The fickle Mutation of a Cytoplasmic Tyrosine Kinase Effects Sensitization but not Dishabituation in Drosophila Melanogaster

fickle is a P-element mutation identified from a screen for defects in courtship behavior and disrupts the fly homolog of Bruton's tyrosine kinase (Btk) gene (Baba et al., 1999). Here, we show that habituation of the olfactory jump reflex also is defective in fickle. Unlike, the prototypical memory mutants, rutabaga and dunce, which habituate more slowly than normal, fickle flies habituate faster than normal. fickle's faster-than-normal response decrement did not appear to be due to sensorimotor fatigue, and dishabituation of the jump response was normal. Based on a long-standing “two opponent process” theory of habituation, these data suggested that behavioral sensitization might be defective in fickle. To test this hypothesis, we designed a olfactory sensitization procedure, using the same stimuli to habituate (odor) and dishabituate (vortexing) flies. Mutant flies failed to show any sensitization with this procedure. Our study reveals a “genetic dissection” of sensitization and dishabituation and, for the first time, provides a biological confirmation of the two opponent process theory of habituation

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.Objective: To investigate the genetic regulation of serum E2 and E1 in men.Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1

Global conformal anomaly in N=2 string

We show the existence of a global anomaly in the one-loop graphs of N=2 string theory, defined by sewing tree amplitudes, unless spacetime supersymmetry is imposed. The anomaly is responsible for the non-vanishing maximally helicity violating amplitudes. The supersymmetric completion of the N=2 string spectrum is formulated by extending the previous cohomological analysis with an external spin factor; the target space-time spin-statistics of these individual fields in a selfdual background are compatible with previous cohomological analysis as fields of arbitrary spin may be bosonized into one another. We further analyze duality relations between the open and closed string amplitudes and demonstrate this in the supersymmetric extension of the target space-time theory through the insertion of zero-momentum operators.Comment: 29 pages, LaTeX, one figur

Exceptional skull of huayqueriana (mammalia, litopterna, macraucheniidae) from the late miocene of Argentina: Anatomy, systematics, and peleobiological implications

The Huayquerías Formation (Late Miocene, Huayquerian SALMA) is broadly exposed in westcentral Argentina (Mendoza). The target of several major paleontological expeditions in the first half of the 20th century, the Mendozan Huayquerías (badlands) have recently yielded a significant number of new fossil finds. In this contribution we describe a complete skull (IANIGLA-PV 29) and place it systematically as Huayqueriana cf. H. cristata (Rovereto, 1914) (Litopterna, Macraucheniidae). The specimen shares some nonexclusive features with H. cristata (similar size, rostral border of the orbit almost level with distal border of M3, convergence of maxillary bones at the level of the P3/P4 embrasure, flat snout, very protruding orbits, round outline of premaxillary area in palatal view, and small diastemata between I3/C and C/P1). Other differences (e.g., lack of sagittal crest) may or may not represent intraspecific variation. In addition to other features described here, endocast reconstruction utilizing computer tomography (CT) revealed the presence of a derived position of the orbitotemporal canal running below the rhinal fissure along the lateroventral aspect of the piriform lobe. CT scanning also established that the maxillary nerve (CN V2) leaves the skull through the sphenoorbital fissure, as in all other litopterns, a point previously contested for macraucheniids. The angle between the lateral semicircular canal and the plane of the base of the skull is about 26°, indicating that in life the head was oriented much as in modern horses. Depending on the variables used, estimates of the body mass of IANIGLA-PV 29 produced somewhat conflicting results. Our preferred body mass estimate is 250 kg, based on the centroid size of 36 3D cranial landmarks and accompanying low prediction error. The advanced degree of tooth wear in IANIGLA-PV 29 implies that the individual died well into old age. However, a count of cementum lines on the sectioned left M2 is consistent with an age at death of 10 or 11 years, younger than expected given its body mass. This suggests that the animal had a very abrasive diet. Phylogenetic analysis failed to resolve the position of IANIGLA-PV 29 satisfactorily, a result possibly influenced by intraspecific variation. There is no decisive evidence for the proposition that Huayqueriana, or any other litoptern, were foregut fermenters.Fil: Forasiepi, Analia Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: MacPhee, Ross D. E.. American Museum Of Natural History; Estados UnidosFil: Hernández del Pino, Santiago Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Schmidt, Gabriela Ines. Provincia de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Universidad Autónoma de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción; ArgentinaFil: Amson, Eli. Universitat Zurich; SuizaFil: Grohé, Camille. American Museum Of Natural History; Estados Unido

The evolution of language: a comparative review

For many years the evolution of language has been seen as a disreputable topic, mired in fanciful "just so stories" about language origins. However, in the last decade a new synthesis of modern linguistics, cognitive neuroscience and neo-Darwinian evolutionary theory has begun to make important contributions to our understanding of the biology and evolution of language. I review some of this recent progress, focusing on the value of the comparative method, which uses data from animal species to draw inferences about language evolution. Discussing speech first, I show how data concerning a wide variety of species, from monkeys to birds, can increase our understanding of the anatomical and neural mechanisms underlying human spoken language, and how bird and whale song provide insights into the ultimate evolutionary function of language. I discuss the ‘‘descended larynx’ ’ of humans, a peculiar adaptation for speech that has received much attention in the past, which despite earlier claims is not uniquely human. Then I will turn to the neural mechanisms underlying spoken language, pointing out the difficulties animals apparently experience in perceiving hierarchical structure in sounds, and stressing the importance of vocal imitation in the evolution of a spoken language. Turning to ultimate function, I suggest that communication among kin (especially between parents and offspring) played a crucial but neglected role in driving language evolution. Finally, I briefly discuss phylogeny, discussing hypotheses that offer plausible routes to human language from a non-linguistic chimp-like ancestor. I conclude that comparative data from living animals will be key to developing a richer, more interdisciplinary understanding of our most distinctively human trait: language

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe