Bilinear modulation models for seasonal tables of counts

We propose generalized linear models for time or age-time tables of seasonal counts, with the goal of better understanding seasonal patterns in the data. The linear predictor contains a smooth component for the trend and the product of a smooth component (the modulation) and a periodic time series of arbitrary shape (the carrier wave). To model rates, a population offset is added. Two-dimensional trends and modulation are estimated using a tensor product B-spline basis of moderate dimension. Further smoothness is ensured using difference penalties on the rows and columns of the tensor product coefficients. The optimal penalty tuning parameters are chosen based on minimization of a quasi-information criterion. Computationally efficient estimation is achieved using array regression techniques, avoiding excessively large matrices. The model is applied to female death rate in the US due to cerebrovascular diseases and respiratory diseases

The Postglacial Phytogeography of the Iowan Lobe

The Iowan lobe of the Wisconsin glaciation is located in northeastern Iowa. Evidence is summarized which pertains to the migrations of the regional vegetation following the Wisconsin glaciations. The most recent climatic fluctuation to influence the distribution of the present flora was the Hypsithermal interval. The present distributions of several species are discussed in relation to the postglacial history of the flora. Eleven distribution maps of representative species are included. Most of the distribution patterns can be attributed to factors other than continuing postglacial migration. It appears that these plant distributions are primarily a function of the distribution of available habitats. Most species appear to have had sufficient time since the Hypsithermal interval to complete their migration into the Iowan lobe and to become well established. The need for additional paleobotanical and phytogeographic research in Iowa is stressed

The Vegetation of the Glacial Border During the Wisconsin Maximum

The climate of the glacial boundary during the Wisconsin maximum was generally cooler and moister than at present. There is some evidence that a frost climate prevailed for some time at the glacial margin, suggesting that a tundra-like vegetation existed there. Pollen profiles indicate that a Picea-Abies forest existed south of the glacial margin and probably extended up to it during periods of climatic amelioration

Hemingway and Bullshit

This paper uses Harry Frankfurt\u27s definition of bullshit as a lens to re-examine Ernest Hemingway\u27s aesthetic of factual details and omission. Frankfurt argues that bullshit consists of speech made with indifference to its veracity, and one who makes a habit of bullshitting may lose touch with reality. By studying three works across the author\u27s career, Big Two-Hearted River, The Short Happy Life of Francis Macomber, and The Old Man and the Sea, one sees that Hemingway\u27s prose style evolves and eventually contradicts his artistic statements. Given the fact that he promotes his aesthetic while discarding it, his theory becomes bullshit. Because normative critical interpretation of the author rests largely on his aesthetic theory, it too is inaccurate. Though Hemingway misrepresents how he writes, the success of his work regardless of aesthetics demonstrates that his writing is more complex than many think and deserves a more thorough re-evaluation

Effect of Different Collegiate Sports on Cortical Bone in the Tibia

Objectives: The purpose of this study was to determine the effect of sports participation on cortical bone in the tibia. Methods: 53 female collegiate athletes (25 cross-country, 16 soccer, and 12 volleyball) and 20 inactive controls had the left distal 20% tibia scanned by pQCT. Cortical volumetric BMD (vBMD) was measured within the cortical shell at the anterior, posterior, medial, and lateral regions and standard deviations were calculated. Results: Total vBMD was greater in the control group (1161±5 mg/mm3) than each of the sports (p\u3c0.05). Soccer players (1147±5 mg/mm3) had greater vBMD than volleyball players (1136±7 mg/mm3) (p\u3c0.05), but similar to cross-country runners (1145±5 mg/mm3). Cortical thickness was greatest in soccer players (4.1±0.1 mm), while cross-country and control subjects (3.8±0.1 mm) had greater thickness than volleyball players (3.4±0.1 mm)(p\u3c0.05). Periosteal circumference was greater in volleyball players (71±1.4 mm) than soccer, cross-country, and control subjects (68±0.9, 69±0.8, and 66±1 mm, respectively; all, p\u3c0.05). vBMD variation within the cortical shell was greater among control subjects (70±6 mg/cm3) than each of the athlete groups, with soccer players having lower variation than cross country runners (within-in person SD 36±6 mg/cm3 and 54±5 mg/cm3 respectively; p\u3c0.05). Conclusion: These results indicate bone geometry and distribution within the cortical shell of the tibia varies depending upon sporting activities of young women

Visualization of Genomic Changes by Segmented Smoothing Using an L0 Penalty

Copy number variations (CNV) and allelic imbalance in tumor tissue can show strong segmentation. Their graphical presentation can be enhanced by appropriate smoothing. Existing signal and scatterplot smoothers do not respect segmentation well. We present novel algorithms that use a penalty on the norm of differences of neighboring values. Visualization is our main goal, but we compare classification performance to that of VEGA

Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turn-over by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by SCFFbxw7. However, N-Myc protein is stabilized in neuroblastoma by Aurora-A kinase in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxw7. We determine the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72 Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxw7 to disfavor the generation of Lys48-linked poly-Ub chains

Evidence That the P\u3csub\u3ei\u3c/sub\u3e Release Event Is the Rate-Limiting Step in the Nitrogenase Catalytic Cycle

Nitrogenase reduction of dinitrogen (N2) to ammonia (NH3) involves a sequence of events that occur upon the transient association of the reduced Fe protein containing two ATP molecules with the MoFe protein that includes electron transfer, ATP hydrolysis, Pi release, and dissociation of the oxidized, ADP-containing Fe protein from the reduced MoFe protein. Numerous kinetic studies using the nonphysiological electron donor dithionite have suggested that the rate-limiting step in this reaction cycle is the dissociation of the Fe protein from the MoFe protein. Here, we have established the rate constants for each of the key steps in the catalytic cycle using the physiological reductant flavodoxin protein in its hydroquinone state. The findings indicate that with this reductant, the rate-limiting step in the reaction cycle is not protein–protein dissociation or reduction of the oxidized Fe protein, but rather events associated with the Pi release step. Further, it is demonstrated that (i) Fe protein transfers only one electron to MoFe protein in each Fe protein cycle coupled with hydrolysis of two ATP molecules, (ii) the oxidized Fe protein is not reduced when bound to MoFe protein, and (iii) the Fe protein interacts with flavodoxin using the same binding interface that is used with the MoFe protein. These findings allow a revision of the rate-limiting step in the nitrogenase Fe protein cycle

Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours

Predictive markers; Sarcoma; Gastrointestinal stromal tumoursMarcadores predictivos; Sarcoma; Tumores del estroma gastrointestinalMarcadors predictius; Sarcoma; Tumors estromals gastrointestinalsBackground Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. Methods We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. Results Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. Conclusions Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.This work was supported in part by an ASCO Young Investigator Award (CS), a Spanish Society of Medical Oncology Translational Award (CS), Río Hortega-ISCIII CM14/00241 (CS) FERO Foundation (CS), US National Institutes of Health grants 1P50CA127003 (GDD, ES, JAF), 1P50CA168512 (JAF, AME), GIST Cancer Research Fund (JAF, MCH), Life Raft Group (JAF, MCH, SB), V Foundation Translational Grant (MCH), VA Merit Review Award (2I01BX000338–05) (MCH) and the Deutsche Krebshilfe (SB). CS acknowledges to the Cellex Foundation for providing facilities and equipment

Oxytocin receptors influence the development and maintenance of social behavior in zebrafish (Danio rerio)

Zebrafish are highly social teleost fish and an excellent model to study social behavior. The neuropeptide Oxytocin is associated different social behaviors as well as disorders resulting in social impairment like autism spectrum disorder. However, how Oxytocin receptor signaling affects the development and expression kinetics of social behavior is not known. In this study we investigated the role of the two oxytocin receptors, Oxtr and Oxtrl, in the development and maintenance of social preference and shoaling behavior in 2- to 8-week-old zebrafish. Using CRISPR/Cas9 mediated oxtr and oxtrl knock-out fish, we found that the development of social preference is accelerated if one of the Oxytocin receptors is knocked-out and that the knock-out fish reach significantly higher levels of social preference. Moreover, oxtr-/- fish showed impairments in the maintenance of social preference. Social isolation prior to testing led to impaired maintenance of social preference in both wild-type and oxtr and oxtrl knock-out fish. Knocking-out either of the Oxytocin receptors also led to increased group spacing and reduced polarization in a 20-fish shoal at 8 weeks post fertilization, but not at 4. These results show that the development and maintenance of social behavior is influenced by the Oxytocin receptors and that the effects are not just pro- or antisocial, but dependent on both the age and social context of the fish