Quantitative Amyloid Imaging Using Image-Derived Arterial Input Function

Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer’s disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (V_T) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVR_kinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVR_REF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum V_T was in line with literature reported values and the variability of cerebellum V_T in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization may not be accurate.     

Optimal molecular structures of prion AGAAAAGA amyloid fibrils formatted by simulated annealing

To date, there is little structural data available on the AGAAAAGA palindrome in the hydrophobic region (113–120) of prion proteins, although many experimental studies have shown that this region has amyloid fibril forming properties. This region belongs to the N-terminal unstructured region (1–123) of prions, the structure of which has proved hard to determine using NMR or X-ray crystallography. This paper reports the successful construction of three amyloid fibril models for this region. The models were formatted by standard simulated annealing using suitable templates from the Protein Data Bank, and were refined using several traditional optimization methods within AMBER. Because the NMR or X-ray structure of the hydrophobic region AGAAAAGA of prion proteins has not yet been determined, these models can be used as a reference for experimental studies on this region. The results presented here confirm standard simulated annealing as an effective tool in molecular modeling. The three constructed models for amyloid fibrils may be useful in furthering the goals of medicinal chemistry in this field.     

Experimental and Analytical Studies of Pteridophytes: XVIII. The Nutritional Status of the Apex and Morphogenesis

The relation between the nutrition of the shoot apex and itsmorphogenetic activity is discussed with special reference tothe ferns. From an early stage in the individual developmentthe distal region of the shoot is dependent on supplies of nutrients(the term is used in a comprehensive sense) passed up from thebasal absorptive region. The obconical enlargement of the shootis attended by an increase in the size of the apical and sub-apicalregions; but whereas the primary morphogenetic activities ofthe apical region are closely comparable in small and largeapices, very pronounced differences in leaf shape and size andin stelar morphology may be induced according to the nutritionalstatus of the sub-apical regions. Large apices, which normallyyield large and complex leaves and an elaborate vascular system,can, by appropriate treatments, be caused to yield 'juvenile'leaves and a simple vascular system. The nutritional statusof the sub-apical regions is thus seen to be of considerableinterest and importance in studies of morphogenesis. A conceptionof the mode of distribution of nutrients in the shoot apex isdescribed and discussed. The need for physiological investigationsof the apex is emphasized and the scope for new work using themethods of tissue culture is indicated by reference to recentpublished work.     

FMDV OH99株基因组全序列的测定及其基因特征研究

采用RT-PCR方法对FMDV OH99株基因组全序列进行了分子克隆与测序。结果表明OH99株基因组全基因组序列长8040nt,其中5’NCR长1026nt,前导蛋白(L)编码区长603nt。该毒株结构蛋白与非结构蛋白编码区的核苷酸序列为6318nt,3’NCR长93nt,其后是poly(A)尾巴,测序结果表明该结构至少含有56个A。应用分子生物学软件,将OH99株与其它参考毒株进行了序列比较,并对其基因特征、推导的氨基酸序列进行了研究分析。结果显示,在分类地位上OH99株归属于O型FMDV,与OTY TW／97具有较高的同源性,而与其他参考毒株的差异性比较大,而且在基因组功能未知区域和3A编码区域具有两处明显的基因片段缺失现象,其中3A编码区缺失30nt,与OTY TW/97株相同,但功能未知区域的缺失状况与OTY TW／97稍有差异。根据VP1基因序列,对OH99株与参考毒株进行了系统发生树分析,分析结果表明OH99株与0TY TW／97株在同一基因型内,其遗传关系最近,而与其毒株遗传关系较远。     

Comparing two sets of community data: A method for testing reserve adequacy

Abstract Comparing a new set of samples to what may be considered a reference set is a common problem in ecology. The investigator may be interested in the degree of correspondence or any anomalies. For example, does a set of existing reserves adequately cover the range of communities sampled in a region? A technique for such comparisons is proposed. Being dependent solely on estimates of ecological resemblance, it is simple, efficient and robust. Significant difference is defined by means of a resemblance coefficient. A threshold value denoting significant difference can be defined either by species overlap or other attributes of the data. For presence/absence data the Czekanowski coefficient provides a suitable measure of ecological resemblance. Traditional discriminant analysis does not provide a viable alternative due to its limitations in accommodating ecological data.     

Merremia discoidesperma: Its taxonomy and capacity of its seeds for ocean drifting

Merremia discoidesperma (Donn. Sm.) O’Donell (Mary’s-bean) is a rarely collected and inadequately described high climbing woody liana of Chiapas, Mexico; Guatemala; Costa Rica; Hispaniola; and Cuba. There is only one record of this species being cultivated and this from Guanajuato, Mexico in 1894, though seeds are used in folk remedies. These seeds are topographically unlike other known convolvulaceous seeds, thus permitting their positive identification. Because seeds remain buoyant for more than three years in seawater, those produced in the Caribbean and Atlantic drainage region may be transported by the Gulf Stream System as far north as the Norwegian coast, a distance of about 9,500 km. Seeds produced in the Pacific drainage region from Chiapas, Mexico south to Costa Rica may be transported by the North Pacific Equatorial Current as far west as Wotho Atoll in the Marshall Islands, a distance of about 11,000 km. Records of drifting and subsequent stranding of these and other tropical New World disseminules are supported by drift bottle studies and drift debris records in the Atlantic Ocean. In the Pacific Ocean region distribution of stranded Mary’s-bean seeds is supported by a similar distribution of New World pumice. There is an indication in the literature that Mary’s-bean seeds may drift to the Philippines. The record from Wotho Atoll to Norway constitutes the widest drift range of any seed or fruit which has been documented. Other tropical disseminules may drift as far or farther, but their origins cannot be ascertained with certainty. The plant is described, its synonyms listed, and its distribution as well as the distribution of its stranded seeds recorded.     

The dendrochronological proof of origin of oak churches located in the Czech Republic

Transcarpathian wooden churches started to dilapidate after World War I. To preserve the architectural heritage, five oak churches were transported from the region to the territory of today's Czech Republic. However, an exact date of their construction and origin of wood have not been specified and evidenced in literature. In this study, 63 samples have been collected and processed using standard dendrochronological methods. Three Baroque churches, coming from the Mukachevo district, were absolutely dated thanks to the preserved waney edge or sapwood tree rings to periods 1734–1744, 1753–1755, and 1783–1795. Two other churches, representing Gothic architecture, were transported from a more eastern part of Transcarpathian Ukraine. One of them was dated to the period after 1655 and the other could not be reliably dated using available reference chronologies. The created mean tree-ring width series representing individual churches showed strong correlations with the reference chronologies for Slovakia and northern Romania whereas correlations with the only Ukrainian chronology (Lviv region) were negligible. This could suggest low Transcarpathian tree-ring coherency and may indicate the need to create a dense network of regional tree-ring width chronologies in the regions surrounding the Carpathian Mountains.     

Making the most of a patient's laboratory data: optimisation of signal-to-noise ratio

All results in laboratory medicine are compared to some reference for interpretation. This reference may be a previous result from the same patient, a reference population--either healthy or diseased, or both--or a decision limit recommended by an expert group. The aim for the medical laboratory is to improve the signal-to-noise ratio by increasing the signal or reducing the noise. This presentation deals with the more general tools for reduction of the noise component, and focuses on biological within-subject variation, reference intervals and decision models. Regarding biological within-subject variation, the estimation of reference change value (RCV) as a yardstick for judging measured differences within the patient over time is an important tool. Here, only type 1 errors are usually applied, but type 2 errors should also be taken into consideration. Moreover, variance homogeneity is assumed for the application of RCV, but this assumption is not always fulfilled, and erroneous interpretations may be introduced. A tool for comparison of different and more complicated algorithms applied to serial measurements is computer simulation (e.g. on data from tumour markers). In order to reduce the noise component from reference intervals, partitioning according to relevant subgroups is a tool, and useful criteria for judging whether subgroups should be combined are reported. Geographical and racial differences may cause different reference distributions (e.g. plasma proteins), but it has been possible to establish common reference intervals for 25 common components in Caucasians in the five Nordic countries. Transformation of data and presentation of accumulated ranked values in rankit plots where Gaussian (or log-Gaussian) distributions show up as straight lines is a valuable tool for interpretation of the distributions and comparison of subgroups. In this way it is often possible to isolate a low-risk group which fits a log-Gaussian distribution. In case of thyroid autoantibodies the distributions look biphasic, even after all possible rule-out criteria have been exhausted, but a composite model makes it possible to extract a reference population from the mixture. The classical decision model is bimodal, reflecting an assumption of two independent but overlapping distributions, with a clear but unknown prevalence for the disease. When a decision limit (cut-off point) is applied, the percentages of false positive and false negative results will be determined, but the underlying prevalence is unchanged. In contrast to this, the unimodal distributions cover a continuum of probabilities for a certain disease (risk) and the decision limit is arbitrarily chosen. Thus, the disease or risk is defined by the measured component. Consequently, the decision limit directly defines the prevalence, and this limit can be different over time and geography as has been the case for cholesterol or glucose.     

Y chromosome and male infertility: what is a normal Y chromosome?

The human Y chromosome contains a number of genes and gene families that are essential for germ cell development and maintenance. Many of these genes are located in highly repetitive elements that are subject to rearrangements. Deletion of azoospermia factor (AZF) regions AZFa, AZFb, and AZFc are found in approximately 10-15% of men with severe forms of spermatogenic failure. Several partial AZFc deletions have been described. One of these, which removes around half of all the genes within the AZFc region, appears to be present as an inconsequential polymorphism in populations of northern Eurasia. A second deletion, termed gr/gr, also results in the absence of several AZFc genes and it may be a genetic risk factor for spermatogenic failure. However, the link between these partial deletions and fertility is unclear. The gr/gr deletion is not a single deletion but a combination of deletions that vary in size and complexity and result in the absence of different genes. There are also regional or ethnic differences in the frequency of gr/gr deletions. In some Y-chromosome lineages, these deletions appear to be fixed and may have little influence on spermatogenesis. Most of these data (gene content and Y chromosome structure) have been deduced from the reference Y chromosome sequence deposited in NCBI. However, recently there have been attempts to define these types of structural rearrangements in the general population. These have highlighted the considerable degree of structural diversity that exist. Trying to correlate these changes with the phenotypic variability is a major challenge and it is likely that there will not be a single reference (or normal) Y chromosome sequence but many.     

A 9.1-kb gap in the genome reference map is shown to be a stable deletion/insertion polymorphism of ancestral origin

We show a mute 9.1-kb gap in the human genome reference map, unraveled by RDA studies, to be a worldwide deletion/insertion polymorphism of stable type. The molecular and population data presented suggest its origin from a unique ancestral transposition event in chromosomal region 22q11.2, overlapping the IglambdaV genes at about 450 kb from the cluster of the IglambdaJ-C genes. These findings are not meant to be just another report of a polymorphic marker suitable for population studies. Rather, we wish to stress that a large number of inborn mute gaps may be spread all over the genome and that the many RDA-detected microdeletions already available are efficient tools for the discovery of this otherwise hidden category of genetic variation. Apart from their possible impact on expression of structural genes, mute gaps must be filled for the reference map of our genome to be truly completed.     

Long-term population and community patterns of benthic macroinvertebrates and fishes in Northern California Mediterranean-climate streams

Long-term studies can document temporal patterns in freshwater ecosystems, and this is particularly important in mediterranean-climate (med-climate) regions because of strong interannual variation in precipitation amounts and consequently stream flow. We review long-term studies of populations and communities of benthic macroinvertebrate and fishes from sites throughout the med-climate region of California and develop generalities that may apply broadly to med-climate streams worldwide. Severe drought may result in community shifts, and alter age-structure in both macroinvertebrates and fishes. Within-year seasonal patterns in macroinvertebrate communities can be influenced by annual variability in flow regimes. Macroinvertebrate biological-monitoring metrics with consistently low intra-annual variability may be especially applicable in med-climate streams, as is the use of different temporal windows to describe reference periods to reduce influence of interannual variability on impact detection. Long-term data can be used to develop macroinvertebrate-based metrics that can either show or be independent of climate-change effects. Most macroinvertebrate species are temporally rare in their annual occurrence. Multiple components of natural flow regimes can favor native over invasive fishes. Long-term, quantitative information from med-climate streams is generally lacking, which is a hindrance to both management practices and development of appropriate ecological constructs.     

Empirical derivation of the reference region for computing diagnostic sensitive ¹⁸fluorodeoxyglucose ratios in Alzheimer's disease based on the ADNI sample

Careful selection of the reference region for non-quantitative positron emission tomography (PET) analyses is critically important for Region of Interest (ROI) data analyses. We introduce an empirical method of deriving the most suitable reference region for computing neurodegeneration sensitive (18)fluorodeoxyglucose (FDG) PET ratios based on the dataset collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Candidate reference regions are selected based on a heat map of the difference in coefficients of variation (COVs) of FDG ratios over time for each of the Automatic Anatomical Labeling (AAL) atlas regions normalized by all other AAL regions. Visual inspection of the heat map suggests that the portion of the cerebellum and vermis superior to the horizontal fissure is the most sensitive reference region. Analyses of FDG ratio data show increases in significance on the order of ten-fold when using the superior portion of the cerebellum as compared with the traditionally used full cerebellum. The approach to reference region selection in this paper can be generalized to other radiopharmaceuticals and radioligands as well as to other disorders where brain changes over time are hypothesized and longitudinal data is available. Based on the empirical evidence presented in this study, we demonstrate the usefulness of the COV heat map method and conclude that intensity normalization based on the superior portion of the cerebellum may be most sensitive to measuring change when performing longitudinal analyses of FDG-PET ratios as well as group comparisons in Alzheimer's disease. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Genome Duplications and Other Features in 12 Mb of DNA Sequence from Human Chromosome 16p and 16q

Several publicly funded large-scale sequencing efforts have been initiated with the goal of completing the first reference human genome sequence by the year 2005. Here we present the results of analysis of 11.8 Mb of genomic sequence from chromosome 16. The apparent gene density varies throughout the region, but the number of genes predicted (84) suggests that this is a gene-poor region. This result may also suggest that the total number of human genes is likely to be at the lower end of published estimates. One of the most interesting aspects of this region of the genome is the presence of highly homologous, recently duplicated tracts of sequence distributed throughout the p-arm. Such duplications have implications for mapping and gene analysis as well as the predisposition to recurrent chromosomal structural rearrangements associated with genetic disease.     

Mechanism of parasitism by Cuscuta reflexa: Distribution of cytokinins in different regions of the parasite vine

Cytokinins in the different regions of Cuscuta reflexa Roxb. vine have been extracted and assayed using the Xanthium cotyledon bioassay with N⁶-benzylaminopurine as the reference cytokinin. Maximum cytokinin level was found in the haustoria-bearing region with the gradient decreasing towards the apex. The cytokinin content of the apex was less than 1% of that in the whole haustorial region. Interestingly, the concave half of the vine contained about forty times more cytokinin in the haustorial region than the corresponding convex half. The high concentration of cytokinin or cytokinin-like substances in the haustoria-bearing site in Cuscuta might be due either to a high RNase activity in the region or translocation from the host to parasite or both.     

Genetic diversity of the allodeterminant alr2 in Hydractinia symbiolongicarpus

Hydractinia symbiolongicarpus, a colonial cnidarian (class Hydrozoa) epibiont on hermit crab shells, is well established as a model for genetic studies of allorecognition. Recently, two linked loci, allorecognition (alr) 1 and alr2, were identified by positional cloning and shown to be major determinants of histocompatibility. Both genes encode putative transmembrane proteins with hypervariable extracellular domains similar to immunoglobulin (Ig)-like domains. We sought to characterize the naturally occurring variation at the alr2 locus and to understand the origins of this molecular diversity. We examined full-length cDNA coding sequences derived from a sample of 21 field-collected colonies, including 18 chosen haphazardly and two laboratory reference strains. Of the 35 alleles recovered from the 18 unbiased samples, 34 encoded unique gene products. We identified two distinct structural classes of alleles that varied over a large central region of the gene but both possessed highly polymorphic extracellular domains I, similar to an Ig-like V-set domain. The discovery of structurally chimeric alleles provided evidence that interallelic recombination may contribute to alr2 variation. Comparisons of the genomic region encompassing alr2 from two field-derived haplotypes and one laboratory reference sequence revealed a history of structural variation at the haplotype level as well. Maintenance of large numbers of equally rare alleles in a natural population is a hallmark of negative frequency-dependent selection and is expected to produce high levels of heterozygosity. The observed alr2 allelic diversity is comparable with that found in immune recognition molecules such as human leukocyte antigens, B cell Igs, or natural killer cell Ig-like receptors.     

The important choice of reference environment in microevolutionary climate response predictions

It is well documented that individuals of wild populations can adjust to climate change by means of phenotypic plasticity, but few reports on adaptation by means of genetically based microevolution caused by selection. Disentanglement of these separate effects requires that the reference environment (the environmental zero point) is defined, and this should not be done arbitrarily. The problem is that an error in the reference environment may lead to large errors in predicted microevolution. Together with parameter values and initial mean trait values, the reference environment can be estimated from environmental, phenotypic and fitness data. A prediction error method for this purpose is described, with the feasibility shown by simulations. As shown in a toy example, an estimated reference environment may have large errors, especially for small populations. This may still be a better choice than use of an initial environmental value in a recorded time series, or the mean value, which is often used. Another alternative may be to use the mean value of a past and stationary stochastic environment, which the population is judged to have been fully adapted to, in the sense that the expected geometric mean fitness was at a global maximum. Exceptions are cases with constant phenotypic plasticity, where the microevolutionary changes per generation follow directly from phenotypic and environmental data, independent of the chosen reference environment.     

A comparison of Australian bean yellow mosaic virus isolates using molecular hybridisation analysis

Twenty-nine isolates of bean yellow mosaic virus (BYMV), obtained over 5 yr by sampling of a limited area in south-eastern South Australia and western Victoria (Collection I), resembled each other in host range and symptomatology. Three reference isolates and nine other isolates (Collection E) from across southern Australia differed in host range and symptomatology from each other, and from the members of collection I. Molecular hybridisation analysis (MHA) using ³H-complementary DNA specific to the RNA of the three reference isolates of BYMV (BYMV-G, -Q and -S) showed that the isolates of collection I were more closely related to BYMV-S, which originated from the same region, than to -G, or -Q which came from outside the region. None of the isolates in collection E were related by MHA to BYMV-S. Only one showed low but significant homology with Q, and none showed homology with G, despite some similarities in host range and symptomatology to the reference isolates. Neither host of origin nor the propagation host influenced percentage homology to reference isolates. The percentage hybridisation values obtained with the RNA of isolates showed no significant variation in homology during regular transfer by mechanical inoculation for 2 yr. We conclude that percentage homology as determined by MHA has an advantage over assessments of biological properties for discriminating between strains or variants of BYMV; it appears to be a stable property which can be determined semiquantitatively.