Miracle-dz/UniFAR-FTUs huggingface dataset:
Challenges of Linkage Analysis in the Era of Whole‐Genome Sequencing

Whole‐genome sequencing (WGS) is becoming an affordable technology for the study of the genetics of complex traits. With any new technology, experimental designs and statistical methods, both old and new, must be evaluated. One design seeing a resurgence of interest is the use of families. Genetic Analysis Workshop 18 provided the opportunity to evaluate statistical methods applied to WGS data for family‐based studies. We summarize the results of five contributions that used linkage in the context of WGS. The investigators took differing approaches, including assessment of false‐positive rates in classic two‐point linkage, the effects of heterogeneity on linkage and association tests, and the use of linkage to focus association tests. We describe the primary findings of each contribution and note challenges that are not new to those working in family designs or specific to WGS data; for example, choice of phenotype definition, covariate adjustment, and use of longitudinal data may produce different results, making comparisons challenging. We detail new issues brought about by WGS, such as the elevated genome‐wide false‐positive rate for classic two‐point parametric linkage analysis, computational demands in multipoint calculations, and lack of clarity in how to best use linkage to focus association testing. Finally, we comment on when linkage may be helpful for WGS, highlighting where additional research is needed; for example, although linkage analysis has been successful in the study of rare variants of large effect, how to best use family information in the context of rare variants of moderate effect remains an open research question.
The Prosody of Information Units in Spontaneous Monologue

Abstract This article describes a perceptual evaluation of the prosodic structure of a spontaneously produced monologue. It was found that the speaker studied demarcates larger-scale topical units in spoken discourse by means of intonation (use of melodic boundary markers, scaling of maxima in pitchmovements, general decline in average pitch) and by the use of pauses with variable durations. In a perception test, it was examined to what extent these prosodic devices may be important to listeners. Subjects were confronted with three unintelligible (band-pass-filtered) versions of a fragment of the elicited monologue: (1) with the original prosody unchanged; (2) with constant pause duration and the original speech melody; (3) with monotonous pitch and the original pause structure. They were instructed to indicate the boundaries of the larger-scale topical units in the three versions. Subjects were able to detect correctly the major discourse boundaries in all three filtered versions in a significant number of cases. They performed best when confronted with version 1. Versions 1 and 2, in their turn, did better than version 3, which suggests that, in the performance of this speaker, intonation is a perceptually more important factor than pause for the clarification of the topical make-up of a text, though the latter dimension is certainly not negligible.
64Cu-Labeled Repebody Molecules for Imaging of Epidermal Growth Factor Receptor–Expressing Tumors

The epidermal growth factor receptor (EGFR) is a member of the erbB family of receptors and is overexpressed in many tumor types. A repebody is a newly designed nonantibody protein scaffold for tumor targeting that contains leucine-rich repeat modules. In this study, 3 64Cu-labeled anti-EGFR repebodies with different chelators were synthesized, and their biologic characteristics were assessed in cultured cells and tumor-bearing mice. Methods: Repebodies were synthesized with the chelators 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-N,N′,N,″-triacetic acid trihydrochloride ([p-SCN-Bn]-NOTA), 2,2′,2″-(10-(2-(2,5-dioxopyrrolidin-1-yloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DOTA-N-hydroxysuccinimide ester), or 1-(p-isothiocyanatobenzyl)diethylenetriamine pentaacetic acid trihydrochloride ([p-SCN-Bn]-DTPA) in 1.0 M NaHCO3 buffer (pH 9.2) for 24 h. Purified NOTA-, DOTA-, and DTPA-conjugated repebody were radiolabeled with 64Cu in 0.1 M NH4OAc buffer (pH 5.5). To compare the EGFR-binding affinities of the repebodies, cellular uptake studies were performed with the human non–small cell lung cancer cell line H1650 (high expression of EGFR) and the human colon adenocarcinoma cell line SW620 (low expression of EGFR). Biodistribution and small-animal PET imaging studies were performed using H1650 tumor–bearing mice. Results: Radiochemical yields of the 64Cu-labeled repebodies were approximately 70%–80%. Cellular uptake of the NOTA-, DOTA-, and DTPA-repebodies was over 4-fold higher in H1650 cells than in SW620 cells at 1 h. The 3 repebodies had accumulated specifically in H1650 tumor–bearing nude mice by 1 h after intravenous injection and were retained for over 24 h, as measured by the percentage injected dose per gram of tissue (%ID/g). Tumor uptake of all repebodies increased from 1 to 6 h (at 1 h, 6.28, 8.46, and 6.91 %ID/g for NOTA-, DOTA-, and DTPA-repebody, respectively; at 6 h, 9.4, 8.28, and 10.1 %ID/g, respectively). H1650 tumors were clearly visible after injection of each repebody, with high tumor-to-background ratios (at 1 h, 3.43, 4.89, and 2.38 for NOTA-, DOTA-, and DTPA-repebody, respectively; at 6 h, 3.05, 4.36, and 2.08; at 24 h, 3.81, 4.58, and 2.86). Conclusion: The 3 64Cu-repebody complexes demonstrated specific and rapid uptake in EGFR-expressing tumors within 1 h and may have potential as novel EGFR imaging agents for PET.
Within-Day Energy Deficiency and Metabolic Perturbation in Male Endurance Athletes.

Endurance athletes are at increased risk of relative energy deficiency associated with metabolic perturbation and impaired health. We aimed to estimate and compare within-day energy balance in male athletes with suppressed and normal resting metabolic rate (RMR) and explore whether within-day energy deficiency is associated with endocrine markers of energy deficiency. A total of 31 male cyclists, triathletes, and long-distance runners recruited from regional competitive sports clubs were included. The protocol comprised measurements of RMR by ventilated hood and energy intake and energy expenditure to predict RMRratio (measured RMR/predicted RMR), energy availability, 24-hr energy balance and within-day energy balance in 1-hr intervals, assessment of body composition by dual-energy X-ray absorptiometry, and blood plasma analysis. Subjects were categorized as having suppressed (RMRratio < 0.90, n = 20) or normal (RMRratio > 0.90, n = 11) RMR. Despite there being no observed differences in 24-hr energy balance or energy availability between the groups, subjects with suppressed RMR spent more time in an energy deficit exceeding 400 kcal (20.9 [18.8-21.8] hr vs. 10.8 [2.5-16.4], p = .023) and had larger single-hour energy deficits compared with subjects with normal RMR (3,265 ± 1,963 kcal vs. -1,340 ± 2,439, p = .023). Larger single-hour energy deficits were associated with higher cortisol levels (r = -.499, p = .004) and a lower testosterone:cortisol ratio (r = .431, p = .015), but no associations with triiodothyronine or fasting blood glucose were observed. In conclusion, within-day energy deficiency was associated with suppressed RMR and catabolic markers in male endurance athletes.
Large-scale clustering using mathematical programming

Cluster analysis is a fundamental task in exploratory data analysis with a wide range of applications. Several clustering approaches based on mathematical programming have been proposed in the literature and were successfully used for small- and medium-scale data sets. However, mathematical programming-based clustering models are rarely used for large-scale data sets due to their extensive running time. In this paper, we propose a general scaling approach for existing mathematical programming-based clustering models that is based on the idea of replacing identical or nearly-identical objects by a small set of representatives. Our computational results indicate that the proposed scaling approach substantially reduces running time with a minor loss in clustering accuracy.
Effect of Long-Term Treatment with the Antiestrogen EM-652.HCl on Pituitary Estrogen Receptor Alpha and Prolactin mRNA Expression in Intact, Ovariectomized and Gonadotropin- Releasing Hormone-Treated Female Rats

Estrogen receptor α (ERα) is the predominant estrogen receptor subtype in the anterior pituitary gland. In order to assess the influence of the pure antiestrogen EM-652.HCl on ERα gene transcription, we have studied the effect of long-term administration of the antiestrogen in ovariectomized rats as well as in intact female rats treated or not with the GnRH-agonist D-trp6, des-Gly-NH210 GnRH ethylamide (GnRH-A), a treatment which induces pharmacological castration. To evaluate the degree of pituitary responsiveness to changes in estrogen exposure, prolactin (PRL) mRNA levels were also measured. ERα and PRL mRNA levels were evaluated by quantitative in situ hybridization. It was found that, 49 weeks after ovariectomy (OVX), pituitary ERα mRNA levels were decreased by 55%. Long-term administration (49 weeks) of EM-652.HCl to OVX animals resulted in a further 41% decrease in ERα mRNA. On the other hand, ovariectomy induced an 82% decrease in PRL mRNA levels while the administration of EM-652.HCl to OVX animals did not further decrease PRL mRNA. The administration of EM.652.HCl or GnRH-A alone to intact rats during 52 weeks did not significantly modify pituitary ERα mRNA levels. Concomitant administration of both GnRH-A and EM-652.HCl induced 41 and 47% decreases in ERα mRNA levels, when compared to the levels measured in vehicle-treated and GnRH-treated animals respectively. Combined administration of EM.652.HCl and GnRH-A induced 56 and 65% decreases in PRL mRNA, respectively. When EM-652.HCl was administered concomitantly with GnRH-A, the inhibitory effect on PRL mRNA levels was more marked than that observed in GnRH-A-treated animals. The present data demonstrate that when circulating estrogens are absent or maintained at very low levels by GnRH administration, EM-652.HCl can still depress ERα gene transcription. It is suggested that estrogens can positively regulate pituitary ERα gene transcription and that the antiestrogen EM-652.HCl can downregulate by itself pituitary ERα gene transcription.
Reorganization of brain connectivity in obesity

Global brain connectivity (GBC) identifies regions of the brain, termed “hubs,” which are densely connected and metabolically costly, and have a wide influence on brain function. Since obesity is associated with central and peripheral metabolic dysfunction we sought to determine if GBC is altered in obesity. Two independent fMRI data sets were subjected to GBC analyses. The first data set was acquired while participants (n = 15 healthy weight and 15 obese) tasted milkshake and the second with participants at rest (n = 33 healthy weight and 28 obese). In the resting state and during milkshake consumption GBC is consistently decreased in the ventromedial and ventrolateral prefrontal cortex, insula and caudate nucleus, and increased in brain regions belonging to the dorsal attention network including premotor areas, superior parietal lobule, and visual cortex. During milkshake consumption, but not at rest, additional decreases in GBC are observed in feeding‐related circuitry including the insula, amygdala, anterior hippocampus, hypothalamus, midbrain, brainstem and somatomotor cortex. Additionally, GBC differences were not accounted for by age. These results demonstrate that obesity is associated with decreased GBC in prefrontal and feeding circuits and increased GBC in the dorsal attention network. We therefore conclude that global brain organization is altered in obesity to favor networks important for external orientation over those monitoring homeostatic state and guiding feeding decisions. Furthermore, since prefrontal decreases are also observed at rest in obese individuals future work should evaluate whether these changes are associated with neurocognitive impairments frequently observed in obesity and diabetes. Hum Brain Mapp 38:1403–1420, 2017. © 2016 Wiley Periodicals, Inc.
Concurrent exercise training: do opposites distract?

Specificity is a core principle of exercise training to promote the desired adaptations for maximising athletic performance. The principle of specificity of adaptation is underpinned by the volume, intensity, frequency and mode of contractile activity and is most evident when contrasting the divergent phenotypes that result after undertaking either prolonged endurance or resistance training. The molecular profiles that generate the adaptive response to different exercise modes have undergone intense scientific scrutiny. Given divergent exercise induces similar signalling and gene expression profiles in skeletal muscle of untrained or recreationally active individuals, what is currently unclear is how the specificity of the molecular response is modified by prior training history. The time course of adaptation and when ‘phenotype specificity’ occurs has important implications for exercise prescription. This context is essential when attempting to concomitantly develop resistance to fatigue (through endurance‐based exercise) and increased muscle mass (through resistance‐based exercise), typically termed ‘concurrent training’. Chronic training studies provide robust evidence that endurance exercise can attenuate muscle hypertrophy and strength but the mechanistic underpinning of this ‘interference’ effect with concurrent training is unknown. Moreover, despite the potential for several key regulators of muscle metabolism to explain an incompatibility in adaptation between endurance and resistance exercise, it now seems likely that multiple integrated, rather than isolated, effectors or processes generate the interference effect. Here we review studies of the molecular responses in skeletal muscle and evidence for the interference effect with concurrent training within the context of the specificity of training adaptation.
Targeting DNA repair: the genome as a potential biomarker

Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best‐known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP‐ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next‐generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high‐grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome‐wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
End‐state comfort in two object manipulation tasks: Investigating how the movement context influences planning in children, young adults, and older adults

The movement context (pantomime, pantomime with image/object as guide, and actual use) has been shown to influence end-state comfort-the propensity to prioritize a comfortable final hand position over an initially comfortable one-across the lifespan. The present study aimed to assess how the movement context (pantomime, using a dowel as the tool, and actual use) influences end-state comfort when acting with objects (glass/hammer) that differ in use-dependent experience. Children (ages 6-11, n = 70), young adults (n = 21), and older adults (n = 21) picked up an overturned glass to pour water and a hammer to hit a nail, where the handle faced away from the participant. End-state comfort was assessed in each movement context. Findings provide support for an increase in end-state comfort with age, adult-like patterns at age 10, and no difference between older adults and 8- to 9-year-old children. In addition, this work revealed that perception of "graspability" led to an increase in end-state comfort in the hammering task; therefore, suggesting our ability to act with objects and tools in the environment is influenced by use-dependent experience and object perception. Results add to our understanding of changes in motor planning abilities with age, and factors underlying these changes.
Selected clinical chemistry analytes correlate with the pathogenesis of inclusion body hepatitis experimentally induced by fowl aviadenoviruses

ABSTRACT In the present study, clinical chemistry was applied to assess the pathogenesis and progression of experimentally induced inclusion body hepatitis (IBH). For this, five fowl aviadenovirus (FAdV) strains from recent IBH field outbreaks were used to orally inoculate different groups of day-old specific pathogen-free chickens, which were weighed, sampled and examined during necropsy by sequential killing. Mortalities of 50% and 30% were recorded in two groups between 6 and 9 days post-infection (dpi), along with a decreased weight of 23% and 20%, respectively, compared to the control group. Macroscopical changes were seen in the liver and kidney between 6 and 10 dpi, with no lesions being observed in the other organs. Histological lesions were observed in the liver and pancreas during the same period. Plasma was collected from killed birds of each group at each time point and the following clinical chemistry analytes were investigated: aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), bile acids, total protein, albumin, uric acid and lipase. Plasma protein profile, AST and GLDH, together with bile acids values paralleled the macroscopical and histopathological lesions in the liver, while plasma lipase activity levels coincided with lesions observed in pancreas. In agreement with the histology and clinical chemistry, viral load in the target organs, liver and pancreas, was highest at 7 dpi. Thus, clinical chemistry was found to be a valuable tool in evaluating and monitoring the progression of IBH in experimentally infected birds, providing a deeper knowledge of the underlying pathophysiological mechanisms of a FAdV infection in chickens.
Overexpression of β1 integrin contributes to polarity reversal and a poor prognosis of breast invasive micropapillary carcinoma

Invasive micropapillary carcinoma (IMPC) of the breast is a highly aggressive breast cancer. Polarity reversal exemplified by cluster growth is hypothesized to contribute to the invasiveness and metastasis of IMPC. In this study, we demonstrate that levels of β1 integrin and Rac1 expression were greater in breast IMPC than in invasive breast carcinoma of no specific type and paraneoplastic benign breast tissue. We show that silencing β1 integrin expression using the β1 integrin inhibitor AIIB2 partially restored polarity in IMPC primary cell clusters and downregulated Rac1. Thus, overexpression of β1 integrin upregulates Rac1. Univariate analysis showed that overexpression of β1 integrin and Rac1 was associated with breast cancer cell polarity reversal, lymph node metastasis, and poor disease-free survival in IMPC patients. Multivariate analysis revealed that polarity reversal was an independent predictor of poor disease-free survival. These findings indicate that overexpression of β1 integrin and the resultant upregulation of Rac1 contribute to polarity reversal and metastasis of breast IMPC, and that β1 integrin and Rac1 could be potential prognostic biomarkers and targets for treatment of breast IMPC.
The Finding of Pacific Transvenid Acanthocephalan in the Arabian Gulf, with the Description of Paratrajectura longcementglandatus N. Gen., N. Sp. from Perciform Fishes and Emendation of Transvenidae

Abstract The acanthocephalan Paratrajectura longcementglandatus n. gen., n. sp. (Transvenidae) is described from specimens of 2 perciform fish species, Nemipterus japonicus Bloch (Nemipteridae) and Otolithes ruber Bloch and Schneider, collected in the marine territorial waters of Iraq and Iran in the Arabian Gulf. Metal analysis of hook tip, middle, and base is also described using energy disruptive analysis for X-ray. The new genus is distinguished from the closely related genus Trajectura Pichelin and Cribb, 2001 described from wrasses (Labridae) (Perciformes) in the Pacific off Australia and Japan by having a proboscis with apical epidermal cone, long rhadinorhynchid-like tubular cement glands, relatively short and lobulated lemnisci, all proboscis hooks with prominent roots, females with subterminal gonopore and a rounded projection on the antero-dorsal end of the trunk, and males with elongate pre-equatorial testes reaching proboscis receptacle. In Trajectura, the proboscis lacks apical epidermal cone, the cement glands are pyriform or ovoid, the lemnisci are digitiform and considerably longer than the receptacle, the posterior proboscis hooks are rootless, the females have prominent finger-like trunk projection and terminal gonopore, and males with equatorial testes that may not be elongate and may be distant from the receptacle. The importance of cement glands in the diagnosis of genera and families in acanthocephalan taxonomy is stressed. Other features especially the type and arrangement of hooks on the proboscis, but not hook roots, are comparable in the 2 genera. Diagnosis of the family Transvenidae is emended.
COMS-Based Retrieval of Daily Actual Evapotranspiration over Korea

Evapotranspiration (ET) from the land surface is an important hydrometeorological factor in the exchange of energy between the atmosphere and land surface. The accurate quantification for management of water resources and understanding of climate change are crucial, requiring continuous temporal and spatial monitoring. The objective of this study is to apply and estimate daily actual ET using semiempirical method, B-method, which is based on surface energy balance over heterogeneous area, Korea. To estimate daily ET, we used geostationary meteorological satellite data (Communication, Ocean and Meteorological Satellite, COMS) and polar-orbiting satellite data (Systeme Pour ľObservation de la Terre, SPOT). Estimated daily ET using only satellite data was relatively accurate and reflects land surface characteristics. It had high periodicity and spatial resolution over a wide area on clear-sky days. The daily ET was overestimated by about 1 mm/day at the two flux tower measurements sites, but the simulated seasonal variation and pattern were in good agreement with flux tower measurements. In the mixed forest, the root-mean-square error (RMSE) was 0.94 mm/day and the bias was 1.05 mm/day, while, in the rice paddy, RMSE was 1.12 mm/day and bias was 1.21 mm/day.