bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rintatolimod in Advanced Pancreatic Cancer Enhances Antitumor Immunity through Dendritic Cell–Mediated T-Cell Responses
Authors: van Eijck Casper W.F. , Haddaoui Hassana el , Kucukcelebi Songul , Vadgama Disha , Fellah Amine , Mustafa Dana A.M. , Aerts Joachim G.J.V. , van Eijck Casper H.J. , Willemsen Marcella 
Published: March 2024

Abstract

Purpose:
Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC.

Experimental Design:
Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models.

Results:
Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1.

Conclusions:
This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.
See related commentary by Martínez-Riaño et al., p. 3355
Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study
Authors: Plante Timothy B. , Juraschek Stephen P. , Howard George , Howard Virginia J. , Tracy Russell P. , Olson Nels C. , Judd Suzanne E. , Kamin Mukaz Debora , Zakai Neil A. , Long D. Leann , Cushman Mary 
Published: March 2024

BACKGROUND:
Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1β, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension.

METHODS:
The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers.

RESULTS:
Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1β among White (1.24 [95% CI, 1.01–1.53]) but not Black participants (1.01 [95% CI, 0.83–1.23]) and higher TNF-α (1.20 [95% CI, 1.02–1.41]) and IFN-γ (1.22 [95% CI, 1.04–1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP.

CONCLUSIONS:
Higher levels of IL-1β, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.
Resampling approaches for the quantitative analysis of spatially distributed cells
Authors: Bertolazzi Giorgio , Tumminello Michele , Morello Gaia , Belmonte Beatrice , Tripodo Claudio 
Published: March 2024

ABSTRACT
Image segmentation is a crucial step in various image analysis pipelines and constitutes one of the cutting-edge areas of digital pathology. The advent of quantitative analysis has enabled the evaluation of millions of individual cells in tissues, allowing for the combined assessment of morphological features, biomarker expression, and spatial context. The recorded cells can be described as a point pattern process. However, the classical statistical approaches to point pattern processes prove unreliable in this context due to the presence of multiple irregularly-shaped interstitial cell-devoid spaces in the domain, which correspond to anatomical features (e.g. vessels, lipid vacuoles, glandular lumina) or tissue artefacts (e.g. tissue fractures), and whose coordinates are unknown. These interstitial spaces impede the accurate calculation of the domain area, resulting in biased clustering measurements. Moreover, the mistaken inclusion of empty regions of the domain can directly impact the results of hypothesis testing. The literature currently lacks any introduced bias correction method to address interstitial cell-devoid spaces. To address this gap, we propose novel resampling methods for testing spatial randomness and evaluating relationships among different cell populations. Our methods obviate the need for domain area estimation and provide non-biased clustering measurements. We created the SpaceR software (https://github.com/GBertolazzi/SpaceR) to enhance the accessibility of our methodologies.
Frequency modulation increases the specificity of time-resolved connectivity: A resting-state fMRI study
Authors: Faghiri Ashkan , Yang Kun , Faria Andreia , Ishizuka Koko , Sawa Akira , Adali Tülay , Calhoun Vince 
Published: March 2024

Abstract
Representing data using time-resolved networks is valuable for analyzing functional data of the human brain. One commonly used method for constructing time-resolved networks from data is sliding window Pearson correlation (SWPC). One major limitation of SWPC is that it applies a high-pass filter to the activity time series. Therefore, if we select a short window (desirable to estimate rapid changes in connectivity), we will remove important low-frequency information. Here, we propose an approach based on single sideband modulation (SSB) in communication theory. This allows us to select shorter windows to capture rapid changes in the time-resolved functional network connectivity (trFNC). We use simulation and real resting-state functional magnetic resonance imaging (fMRI) data to demonstrate the superior performance of SSB+SWPC compared to SWPC. We also compare the recurring trFNC patterns between individuals with the first episode of psychosis (FEP) and typical controls (TC) and show that FEPs stay more in states that show weaker connectivity across the whole brain. A result exclusive to SSB+SWPC is that TCs stay more in a state with negative connectivity between subcortical and cortical regions. Based on all the results, we argue that SSB+SWPC is more sensitive for capturing temporal variation in trFNC.
Secondary Ice Production in Simulated Deep Convective Clouds: A Sensitivity Study
Authors: Han Cunbo , Hoose Corinna , Dürlich Viktoria 
Published: March 2024

Abstract
Multiple mechanisms have been proposed to explain secondary ice production (SIP), and SIP has been recognized to play a vital role in forming cloud ice crystals. However, most weather and climate models do not consider SIP in their cloud microphysical schemes. In this study, in addition to the default rime splintering (RS) process, two SIP processes, namely, shattering/fragmentation during freezing of supercooled rain/drizzle drops (DS) and breakup upon ice–ice collisions (BR), were implemented into a two-moment cloud microphysics scheme. Besides, two different parameterization schemes for BR were introduced. A series of sensitivity experiments were performed to investigate how SIP impacts cloud microphysics and cloud phase distributions in warm-based deep convective clouds developed in the central part of Europe. Simulation results revealed that cloud microphysical properties were significantly influenced by the SIP processes. Ice crystal number concentrations (ICNCs) increased up to more than 20 times and surface precipitation was reduced by up to 20% with the consideration of SIP processes. Interestingly, BR was found to dominate SIP, and the BR process rate was larger than the RS and DS process rates by four and three orders of magnitude, respectively. Liquid pixel number fractions inside clouds and at the cloud top decreased when implementing all three SIP processes, but the decrease depended on the BR scheme. Peak values of ice enhancement factors (IEFs) in the simulated deep convective clouds were 102–104 and located at −24°C with the consideration of all three SIP processes, while the temperature dependency of IEF was sensitive to the BR scheme. However, if only RS or RS and DS processes were included, the IEFs were comparable, with peak values of about 6, located at −7°C. Moreover, switching off the cascade effect led to a remarkable reduction in ICNCs and ice crystal mass mixing ratios.

Significance Statement
The cloud phase is found to have a significant impact on cloud evolution, radiative properties, and precipitation formation. However, the simulation of the cloud phase is a big challenge for cloud research because multiple processes are not well described or missing in numerical models. In this study, we implemented two secondary ice production (SIP) processes, namely, shattering/fragmentation during the freezing of supercooled rain/drizzle drops and breakup upon ice–ice collisions, which are missing in most numerical models. Sensitivity experiments were conducted to investigate how SIP impacts cloud microphysics and cloud phase in deep convective clouds. We found that SIP significantly impacts in-cloud and cloud-top phase distribution. We also identified that the collisional breakup of ice particles is the dominant SIP process in the simulated deep convective clouds.
Sensitivity of Easterly QBO’s Boreal Winter Teleconnections and Surface Impacts to SSWs
Authors: Elsbury Dillon , Butler Amy , Peings Yannick , Magnusdottir Gudrun 
Published: March 2024

Abstract
The quasi-biennial oscillation (QBO) is thought to influence boreal winter surface conditions over Asia and around the North Atlantic. Confirming if these responses are robust is complicated by the QBO having multiple pathways to influence surface conditions as well as internal variability. The reanalysis record suggests that sudden stratospheric warmings (SSWs), breakdowns of the polar vortex that can elicit persistent surface impacts, are more frequent during easterly QBO (EQBO). Hence, this modulated frequency of SSWs may account for some of the EQBO surface responses. However, many climate models do not reproduce this QBO–SSW relationship, perhaps because it is noise or because the model QBOs are deficient. We circumvent these issues by using an ensemble of fixed boundary condition branched simulations in which a realistic EQBO is prescribed in control simulations previously devoid of a QBO, allowing us to isolate the transient atmospheric response to EQBO. Imposing EQBO accelerates the tropical upper-tropospheric wind, shifts the subtropical jet poleward, and attenuates the polar vortex. Interestingly, the latter is not entirely dependent on the statistically significant increase in SSW frequency due to EQBO. Corroborating observations, EQBO is associated with warmer surface temperatures over Asia and negative North Atlantic Oscillation (NAO) conditions. We then subsample the branched/control simulations based on which EQBO members have SSWs. The negative NAO response is primarily associated with more frequent SSWs, while the Asia warming develops irrespective of SSWs. These results have implications for wintertime predictability and clarify the pairing of particular QBO teleconnections with certain surface impacts.

Significance Statement
The QBO is one of the few parts of the Earth system that is predictable months in advance and that also elicits global effects on surface temperature, circulation, and precipitation. Unfortunately, climate models and operational forecast systems do not simulate the QBO well and it is not always clear how robust the global impacts of the QBO are. Here, we impose the QBO in idealized model simulations, which modulates wintertime surface temperature and precipitation over Asia, the North Atlantic, Europe, and Africa in a manner consistent with observations. This work substantiates the importance of climate and forecast models properly simulating the QBO.
Linearity of the Climate Response to Increasingly Strong Tropical Volcanic Eruptions in a Large Ensemble Framework
Authors: Timmreck Claudia , Olonscheck Dirk , Ballinger Andrew P. , D’Agostino Roberta , Fang Shih-Wei , Schurer Andrew P. , Hegerl Gabriele C. 
Published: March 2024

Abstract
Large explosive volcanic eruptions cause short-term climatic impacts on both regional and global scales. Their impact on tropical climate variability, in particular El Niño–Southern Oscillation (ENSO), is still uncertain, as is their combined and separate effect on tropical and global precipitation. Here, we investigate the relationship between large-scale temperature and precipitation and tropical volcanic eruption strength, using 100-member MPI-ESM ensembles for idealized equatorial symmetric Northern Hemisphere summer eruptions of different sulfur emission strengths. Our results show that for idealized tropical eruptions, global and hemispheric mean near-surface temperature and precipitation anomalies are negative and linearly scalable for sulfur emissions between 10 and 40 Tg S. We identify 20 Tg S emission as a threshold where the global ensemble-mean near-surface temperature and precipitation signals exceed the range of internal variability, even though some ensemble members emerge from variability for lower eruption strengths. Seasonal and ensemble mean patterns of near-surface temperature and precipitation anomalies are highly correlated across eruption strengths, in particular for larger emission strengths in the tropics, and strongly modulated by ENSO. There is a tendency to shift toward a warm ENSO phase for the first postvolcanic year as the emission strength increases. Volcanic cooling emerges on a hemisphere-wide scale, while the precipitation response is more localized, and emergence is mainly confined to the tropics and subtropics.

Significance Statement
The purpose of this study is to investigate at which strength the climate responses of volcanic forcing can be distinguished from the internal climate variability and whether the responses will linearly increase as the emission strengths become stronger. We ran 100-member MPI-ESM ensembles of idealized equatorial volcanic eruptions of different sulfur emission strengths and find that seasonal and ensemble mean patterns of near-surface temperature and precipitation anomalies are distinguishable and linearly scalable for sulfur emissions from 10 to 40 Tg S if their forcing patterns are similar. The identification of volcanic fingerprints is important for seasonal to decadal forecasts in the case of potential future eruptions and could help to prepare society for the regional climatic consequences of such an event.
Multicycle Parameter Estimations in Coupled Earth System Models Based on Multiscale Sensitivity Responses in the Context of Low-Order Models
Authors: Yang Haoyu , Zhang Shaoqing , Cai Jinzhuo , Wang Dong , Deng Xiong , Gao Yang 
Published: March 2024

Abstract
Climate model simulations tend to drift away from the real world because of model errors induced by an incomplete understanding and implementation of dynamics and physics. Parameter estimation uses data assimilation methods to optimize model parameters, which minimizes model errors by incorporating observations into the model through state-parameter covariance. However, traditional parameter estimation schemes that simultaneously estimate multiple parameters using observations could fail to reduce model errors because of the low signal-to-noise ratio in the covariance. Here, based on the saturation time scales of model sensitivity that depend on different parameters and model components, we design a new multicycle parameter estimation scheme, where each cycle is determined by the saturation time scale of sensitivity of the model state associated with observations in each climate system component. The new scheme is evaluated using two low-order models. The results show that due to high signal-to-noise ratios sustained during the parameter estimation process, the new scheme consistently reduces model errors as the number of estimated parameters increases. The new scheme may improve comprehensive coupled climate models by optimizing multiple parameters with multisource observations, thereby addressing the multiscale nature of component motions in the Earth system.

Significance Statement
Parameter estimation is used to reduce model errors by optimizing the model parameter values with observational information, which is important for improving long-term predictions. In previous parameter estimation methods, multisource observations have not yet been sufficiently used because the quality and dimension size of the optimized parameters are limited. Here, based on the multiscale nature of component motion in the Earth system, we develop a new parameter estimation method that makes full use of multisource observations. The new method processes the parameters being estimated sequentially according to sensitivity magnitudes and saturation time scales so that the parameters can be continuously optimized. This new method has large application potential for weather and climate reanalyses and predictions.
The Brazil Basin Tracer Release Experiment: Observations
Authors: Ledwell James R. 
Published: March 2024

Abstract
Lightening of bottom water is required to close the abyssal overturning circulation, believed to play an important role in the climate system. A tracer release experiment and turbulence measurement programs have revealed how bottom water is lightened, and illuminated the associated circulation in the deep Brazil Basin, a representative region of the global ocean. Tracer was released on an isopycnal surface about 4000 m deep, over one of the fracture zones emanating from the Mid-Atlantic Ridge (MAR). Tracer that mixed toward the bottom moved toward the MAR across isopycnal surfaces that bend down to intersect the bottom at a rate implying a near-bottom buoyancy flux of 1.5 × 10−9 m2 s−3, somewhat larger than inferred from dissipation measurements. The diffusivity at the level of the tracer release is estimated at 4.4 ± 1 × 10−4 m2 s−1, again larger than inferred from dissipation rates. The main patch moved southwest at about 2 cm s−1 while sinking due to the divergence of buoyancy flux above the bottom layer. The isopycnal eddy diffusivity was about 100 m2 s−1. Westward flow away from the MAR is the return flow balancing the eastward near-bottom upslope flow. The southward component of the flow is roughly consistent with conservation of potential vorticity. The circulation as well as the pattern of diapycnal flux are qualitatively the same as in St. Laurent et al. (2001) but are more robust. The results indicate that diapycnal diffusivity is about twice that invoked by Morris et al. (2001) in calculating the basinwide buoyancy budget.

Significance Statement
Buoyancy flux into the abyssal waters is required to close the overturning circulation of those waters, an important part of the climate system. This contribution presents a robust view of the strength of that buoyancy flux and the associated circulation.
An Automobile’s Tail Lights: Sacrificing Safety for Playful Design?
Authors: Burns-Hemingway Fiona , Feltmate Brett B. T. , Klein Raymond M. 
Published: March 2024

Objective The counterintuitive “Union Jack”-inspired turn signals on versions of BMW’s Mini vehicles was investigated to reveal potential impacts on human performance. Background When some Mini drivers indicate a change in direction, they do so with an oppositely oriented arrow. This conflict, between the task-irrelevant spatial shape and task-relevant location of the signal, mimics a “converse” spatial-Stroop effect that, in combination with the ubiquitous use of arrows on road signs, may be confusing. Method Participants ( n = 30) responded—via right and left keypresses—to the directions of road signs and turn signals in both pure and mixed blocks. Reaction times and accuracies were recorded to determine performance in each condition (compatible, neutral, incompatible). Results Performance suffered when the location and direction of the stimuli did not correspond. When responding to turn signals the cost to performance was especially salient in mixed blocks. Thus, when driving on roads where the meanings of arrows on road signs is important, turn signals pointing in a direction opposite from the directional intention indicated by the signals’ location are likely to be confusing. Conclusion The design of some Mini’s “Union Jack” style taillights opposes well-established principles of cognitive functioning, caused confusion in our laboratory study and therefore may be a safety hazard—a possibility that ought to be explored in more realistic (e.g., driving simulator) situations. Application BMW designers should consider universally adopting the neutral, “horizontal line,” illumination style that is currently available in the aftermarket.