Beautiful Eyes

https://digitalcommons.library.umaine.edu/mmb-vp/1082/thumbnail.jp

Handboek Melkwinning

De Nederlandse melkveehouderij blijft volop in ontwikkeling. Nieuwe inzichten in wetenschap, technologie en techniek vergroten de mogelijkheden voor de landbouw. Anderzijds legt het streven naar een grotere duurzaamheid en een in alle opzichten verantwoorde voedselproductie de veehouder veel beperkingen op. Tegen de achtergrond van deze ontwikkelingen is tien jaar na de verschijning van de vorige druk een vijfde druk van het boek “Melkwinning” samengesteld. Aan de herziening van “Melkwinning” is een uitvoerige oriëntatie bij de gebruikers vooraf gegaan. Dit heeft tot een aantal aanpassingen geleid; immers de samenleving verandert en daarmee ook de plaats en de rol van de melkveehouder daarin. De schaal waarop de veehouder werkt blijft groeien. In toenemende mate heeft hij rekening te houden met zijn omgeving en zijn afnemers. Door de ontwikkelingen in de techniek en de elektronica zijn echter ook zijn mogelijkheden aanmerkelijk toegenomen. Het heeft ons evenwel ook getoond dat de basisprincipes van het melken dermate elementair zijn dat ze vrijwel tijdloos zijn. Niettemin werd de noodzaak gevoeld voor het opnemen van een apart hoofdstuk over het melken van geiten en schapen in deze uitgave, evenals een hoofdstuk over de uitbetaling van de melk naar kwaliteit en gehalten ingekaderd in het brede veld van zorg voor en borging van kwaliteit. “Melkwinning” is evenals de voorgaande drukken bedoeld als handboek voor allen die zich beroepsmatig interesseren voor de achtergronden van de melkwinning. De doelgroep bestaat in de eerste plaats uit mensen die kennis over het melken en de achtergronden van het melken willen overdragen, zoals in het beroepsonderwijs en bij scholing en opleiding van voorlichters en technici. Daarnaast kan het boek een belangrijke informatiebron zijn voor veehouders, onderzoekers, dierenartsen en andere betrokkenen bij de melkveehouderij

What is Quantum? Unifying Its Micro-Physical and Structural Appearance

We can recognize two modes in which 'quantum appears' in macro domains: (i) a 'micro-physical appearance', where quantum laws are assumed to be universal and they are transferred from the micro to the macro level if suitable 'quantum coherence' conditions (e.g., very low temperatures) are realized, (ii) a 'structural appearance', where no hypothesis is made on the validity of quantum laws at a micro level, while genuine quantum aspects are detected at a structural-modeling level. In this paper, we inquire into the connections between the two appearances. We put forward the explanatory hypothesis that, 'the appearance of quantum in both cases' is due to 'the existence of a specific form of organisation, which has the capacity to cope with random perturbations that would destroy this organisation when not coped with'. We analyse how 'organisation of matter', 'organisation of life', and 'organisation of culture', play this role each in their specific domain of application, point out the importance of evolution in this respect, and put forward how our analysis sheds new light on 'what quantum is'.Comment: 10 page

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

Research misconduct in the fields of ethics and philosophy: researchers’ perceptions in Spain

This is the Author’s Original Manuscript (AOM) (also called a “preprint”) sent to review to Science and Engineering Ethics on 11/10/2020. The final version of the article was published online at SEE on 21/01/2021. The online version is available at: https://doi.org/10.1007/s11948-021-00278-wEmpirical studies have revealed a disturbing prevalence of research misconduct in a wide variety of disciplines, although not, to date, in the areas of ethics and philosophy. This study aims to provide empirical evidence on perceptions of how serious a problem research misconduct is in these two disciplines in Spain, particularly regarding the effects that the model used to evaluate academics’ research performance may have on their ethical behaviour. The methodological triangulation applied in the study combines a questionnaire, a debate at the annual meeting of scientific association, and in-depth interviews. Of the 541 questionnaires sent out, 201 responses were obtained (37.1% of the total sample), with a significant difference in the participation of researchers in philosophy (30.5%) and in ethics (52.8%); 26 researchers took part in the debate and 14 interviews were conducted. The questionnaire results reveal that 91.5% of the respondents considered research misconduct to be on the rise; 63.2% considered at least three of the fraudulent practices referred to in the study to be commonplace, and 84.1% identified two or more such practices. The researchers perceived a high prevalence of duplicate publication (66.5%) and self-plagiarism (59.0%), use of personal influence (57.5%) and citation manipulation (44.0%), in contrast to a low perceived incidence of data falsification or fabrication (10.0%). The debate and the interviews corroborated these data. Researchers associated the spread of these misconducts with the research evaluation model applied in Spain

Sea surface temperatures of the western Arabian Sea during the last deglaciation.

In this study we present a sea surface temperature (SST) record from the western Arabian Sea for the last\ud 20,000 years. We produced centennial-scale d18O and Mg/Ca SST time series of core NIOP929 with focus on\ud the glacial-interglacial transition. The western Arabian Sea is influenced by the seasonal NE and SW monsoon\ud wind systems. Lowest SSTs occur during the SW monsoon season because of upwelling of cold water, and\ud highest SSTs can be found in the low-productivity intermonsoon season. The Mg/Ca-based temperature record\ud reflects the integrated SST of the SW and NE monsoon seasons. The results show a glacial-interglacial SST\ud difference of 2C, which is corroborated by findings from other Arabian Sea cores. At 19 ka B.P. a yet\ud undescribed warm event of several hundred years duration is found, which is also reflected in the d18O record. A\ud second centennial-scale high SST/low d18O event is observed at 17 ka B.P. This event forms the onset of the\ud stepwise yet persistent trend toward Holocene temperatures. Highest Mg/Ca-derived SSTs in the NIOP929\ud record occurred between 13 and 10 ka B.P. Interglacial SST is 24C, indicating influence of upwelling. The\ud onset of Arabian Sea warming occurs when the North Atlantic is experiencing minimum temperatures. The rapid\ud temperature variations at 19, 17, and 13 ka B.P. are difficult to explain with monsoon changes alone and are\ud most likely also linked to regional hydrographic changes, such as trade wind induced variations in warm water\ud advection

Oceanic response to Pliensbachian and Toarcian magmatic events: Implications from an organic-rich basinal succession in the NW Tethys

The Bächental bituminous marls (Bächentaler Bitumenmergel) belonging to the Sachrang Member of the Lower Jurassic Middle Allgäu Formation were investigated using a multidisciplinary approach to determine environmental controls on the formation of organic-rich deposits in a semi-restricted basin of the NW Tethys during the Early Jurassic. The marls are subdivided into three units on the basis of mineralogical composition, source-rock parameters, redox conditions, salinity variations, and diagenetic processes. Redox proxies (e.g., pristane/phytane ratio; aryl isoprenoids; bioturbation; ternary plot of iron, total organic carbon, and sulphur) indicate varying suboxic to euxinic conditions during deposition of the Bächental section. Redox variations were mainly controlled by sea-level fluctuations with the tectonically complex bathymetry of the Bächental basin determining watermass exchange with the Tethys Ocean. Accordingly, strongest anoxia and highest total organic carbon content (up to 13%) occur in the middle part of the profile (upper tenuicostatum and lower falciferum zones), coincident with an increase in surface-water productivity during a period of relative sea-level lowstand that induced salinity stratification in a stagnant basin setting. This level corresponds to the time interval of the lower Toarcian oceanic anoxic event (T-OAE). However, the absence of the widely observed lower Toarcian negative carbon isotope excursion in the study section questions its unrestricted use as a global chemostratigraphic marker. Stratigraphic correlation of the thermally immature Bächental bituminous marls with the Posidonia Shale of SW Germany on the basis of C27/C29 sterane ratio profiles and ammonite data suggests that deposition of organic matter-rich sediments in isolated basins in the Alpine realm commenced earlier (late Pliensbachian margaritatus Zone) than in regionally proximal epicontinental seas (early Toarcian tenuicostatum Zone). The late Pliensbachian onset of reducing conditions in the Bächental basin coincided with an influx of volcaniclastic detritus that was possibly connected to complex rifting processes of the Alpine Tethys and with a globally observed eruption-induced extinction event. The level of maximum organic matter accumulation in the Bächental basin corresponds to the main eruptive phase of the Karoo-Ferrar large igneous province (LIP), confirming its massive impact on global climate and oceanic conditions during the Early Jurassic. The Bächental marl succession is thus a record of the complex interaction of global (i.e., LIP) and local (e.g., redox and salinity variations, basin morphology) factors that caused reducing conditions and organic matter enrichment in the Bächental basin. These developments resulted in highly inhomogeneous environmental conditions in semi-restricted basins of the NW Tethyan domain during late Pliensbachian and early Toarcian time

Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4-d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine (BOS172722)

Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4-d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4-d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice