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Abstract Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (

Abstract The Community Earth System Model (CESM) is widely used for the prediction and understanding of climate variability and change. Accurate simulation of the behavior of near surface air temperature (T2m) is critical in such a model for addressing societally relevant problems. However, previous versions of CESM suffered from an overestimation of wintertime T2m variability in Northern Hemisphere (NH) land regions. Here, it is shown that the latest version of CESM (CESM2) exhibits a much improved representation of wintertime T2m variability compared to its predecessor and it now compares well with observations. A series of targeted experiments reveal that an important contributor to this improvement is the local effects of changes to the representation of snow density within the land surface component. Increased snow densities in CESM2 lead to enhanced conductance of the snow layer. As a result, larger heat fluxes across the snow layer are induced in the presence of T2m anomalies, leading to a greater dampening of surface and near surface atmospheric temperature anomalies. The implications for future projections with CESM2 are also considered through comparison of the CESM1 and CESM2 large ensembles. Aligned with the reduction in surface temperature variability, compared to CESM1, CESM2 exhibits reduced ensemble spread in future projections of NH winter mean temperature and a smaller decline in daily wintertime T2m variability under climate change. Overall, this improvement has increased the accuracy of CESM2 as a tool for the study of wintertime T2m variability and change.

Abstract 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.

Dengue virus is a major global health threat and can lead to life-threatening hemorrhagic complications due to immune activation and cytokine production. Cross-reactive antibodies to an earlier dengue virus infection are a recognized risk factor for severe disease. These antibodies bind heterologous dengue serotypes and enhance infection into Fc-receptor-bearing cells, a process known as antibody-dependent enhancement of infection. One crucial cytokine seen elevated in severe dengue patients is IL-1β, a potent inflammatory cytokine matured by the inflammasome. We used a highly-physiologic system by studying antibody-dependent enhancement of IL-1β in primary human monocytes with anti-dengue human monoclonal antibodies isolated from patients. Antibody-enhancement increased viral replication in primary human monocytes inoculated with supernatant harvested from Vero cells infected with dengue virus serotype 2 (DENV-2) 16681. Surprisingly, IL-1β secretion induced by infectious supernatant harvested from two independent Vero cell lines was not enhanced by antibody. Secretion of multiple other inflammatory cytokines was also independent of antibody signaling. However, IL-1β secretion did require NLRP3 and caspase-1 activity. Immunodepletion of dengue virions from the infectious supernatant confirmed that virus was not the main IL-1β-inducing agent, suggesting that a supernatant component(s) not associated with the virion induced IL-1β production. We excluded RNA, DNA, contaminating LPS, viral NS1 protein, complement, and cytokines. In contrast, purified Vero-derived DENV-2 16681 exhibited antibody-enhancement of both infection and IL-1β induction. Furthermore, C6/36 mosquito cells did not produce such an inflammatory component, as crude supernatant harvested from insect cells infected with DENV-2 16681 induced antibody-dependent IL-1β secretion. This study indicates that Vero cells infected with DENV-2 16681 may produce inflammatory components during dengue virus propagation that mask the virus-specific immune response. Thus, the choice of host cell and viral purity should be carefully considered, while insect-derived virus represents a system that elicits antibody-dependent cytokine responses to dengue virus with fewer confounding issues.

Neisseria gonorrhoeae is the second most common sexually transmitted bacterial pathogen worldwide. Diseases associated with N. gonorrhoeae cause localized inflammation of the urethra and cervix. Despite this inflammatory response, infected individuals do not develop protective adaptive immune responses to N. gonorrhoeae. N. gonorrhoeae is a highly adapted pathogen that has acquired multiple mechanisms to evade its host's immune system, including the ability to manipulate multiple immune signaling pathways. N. gonorrhoeae has previously been shown to engage immunosuppressive signaling pathways in B and T lymphocytes. We have now found that N. gonorrhoeae also suppresses adaptive immune responses through effects on antigen presenting cells. Using primary, murine bone marrow-derived dendritic cells and lymphocytes, we show that N. gonorrhoeae-exposed dendritic cells fail to elicit antigen-induced CD4+ T lymphocyte proliferation. N. gonorrhoeae exposure leads to upregulation of a number of secreted and dendritic cell surface proteins with immunosuppressive properties, particularly Interleukin 10 (IL-10) and Programmed Death Ligand 1 (PD-L1). We also show that N. gonorrhoeae is able to inhibit dendritic cell- induced proliferation of human T-cells and that human dendritic cells upregulate similar immunosuppressive molecules. Our data suggest that, in addition to being able to directly influence host lymphocytes, N. gonorrhoeae also suppresses development of adaptive immune responses through interactions with host antigen presenting cells. These findings suggest that gonococcal factors involved in host immune suppression may be useful targets in developing vaccines that induce protective adaptive immune responses to this pathogen.

Abstract The Central American Dry Corridor experienced five consecutive years of drought from 2015 to 2019. Here, we find that the severity of this drought was driven primarily by rainfall deficits in July–August. To determine if the magnitude of this event was outside the range of natural variability, we apply a statistical resampling method to observations that emulates internal climate variability. Our analyses show that droughts similar to the 2015–2019 event are possible, although extremely rare, even without anthropogenic influences. Persistent droughts in our ensemble are consistently linked to stronger easterly winds associated with the Caribbean Low‐Level Jet. We also examine the effects of temperature on soil moisture during this drought using the Palmer Drought Severity Index and show that anthropogenic warming increases the likelihood of severe deficits. Multi‐year droughts are likely to worsen by the end of the 21st century due to the compound effects of anthropogenic climate change.