It has traditionally been believed that resistance training can only induce muscle growth when the exercise intensity is greater than 65 % of the 1-repetition maximum (RM). However, more recently, the use of low-intensity resistance exercise with blood-flow restriction (BFR) has challenged this theory and consistently shown that hypertrophic adaptations can be induced with much lower exercise intensities (<50 % 1-RM). Despite the potent hypertrophic effects of BFR resistance training being demonstrated by numerous studies, the underlying mechanisms responsible for such effects are not well defined. Metabolic stress has been suggested to be a primary factor responsible, and this is theorised to activate numerous other mechanisms, all of which are thought to induce muscle growth via autocrine and/or paracrine actions. However, it is noteworthy that some of these mechanisms do not appear to be mediated to any great extent by metabolic stress but rather by mechanical tension (another primary factor of muscle hypertrophy). Given that the level of mechanical tension is typically low with BFR resistance exercise (<50 % 1-RM), one may question the magnitude of involvement of these mechanisms aligned to the adaptations reported with BFR resistance training. However, despite the low level of mechanical tension, it is plausible that the effects induced by the primary factors (mechanical tension and metabolic stress) are, in fact, additive, which ultimately contributes to the adaptations seen with BFR resistance training. Exercise-induced mechanical tension and metabolic stress are theorised to signal a number of mechanisms for the induction of muscle growth, including increased fast-twitch fibre recruitment, mechanotransduction, muscle damage, systemic and localised hormone production, cell swelling, and the production of reactive oxygen species and its variants, including nitric oxide and heat shock proteins. However, the relative extent to which these specific mechanisms are induced by the primary factors with BFR resistance exercise, as well as their magnitude of involvement in BFR resistance training-induced muscle hypertrophy, requires further exploration.
ABSTRACT Background: Health is an important aspect of individuals' lives as they age. The aim of this study was to examine the relationship of sociodemographic factors, diagnosed chronic health conditions, and current depression with attitudes to aging in midlife.
Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first genome-wide study to explore the role of common and rare germline copy number variants (CNVs) in predisposition to endometrial cancer. CNVs were called from germline DNA of 1,209 endometrioid endometrial cancer cases and 528 cancer-unaffected female controls. Overall CNV load of deletions or DNA gains did not differ significantly between cases and controls (P > 0.05), but cases presented with an excess of rare germline deletions overlapping likely functional genomic regions including genes (P = 8 × 10(-10)), CpG islands (P = 1 × 10(-7)) and sno/miRNAs regions (P = 3 × 10(-9)). On average, at least one additional gene and two additional CpG islands were disrupted by rare deletions in cases compared to controls. The most pronounced difference was that over 30 sno/miRNAs were disrupted by rare deletions in cases for every single disruption event in controls. A total of 13 DNA repair genes were disrupted by rare deletions in 19/1,209 cases (1.6 %) compared to one gene in 1/528 controls (0.2 %; P = 0.007), and this increased DNA repair gene loss in cases persisted after excluding five individuals carrying CNVs disrupting mismatch repair genes MLH1, MSH2 and MSH6 (P = 0.03). There were 34 miRNA regions deleted in at least one case but not in controls, the most frequent of which encompassed hsa-mir-661 and hsa-mir-203. Our study implicates rare germline deletions of functional and regulatory regions as possible mechanisms conferring endometrial cancer risk, and has identified specific regulatory elements as candidates for further investigation.
Cardiovascular disease is a leading cause of death in New Zealand, but risk factors may be decreased by consuming a heart healthy diet. This pilot study investigated whether participants met the guidelines for a heart healthy diet and whether a novel heart healthy dietary pattern could be identified using principal components analysis (PCA). The second aim of this project was to assess if higher education, standard of living and nutrition literacy are associated with a heart healthy dietary pattern.
We aimed to evaluate the effects of Temperament and Character Inventory (TCI) personality measures on well-being scores in a sample of 49-51 year old New Zealanders. Previous research has linked high self-directedness (SD) and low harm avoidance (HA) with well-being. We hypothesised that SD and HA would have predictive power for Warwick-Edinburgh Mental Well-being Scale (WEMWBS) well-being. We anticipated that character profiles with high SD and cooperativeness (CO) would be associated with higher well-being scores while high self transcendence (ST) scores would have less of an influence on well-being in a secular population such as New Zealand. Additionally we aimed to describe and assess the performance of a well-being measure, the WEMWBS and we intended to clarify the factors that underlie the questionnaire.
Neuroeconomics applies models from economics and psychology to inform neurobiological studies of choice. This approach has revealed neural signatures of concepts like value, risk, and ambiguity, which are known to influence decision making. Such observations have led theorists to hypothesize a single, unified decision process that mediates choice behavior via a common neural currency for outcomes like food, money, or social praise. In parallel, recent neuroethological studies of decision making have focused on natural behaviors like foraging, mate choice, and social interactions. These decisions strongly impact evolutionary fitness and thus are likely to have played a key role in shaping the neural circuits that mediate decision making. This approach has revealed a suite of computational motifs that appear to be shared across a wide variety of organisms. We argue that the existence of deep homologies in the neural circuits mediating choice may have profound implications for understanding human decision making in health and disease.
The gradient of Bicoid (Bcd) is key for the establishment of the anterior-posterior axis in Drosophila embryos. The gradient properties are compatible with the SDD model in which Bcd is synthesized at the anterior pole and then diffuses into the embryo and is degraded with a characteristic time. Within this model, the Bcd diffusion coefficient is critical to set the timescale of gradient formation. This coefficient has been measured using two optical techniques, Fluorescence Recovery After Photobleaching (FRAP) and Fluorescence Correlation Spectroscopy (FCS), obtaining estimates in which the FCS value is an order of magnitude larger than the FRAP one. This discrepancy raises the following questions: which estimate is "correct''; what is the reason for the disparity; and can the SDD model explain Bcd gradient formation within the experimentally observed times? In this paper, we use a simple biophysical model in which Bcd diffuses and interacts with binding sites to show that both the FRAP and the FCS estimates may be correct and compatible with the observed timescale of gradient formation. The discrepancy arises from the fact that FCS and FRAP report on different effective (concentration dependent) diffusion coefficients, one of which describes the spreading rate of the individual Bcd molecules (the messengers) and the other one that of their concentration (the message). The latter is the one that is more relevant for the gradient establishment and is compatible with its formation within the experimentally observed times.
The prevalence of MS in New Zealand in 2006 was 73.2 (age standardized per 100,000) while for those with indigenous M?ori ancestry it was 3.6 times lower at 20.6. Earlier regional surveys (1968-2001) all reported much lower, or zero, prevalence for M?ori than European. There was no evidence for differences in MS between those with and without M?ori ancestry in either clinical features or latitude, confirming that M?ori ancestry does not produce the reported increase in prevalence with latitude. It is likely that prevalence is increasing in low risk M?ori; however, MS prognosis is independent of M?ori ancestry.
Patellar tendinopathy is a common painful musculoskeletal disorder with a very high prevalence in the athletic population that can severely limit or even end an athletic career. To date, the underlying pathophysiology leading to the condition remains poorly understood, although reports suggesting that patellar tendinopathy most frequently concerns the proximal posterior region of the tendon has prompted some researchers to examine region-specific tendon properties for a better understanding of the etiology and potential risk factors associated with the condition. However, to date, research concerning the in vivo region-specific tendon properties in relation to patellar tendinopathy is very scarce, perhaps due to the lack of validated techniques that can determine such properties in vivo. In recent years, a technique has been developed involving an automated tendon-tracking program that appears to be very useful in the determination of region-specific tendon properties in vivo. In terms of regional variations in tendon properties, previous research has demonstrated differences in structural, mechanical, and biochemical properties between the discrete regions of the patellar tendon, but the extent to which these regional variations contribute to patellar tendinopathy remains elusive. In addition, with respect to treatment strategies for patellar tendinopathy, previous research has utilized a wide range of interventions, but the use of eccentric exercise (EE) and/or heavy-slow resistance (HSR) training appear to be most promising. However, the optimal program design variables of EE and HSR training that induce the most favorable effects are yet to be determined. This review article provides a detailed discussion of all of the above to allow a better understanding of the etiology and potential risk factors associated with the condition as well as the most effective treatment strategies. First, a comprehensive literature review is provided with respect to region-specific structural, mechanical, and biochemical properties, in association with patellar tendinopathy. Second, the automated tendon-tracking methodology is outlined to assist future researchers in the determination of region-specific tendon properties. Finally, potential treatment strategies are discussed, particularly with regards to the use of EE and HSR training for the management of patellar tendinopathy.
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
In September 2010 Christchurch, New Zealand, was struck by a 7.1 magnitude earthquake, followed by a prolonged sequence of significant aftershocks including a fatal aftershock in February 2011. Christchurch City has experienced widespread damage, ongoing disruption and building demolitions resulting in many difficulties for the residents of the Christchurch area. We explore what impact the earthquakes have had on the mental and physical health of a random sample of 50-year-olds who live in the Christchurch area.
The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-?, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.
In social environments, decisions not only determine rewards for oneself but also for others. However, individual differences in pro-social behaviors have been typically studied through self-report. We developed a decision-making paradigm in which participants chose from card decks with differing rewards for themselves and charity; some decks gave similar rewards to both, while others gave higher rewards for one or the other. We used a reinforcement-learning model that estimated each participant's relative weighting of self versus charity reward. As shown both in choices and model parameters, individuals who showed relatively better learning of rewards for charity--compared to themselves--were more likely to engage in pro-social behavior outside of a laboratory setting indicated by self-report. Overall rates of reward learning, however, did not predict individual differences in pro-social tendencies. These results support the idea that biases toward learning about social rewards are associated with one's altruistic tendencies.
Somatic rearrangements, which are commonly found in human cancer genomes, contribute to the progression and maintenance of cancers. Conventionally, the verification of somatic rearrangements comprises many manual steps and Sanger sequencing. This is labor intensive when verifying a large number of rearrangements in a large cohort. To increase the verification throughput, we devised a high-throughput workflow that utilizes benchtop next-generation sequencing and in-house bioinformatics tools to link the laboratory processes. In the proposed workflow, primers are automatically designed. PCR and an optional gel electrophoresis step to confirm the somatic nature of the rearrangements are performed. PCR products of somatic events are pooled for Ion Torrent PGM and/or Illumina MiSeq sequencing, the resulting sequence reads are assembled into consensus contigs by a consensus assembler, and an automated BLAT is used to resolve the breakpoints to base level. We compared sequences and breakpoints of verified somatic rearrangements between the conventional and high-throughput workflow. The results showed that next-generation sequencing methods are comparable to conventional Sanger sequencing. The identified breakpoints obtained from next-generation sequencing methods were highly accurate and reproducible. Furthermore, the proposed workflow allows hundreds of events to be processed in a shorter time frame compared with the conventional workflow.
Disclosure of individual results to participants in genomic research is a complex and contentious issue. There are many existing commentaries and opinion pieces on the topic, but little empirical data concerning actual cases describing how individual results have been returned. Thus, the real life risks and benefits of disclosing individual research results to participants are rarely if ever presented as part of this debate.
Complex natural environments favor the dynamic alignment of neural processing between goal-relevant stimuli and conflicting but biologically salient stimuli like social competitors or predators. The biological mechanisms that regulate dynamic changes in vigilance have not been fully elucidated. Arousal systems that ready the body to respond adaptively to threat may contribute to dynamic regulation of vigilance. Under conditions of constant luminance, pupil diameter provides a peripheral index of arousal state. Although pupil size varies with the processing of goal-relevant stimuli, it remains unclear whether pupil size also predicts attention to biologically salient objects and events like social competitors, whose presence interferes with current goals. Here we show that pupil size in rhesus macaques both reflects the biological salience of task-irrelevant social distractors and predicts vigilance for these stimuli. We measured pupil size in monkeys performing a visual orienting task in which distractors-monkey faces and phase-scrambled versions of the same images-could appear in a congruent, incongruent, or neutral position relative to a rewarded target. Baseline pupil size under constant illumination predicted distractor interference, consistent with the hypothesis that pupil-linked arousal mechanisms regulate task engagement and distractibility. Notably, pupil size also predicted enhanced vigilance for social distractors, suggesting that pupil-linked arousal may adjust the balance of processing resources between goal-relevant and biologically important stimuli. The magnitude of pupil constriction in response to distractors closely tracked distractor interference, saccade planning and the social relevance of distractors, endorsing the idea that the pupillary light response is modulated by attention. These findings indicate that pupil size indexes dynamic changes in attention evoked by both the social environment and arousal.
Telomeres are specialised structures that cap the ends of chromosomes. They shorten with each cell division and have been proposed as a marker of cellular aging. Previous studies suggest that early life stressors increase the rate of telomere shortening with potential impact on disease states and mortality later in life. This study examined the associations between telomere length and exposure to a number of stressors that arise during development from the antenatal/perinatal period through to young adulthood. Participants were from the Christchurch Health and Development Study (CHDS), a New Zealand longitudinal birth cohort which has followed participants from birth until age 30. Telomere length was obtained on DNA from peripheral blood samples collected from consenting participants (n?=?677) at age 28-30, using a quantitative PCR assay. These data were assessed for associations with 26 measures of life course adversity or stress which occurred prior to 25 years of age. No associations were found between telomere length measured at age 28-30 years and life course adversity or stress for specific measures and for the summary risk scores for each developmental domain. The correlations were very small ranging from -0.06 to 0.06 with a median of 0.01, and none were statistically significant. Our results in this well-studied birth cohort do not support prior reports of such associations, and underscore the need for more extensive replication of proposed links between stress and telomere biology in larger cohorts with appropriate phenotypic data.
Ascorbate is a co-factor for the hydroxylases that regulate the transcription factor hypoxia-inducible factor (HIF)-1, which provides cancer cells with a metabolic and survival advantage in the hypoxic environment of solid tumors. However, whether ascorbate affects tumor development is a highly debated issue. We aimed to determine whether tumor ascorbate was associated with HIF-1 activation and patient disease-free survival. In this study, we undertook a retrospective observational analysis of tissue-banked tumor and paired normal tissue from 49 colorectal cancer patients, measuring ascorbate levels, HIF-1? and its downstream gene products BNIP3, and vascular endothelial cell growth factor (VEGF). Patient survival was monitored for the first 6?years after surgery. We found that ascorbate levels were lower in tumor tissue compared to normal tissue (p?0.001) but overall levels varied considerably. HIF-1?, VEGF, and BNIP3 were elevated in tumor samples (p?0.01). There was an inverse relationship between tumor ascorbate content and HIF-1 pathway activation (p?=?0.002) and tumor size (p?=?0.018). Higher tumor ascorbate content was associated with significantly improved disease-free survival in the first 6?years after surgery (p?=?0.006), with 141-1,094 additional disease-free days. This was independent of tumor grade and stage. Survival advantage was associated with the amount of ascorbate in the tumor, but not with the amount in adjacent normal tissue. Our results demonstrate that higher tumor ascorbate content is associated with decreased HIF-1 activation, most likely due to the co-factor activity of ascorbate for the regulatory HIF hydroxylases. Our findings support the need for future studies to determine whether raising tumor ascorbate is possible with clinical intervention and whether this results in modification of hydroxylase-dependent pathways in the tumor.
Colorectal cancer (CRC) is a common problem in New Zealand and there is significant pressure on colonoscopy resources. Lower gastrointestinal symptoms are common in the community hence the appropriate selection of patients for colonoscopy is problematic. The Canterbury District Health Board recently developed the Canterbury Colorectal Symptom Pathway (CCrSP) to attempt to improve prioritisation using a combination of presenting clinical features integrated into a scoring tool. This study describes that pathway and its outcomes over a 6-month period.
Abstract Postactivation potentiation (PAP) is a strategy that has been used to acutely enhance the performance of explosive activities. Although, isometric maximal voluntary contractions (MVCs) have previously been shown to enhance subsequent explosive performance, no information currently exists regarding (1) the optimal variables (intensity/volume) of a MVC that best elicits a PAP response, and (2) the utilisation of evoked isometric twitch contractions in combination with performance measures to directly ascertain the presence of PAP following a MVC, and its relationship to performance. Thus, the purpose of this study was to (1) investigate the influence of isometric contraction duration on the PAP response, and (2) to determine the relationship between PAP, indicated as potentiation of muscle twitch force and subsequent jump performance following different-duration MVCs. Eight males (age: 21 ± 0.99) were assessed using performance measures [countermovement jumps] and evoked twitch contractions, before and 4 minutes after three different conditioning contractions (CCs), (1) a 3-second MVC (MVC3), (2) a 5-second MVC (MVC5) and (3) a 7-second MVC (MVC7). Following all CCs, peak twitch torque of the knee extensor muscles was found to increase (MVC3, + 3.9%; MVC5, + 9.6%; MVC7, + 5.2%), although not significantly (P > 0.05). No significant increases in jump height, jump power, rate of force development or takeoff velocity were observed following any of the CCs (P > 0.05). There was also a lack of association between the changes in PAP (twitch torque) and jump height following all CCs (MVC3, r = 0.25; MVC5, r = 0.28; MVC7, r = -0.47). These data indicate that PAP as assessed via twitch contractions is not associated with performance measures subsequent to single-set isometric CCs of varying durations.
Dopamine neurons are well known for signaling reward-prediction errors. In this issue, Matsumoto and Takada (2013) show that some dopamine neurons also signal salient events during progression through a visual search task requiring working memory and sustained attention.
We investigated the precision of the approximate number system (ANS) in three lemur species (Lemur catta, Eulemur mongoz, and Eulemur macaco flavifrons), one Old World monkey species (Macaca mulatta) and humans (Homo sapiens). In Experiment 1, four individuals of each nonhuman primate species were trained to select the numerically larger of two visual arrays on a touchscreen. We estimated numerical acuity by modeling Weber fractions (w) and found quantitatively equivalent performance among all four nonhuman primate species. In Experiment 2, we tested adult humans in a similar procedure, and they outperformed the four nonhuman species but showed qualitatively similar performance. These results indicate that the ANS is conserved over the primate order.
Intertemporal choice tasks, which pit smaller/sooner rewards against larger/later ones, are frequently used to study time preferences and, by extension, impulsivity and self-control. When used in animals, many trials are strung together in sequence and an adjusting buffer is added after the smaller/sooner option to hold the total duration of each trial constant. Choices of the smaller/sooner option are not reward maximizing and so are taken to indicate that the animal is discounting future rewards. However, if animals fail to correctly factor in the duration of the postreward buffers, putative discounting behavior may instead reflect constrained reward maximization. Here, we report three results consistent with this discounting-free hypothesis. We find that (i) monkeys are insensitive to the association between the duration of postreward delays and their choices; (ii) they are sensitive to the length of postreward delays, although they greatly underestimate them; and (iii) increasing the salience of the postreward delay biases monkeys toward the larger/later option, reducing measured discounting rates. These results are incompatible with standard discounting-based accounts but are compatible with an alternative heuristic model. Our data suggest that measured intertemporal preferences in animals may not reflect impulsivity, or even mental discounting of future options, and that standard human and animal intertemporal choice tasks measure unrelated mental processes.
Conspicuous, multicomponent ornamentation in male animals can be favored by female mate choice but we know little about the cognitive processes females use to evaluate these traits. Sexual selection may favor attention mechanisms allowing the choosing females to selectively and efficiently acquire relevant information from complex male display traits and, in turn, may favor male display traits that effectively capture and hold female attention. Using a miniaturized telemetric gaze-tracker, we show that peahens (Pavo cristatus) selectively attend to specific components of peacock courtship displays and virtually ignore other, highly conspicuous components. Females gazed at the lower train but largely ignored the head, crest and upper train. When the lower train was obscured, however, females spent more time gazing at the upper train and approached the upper train from a distance. Our results suggest that peahens mainly evaluate the lower train during close-up courtship but use the upper train as a long-distance attraction signal. Furthermore, we found that behavioral display components (train rattling and wing shaking) captured and maintained female attention, indicating that interactions between display components may promote the evolution of multicomponent displays. Taken together, these findings suggest that selective attention plays a crucial role in sexual selection and likely influences the evolution of male display traits.
A neuroethological approach to human and nonhuman primate behavior and cognition predicts biological specializations for social life. Evidence reviewed here indicates that ancestral mechanisms are often duplicated, repurposed, and differentially regulated to support social behavior. Focusing on recent research from nonhuman primates, we describe how the primate brain might implement social functions by coopting and extending preexisting mechanisms that previously supported nonsocial functions. This approach reveals that highly specialized mechanisms have evolved to decipher the immediate social context, and parallel circuits have evolved to translate social perceptual signals and nonsocial perceptual signals into partially integrated social and nonsocial motivational signals, which together inform general-purpose mechanisms that command behavior. Differences in social behavior between species, as well as between individuals within a species, result in part from neuromodulatory regulation of these neural circuits, which itself appears to be under partial genetic control. Ultimately, intraspecific variation in social behavior has differential fitness consequences, providing fundamental building blocks of natural selection. Our review suggests that the neuroethological approach to primate behavior may provide unique insights into human psychopathology.
Success in many decision-making scenarios depends on the ability to maximize gains and minimize losses. Even if an agent knows which cues lead to gains and which lead to losses, that agent could still make choices yielding suboptimal rewards. Here, by analyzing event-related potentials (ERPs) recorded in humans during a probabilistic gambling task, we show that individuals behavioral tendencies to maximize gains and to minimize losses are associated with their ERP responses to the receipt of those gains and losses, respectively. We focused our analyses on ERP signals that predict behavioral adjustment: the frontocentral feedback-related negativity (FRN) and two P300 (P3) subcomponents, the frontocentral P3a and the parietal P3b. We found that, across participants, gain maximization was predicted by differences in amplitude of the P3b for suboptimal versus optimal gains (i.e., P3b amplitude difference between the least good and the best gains). Conversely, loss minimization was predicted by differences in the P3b amplitude to suboptimal versus optimal losses (i.e., difference between the worst and the least bad losses). Finally, we observed that the P3a and P3b, but not the FRN, predicted behavioral adjustment on subsequent trials, suggesting a specific adaptive mechanism by which prior experience may alter ensuing behavior. These findings indicate that individual differences in gain maximization and loss minimization are linked to individual differences in rapid neural responses to monetary outcomes.
Surveying volunteer members of a multiple sclerosis registry is a very cost-effective way of assessing the impact of the disease on life outcomes. However, whether the data from such a study can be generalised to the whole population of persons living with MS in a country or region is unclear.
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
Lower limb cellulitis and deep vein thrombosis share clinical features and investigation of patients with cellulitis for concurrent DVT is common. The prevalence of DVT in this group is uncertain. This study aimed to determine the prevalence of deep vein thrombosis (DVT) in patients with lower limb cellulitis and to investigate the utility of applying the Wells algorithm to this patient group.
The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype.
Data recordings often include high-frequency noise and baseline fluctuations that are not generated by the system under investigation, which need to be removed before analyzing the signal for the systems behavior. In the absence of an automated method, experimentalists fall back on manual procedures for removing these fluctuations, which can be laborious and prone to subjective bias. We introduce a maximum likelihood formalism for separating signal from a drifting baseline plus noise, when the signal takes on integer multiples of some value, as in ion channel patch-clamp current traces. Parameters such as the quantal step size (e.g., current passing through a single channel), noise amplitude, and baseline drift rate can all be optimized automatically using the expectation-maximization algorithm, taking the number of open channels (or molecules in the on-state) at each time point as a hidden variable. Our goal here is to reconstruct the signal, not model the (possibly highly complex) underlying system dynamics. Thus, our likelihood function is independent of those dynamics. This may be thought of as restricting to the simplest possible hidden Markov model for the underlying channel current, in which successive measurements of the state of the channel(s) are independent. The resulting method is comparable to an experienced human in terms of results, but much faster. FORTRAN 90, C, R, and JAVA codes that implement the algorithm are available for download from our website.
Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.
As studies of the neural circuits underlying choice expand to include more complicated behaviors, analysis of behaviors elicited in laboratory paradigms has grown increasingly difficult. Social behaviors present a particular challenge, since inter- and intra-individual variation are expected to play key roles. However, due to limitations on data collection, studies must often choose between pooling data across all subjects or using individual subjects data in isolation. Hierarchical models mediate between these two extremes by modeling individual subjects as drawn from a population distribution, allowing the population at large to serve as prior information about individuals behavior. Here, we apply this method to data collected across multiple experimental sessions from a set of rhesus macaques performing a social information valuation task. We show that, while the values of social images vary markedly between individuals and between experimental sessions for the same individual, individuals also differentially value particular categories of social images. Furthermore, we demonstrate covariance between values for image categories within individuals and find evidence suggesting that magnitudes of stimulus values tend to diminish over time.
Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.
The Protein Interaction Network Analysis (PINA) platform is a comprehensive web resource, which includes a database of unified protein-protein interaction data integrated from six manually curated public databases, and a set of built-in tools for network construction, filtering, analysis and visualization. The second version of PINA enhances its utility for studies of protein interactions at a network level, by including multiple collections of interaction modules identified by different clustering approaches from the whole network of protein interactions (interactome) for six model organisms. All identified modules are fully annotated by enriched Gene Ontology terms, KEGG pathways, Pfam domains and the chemical and genetic perturbations collection from MSigDB. Moreover, a new tool is provided for module enrichment analysis in addition to simple query function. The interactome data are also available on the web site for further bioinformatics analysis. PINA is freely accessible at http://cbg.garvan.unsw.edu.au/pina/.
Icy bodies may have delivered the oceans to the early Earth, yet little is known about water in the ice-dominated regions of extrasolar planet-forming disks. The Heterodyne Instrument for the Far-Infrared on board the Herschel Space Observatory has detected emission lines from both spin isomers of cold water vapor from the disk around the young star TW Hydrae. This water vapor likely originates from ice-coated solids near the disk surface, hinting at a water ice reservoir equivalent to several thousand Earth oceans in mass. The waters ortho-to-para ratio falls well below that of solar system comets, suggesting that comets contain heterogeneous ice mixtures collected across the entire solar nebula during the early stages of planetary birth.
We report the first demonstration of a continuous wave coherent source covering 2.48-2.75 THz, with greater than 10% instantaneous tuning bandwidth and having 1-14 ?W of output power at room temperature. This source is based on a 91.8-101.8 GHz synthesizer followed by a power amplifier and three cascaded frequency triplers. It demonstrates for the first time that purely electronic solid-state sources can generate a useful amount of power in a region of the electromagnetic spectrum where lasers (solid state or gas) were previously the only available coherent sources. The bandwidth, agility, and operability of this THz source have enabled wideband, high resolution spectroscopic measurements of water, methanol, and carbon monoxide with a resolution and signal-to-noise ratio unmatched by any other existing system, providing new insight in the physics of these molecules. Furthermore, the power and optical beam quality are high enough to observe the Lamb-dip effect in water. The source frequency has an absolute accuracy better than 1 part in 10(12) and the spectrometer achieves sub-Doppler frequency resolution better than 1 part in 10(8). The harmonic purity is better than 25 dB. This source can serve as a coherent signal for absorption spectroscopy, a local oscillator for a variety of heterodyne systems and can be used as a method for precision control of more powerful but much less frequency agile quantum mechanical terahertz sources.
The newly developed hydrogen sensor, based on a network of ultrasmall pure palladium nanowires sputter-deposited on a filtration membrane, takes advantage of single palladium nanowires characteristics of high speed and sensitivity while eliminating their nanofabrication obstacles. However, this new type of sensor, like the single palladium nanowires, cannot distinguish hydrogen concentrations above 3%, thus limiting the potential applications of the sensor. This study reports hydrogen sensors based on a network of ultrasmall Cr-buffered Pd (Pd/Cr) nanowires on a filtration membrane. These sensors not only are able to outperform their pure Pd counterparts in speed and durability but also allow hydrogen detection at concentrations up to 100%. The new networks consist of a thin layer of palladium deposited on top of a Cr adhesion layer 1-3 nm thick. Although the Cr layer is insensitive to hydrogen, it enables the formation of a network of continuous Pd/Cr nanowires with thicknesses of the Pd layer as thin as 2 nm. The improved performance of the Pd/Cr sensors can be attributed to the increased surface area to volume ratio and to the confinement-induced suppression of the phase transition from Pd/H solid solution (?-phase) to Pd hydride (?-phase).
Advancement in heterogeneous catalysis relies on the capability of altering material structures at the nanoscale, and that is particularly important for the development of highly active electrocatalysts with uncompromised durability. Here, we report the design and synthesis of a Pt-bimetallic catalyst with multilayered Pt-skin surface, which shows superior electrocatalytic performance for the oxygen reduction reaction (ORR). This novel structure was first established on thin film extended surfaces with tailored composition profiles and then implemented in nanocatalysts by organic solution synthesis. Electrochemical studies for the ORR demonstrated that after prolonged exposure to reaction conditions, the Pt-bimetallic catalyst with multilayered Pt-skin surface exhibited an improvement factor of more than 1 order of magnitude in activity versus conventional Pt catalysts. The substantially enhanced catalytic activity and durability indicate great potential for improving the material properties by fine-tuning of the nanoscale architecture.
Treatment acceptance by patients is influenced by the way treatment effects are presented. Presentation of benefits using relative risk increases treatment acceptance compared to the use of absolute risk. It is not known whether this effect is modified by prior presentation of a patients individualised risk estimate or how presentation of treatment harms by relative or absolute risk affects acceptance.
2-Aminoacetophenone can be detected in the breath of Pseudomonas aeruginosa colonized cystic fibrosis patients; however, low levels were also detected in a small proportion of healthy subjects. It was hypothesized that food, beverages, cosmetics or medications could be a source of contamination of 2-aminoacetophenone in breath. To determine the potential confounding of these products on 2-aminoacetophenone breath analysis, screening for this volatile was performed in the laboratory by gas chromatography/mass spectrometry and a food challenge study carried out. 2-Aminoacetophenone was detected in four of the 78 samples tested in vitro: corn chips and canned tuna (high pmol mol(-1)) and egg white and one of the three beers (low pmol mol(-1)). No 2-aminoacetophenone was detected in the CF medication or cosmetics tested. Twenty-eight out of 30 environmental air samples were negative for 2-aminoacetophenone (below 50 pmol mol(-1)). A challenge study with ten healthy subjects was performed to determine if 2-aminoacetophenone from corn chips was detectable on the breath after consumption. Analysis of mixed breath samples reported that the levels of 2-aminoacetophenone were immediately elevated after corn chip consumption, but after 2 h the level of 2-aminoacetophenone had reduced back to the baseline for each subject.
Aspergillus fumigatus produces 2-pentyl furan (2-PF), a volatile compound not produced by many other pathogens or normal human metabolism. 2-Pentyl furan has been detected in the breath of patients with invasive aspergillosis (IA) by SPME pre-concentration coupled with CG/MS providing the possibility of an attractive diagnostic test. The limit of detection (LOD) and quantification (LOQ) for peak integration were assessed both statistically and empirically respectively. 2-Pentyl furan was detected from 10 of 45 food stuffs tested. Levels were highest from soymilk (3 of 3 brands), lower from pumpkin, peanuts, rolled oats 2, Ensure Plus, tinned asparagus, tinned beans and a vegetable exact (Marmite). No 2-PF was detectable in anti-fungal medications used to treat IA or commonly used cosmetics tested. There was no difference in 2-PF breath levels between morning and afternoon or fasting and non fasting samples taken from healthy subjects eating a diet without 2-PF rich foods. 2-Pentyl furan levels were present in breath samples immediately after a mouth rinse with soy milk (P<0.001), and in some subjects after ingesting soy milk and rinsing their mouth with water. The breath test for 2-PF can be conducted without an overnight fast or at a specified time provided the mouth has been rinsed 30 min or more from when 2-PF containing products have been ingested.
Human tendon mechanical properties are modified with loading. Moreover, there are indications that the training response in the tendon is gender specific. The aim of the current study was to examine whether in vivo patella tendon stiffness (K) differentially alters with training in older males compared with females. We also aimed to identify which endocrine pathway underlies the responses. Maximal knee extensor forces were also monitored to determine the training effect on muscle function. Fourteen healthy, habitually active older persons (seven males aged 74.0 ± 1.2 years (mean±SEM) and seven females aged 76.7 ± 1.2 years) were tested at baseline and after 12 weeks of weekly, progressive resistance training. With training, percentage increase in quadriceps maximum voluntary isometric force (MVC) was similar in males (2,469.6 ± 168.0 to 3,097.3 ± 261.9 N; +25.3 ± 6.1% (p < 0.01)) and females (1,728.8 ± 136.3 to 2,166.5 ± 135.8 N; +30.4 ± 15.1% (p < 0.05)), respectively. K increased more in males (338.0 ± 26.6 to 616.9 ± 58.7 N/mm; 79.8 ± 4.2% (p < 0.001)) compared to females (338.9 ± 31.0 to 373.2 ± 25.8 N/mm; +13.0 ± 3.7% (p < 0.001)). Interestingly, a pattern was found whereby below ~40% MVC, the females showed their greatest degree of K changes, whereas the males showed their greatest degree of K change above this relative force level. This gender contrast was also true at a standardised force level (1,200 N), with 5.8 ± 0.4% vs. 82.5 ± 1.8% increments in the females (i.e. value change from 380.3 ± 14.1 to 402.4 ± 13.3 N/mm) and the males (i.e. value change from 317.8 ± 13.8 to 580.2 ± 30.9 N/mm), respectively (p < 0.001). While circulating levels of both IGF-I and IL-6 did not alter with training, IGFBP-3 showed a significant training effect (19.1 ± 4.8%, p < 0.001) and only in the male sub-group (p = 0.038). We show here that with training, in vivo older females tendon is less dramatically modulated than that of males. We also show that the relative forces, at which the greatest adaptations are exhibited, differ by gender, with a suggestion of endocrine adaptations in males only. We thus propose that both training and rehabilitation regimens should consider gender-specific tendon responsiveness, at least in older persons.
Deciding when to leave a depleting resource to exploit another is a fundamental problem for all decision makers. The neuronal mechanisms mediating patch-leaving decisions remain unknown. We found that neurons in primate (Macaca mulatta) dorsal anterior cingulate cortex, an area that is linked to reward monitoring and executive control, encode a decision variable signaling the relative value of leaving a depleting resource for a new one. Neurons fired during each sequential decision to stay in a patch and, for each travel time, these responses reached a fixed threshold for patch-leaving. Longer travel times reduced the gain of neural responses for choosing to stay in a patch and increased the firing rate threshold mandating patch-leaving. These modulations more closely matched behavioral decisions than any single task variable. These findings portend an understanding of the neural basis of foraging decisions and endorse the unification of theoretical and experimental work in ecology and neuroscience.
In attentional models of learning, associations between actions and subsequent rewards are stronger when outcomes are surprising, regardless of their valence. Despite the behavioral evidence that surprising outcomes drive learning, neural correlates of unsigned reward prediction errors remain elusive. Here we show that in a probabilistic choice task, trial-to-trial variations in preference track outcome surprisingness. Concordant with this behavioral pattern, responses of neurons in macaque (Macaca mulatta) dorsal anterior cingulate cortex (dACC) to both large and small rewards were enhanced when the outcome was surprising. Moreover, when, on some trials, probabilities were hidden, neuronal responses to rewards were reduced, consistent with the idea that the absence of clear expectations diminishes surprise. These patterns are inconsistent with the idea that dACC neurons track signed errors in reward prediction, as dopamine neurons do. Our results also indicate that dACC neurons do not signal conflict. In the context of other studies of dACC function, these results suggest a link between reward-related modulations in dACC activity and attention and motor control processes involved in behavioral adjustment. More speculatively, these data point to a harmonious integration between reward and learning accounts of ACC function on one hand, and attention and cognitive control accounts on the other.
There is a need for objective imaging markers of Parkinsons disease status and progression. Positron emission tomography and single photon emission computed tomography studies have suggested patterns of abnormal cerebral perfusion in Parkinsons disease as potential functional biomarkers. This study aimed to identify an arterial spin labelling magnetic resonance-derived perfusion network as an accessible, non-invasive alternative. We used pseudo-continuous arterial spin labelling to measure cerebral grey matter perfusion in 61 subjects with Parkinsons disease with a range of motor and cognitive impairment, including patients with dementia and 29 age- and sex-matched controls. Principal component analysis was used to derive a Parkinsons disease-related perfusion network via logistic regression. Region of interest analysis of absolute perfusion values revealed that the Parkinsons disease pattern was characterized by decreased perfusion in posterior parieto-occipital cortex, precuneus and cuneus, and middle frontal gyri compared with healthy controls. Perfusion was preserved in globus pallidus, putamen, anterior cingulate and post- and pre-central gyri. Both motor and cognitive statuses were significant factors related to network score. A network approach, supported by arterial spin labelling-derived absolute perfusion values may provide a readily accessible neuroimaging method to characterize and track progression of both motor and cognitive status in Parkinsons disease.
Next-generation sequencing enables use of whole-genome sequence typing (WGST) as a viable and discriminatory tool for genotyping and molecular epidemiologic analysis. We used WGST to confirm the linkage of a cluster of Coccidioides immitis isolates from 3 patients who received organ transplants from a single donor who later had positive test results for coccidioidomycosis. Isolates from the 3 patients were nearly genetically identical (a total of 3 single-nucleotide polymorphisms identified among them), thereby demonstrating direct descent of the 3 isolates from an original isolate. We used WGST to demonstrate the genotypic relatedness of C. immitis isolates that were also epidemiologically linked. Thus, WGST offers unique benefits to public health for investigation of clusters considered to be linked to a single source.
When has the world changed enough to warrant a new approach? The answer depends on current needs, behavioral flexibility and prior knowledge about the environment. Formal approaches solve the problem by integrating the recent history of rewards, errors, uncertainty and context via Bayesian inference to detect changes in the world and alter behavioral policy. Neuronal activity in posterior cingulate cortex - a key node in the default network - is known to vary with learning, memory, reward and task engagement. We propose that these modulations reflect the underlying process of change detection and motivate subsequent shifts in behavior.
Viral production from infected cells can occur continuously or in a burst that generally kills the cell. For HIV infection, both modes of production have been suggested. Standard viral dynamic models formulated as sets of ordinary differential equations can not distinguish between these two modes of viral production, as the predicted dynamics is identical as long as infected cells produce the same total number of virions over their lifespan. Here we show that in stochastic models of viral infection the two modes of viral production yield different early term dynamics. Further, we analytically determine the probability that infections initiated with any number of virions and infected cells reach extinction, the state when both the population of virions and infected cells vanish, and show this too has different solutions for continuous and burst production. We also compute the distributions of times to establish infection as well as the distribution of times to extinction starting from both a single virion as well as from a single infected cell for both modes of virion production.
In recent years, vigorous debate has developed concerning how conflicts contribute to the spread of infectious diseases, and in particular, the role of post-conflict situations in the epidemiology of HIV/AIDS. This study details the age-specific mortality patterns among the population in the central provincial capital of Beira, Mozambique, during and after the Mozambican civil war which ended in 1992.
Accurate and complete mapping of short-read sequencing to a reference genome greatly enhances the discovery of biological results and improves statistical predictions. We recently presented RNA-MATE, a pipeline for the recursive mapping of RNA-Seq datasets. With the rapid increase in genome re-sequencing projects, progression of available mapping software and the evolution of file formats, we now present X-MATE, an updated version of RNA-MATE, capable of mapping both RNA-Seq and DNA datasets and with improved performance, output file formats, configuration files, and flexibility in core mapping software.
Pooling genomic DNA samples within clinical classes of disease for use in whole-genome single nucleotide polymorphism (SNP) genotyping allows for rapid and inexpensive genome-wide association studies (GWAS). We describe here a general outline for combining hundreds of genomic DNA samples prior to genotyping on commercially available high-density SNP microarrays. The pool construction approach is universal, and independent of the SNP genotyping platform utilized, and therefore provides a quick, efficient, and low-cost alternative to interrogating thousands of individual samples on singular SNP microarrays. While the strategy for pooled DNA genotyping on SNP microarrays is straightforward, the success of such studies is critically dependent upon the accuracy of allelic frequency calculations, the -ability to identify falsely positive results arising from assay variability, and the willingness to better resolve association signals through investigation of neighboring SNPs.
Recent legislation in the US requires that all medical records become electronic over the next decade. In addition, ongoing developments in patient-oriented care, most notably with the advent of health social networking and personal health records, provide a plethora of new information sources for research.
Advanced prostate cancer can progress to systemic metastatic tumors, which are generally androgen insensitive and ultimately lethal. Here, we report a comprehensive genomic survey for somatic events in systemic metastatic prostate tumors using both high-resolution copy number analysis and targeted mutational survey of 3508 exons from 577 cancer-related genes using next generation sequencing. Focal homozygous deletions were detected at 8p22, 10q23.31, 13q13.1, 13q14.11, and 13q14.12. Key genes mapping within these deleted regions include PTEN, BRCA2, C13ORF15, and SIAH3. Focal high-level amplifications were detected at 5p13.2-p12, 14q21.1, 7q22.1, and Xq12. Key amplified genes mapping within these regions include SKP2, FOXA1, and AR. Furthermore, targeted mutational analysis of normal-tumor pairs has identified somatic mutations in genes known to be associated with prostate cancer including AR and TP53, but has also revealed novel somatic point mutations in genes including MTOR, BRCA2, ARHGEF12, and CHD5. Finally, in one patient where multiple independent metastatic tumors were available, we show common and divergent somatic alterations that occur at both the copy number and point mutation level, supporting a model for a common clonal progenitor with metastatic tumor-specific divergence. Our study represents a deep genomic analysis of advanced metastatic prostate tumors and has revealed candidate somatic alterations, possibly contributing to lethal prostate cancer.
Humans acquire vitamin C (ascorbate) from their diet, and optimal tissue concentrations are required to maintain its enzyme cofactor and antioxidant activities. How dietary intake affects tissue concentrations is difficult to monitor and has generally been based on the measurement of plasma concentrations.
Complete and reliable knowledge of the ammonia spectrum is needed to enable the analysis and interpretation of astrophysical and planetary observations. Ammonia has been observed in the interstellar medium up to J=18 and more highly excited transitions are expected to appear in hot exoplanets and brown dwarfs. As a result, there is considerable interest in observing and assigning the high J (rovibrational) spectrum. In this work, numerous spectroscopic techniques were employed to study its high J transitions in the ground and ?(2)=1 states. Measurements were carried out using a frequency multiplied submillimeter spectrometer at Jet Propulsion Laboratory (JPL), a tunable far-infrared spectrometer at University of Toyama, and a high-resolution Bruker IFS 125 Fourier transform spectrometer (FTS) at Synchrotron SOLEIL. Highly excited ammonia was created with a radiofrequency discharge and a dc discharge, which allowed assignments of transitions with J up to 35. One hundred and seventy seven ground state and ?(2)=1 inversion transitions were observed with microwave accuracy in the 0.3-4.7 THz region. Of these, 125 were observed for the first time, including 26 ?K=3 transitions. Over 2000 far-infrared transitions were assigned to the ground state and ?(2)=1 inversion bands as well as the ?(2) fundamental band. Of these, 1912 were assigned using the FTS data for the first time, including 222 ?K=3 transitions. The accuracy of these measurements has been estimated to be 0.0003-0.0006?cm(-1). A reduced root mean square error of 0.9 was obtained for a global fit of the ground and ?(2)=1 states, which includes the lines assigned in this work and all previously available microwave, terahertz, far-infrared, and mid-infrared data. The new measurements and predictions reported here will support the analyses of astronomical observations by high-resolution spectroscopy telescopes such as Herschel, SOFIA, and ALMA. The comprehensive experimental rovibrational energy levels reported here will permit further refinement of the potential energy surface to improve ammonia ab initio calculations and facilitate assignment of new high-resolution spectra of hot ammonia.
Endoscopic surgery to the nasopharyngeal portion of the Eustachian tube (ET) has been advocated for ET dysfunction. It is therefore essential to understand the relationship between the ET and the internal carotid artery (ICA) from an endoscopic perspective.
The prevalence of multiple sclerosis (MS) is not uniform, with a latitudinal gradient of prevalence present in most studies. Understanding the drivers of this gradient may allow a better understanding of the environmental factors involved in MS pathogenesis.
We report the design and synthesis of multimetallic Au/Pt-bimetallic nanoparticles as a highly durable electrocatalyst for the oxygen reduction reaction (ORR) in proton exchange membrane fuel cells. This system was first studied on well-defined Pt and FePt thin films deposited on a Au(111) surface, which has guided the development of novel synthetic routes toward shape-controlled Au nanoparticles coated with a Pt-bimetallic alloy. It has been demonstrated that these multimetallic Au/FePt(3) nanoparticles possess both the high catalytic activity of Pt-bimetallic alloys and the superior durability of the tailored morphology and composition profile, with mass-activity enhancement of more than 1 order of magnitude over Pt catalysts. The reported synergy between well-defined surfaces and nanoparticle synthesis offers a persuasive approach toward advanced functional nanomaterials.
Recent studies have drawn attention to the adverse effects of ambient air pollutants such as particulate matter 2.5 (PM2.5) on human health. We evaluated the association between PM2.5 exposure and diabetes prevalence in the U.S. and explored factors that may influence this relationship.
The rotational spectrum of n-propanol (n-CH(3)CH(2)CH(2)OH) was studied with several techniques of contemporary broadband rotational spectroscopy at frequencies from 8 to 550 GHz. Rotational transitions in all five conformers of the molecule, Gt, Gg, Gg, Tt, and Tg, have been unambiguously assigned. Over 6700 lines of the Gt, Gg, and Gg species, for quantum number values reaching K(a) = 33 and J = 67, were fitted in a joint analysis leading to the determination of DeltaE(Gg-Gt) = 47.82425(25) cm(-1) and DeltaE (Gg-Gg) = 3.035047(11) cm(-1). Stark effect measurements in supersonic expansion were used to further confirm the assignment. The results are compared with those for the ethanol molecule and with ab initio calculations, allowing several inferences to be drawn concerning the differences in the large amplitude torsional potential of the hydroxyl group in the two molecules.
The development of suitable experimental systems for studying HIV latency in primary cells that permit detailed biochemical analyses and the screening of drugs is a critical step in the effort to develop viral eradication strategies. Primary CD4(+) T cells were isolated from peripheral blood and amplified by antibodies to the T-cell receptor (TCR). The cells were then infected by lentiviral vectors carrying fluorescent reporters and either the wild-type Tat gene or the attenuated H13L Tat gene. After sorting for the positive cells and reamplification, the infected cells were allowed to spontaneously enter latency by long-term cultivation on the H80 feeder cell line in the absence of TCR stimulation. By 6 weeks almost all of the cells lost fluorescent protein marker expression; however, more than 95% of these latently infected cells could be reactivated after stimulation of the TCR by alpha-CD3/CD28 antibodies. Chromatin immunoprecipitation assays showed that, analogously to Jurkat T cells, latent proviruses in primary CD4(+) T cells are enriched in heterochromatic markers, including high levels of CBF-1, histone deacetylases, and methylated histones. Upon TCR activation, there was recruitment of NF-kappaB to the promoter and conversion of heterochromatin structures present on the latent provirus to active euchromatin structures containing acetylated histones. Surprisingly, latently infected primary cells cannot be induced by tumor necrosis factor alpha because of a restriction in P-TEFb levels, which can be overcome by activation of the TCR. Thus, a combination of restrictive chromatin structures at the HIV long terminal repeat and limiting P-TEFb levels contribute to transcriptional silencing leading to latency in primary CD4(+) T cells.
Pseudomonas aeruginosa infections are associated with progressive life threatening decline of lung function in cystic fibrosis sufferers. Growth of Ps. aeruginosa releases a "grape-like" odour that has been identified as the microbial volatile organic compound 2-aminoacetophenone (2-AA).
The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
In most natural decision contexts, the process of selecting among competing actions takes place in the presence of informative, but potentially ambiguous, stimuli. Decisions about magnitudes - quantities like time, length, and brightness that are linearly ordered - constitute an important subclass of such decisions. It has long been known that perceptual judgments about such quantities obey Webers Law, wherein the just-noticeable difference in a magnitude is proportional to the magnitude itself. Current physiologically inspired models of numerical classification assume discriminations are made via a labeled line code of neurons selectively tuned for numerosity, a pattern observed in the firing rates of neurons in the ventral intraparietal area (VIP) of the macaque. By contrast, neurons in the contiguous lateral intraparietal area (LIP) signal numerosity in a graded fashion, suggesting the possibility that numerical classification could be achieved in the absence of neurons tuned for number. Here, we consider the performance of a decision model based on this analog coding scheme in a paradigmatic discrimination task - numerosity bisection. We demonstrate that a basic two-neuron classifier model, derived from experimentally measured monotonic responses of LIP neurons, is sufficient to reproduce the numerosity bisection behavior of monkeys, and that the threshold of the classifier can be set by reward maximization via a simple learning rule. In addition, our model predicts deviations from Weber Law scaling of choice behavior at high numerosity. Together, these results suggest both a generic neuronal framework for magnitude-based decisions and a role for reward contingency in the classification of such stimuli.
Human beta-defensin 2 (hBD-2 or DEFB4) is a highly inducible, antimicrobial peptide, which may have an important role in the innate immune response at epithelial surfaces. Genomic copy number of DEFB4 is polymorphic, with most individuals possessing 3-5 copies. Increased DEFB4 copy number is a susceptibility factor for psoriasis, whereas a single study in a Crohns disease (CD) cohort reported that decreased DEFB4 copy number is associated with colonic inflammation. Here, we analyze association of DEFB4 copy number with CD in a New Zealand case-control cohort of European origin.
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