The value of initial condition large ensembles to robust adaptation decision-making

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mankin, J. S., Lehner, F., Coats, S., & McKinnon, K. A. The value of initial condition large ensembles to robust adaptation decision-making. Earth's Future, 8(10), (2020): e2012EF001610, doi:10.1029/2020EF001610.The origins of uncertainty in climate projections have major consequences for the scientific and policy decisions made in response to climate change. Internal climate variability, for example, is an inherent uncertainty in the climate system that is undersampled by the multimodel ensembles used in most climate impacts research. Because of this, decision makers are left with the question of whether the range of climate projections across models is due to structural model choices, thus requiring more scientific investment to constrain, or instead is a set of equally plausible outcomes consistent with the same warming world. Similarly, many questions faced by scientists require a clear separation of model uncertainty and that arising from internal variability. With this as motivation and the renewed attention to large ensembles given planning for Phase 7 of the Coupled Model Intercomparison Project (CMIP7), we illustrate the scientific and policy value of the attribution and quantification of uncertainty from initial condition large ensembles, particularly when analyzed in conjunction with multimodel ensembles. We focus on how large ensembles can support regional‐scale robust adaptation decision‐making in ways multimodel ensembles alone cannot. We also acknowledge several recently identified problems associated with large ensembles, namely, that they are (1) resource intensive, (2) redundant, and (3) biased. Despite these challenges, we show, using examples from hydroclimate, how large ensembles provide unique information for the scientific and policy communities and can be analyzed appropriately for regional‐scale climate impacts research to help inform risk management in a warming world.F. L. has been supported by the Swiss NSF (grant no. PZ00P2_174128), the NSF Division of Atmospheric and Geospace Sciences (grant no. AGS‐0856145, Amendment 87), and the Regional and Global Model Analysis (RGMA) component of the Earth and Environmental System Modeling Program of the U.S.Department of Energy’s Office of Biological & Environmental Research (BER) via NSF IA 1844590. This is SOEST publication no. 11115

The power of social networks: A model for weaving the Scholarship of Teaching and Learning into institutional culture

This paper offers a guide for those seeking to integrate the Scholarship of Teaching and Learning (SoTL) into higher education institutions to improve the quality of student learning. The authors posit that weaving SoTL into institutional cultures requires the coordinated actions of individuals working in linked social networks rather than individuals acting in isolation. Analyzing both the barriers and potential pathways to integrating SoTL into institutional cultures, the authors provide a conceptual model along with examples of practical strategies for overcoming resistance to change within institutions. The paper provides examples from a variety of different international contexts to show how incentives and other non-coercive measures can motivate faculty and administrators to weave SoTL into institutional fabrics. Drawing on social network theory and the concept of communities of practice, the paper presents a model with attendant strategies for disseminating SoTL values and practices across all three levels of postsecondary institutions: the micro, the meso, and the macro. The authors argue that for SoTL to take root in organizational cultures, there must be 1) effective communication and dissemination of SoTL activity across all levels, 2) well established social networks and links between these levels (nodes), and 3) sustained support by senior administration. The authors conclude by suggesting ways their model could be tested

An Unexpected Decline in Spring Atmospheric Humidity in the Interior Southwestern United States and Implications for Forest Fires

On seasonal time scales, vapor pressure deficit (VPD) is a known predictor of burned area in the southwest- ern United States (“the Southwest”). VPD increases with atmospheric warming due to the exponential relationship be- tween temperature and saturation vapor pressure. Another control on VPD is specific humidity, such that increases in specific humidity can counteract temperature-driven increases in VPD. Unexpectedly, despite the increased capacity of a warmer atmosphere to hold water vapor, near-surface specific humidity decreased from 1970 to 2019 in much of the South- west, particularly in spring, summer, and fall. Here, we identify declining near-surface humidity from 1970 to 2019 in the southwestern United States with both reanalysis and in situ station data. Focusing on the interior Southwest in the months preceding the summer forest fire season, we explain the decline in terms of changes in atmospheric circulation and mois- ture fluxes between the surface and the atmosphere. We find that an early spring decline in precipitation in the interior re- gion induced a decline in soil moisture and evapotranspiration, drying the lower troposphere in summer. This prior season precipitation decline is in turn related to a trend toward a Northern Hemisphere stationary wave pattern. Finally, using fixed humidity scenarios and the observed exponential relationship between VPD and burned forest area, we estimate that with no increase in temperature at all, the humidity decline alone would still lead to nearly one-quarter of the observed VPD-induced increase in burned area over 1984–2019

Observed humidity trends in dry regions contradict climate models

Arid and semi-arid regions of the world are particularly vulnerable to greenhouse gas–driven hydroclimate change. Climate models are our primary tool for projecting the future hydroclimate that society in these regions must adapt to, but here, we present a concerning discrepancy between observed and model-based historical hydroclimate trends. Over the arid/semi-arid regions of the world, the predominant signal in all model simulations is an increase in atmospheric water vapor, on average, over the last four decades, in association with the increased water vapor–holding capacity of a warmer atmosphere. In observations, this increase in atmospheric water vapor has not happened, suggesting that the availability of moisture to satisfy the increased atmospheric demand is lower in reality than in models in arid/semi-arid regions. This discrepancy is most clear in locations that are arid/semi-arid year round, but it is also apparent in more humid regions during the most arid months of the year. It indicates a major gap in our understanding and modeling capabilities which could have severe implications for hydroclimate projections, including fire hazard, moving forward

Protocol for the OUTREACH trial: a randomised trial comparing delivery of cancer systemic therapy in three different settings: patient's home, GP surgery and hospital day unit.

BACKGROUND: The national Cancer Reform Strategy recommends delivering care closer to home whenever possible. Cancer drug treatment has traditionally been administered to patients in specialist hospital-based facilities. Technological developments mean that nowadays, most treatment can be delivered in the out-patient setting. Increasing demand, care quality improvements and patient choice have stimulated interest in delivering some treatment to patients in the community, however, formal evaluation of delivering cancer treatment in different community settings is lacking. This randomised trial compares delivery of cancer treatment in the hospital with delivery in two different community settings: the patient's home and general practice (GP) surgeries. METHODS/DESIGN: Patients due to receive a minimum 12 week course of standard intravenous cancer treatment at two hospitals in the Anglia Cancer Network are randomised on a 1:1:1 basis to receive treatment in the hospital day unit (control arm), or their own home, or their choice of one of three neighbouring GP surgeries. Overall patient care, treatment prescribing and clinical review is undertaken according to standard local practice. All treatment is dispensed by the local hospital pharmacy and treatment is delivered by the hospital chemotherapy nurses. At four time points during the 12 week study period, information is collected from patients, nursing staff, primary and secondary care teams to address the primary end point, patient-perceived benefits (using the emotional function domain of the EORTC QLQC30 patient questionnaire), as well as secondary end points: patient satisfaction, safety and health economics. DISCUSSION: The Outreach trial is the first randomised controlled trial conducted which compares delivery of out-patient based intravenous cancer treatment in two different community settings with standard hospital based treatment. Results of this study may better inform all key stakeholders regarding potential costs and benefits of transferring clinical services from hospital to the community. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN66219681.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

Claudin-low breast cancer is an aggressive subtype that confers poor prognosis and is found largely within the clinical triple-negative group of breast cancer patients. Here, we have shown that intrinsic and immune cell gene signatures distinguish the claudin-low subtype clinically as well as in mouse models of other breast cancer subtypes. Despite adaptive immune cell infiltration in claudin-low tumors, treatment with immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were ineffective in controlling tumor growth. CD4+FoxP3+ Tregs represented a large proportion of the tumor-infiltrating lymphocytes (TILs) in claudin-low tumors, and Tregs isolated from tumor-bearing mice were able to suppress effector T cell responses. Tregs in the tumor microenvironment highly expressed PD-1 and were recruited partly through tumor generation of the chemokine CXCL12. Antitumor efficacy required stringent Treg depletion combined with checkpoint inhibition; delays in tumor growth were not observed using therapies that modestly diminished the number of Tregs in the tumor microenvironment. This study provides evidence that the recruitment of Tregs to the tumor microenvironment inhibits an effective antitumor immune response and highlights early Treg recruitment as a possible mechanism for the lack of response to immune checkpoint blockade antibodies in specific subtypes of cancer that are heavily infiltrated with adaptive immune cells

Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection

Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue

5-hydroxytryptamine (5-HT) cellular sequestration during chronic exposure delays 5-HT₃ receptor resensitization due to Its subsequent release

The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT(3)) receptors. We report that recombinantly expressed 5-HT(3) receptor binding sites are reduced by chronic exposure to 5-HT (IC(50) of 154.0 ± 45.7 μm, t(½) = 28.6 min). This is confirmed for 5-HT(3) receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC(50) of 2.3 ± 1.0 μm, t(½) = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization