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Abstract Exosomal PD-L1 (exoPD-L1) has recently received significant attention as a biomarker predicting immunotherapeutic responses involving the PD1/PD-L1 pathway. However, current technologies for exosomal analysis rely primarily on bulk measurements that do not consider the heterogeneity found within exosomal subpopulations. Here, we present a nanoscale cytometry platform NanoEPIC, enabling phenotypic sorting and exoPD-L1 profiling from blood plasma. We highlight the efficacy of NanoEPIC in monitoring anti-PD-1 immunotherapy through the interrogation of exoPD-L1. NanoEPIC generates signature exoPD-L1 patterns in responders and non-responders. In mice treated with PD1-targeted immunotherapy, exoPD-L1 is correlated with tumor growth, PD-L1 burden in tumors, and the immune suppression of CD8+ tumor-infiltrating lymphocytes. Small extracellular vesicles (sEVs) with different PD-L1 expression levels display distinctive inhibitory effects on CD8 + T cells. NanoEPIC offers robust, high-throughput profiling of exosomal markers, enabling sEV subpopulation analysis. This platform holds the potential for enhanced cancer screening, personalized treatment, and therapeutic response monitoring.

Summary: By sorting receptor tyrosine kinases into endolysosomes, the endosomal sorting complexes required for transport (ESCRTs) are thought to attenuate oncogenic signaling in tumor cells. Paradoxically, ESCRT members are upregulated in tumors. Here, we show that disruption of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a pivotal ESCRT component, inhibited tumor growth by promoting CD8+ T cell infiltration in melanoma and colon cancer mouse models. HRS ablation led to misfolded protein accumulation and triggered endoplasmic reticulum (ER) stress, resulting in the activation of the type I interferon pathway in an inositol-requiring enzyme-1α (IRE1α)/X-box binding protein 1 (XBP1)-dependent manner. HRS was upregulated in tumor cells with high tumor mutational burden (TMB). HRS expression associates with the response to PD-L1/PD-1 blockade therapy in melanoma patients with high TMB tumors. HRS ablation sensitized anti-PD-1 treatment in mouse melanoma models. Our study shows a mechanism by which tumor cells with high TMB evade immune surveillance and suggests HRS as a promising target to improve immunotherapy.

Oil sands development in the Athabasca and Cold Lake oil sands regions of Alberta has raised concerns about potential impacts to groundwater and groundwater dependent ecosystems. This review summarizes the current state of understanding as to how oil sands mining and in situ activities can affect groundwater systems using a stressor-mechanism-response framework. Specific oil sands activities and practices are reviewed, and where possible, described in terms of how they can impact hydraulic head, the hydraulic properties of aquifers, recharge and transport of constituents of concern and linked to observed or potential impacts to groundwater quantity and quality. Groundwater is an important component of the water balance in boreal ecosystems, and specific vulnerabilities related to development are reviewed, including water use, landscape disturbance, groundwater withdrawals, tailings pond seepage, deep well disposal and thermal impacts. Knowledge gaps include lack of baseline data and monitoring of the quantity and quality of groundwater discharge to rivers, lakes and wetlands. One key monitoring challenge is attribution of hydrogeologic responses to specific oil sands stressors given the range of other natural and anthropogenic factors contributing to their variability. Quantitative groundwater exchange mapping, regional-scale isotope mass balance assessment, and broader incorporation of isotopic and geochemical tracers for fingerprinting water sources and incorporation of Indigenous Knowledge appear promising for improved effectiveness of monitoring. [ABSTRACT FROM AUTHOR]

Surfactant replacement therapy is crucial in managing neonatal respiratory distress syndrome (RDS). Currently licensed clinical surfactants in the United States and Europe, including Survanta, Infasurf, Curosurf, and Alveofact, are all derived from bovine or porcine sources. We conducted a comprehensive examination of the biophysical properties of these four clinical surfactant preparations under physiologically relevant conditions, using constrained drop surfactometry (CDS). The assessed biophysical properties included the adsorption rate, quasi-static and dynamic surface activity, resistance to surfactant inhibition by meconium, and the morphology of the adsorbed surfactant films. This comparative study unveiled distinct in vitro biophysical properties of these clinical surfactants and revealed correlations between their chemical composition, lateral film structure, and biophysical functionality. Notably, at 1 mg/mL, Survanta exhibited a significantly lower adsorption rate compared with the other preparations at the same surfactant concentration. At 10 mg/mL, Infasurf, Curosurf, and Survanta all demonstrated excellent dynamic surface activity, whereas Alveofact exhibited the poorest quasi-static and dynamic surface activity. The suboptimal surface activity of Alveofact is found to be correlated with its unique monolayer-predominant morphology, in contrast to other surfactants forming multilayers. Curosurf, in particular, showcased superior resistance to biophysical inhibition by meconium compared with other preparations. Understanding the diverse biophysical behaviors of clinical surfactants provides crucial insights for precision and personalized design in treating RDS and other respiratory conditions. The findings from this study contribute valuable perspectives for the development of more efficacious and fully synthetic surfactant preparations. NEW & NOTEWORTHY: A thorough investigation into the biophysical properties of four animal-derived clinical surfactant preparations was conducted through constrained drop surfactometry under physiologically relevant conditions. This comparative study unveiled unique in vitro biophysical characteristics among these clinical surfactants, establishing correlations between their chemical composition, lateral film structure, and biophysical functionality. The acquired knowledge offers essential insights for the precise and personalized design of clinical surfactant for the treatment of respiratory distress syndrome and other respiratory conditions. [ABSTRACT FROM AUTHOR]

Terrestrial gross primary productivity (GPP) is the largest carbon flux in the global carbon cycle and plays a crucial role in terrestrial carbon sequestration. However, historical and future global GPP estimates still vary markedly. In this study, we reduced uncertainties in global GPP estimates by employing an innovative emergent constraint method on remote sensing‐based GPP datasets (RS‐GPP), using ground‐based estimates of GPP from flux towers as the observational constraint. Using this approach, the global GPP in 2001–2014 was estimated to be 126.8 ± 6.4 PgC year−1, compared to the original RS‐GPP ensemble mean of 120.9 ± 10.6 PgC year−1, which reduced the uncertainty range by 39.6%. Independent space‐ and time‐based (different latitudinal zones, different vegetation types, and individual year) constraints further confirmed the robustness of the global GPP estimate. Building on these insights, we extended our constraints to project global GPP estimates in 2081–2100 under various Shared Socioeconomic Pathway (SSP) scenarios: SSP126 (140.6 ± 9.3 PgC year−1), SSP245 (153.5 ± 13.4 PgC year−1), SSP370 (170.7 ± 16.9 PgC year−1), and SSP585 (194.1 ± 23.2 PgC year−1). These findings have important implications for understanding and projecting climate change, helping to develop more effective climate policies and carbon reduction strategies. [ABSTRACT FROM AUTHOR]

Whistler-mode waves have been extensively observed and investigated in terrestrial space. In this study, we present the dynamic response of whistler-mode waves to different solar wind conditions in the dayside terrestrial space based on Magnetospheric Multiscale (MMS) data. Statistical results show that the occurrence rate, amplitudes, and corresponding electron temperature anisotropy of whistler-mode waves increase with P sw in the dayside terrestrial space, which is attributed to the compression of magnetic fields in these magnetosheath and outer magnetosphere. Furthermore, whistler-mode waves under the southward interplanetary magnetic fields (IMFs) show a higher occurrence rate than that under the northward IMFs, mostly corresponding to T e ⊥/ T e ∥ > 1, and have a higher occurrence rate during quasi-radial IMFs. These results present that whistler-mode waves in these magnetosheath and outer magnetosphere are also modulated by the solar wind as clearly as the inner magnetosphere. This work advanced our understanding in the solar–terrestrial interaction. [ABSTRACT FROM AUTHOR]

The 2015–2016 Amazon drought was characterized by below-average regional precipitation for an entire year, which distinguishes it from the dry-season-only droughts in 2005 and 2010. Studies of vegetation indices (VIs) derived from optical remote sensing over the Amazonian forests indicated three stages in canopy response during the 2015–2016 drought, with below-average greenness during the onset and end of the drought, and above-average greenness during the intervening months. To date, a satisfactory explanation for this broad temporal pattern has not been found. A better understanding of rainforest behaviors during this unusually long drought should help predict their response to future droughts. We hypothesized that negative VI anomalies could be caused by water and heat stress exceeding the tolerance ranges of the rainforest. To test our hypothesis, based on monthly observations of terrestrial water storage (TWS), land surface temperature (LST), and vapor pressure deficit (VPD) for January 2003 to December 2016, we proposed an approach to categorize regions into two groups: (1) those exceeding normal hydrological and thermal ranges and (2) those within normal ranges. Accordingly, regions exceeding normal ranges during different stages of the 2015–2016 event were delineated. The results showed a gradual southward shift in these regions: from the northeastern Amazon during August to October 2015 to the north–central part during November 2015 to February 2016 and finally to the southern Amazon in July 2016. Over these regions exceeding normal ranges during droughts, negative VI anomalies were expected, irrespective of radiation anomalies. Over the regions within normal ranges, VI anomalies were assumed to respond positively to radiation anomalies, as is expected under normal conditions. We found that our proposed approach can explain more than 70 % of the observed spatiotemporal patterns in VI anomalies during the 2015–2016 drought. These results suggest that our "exceeding normal ranges"-based approach combining (i) water storage, (ii) temperature, and (iii) atmospheric moisture demand drivers can reasonably identify the most likely drought-affected regions at monthly to seasonal timescales. Using observation-based hydrological and thermal condition thresholds can help with interpreting the response of the Amazon rainforest to future drought events. [ABSTRACT FROM AUTHOR]