The Neuropharmacology of (-)-Stepholidine and its Potential Applications

(-)-Stepholidine (SPD), a natural product isolated from the Chinese herb Stephania, possesses dopamine (DA) D1 partial agonistic and D2 antagonistic properties in the nigrostriatal and mesocorticolimbic DAergic pathways. These unique dual effects have suggested that SPD can effectively restore previously imbalanced functional linkage between D1 and D2 receptors under schizophrenic conditions, in which, SPD improves both the negative and positive symptoms of schizophrenia. SPD also relieves the motor symptoms of Parkinson’s disease (PD) when co-administered with Levodopa. Furthermore, SPD exhibits neuroprotective effects through an antioxidative mechanism and slows down the progression of neuronal degeneration in the substantia nigra (SN) of PD patients and/or animal models. Therefore, SPD is a novel, natural compound with potentially therapeutic roles in the treatment of schizophrenia and/or PD

Generative Retrieval with Semantic Tree-Structured Item Identifiers via Contrastive Learning

The retrieval phase is a vital component in recommendation systems, requiring the model to be effective and efficient. Recently, generative retrieval has become an emerging paradigm for document retrieval, showing notable performance. These methods enjoy merits like being end-to-end differentiable, suggesting their viability in recommendation. However, these methods fall short in efficiency and effectiveness for large-scale recommendations. To obtain efficiency and effectiveness, this paper introduces a generative retrieval framework, namely SEATER, which learns SEmAntic Tree-structured item identifiERs via contrastive learning. Specifically, we employ an encoder-decoder model to extract user interests from historical behaviors and retrieve candidates via tree-structured item identifiers. SEATER devises a balanced k-ary tree structure of item identifiers, allocating semantic space to each token individually. This strategy maintains semantic consistency within the same level, while distinct levels correlate to varying semantic granularities. This structure also maintains consistent and fast inference speed for all items. Considering the tree structure, SEATER learns identifier tokens' semantics, hierarchical relationships, and inter-token dependencies. To achieve this, we incorporate two contrastive learning tasks with the generation task to optimize both the model and identifiers. The infoNCE loss aligns the token embeddings based on their hierarchical positions. The triplet loss ranks similar identifiers in desired orders. In this way, SEATER achieves both efficiency and effectiveness. Extensive experiments on three public datasets and an industrial dataset have demonstrated that SEATER outperforms state-of-the-art models significantly.Comment: 8 main pages, 3 pages for appendi

Functional Nicotinic Acetylcholine Receptors Containing α6 Subunits Are On Gabaergic Neuronal Boutons Adherent To Ventral Tegmental Area Dopamine Neurons

Diverse nicotinic acetylcholine receptor (nAChR) subtypes containing different subunit combinations can be placed on nerve terminals or soma/dendrites in the ventral tegmental area (VTA). nAChR α6 subunit message is abundant in the VTA, but α6*-nAChR cellular localization, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons within the VTA are not well understood. Here, we report evidence for α6β2*-nAChR expression on GABA neuronal boutons terminating on VTA DA neurons. α-Conotoxin (α-Ctx) MII labeling coupled with immunocytochemical staining localizes putative α6*-nAChRs to presynaptic GABAergic boutons on acutely dissociated, rat VTA DA neurons. Functionally, acetylcholine (ACh) induces increases in the frequency of bicuculline-, picrotoxin-, and 4-aminopyridine-sensitive miniature IPSCs (mIPSCs) mediated by GABAA receptors. These increases are abolished by α6*-nAChR-selective α-Ctx MII or α-Ctx PIA (1 nM) but not by α7 (10 nM methyllycaconitine) or α4* (1 μM dihydro-β-erythroidine)-nAChR-selective antagonists. ACh also fails to increase mIPSC frequency in VTA DA neurons prepared from nAChR β2 knock-out mice. Moreover, ACh induces an α-Ctx PIA-sensitive elevation in intraterminal Ca2+ in synaptosomes prepared from the rat VTA. Subchronic exposure to 500 nM nicotine reduces ACh-induced GABA release onto the VTA DA neurons, as does 10 d of systemic nicotine exposure. Collectively, these results indicate that α6β2*-nAChRs are located on presynaptic GABAergic boutons within the VTA and modulate GABA release onto DA neurons. These presynaptic α6β2*-nAChRs likely play important roles in nicotinic modulation of DA neuronal activity. Copyright © 2011 the authors

Functional presynaptic [alpha]6-containing nicotinic acetylcholine receptors participate in nicotine reward in the VTA: where and how

In the ventral tegmental area (VTA), [alpha]6-nAChRs express abundantly, but their location, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons remain elusive. Using a VTA neuron-adherent bouton preparation, we report that functional [alpha]6-nAChRs are located on GABAergic presynaptic boutons, where they mediate cholinergic modulation of GABA release onto DA neurons. Smoking-relevant concentrations of nicotine desensitize [alpha]6-nAChRs, cause a disinhibition in DA neurons and consequently mediate nicotine reward

Simple Synthesis and Growth Mechanism of Core/Shell CdSe/ SiO

Core-shell-structured CdSe/SiOx nanowires were synthesized on an equilateral triangle Si (111) substrate through a simple one-step thermal evaporation process. SEM, TEM, and XRD investigations confirmed the core-shell structure; that is, the core zone is single crystalline CdSe and the shell zone is SiOx amorphous layer and CdSe core was grown along (001) direction. Two-stage growth process was present to explain the growth mechanism of the core/shell nanwires. The silicon substrate of designed equilateral triangle providing the silicon source is the key factor to form the core-shell nanowires, which is significant for fabrication of nanowire-core sheathed with a silica system. The PL of the product studied at room temperature showed two emission bands around 715 and 560 nm, which originate from the band-band transition of CdSe cores and the amorphous SiOx shells, respectively

Influence Factors on Stress Distribution of Electric Furnace Roof

Electric furnace roof is an important device for electric steel making, whose heat preservation performance and life-span have a direct impact on the economic benefits of iron and steel enterprise. This paper investigates the effect between the stress level of electric furnace roof and the material parameters. Research indicates that they have a trend to change in the same direction

Longer-term effectiveness of a heterologous coronavirus disease 2019 (COVID-19) vaccine booster in healthcare workers in Brazil

Abstract Objective: To compare the long-term vaccine effectiveness between those receiving viral vector [Oxford-AstraZeneca (ChAdOx1)] or inactivated viral (CoronaVac) primary series (2 doses) and those who received an mRNA booster (Pfizer/BioNTech) (the third dose) among healthcare workers (HCWs). Methods: We conducted a retrospective cohort study among HCWs (aged ≥18 years) in Brazil from January 2021 to July 2022. To assess the variation in the effectiveness of booster dose over time, we estimated the effectiveness rate by taking the log risk ratio as a function of time. Results: Of 14,532 HCWs, coronavirus disease 2019 (COVID-19) was confirmed in 56.3% of HCWs receiving 2 doses of CoronaVac vaccine versus 23.2% of HCWs receiving 2 doses of CoronaVac vaccine with mRNA booster (P < .001), and 37.1% of HCWs receiving 2 doses of ChAdOx1 vaccine versus 22.7% among HCWs receiving 2 doses of ChAdOx1 vaccine with mRNA booster (P < .001). The highest vaccine effectiveness with mRNA booster was observed 30 days after vaccination: 91% for the CoronaVac vaccine group and 97% for the ChAdOx1 vaccine group. Vacine effectiveness declined to 55% and 67%, respectively, at 180 days. Of 430 samples screened for mutations, 49.5% were SARS-CoV-2 delta variants and 34.2% were SARS-CoV-2 omicron variants. Conclusions: Heterologous COVID-19 vaccines were effective for up to 180 days in preventing COVID-19 in the SARS-CoV-2 delta and omicron variant eras, which suggests the need for a second booster