Discovery of novel benzimidazole derivatives as selective and reversible monoamine oxidase B inhibitors for Parkinson's disease treatment.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC50 value of 67.3 nM, comparable to safinamide (IC50 = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (Ki = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.

Comprehensive safety evaluation of a novel multitargeting compound XYY-CP1106: A candidate for Alzheimer's disease.

Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering the complexity of molecular mechanisms in AD pathology. In most pre-clinical studies, the effectiveness of these multi-targeted anti-AD drugs has been demonstrated but comprehensive safety assessments are lacking. Here, the safety evaluation of a novel multi-targeted candidate in AD (XYY-CP1106), characterized by its dual-property of iron chelation and monoamine oxidase B inhibition, was conducted by multifaceted analysis. Acute toxicity in mice was conducted to investigate the safety of oral administration and the maximum tolerated dose of the agent. In vitro Ames analysis, CHL chromosomal aberration analysis, and bone marrow micronucleus analysis were executed to evaluate the genotoxicity. A teratogenesis investigation in pregnant mice were meticulously performed to evaluate the teratogenesis of XYY-CP1106. Furthermore, a 90-day long-term toxicity analysis in rats was investigated to evaluate the cumulative toxicity after long-term administration. Strikingly, no toxic phenomena were found in all investigations, demonstrating relatively high safety profile of the candidate compound. The securing of safety heightened the translational significance of XYY-CP1106 as a novel multi-targeted anti-AD candidate, supporting the rationality of multitargeting strategy in the designs of smart anti-AD drugs.

Soil bacterial community characteristics and its effect on organic carbon under different fertilization treatments.

Introduction: By implementing small-scale and efficient fertilization techniques, it is possible to enhance the activity of microorganisms, thereby improving soil carbon sequestration and ecological value in agriculture. Methods: In this study, field experiments were conducted using various types of fertilizers: organic fertilizer, microbial fungal fertilizer, composite fertilizer, and an unfertilized control (CK). Additionally, different dosages of compound fertilizers were applied, including 0.5 times compound fertilizers, constant compound fertilizers, 1.5 times compound fertilizers and CK. Using advanced technologies such as Illumina MiSeq high-throughput sequencing, PICRUSt2 prediction, Anosim analysis, redundancy analysis, canonical correlation analysis, and correlation matrix, soil organic carbon (SOC) content and components, bacterial diversity, metabolic functions, and interaction mechanisms were examined in different fields. Results and Discussion: The results showed pronounced effects of various fertilization modes on SOC and the bacterial community, particularly in the topsoil layer (0-20 cm). Organic fertilizer treatments increased the richness and diversity of bacterial communities in the soil. However, conventional doses and excessive application of compound fertilizers reduced the diversity of soil bacterial communities and SOC content. Additionally, different fertilization treatments led to an increase in easily oxidizable organic carbon (EOC) contents. Interestingly, the relationship between SOC components and soil bacteria exhibited inconsistency. EOC was positively correlated with the bacterial diversity index. Additionally, Chloroflexi exhibited a negative correlation with both SOC and its components. The influence of metabolismon primary metabolic functions on the content of SOC components in the soil was more notable. It included seven types of tertiary functional metabolic pathways significantly correlated with SOC components (p < 0.05). Purpose and Significance: These findings enhance the understanding of the relative abundance of bacterial communities, particularly those related to the carbon cycle, by adjusting agricultural fertilization patterns. This adjustment serves as a reference for enhancing carbon sinks and reducing emissions in agricultural soils.

Quantified impacts of international trade on the United States' carbon intensity.

After the USA reached its carbon emission peak in 2007, the share of carbon emissions from its energy activities showed a downward trend. As a country that accounts for even close to 80% of the tertiary industry, the final demands from other industries are usually met by other countries in the form of international trade. While trade is realizing economic transfer, it also realizes the transfer of carbon emissions to a certain extent, helping the country achieve the peaks. From the perspective of combining carbon emission transfer and economic transfer, are there transfers and impacts? In this study, the quantified impact of international trade on the USA's carbon intensity has been investigated by a novel framework, based on a porposed scenario analysis using MRIO. As it gets lower aggregate carbon intensity value under trade scenario, it concludes that international trade is more conducive to the needs of this country for carbon emission reduction and economic development in general. From the different trade patterns, all of them get lower carbon intensity values under trade than no-trade scenario. From trade partners' perspectives, the positive and negative of the intensity gap cannot be kept uniform for all traders. Sectoral driving factors are decomposed by LMDI method, with the sectoral effect of aggrerate value-added structure and sectoral aggregate embodied carbon intensity. Among obvious carbon-intensive sectors, transport sectors always show a negative effect for the gap, and heavy manufacturing and electricity sectors usually give positive effects. As a major trading country in the world, trade and exchanges with other countries are more conducive to this country with a lower carbon intensity, and it also requires the country to shoulder coresponding responsiblities as a great power while enjoying the benefies. It is conducive to the further strengthening of unity of the international community, to jointly address the challenges of climate change and achieve the subsequent carbon neutral targets.

Efficient and sustainable phosphate removal from water by small-sized Al(OH)3 nanocrystals confined in discarded Artemia Cyst-shell: Ultrahigh sorption capacity and rapid sequestration.

We reported a new strategy for efficient phosphate removal from wastewaters, it relies on the discarded Artemia Cyst-shell in-situ growth of Al(OH)3 nanocluster, the charged amino-acids components of skeleton make available for the small size of Al(OH)3 formation (< 10 nm) with high activity, and the three-dimensional porous structure of discarded matrix provides fast kinetics and efficient Al(OH)3 nanoparticles utilization. These hybrid adsorbents exhibit ultrahigh capacity (850.5 mg/g) and fast kinetics (~2 min) by recent ten-years (2011-2020) survey, the superior selectivity against various foreign ions, with a distribution coefficient (Kd) as high as 4820 mL/g, the porous structure and fast kinetics also accelerate the phosphate accessibility, yielding a satisfactory capacity of ~3000 L/kg sorbent (Artemia CS-Al) for the application, even varying at high feeding-speeds. The saturated adsorbent can be readily regenerated and reused without decrease in performance, this technology is promising for mitigating the contamination problem of excess phosphate worldwide.

Rhoifolin Alleviates Inflammation of Acute Inflammation Animal Models and LPS-Induced RAW264.7 Cells via IKKß/NF-κB Signaling Pathway.

Rhoifolin (ROF) is a main effective component in Citrus grandis 'Tomentosa'. ROF has a potential anti-inflammatory activity, but its specific effects and mechanisms have not been studied. This study investigated the anti-inflammatory activity of ROF and searched for its possible molecular mechanisms. A mouse model of acute inflammation was induced by lipopolysaccharide, and the effects of ROF on pathological damages of the lung and liver were observed. Carrageenan-induced paw edema rat model was used to evaluate the effect of ROF on the volume of swelling paw. In LPS-induced RAW264.7 macrophages, the expression levels of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α were measured using ELISA. Real-time PCR was used to measure the mRNA levels of iNOS and CCL2. Western blot was used to detect the activation of IκBα and IKKß in NF-κB signaling pathways. The results showed that ROF accelerated the recoveries of liver and lung tissue damages in acute inflammation mice and inhibited carrageenan-induced paw edema in rats; in addition, ROF significantly suppressed the secretion of TNF-α, IL-1ß, and IL-6 in the serum of rats and mouse model. In LPS-induced RAW264.7 cells, 100 µmol/L ROF enhanced cell viability and suppressed the production of TNF-α, IL-6, and IL-1ß significantly. ROF also decreased the mRNA expression of iNOS and CCL2 and inhibited IκBα and IKKß phosphorylation. In summary, ROF had a potential therapeutic value for inflammation. Our research provided experimental basis for the further development of ROF as an anti-inflammatory drug and for clarifying the anti-inflammatory substance basis of Citrus grandis 'Tomentosa'. Graphical Abstract.

China's coal consumption in a globalizing world: Insights from Multi-Regional Input-Output and structural decomposition analysis.

The growth of global carbon emissions is largely driven by coal-burning in China. China has consumed approximately half of global coal; as such, limiting its coal demand is important for curbing carbon emissions in the country and around the world. Developing effective approaches to limit China's coal demand requires comprehensively understanding the trajectory and drivers shaping its coal footprint in the globalized world. Past studies have investigated production-based coal consumption within China's sovereign territory boundary, but have not addressed consumption-based coal consumption and the globalization background. To fill this research gap, this study conducted a multi-regional input-output analysis - structural decomposition analysis to analyze China's coal footprint in a globalized world. The results show a continued rise in the influence of globalization on China's coal consumption, despite the 1997 Asian financial crisis and 2008-09 global economic crisis lowering of global trade. The percentage of other countries' coal demand on China's production-based coal footprint increased from 20% in 1995 to nearly 30% in 2011, through a global transfer of virtual coal through trade. Virtual coal refers to the coal consumed to support production activities. Meanwhile, the impact of other countries' coal supply on China's consumption-based coal footprint increased from less than 2% in 1995 to more than 4% in 2011. However, the decomposition results showed that domestic demand was the leading contributor to Chinese production-based and consumption-based coal footprint. This was offset by the domestic coal intensity effect. To cut China's coal, strategies to cap its total coal consumption should be considered in a globalized world. Improving energy intensity is an effective approach for the country; China should be leveraging the globalized world, rather than serving as the world's factory through high coal consumption and exports.

Differential proteomic analysis revealing the ovule abortion in the female-sterile line of Pinus tabulaeformis Carr.

Ovule abortion affects the yield and quality of Pinus tabulaeformis Carr. seeds. Research into ovule abortion has importance for improving the seed setting rate and establishing artificial seed production techniques. Fertile line (FL) ovules (FL-E) and sterile line (SL) ovules (SL-E) in the early stage of free nuclear mitosis of megagametophyte (FNMM), FL ovules (FL-L) and SL ovules (SL-L) in the late stage of FNMM of P. tabulaeformis were collected as materials. 4192 proteins were identified by isobaric tags for relative and absolute quantitation (iTRAQ)-based analysis. Bioinformatics analysis implied that in SL ovules, substances and energy might be deficient, perhaps leading to abnormal DNA replication. Because the incomplete antioxidant system and the abnormal expression levels of enzymes involved in cell signal transduction, DNA DSBs probably occurs. Facing the abnormities of DNA replication and damage, the cell cycle was arrested and the DNA damage failed to be repaired, potentially resulting in the occurrence of PCD. Taken together, an inference can be drawn from our study - substance and energy deficiencies, reactive oxygen stress, and the failure of both cell cycle progression and DNA damage repair, which possibly hinder FNMM, leading to ovule abortion in the female-sterile line of P. tabulaeformis.

An 8-GW long-pulse generator based on Tesla transformer and pulse forming network.

A long-pulse generator TPG700L based on a Tesla transformer and a series pulse forming network (PFN) is constructed to generate intense electron beams for the purpose of high power microwave (HPM) generation. The TPG700L mainly consists of a 12-stage PFN, a built-in Tesla transformer in a pulse forming line, a three-electrode gas switch, a transmission line with a trigger, and a load. The Tesla transformer and the compact PFN are the key technologies for the development of the TPG700L. This generator can output electrical pulses with a width as long as 200 ns at a level of 8 GW and a repetition rate of 50 Hz. When used to drive a relative backward wave oscillator for HPM generation, the electrical pulse width is about 100 ns on a voltage level of 520 kV. Factors affecting the pulse waveform of the TPG700L are also discussed. At present, the TPG700L performs well for long-pulse HPM generation in our laboratory.