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Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8 + T cells from systemic circulation. Within the liver, activated antigen-specific Fas + CD8 + T cells undergo apoptosis following their interaction with FasL + CD11b + F4/80 + monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8 + T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity. Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8 + T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.

The mass cycle of solar prominences or filaments is still not completely understood. Researchers agree that these dense structures form by coronal in situ condensations and plasma siphoning from the underlying chromosphere. In the evaporation–condensation model siphoning arises due to evaporation of chromospheric plasma from localized footpoint heating, but this is challenging to justify observationally. Here, we simulate the reconnection–condensation model at extreme resolutions down to 20.8 km within a three-dimensional (3D) magnetohydrodynamic coronal volume. We form a draining, quiescent prominence and associated coronal rain simultaneously. We show that thermal instability—acting as a trigger for local condensation formation—by itself drives siphoning flows from the low corona without the need of any localized heating. In addition, for the first time, we demonstrate through a statistical analysis along more than 1000 magnetic field lines that cold condensations give rise to siphoning flows within magnetic threads. This siphoning arises from the strong pressure gradient along field lines induced by thermal instability. No correlation is found between siphoning flows and the prominence mass, making thermal instability the main in situ mass-collection mechanism. Our simulated prominence drains by gliding along strongly sheared, asymmetric, dipped magnetic arcades, and develops natural vertical fine structure in an otherwise horizontal magnetic field due to the magnetic Rayleigh–Taylor instability. By synthesising our data, our model shows remarkable agreement with observations of quiescent prominences such as its dark coronal cavity in extreme-ultraviolet emission channels, fine-scale vertical structure, and reconnection outflows, which, for the first time, have been self-consistently obtained as the prominence evolves.

Diclofenac (DCF), one of the most current and widely used nonsteroidal anti-inflammatory drugs (NSAIDs), has been frequently detected in aquatic environments worldwide. However, the ecotoxicological effects of DCF on freshwater invertebrates remain largely unknown. In the present study, Corbicula fluminea were exposed to environmentally relevant concentrations of DCF (0, 2, 20, and 200 μg/L) for 28 days, and the potential adverse effects of DCF on siphoning behavior, antioxidant responses, and apoptosis were investigated. Our results showed that the siphon efficiencies of clams were significantly suppressed under DCF stress. DCF exerted neurotoxicity via reducing the activity of acetylcholinesterase (AChE) in gills and digestive gland of C. fluminea . Exposure to DCF induced antioxidant stress and increased malondialdehyde (MDA) levels in both gills and digestive gland of C. fluminea . Transcriptional alterations of apoptosis-related genes indicated that DCF might induce apoptosis by triggering mitochondrial apoptotic pathway. These findings can improve our understanding of the ecological risk of DCF in freshwater ecosystems.

Due to geological complexities and observational gaps, it is challenging to identify the governing physical processes of geothermal field deformation including ground subsidence and earthquakes. In the west and east regions of the Heber Geothermal Field (HGF), decade-long subsidence was occurring despite injection of heat-depleted brines, along with transient reversals between uplift and subsidence. These observed phenomena contradict current knowledge that injection leads to surface uplift. Here we show that high-yield production wells at the HGF center siphon fluid from surrounding regions, which can cause subsidence at low-rate injection locations. Moreover, the thermal contraction effect by cooling increases with time and eventually overwhelms the pressure effects of pressure fluctuation and poroelastic responses, which keep relatively stable during geothermal operations. The observed subsidence anomalies result from the siphoning effect and thermal contraction. We further demonstrate that thermal contraction dominates long-term trends of surface displacement and seismicity growth, while pressure effects drive near-instantaneous changes. Thermal contraction effect increases with time dominates the long-term deformation trend of the Heber geothermal field, while pressure effects of pressure fluctuation and poroelastic responses keep relatively stable and drive short-term changes.

Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorous vacuole (PV), the parasite must acquire resources across the limiting membrane of its replicative niche, which is decorated with parasite proteins including those secreted from dense granules. We discovered a role for the host Endosomal Sorting Complex Required for Transport (ESCRT) machinery in host cytosolic protein uptake by T . gondii by disrupting host ESCRT function. We identified the transmembrane dense granule protein TgGRA14, which contains motifs homologous to the late domain motifs of HIV-1 Gag, as a candidate for the recruitment of the host ESCRT machinery to the PV membrane. Using an HIV-1 virus-like particle (VLP) release assay, we found that the motif-containing portion of TgGRA14 is sufficient to substitute for HIV-1 Gag late domain to mediate ESCRT-dependent VLP budding. We also show that TgGRA14 is proximal to and interacts with host ESCRT components and other dense granule proteins during infection. Furthermore, analysis of TgGRA14-deficient parasites revealed a marked reduction in ingestion of a host cytosolic protein compared to WT parasites. Thus, we propose a model in which T . gondii recruits the host ESCRT machinery to the PV where it can interact with TgGRA14 for the internalization of host cytosolic proteins across the PV membrane (PVM). These findings provide new insight into how T . gondii accesses contents of the host cytosol by exploiting a key pathway for vesicular budding and membrane scission.

Achieving efficient economic growth in a low-carbon manner is becoming a crucial aspect of sustainable development. Meanwhile, promoting coordinated development to achieve synergistic carbon reduction and efficiency enhancement across cities from a holistic perspective holds significant practical importance. Based on panel data from 282 Chinese cities spanning 2005 to 2019, this study employs staggered difference-in-differences (DID) and spatial Durbin DID models to investigate the direct and spatial spillover effects of China’s low-carbon city pilot (LCCP) policy on green economic efficiency. The findings reveal several key insights: First, the LCCP policy significantly enhances green economic efficiency, primarily through advancements in green transportation, employment, and technology. Second, a notable spatial correlation exits in the green economic efficiency of Chinese cities, with spatial agglomeration generally trending upward over time. Third, local low-carbon city pilots can create a “siphoning effect” through technology and population concentration, inhibiting improvements in neighboring areas and impeding coordinated sustainable development among cities. Therefore, adopting a holistic perspective, establishing coordination mechanisms among cities, and promoting the optimal overall green economic efficiency within the region are essential for effective policy outcomes.

The La Jolla Canyon System (LJCS) is a small, steep, shelf-incising canyon offshore of San Diego, California. Observations conducted in the fall of 2016 capture the dynamics of internal tides and turbulence patterns. Semidiurnal (D 2 ) energy flux was oriented up-canyon; 62% ± 20% of the signal was contained in mode 1 at the offshore mooring. The observed mode-1 D 2 tide was partly standing based on the ratio of group speed times energy c g E and energy flux F . Enhanced dissipation occurred near the canyon head at middepths associated with elevated strain arising from the standing wave pattern. Modes 2–5 were progressive, and energy fluxes associated with these modes were oriented down-canyon, suggesting that incident mode-1 waves were back-reflected and scattered. Flux integrated over all modes across a given canyon cross section was always onshore and generally decreased moving shoreward (from 240 ± 15 to 5 ± 0.3 kW), with a 50-kW increase in flux occurring on a section inshore of the canyon’s major bend, possibly due to reflection of incident waves from the supercritical sidewalls of the bend. Flux convergence from canyon mouth to head was balanced by the volume-integrated dissipation observed. By comparing energy budgets from a global compendium of canyons with sufficient observations (six in total), a similar balance was found. One exception was Juan de Fuca Canyon, where such a balance was not found, likely due to its nontidal flows. These results suggest that internal tides incident at the mouth of a canyon system are dissipated therein rather than leaking over the sidewalls or siphoning energy to other wave frequencies.

China’s ongoing digital transformation, supported by proactive government policies, is fundamentally reshaping urban tourism through strategic development of digital infrastructure. This study employs a Difference-in-Differences (DID) model, taking the Broadband China policy as a quasi-natural experiment, to examine the driving effects and mechanisms of digital infrastructure development on emerging forms of urban digital tourism entrepreneurship. The results show that: (1) digital infrastructure development can facilitate the development of emerging forms for urban digital tourism entrepreneurship. Even after controlling for endogeneity, other policy intervention, and robustness in parallel trend testing, the outcome remains unchanged. Digital infrastructure has the potential to foster the growth of new types of urban digital tourism businesses by increasing the concentration of digital talent, the rate of technological innovation and application, and the level of government support. The driving effect is stronger in cities that have exceptional cultural value, well-allocated administrative resources, and excellent tourist resources. Coordination and information exchange in industrial chains are beneficial for nearby regions, but they pose a threat of marginalization to areas that aren’t immediately adjacent due to the impacts of resource siphoning. Therefore, the government should promote the transformation of urban tourism into intelligent and convenient, establish cross-city tourism alliances, and form a complementary mode of “technology and resources.” Simultaneously, it should make use of digital technology to accurately match the characteristics of the city and guide operators of the industry to efficiently make use of digital technology to identify market opportunities, integrate resources, and unleash the new kinetic energy of the industry’s development.

Urban infrastructure resilience is an important perspective for measuring the development quality of resilient cities and an important way to measure the level of infrastructure development. This paper uses the kernel density estimation, exploratory spatial data analysis, and spatial econometric models to analyze the characteristics of dynamic evolution and the spillover effects of the infrastructure resilience levels in 283 prefecture-level and above cities in China from 2010 to 2019. Our results are as follows. (1) The overall level of urban infrastructure resilience increased. The eastern region had a higher level than the national average. In contrast, the central, western and north-eastern regions had a slightly lower level than the national average. (2) The areas with high and higher resilience levels were mostly cities with more developed economic and social conditions in Eastern China. The areas below moderate resilience levels show a certain degree of clustering and mainly include some cities in Central, Western, and Northeast China. (3) The national level of urban infrastructure resilience shows significant spatial clustering characteristics, and the spatial pattern from coastal to inland regions presents a hotspot-subhotspot-subcoldspot-coldspot distribution. (4) There is a differential spatial spillover effect of national urban infrastructure resilience, which is gradually strengthened under the role of the economy, financial development, population agglomeration and government funding and weakened under the role of urbanization, market consumption and infrastructure investment. By exploring the dynamic evolution of infrastructure resilience in cities at the prefecture level and above and its spatial spillover effects, we provide a scientific basis for avoiding the siphoning effect among cities, improving the level of infrastructure resilience, and guiding the construction and development of resilient cities.

Background With the development of the economy, public health has become increasingly important. Therefore, it is important to establish a comprehensive and scientific the public health level index (PHL) system to measure public health level as a research priority. The current research has limitations in exploring the PHL system; therefore, the field still lacks a comprehensive indicator system to measure the level of public health. Therefore, this paper aims to develop a multi-level public health index system and utilizes China as a case study to evaluate its public health status. The objective is to offer insights and recommendations for the improvement of public health initiatives in China and other regions. Methods Utilizing data from 2011 to 2020, a comprehensive PHL was developed to encompass three vital indices: the Public Health Service Index (PHS), the Public Health Resource Index (PHR), and the Population Health Level Index (PHL). Subsequently, the PHL, PHS, PHR, and PH were meticulously calculated using a comprehensive evaluation method. Amid the current disparity between public health and economic progress, both the spatial Durbin model and the spatial lag model were finally employed to examine the influence of economic level (EL) on PHL, thus affirming the consistent reliability and accuracy of PHS. Results Our findings revealed the following: ( i ) the PHL, PHS, and PHR indices show increasing trends in China; ( ii ) both EL and PHL exhibit high-high clustering and low-low clustering states; ( iii ) the PHL in the area has a positive spatial spillover effect on the surrounding area; ( iv ) EL will result in the siphoning effect of PHL; and ( v ) EL can enhance PHL through urbanization, PH, and PHS. Conclusions The PHL system constructed in this paper demonstrates multiple levels, pluralism, spatio-temporal comparability, and robustness. It can reflect not only the input and output of public health initiatives but also the interconnectedness and autonomy within the public health system. Therefore, it can be widely utilized in other areas of public health research.