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Dementia, as an advanced diabetes-associated cognitive dysfunction (DACD), has become the second leading cause of death among diabetes patients. Given that little guidance is currently available to address the DACD process, it is imperative to understand the underlying mechanisms and screen out specific therapeutic targets. The excessive endogenous fructose produced under high glucose conditions can lead to metabolic syndrome and peripheral organ damage. Although generated by the brain, the role of endogenous fructose in the exacerbation of cognitive dysfunction is still unclear. Here, we performed a comprehensive study on leptin receptor-deficient T2DM mice and their littermate m/m mice and revealed that 24-week-old db/db mice had cognitive dysfunction and excessive endogenous fructose metabolism in the hippocampus by multiomics analysis and further experimental validation. We found that the rate-limiting enzyme of fructose metabolism, ketohexokinase, is primarily localized in microglia. It is upregulated in the hippocampus of db/db mice, which enhances mitochondrial damage and reactive oxygen species production by promoting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression and mitochondrial translocation. Inhibiting fructose metabolism via ketohexokinase depletion reduces microglial activation, leading to the restoration of mitochondrial homeostasis, recovery of structural synaptic plasticity, improvement of CA1 pyramidal neuron electrophysiology and alleviation of cognitive dysfunction. Our findings demonstrated that enhanced endogenous fructose metabolism in microglia plays a dominant role in diabetes-associated cognitive dysfunction and could become a potential target for DACD. Fructose metabolism in microglia: a new player in diabetes-linked cognitive dysfunction Researchers found that the rate-limiting enzyme of fructose metabolism, ketohexokinase (KHK), is primarily localized in microglia and upregulated in the hippocampus of diabetic mice, leading to mitochondrial damage and reactive oxygen species production. Inhibiting fructose metabolism via KHK depletion reduces microglia activation, restores mitochondrial homeostasis, improves structural synaptic plasticity, and alleviates cognitive dysfunction. This study demonstrates the dominant role of enhanced endogenous fructose metabolism in microglia in the process of diabetes-associated cognitive dysfunction and suggests KHK as a potential therapeutic target for this condition.

Background: The key pathophysiological mechanism of executive dysfunction in patients with bipolar disorder type I (BD-I) is still unclear. Previous studies have demonstrated that it may be related to disbalance of the sensory motor network (SMN). Objective: This study was designed to explore the aberrant functional connectivity (FC) of SMN in BD-I patients, and its potential associations with executive dysfunction. Methods: 18 BD-I patients and 20 health controls (HC) underwent resting-state fMRI scans. The intra- and internetwork functional connectivity of SMN were extracted by independent component analysis (ICA). Clinical symptoms were assessed by the Bech-Rafaelsen Mania Rating Scale (BRMS) and Positive and Negative Syndrome Scale (PANSS). Executive function was measured by Digit span tasks and Verbal Fluency Test. Finally, linear regression and correlation analyses were applied to measure the potential associations between clinical symptoms, intra- and internetwork functional connectivity, and executive function performance. Results: (1) Patients with BD-I showed increased connectivity in the right paracentral lobule and the right postcentral gyrus within the SMN, and the increased connectivity value was positively correlated with BRMS score (P<0.05), but negatively correlated with Digit span forward scores (P<0.05); (2) Compared with HC, the connectivity value increased between SMN and dorsal attention network (DAN) (P<0.01), the default network (DMN) and DAN (P<0.05), but decreased between DAN and auditory network (AN) (P<0.05), SMN and DMN (P<0.01) in patients with BD-I; (3) Digit span forward scores and education of all participants were negatively correlated with FC between SMN and DAN. Age of all subjects was positively correlated with FC between SMN and DMN. Conclusion: Our findings suggest that the sensorimotor network of BD-I has abnormal functional connections within and between networks, and the abnormal FC value correlated with clinical symptoms and executive function, which provide new information for exploring the neural physiopathology of executive dysfunction in BD-I patients.

Background Type 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood. Methods Here, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction. Results As previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3β to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings. Conclusions Overall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD. Graphical Abstract Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3β and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis. 4fVNd5UMHP9GEmZKs4s8VH Video Abstract

Fiber elongation is the key determinant of fiber quality and output in cotton (Gossypium hirsutum). Although expression profiling and functional genomics provide some data, the mechanism of fiber development is still not well understood. Here, a gene encoding a calcium sensor, GhCaM7, was isolated based on its high expression level relative to other GhCaMs in fiber cells at the fast elongation stage. The level of expression of GhCaM7 in the wild‐type and the fuzzless/lintless mutant correspond to the presence and absence, respectively, of fiber initials. Overexpressing GhCaM7 promotes early fiber elongation, whereas GhCaM7 suppression by RNAi delays fiber initiation and inhibits fiber elongation. Reactive oxygen species (ROS) play important roles in early fiber development. ROS induced by exogenous hydrogen peroxide (H₂O₂) and Ca²⁺ starvation promotes early fiber elongation. GhCaM7 overexpression fiber cells show increased ROS concentrations compared with the wild‐type, while GhCaM7 RNAi fiber cells have reduced concentrations. Furthermore, we show that H₂O₂ enhances Ca²⁺ influx into the fiber and feedback‐regulates the expression of GhCaM7. We conclude that GhCaM7, Ca²⁺ and ROS are three important regulators involved in early fiber elongation. GhCaM7 might modulate ROS production and act as a molecular link between Ca²⁺ and ROS signal pathways in early fiber development.

As the most important natural raw material for textile industry, cotton fibres are an excellent model for studying single-cell development. Although expression profiling and functional genomics have provided some data, the mechanism of fibre development is still not well known. A class I TCP transcription factor (designated GbTCP), encoding 344 amino acids, was isolated from the normalized cDNA library of sea-island cotton fibre (from –2 to 25 days post anthesis). GbTCP was preferentially expressed in the elongating cotton fibre from 5 to 15 days post anthesis. Some expression was also observed in stems, apical buds, and petals. RNAi silencing of GbTCP produced shorter fibre, a reduced lint percentage, and a lower fibre quality than the wild-type plants. Overexpression of GbTCP enhanced root hair initiation and elongation in Arabidopsis and regulated branching. Solexa sequencing and Affymetrix GeneChip analysis indicated that GbTCP positively regulates the level of jasmonic acid (JA) and, as a result, activates downstream genes (reactive oxygen species, calcium signalling, ethylene biosynthesis and response, and several NAC and WRKY transcription factors) necessary for elongation of fibres and root hairs. JA content analysis in cotton also confirmed that GbTCP has a profound effect on JA biosynthesis. In vitro ovule culture showed that an appropriate concentration of JA promoted fibre elongation. The results suggest that GbTCP is an important transcription factor for fibre and root hair development by regulating JA biosynthesis and response and other pathways, including reactive oxygen species, calcium channel and ethylene signalling.

The formation of cell polarity is essential for many developmental processes such as polar cell growth and spatial patterning of cell division. A plant-specific ROP (Rho-like GTPases from Plants) subfamily of conserved Rho GTPase plays a crucial role in the regulation of cell polarity. However, the functional study of ROPs in angiospermis challenging because of their functional redundancy. The Marchantia polymorpha genome encodes a single ROP gene, MpROP, providing an excellent genetic system to study ROP-dependent signaling pathways. Mprop knockout mutants exhibited rhizoid growth defects, and MpROP was localized at the tip of elongating rhizoids, establishing a role for MpROP in the control of polar cell growth and its functional conservation in plants. Furthermore, the Mprop knockout mutant showed defects in the formation of meristem notches associated with disorganized cell division patterns. These results reveal a critical function of MpROP in the regulation of plant development. Interestingly, these phenotypes were complemented not only by MpROP but also Arabidopsis AtROP2, supporting the conservation of ROP’s function among land plants. Our results demonstrate a great potential for M. polymorpha as a powerful genetic system for functional and mechanistic elucidation of ROP signaling pathways during plant development.

Directional auxin transport and formation of auxin maxima are critical for embryogenesis, organogenesis, pattern formation, and growth coordination in plants, but the mechanisms underpinning the initiation and establishment of these auxin dynamics are not fully understood. Here we show that a self-initiating and -terminating transient auxin flow along the marginal cells (MCs) contributes to the formation of an auxin maximum at the tip of Arabidopsis cotyledon that globally coordinates the interdigitation of puzzle-shaped pavement cells in the cotyledon epidermis. Prior to the interdigitation, indole butyric acid (IBA) is converted to indole acetic acid (IAA) to induce PIN2 accumulation and polarization in the marginal cells, leading to auxin flow toward and accumulation at the cotyledon tip. Once IAA levels at the cotyledon tip reaches a maximum, it activates pavement cell interdigitation as well as the accumulation of the IBA transporter TOB1 in MCs, which sequesters IBA to the vacuole and reduces IBA availability and IAA levels. The reduction of IAA levels results in PIN2 down-regulation and cessation of the auxin flow. Hence, our results elucidate a self-activating and self-terminating transient polar auxin transport system in cotyledons, contributing to the formation of localized auxin maxima that spatiotemporally coordinate pavement cell interdigitation. This study demonstrated that a PIN2-based transient polar auxin transport, through a file of elongated marginal cells (MCs), in the borders of cotyledons, underpins the formation of an auxin maximum at the tip of cotyledons. This auxin maximum contributes to the coordinated morphogenesis of the interdigitated puzzle-shaped pavement cells at the very early stage of cotyledon expansion.

[This corrects the article DOI: 10.3389/fnins.2021.823550.].

Introduction Neuropathic pain (NP) is the most debilitating of all clinical pain syndromes and may be a consequence of dysfunction in the somatosensory nervous system. Unfortunately, the pathogenesis of NP is not fully understood yet and it cannot be cured totally. Long noncoding RNA (lncRNA) is a type of RNA molecule greater than 200 nucleotides, and dysregulated expression of lncRNAs play a critical role in the facilitation of NP. Previous study showed the expression level of LOC100911498 in the spinal cords of spared nerve injury (SNI) rats were increased. This research was aimed at exploring what role LOC100911498 plays in the pathophysiological process of NP. Methods The mechanical withdrawal threshold (MWT) of rats was measured by the von Frey test. The expression levels of P2X4 receptor (P2X4R), ionized calcium‐binding adaptor molecule 1 (Iba‐1), p‐p38 and brain‐derived neurotrophic factor (BDNF) in spinal cords were detected, respectively. Results Our results suggested that the level of LOC100911498 in SNI rats was markedly higher than that in the sham group; the MWT values in rats were treated with LOC100911498siRNA were increased, and the expression levels of P2X4R, Iba‐1, p‐p38 and BDNF in SNI+ LOC100911498siRNA group were reduced compared with those in the SNI group. Conclusion Our study indicated the effects lncRNA LOC100911498 siRNA exerted on NP were mediated by P2X4R on microglia in the spinal cords of rats. Further, LOC100911498 may be a novel positive regulator of NP by regulating the expression and function of the P2X4R. LOC100911498 might participate in the development of neuropathic pain. LOC100911498 siRNA treatment could relieve the pain. LOC100911498 siRNA could block P2X4Rs‐mediated p38MAPK activation and BDNF release.

Obsessive-compulsive disorder (OCD) is a clinically challenging and refractory psychiatric disorder characterized by pathologically hyperactivated brain activity. Continuous theta burst stimulation (cTBS) is considered a potentially non-invasive treatment for inducing inhibitory effects on the underlying cortex. Numerous studies showed an unsatisfactory efficacy of cTBS for OCD. Accordingly, it seems that cTBS is ineffective for OCD. However, the neglect of varying OCD severities, modest sample size, absence of a multicenter design incorporating inpatients and outpatients, and lack of personalized imaging-guided targeting may constrain the conclusive findings of cTBS efficacy for OCD. In the preliminary experiment, 50 inpatients with OCD were enrolled to receive cTBS (10 sessions/day for five continuous days) or sham over the personalized right pre-supplementary motor area determined by the highest functional connectivity with the subthalamic nucleus according to our prior study. In the extension experiment, 32 outpatients with OCD received cTBS to generalize the treatment effects. The Yale-Brown Obsessive-Compulsive Scale (YBOCS) was assessed before and after treatment. In the preliminary experiment, the response rates in the cTBS group were 56.52%, respectively, significantly higher than those in the sham group. Further analysis revealed significant YBOCS improvement in patients with moderate OCD symptoms than those with severe OCD symptoms. In the extension experiment, the response rates were 50.00%. Additionally, a significant decrease in YBOCS scores was only found in patients with moderate OCD symptoms. This is the first study with an external validation design across two centers to identify OCD symptoms as playing an important role in cTBS treatment effects, especially in patients with moderate OCD symptoms.