Spatial-temporal differentiation and influencing factors of carbon emission trajectory in Chinese cities - A case study of 247 prefecture-level cities.

Cities, where human energy activities and greenhouse gas emissions are concentrated, contribute significantly to alleviating the impacts of global climate change. Utilizing the China Carbon Emissions Accounting Database (CEADs) to provide carbon dioxide emission inventories for urban areas in China at the prefecture level, this study closely examines the historical evolution trajectories of carbon emissions across 247 urban units from 2005 to 2019. The logarithmic cubic function model was employed to simulate these trajectories, evaluating urban emission peaks and classifying the different carbon emission trajectories. Further, the Geographical and Temporal Weighted Regression model was employed to explore spatiotemporal traits and essential variables that impact the variations in carbon emissions among four identified trajectory types. Our results showed that Chinese urban carbon emission trajectories can be classified into four categories: a) peaking emissions, b) fluctuating growth, c) continuous growth, and d) passive decline. Specifically, 43 cities, primarily in North China, proactively attained their emission peak post-2010, driven by the reduction in secondary industry and energy intensity. 90 cities, largely industrial hubs in the southeast coast and inland, reached an emission plateau around 2015, exhibiting fluctuating growth due to dependencies on secondary industries. 101 cities, predominantly located in western and central regions, demonstrated a clear upward trend in carbon emissions, propelled by rapid urbanization and heavy industry-oriented economic development. Lastly, 13 cities, typically in the northeastern and southwestern regions, experienced a passive decline in carbon emissions, attributable to resource depletion or economic downturns. It is evident that China's city-level carbon peaking has demonstrated some effectiveness, yet considerable progress is still required.

Hybrid imidazo[1,2-a]pyridine analogs as potent ATX inhibitors with concrete in vivo antifibrosis effect.

In recent years, small-molecule inhibitors targeting the autotaxin (ATX)/lysophosphatidic acid axis gradually brought excellent disease management benefits. Herein, a series of imidazo[1,2-a]pyridine compounds (1-11) were designed as ATX inhibitors through a hybrid strategy by combining the imidazo[1,2-a]pyridine skeleton in GLPG1690 and the benzyl carbamate moiety in PF-8380. As indicated by FS-3-based enzymatic assay, the carbamate derivatives revealed moderate to satisfying ATX inhibitory potency (IC50 = 23-343 nM). Subsequently, the carbamate linker was altered to a urea moiety (12-19) with the aim of retaining ATX inhibition and improving the druglikeness profile. The binding mode analysis all over the modification process well rationalized the leading activity of urea derivatives in an enzymatic assay. Following further structural optimization, the diethanolamine derivative 19 exerted an amazing inhibitory activity (IC50 = 3.98 nM) similar to the positive control GLPG1690 (IC50 = 3.72 nM) and PF-8380 (IC50 = 4.23 nM). Accordingly, 19 was tested directly for in vivo antifibrotic effects through a bleomycin model (H&E staining), in which 19 effectively alleviated lung structural damage and fibrosis at an oral dose of 20 and 60 mg/kg. Collectively, 19 qualified as a promising ATX inhibitor for potential application in fibrosis-relevant disease treatment.

Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model.

Aiming to develop novel allosteric autotaxin (ATX) inhibitors, hybrid strategy was utilized by assembling the benzyl carbamate fragment in PF-8380 onto the imidazo[1,2-a]pyridine skeleton of GLPG-1690. The piperazine moiety in GLPG-1690 was replaced with phenyl ring to enhance the π-π interactions with adjacent residues. In the light of FS-3 based ATX enzymatic assay, further structure-guided optimizations were implemented by exploring the substituents within the carbamate aromatic moiety and examining the effect of the 2-ethyl. Eventually, 13c bearing 1,3-benzodioxole and 2-hydroxyethyl piperazine group was identified as a powerful ATX inhibitor with an IC50 value of 2.7 nM. Subsequently, 13c was forwarded into an in vivo bleomycin-induced mice lung fibrosis model. In histopathological and immunohistochemical assays, 13c could typically alleviate the severity of fibrosis tissues and effectively reduce the deposition of fibrotic biomarker α-SMA. At a dose of 60 mg/kg, 13c was observed equivalent or even better potency than GLPG-1690 with a significant inhibition of the in vivo ATX activity. Except for the fundamental H-bond and π-π interactions, an extra H-bond between the 1,3-benzodioxole (O atom) and Phe306 offered great rationale in constraining the binding conformation of 13c. Finally, binding free energy calculation was conducted to assist in the efficient identification of allosteric ATX inhibitors.