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The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy. [ABSTRACT FROM AUTHOR]

Land use and land cover changes (LULCCs) can influence surface temperature through local and nonlocal biophysical processes, which remain inadequately addressed. In this study, we separate the local and nonlocal effects of historical (1850–2014) LULCCs based on model outputs from the Coupled Model Intercomparison Project Phase 6. We also attempt to explore the sources of intermodel differences in the effects of LULCCs. The multimodel mean shows a cooling effect of −0.05°C (with an intermodel range of −0.24–0.06°C) at the global scale due to cropland and pastureland expansion, consisting of dominant nonlocal cooling of −0.06°C (with an intermodel range of −0.26–0.06°C) and slight local warming of 0.01°C (with an intermodel range of −0.01–0.05°C). The modeling results show some clear consistency in the effects of LULCCs despite considerable intermodel uncertainties. The local effects cause warming at low latitudes and cooling in boreal regions via changes in upward shortwave radiation and sensible and latent heat fluxes. The nonlocal effects mainly cause cooling via decreases in downward longwave radiation and increases in upward shortwave radiation. Intermodel differences in the total effects are dominated by those in the nonlocal effects, which are further attributed to divergent changes in downward longwave radiation and sensible heat flux across the models. This study highlights the importance of the nonlocal effects of LULCCs in terms of strength and intermodel uncertainty, with implications for designing land‐based solutions aimed at climate change mitigation. Plain Language Summary: Land use and land cover changes (LULCCs) can alter surface properties and thereby influence surface temperature through land–atmosphere interactions. LULCCs influence the climate not only at the location of LULCCs (local effects) but also elsewhere (nonlocal effects) through atmospheric and oceanic feedbacks. However, the local and nonlocal effects of realistic LULCCs still lack explicit investigation. In this study, we quantify the local and nonlocal effects of historical (1850–2014) LULCCs and their intermodel differences based on a set of simulations from four earth system models. The multimodel mean suggests that historical cropland and pastureland expansion has caused a nonlocal cooling effect of −0.06°C and a local warming effect of 0.01°C, creating a net cooling effect of −0.05°C at the global scale. The local and nonlocal effects of LULCCs can be attributed to changes in surface fluxes and atmospheric feedbacks, whereas the strength and sign vary substantially across the models. Large intermodel differences in the total effects of LULCCs mostly result from those in the nonlocal effects. This study highlights the importance of the nonlocal effects of LULCCs and has implications for developing land‐use strategies aimed at climate change mitigation. Key Points: The local and nonlocal biophysical effects of historical land use and land cover changes (LULCCs) are investigated using CMIP6 modelsThe multimodel mean shows that, overall, historical LULCCs cool the land surface through nonlocal processesThe intermodel divergence in the total effects of historical LULCCs mainly results from low intermodel agreement on the nonlocal effects [ABSTRACT FROM AUTHOR]

Mercury (Hg), a potent neurotoxin posing risks to human health, is cycled through vegetation uptake, which is susceptible to climate change impacts. However, the extent and pattern of these impacts are largely unknown, obstructing predictions of Hg's fate in terrestrial ecosystems. Here, we evaluate the effects of climate change on vegetation elemental Hg [Hg(0)] uptake using a state-of-the-art global terrestrial Hg model (CLM5-Hg) that incorporates plant physiology. In a business-as-usual scenario, the terrestrial Hg(0) sink is predicted to decrease by 1870 Mg yr−1 in 2100, that is ~60% lower than the present-day condition. We find a potential decoupling between the trends of CO2 assimilation and Hg(0) uptake process by vegetation in the 21st century, caused by the decreased stomatal conductance with increasing CO2. This implies a substantial influx of Hg into aquatic ecosystems, posing an elevated threat that warrants consideration during the evaluation of the effectiveness of the Minamata Convention. The uptake of gaseous elementary mercury by terrestrial vegetation in 2100 is likely to decrease by more than half compared to present-day conditions. This decrease is caused by the reduced stomatal conductance associated with increasing CO2 levels. [ABSTRACT FROM AUTHOR]

Eel (Anguilla sp.) is an important freshwater‐cultured species with high economic value in China. Anguillid herpesvirus 1 (AngHV‐1) has been proven to be the pathogen of "mucus sloughing and haemorrhagic septicaemia disease" in eels, resulting in significant mortality and substantial losses to the eel industry. Current diagnostic methods for detecting AngHV‐1 are limited to laboratory‐based tests, for example, conventional end‐point PCR and qPCR. Therefore, there is an urgent need to develop an accurate, rapid, and simple detection method for on‐site diagnosis of AngHV‐1. In this study, we developed a recombinase‐aided amplification combined lateral flow dipstick (RAA‐LFD) assay for the detection of AngHV‐1. The RAA‐LFD assay can be performed within a temperature range of 18–45°C, with a reaction time of just 10 min for amplification. Importantly, the established RAA‐LFD assay exhibited no reactivity with other common aquatic viral pathogens, indicating its high specificity. The limit of detection for this method is 102 copies of AngHV‐1, which is more sensitive than the established conventional end‐point PCR method similarly targeting ORF95. Clinical detection of the diseased samples demonstrated that the accuracy of RAA‐LFD was significantly higher than that of the conventional end‐point PCR. In conclusion, the developed RAA‐LFD assay has proven to be a convenient, rapid, sensitive, and reliable tool for on‐site diagnosis of AngHV‐1. This advancement will be invaluable for the prevention and control of AngHV‐1 in the eel farming industry. [ABSTRACT FROM AUTHOR]