Black carbon (BC) aerosols are significant contributors to anthropogenic climate change and are considered as the second largest warming agent only after CO₂. To better quantify the present-day Asian BC aerosol forcing, in Chapter 2 we utilize both a top-down approach using ground -based and satellite observations, as well as a bottom-up approach using a latest global climate model. By comparing the observations with the model simulations, we show that the emission inventory over Asia used in the model needs to be adjusted by a factor of two to four. The global mean BC forcing since pre-industrial in the model is 0.5 to 0.8 W/m², larger than the unconstrained model forcing of 0.2 W /m². In understanding the climate system response to external forcing such as BC, we first show in Chapter 3 that the north-south contrast of land and ocean distribution determines the latitudinal asymmetry of climate change, which is an intrinsic characteristic of the climate system. The main thrust of this dissertation is that in Chapter 4, we demonstrate with the improved CESM that BC aerosols play a vital role in causing the observed surface warming, snow cover and snow depth reduction over Tibet and Himalaya region. Due to BC aerosols, the simulated snow cover fraction over Tibet is reduced by more than 2% and snow depth is reduced by 5%. The model simulated warming enhancement at high altitude surface (more than 1 K at 5000 m) due to the direct atmospheric heating of BC and the BC deposition on the snow surface are similar to observations. The relative contributions from greenhouse gases and cooling aerosols are also assessed with the model. In Chapter 5, we evaluate the climate mitigation benefits associated with a rapid reduction of BC aerosols. We show that aggressive BC reduction leads to warming mitigation and snow recovery over Tibet. We further discussed the major sources of BC emissions from China and the potential practical measures to cut BC emissions. The costs and benefits on public health due to cook-stove improvement are also discussed

Though highly motivated to slow the climate crisis, governments may struggle to impose costly polices on entrenched interest groups, resulting in a greater need for negative emissions. Here, we model wartime-like crash deployment of direct air capture (DAC) as a policy response to the climate crisis, calculating funding, net CO₂ removal, and climate impacts. An emergency DAC program, with investment of 1.2-1.9% of global GDP annually, removes 2.2-2.3 GtCO₂ yr^-1 in 2050, 13-20 GtCO₂ yr^-1 in 2075, and 570-840 GtCO₂ cumulatively over 2025-2100. Compared to a future in which policy efforts to control emissions follow current trends (SSP2-4.5), DAC substantially hastens the onset of net-zero CO₂ emissions (to 2085-2095) and peak warming (to 2090-2095); yet warming still reaches 2.4-2.5 °C in 2100. Such massive CO₂ removals hinge on near-term investment to boost the future capacity for upscaling. DAC is most cost-effective when using electricity sources already available today: hydropower and natural gas with renewables; fully renewable systems are more expensive because their low load factors do not allow efficient amortization of capital-intensive DAC plants.

Fungal infections, widespread throughout the world, affect a broad range of life forms, including agriculturally relevant plants, humans, and insects. In defending against fungal infections, the fruit fly Drosophila melanogaster employs the Toll pathway to induce a large number of immune peptides. Some have been investigated, such as the antimicrobial peptides (AMPs) and Bomanins (Boms); many, however, remain uncharacterized. Here, we examine the role in innate immunity of two related peptides, Daisho1 and Daisho2 (formerly IM4 and IM14, respectively), found in hemolymph following Toll pathway activation. By generating a CRISPR/Cas9 knockout of both genes, Δdaisho, we find that the Daisho peptides are required for defense against a subset of filamentous fungi, including Fusarium oxysporum, but not other Toll-inducible pathogens, such as Enterococcus faecalis and Candida glabrata. Analysis of null alleles and transgenes revealed that the two daisho genes are each required for defense, although their functions partially overlap. Generating and assaying a genomic epitope-tagged Daisho2 construct, we detected interaction in vitro of Daisho2 peptide in hemolymph with the hyphae of F. oxysporum. Together, these results identify the Daisho peptides as a new class of innate immune effectors with humoral activity against a select set of filamentous fungi.

The ongoing and projected impacts from human-induced climate change highlight the need for mitigation approaches to limit warming in both the near term (<2050) and the long term (>2050). We clarify the role of non-CO2 greenhouse gases and aerosols in the context of near-term and long-term climate mitigation, as well as the net effect of decarbonization strategies targeting fossil fuel (FF) phaseout by 2050. Relying on Intergovernmental Panel on Climate Change radiative forcing, we show that the net historical (2019 to 1750) radiative forcing effect of CO2 and non-CO2 climate forcers emitted by FF sources plus the CO2 emitted by land-use changes is comparable to the net from non-CO2 climate forcers emitted by non-FF sources. We find that mitigation measures that target only decarbonization are essential for strong long-term cooling but can result in weak near-term warming (due to unmasking the cooling effect of coemitted aerosols) and lead to temperatures exceeding 2 °C before 2050. In contrast, pairing decarbonization with additional mitigation measures targeting short-lived climate pollutants and N2O, slows the rate of warming a decade or two earlier than decarbonization alone and avoids the 2 °C threshold altogether. These non-CO2 targeted measures when combined with decarbonization can provide net cooling by 2030 and reduce the rate of warming from 2030 to 2050 by about 50%, roughly half of which comes from methane, significantly larger than decarbonization alone over this time frame. Our analysis demonstrates the need for a comprehensive CO2 and targeted non-CO2 mitigation approach to address both the near-term and long-term impacts of climate disruption.

Fungal infections, widespread throughout the world, affect a broad range of life forms, including agriculturally relevant plants, humans, and insects. In defending against fungal infections, the fruit fly Drosophila melanogaster employs the Toll pathway to induce a large number of immune peptides. Some have been investigated, such as the antimicrobial peptides (AMPs) and Bomanins (Boms); many, however, remain uncharacterized. Here, we examine the role in innate immunity of two related peptides, Daisho1 and Daisho2 (formerly IM4 and IM14, respectively), found in hemolymph following Toll pathway activation. By generating a CRISPR/Cas9 knockout of both genes, Δdaisho, we find that the Daisho peptides are required for defense against a subset of filamentous fungi, including Fusarium oxysporum, but not other Toll-inducible pathogens, such as Enterococcus faecalis and Candida glabrata. Analysis of null alleles and transgenes revealed that the two daisho genes are each required for defense, although their functions partially overlap. Generating and assaying a genomic epitope-tagged Daisho2 construct, we detected interaction in vitro of Daisho2 peptide in hemolymph with the hyphae of F. oxysporum. Together, these results identify the Daisho peptides as a new class of innate immune effectors with humoral activity against a select set of filamentous fungi.

Background

We conducted a meta-analysis to systematically evaluate the relationship between programmed death-ligand 1 (PD-L1) expression and survival in patients with lung cancer.

Methods

The electronic databases PubMed, Embase, Cochrane, and Web of Science were searched up to January 2^nd, 2018, for articles relating to PD-L1 expression detected by immunohistochemistry (IHC) and lung cancer patient prognosis.

Results

Fifty studies including 11,383 patients published between 2011 and 2017 were enrolled in this meta-analysis. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) suggested that PD-L1 IHC expression was related to poor overall survival (OS) (HR =1.45, 95% CI: 1.24-1.68). In subgroup analysis categorized according to sample type, cut-off value, ethnicity and TNM stage, the pooled results demonstrated inferior survival in the PD-L1 positive group when the PD-L1 expression was detected by resection specimens (P=0.000), 5% was taken as the cutoff value (P=0.000), the patients were in early stage (I-III) (P=0.000), and the geographic setting of the study was in Asia (P=0.000). Besides, patients with high PD-L1 expression had shorter OS in NSCLC (P=0.000), ADC (P=0.000), SCC (P=0.353) and LELC (P=0.810), while no significant difference was observed in SCLC (P=0.000). The pooled odds ratios (ORs) suggested that PD-L1 expression was associated with male (P<0.001), smoker (P<0.001), poor tumor differentiation (P=0.014), large tumor size (P=0.132), positive lymph nodal metastasis (P=0.002), EGFR wild-type status (P<0.001) and KRAS mutations (P=0.393). However, age (P=0.15) and ALK rearrangements (P=0.567) had no bearing on PD-L1 expression.

Conclusions

PD-L1 expression that is associated with several clinicopathological feactures may serve as a poor prognostic biomarker for patients with lung cancer.

The Paris Agreement of December 2015 stated a goal to pursue efforts to keep global temperatures below 1.5°C above preindustrial levels and well below 2°C. The IPCC was charged with assessing climate impacts at these temperature levels, but fully coupled equilibrium climate simulations do not currently exist to inform such assessments. In this study, we produce a set of scenarios using a simple model designed to achieve long-term 1.5 and 2°C temperatures in a stable climate. These scenarios are then used to produce century-scale ensemble simulations using the Community Earth System Model, providing impact-relevant long-term climate data for stabilization pathways at 1.5 and 2°C levels and an overshoot 1.5°C case, which are realized (for the 21st century) in the coupled model and are freely available to the community. Here we describe the design of the simulations and a brief overview of their impact-relevant climate response. Exceedance of historical record temperature occurs with 60% greater frequency in the 2°C climate than in a 1.5°C climate aggregated globally, and with twice the frequency in equatorial and arid regions. Extreme precipitation intensity is statistically significantly higher in a 2.0°C climate than a 1.5°C climate in some specific regions (but not all). The model exhibits large differences in the Arctic, which is ice-free with a frequency of 1 in 3 years in the 2.0°C scenario, and 1 in 40 years in the 1.5°C scenario. Significance of impact differences with respect to multi-model variability is not assessed.

The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.

The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.