Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, drug discovery for PDAC treatment has proven complicated, leading to stagnant therapeutic outcomes. Here, we identify Glycogen synthase kinase 3 (GSK3) as a therapeutic target through a whole-body genetic screening utilizing a '4-hit' Drosophila model mimicking the PDAC genotype. Reducing the gene dosage of GSK3 in a whole-body manner or knocking down GSK3 specifically in transformed cells suppressed 4-hit fly lethality, similar to Mitogen-activated protein kinase kinase (MEK), the therapeutic target in PDAC we have recently reported. Consistently, a combination of the GSK3 inhibitor CHIR99021 and the MEK inhibitor trametinib suppressed the phosphorylation of Polo-like kinase 1 (PLK1) as well as the growth of orthotopic human PDAC xenografts in mice. Additionally, reducing PLK1 genetically in 4-hit flies rescued their lethality. Our results reveal a therapeutic vulnerability in PDAC that offers a treatment opportunity for patients by inhibiting multiple targets.

Drosophila Screening Identifies Dual Inhibition of MEK and AURKB as an Effective Therapy for Pancreatic Ductal Adenocarcinoma.

Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The '4-hit' flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC. SIGNIFICANCE: Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.

The timing of unprecedented hydrological drought under climate change.

Droughts that exceed the magnitudes of historical variation ranges could occur increasingly frequently under future climate conditions. However, the time of the emergence of unprecedented drought conditions under climate change has rarely been examined. Here, using multimodel hydrological simulations, we investigate the changes in the frequency of hydrological drought (defined as abnormally low river discharge) under high and low greenhouse gas concentration scenarios and existing water resource management measures and estimate the time of the first emergence of unprecedented regional drought conditions centered on the low-flow season. The times are detected for several subcontinental-scale regions, and three regions, namely, Southwestern South America, Mediterranean Europe, and Northern Africa, exhibit particularly robust results under the high-emission scenario. These three regions are expected to confront unprecedented conditions within the next 30 years with a high likelihood regardless of the emission scenarios. In addition, the results obtained herein demonstrate the benefits of the lower-emission pathway in reducing the likelihood of emergence. The Paris Agreement goals are shown to be effective in reducing the likelihood to the unlikely level in most regions. However, appropriate and prior adaptation measures are considered indispensable when facing unprecedented drought conditions. The results of this study underscore the importance of improving drought preparedness within the considered time horizons.

Implications of changes in climate and human development on 21st-century global drought risk.

Climate change is expected to exacerbate drought conditions over many global regions. However, the future risk posed by droughts depends not only on the climate-induced changes but also on the changes in societal exposure and vulnerability to droughts. Here we illustrate how the consideration of human vulnerability alters global drought risk associated with runoff (hydrological) and soil moisture (agriculture) droughts during the 21st-century. We combine the changes in drought frequency, population growth, and human development as a proxy of vulnerability to project global drought risk under plausible climate and socioeconomic development pathways. Results indicate that the shift toward a pathway of high greenhouse gas emissions and socioeconomic inequality leads to i) increased population exposure to runoff and soil moisture droughts by 81% and seven folds, respectively, and ii) a stagnation of human development. These consequences are more pronounced for populations living in low than in very high human development countries. In particular, Sub-Saharan Africa and South Asia, where the majority of the world's less developed countries are located, fare the worst in terms of future drought risk. The disparity in risk between low and very high human development countries can be substantially reduced in the presence of a shift toward a world of rapid and sustainable development that actively reduces social inequality and emissions. Our results underscore the importance of rapid human development in hotspots of drought risk where effective adaptation is most needed to reduce future drought impacts.

Globally observed trends in mean and extreme river flow attributed to climate change.

Anthropogenic climate change is expected to affect global river flow. Here, we analyze time series of low, mean, and high river flows from 7250 observatories around the world covering the years 1971 to 2010. We identify spatially complex trend patterns, where some regions are drying and others are wetting consistently across low, mean, and high flows. Trends computed from state-of-the-art model simulations are consistent with the observations only if radiative forcing that accounts for anthropogenic climate change is considered. Simulated effects of water and land management do not suffice to reproduce the observed trend pattern. Thus, the analysis provides clear evidence for the role of externally forced climate change as a causal driver of recent trends in mean and extreme river flow at the global scale.

Highly Ordered Nanoscale Film Morphologies of Block Copolymers Governed by Nonlinear Topologies.

Among many properties of cyclic block copolymers, the notable domain spacing (d-spacing) reduction offers nonlinear topology as an effective tool for developing block copolymers for nanolithography. However, the current consensus regarding the topology-morphology correlation is ambiguous and in need of more studies. Here we present the morphological investigation on nanoscale films of cyclic and tadpole-shaped poly(n-decyl glycidyl ether-block-2-(2-(2-methoxyethoxy)ethoxy)ethyl glycidyl ether)s and their linear counterpart via synchrotron grazing-incidence X-ray scattering. All copolymers form phase-separated nanostructures, in which only the nonlinear copolymers form highly ordered and unidirectional nanostructures. Additionally, d-spacings of cyclic and tadpole-shaped block copolymers are 49.3-53.7% and 25.0-32.5% shorter than that of their linear counterpart, respectively, exhibiting greater or comparable d-spacing reductions against the experimentally and theoretically achieved values from the literature. Overall, this study demonstrates that cyclic and tadpole topologies can be utilized in developing materials with miniaturized dimensions, high structural ordering, and unidirectional orientation for various nanotechnology applications.

Model improvement and future projection of permafrost processes in a global land surface model.

To date, the treatment of permafrost in global climate models has been simplified due to the prevailing uncertainties in the processes involving frozen ground. In this study, we improved the modeling of permafrost processes in a state-of-the-art climate model by taking into account some of the relevant physical properties of soil such as changes in the thermophysical properties due to soil freezing. As a result, the improved version of the global land surface model was able to reproduce a more realistic permafrost distribution at the southern limit of the permafrost area by increasing the freezing of soil moisture in winter. The improved modeling of permafrost processes also had a significant effect on future projections. Using the conventional formulation, the predicted cumulative reduction of the permafrost area by year 2100 was approximately 60% (40-80% range of uncertainty from a multi-model ensemble) in the RCP8.5 scenario, while with the improved formulation, the reduction was approximately 35% (20-50%). Our results indicate that the improved treatment of permafrost processes in global climate models is important to ensuring more reliable future projections.

Bicyclic Topology Transforms Self-Assembled Nanostructures in Block Copolymer Thin Films.

Ongoing efforts in materials science have resulted in linear block copolymer systems that generate nanostructures via the phase separation of immiscible blocks; however, such systems are limited with regard to their domain miniaturization and lack of orientation control. We overcome these limitations through the bicyclic topological alteration of a block copolymer system. Grazing incidence X-ray scattering analysis of nanoscale polymer films revealed that bicyclic topologies achieve 51.3-72.8% reductions in domain spacing when compared against their linear analogue, which is more effective than the theoretical predictions for conventional cyclic topologies. Moreover, bicyclic topologies achieve unidirectional orientation and a morphological transformation between lamellar and cylindrical domains with high structural integrity. When the near-equivalent volume fraction between the blocks is considered, the formation of hexagonally packed cylindrical domains is particularly noteworthy. Bicyclic topological alteration is therefore a powerful strategy for developing advanced nanostructured materials for microelectronics, displays, and membranes.

Supplementation of l-arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor-bearing hosts. MDSCs express arginase-I and indoleamine 2,3-dioxygenase; they suppress T-cell function by reducing the levels of l-arginine and l-tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma-bearing mice. Oral supplementation of l-arginine or l-tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation of d-arginine was lethal. Supplementation of l-arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26-bearing mice. l-Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels of l-arginine in CT26-bearing mice and significantly increased the number of tumor-infiltrating CD8+ T cells. In addition, l-arginine supplementation significantly increased the proportions of tumor peptide-specific CD8+ T cells in draining lymph nodes. Importantly, additional supplementation of l-arginine significantly increased the number of cured mice that were treated with CP and anti-PD-1 antibody. Totally, l-arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.

State-of-the-art global models underestimate impacts from climate extremes.

Global impact models represent process-level understanding of how natural and human systems may be affected by climate change. Their projections are used in integrated assessments of climate change. Here we test, for the first time, systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions. Using the 2003 European heat wave and drought as a historical analogue for comparable events in the future, we find that a majority of models underestimate the extremeness of impacts in important sectors such as agriculture, terrestrial ecosystems, and heat-related human mortality, while impacts on water resources and hydropower are overestimated in some river basins; and the spread across models is often large. This has important implications for economic assessments of climate change impacts that rely on these models. It also means that societal risks from future extreme events may be greater than previously thought.

Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate.

Hematopoietic stem cells (HSCs) comprise a heterogeneous population exhibiting self-renewal and differentiation capabilities; however, the mechanisms involved in maintaining this heterogeneity remain unclear. Here, we show that SATB1 is involved in regulating HSC heterogeneity. Results in conditional Satb1-knockout mice revealed that SATB1 was important for the self-renewal and lymphopoiesis of adult HSCs. Additionally, HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1- HSCs followed the myeloid lineage in agreement with genome-wide transcription and cell culture studies. Importantly, SATB1- and SATB1+ HSC populations were interconvertible upon transplantation, with SATB1+ HSCs showing higher reconstituting and lymphopoietic potentials in primary recipients relative to SATB1- HSCs, whereas both HSCs exhibited equally efficient reconstituted lympho-hematopoiesis in secondary recipients. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to HSC heterogeneity.

Neuroendoscopic Cylinder Surgery and 5-Aminolevulinic Acid Photodynamic Diagnosis of Deep-Seated Intracranial Lesions.

BACKGROUND: Microscopic detection of intracranial brain tumors with 5-aminolevulinic acid (5-ALA) has proven extremely useful, and reports the use of 5-ALA have recently increased. However, few reports have described 5-ALA photodynamic diagnosis (PDD) using a neuroendoscope. We performed neuroendoscopic 5-ALA PDD for various brain lesions and present a procedure using only a neuroendoscope. METHODS: We describe the diagnosis of 20 intracranial brain lesion cases with a 5-ALA-guided fluorescence endoscope. A light-emitting diode that emitted either white light or 400- to 410-nm violet light was attached to a neuroendoscope. We performed cylinder surgery with a transparent sheath under observation with a rigid neuroendoscope. RESULTS: Neuroendoscopic biopsies were performed in 11 patients, and resections were performed in 9 patients. All lesions were observed with a neuroendoscope under sequential white light and violet light. We confirmed the presence of a red fluorescent lesion under violet light in 15 patients, including 4 of 5 glioblastoma cases (80%); 1 of 2 anaplastic astrocytoma cases (50%); 4 of 5 diffuse large B cell lymphoma cases (80%); 2 of 2 metastatic brain tumors; 1 of 1 case each of diffuse astrocytoma, pilocytic astrocytoma, inflammatory change, and germinoma (100%); and no cases of anaplastic ependymoma or cysticercosis. Pretargeted lesions were accurately harvested from all biopsy specimens. Gross total resection was achieved in 5 of 9 patients using a resection procedure. CONCLUSIONS: Our described method offers a promising technique for achieving precise brain tumor biopsies and safe resection.

A Comparative Study of Dynamic Light and X-ray Scatterings on Micelles of Topological Polymer Amphiphiles.

Micelles were prepared in organic solvents by using three topological polymer amphiphiles: (i) cyclic poly(n-decyl glycidyl ether-block-2-(2-(2-methoxyethoxy)ethoxy)ethyl glycidyl ether) (c-PDGE-b-PTEGGE) and (ii) its linear analogue (l-PDGE-b-PTEGGE); (iii) linear poly(6-phosphorylcholinehexylthiopropyl glycidyl ether-block-n-dodecanoyl glycidyl ether) (l-PPCGE-b-PDDGE). For the individual micelle solutions, the size and distribution were determined by dynamic light scattering (DLS) and synchrotron X-ray scattering analyses. The synchrotron X-ray scattering analysis further found that c-PDGE-b-PTEGGE forms oblate ellipsoidal micelle in an ethanol/water mixture, l-PDGE-b-PTEGGE makes prolate ellipsoidal micelle in an ethanol/water mixture, and l-PPCGE-b-PDDGE forms cylindrical micelle in chloroform. This comparative study found that there are large differences in the size and distribution results extracted by DLS and X-ray scattering analyses. All possible factors to cause such large differences are discussed. Moreover, a better use of the DLS instrument with keeping its merits is proposed.

Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis.

Information of myeloid lineage-related antigen on hematopoietic stem/progenitor cells (HSPCs) is important to clarify the mechanisms regulating hematopoiesis, as well as for the diagnosis and treatment of myeloid malignancies. We previously reported that special AT-rich sequence binding protein 1 (SATB1), a global chromatin organizer, promotes lymphoid differentiation from HSPCs. To search a novel cell surface molecule discriminating early myeloid and lymphoid differentiation, we performed microarray analyses comparing SATB1-overexpressed HSPCs with mock-transduced HSPCs. The results drew our attention to membrane-spanning 4-domains, subfamily A, member 3 (Ms4a3) as the most downregulated molecule in HSPCs with forced overexpression of SATB1. Ms4a3 expression was undetectable in hematopoietic stem cells, but showed a concomitant increase with progressive myeloid differentiation, whereas not only lymphoid but also megakaryocytic-erythrocytic progenitors were entirely devoid of Ms4a3 expression. Further analysis revealed that a subset of CD34+CD38+CD33+ progenitor population in human adult bone marrow expressed MS4A3, and those MS4A3+ progenitors only produced granulocyte/macrophage colonies, losing erythroid colony- and mixed colony-forming capacity. These results suggest that cell surface expression of MS4A3 is useful to distinguish granulocyte/macrophage lineage-committed progenitors from other lineage-related ones in early human hematopoiesis. In conclusion, MS4A3 is useful to monitor early stage of myeloid differentiation in human hematopoiesis.

Self-inverted reciprocation of an oil droplet on a surfactant solution.

Self-motion of an oil droplet was investigated on a sodium dodecyl sulfate (SDS) aqueous phase. With an increase in the concentration of SDS, the nature of self-motion of a butyl salicylate (BS) droplet as the oil droplet was changed, i.e., no motion, reciprocation with a small amplitude, and reciprocation with a large amplitude, which was a value close to the half-length of the chamber. The interfacial tension, contact angle, and convective flow around the droplet were measured to clarify the driving force of reciprocation. The mechanisms of two types of reciprocation and mode-change were discussed in terms of the adsorption of SDS molecules at the BS/water interface and the dissolution of a mixture of BS and SDS into the bulk phase, the convective flow, and the Young's equation. The features of reciprocation and mode-change depending on the concentration of SDS were qualitatively reproduced by numerical calculation based on an equation of motion and the kinetics of SDS and BS at the air/aqueous interface.

Multimodel uncertainty changes in simulated river flows induced by human impact parameterizations.

Human impacts increasingly affect the global hydrological cycle and indeed dominate hydrological changes in some regions. Hydrologists have sought to identify the human-impact-induced hydrological variations via parameterizing anthropogenic water uses in global hydrological models (GHMs). The consequently increased model complexity is likely to introduce additional uncertainty among GHMs. Here, using four GHMs, between-model uncertainties are quantified in terms of the ratio of signal to noise (SNR) for average river flow during 1971-2000 simulated in two experiments, with representation of human impacts (VARSOC) and without (NOSOC). It is the first quantitative investigation of between-model uncertainty resulted from the inclusion of human impact parameterizations. Results show that the between-model uncertainties in terms of SNRs in the VARSOC annual flow are larger (about 2% for global and varied magnitude for different basins) than those in the NOSOC, which are particularly significant in most areas of Asia and northern areas to the Mediterranean Sea. The SNR differences are mostly negative (-20% to 5%, indicating higher uncertainty) for basin-averaged annual flow. The VARSOC high flow shows slightly lower uncertainties than NOSOC simulations, with SNR differences mostly ranging from -20% to 20%. The uncertainty differences between the two experiments are significantly related to the fraction of irrigation areas of basins. The large additional uncertainties in VARSOC simulations introduced by the inclusion of parameterizations of human impacts raise the urgent need of GHMs development regarding a better understanding of human impacts. Differences in the parameterizations of irrigation, reservoir regulation and water withdrawals are discussed towards potential directions of improvements for future GHM development. We also discuss the advantages of statistical approaches to reduce the between-model uncertainties, and the importance of calibration of GHMs for not only better performances of historical simulations but also more robust and confidential future projections of hydrological changes under a changing environment.

ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias.

Reliable markers are essential to increase our understanding of the biological features of human hematopoietic stem cells and to facilitate the application of hematopoietic stem cells in the field of transplantation and regenerative medicine. We previously identified endothelial cell-selective adhesion molecule (ESAM) as a novel functional marker of hematopoietic stem cells in mice. Here, we found that ESAM can also be used to purify human hematopoietic stem cells from all the currently available sources (adult bone marrow, mobilized peripheral blood, and cord blood). Multipotent colony-forming units and long-term hematopoietic-reconstituting cells in immunodeficient mice were found exclusively in the ESAM(High) fraction of CD34(+)CD38(-) cells. The CD34(+)CD38(-) fraction of cord blood and collagenase-treated bone marrow contained cells exhibiting extremely high expression of ESAM; these cells are likely to be related to the endothelial lineage. Leukemia cell lines of erythroid and megakaryocyte origin, but not those of myeloid or lymphoid descent, were ESAM positive. However, high ESAM expression was observed in some primary acute myeloid leukemia cells. Furthermore, KG-1a myeloid leukemia cells switched from ESAM negative to ESAM positive with repeated leukemia reconstitution in vivo. Thus, ESAM is a useful marker for studying both human hematopoietic stem cells and leukemia cells.

Hydrological droughts in the 21st century, hotspots and uncertainties from a global multimodel ensemble experiment.

Increasing concentrations of greenhouse gases in the atmosphere are expected to modify the global water cycle with significant consequences for terrestrial hydrology. We assess the impact of climate change on hydrological droughts in a multimodel experiment including seven global impact models (GIMs) driven by bias-corrected climate from five global climate models under four representative concentration pathways (RCPs). Drought severity is defined as the fraction of land under drought conditions. Results show a likely increase in the global severity of hydrological drought at the end of the 21st century, with systematically greater increases for RCPs describing stronger radiative forcings. Under RCP8.5, droughts exceeding 40% of analyzed land area are projected by nearly half of the simulations. This increase in drought severity has a strong signal-to-noise ratio at the global scale, and Southern Europe, the Middle East, the Southeast United States, Chile, and South West Australia are identified as possible hotspots for future water security issues. The uncertainty due to GIMs is greater than that from global climate models, particularly if including a GIM that accounts for the dynamic response of plants to CO2 and climate, as this model simulates little or no increase in drought frequency. Our study demonstrates that different representations of terrestrial water-cycle processes in GIMs are responsible for a much larger uncertainty in the response of hydrological drought to climate change than previously thought. When assessing the impact of climate change on hydrology, it is therefore critical to consider a diverse range of GIMs to better capture the uncertainty.

Constraints and potentials of future irrigation water availability on agricultural production under climate change.

We compare ensembles of water supply and demand projections from 10 global hydrological models and six global gridded crop models. These are produced as part of the Inter-Sectoral Impacts Model Intercomparison Project, with coordination from the Agricultural Model Intercomparison and Improvement Project, and driven by outputs of general circulation models run under representative concentration pathway 8.5 as part of the Fifth Coupled Model Intercomparison Project. Models project that direct climate impacts to maize, soybean, wheat, and rice involve losses of 400-1,400 Pcal (8-24% of present-day total) when CO2 fertilization effects are accounted for or 1,400-2,600 Pcal (24-43%) otherwise. Freshwater limitations in some irrigated regions (western United States; China; and West, South, and Central Asia) could necessitate the reversion of 20-60 Mha of cropland from irrigated to rainfed management by end-of-century, and a further loss of 600-2,900 Pcal of food production. In other regions (northern/eastern United States, parts of South America, much of Europe, and South East Asia) surplus water supply could in principle support a net increase in irrigation, although substantial investments in irrigation infrastructure would be required.

First look at changes in flood hazard in the Inter-Sectoral Impact Model Intercomparison Project ensemble.

Climate change due to anthropogenic greenhouse gas emissions is expected to increase the frequency and intensity of precipitation events, which is likely to affect the probability of flooding into the future. In this paper we use river flow simulations from nine global hydrology and land surface models to explore uncertainties in the potential impacts of climate change on flood hazard at global scale. As an indicator of flood hazard we looked at changes in the 30-y return level of 5-d average peak flows under representative concentration pathway RCP8.5 at the end of this century. Not everywhere does climate change result in an increase in flood hazard: decreases in the magnitude and frequency of the 30-y return level of river flow occur at roughly one-third (20-45%) of the global land grid points, particularly in areas where the hydrograph is dominated by the snowmelt flood peak in spring. In most model experiments, however, an increase in flooding frequency was found in more than half of the grid points. The current 30-y flood peak is projected to occur in more than 1 in 5 y across 5-30% of land grid points. The large-scale patterns of change are remarkably consistent among impact models and even the driving climate models, but at local scale and in individual river basins there can be disagreement even on the sign of change, indicating large modeling uncertainty which needs to be taken into account in local adaptation studies.