A secondary RET mutation in the activation loop conferring resistance to vandetanib

Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects

Effects of degree and timing of social housing on reversal learning and response to novel objects in dairy calves

Rodents and primates deprived of early social contact exhibit deficits in learning and behavioural flexibility. They often also exhibit apparent signs of elevated anxiety, although the relationship between these effects has not been studied. To investigate whether dairy calves are similarly affected, we first compared calves housed in standard individual pens (n = 7) to those housed in a dynamic group with access to their mothers (n = 8). All calves learned to approach the correct stimulus in a visual discrimination task. Only one individually housed calf was able to re-learn the task when the stimuli were reversed, compared to all but one calf from the group. A second experiment investigated whether this effect might be explained by anxiety in individually housed animals interfering with their learning, and tested varying degrees of social contact in addition to the complex group: pair housing beginning early (approximately 6 days old) and late (6 weeks old). Again, fewer individually reared calves learned the reversal task (2 of 10 or 20%) compared to early paired and grouped calves (16 of 21 or 76% of calves). Late paired calves had intermediate success. Individually housed calves were slower to touch novel objects, but the magnitude of the fear response did not correlate with reversal performance. We conclude that individually housed calves have learning deficits, but these deficits were not likely associated with increased anxiety

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

PRospective Observational POLIsh Study on post-stroke delirium (PROPOLIS): methodology of hospital-based cohort study on delirium prevalence, predictors and diagnostic tools

BACKGROUND: Between 10 % to 48 % of patients develop delirium in acute phase of stroke. Delirium determinants and its association with other neuropsychiatric disturbances in stroke are poorly understood. The wildly accepted predictive model of post-stroke delirium is still lacking. METHODS/DESIGN: This is a prospective, observational, single-center study in patients with acute phase of stroke. We aim to include 750 patients ≥18 years with acute stroke or transient ischemic attack admitted to the stroke unit within 48 hours after stroke onset. The goals of the study are: 1) to determine frequency of delirium and subsyndromal delirium in Polish stroke patients within 7 days after admission to the hospital; 2) to determine factors associated with incidence, severity and duration of delirium and subsyndromal delirium and to create a predictive model for post-stroke delirium; 3) to determine the association between delirium and its cognitive, psychiatric, behavioral and functional short and long-term consequences; 4) to validate scales used for delirium diagnosis in stroke population. Patients will be screened for delirium on daily basis. The diagnosis of delirium will be based on DSM-V criteria. Abbreviated version of Confusion Assessment Method and Confusion Assessment Method for the Intensive Care Unit will be used for delirium and sub-delirium screening. Severity of delirium symptoms will be assessed by Delirium Rating Scale Revised 98 and Cognitive Test for Delirium. Patients who survive will undergo extensive neuropsychological, neuropsychiatric and functional assessment 3 and 12 months after the stroke. DISCUSSION: This study is designed to provide information on clinical manifestation, diagnostic methods and determinants of delirium spectrum disorders in acute stroke phase and their short and long-term consequences. Collected information allow us to create a predictive model for post-stroke delirium

Characterization of Profilin Polymorphism in Pollen with a Focus on Multifunctionality

Profilin, a multigene family involved in actin dynamics, is a multiple partners-interacting protein, as regard of the presence of at least of three binding domains encompassing actin, phosphoinositide lipids, and poly-L-proline interacting patches. In addition, pollen profilins are important allergens in several species like Olea europaea L. (Ole e 2), Betula pendula (Bet v 2), Phleum pratense (Phl p 12), Zea mays (Zea m 12) and Corylus avellana (Cor a 2). In spite of the biological and clinical importance of these molecules, variability in pollen profilin sequences has been poorly pointed out up until now. In this work, a relatively high number of pollen profilin sequences have been cloned, with the aim of carrying out an extensive characterization of their polymorphism among 24 olive cultivars and the above mentioned plant species. Our results indicate a high level of variability in the sequences analyzed. Quantitative intra-specific/varietal polymorphism was higher in comparison to inter-specific/cultivars comparisons. Multi-optional posttranslational modifications, e.g. phosphorylation sites, physicochemical properties, and partners-interacting functional residues have been shown to be affected by profilin polymorphism. As a result of this variability, profilins yielded a clear taxonomic separation between the five plant species. Profilin family multifunctionality might be inferred by natural variation through profilin isovariants generated among olive germplasm, as a result of polymorphism. The high variability might result in both differential profilin properties and differences in the regulation of the interaction with natural partners, affecting the mechanisms underlying the transmission of signals throughout signaling pathways in response to different stress environments. Moreover, elucidating the effect of profilin polymorphism in adaptive responses like actin dynamics, and cellular behavior, represents an exciting research goal for the future

Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

Measurement of the Atmospheric νe Flux in IceCube

We report the first measurement of the atmospheric electron neutrino flux in the energy range between approximately 80 GeV and 6 TeV, using data recorded during the first year of operation of IceCube’s DeepCore low-energy extension. Techniques to identify neutrinos interacting within the DeepCore volume and veto muons originating outside the detector are demonstrated. A sample of 1029 events is observed in 281 days of data, of which 496±66(stat)±88(syst) are estimated to be cascade events, including both electron neutrino and neutral current events. The rest of the sample includes residual backgrounds due to atmospheric muons and charged current interactions of atmospheric muon neutrinos. The flux of the atmospheric electron neutrinos is consistent with models of atmospheric neutrinos in this energy range. This constitutes the first observation of electron neutrinos and neutral current interactions in a very large volume neutrino telescope optimized for the TeV energy range.We acknowledge the support from the following agencies: U.S. National Science Foundation-Office of Polar Programs, U.S. National Science Foundation-Physics Division, University of Wisconsin Alumni Research Foundation, the Grid Laboratory Of Wisconsin (GLOW) grid infrastructure at the University of Wisconsin-Madison, the Open Science Grid (OSG) grid infrastructure; U.S. Department of Energy, and National Energy Research Scientific Computing Center, the Louisiana Optical Network Initiative (LONI) grid computing resources; National Science and Engineering Research Council of Canada; Swedish Research Council, Swedish Polar Research Secretariat, Swedish National Infrastructure for Computing (SNIC), and Knut and Alice Wallenberg Foundation, Sweden; German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Helmholtz Alliance for Astroparticle Physics (HAP), Research Department of Plasmas with Complex Interactions (Bochum), Germany; Fund for Scientific Research (FNRS-FWO), FWO Odysseus programme, Flanders Institute to encourage scientific and technological research in industry (IWT), Belgian Federal Science Policy Office (Belspo); University of Oxford, U.K.; Marsden Fund, New Zealand; Australian Research Council; Japan Society for Promotion of Science (JSPS); the Swiss National Science Foundation (SNSF), Switzerland

Iberomeryx minor (Mammalia, Artiodactyla) from the Early Oligocene of Soulce (Canton Jura, NW Switzerland): systematics and palaeodiet

The primitive ruminant genus Iberomeryx is poorly documented, as it is essentially only known from rare occurrences of dental remains. Therefore, the phylogeny and palaeobiology of Iberomeryx remain rather enigmatic. Only two species have been described: the type species I. parvus from the Benara locality in Georgia, and the Western European species I. minor reported from France, Spain, and Switzerland. Iberomeryx savagei from India has recently been placed in the new genus Nalameryx. All these localities are dated to the Rupelian and correspond mainly to MP23 (European mammal reference level). Based on the short height of the tooth-crown and the bunoselenodont pattern of the molars, Iberomeryx has often been considered as a folivore/frugivore. The I. minor remains from Soulce (NW Switzerland) are preserved in Rupelian lacustrine lithographic limestones. One specimen from this locality represents the most complete mandible of the taxon with a partially persevered ramus. Moreover, the unpreserved portion of the mandible left an imprint in the sediment, permitting the reconstruction of the mandible outline. Based on a new description of these specimens, anatomical comparisons and Relative Warp Analysis (24 landmarks) of 94 mandibles (11 fossil and 83 extant) from 31 ruminant genera (10 fossil and 21 extant) and 40 species (11 fossil and 29 extant), this study attempts a preliminary discussion of the phylogeny and the diet of the species I. minor. The results permit to differentiate Pecora and Tragulina on the first principal component axis (first Relative warp) on behalf of the length of the diastema c/cheek teeth, the length of the premolars and the angular process. The mandible shape of I. minor is similar to those of the primitive Tragulina, but it differs somewhat from those of the extant Tragulidae, the only extant family in the Tragulina. This difference is essentially due to a stockier mandible and a deeper incisura vasorum. However, in consideration of the general pattern of its cheek teeth, I. minor as well as possibly Nalameryx should be considered to represent the only known primitive Tragulidae from the Oligocene. Moreover, I. minor should have been a selective browser (fruit and dicot foliage) but, similarly to small Hypertragulidae and Tragulidae, may also have exceptionally consumed animal matter