Dominant negative ATM mutations in breast cancer families

BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.

A genomewide screen for autism susceptibility loci

We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Corneal confocal microscopy detects neuropathy in patients with type 1 diabetes without retinopathy or microalbuminuria

Objective Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria. Materials and Methods All participants underwent detailed assessment of peripheral neuropathy [neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM)], retinopathy (digital fundus photography) and albuminuria status [albumin: creatinine ratio (ACR)]. Results 53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria. Conclusions IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.

The inferior whorl for detecting diabetic peripheral neuropathy using corneal confocal microscopy

PURPOSE: In vivo corneal confocal microscopy (CCM) is increasingly used as a surrogate endpoint in studies of diabetic polyneuropathy (DPN). However, it is not clear whether imaging the central cornea provides optimal diagnostic utility for DPN. Therefore, we compared nerve morphology in the central cornea and the inferior whorl, a more distal and densely innervated area located inferior and nasal to the central cornea. METHODS: A total of 53 subjects with type 1/type 2 diabetes and 15 age-matched control subjects underwent detailed assessment of neuropathic symptoms (NPS), deficits (neuropathy disability score [NDS]), quantitative sensory testing (vibration perception threshold [VPT], cold and warm threshold [CT/WT], and cold- and heat-induced pain [CIP/HIP]), and electrophysiology (sural and peroneal nerve conduction velocity [SSNCV/PMNCV], and sural and peroneal nerve amplitude [SSNA/PMNA]) to diagnose patients with (DPN+) and without (DPN-) neuropathy. Corneal nerve fiber density (CNFD) and length (CNFL) in the central cornea, and inferior whorl length (IWL) were quantified. RESULTS: Comparing control subjects to DPN- and DPN+ patients, there was a significant increase in NDS (0 vs. 2.6 ± 2.3 vs. 3.3 ± 2.7, P < 0.01), VPT (V; 5.4 ± 3.0 vs. 10.6 ± 10.3 vs. 17.7 ± 11.8, P < 0.01), WT (°C; 37.7 ± 3.5 vs. 39.1 ± 5.1 vs. 41.7 ± 4.7, P < 0.05), and a significant decrease in SSNCV (m/s; 50.2 ± 5.4 vs. 48.4 ± 5.0 vs. 39.5 ± 10.6, P < 0.05), CNFD (fibers/mm2; 37.8 ± 4.9 vs. 29.7 ± 7.7 vs. 27.1 ± 9.9, P < 0.01), CNFL (mm/mm2; 27.5 ± 3.6 vs. 24.4 ± 7.8 vs. 20.7 ± 7.1, P < 0.01), and IWL (mm/mm2; 35.1 ± 6.5 vs. 26.2 ± 10.5 vs. 23.6 ± 11.4, P < 0.05). For the diagnosis of DPN, CNFD, CNFL, and IWL achieved an area under the curve (AUC) of 0.75, 0.74, and 0.70, respectively, and a combination of IWL-CNFD achieved an AUC of 0.76. CONCLUSIONS: The parameters of CNFD, CNFL, and IWL have a comparable ability to diagnose patients with DPN. However, IWL detects an abnormality even in patients without DPN. Combining IWL with CNFD may improve the diagnostic performance of CCM.

Quantitative trait loci detection and benefits from marker-assisted selection in dairy cattle

Knowing the chromosomal areas or actual genes affecting the traits under selection would add more information to be used in the selection decisions which would potentially lead to higher genetic response. The first objective of this study was to map quantitative trait loci (QTL) affecting economically important traits in the Finnish Ayrshire population. The second objective was to investigate the effects of using QTL information in marker-assisted selection (MAS) on the genetic response and the linkage disequilibrium between the different parts of the genome. Whole genome scans were carried out on a grand-daughter design with 12 half-sib families and a total of 493 sons. Twelve different traits were studied: milk yield, protein yield, protein content, fat yield, fat content, somatic cell score (SCS), mastitis treatments, other veterinary treatments, days open, fertility treatments, non-return rate, and calf mortality. The average spacing of the typed markers was 20 cM with 2 to 14 markers per chromosome. Associations between markers and traits were analyzed with multiple marker regression. Significance was determined by permutation and genome-wise P-values obtained by Bonferroni correction. The benefits from MAS were investigated by simulation: a conventional progeny testing scheme was compared to a scheme where QTL information was used within families to select among full-sibs in the male path. Two QTL on different chromosomes were modelled. The effects of different starting frequencies of the favourable alleles and different size of the QTL effects were evaluated. A large number of QTL, 48 in total, were detected at 5% or higher chromosome-wise significance. QTL for milk production were found on 8 chromosomes, for SCS on 6, for mastitis treatments on 1, for other veterinary treatments on 5, for days open on 7, for fertility treatments on 7, for calf mortality on 6, and for non-return rate on 2 chromosomes. In the simulation study the total genetic response was faster with MAS than with conventional selection and the advantage of MAS persisted over the studied generations. The rate of response and the difference between the selection schemes reflected clearly the changes in allele frequencies of the favourable QTL. The disequilibrium between the polygenes and QTL was always negative and it was larger with larger QTL size. The disequilibrium between the two QTL was larger with QTL of large effect and it was somewhat larger with MAS for scenarios with starting frequencies below 0.5 for QTL of moderate size and below 0.3 for large QTL. In conclusion, several QTL affecting economically important traits of dairy cattle were detected. Further studies are needed to verify these QTL, check their presence in the present breeding population, look for pleiotropy and fine map the most interesting QTL regions. The results of the simulation studies show that using MAS together with embryo transfer to pre-select young bulls within families is a useful approach to increase the genetic merit of the AI-bulls compared to conventional selection.

Winter feeding strategies for suckler cows in cold climatic conditions

In Finland, suckler cow production is carried out in circumstances characterized by a long winter period and a short grazing period. The traditional winter housing system for suckler cows has been insulated or uninsulated buildings, but there is a demand for developing less expensive housing systems. In addition, more information is needed on new winter feeding strategies, carried out in inexpensive winter facilities with conventional (hay, grass silage, straw) or alternative (treated straw, industrial by-product, whole-crop silage) feeds. The new feeding techniques should not have any detrimental effects on animal welfare in order to be acceptable to both farmers and consumers. Furthermore, no official feeding recommendations for suckler cows are available in Finland and, thus, recommendations for dairy cows have been used. However, this may lead to over- or underfeeding of suckler cows and, finally, to decreased economic output. In Experiment I, second-calf beef-dairy suckler cows were used to compare the effects of diets based on hay (H) or urea-treated straw (US) at two feeding levels (Moderate; M vs. Low; L) on the performance of cows and calves. Live weight (LW) gain during the indoor feeding was lower for cows on level L than on level M. Cows on diet US lost more LW indoors than those on diet H. The cows replenished the LW losses on good pasture. Calf LW gain and cow milk production were unaffected by the treatments. Conception rate was unaffected by the treatments but was only 69%. Urea-treated straw proved to be a suitable winter feed for spring-calving suckler cows. Experiment II studied the effects of feeding accuracy on the performance of first- and second-calf beef-dairy cows and calves. In II-1, the day-to-day variation in the roughage offered ranged up to ± 40%. In II-2, the same variation was used in two-week periods. Variation of the roughages offered had minor effects on cow performance. Reproduction was unaffected by the feeding accuracy. Accurate feeding is not necessary for young beef-dairy crosses, if the total amount of energy offered over a period of a few weeks fulfills the energy requirements. Effects of feeding strategies with alternative feeds on the performance of mature beef-dairy and beef cows and calves were evaluated in Experiment III. Two studies consisted of two feeding strategies (Step-up vs. Flat-rate) and two diets (Control vs. Alternative). There were no differences between treatments in the cow LW, body condition score (BCS), calf pre-weaning LW gain and cow reproduction. A flat-rate strategy can be practised in the nutrition of mature suckler cows. Oat hull based flour-mill by product can partly replace grass silage and straw in the winter diet. Whole-crop barley silage can be offered as a sole feed to suckler cows. Experiment IV evaluated during the winter feeding period the effects of replacing grass silage with whole-crop barley or oat silage on mature beef cow and calf performance. Both whole-crop silages were suitable winter feeds for suckler cows in cold outdoor winter conditions. Experiment V aimed at assessing the effects of daily feeding vs. feeding every third day on the performance of mature beef cows and calves. No differences between the treatments were observed in cow LW, BCS, milk production and calf LW. The serum concentrations of urea and long-chain fatty acids were increased on the third day after feeding in the cows fed every third day. Despite of that the feeding every third day is an acceptable feeding strategy for mature suckler cows. Experiment VI studied the effects of feeding levels and long-term cold climatic conditions on mature beef cows and calves. The cows were overwintered in outdoor facilities or in an uninsulated indoor facility. Whole-crop barley silage was offered either ad libitum or restricted. All the facilities offered adequate shelter for the cows. The restricted offering of whole-crop barley silage provided enough energy for the cows. The Finnish energy recommendations for dairy cows were too high for mature beef breed suckler cows in good body condition at housing, even in cold conditions. Therefore, there is need to determine feeding recommendations for suckler cows in Finland. The results showed that the required amount of energy can be offered to the cows using conventional or alternative feeds provided at a lower feeding level, with an inaccurate feeding, flat-rate feeding or feeding every third day strategy. The cows must have an opportunity to replenish the LW and BCS losses at pasture before the next winter. Production in cold conditions can be practised in inexpensive facilities when shelter against rain and wind, a dry resting place, adequate amounts of feed suitable for cold conditions and water are provided for the animals as was done in the present study.

Hakoah men's soccer team at a game against Graz Hasair; Vienna Portraits Men

Score 2:1 Hakoah; Names of players with numbers handwritten on verso

Effects of self-reported wisdom on happiness: Not much more than emotional intelligence?

Wisdom and emotional intelligence are increasingly popular topics among happiness scholars. Despite their conceptual overlap, no empirical research has examined their interrelations and incremental predictive validities. The aims of this study were (a) to investigate associations between multidimensional conceptualizations of self-reported wisdom (Ardelt in Res Aging 25(3):275-324, 2003, 2004) and emotional intelligence (Davies et al. in J Pers Soc Psychol 75:989-1015, 1998) and (b) to examine the joint effects of self-reported wisdom and emotional intelligence on dimensions of happiness (life satisfaction as well as positive and negative affect). Data were provided by two samples: 175 university students and 400 online workers. Correlations between a composite wisdom score, a composite emotional intelligence score, and happiness facets were positive and moderate in size. Regression analyses showed that the effects of composite wisdom on life satisfaction and positive affect (but not negative affect) became weaker and non-significant when composite emotional intelligence was controlled. Additional analyses including three dimensions of the self-reported wisdom (cognitive, reflective, and affective wisdom) and four dimensions of emotional intelligence (self- and others-emotions appraisal, use and regulation of emotion) revealed a more differentiated pattern of results. Implications for future research on wisdom and happiness are discussed.

Integrated disease management of stem end rot of mango in the Southern Philippines

This research aimed to develop and evaluate pre- and postharvest management strategies to reduce stem end rot (SER) incidence and extend saleable life of 'Carabao' mango fruits in Southern Philippines. Preharvest management focused on the development and improvement of fungicide spray program, while postharvest management aimed to develop alternative interventions aside from hot water treatment (HWT). Field evaluation of systemic fungicides, namely azoxystrobin ( Amistar 25SC), tebuconazole ( Folicur 25WP), carbendazim ( Goldazim 500SC), difenoconazole ( Score 250SC) and azoxystrobin+difenoconazole ( Amistar Top), reduced blossom blight severity and improved fruit setting and retention, resulting in higher fruit yield but failed to sufficiently suppress SER incidence. Based on these findings, an improved fungicide spray program was developed taking into account the infection process of SER pathogens and fungicide resistance. Timely application of protectant (mancozeb) and systemic fungicides (azoxystrobin, carbendazim and difenoconazole) during the most critical stages of mango flower and fruit development ensured higher harvestable fruit yield and minimally lowered SER incidence. Control of SER was also achieved by employing postharvest treatment such as HWT (52-55°C for 10 min), which significantly prolonged the saleable life of mango fruits. However, extended hot water treatment (EHWT; 46°C pulp temperature for 15 min), rapid heat treatment (RHT; 59°C for 30-60 sec), fungicide dip and promising biological control agents failed to satisfactorily reduce SER and prolong saleable life. In contrast, the integration of the improved spray program as preharvest management practice, and postharvest treatments such as HWT and fungicide dips (azoxystrobin, 150-175 ppm; carbendazim, 312.5 ppm; and tebuconazole, 125-156 ppm), significantly reduced disease and extended marketable life for utmost 8 days.

Multi-trait assessment of early-in-life female, male and genomic measures for use in genetic selection to improve female reproductive performance of Brahman cattle

Early-in-life female and male measures with potential to be practical genetic indicators were chosen from earlier analyses and examined together with genomic measures for multi-trait use to improve female reproduction of Brahman cattle. Combinations of measures were evaluated on the genetic gains expected from selection of sires and dams for each of age at puberty (AGECL, i.e. first observation of a corpus luteum), lactation anoestrous interval in 3-year-old cows (LAI), and lifetime annual weaning rate (LAWR, i.e. the weaning rate of cows based on the number of annual matings they experienced over six possible matings). Selection was on an index of comparable records for each combination. Selection intensities were less than theoretically possible but assumed a concerted selection effort was able to be made across the Brahman breed. The results suggested that substantial genetic gains could be possible but need to be confirmed in other data. The estimated increase in LAWR in 10 years, for combinations without or with genomic measures, ranged from 8 to 12 calves weaned per 100 cows from selection of sires, and from 12 to 15 calves weaned per 100 cows from selection of sires and dams. Corresponding reductions in LAI were 60-103 days or 94-136 days, and those for AGECL were 95-125 or 141-176 days, respectively. Coat score (a measure of the sleekness or wooliness of the coat) and hip height in females, and preputial eversion and liveweight in males, were measures that may warrant wider recording for Brahman female reproduction genetic evaluation. Pregnancy-test outcomes from Matings 1 and 2 also should be recorded. Percentage normal sperm may be important to record for reducing LAI and scrotal size and serum insulin-like growth factor-I concentration in heifers at 18 months for reducing AGECL. Use of a genomic estimated breeding value (EBV) in combination with other measures added to genetic gains, especially at genomic EBV accuracies of 40%. Accuracies of genomic EBVs needed to approach 60% for the genomic EBV to be the most important contributor to gains in the combinations of measures studied.

Openness to experience as a predictor and outcome of upward job changes into managerial and professional positions

In industrial and organizational psychology, there is a long tradition of studying personality as an antecedent of work outcomes. Recently, however, scholars have suggested that personality characteristics may not only predict, but also change due to certain work experiences, a notion that is depicted in the dynamic developmental model (DDM) of personality and work. Upward job changes are an important part of employees’ careers and career success in particular, and we argue that these career transitions can shape personality over time. In this study, we investigate the Big Five personality characteristics as both predictors and outcomes of upward job changes into managerial and professional positions. We tested our hypotheses by applying event history analyses and propensity score matching to a longitudinal dataset collected over five years from employees in Australia. Results indicated that participants’ openness to experience not only predicted, but that changes in openness to experience also followed from upward job changes into managerial and professional positions. Our findings thus provide support for a dynamic perspective on personality characteristics in the context of work and careers.

Supporting sleep in early care and education: An assessment of observed sleep-times using a sleep practices optimality index

Aim: The aim was to investigate whether the sleep practices in early childhood education (ECE) settings align with current evidence on optimal practice to support sleep. Background: Internationally, scheduled sleep times are a common feature of daily schedules in ECE settings, yet little is known about the degree to which care practices in these settings align with the evidence regarding appropriate support of sleep. Methods: Observations were conducted in 130 Australian ECE rooms attended by preschool children (Mean = 4.9 years). Of these rooms, 118 had daily scheduled sleep times. Observed practices were scored against an optimality index, the Sleep Environment and Practices Optimality Score, developed with reference to current evidence regarding sleep scheduling, routines, environmental stimuli, and emotional climate. Cluster analysis was applied to identify patterns and prevalence of care practices in the sleep time. Results: Three sleep practices types were identified. Supportive rooms (36%) engaged in practices that maintained regular schedules, promoted routine, reduced environmental stimulation, and maintained positive emotional climate. The majority of ECE rooms (64%), although offering opportunity for sleep, did not engage in supportive practices: Ambivalent rooms (45%) were emotionally positive but did not support sleep; Unsupportive rooms (19%) were both emotionally negative and unsupportive in their practices. Conclusions: Although ECE rooms schedule sleep time, many do not adopt practices that are supportive of sleep. Our results underscore the need for education about sleep supporting practice and research to ascertain the impact of sleep practices in ECE settings on children’s sleep health and broader well-being.

The Genetic Architecture of Climatic Adaptation of Tropical Cattle

Adaptation of global food systems to climate change is essential to feed the world. Tropical cattle production, a mainstay of profitability for farmers in the developing world, is dominated by heat, lack of water, poor quality feedstuffs, parasites, and tropical diseases. In these systems European cattle suffer significant stock loss, and the cross breeding of taurine x indicine cattle is unpredictable due to the dilution of adaptation to heat and tropical diseases. We explored the genetic architecture of ten traits of tropical cattle production using genome wide association studies of 4,662 animals varying from 0% to 100% indicine. We show that nine of the ten have genetic architectures that include genes of major effect, and in one case, a single location that accounted for more than 71% of the genetic variation. One genetic region in particular had effects on parasite resistance, yearling weight, body condition score, coat colour and penile sheath score. This region, extending 20 Mb on BTA5, appeared to be under genetic selection possibly through maintenance of haplotypes by breeders. We found that the amount of genetic variation and the genetic correlations between traits did not depend upon the degree of indicine content in the animals. Climate change is expected to expand some conditions of the tropics to more temperate environments, which may impact negatively on global livestock health and production. Our results point to several important genes that have large effects on adaptation that could be introduced into more temperate cattle without detrimental effects on productivity.