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Abnormal aggregation of α-synuclein is a key element in the pathogenesis of several neurodegenerative diseases, including Parkinsons disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-synuclein aggregation spreads through various brain regions during the course of disease progression, a propagation that is thought to be mediated by the secretion and subsequent uptake of extracellular α-synuclein aggregates between neuronal cells. Thus, aggregated forms of this protein have emerged as promising targets for disease-modifying therapy for PD and related diseases. Here, we generated and characterized conformation-specific antibodies that preferentially recognize aggregated forms of α-synuclein. These antibodies promoted phagocytosis of extracellular α-synuclein aggregates by microglial cells and interfered with cell-to-cell propagation of α-synuclein. In an α-synuclein transgenic model, passive immunization with aggregate-specific antibodies significantly ameliorated pathological phenotypes, reducing α-synuclein aggregation, gliosis, inflammation, and neuronal loss. These results suggest that conformation-specific antibodies targeting α-synuclein aggregates are promising therapeutic agents for PD and related synucleinopathies.

Simple Summary: Treatment resistant recurrent disease is the main cause of death in patients diagnosed with ovarian cancer. The aim of this study is to better understand the mechanisms of chemoresistance, which can be targeted to improve therapeutic efficacy of current therapies in ovarian cancer. We identified SORL1 as a gene promoting drug resistance in recurrent ovarian cancer. We demonstrated the molecular mechanism by which SORL1 enhances cancer cell proliferation and platinum resistance through stabilizing the receptors of several growth factors. Therapeutic agents targeting SORL1 and its related pathways have potential to overcome the platinum resistance of recurrent ovarian cancer. Recurrent tumors that are resistant to conventional chemotherapy are a major challenge of ovarian cancer treatment. A better understanding of the underlying molecular mechanisms of chemoresistance is critical for developing more effective targeted therapies for ovarian cancer. In this study, we analyzed the transcriptomic profiles of thirteen pairs of matching primary and recurrent ovarian cancers to identify genes that were upregulated in the recurrent tumors. Among these genes, we identified sortilin-related receptor 1 (SORL1) and its role in promoting carboplatin resistance through regulating the stability of epidermal growth factor receptor (EGFR) and fibroblast growth receptor 4 (FGFR4) using ovarian cancer models in vitro and in vivo. We further identified that an anti-SORL1 antibody inhibited the pro-tumor functions of SORL1. Our data showed that a selective inhibitor of FGFR4, FGF401, can improve the therapeutic efficacy of carboplatin in a xenograft mouse model of ovarian cancer. This study has demonstrated the therapeutic potential of targeting the SORL1/FGFR4 pathway to improve the chemoresponse of patients with recurrent and/or resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Perovskite solar cells (PSCs) characterized by high energy conversion efficiency (ECE) and low manufacturing costs, exhibit promising potential for commercialization in the near term. For commercialization, it is very important to prevent the decomposition of perovskite by ultraviolet (UV) radiation in the air environment. Also, the mesoscopic architecture of PSCs presents considerable opportunities for the solar cell industry, offering potential for recycling of spent photocatalytic materials such as TiO2, and exploration of new energy resources. To solve these problems, therefore, this study introduces a strategy to mitigate these challenges using a crystalline Al-doped TiO2 buffer layer as the electron transport layer (ETL) in conjunction with a mesoporous TiO2 layer in the fabrication of PSCs. Among various Al concentrations in the crystalline Al-doped TiO2 buffer layer fabricated via spin-coating, an optimum concentration of 7 mol% Al yielded the highest cell performance in the specific perovskite solar cell structure. These solar cells exhibited an impressive ECE of 11.87%, representing a substantial enhancement of nearly double the ECE (6.37%) achieved with the conventional ETL. This remarkable improvement can be attributed to the passivation effect of the newly developed ETL, which combines a crystalline Al-doped TiO2 buffer layer with a mesoporousTiO2 layer. Electrochemical impedance spectroscopy (EIS) analysis was performed in conjunction with theoretical calculations of charge transport parameters to substantiate this claim. [ABSTRACT FROM AUTHOR]

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

This paper provides an ex‐post impact assessment of the Russian invasion of Ukraine on international grain and oilseed trade. We use a commodity‐level empirical model to assess the counterfactual trade effects and evaluate the region‐specific global trade reallocation effects. We find that grain and oilseed imports from Ukraine were 78.2% below the counterfactual between February and July 2022. The Russia–Ukraine war caused substantial trade diversion, mainly benefiting countries in North America and Europe. The adjustment of global grain and oilseed trade operates primarily through price adjustments, with considerable heterogeneity across commodity groups. Our ex‐ante analysis demonstrates that the Ukraine–Russia war had substantial trade implications for the directly involved countries but only limited ones for the global grain and oilseed markets in terms of traded quantity. [ABSTRACT FROM AUTHOR]