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Abstract Depression is a leading cause of mortality and morbidity. Selective serotonin reuptake inhibitors, such as fluoxetine, are the most commonly prescribed antidepressant medication. SSRIs produce their therapeutic effects by elevating extracellular concentrations of serotonin. Although this elevation occurs rapidly, there is a paradoxical delay of weeks-to-months of continuous treatment before most patients experience meaningful relief of their depressive symptoms. Here, we address the effects of chronic fluoxetine treatment and prolonged elevation of serotonin in the rat hippocampus. Previous work has shown that acute administration of fluoxetine rapidly potentiates the excitatory temporoammonic synapse onto CA1 pyramidal cells in the hippocampus via activation of serotonin 1B receptor in brain slices. In contrast to observations in brain slices, we report here that prolonged administration of fluoxetine was required to produce significant changes in temporoammonic-CA1 synaptic strength in ex vivo brain slices. Evidence of potentiation included increases in the ratio of AMPA receptor-to NMDA receptor-mediated temporoammonic-CA1 synaptic responses, occlusion of electrically evoked long-term potentiation, enhanced long-term depression, impaired anpirtoline-mediated potentiation, and impaired memory recall in the Morris water maze task. These synaptic and behavioral changes coincided with the alleviation of anhedonic behavioral state. We conclude that the effects of elevated serotonin accumulate slowly in vivo and may account for the delay to relief of depressive symptoms by selective serotonin reuptake inhibitors. Acceleration of this process should lead to faster therapeutic responses to antidepressants. Highlights • Fluoxetine potentiates hippocampal excitatory synapses in brain slices rapidly. • Chronic fluoxetine in vivo increases synaptic strength in ex vivo slices slowly. • Chronic fluoxetine occludes long-term potentiation and favors long-term depression. • Chronic fluoxetine impairs long-term memory consolidation in the Morris water maze. • Serotonin's synaptic effects are slow, contributing to slow therapeutic benefits. [ABSTRACT FROM AUTHOR]

Hemispheric asymmetry has been reported for global-local processing in young and older adults, with global processing specialised in the right hemisphere (RH-global specialisation) and local processing specialised in the left hemisphere (LH-local specialisation). Questions persist regarding the extent to which hemispheric asymmetry is influenced by stimulus category (verbal stimuli processed in the left hemisphere; visuospatial stimuli processed in the right hemisphere). Some evidence suggests stimulus category does not influence hemispheric asymmetry (stimulus-independent account) while other evidence suggests it does (stimulus-dependent account). In older adults, there is evidence of a local-processing advantage, believed to result from slower and less accurate performance in right-hemisphere compared to left-hemisphere functioning-the right-hemisphere ageing hypothesis. We examined hemispheric asymmetry for global-local processing in young and older participants with three hierarchical figures (letters, verbalisable objects, and nonverbalisable shapes), in a within-subjects design using a divided-attention paradigm and unilateral presentation. Our findings for letters and verbalisable objects support the stimulus-independent account-young and older participants demonstrated RH-global specialisation and LH-local specialisation regardless of stimulus category. In older participants, we also found a local-processing advantage for all three stimulus categories-an advantage best explained as faster and more accurate performance in local processing regardless of the visual field of stimulus presentation. Overall, we found hemispheric asymmetry for global-local processing in both young and older adults, and differences in global processing between young and older adults. Future investigation is suggested for the hemispheric asymmetry found in global-local processing of nonverbalisable shapes, and the mechanisms underlying age-related changes in global processing., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct demyelinating disease of the central nervous system. Immunoglobulin (Ig) has been used as a maintenance therapy to prevent relapses in MOGAD, but the impact of Ig on serum MOG-IgG titers is unclear., Objective: To characterize the variation in serum MOG-IgG titers after initiation of Ig treatment in people with MOGAD., Methods: We conducted a retrospective study of 10 patients with a diagnosis of MOGAD and available serum MOG-IgG titers before and after initiation of maintenance Ig treatment., Results: We found that most of the patients remained MOG-IgG seropositive while on Ig treatment with a reduced or unchanged titer, despite a lack of disease activity., Conclusions: This case series suggests that the mechanism of action of Ig therapy in MOGAD is not exclusively dependent on MOG-IgG titer reduction., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.R. has served on scientific advisory boards for Horizon Therapeutics. E.V., P.B., G.A., H.C., W.S., A.K., and I.K. have nothing to disclose. E.S.S. has received speaker honoraria from Alexion and Viela Bio, and has served on scientific advisory boards for Alexion, Viela Bio, Horizon Therapeutics, and Genentech.

In this study, we investigated the functional role of eukaryotic initiation factor 5B (EIF5B) in hepatocellular carcinoma (HCC) and the underlying mechanisms. Bioinformatics analysis demonstrated that the EIF5B transcript and protein levels as well as the EIF5Bcopy number were significantly higher in the HCC tissues compared with the non-cancerous liver tissues. Down-regulation of EIF5B significantly decreased proliferation and invasiveness of the HCC cells. Furthermore, EIF5B knockdown suppressed epithelial-mesenchymal transition (EMT) and the cancer stem cell (CSC) phenotype. Down-regulation of EIF5B also increased the sensitivity of HCC cells to 5-fluorouracil (5-FU). In the HCC cells, activation of the NF-kappa B signaling pathway and IkB phosphorylation was significantly reduced by EIF5B silencing. IGF2BP3 increased the stability of the EIF5B mRNA in an m6A-dependent manner. Our data suggested that EIF5B is a promising prognostic biomarker and therapeutic target in HCC., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2022 Li et al.)

AMPA receptor (AMPAR) mobility within synapses has been extensively studied in vitro However, whether similar mobility properties apply to AMPARs in vivo has yet to be determined. Here, we use two-photon fluorescence recovery after photobleaching (FRAP) to study AMPAR mobility within individual dendritic spines in live animals using an overexpression vector. We demonstrate the existence of mobile and immobile fractions of AMPARs across multiple cortical regions and layers. Additionally, we find that AMPAR mobility can be altered in vivo in response to administration of corticosterone, a condition that mimics exposure to stress., (Copyright © 2021 Chen et al.)

Background: Peanut is one of the primary sources for vegetable oil worldwide, and enhancing oil content is the main objective in several peanut breeding programs of the world. Tightly linked markers are required for faster development of high oil content peanut varieties through genomics-assisted breeding (GAB), and association mapping is one of the promising approaches for discovery of such associated markers., Results: An association mapping panel consisting of 292 peanut varieties extensively distributed in China was phenotyped for oil content and genotyped with 583 polymorphic SSR markers. These markers amplified 3663 alleles with an average of 6.28 alleles per locus. The structure, phylogenetic relationship, and principal component analysis (PCA) indicated two subgroups majorly differentiating based on geographic regions. Genome-wide association analysis identified 12 associated markers including one (AGGS1014_2) highly stable association controlling up to 9.94% phenotypic variance explained (PVE) across multiple environments. Interestingly, the frequency of the favorable alleles for 12 associated markers showed a geographic difference. Two associated markers (AGGS1014_2 and AHGS0798) with 6.90-9.94% PVE were verified to enhance oil content in an independent RIL population and also indicated selection during the breeding program., Conclusion: This study provided insights into the genetic basis of oil content in peanut and verified highly associated two SSR markers to facilitate marker-assisted selection for developing high-oil content breeding peanut varieties.

Key Message: Two novel and adjacent genomics and candidate genes for bacterial wilt resistance were identified on chromosome B02 in peanut variety Zhonghua 6 using both traditional QTL mapping and QTL-seq methods. Peanut (Arachis hypogaea) is an important oilseed crop worldwide. Utilization of genetic resistance is the most economic and effective approach to control bacterial wilt, one of the most devastating plant diseases, in peanut production. To accelerate the genetic improvement of bacterial wilt resistance (BWR) in peanut breeding programs, quantitative trait locus (QTL) mapping has been conducted for two resistant varieties. In this context, we deployed linkage mapping as well as sequencing-based mapping approach, QTL-seq, to identify genomic regions and candidate genes for BWR in another highly resistant variety Zhonghua 6. The recombination inbred line population (268 progenies) from the cross Xuhua 13 × Zhonghua 6 was used in BWR evaluation across five environments. QTL mapping using both SSR- and SNP-based genetic maps identified a stable QTL (qBWRB02-1) on chromosome B02 with 37.79-78.86% phenotypic variation explained (PVE) across five environments. The QTL-seq facilitated further dissection of qBWRB02-1 into two adjacent genomic regions, qBWRB02-1-1 (2.81-4.24 Mb) and qBWRB02-1-2 (6.54-8.75 Mb). Mapping of newly developed Kompetitive allele-specific PCR (KASP) markers on the genetic map confirmed their stable expressions across five environments. The effects of qBWRB02-1-1 (49.43-68.86% PVE) were much higher than qBWRB02-1-2 (3.96-6.48% PVE) and other previously reported QTLs. Nineteen putative candidate genes affected by 49 non-synonymous SNPs were identified for qBWRB02-1-1, and ten of them were predicted to code for disease resistance proteins. The major and stable QTL qBWRB02-1-1 and validated KASP markers could be deployed in genomics-assisted breeding (GAB) to develop improved peanut varieties with enhanced BWR.

Clinical named entity recognition (CNER), which intends to automatically detect clinical entities in electronic health record (EHR), is a committed step for further clinical text mining. Recently, more and more deep learning models are used to Chinese CNER. However, these models do not make full use of the information in EHR, for these models are either word-based or character-based. In addition, neural models tend to be locally unstable and even tiny perturbation may mislead them. In this paper, we firstly propose a novel adversarial training based lattice LSTM with a conditional random field layer (AT-lattice LSTM-CRF) for Chinese CNER. Lattice LSTM is used to capture richer information in EHR. As a powerful regularization method, AT can be used to improve the robustness of neural models by adding perturbations to the training data. Then, we conduct experiments on the proposed neural model with dataset of CCKS-2017 Task 2. The results show that the proposed model achieves a highly competitive performance (with an F1 score of 89.64%) compared to other prevalent neural models, which can be a reinforced baseline for further research in this field., (Copyright © 2019. Published by Elsevier Inc.)

The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC., (Copyright © 2017. Published by Elsevier Masson SAS.)

Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency., Competing Interests: The authors declare no competing financial interests.