Genetic Loci Associated with Alzheimer’s Disease and Cerebrospinal Fluid Biomarkers in a Finnish Case-Control Cohort

Objectives

To understand the relation between risk genes for Alzheimer’s disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aβ_1–42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF).

Methods

We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland.

Results

APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aβ_1–42 (corrected p<0.05). At an uncorrected p<0.05, PPP3R1 rs1868402 and MAPT rs2435211 were related with increased t-tau; while SORL1 rs73595277 and MAPT rs16940758, with increased p-tau. Only TOMM40 rs2075650 showed association with clinical AD after adjusting for APOE-ε4 (p = 0.007), but not after multiple test correction (p>0.05).

Conclusions

We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aβ_1–42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ_1–42.     

Overexpression of IRM1 Enhances Resistance to Aphids in Arabidopsis thaliana

Aphids are insects that cause direct damage to crops by the removal of phloem sap, but more importantly they spread devastating viruses. Aphids use their sophisticated mouthpart (i.e. stylet) to feed from the phloem sieve elements of the host plant. To identify genes that affect host plant resistance to aphids, we previously screened an Arabidopsis thaliana activation tag mutant collection. In such mutants, tagged genes are overexpressed by a strong 35S enhancer adjacent to the natural promoter, resulting in a dominant gain-of-function phenotype. We previously identified several of these mutants on which the aphid Myzus persicae showed a reduced population development compared with wild type. In the present study we show that the gene responsible for the phenotype of one of the mutants is At5g65040 and named this gene Increased Resistance to Myzus persicae 1 (IRM1). Overexpression of the cloned IRM1 gene conferred a phenotype identical to that of the original mutant. Conversely, an IRM1 knockout mutant promoted aphid population development compared to the wild type. We performed Electrical Penetration Graph analysis to investigate how probing and feeding behaviour of aphids was affected on plants that either overexpressed IRM1 or contained a knockout mutation in this gene. The EPG results indicated that the aphids encounter resistance factors while reaching for the phloem on the overexpressing line. This resistance mechanism also affected other aphid species and is suggested to be of mechanical nature. Interestingly, genetic variation for IRM1 expression in response to aphid attack was observed. Upon aphid attack the expression of IRM1 was initially (after 6 hours) induced in ecotype Wassilewskija followed by suppression. In Columbia-0, IRM1 expression was already suppressed six hours after the start of the infestation. The resistance conferred by the overexpression of IRM1 in A. thaliana trades off with plant growth.     

Modeling mate-finding behavior of the swarming polychaete,Nereis succinea,with TangoInSilico,a scientific orkflow-based simulation system for sexual searching

Summary

Pheromones can be used as attractants for the opposite sex in many environments; however, little is known about the search strategies employed in responding to pheromones in the marine environment. The spawning behavior of males of the polychaete Nereis succinea is known to be triggered at close range by a high concentration (>～10^?7 M) of pheromone, cysteine glutathione disulfide (CSSG), released by females. Since CSSG also causes acceleration of swimming and increased turning, in addition to eliciting ejaculation, we proposed the hypothesis that these behaviors elicited by low concentrations of pheromone can be used by males to find females. The current study develops a computer simulation model of male and female N. succinea behavior for testing whether male responses to low concentrations of CSSG can facilitate finding females. Video recording of female swimming behavior in the field showed spontaneous loops, spirals, and circles that have been incorporated into the model. The scientific workflow paradigm within which the computer model has been developed also incorporates a data provenance system to enable systematic replay and testing of responses to individual parameters. Output of the model shows complex turning behavior leading to successful mating encounters at concentrations as low as 3×10^?9 M CSSG. Behavior resembling the output of the model was recorded in field observations. Application of the model in the future will be used to determine what pheromone concentrations produce significant increases in the probability of mating encounters.     

Biometry of Cenomanian–Turonian placoliths: a proxy for changes of fertility and surface‐water temperature?

Most publications discussing Cenomanian–Turonian calcareous nannofossils focus on abundance fluctuations across the boundary interval. So far, there have been no studies that deal with the influence of palaeoenvironmental changes on the size of common Cenomanian–Turonian nannofossil taxa. The genera Biscutum, Broinsonia, Prediscosphaera, Retecapsa and Watznaueria have therefore been analysed from 19 samples of Cenomanian–Turonian age from the Goban Spur, northeast Atlantic. The genus Biscutum shows a slight decrease of mean length from 4.14 μm in the Cenomanian to 3.94 μm in the Turonian. Broinsonia is marked by a decrease from 6.07 μm in the Cenomanian to 5.64 μm in the Turonian. On the other hand, Prediscospheara increases in size from 4.98 μm in the Cenomanian to 5.61 μm in the Turonian. Two genera (Retecapsa, Watznaueria) show no significant changes in their mean length. The mean size of Biscutum is perhaps controlled by nutrients, where larger specimens may have preferred the more fertile palaeoenvironment of the Late Cenomanian. The size decrease of Biscutum in the Turonian is probably related to reduced nutrient availability. The genus Prediscosphaera spp., may have favoured low‐fertility conditions, as its mean size increases in the Turonian. A worldwide decline of the frequency of Broinsonia spp. during the Cenomanian–Turonian transition implies that this genus is not solely controlled by the nutrient content. The size of Broinsonia spp. may have been therefore influenced by the latest Cenomanian warming event. The increase in sea‐surface temperature may have been unfavourable for Broinsonia spp. as reflected by decreasing mean size and frequency. □Calcareous nannofossils, biometry, morphometry, Oceanic Anoxic Event 2.     

Phylogenetic analysis reveals that Rhabdopleura is an extant graptolite

A phylogenetic analysis of morphological data from modern pterobranch hemichordates (Cephalodiscus, Rhabdopleura) and representatives of each of the major graptolite orders reveals that Rhabdopleura nests among the benthic, encrusting graptolite taxa as it shares all of the synapomorphies that unite the graptolites. Therefore, rhabdopleurids can be regarded as extant members of the Subclass Graptolithina (Class Pterobranchia). Combined with the results of previous molecular phylogenetic studies of extant deuterostomes, these results also suggest that the Graptolithina is a sister taxon to the Subclass Cephalodiscida. The Graptolithina, as an important component of Early–Middle Palaeozoic biotas, provide data critical to our understanding of early deuterostome phylogeny. This result allows one to infer the zooid morphology, mechanics of colony growth and palaeobiology of fossil graptolites in direct relation to the living members of the clade. The Subdivision Graptoloida (nom. transl.), which are all planktic graptolites, is well supported in this analysis. In addition, we recognize the clade Eugraptolithina (nov.). This clade comprises the Graptoloida and all of the other common and well‐known graptolites of the distinctive Palaeozoic fauna. Most of the graptolites traditionally regarded as tuboids and dendroids appear to be paraphyletic groups within the Eugraptolithina; however, Epigraptus is probably not a member of this clade. The Eugraptolithina appear to be derived from an encrusting, Rhabdopleura‐like species, but the available information is insufficient to resolve the phylogeny of basal graptolites. The phylogenetic position of Mastigograptus and the status of the Dithecoidea and Mastigograptida also remain unresolved. □ Biodiversity, Cambrian, Hemichordata, Deuterostomia, Ordovician.     

Identification and QTL mapping of whitefly resistance components in Solanum galapagense

Solanum galapagense is closely related to the cultivated tomato and can show a very good resistance towards whitefly. A segregating population resulting from a cross between the cultivated tomato and a whitefly resistant S. galapagense was created and used for mapping whitefly resistance and related traits, which made it possible to study the genetic basis of the resistance. Quantitative trait loci (QTL) for adult survival co-localized with type IV trichome characteristics (presence, density, gland longevity and gland size). A major QTL (Wf-1) was found for adult survival and trichome characters on Chromosome 2. This QTL explained 54.1 % of the variation in adult survival and 81.5 % of the occurrence of type IV trichomes. A minor QTL (Wf-2) for adult survival and trichome characters was identified on Chromosome 9. The major QTL was confirmed in F3 populations. Comprehensive metabolomics, based on GCMS profiling, revealed that 16 metabolites segregating in the F2 mapping population were associated with Wf-1 and/or Wf-2. Analysis of the 10 most resistant and susceptible F2 genotypes by LCMS showed that several acyl sugars were present in significantly higher concentration in the whitefly resistant genotypes, suggesting a role for these components in the resistance as well. Our results show that whitefly resistance in S. galapagense seems to inherit relatively simple compared to whitefly resistance from other sources and this offers great prospects for resistance breeding as well as elucidating the underlying molecular mechanism(s) of the resistance.     

Variation in eggshell traits between geographically distant populations of pied flycatchers Ficedula hypoleuca

The expression and impact of maternal effects may vary greatly between populations and environments. However, little is known about large‐scale geographical patterns of variation in maternal deposition to eggs. In birds, as in other oviparous animals, the outermost maternal component of an egg is the shell, which protects the embryo, provides essential mineral resources and allows its interaction with the environment in the form of gas exchange. In this study, we explored variation of eggshell traits (mass, thickness, pore density and pigmentation) across 15 pied flycatcher populations at a large geographic scale. We found significant between‐population variation in all eggshell traits, except in pore density, suggesting spatial variation in their adaptive benefits or in the females’ physiological limitations during egg laying. Between‐ population variation in shell structure was not due to geographic location (latitude and longitude) or habitat type. However, eggshells were thicker in populations that experienced higher ambient temperature during egg laying. This could be a result of maternal resource allocation to the shell being constrained under low temperatures or of an adaptation to reduce egg water loss under high temperatures. We also found that eggshell colour intensity was positively associated with biliverdin pigment concentration, shell thickness and pore density. To conclude, our findings reveal large‐ scale between‐population variation of eggshell traits, although we found little environmental dependency in their expression. Our findings call for further studies that explore other environmental factors (e.g. calcium availability and pollution levels) and social factors like sexual selection intensity that may account for differences in shell structure between populations.     

Great tits provided with ad libitum food lay larger eggs when exposed to colder temperatures

The amount of nutrients deposited into a bird egg varies both between and within clutches of the same female. Larger eggs enhance offspring traits, but as a tradeoff, laying large eggs also infers energetic costs to the female. Income breeders usually lay larger eggs later in the season, when temperatures and food availability are higher. Egg size is thus affected by the daily amount of energy available to produce an egg under cold conditions, but it is less well known in how far temperature exerts direct effects on egg size. We show that great tit females Parus major with access to ad libitum food and breeding in climate‐controlled aviaries varied their egg investments. The size of an individual egg was best predicted by mean temperatures one week pre‐laying, with females laying larger, rather than smaller, eggs under colder conditions. Eggs increased in size over the season, but not significantly over the laying sequence. The degree of daily temperature fluctuation did not influence egg size. In addition to a substantial between‐female variation, sisters were more similar to each other than unrelated females, showing that egg size does also reflect heritable intrinsic female properties. Natural variation in egg size is thus not only determined by energy‐limitation, but also due to females allocating more resources to eggs laid in colder environments, thus increasing early survival of the chicks. That the positive correlation between temperature and egg investments that is found in a natural population is reversed under ad libitum food conditions demonstrates that wild great tits tradeoff own condition with survival prospects of their chicks as a function of available food, not ambient temperature.     

Somatoform disorders among patients attending walk-in clinics in Trinidad: prevalence and association with depression and anxiety

Objectives Somatoform disorders are common in international primary care settings, but have been little studied in the developing world. The objective of this study was to determine the prevalence of severe undifferentiated somatoform disorder, and its relationship to depression and anxiety, among patients attending walk-in clinics in Trinidad.Methods The study participants, who were all aged 18 years or older and attending walk-in clinics at 16 randomly selected health centres, were surveyed between May and August 2007 using the PRIME-MD questionnaire.Results There were 594 participants (the response rate was 92%), of whom 72.7% were female. Their ages ranged from 18 to 93 years, and 54.5% were over 50 years of age. In total, 37.2% were married and 25.9% were single. Indo-Trinidadians represented 43.1% and Afro-Trinidadians represented 36% of the study sample; 56.5% of the participants reported that their income was less than US$ 400 per month, and 65.7% were unemployed. At walk-in clinics in Trinidad, the estimated prevalence of severe undifferentiated somatoform disorder was 10.3% (95% CI: 7.86–12.74), that of hypochondriasis was 28.5% (95% CI: 24.9–32.1), and that of body dysmorphic disorder was 15.8% (95% CI: 11.9–18.7). Severe undifferentiated somatoform disorder was statistically significantly associated with gender and ethnicity but not with age, level of education, employment status or income. Chi-square testing found significant associations between the presence of severe undifferentiated somatoform disorder and both depression and anxiety (P < 0.05), between hypochondriasis and both anxiety and depression (P < 0.05), and between body dysmorphic disorder and depression (P < 0.05) but not anxiety. Regression analysis suggested that the demographic features that predicted severe undifferentiated somatoform disorder were being female or Indo-Trinidadian.Conclusions Walk-in clinics in Trinidad that serve older patients on a lower income have a high proportion of patients with somatoform disorders as measured by the PRIME-MD scale. These patients exhibit many features of anxiety and depression. These findings have implications for medical training and service delivery.     

Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

Rhabdomyolysis is common in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies, but its pathogenic basis is poorly understood. Here, we show that prolonged bicycling exercise against a standardized moderate workload in VLCADD patients is associated with threefold bigger changes in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations in quadriceps muscle and twofold lower changes in plasma acetyl-carnitine levels than in healthy subjects. This result is consistent with the hypothesis that muscle ATP homeostasis during exercise is compromised in VLCADD. However, the measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in VLCADD muscle was normal. Mathematical modeling of oxidative ATP metabolism in muscle composed of three different fiber types indicated that the observed altered energy balance during submaximal exercise in VLCADD patients may be explained by a slow-to-fast shift in quadriceps fiber-type composition corresponding to 30% of the slow-twitch fiber-type pool in healthy quadriceps muscle. This study demonstrates for the first time that quadriceps energy balance during exercise in VLCADD patients is altered but not because of failing mitochondrial function. Our findings provide new clues to understanding the risk of rhabdomyolysis following exercise in human VLCADD.