Rapid Discovery of Pyrido[3,4- d ]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft mode

Building block libraries and structural considerations in the self-assembly of polyoxometalate and polyoxothiometalate systems

Inorganic metal-oxide clusters form a class of compounds that are unique in their topological and electronic versatility and are becoming increasingly more important in a variety of applications. Namely, Polyoxometalates (POMs) have shown an unmatched range of physical properties and the ability to form structures that can bridge several length scales. The formation of these molecular clusters is often ambiguous and is governed by self-assembly processes that limit our ability to rationally design such molecules. However, recent years have shown that by considering new building block principles the design and discovery of novel complex clusters is aiding our understanding of this process. Now with current progress in thiometalate chemistry, specifically polyoxothiometalates (POTM), the field of inorganic molecular clusters has further diversified allowing for the targeted development of molecules with specific functionality. This chapter discusses the main differences between POM and POTM systems and how this affects synthetic methodologies and reactivities. We will illustrate how careful structural considerations can lead to the generation of novel building blocks and further deepen our understanding of complex systems

Measurement of the B0 anti-B0 oscillation frequency using l- D*+ pairs and lepton flavor tags

The oscillation frequency Delta-md of B0 anti-B0 mixing is measured using the partially reconstructed semileptonic decay anti-B0 -> l- nubar D*+ X. The data sample was collected with the CDF detector at the Fermilab Tevatron collider during 1992 - 1995 by triggering on the existence of two lepton candidates in an event, and corresponds to about 110 pb-1 of pbar p collisions at sqrt(s) = 1.8 TeV. We estimate the proper decay time of the anti-B0 meson from the measured decay length and reconstructed momentum of the l- D*+ system. The charge of the lepton in the final state identifies the flavor of the anti-B0 meson at its decay. The second lepton in the event is used to infer the flavor of the anti-B0 meson at production. We measure the oscillation frequency to be Delta-md = 0.516 +/- 0.099 +0.029 -0.035 ps-1, where the first uncertainty is statistical and the second is systematic.Comment: 30 pages, 7 figures. Submitted to Physical Review

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

Quantifying economic risks to dairy farms from volcanic hazards in Taranaki, Aotearoa / New Zealand

The volcanic hazard and risk science for Taranaki Mounga (Taranaki volcano) in Aotearoa / New Zealand is in an advanced state, with robust probabilistic data and a series of direct impact scenarios modelled for the region. Here, we progress this work and demonstrate a method to provide risk information that is nuanced for factors such as location and economic sector and considers the dynamic nature of volcanism with hazards potentially repeated over time. Recognising the fundamental importance of the dairy sector to Taranaki region, this paper provides valuable insights into the potential impacts and risks to heterogeneous dairy cattle farms within the region from volcanic hazards. We provide volcanic impact and risk metrics in economic or monetary terms in order to improve its relevance to decision-makers while reducing the complexity of the impacts. To do this, we developed a dynamic, multi-event farm system model of response and recovery, which takes in hazard intensity metrics from a series of volcanic events and generates the resulting annualised revenues, expenditures, and recovery costs through time. The model is formulated in a generalised way such that it can be used for various other hazard types and agricultural land uses. In our application of the model, we create and apply a suite of 10 000 simulations that capture different iterations of possible future volcanic activity over a 50-year period. These include the generation of lahars following eruptions and associated failures for transport and water supply networks. Farms at five case study locations were modelled to capture the diversity in farm management and the spatial variation in hazard intensities and likelihoods across the region. We provide summaries of the distributions of economic impacts generated, both for individual events and for the 50-year volcanic future horizon. Drawing the information together, we also summarise the results for each case study farm in terms of the value at risk statistic. For the case study farms with negligible lahar risk, we find, with 90 % confidence, that volcanic losses over the next 50 years will not exceed around 10 % of property value. By comparison, for the farm with the most severe lahar and ashfall exposure, we find that, at the same level of confidence, losses extend to approximately half the property value. These results indicate that with access to sufficient risk information, we should anticipate volcanic risk as playing an important role in shaping the future dairy sector in Taranaki region. The modelling pipeline and assessment metrics demonstrated in this paper could be used to assess mitigation and adaptation strategies to reduce the risk from volcanic hazards and improve the resilience of farm businesses.fals

Small bowel MRI in adult patients: not just Crohn’s disease—a tutorial

To provide an overview of less well-known small bowel and mesenteric diseases found at small bowel magnetic resonance (MR) enterography/enteroclysis and to review the imaging findings. MR enterography and enteroclysis are important techniques for evaluation of small bowel diseases. In most centres these techniques are primarily used in Crohn's disease, and most radiologists are familiar with these MRI findings. However, the knowledge of findings in other diseases is often sparse, including diseases that may cause similar clinical symptoms to those of Crohn's disease. We present a spectrum of less common and less well-known bowel and mesenteric diseases (e.g. internal hernia, intussusception, neuroendocrine tumour) from our small bowel MR database of over 2,000 cases. These diseases can be found in patients referred for bowel obstruction, abdominal pain or rectal blood loss. Further, in patients with (or suspected to have) Crohn's disease, some of these diseases (e.g. neuroendocrine tumour, familial Mediterranean fever) may mislead radiologists to erroneously diagnose active Crohn's disease. Radiologists should be familiar with diseases affecting the small bowel other than Crohn's disease, including diseases that may mimic Crohn's diseas

Glacial vicariance drives phylogeographic diversification in the amphi-boreal kelp Saccharina latissima

Glacial vicariance is regarded as one of the most prevalent drivers of phylogeographic structure and speciation among high-latitude organisms, but direct links between ice advances and range fragmentation have been more difficult to establish in marine than in terrestrial systems. Here we investigate the evolution of largely disjunct (and potentially reproductively isolated) phylogeographic lineages within the amphi-boreal kelp Saccharina latissima s.l. Using molecular data (COI, microsatellites) we confirm that S. latissima comprises also the NE Pacific S. cichorioides complex and is composed of divergent lineages with limited range overlap and genetic admixture. Only a few genetic hybrids were detected throughout a Canadian Arctic/NW Greenland contact zone. The degree of genetic differentiation and sympatric isolation of phylogroups suggest that S. latissima s.l. represents a complex of incipient species. Phylogroup distributions compared with paleo-environmental reconstructions of the cryosphere further suggest that diversification within S. latissima results from chronic glacial isolation in disjunct persistence areas intercalated with ephemeral interglacial poleward expansions and admixture at high-latitude (Arctic) contact zones. This study thus supports a role for glaciations not just in redistributing pre-existing marine lineages but also as a speciation pump across multi-glacial cycles for marine organisms otherwise exhibiting cosmopolite amphi-boreal distributions.Pew Foundation (USA); Portuguese FCT (Fundacao para a Ciencia e a Tecnologia) through program GENEKELP [PTDC/MAR-EST/6053/2014]; Portuguese FCT (Fundacao para a Ciencia e a Tecnologia) through program MARFOR [Biodiversa/0004/2015]; Portuguese FCT (Fundacao para a Ciencia e a Tecnologia) [UID/Multi/04326/2013, SFRH/BPD/88935/2012, SFRH/BPD/111003/2015]; NSERC; FRQNT; Canada Foundation for Innovation; New Brunswick Innovation Foundation; European Union's Seventh Framework Programme [226248]; Danish Environmental Protection Agency within the Danish Cooperation for Environment in the Arctic (DANCEA)info:eu-repo/semantics/publishedVersio

Management of peripheral facial nerve palsy

Peripheral facial nerve palsy (FNP) may (secondary FNP) or may not have a detectable cause (Bell’s palsy). Three quarters of peripheral FNP are primary and one quarter secondary. The most prevalent causes of secondary FNP are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immunological disorders, or drugs. The diagnosis of FNP relies upon the presence of typical symptoms and signs, blood chemical investigations, cerebro-spinal-fluid-investigations, X-ray of the scull and mastoid, cerebral MRI, or nerve conduction studies. Bell’s palsy may be diagnosed after exclusion of all secondary causes, but causes of secondary FNP and Bell’s palsy may coexist. Treatment of secondary FNP is based on the therapy of the underlying disorder. Treatment of Bell’s palsy is controversial due to the lack of large, randomized, controlled, prospective studies. There are indications that steroids or antiviral agents are beneficial but also studies, which show no beneficial effect. Additional measures include eye protection, physiotherapy, acupuncture, botulinum toxin, or possibly surgery. Prognosis of Bell’s palsy is fair with complete recovery in about 80% of the cases, 15% experience some kind of permanent nerve damage and 5% remain with severe sequelae

Understanding the retinal basis of vision across species

The vertebrate retina first evolved some 500 million years ago in ancestral marine chordates. Since then, the eyes of different species have been tuned to best support their unique visuoecological lifestyles. Visual specializations in eye designs, large-scale inhomogeneities across the retinal surface and local circuit motifs mean that all species' retinas are unique. Computational theories, such as the efficient coding hypothesis, have come a long way towards an explanation of the basic features of retinal organization and function; however, they cannot explain the full extent of retinal diversity within and across species. To build a truly general understanding of vertebrate vision and the retina's computational purpose, it is therefore important to more quantitatively relate different species' retinal functions to their specific natural environments and behavioural requirements. Ultimately, the goal of such efforts should be to build up to a more general theory of vision