The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials

Lasmiditan is a novel selective 5-HT1F receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT1F receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5–45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT1F receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients’ preferences are necessary to accurately position this new treatment principle in relation to the triptans

Occurrence of testicular microlithiasis in androgen insensitive hypogonadal mice

&lt;b&gt;Background&lt;/b&gt;: Testicular microliths are calcifications found within the seminiferous tubules. In humans, testicular microlithiasis (TM) has an unknown etiology but may be significantly associated with testicular germ cell tumors. Factors inducing microlith development may also, therefore, act as susceptibility factors for malignant testicular conditions. Studies to identify the mechanisms of microlith development have been hampered by the lack of suitable animal models for TM.&lt;BR/&gt; &lt;b&gt;Methods&lt;/b&gt;: This was an observational study of the testicular phenotype of different mouse models. The mouse models were: cryptorchid mice, mice lacking androgen receptors (ARs) on the Sertoli cells (SCARKO), mice with a ubiquitous loss of androgen ARs (ARKO), hypogonadal (hpg) mice which lack circulating gonadotrophins, and hpg mice crossed with SCARKO (hpg.SCARKO) and ARKO (hpg.ARKO) mice.&lt;BR/&gt; &lt;b&gt;Results&lt;/b&gt;: Microscopic TM was seen in 94% of hpg.ARKO mice (n=16) and the mean number of microliths per testis was 81 +/- 54. Occasional small microliths were seen in 36% (n=11) of hpg testes (mean 2 +/- 0.5 per testis) and 30% (n=10) of hpg.SCARKO testes (mean 8 +/- 6 per testis). No microliths were seen in cryptorchid, ARKO or SCARKO mice. There was no significant effect of FSH or androgen on TM in hpg.ARKO mice.&lt;BR/&gt; &lt;b&gt;Conclusions&lt;/b&gt;: We have identified a mouse model of TM and show that lack of endocrine stimulation is a cause of TM. Importantly, this model will provide a means with which to identify the mechanisms of TM development and the underlying changes in protein and gene expression

Crystallographic Preferred Orientation of Olivine in Sheared Partially Molten Rocks: The Source of the “a-c Switch”

© 2018. American Geophysical Union. All Rights Reserved. To investigate the mechanism that produces the crystallographic preferred orientations (CPO) characteristic of sheared partially molten rocks of mantle composition, we analyzed the microstructures of samples of olivine plus 7% basaltic melt deformed in torsion to shear strains as large as γ = 13.3 Electron backscattered diffraction (EBSD) observations reveal a CPO characterized by a weak a-c girdle in the shear plane that develops by γ = 4. This CPO, which exhibits a slightly stronger alignment of 001 than 100 axes in the shear direction, changes little in both strength and distribution with increasing stress and with increasing strain. Furthermore, it is significantly weaker than the CPO observed for dry, melt-free olivine aggregates. Orientation maps correlated with grain shape measurements from tangential, radial, and transverse sections indicate that olivine grains are longer along 001 axes than along 100 axes and shortest along 010 axes. This morphology is similar to that of olivine grains in a mafic melt. We conclude that the weak a-c girdle observed in sheared partially molten rocks reflects contributions from two processes. Due to their shape-preferred orientation (SPO), grains rotate to align their 001 axes parallel to the flow direction. At the same time, dislocation glide on the (010)100 slip system rotates 100 axes into the flow direction. The presence of this CPO in partially molten regions of the upper mantle significantly impacts the interpretation of seismic anisotropy and kinematics of flow

The structure of iterative methods for symmetric linear discrete ill-posed problems

The iterative solution of large linear discrete ill-posed problems with an error contaminated data vector requires the use of specially designed methods in order to avoid severe error propagation. Range restricted minimal residual methods have been found to be well suited for the solution of many such problems. This paper discusses the structure of matrices that arise in a range restricted minimal residual method for the solution of large linear discrete ill-posed problems with a symmetric matrix. The exploitation of the structure results in a method that is competitive with respect to computer storage, number of iterations, and accuracy.Acknowledgments We would like to thank the referees for comments. The work of F. M. was supported by Dirección General de Investigación Científica y Técnica, Ministerio de Economía y Competitividad of Spain under grant MTM2012-36732-C03-01. Work of L. R. was supported by Universidad Carlos III de Madrid in the Department of Mathematics during the academic year 2010-2011 within the framework of the Chair of Excellence Program and by NSF grant DMS-1115385

Paleoclimate Implications for Human-Made Climate Change

Paleoclimate data help us assess climate sensitivity and potential human-made climate effects. We conclude that Earth in the warmest interglacial periods of the past million years was less than 1{\deg}C warmer than in the Holocene. Polar warmth in these interglacials and in the Pliocene does not imply that a substantial cushion remains between today's climate and dangerous warming, but rather that Earth is poised to experience strong amplifying polar feedbacks in response to moderate global warming. Thus goals to limit human-made warming to 2{\deg}C are not sufficient - they are prescriptions for disaster. Ice sheet disintegration is nonlinear, spurred by amplifying feedbacks. We suggest that ice sheet mass loss, if warming continues unabated, will be characterized better by a doubling time for mass loss rate than by a linear trend. Satellite gravity data, though too brief to be conclusive, are consistent with a doubling time of 10 years or less, implying the possibility of multi-meter sea level rise this century. Observed accelerating ice sheet mass loss supports our conclusion that Earth's temperature now exceeds the mean Holocene value. Rapid reduction of fossil fuel emissions is required for humanity to succeed in preserving a planet resembling the one on which civilization developed.Comment: 32 pages, 9 figures; final version accepted for publication in "Climate Change at the Eve of the Second Decade of the Century: Inferences from Paleoclimate and Regional Aspects: Proceedings of Milutin Milankovitch 130th Anniversary Symposium" (eds. Berger, Mesinger and Sijaci

Winter wheat roots grow twice as deep as spring wheat roots, is this important for N uptake and N leaching losses?

Cropping systems comprising winter catch crops followed by spring wheat could reduce N leaching risks compared to traditional winter wheat systems in humid climates. We studied the soil mineral N (Ninorg) and root growth of winter- and spring wheat to 2.5 m depth during three years. Root depth of winter wheat (2.2 m) was twice that of spring wheat, and this was related to much lower amounts of Ninorg in the 1 to 2.5 m layer after winter wheat (81 kg Ninorg ha-1 less). When growing winter catch crops before spring wheat, N content in the 1 to 2.5 m layer after spring wheat was not different from that after winter wheat. The results suggest that by virtue of its deep rooting, winter wheat may not lead to high levels of leaching as it is often assumed in humid climates. Deep soil and root measurements (below 1 m) in this experiment were essential to answer the questions we posed

Backbone and side-chain 1H, 13C and 15N assignments of the ubiquitin-associated domain of human X-linked inhibitor of apoptosis protein

X-linked inhibitor of apoptosis protein (XIAP), a leading member of the family of inhibitor of apoptosis (IAP) proteins, is considered as the most potent and versatile inhibitor of caspases and apoptosis. It has been reported that XIAP is frequently overexpressed in cancer and its expression level is implicated in contributing to tumorigenesis, disease progression, chemoresistance and poor patient-survival. Therefore, XIAP is one of the leading targets in drug development for cancer therapy. Recently, based on bioinformatics study, a previously unrecognized but evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs was identified. The UBA domain is found to be essential for the oncogenic potential of IAP, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP to activate NF-κB. In the present study, we report the near complete resonance assignments of the UBA domain-containing region of human XIAP protein. Secondary structure prediction based on chemical shift index (CSI) analysis reveals that the protein is predominately α-helical, which is consistent with the structures of known UBA proteins

Chromatic Illumination Discrimination Ability Reveals that Human Colour Constancy Is Optimised for Blue Daylight Illuminations

The phenomenon of colour constancy in human visual perception keeps surface colours constant, despite changes in their reflected light due to changing illumination. Although colour constancy has evolved under a constrained subset of illuminations, it is unknown whether its underlying mechanisms, thought to involve multiple components from retina to cortex, are optimised for particular environmental variations. Here we demonstrate a new method for investigating colour constancy using illumination matching in real scenes which, unlike previous methods using surface matching and simulated scenes, allows testing of multiple, real illuminations. We use real scenes consisting of solid familiar or unfamiliar objects against uniform or variegated backgrounds and compare discrimination performance for typical illuminations from the daylight chromaticity locus (approximately blue-yellow) and atypical spectra from an orthogonal locus (approximately red-green, at correlated colour temperature 6700 K), all produced in real time by a 10-channel LED illuminator. We find that discrimination of illumination changes is poorer along the daylight locus than the atypical locus, and is poorest particularly for bluer illumination changes, demonstrating conversely that surface colour constancy is best for blue daylight illuminations. Illumination discrimination is also enhanced, and therefore colour constancy diminished, for uniform backgrounds, irrespective of the object type. These results are not explained by statistical properties of the scene signal changes at the retinal level. We conclude that high-level mechanisms of colour constancy are biased for the blue daylight illuminations and variegated backgrounds to which the human visual system has typically been exposed

Big-Data-Driven Materials Science and its FAIR Data Infrastructure

This chapter addresses the forth paradigm of materials research -- big-data driven materials science. Its concepts and state-of-the-art are described, and its challenges and chances are discussed. For furthering the field, Open Data and an all-embracing sharing, an efficient data infrastructure, and the rich ecosystem of computer codes used in the community are of critical importance. For shaping this forth paradigm and contributing to the development or discovery of improved and novel materials, data must be what is now called FAIR -- Findable, Accessible, Interoperable and Re-purposable/Re-usable. This sets the stage for advances of methods from artificial intelligence that operate on large data sets to find trends and patterns that cannot be obtained from individual calculations and not even directly from high-throughput studies. Recent progress is reviewed and demonstrated, and the chapter is concluded by a forward-looking perspective, addressing important not yet solved challenges.Comment: submitted to the Handbook of Materials Modeling (eds. S. Yip and W. Andreoni), Springer 2018/201

A meta-analysis of long-term effects of conservation agriculture on maize grain yield under rain-fed conditions

Conservation agriculture involves reduced tillage, permanent soil cover and crop rotations to enhance soil fertility and to supply food from a dwindling land resource. Recently, conservation agriculture has been promoted in Southern Africa, mainly for maize-based farming systems. However, maize yields under rain-fed conditions are often variable. There is therefore a need to identify factors that influence crop yield under conservation agriculture and rain-fed conditions. Here, we studied maize grain yield data from experiments lasting 5 years and more under rain-fed conditions. We assessed the effect of long-term tillage and residue retention on maize grain yield under contrasting soil textures, nitrogen input and climate. Yield variability was measured by stability analysis. Our results show an increase in maize yield over time with conservation agriculture practices that include rotation and high input use in low rainfall areas. But we observed no difference in system stability under those conditions. We observed a strong relationship between maize grain yield and annual rainfall. Our meta-analysis gave the following findings: (1) 92% of the data show that mulch cover in high rainfall areas leads to lower yields due to waterlogging; (2) 85% of data show that soil texture is important in the temporal development of conservation agriculture effects, improved yields are likely on well-drained soils; (3) 73% of the data show that conservation agriculture practices require high inputs especially N for improved yield; (4) 63% of data show that increased yields are obtained with rotation but calculations often do not include the variations in rainfall within and between seasons; (5) 56% of the data show that reduced tillage with no mulch cover leads to lower yields in semi-arid areas; and (6) when adequate fertiliser is available, rainfall is the most important determinant of yield in southern Africa. It is clear from our results that conservation agriculture needs to be targeted and adapted to specific biophysical conditions for improved impact