Spatiotemporal characterization of PM2.5, O3, and trace gases associated with East Asian continental outflows via drone sounding.

East Asian continental outflows with PM2.5, O3, and other species may determine the baseline conditions and affect the air quality in downwind areas via long-range transport (LRT). To gain insight into the impact and spatiotemporal characteristics of airborne pollutants in East Asian continental outflows, a versatile multicopter drone sounding platform was used to simultaneously observe PM2.5, O3, CO2, and meteorological variables (temperature, specific humidity, pressure, and wind vector) above the northern tip of Taiwan, Cape Fuiguei, which often encounters continental outflows during winter monsoon periods. By coordinating hourly high-spatial-resolution profiles provided by drone soundings, WRF/CMAQ model air quality predictions, HYSPLIT-simulated backward trajectories, and MERRA-2 reanalysis data, we analyzed two prominent phenomena of airborne pollutants in continental outflows to better understand their physical/chemical characteristics. First, we found that pollutants were well mixed within a sounding height of 500 m when continental outflows passed through and completely enveloped Cape Fuiguei. Eddies induced by significant fluctuations in wind speeds coupled with minimal temperature inversion and LRT facilitated vertical mixing, possibly resulting in high homogeneity of pollutants within the outflow layer. Second, the drone soundings indicated exceptionally high O3 concentrations (70-100 ppbv) but relatively low concentrations of PM2.5 (10-20 µg/m3), CO2 (420-425 ppmv), and VOCs in some air masses. The low levels of PM2.5, CO2, and VOCs ruled out photochemistry as the cause of the formation of high-level O3. Further coordination of spatiotemporal data with air mass trajectories and O3 cross sections provided by MERRA-2 suggested that the high O3 concentrations could be attributed to stratospheric intrusion and advection via continental outflows. High-level O3 concentrations persisted in the lower troposphere, even reaching the surface, suggesting that stratospheric intrusion O3 may be involved in the rising trend in O3 concentrations in parts of East Asia in recent years in addition to surface photochemical factors.

INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control.

The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreases proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and ultimately attenuates IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.

TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation.

Activation of tumor-intrinsic innate immunity has been a major strategy for improving immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating enzyme TRABID. Here, we identify a critical role of TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID is upregulated in mitosis and governs mitotic cell division by removing K29-linked polyubiquitin chain from Aurora B and Survivin, thereby stabilizing the entire chromosomal passenger complex. TRABID inhibition causes micronuclei through a combinatory defect in mitosis and autophagy and protects cGAS from autophagic degradation, thereby activating the cGAS/STING innate immunity pathway. Genetic or pharmacological inhibition of TRABID promotes anti-tumor immune surveillance and sensitizes tumors to anti-PD-1 therapy in preclinical cancer models in male mice. Clinically, TRABID expression in most solid cancer types correlates inversely with an interferon signature and infiltration of anti-tumor immune cells. Our study identifies a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and highlights TRABID as a promising target for sensitizing solid tumors to immunotherapy.

Distinct transport mechanisms of East Asian dust and the impact on downwind marine and atmospheric environments.

East Asian dust episodes have a multitude of impacts, including on human health, environment, and climate over near-source and receptor regions. However, the mechanistic understanding of the synoptic conditions of these outbreaks at different altitude layers, and their eventual environmental impacts are less studied. The present study analyzed the synoptic transport patterns of East Asian dust during multiple dust generation episodes that occurred over only a few days apart in northern China, and which eventually delivered high PM10 concentrations to surface level and high-altitude locations in Taiwan. Whether the dust plume was uplifted ahead of or behind the 700 hPa trough over East Asia determined its trajectory and eventual impact on the environment downwind. The total dust (iron) deposition over the ocean surface preceding arrival to Taiwan was 2.4 mg m-2 (0.95 µg m-2) for the episode impacting the surface level and 5.0 mg m-2 (4.6 µg m-2) for the episode impacting high-altitude Taiwan. Dust deposition in marine areas east of China was more intense for the higher altitude transport event that was uplifted behind the 700 hPa trough and resulted in twice higher marine Chl-a concentrations. Furthermore, we estimated a dust-induced direct radiative effect over a high mountainous region in Taiwan of -6.2 to -8.2 W m-2 at the surface, -1.9 to -2.9 W m-2 at the top of the atmosphere and +3.9 to +5.3 W m-2 in the atmosphere. This dust-induced atmospheric warming and surface cooling are non-negligible influences on the atmospheric thermal structure and biogeochemical cycle over the western North Pacific. Overall, this study highlights the significant impacts of dust particles on the marine ecosystem and atmospheric radiation budget over the downwind region, thus lays the foundation for linking these impacts to the initial synoptic conditions in the source area.

TFEB- and TFE3-dependent autophagy activation supports cancer proliferation in the absence of centrosomes.

Centrosome amplification is a phenomenon frequently observed in human cancers, so centrosome depletion has been proposed as a therapeutic strategy. However, despite being afflicted with a lack of centrosomes, many cancer cells can still proliferate, implying there are impediments to adopting centrosome depletion as a treatment strategy. Here, we show that TFEB- and TFE3-dependent autophagy activation contributes to acentrosomal cancer proliferation. Our biochemical analyses uncover that both TFEB and TFE3 are novel PLK4 (polo like kinase 4) substrates. Centrosome depletion inactivates PLK4, resulting in TFEB and TFE3 dephosphorylation and subsequent promotion of TFEB and TFE3 nuclear translocation and transcriptional activation of autophagy- and lysosome-related genes. A combination of centrosome depletion and inhibition of the TFEB-TFE3 autophagy-lysosome pathway induced strongly anti-proliferative effects in cancer cells. Thus, our findings point to a new strategy for combating cancer.Abbreviations: AdCre: adenoviral Cre recombinase; AdLuc: adenoviral luciferase; ATG5: autophagy related 5; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; GFP: green fluorescent protein; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LTR: LysoTracker Red; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MITF: melanocyte inducing transcription factor; PLK4: polo like kinase 4; RFP: red fluorescent protein; SASS6: SAS-6 centriolar assembly protein; STIL: STIL centriolar assembly protein; TFEB: transcription factor EB; TFEBΔNLS: TFEB lacking a nuclear localization signal; TFE3: transcription factor binding to IGHM enhancer 3; TP53/p53: tumor protein p53.

Lamin A-mediated nuclear lamina integrity is required for proper ciliogenesis.

The primary cilium is a sensory organelle that receives specific signals from the extracellular environment important for vertebrate development and tissue homeostasis. Lamins, the major components of the nuclear lamina, are required to maintain the nuclear structure and are involved in most nuclear activities. In this study, we show that deficiency in lamin A/C causes defective ciliogenesis, accompanied by increased cytoplasmic accumulation of actin monomers and increased formation of actin filaments. Disruption of actin filaments by cytochalasin D rescues the defective ciliogenesis in lamin A/C-depleted cells. Moreover, lamin A/C-deficient cells display lower levels of nesprin 2 and defects in recruiting Arp2, myosin Va, and tau tubulin kinase 2 to the basal body during ciliogenesis. Collectively, our results uncover a functional link between nuclear lamina integrity and ciliogenesis and implicate the malfunction of primary cilia in the pathogenesis of laminopathy.

Long-range air pollution transport in East Asia during the first week of the COVID-19 lockdown in China.

Long-range transport (LRT) of air pollutants from East Asia during the northeast monsoon season impacts several downwind locations. In 2020, the initial COVID-19 lockdowns in China overlapped with Week 3 of the Chinese New Year (CNY) holiday, and an Asian outflow event. Thus, movement of the Chinese populace from city to city was already greatly reduced by the time of the LRT episode, although the reductions in industrial output are less clear. We found NO2 column concentrations were reduced by 24% during the CNY Week 3 this year compared to previous years. The attenuated transport event arrived to northern Taiwan with a PM2.5 concentration <45 µg m-3 and most often <35 µg m-3, which is 2-3 times lower than LRT episodes of similar back-trajectory and synoptic patterns. The whole episode persisted for about 60 h, longer than most LRT episodes from China to Taiwan. CMAQ v5.2.1 modeling of the LRT event with 100% emission and reduced emission scenarios, revealed emissions in China were approximately 50% less than normal periods. Due to the length of the episode and the significant reduction in emissions, Taiwan avoided a PM2.5 surplus of 19.2 µg m-3 on average during the episode, equivalent to a 0.5 µg m-3 reduction for the whole 3-month winter season. Employing the 100% emission model scenario and scaling up to the average episode hours each winter, the PM2.5 surplus delivered via plumes on the northeast monsoon is equivalent to a 0.5 µg m-3 surplus for the whole year.