distinct populations, such as Neanderthals and modern humans, introduces blocks of archaic ancestry into the modern human background that break down at an approximately constant rate per generation as crossovers occur (13–15). Thus, by jointly modeling the decay of Neanderthal ancestry and recombination rates across the genome, we can estimate the date of Neanderthal gene flow, measured in units of generations. Similar ideas have been used to estimate the time of admixture events between contemporary human populations (14–16), as well as between Eurasians and Neanderthals (9, 17). An important feature of our method is that it is expected to give more precise results for samples that are older because these samples are closer in time to the Neanderthal introgression event, thus it is easier to accurately estimate the time of the admixture event for them. Thus, unlike ¹⁴C dating, the genetic approach becomes more reliable with age and, in that regard, complements ¹⁴C dating.     

Antiobesity,hypolipidemic, antioxidant and hepatoprotective effects of Achyranthes aspera seed saponins in high cholesterol fed albino rats

Introduction

Numerous herbal medicines have been recommended for the treatment of different diseases. Achyranthes aspera, Linn. (Family: Amaranthaceae), popularly known as Charchitta or Pitpapra, is commonly used by traditional healers for the treatment of fever, malaria, dysentery, asthma, arterial hypertension, pneumonia, and diabetes. The root extract is well reputed for its insect molting hormonal activity. This investigation was conducted to evaluate the effects of saponins from Achyranthes aspera seeds on the serum lipid profile of albino rats fed a high cholesterol diet.

Material and methods

Hypolipidemic, antioxidant and hepatoprotective activities of these saponins were tested as described previously. To determine the mechanism underlying the observed effects, serum antioxidant status was assessed according to ABTS (2,2’-azino-bis-3-ethylbenzo-thiazoline-6-sulfonic acid), superoxide dismutase and ferric ion reducing antioxidant power (FRAP) assays in saponin-treated hyperlipidemic animals. Liver enzyme levels were determined to reveal any possible hepatotoxicity.

Results

Four-week oral administration of A. aspera seed saponins produced a significant (p < 0.05) decrease of total cholesterol, total triglycerides and LDL-C and a significant increase of HDL-C level in hyperlipidemic rats. Treatment with A. aspera seed saponins also showed a significant (p < 0.01) improvement of serum antioxidant status in tested animals. No significant hepatotoxicity was produced by such treatment as the serum liver enzyme activity remained unaltered.

Conclusions

Saponins from A. aspera seeds possess antihyperlipidemic and antioxidant properties which might lead to improvement of serum lipid profile and blood antioxidant status. Our findings support the folkloric use of this indigenous plant in the treatment of hyperlipidemia. However, its exact mechanism of action remains to be elucidated.     

Temperature drives global patterns in forest biomass distribution in leaves,stems, and roots

Whether the fraction of total forest biomass distributed in roots, stems, or leaves varies systematically across geographic gradients remains unknown despite its importance for understanding forest ecology and modeling global carbon cycles. It has been hypothesized that plants should maintain proportionally more biomass in the organ that acquires the most limiting resource. Accordingly, we hypothesize greater biomass distribution in roots and less in stems and foliage in increasingly arid climates and in colder environments at high latitudes. Such a strategy would increase uptake of soil water in dry conditions and of soil nutrients in cold soils, where they are at low supply and are less mobile. We use a large global biomass dataset (>6,200 forests from 61 countries, across a 40 °C gradient in mean annual temperature) to address these questions. Climate metrics involving temperature were better predictors of biomass partitioning than those involving moisture availability, because, surprisingly, fractional distribution of biomass to roots or foliage was unrelated to aridity. In contrast, in increasingly cold climates, the proportion of total forest biomass in roots was greater and in foliage was smaller for both angiosperm and gymnosperm forests. These findings support hypotheses about adaptive strategies of forest trees to temperature and provide biogeographically explicit relationships to improve ecosystem and earth system models. They also will allow, for the first time to our knowledge, representations of root carbon pools that consider biogeographic differences, which are useful for quantifying whole-ecosystem carbon stocks and cycles and for assessing the impact of climate change on forest carbon dynamics.After acquisition via photosynthesis (gross primary production), new plant carbon (C) is respired, transferred to mycorrhizal symbionts, exuded, or converted into new biomass (net primary production). The new biomass can be foliage, stems (including boles, branches, and bark), roots, or reproductive parts. The proportional allocation of new C to these four plant biomass pools, when combined with their turnover rates, results in the proportional distribution of standing biomass among these pools. Such processes can be influenced by plant size, resource supply, and/or climate (1–10). Although simple in concept, our understanding of these processes and our ability to quantify and predict them remain surprisingly rudimentary (3–13).The general lack of knowledge about C partitioning is important for a number of reasons, including its implications for the accuracy of global C cycle modeling and accounting. A recent study (11) concluded

different carbon partitioning schemes resulted in large variations in estimates of global woody carbon flux and storage, indicating that stand-level controls on carbon partitioning are not yet accurately represented in ecosystem models.

Uncertainty about C partitioning in relation to biogeography and environmental effects is a particularly critical knowledge gap, because the direct and indirect influence of temperature or moisture availability on biomass partitioning could be important to growth, nutrient cycling, productivity, ecosystem fluxes, and other key plant and ecosystem processes (5, 7–10, 12). Additionally, uncertainty about belowground C allocation and biomass dynamics represents a major information gap that hampers efforts to estimate belowground C pools at continental to global scales (cf. 13 and 14).Some of the limited evidence available supports the hypothesis that under low temperatures both selection and phenotypic plasticity should promote a relatively greater fraction of forest biomass in roots (5, 7, 8, 12, 15–18), as a result of adaptation to low nutrient supply (7, 19–22) driven by low nutrient cycling rates and limited soil solution movement. Cold environments also are often periodically dry and exhibit low plant production (19–26). Belowground resource limitations obviously also rise with increasing shortage of rainfall relative to evaporative demand, which can influence biomass distribution as well (4, 5, 17). Uncertainties include whether there are differences across climate gradients in the fraction of gross primary production respired vs. converted into new biomass; how new biomass is partitioned to foliage, stems, and roots; what the turnover rates are for these different tissues; and what are the consequences of the biomass distribution in foliage, stem, and root. In this study we focus on the last uncertainty—biomass distributions in standing pools—which is a direct consequence of new biomass allocation and subsequent turnover rate. Following optimal partitioning theory (1–4), we posit that the fraction of total forest biomass in roots should increase and in foliage should decrease when belowground resources are scarce.We use a large dataset based on more than 6,200 observations of forest stands in 61 countries (Tables S1–S3 and Fig. 1) to test the following hypotheses: (i) with increasing temperature, proportional biomass distribution (i.e., fraction of total biomass) should decrease in roots and increase in foliage; (ii) with increasing water shortage (estimated by an index of rainfall to evaporative demand), proportional biomass distribution should increase in roots and decrease in foliage; and (iii) gymnosperm and angiosperm forests should follow similar patterns. The dataset comprises data entries for individual stands including total foliage mass per hectare (M_fol), total stem mass per hectare (M_stem), total root mass per hectare (M_root), and, where available, total mass per hectare (M_tot = M_fol + M_stem + M_root). Forests were either naturally regenerated or plantations. Stands were classified as gymnosperm or angiosperm based on whichever represented a greater fraction of basal area or biomass; almost all native forests were of mixed species.Open in a separate windowFig. 1.Map showing location of all stands in the assembled database (see Tables S1 and S2 for additional information specific to those with root, foliage, and stem biomass data or with foliage and stem biomass data) across color-coded ranges of MAT.The sampled forests varied widely in age (from 3–400 y) and size (with M_tot ranging from near zero to 300 Mg/ha). Differences in biomass (which we refer to as size) reflect differences in productivity, density, and especially the range of ages of sampled stands. Because tree-size scaling is allometric (3, 4, 7, 9), we use an allometric approach to account for size-related changes in biomass partitioning in examining broad biogeographic patterns. Forests with high biomass have larger trees on average than forests with low biomass (given that tree density typically is lower in the former), so the forest size allometry characterized herein likely has its roots at the individual tree scale, but our analyses use stand M_tot, not individual tree biomass. We also examine biogeographic differences in the fraction of M_tot in foliage (F_fol), stem (F_stem), and root (F_root).The term “allocation” has been used historically to describe both the onward distribution, or flux, of newly acquired substances (usually C or biomass) to different plant functions and differences in how those pools are distributed at any point in time. To minimize confusion about these different measures. we hereafter use the term “allocation” along with “new biomass” or “new C” only to indicate the former and discuss either the proportion of biomass or the fraction of biomass distributed in foliage, stems, or roots to indicate the latter.The sampled forests varied widely geographically and in mean annual temperature (MAT) (from −13 to 29 °C) and mean annual precipitation (MAP) (from 20–420 cm) (Tables S1 and S2 and Fig. 1). Because a number of seasonal and annual climatic factors covary, it is difficult to ascertain which are responsible for the observed patterns (Materials and Methods and SI Materials and Methods). Because MAP is strongly correlated with MAT and is not a good global measure of water availability, we used an aridity index, the ratio of MAP to annual potential evapotranspiration (MAP/PET) (27) as a measure of relative water availability. MAP/PET ranged from <0.5 in cold, high-latitude zones to >3 in temperate and tropical rainforests. The forests ranged from sea level to >4,000 m elevation, with the large majority at <1,000 m elevation. More sampled forests were from Asia and Europe than other continents, and more were boreal and temperate than tropical. Thus, inferences from these data are likely to be most reliable across the gradient from subtropical to cold boreal forests.     

3D-Planung in der Implantologie

Der Freie Zahnarzt - „Die Digitalisierung wird sämtliche Lebensbereiche revolutionieren.“ „Wer sich nicht damit auseinandersetzt, wird untergehen.“ „Wer nicht...     

Comparison of caregiver strain in Parkinson's disease between Yamagata,Japan, and Maryland,The United States

BackgroundJapan and the United States (US) have different cultures of caregiving including differences in family structure and social programs that may influence caregiver strain. Differences in caregiver strain between regions in Japan and in the US have not been investigated in patient–spouse dyads in PD.ObjectivesTo compare caregiver strain in spouses of PD patients between Yamagata, Japan and Maryland, US. Correlations between caregiver strain and patient/spousal variables are also examined.MethodsIn Yamagata and Maryland, spouses of patients with PD completed questionnaires assessing caregiver strain. Patients and spouses completed scales assessing mental health, and medical co-morbidity. PD severity and disability were assessed with the Unified Parkinson's Disease Rating Scale and the Schwab and England Activities of Daily Living Scale. Results in the two regions were compared with Chi-square and Student's t-tests. Relationships between caregiver strain and patient/spousal variables were analyzed with univariate correlations and multivariate regression.Results178 Spouse–patient pairs were assessed. The level of caregiver strain in PD did not differ between Yamagata, Japan and Maryland, US despite differences in demographics and social support programs in the two regions. Yamagata spouses reported physical, time and financial constraints, while Maryland spouses reported more emotional distress. In both regions, spousal depression was a significant contributor to caregiver strain.ConclusionDifferent approaches to reduce caregiver strain will likely be necessary in Yamagata and Maryland since the contributing factors to caregiver strain are influenced by differences in culture and social supports in each country.     

Chair-side generated posterior lithium disilicate crowns after 4 years

Objectives

The objective of this prospective clinical study was to evaluate the performance of chair-side generated crowns after 48 months.

Materials and methods

Forty-one posterior full contour crowns made of a machinable lithium disilicate ceramic (e.max CAD LT) were inserted in 34 patients applying a chair-side CAD/CAM technique. One crown per patient was randomly selected for evaluation at baseline, after 6, 12, 24, 36, and 48 months according to modified US Public Health Service criteria.

Results

After a mean observation time of 51 months (min, 48 months; max, 56 months; SD?±?2.3 months), 29 crowns were available for re-examination. Within the observation period, one failure occurred due to a crown fracture after 2.8 years. Four abutment teeth revealed signs of biological complications: Two abutment changed sensibility perception from positive to negative within the first 13 month. Two abutment teeth showed secondary caries below the crown margin, one after the 24, and another after the 48 month recall. Both abutments received cervical adhesive composite fillings. The failure-free rate was 96.3 % after 4 years according to Kaplan–Meier (CI: upper bound, 4.4 years; lower bound, 4.7 years).

Conclusions

Due to the fact that the secondary caries was not caused as a result of an inaccuracy of the crown margins and the endodontic complications were in a normal range, the clinical performance of the crowns was completely satisfying.

Clinical relevance

The chair-side application of lithium disilicate crowns can be recommended.