Dorsal CA3 overactivation mediates witnessing stress-induced recognition memory deficits in adolescent male mice.

Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.

Fluoxetine reverses early-life stress-induced depressive-like behaviors and region-specific alterations of monoamine transporters in female mice.

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.

Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy.

Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8+ T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8+ T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8+ T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8+ T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8+ T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8+ T cell infiltration and improve ICI efficacy.

Ce-mediated molecular tailoring on gigantic polyoxometalate {Mo132} into half-closed {Ce11Mo96} for high proton conduction.

Precise synthesis of polyoxometalates (POMs) is important for the fundamental understanding of the relationship between the structure and function of each building motif. However, it is a great challenge to realize the atomic-level tailoring of specific sites in POMs without altering the major framework. Herein, we report the case of Ce-mediated molecular tailoring on gigantic {Mo132}, which has a closed structural motif involving a never seen {Mo110} decamer. Such capped wheel {Mo132} undergoes a quasi-isomerism with known {Mo132} ball displaying different optical behaviors. Experiencing an 'Inner-On-Outer' binding process with the substituent of {Mo2} reactive sites in {Mo132}, the site-specific Ce ions drive the dissociation of {Mo2*} clipping sites and finally give rise to a predictable half-closed product {Ce11Mo96}. By virtue of the tailor-made open cavity, the {Ce11Mo96} achieves high proton conduction, nearly two orders of magnitude than that of {Mo132}. This work offers a significant step toward the controllable assembly of POM clusters through a Ce-mediated molecular tailoring process for desirable properties.

[Decreased Expression of Mitochondrial Calcium Uptake Protein 1 Leads to Skeletal Muscle Dysfunction in Septic Mice].

Objective: To observe the effect of sepsis on skeletal muscle function and to explore the role of skeletal muscle mitochondrial calcium uptake protein 1 (MICU1). Methods: A total of 40 specific-pathogen-free (SPF) healthy male C57BL/6J mice were randomly assigned to 4 groups, a sham operation group (Sham group, n=8), a sepsis modeling 6 h group (cecal ligation and puncture [CLP]-6 h group, n=10), a sepsis modeling 12 h group (CLP-12 h group, n=10), and a sepsis modeling 24 h group (CLP-24 h, n=12). The sepsis model was established by CLP. Mice in the Sham group only underwent laparotomic exploration of the cecum. Another 20 SPF mice were selected. The tibialis anterior muscle on one side was empty-transfected with adeno-associated virus (AAV) as controls (AAV-C), and the tibialis anterior muscle on the other side was transfected with AAV to enhance MICU1 expression (AAV-M). The mice were randomly assigned to two groups, a sham operation group (AAV-C-Sham and AAV-M-Sham, n=8) and a sepsis model 24 h group (AAV-C-CLP and AAV-M-CLP, n=12). The grip strength and compound muscle action potential (CMAP) of the tibialis anterior muscle were measured in each group at the corresponding time points. The levels of inflammatory factors, including tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), in the skeletal muscle were measured by ELISA. The morphological changes of skeletal muscle cells were observed through H&E staining. The expression levels of MICU1 and muscle atrophy-related proteins, including muscle RING-finger containing protein 1 (MuRF1) and muscle atrophy Fbox protein (MAFbx), were determined by Western blot. The expression levels of MICU1 mRNA in skeletal muscle were determined by RT-qPCR. Results: Compared with mice in the Sham group, mice in the CLP group showed decreased body weight ( P<0.05); their grip strength decreased with the prolongation of CLP modeling time ( P<0.05); the amplitude of CMAP decreased, showing prolonged duration and latency ( P<0.05); the expression levels of inflammatory factors, including TNF-α and IL-6, in skeletal muscle increased gradually ( P<0.05); the fiber diameter and cross-sectional area of skeletal muscle decreased gradually with the prolongation of modeling time ( P<0.05); the protein expression levels of MuRF1and MAFbx proteins increased gradually ( P<0.05); the expression levels of MICU1 protein and mRNA decreased gradually ( P<0.05). There was no significant difference in all indices between AAV-M-Sham and AAV-C-Sham groups ( P>0.05). Compared with mice in the AAV-C-CLP group, mice in the AAV-M-CLP group showed increased grip strength ( P<0.05); the amplitude of CMAP increased, showing shortened duration and latency ( P <0.05); the fiber diameter and cross-sectional area of skeletal muscle increased ( P<0.05); the expression levels of MuRF1and MAFbx decreased ( P<0.05). Conclusion: Sepsis leads to skeletal muscle dysfunction, which is related to the decrease in mitochondrial MICU1 expression.

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

An unprecedented fully reduced {MoV 60} polyoxometalate: from an all-inorganic molecular light-absorber model to improved photoelectronic performance.

Fully reduced polyoxometalates are predicted to give rise to a broad and strong absorption spectrum, suitable energy levels, and unparalleled electronic and optical properties. However, they are not available to date. Here, an unprecedented fully reduced polyoxomolybdate cluster, namely Na8[MoV 60O140(OH)28]·19H2O {MoV 60}, was successfully designed and obtained under hydrothermal conditions, which is rare and is the largest fully reduced polyoxometalate reported so far. The MoV 60 molecule describes one Keggin {ε-Mo12} encapsulated in an unprecedented {Mo24} cage, giving rise to a double truncated tetrahedron quasi-nesting architecture, which is further face-capped by another four {Mo6} tripods. Its crystalline stability in air, solvent tolerance, and photosensitivity were all shown. As a cheap and robust molecular light-absorber model possessing wide light absorption, MoV 60 was applied to build a co-sensitized solar cell photoelectronic device along with N719 dyes and the optimal power conversion efficiency was 28% higher than that of single-dye sensitization. These results show that MoV 60 polyoxometalate could serve as an ideal model for the design and synthesis of all-inorganic molecular light-absorbers for other light-driven processes in the future.

Gut microbiota and diabetic kidney diseases: Pathogenesis and therapeutic perspectives.

Diabetic kidney disease (DKD) is one of the major chronic complications of diabetes mellitus (DM), as well as a main cause of end-stage renal disease. Over the last few years, substantial research studies have revealed a contributory role of gut microbiota in the process of DM and DKD. Metabolites of gut microbiota like lipopolysaccharide, short-chain fatty acids, and trimethylamine N-oxide are key mediators of microbial-host crosstalk. However, the underlying mechanisms of how gut microbiota influences the onset and progression of DKD are relatively unknown. Besides, strategies to remodel the composition of gut microbiota or to reduce the metabolites of microbiota have been found recently, representing a new potential remedial target for DKD. In this mini-review, we will address the possible contribution of the gut microbiota in the pathogenesis of DKD and its role as a therapeutic target.