Interaction of CK1δ with γTuSC ensures proper microtubule assembly and spindle positioning.

Casein kinase 1δ (CK1δ) family members associate with microtubule-organizing centers (MTOCs) from yeast to humans, but their mitotic roles and targets have yet to be identified. We show here that budding yeast CK1δ, Hrr25, is a γ-tubulin small complex (γTuSC) binding factor. Moreover, Hrr25's association with γTuSC depends on its kinase activity and its noncatalytic central domain. Loss of Hrr25 kinase activity resulted in assembly of unusually long cytoplasmic microtubules and defects in spindle positioning, consistent with roles in regulation of γTuSC-mediated microtubule nucleation and the Kar9 spindle-positioning pathway, respectively. Hrr25 directly phosphorylated γTuSC proteins in vivo and in vitro, and this phosphorylation promoted γTuSC integrity and activity. Because CK1δ and γTuSC are highly conserved and present at MTOCs in diverse eukaryotes, similar regulatory mechanisms are expected to apply generally in eukaryotes

Telomeres Cluster De Novo before the Initiation of Synapsis: A Three-dimensional Spatial Analysis of Telomere Positions before and during Meiotic Prophase

We have analyzed the progressive changes in the spatial distribution of telomeres during meiosis using three-dimensional, high resolution fluorescence microscopy. Fixed meiotic cells of maize (Zea mays L.) were subjected to in situ hybridization under conditions that preserved chromosome structure, allowing identification of stage-dependent changes in telomere arrangements. We found that nuclei at the last somatic prophase before meiosis exhibit a nonrandom, polarized chromosome organization resulting in a loose grouping of telomeres. Quantitative measurements on the spatial arrangements of telomeres revealed that, as cells passed through premeiotic interphase and into leptotene, there was an increase in the frequency of large telomere-to-telomere distances and a decrease in the bias toward peripheral localization of telomeres. By leptotene, there was no obvious evidence of telomere grouping, and the large, singular nucleolus was internally located, nearly concentric with the nucleus. At the end of leptotene, telomeres clustered de novo at the nuclear periphery, coincident with a displacement of the nucleolus to one side. The telomere cluster persisted throughout zygotene and into early pachytene. The nucleolus was adjacent to the cluster at zygotene. At the pachytene stage, telomeres rearranged again by dispersing throughout the nuclear periphery. The stagedependent changes in telomere arrangements are suggestive of specific, active telomere-associated motility processes with meiotic functions. Thus, the formation of the cluster itself is an early event in the nuclear reorganizations associated with meiosis and may reflect a control point in the initiation of synapsis or crossing over

Climate change 2014 : impacts, adaptation, and vulnerability

Current and future climate-related drivers of risk for small islands during the 21st century include sea level rise (SLR), tropical and extratropical cyclones, increasing air and sea surface temperatures, and changing rainfall patterns (high confidence; robust evidence, high agreement). Current impacts associated with these changes confirm findings reported on small islands from the Fourth Assessment Report (AR4) and previous IPCC assessments. The future risks associated with these drivers include loss of adaptive capacity and ecosystem services critical to lives and livelihoods in small islands.peer-reviewe

Big data, small concepts:Histosophy as an approach to longue-durée history

In this essay, we sketch out a method, histosophy, which makes possible the study of intellectual history and conceptual genealogy both in depth and over long periods of time. Histosophy uses digital tools to survey ‘large issues within small compasses.’ A genealogy of signifiers, it considers metonymic parts of a problem in order to contribute precisely and coherently to a larger perspective. We outline the theoretical contours of our approach. We exemplify how it works in practice by looking at the signifier ‘esprit de corps’, the study of which is presented in detail in the histosophical book The Genealogy of Esprit de Corps(Edinburgh University Press, 2019). The phrase ‘esprit de corps’ has been widely used since the eighteenth century in different discourses (political, military, sociological, etc.), but it is sufficiently limited that its genealogy can be traced across centuries and nations with precision, coherence, clarity, and with the help of automated search engines. By contrast, related but bigger concepts like freedom, individualism or solidarity are part of dozens of disparate and fuzzy discourses, so often uttered that the analysis of modern uses is problematic. The histosophical methodology is applicable in six discrete stages, here outlined

Big geochemical data through remote sensing for dynamic mineral resource monitoring in tailing storage facilities

Evolution in geoscientific data provides the mineral industry with new opportunities. A direction of geochemical data generation evolution is towards big data to meet the demands of data-driven usage scenarios that rely on data velocity. This direction is more significant where traditional geochemical data are not ideal, which is the case for evaluating unconventional resources, such as tailing storage facilities (TSFs), because they are not static due to sedimentation, compaction and changes associated with hydrospheric and lithospheric processes (e.g., erosion, saltation and mobility of chemical constituents). In this paper, we generate big secondary geochemical data derived from Sentinel-2 satellite-remote sensing data to showcase the benefits of big geochemical data using TSFs from the Witwatersrand Basin (South Africa). Using spatially fused remote sensing and legacy geochemical data on the Dump 20 TSF, we trained a machine learning model to predict in-situ gold grades. Subsequently, we deployed the model to the Lindum TSF, which is 3 km away, over a period of a few years (2015-2019). We were able to visualize and analyze the temporal variation in the spatial distributions of the gold grade of the Lindum TSF. Additionally, we were able to infer extraction sequencing (to the resolution of the data), acid mine drainage formation and seasonal migration. These findings suggest that dynamic mineral resource models and live geochemical monitoring (e.g., of elemental mobility and structural changes) are possible without additional physical sampling

Quaternary geology of the Northern Great Plains

The Great Plains physiographic province lies east of the Rocky Mountains and extends from southern Alberta and Saskatchewan nearly to the United States-Mexico border. This chapter covers only the northern part of the unglaciated portion of this huge region, from Oklahoma almost to the United StatesCanada border, a portion that herein will be referred to simply as the Northern Great Plains (Fig. 1). This region is in the rain shadow of the Rocky Mountains. Isoheyets are roughly longitudinal, and mean annual precipitation decreases from about 750 mm at the southeastern margin to less than 380 mm in the western and northern parts (Fig. 2). Winters typically are cold with relatively little precipitation, mostly as snow; summers are hot with increased precipitation, chiefly associated with movement of Pacific and Arctic air masses into warm, humid air masses from the Gulf of Mexico. Vegetation is almost wholly prairie grassland, due to the semiarid, markedly seasonal climate. The Northern Great Plains is a large region of generally low relief sloping eastward from the Rocky Mountains toward the Missouri and Mississippi Rivers. Its basic bedrock structure is a broad syncline, punctuated by the Black Hills and a few smaller uplifts, and by structural basins such as the Williston, Powder River, and Denver-Julesburg Basins (Fig. 3). Its surface bedrock is chiefly Cretaceous and Tertiary sediments, with small areas of older rocks in the Black Hills, central Montana, and eastern parts of Wyoming, Kansas, and Oklahoma. During the Laramide orogeny (latest Cretaceous through Eocene), while the Rocky Mountains and Black Hills were rising, synorogenic sediments (frequently with large amounts of volcanic ash from volcanic centers in the Rocky Mountains) were deposited in the subsiding Denver-Julesburg, Powder River, and other basins. From Oligocene to Miocene time, sedimentation generally slowed with declining tectonism and volcanism in the Rocky Mountains. However, since the later Miocene, epeirogenic uplift, probably associated with the East Pacific Rise, affected the Great Plains and particularly the Rocky Mountains. During the last 10 m.y. the Rocky Mountain front has risen 1.5 to 2 km, and the eastern margin of the Great Plains 100 to 500 m (Gable and Hatton, 1983), with half to one-quarter of these amounts during the last 5 m.y. Thus, during the later Miocene the Great Plains became a huge aggrading piedmont sloping gently eastward from the Rocky Mountains and Black Hills, with generally eastward drainage, on which the Ogallala Formation and equivalents was deposited. The Ogallala underlies the High Plains Surface, the highest and oldest geomorphic surface preserved in this region. It has been completely eroded along some parts of the western margin of the region (e.g., the Colorado Piedmont), but eastward, it (and its equivalents, such as the Flaxville gravels in Montana) locally is preserved as caprock or buried by Quaternary sediments (Alden, 1924, 1932; Howard, 1960; Stanley, 1971, 1976; Pearl, 1971; Scott, 1982; Corner and Diffendal, 1983; Diffendal and Corner, 1984; Swinehart and others, 1985; Aber, 1985). During the Pliocene, regional aggradation slowly changed to dissection by the principal rivers. In the western part of the region the rivers flowed eastward, but the continental drainage divide Figure 3. Major bedrock structures of the Northern Great Plains. extended northeast from the Black Hills through central South Dakota, far south of its present position. The ancestral upper Missouri, Little Missouri, Yellowstone, and Cheyenne Rivers drained northeast to Hudson Bay, whereas the ancestral White, Platte, and Arkansas Rivers went to the Gulf of Mexico (Fig 4A). Their courses are marked by scattered surface and subsurface gravel remnants; in Montana and North Dakota, deposits of the preglacial Missouri River and its tributaries are buried deeply beneath glacial and other sediments (Howard, 1960; Bluemle, 1972)

Current and future interactions between nature and society

One hundred per cent of the natural units of analysis will continue to be negatively affected, with a concomitant decrease in natures contributions to people, given current trends (business as usual), though the magnitude and exact mechanism of the individual drivers will vary by driver and unit of analysis (established but incomplete){5.4}. For example, tropical moist and dry forest and coastal mangroves will continue to exhibit a decline due to land use change regardless of the scenarios considered, but different local factors (agriculturalization and urbanization, respectively) will be involved (well established) {5.4.1, 5.4.11}. Additionally, some drivers will affect units of analysis differently. Empirical evidence indicates differential effects of climate change: boreal forest is extending northward {5.4.2}, while tundra is diminishing in land area (established but incomplete) {5.4.3}. Thus, some drivers, and their relative roles, will need to be further refined on a local scale and with respect to their proximate factors.2. Multiple drivers will act in synergy and further produce biodiversity loss and impact nature?s contributions to people in most of the units of analysis for the Americas (established but incomplete){5.4}. Climate change, combined with other drivers, is predicted to account for an increasingly larger proportion of biodiversity loss in the future, in both terrestrial and aquatic ecosystems {5.3}. Forest fragmentation, climate change and industrial development increase risk of biodiversity and nature?s contributions to people loss i.e. dry forest unit of analysis {5.4.1.2}. Predictions on invasive species and climate change indicates an increase in habitable areas and their potential impacts on different units of analysis {5.3}.3. Changes in temperature, precipitation regime and extreme climate events are predicted to impact all units of analysis in the Americas (well established) {5.4}. Climate change and the potential impacts on tropical dry forests by changing the frequency of wildfires; change in forest structure and functional composition in the Amazon tropical moist forest; extreme drought events changing nature?s contributions to people in the Amazon region; insect outbreaks and changes in albedo are predicted to significantly impact temperate, boreal and tundra units of analysis, affecting society and indigenous communities and well-being {5.4}.4. Thresholds, or tipping points (conditions resulting in rapid and potentially irreversible changes) may have already been exceeded for some ecosystems and are likely for others (established but incomplete). For instance, it is considered more likely than not that such a threshold has already been passed in the cryosphere with respect to summer sea ice (established but incomplete) {5.4.12}. Model simulations indicate changes in forest structure and species distribution in the Amazon forest in response to global warming and change in precipitation patterns (forest die-back) (established but incomplete) {5.4.1}. So too, a 4oC increase in global temperatures is predicted to likely cause widespread die off of boreal forest due to greater susceptibility to disease {5.4.2} and global temperature increases may have already started persistent thawing of the permafrost {5.4.3}. Under 4°C warming, widespread coral reef mortality is expected with significant impacts on coral reef ecosystems {5.4.11}. Sea surface water temperature increase will cause a reduction of sea grass climatic niche: those populations under seawater surface temperature thresholds higher than the temperature ranges required by the species could become extinct by 2100 with concomitant loss of ecosystem services.IPBES/6/INF/4/Rev.15415. Changes in nature and nature?s contributions to people in most units of analysis are increasingly driven by causal interactions between distant places (i.e. telecouplings) (well established) {5.6.3}, thus scenarios and models that incorporate telecouplings will better inform future policy decisions. Nature and nature?s contributions to people in telecoupled systems can be affected negatively or positively by distant causal interactions. Provision of food and medicine from wild organisms in temperate and tropical grasslands, savannas and forests of South America is being dramatically reduced due to land-use changes driven by the demand of agricultural commodities (e.g. soybeans) mainly from Europe and China. Conservation of insectivorous migratory bats in Mexico benefits pest control in agroecosystems of North America, resulting in increased yields and reduced pesticide costs. Trade policies and international agreements will thus have an increasingly strong effect on environmental outcomes in telecoupled systems.6. Policy interventions have resulted in significant land use changes at the local and regional scales and will continue to do so through 2050. These policies have affected nature?s contributions to people both positively and negatively, and provide an opportunity to manage trade-offs among nature?s contributions to people (well established) {5.4}. Land use changes are now mainly driven by high crop demand, big hydropower plans, rapid urban growth and result in a continued loss of grasslands {5.4.4, 5.4.5}. However, strategies for establishing conservation units have helped in reducing deforestation in the Brazilian Amazon from the period of 2004 to 2011 (well established) {5.4.1}. Similarly, wetland protection policies and regulation have helped reduce the conversion of wetlands in North America {5.4.7}. Policies based on command and control measures may be limited in providing effective reduction in ecosystem loss and should be complemented with policies acknowledging multiple values {5.6.3}.7. Policy interventions at vastly differing scales (from national to local) lead to successful outcomes in mitigating impacts to biodiversity (established but incomplete){5.4}. For instance, long-established governmental protections of wetlands in North America have significantly slowed and may have stopped wetland loss based on acreage {5.4.7}. In South America, where mangrove loss continues at a rate of one to two per cent, different stakeholders such as local communities and/or governments have been successful in protecting mangroves based on empowerment and shared interests in their preservation {5.4.11}.8. Pressures to nature are projected to increase by 2050, negatively affecting biodiversity as indicated by a potential reduction of the mean species abundance index. However, the magnitude of the pressures by 2050 are expected to be less under transition pathways to sustainability in comparison to the business as usual scenario (established but incomplete), {5.5}. The Global Biodiversity model projected that under the business as usual scenario mean species abundance had decreased in the Americas by approximately 30 per cent by 2010 compared to its values prior to European settlement of the New World, with historical losses primarily attributed to land transformation to agricultural uses. Using the Global Biodiversity model, there is an additional projected loss of 9.6 per cent by 2050, primarily attributed to some additional land use changes , and especially to climate change, which will steadily increase relative to other drivers considered in the model. However, under the transition pathways to sustainability of global technologies, decentralised solutions, and consumption change pathways, the projected losses are 6 per cent, 5 per cent, and 5 per cent, respectively,IPBES/6/INF/4/Rev.1542achieving a relative improvement of approximately 30 per cent to 50 per cent compared to the business as usual scenario. Under these pathways, climate change mitigation, the expansion of protected areas and the recovery of abandoned lands would significantly contribute to reducing biodiversity loss.9. Participative scenarios have proven to be a successful tool for envisioning potential futures and pathways and to embrace and integrate multiple and sometime conflicting values and their role in promoting bottom-up decision making in the face of futures uncertainties (well established) {5.3}. The use of participative approaches to develop scenarios has increased during recent years in the Americas. The inclusion of different stakeholders and their knowledges in the process of constructing potential futures has promoted a better understanding of the complexity of the social-ecological systems in which they are embedded. This has enhanced co-learning processes between all actors involved, even those normally under-represented in decision-making activities. As a result, several participative scenario exercises have motivated community-based solutions and local governance initiatives all pointing towards the development of adaptive management strategies {5.3}.10. Pathways that consider changes in societal options will lead to less pressure to nature (established but incomplete) {5.6.3}. An example is the indirect impact that shifts in urban dietary preferences have on agricultural production and expansion, and food options that are expected to continue growing into the future. Therefore, not only is there a strong connection between urbanization and economic growth, but also between affluence (and urban preferences) and the global displacement of land use particularly from high-income to low-income countries.11. Available local studies informing regional futures of nature and natures benefit to people do not allow scalability as of yet (well established) {5.3}. The challenge in expanding the findings from local studies resides in the fact that a number of comparable local studies are still not available. Information is scattered throughout the region by the use of different units, methods and scales, which prevents a local-to-regional generalization. The list of nature indicators used in studies at local scales is large and heterogeneous (well established). Even for the same indicator (e.g. biodiversity), different metrics are used (e.g. species-area curve, mean species abundance) {5.5}. In other cases, multiple indicators are used to describe different aspects of biodiversity and ecosystem services. In this latter case, synergies and trade-offs are explicitly mentioned with a clear pattern in which increasing the provision of some indicators result in the detriment of others {5.3}. For example, agriculture expansion leading to loss in biodiversity illustrates a common trend from local studies expected to continue into the future.12. There is a significant research gap in the development of models and scenarios that integrate drivers, nature, natures contributions to people and good quality of life (well established){5.3}. Models and scenarios can be powerful tools to integrate and synthesize the complex dynamics of coupled human and nature systems, and to project their plausible behaviors into the future. Most existing models and scenarios focus on the link between drivers and its impacts on nature. Few cases exist in which models or scenarios integrate the relationships between changes in nature and changes in natures contributions to people and good quality of life {5.3}. Inter-and trans-disciplinary modeling efforts will be required to address this research gap {5.3}.Fil: Klatt, Brian. Michigan State University; Estados UnidosFil: Ometto, Jean Pierre. National Institute For Space Research; BrasilFil: García Marquez, Jaime. Universität zu Berlin; AlemaniaFil: Baptiste, María Piedad. Instituto Alexander Von Humboldt; ColombiaFil: Instituto Alexander von Humboldt. Independent Consultant; CanadáFil: Acebey, Sandra Verónica. No especifíca;Fil: Guezala, María Claudia. Inter-american Institute For Global Change Research; PerúFil: Mastrangelo, Matias Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pengue, Walter Alberto. Universidad Nacional de General Sarmiento; ArgentinaFil: Blanco, Mariela Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Centro de Estudios e Investigaciones Laborales; ArgentinaFil: Gadda, Tatiana. Universidade Tecnológica Federal Do Paraná; BrasilFil: Ramírez, Wilson. Instituto Alexander Von Humboldt; ColombiaFil: Agard, John. University Of West Indies; Trinidad y TobagoFil: Valle, Mireia. Universidad Laica Eloy Alfaro de Manabí; Ecuado

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease