Artificial fluorescent sensor reveals pre-synaptic NMDA receptors switch cholecystokinin release and LTP in the hippocampus.

Cholecystokinin (CCK) has been confirmed to be essential in NMDA-dependent long-term potentiation (LTP) at mouse cortical synapses. This paper has proven that CCK is necessary for LTP induced by high-frequency stimulation of mouse hippocampal synapses projected from the entorhinal cortex. We show that the subunit of the axonal NMDA receptor dominant modulates the activity-induced LTP by triggering pre-synaptic CCK release. A functional pre-synaptic NMDA receptor is required to induce LTP mediated by the axonal Ca2+ elevation and CCK exocytosis at CCK-specific neurons. Genetic depletion of the GluN1 subunit of NMDA receptors on CCK neurons, which projected from the entorhinal cortex largely abolished the axonal Ca2+ elevation and disturbed the secretion of CCK in hippocampus. These results demonstrate that activity-induced LTP at the hippocampal synapse is CCK-dependent, and CCK secretion from the axonal terminal is modulated by pre-synaptic NMDA receptors.

Heterosynaptic plasticity of the visuo-auditory projection requires cholecystokinin released from entorhinal cortex afferents.

The entorhinal cortex is involved in establishing enduring visuo-auditory associative memory in the neocortex. Here we explored the mechanisms underlying this synaptic plasticity related to projections from the visual and entorhinal cortices to the auditory cortex in mice using optogenetics of dual pathways. High-frequency laser stimulation (HFS laser) of the visuo-auditory projection did not induce long-term potentiation. However, after pairing with sound stimulus, the visuo-auditory inputs were potentiated following either infusion of cholecystokinin (CCK) or HFS laser of the entorhino-auditory CCK-expressing projection. Combining retrograde tracing and RNAscope in situ hybridization, we show that Cck expression is higher in entorhinal cortex neurons projecting to the auditory cortex than in those originating from the visual cortex. In the presence of CCK, potentiation in the neocortex occurred when the presynaptic input arrived 200 ms before postsynaptic firing, even after just five trials of pairing. Behaviorally, inactivation of the CCK+ projection from the entorhinal cortex to the auditory cortex blocked the formation of visuo-auditory associative memory. Our results indicate that neocortical visuo-auditory association is formed through heterosynaptic plasticity, which depends on release of CCK in the neocortex mostly from entorhinal afferents.

Inhibition of Wnt Signaling by Atovaquone Inhibits Gastric Cancer and Enhances Chemotherapy Effectiveness Through Activation of Casein Kinase 1α.

Abnormal activation of the Wnt/ß-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone's effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated ß-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced ß-catenin. The inhibitory effects of atovaquone on ß-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.

Grain-filling characteristics and yield formation of wheat in two different soil fertility fields in the Huang-Huai-Hai Plain.

Clarifying factors that underpinning the variation in wheat yield components between high and middle soil fertility fields is critical to increase grain production and narrow yield gap for smallholder farming systems in the Huang-Huai-Hai Plain (3HP), which characterized by a large variation in soil fertility. Two-year field experiments were conducted to investigate wheat tillering, leaf photosynthesis, and grain filling characteristics in different soil fertility fields: high soil fertility field (HF) and middle soil fertility field (MF). Results showed that the spike formation rate in HF was 12.7%-13.0% higher than that in MF, leading to an 18.0%-19.8% increase in spike number. In addition, HF improved canopy light interception and leaf photosynthesis characteristics after anthesis and delayed leaf senescence, contributing to the increase in both the active grain filling period and grain filling rate. This resulted in a higher 1,000 grain weight in HF, which was 8.2%-8.3% higher than that in MF. Compared to MF, HF obtained higher yields at 9,840 kg ha-1 in 2017/18 and 11,462 kg ha-1 in 2018/19, respectively. In summary, higher spike number and 1,000-grain weight, which were mediated by spike-formation rate, maximization of light interception and improved leaf photosynthesis. These results would have important implications for narrowing yield gap between MF and HF in the 3HP.

Phase Engineering of Defective Copper Selenide toward Robust Lithium-Sulfur Batteries.

The shuttling of soluble lithium polysulfides (LiPS) and the sluggish Li-S conversion kinetics are two main barriers toward the practical application of lithium-sulfur batteries (LSBs). Herein, we propose the addition of copper selenide nanoparticles at the cathode to trap LiPS and accelerate the Li-S reaction kinetics. Using both computational and experimental results, we demonstrate the crystal phase and concentration of copper vacancies to control the electronic structure of the copper selenide, its affinity toward LiPS chemisorption, and its electrical conductivity. The adjustment of the defect density also allows for tuning the electrochemically active sites for the catalytic conversion of polysulfide. The optimized S/Cu1.8Se cathode efficiently promotes and stabilizes the sulfur electrochemistry, thus improving significantly the LSB performance, including an outstanding cyclability over 1000 cycles at 3 C with a capacity fading rate of just 0.029% per cycle, a superb rate capability up to 5 C, and a high areal capacity of 6.07 mAh cm-2 under high sulfur loading. Overall, the present work proposes a crystal phase and defect engineering strategy toward fast and durable sulfur electrochemistry, demonstrating great potential in developing practical LSBs.

Fault Diagnosis Method for Industrial Robots Based on DBN Joint Information Fusion Technology.

Aiming at the problems of the traditional industrial robot fault diagnosis model, such as low accuracy, low efficiency, poor stability, and real-time performance in multi-fault state diagnosis, a fault diagnosis method based on DBN joint information fusion technology is proposed. By studying the information processing method and the deep learning theory, this paper takes the fault of the joint bearing of the industrial robot as the research object. It adopts the technique of combining the deep belief network (DBN) and wavelet energy entropy, and the fault diagnosis of industrial robot is studied. The wavelet transform is used to denoise, decompose, and reconstruct the vibration signal of the joint bearing of the industrial robot. The normalized eigenvector of the reconstructed energy entropy is established, and the normalized eigenvector is used as the input of the DBN. The improved D-S evidence theory is used to solve the problem of fusion of high conflict evidence to improve the fault model's recognition accuracy. Finally, the feasibility of the model is verified by collecting the fault sample data and creating the category sample label. The experiment shows that the fault diagnosis method designed can complete the fault diagnosis of industrial robot well, and the accuracy of the test set is 97.96%. Compared with the traditional fault diagnosis model, the method is improved obviously, and the stability of the model is good; the utility model has the advantages of short time and high diagnosis efficiency and is suitable for the diagnosis work under the condition of coexisting multiple faults. The reliability of this method in the fault diagnosis of the joint bearing of industrial robot is verified.

An incomplete form of anti-ganglioside antibody-positive Miller Fisher syndrome after an Epstein-Barr virus infection: A case report.

RATIONALE: The Miller Fisher syndrome (MFS) is an acute polyradiculoneuritis regarded as an uncommon clinical variant of the Guillain-Barre syndrome (GBS). It is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. The diagnosis of MFS is based on clinical presentation, presence of albuminocytologic dissociation in the cerebrospinal fluid (CSF), and normal brain imaging results. The presence of anti-ganglioside antibodies (GQlb) in the serum is helpful for the diagnosis. A history of upper respiratory tract infection or diarrhea 3 days to 6 weeks before the onset of MFS is common. However, there are some patients with atypical manifestations who are difficult to diagnose. Here, we present an incomplete form of MFS where antibodies against GQ1b were detected in the serum following an Epstein Barr virus (EBV) infection. PATIENT CONCERNS: A 77-year-old Chinese woman was admitted to the hospital with acute diplopia and right blepharoptosis. She had a history of mild upper respiratory tract infection 2 weeks ago. In 1 week, the symptoms rapidly progressed into bilateral ophthalmoplegia and hyporeflexia of the limbs without ataxia. CSF analysis on the third day after onset was normal, without albuminocytologic dissociation. EBV immunoglobulin G (IgG) antibodies were detected in the CSF. GQ1b and GD1b IgG antibodies were positive in the serum and negative in the CSF. No responsible lesion was found on brain imaging examination. DIAGNOSES: In accordance with the progressive bilateral ophthalmoplegia and hyporeflexia, the history of upper respiratory tract infection, the detection of EBV and GQ1b antibodies, and the negative brain imaging examination, the diagnosis of MFS was confirmed. INTERVENTIONS: The patient was administered intravenous immunoglobulin for 5 days. OUTCOMES: She had a favorable outcome after treatment. At the 6-week follow-up, bilateral ocular movement limitation and tendon reflexes had recovered. LESSONS: The diagnosis of MFS can be challenging, especially when encountered with incomplete symptoms and normal CSF results. Attention should be paid to the presence of anti-GQ1b IgG antibodies when the clinical manifestations are incomplete. Furthermore, EBV primary infection could be associated with MFS and considered a potential causative agent.

Differences in Water Consumption of Wheat Varieties Are Affected by Root Morphology Characteristics and Post-anthesis Root Senescence.

Selecting high-yielding wheat varieties for cultivation can effectively increase water use efficiency (WUE) in the Huang-Huai-Hai Plain, where is threatened by increasing water shortages. To further identify the difference in water use and its relationship with root morphology and senescence characteristics, wheat varieties with different yield potentials-Yannong 1212 (YN), Jimai 22 (JM), and Liangxing 99 (LX)-were studied in a high-yielding wheat field. The water consumption percentage (CP) in YN decreased from planting to anthesis; however, crop evapotranspiration and CP increased from anthesis to maturity compared with JM and LX. In YN, a higher soil water consumption from anthesis to maturity in the 0-100 cm soil layer was partly attributed to the greater root weight density in the 20-60 cm soil layer. In topsoil (0-40 cm), root length density, root surface area density, and root diameter at 20 days after anthesis, root superoxide dismutase activity, and root triphenyl tetrazolium chloride reduction activity during mid grain filling stage were higher in YN than in JM and LX. YN had the highest grain yields of 9,840 and 11,462 kg ha-1 and increased grain yield and WUE by 12.0 and 8.4%, respectively, as compared with JM, and by 30.3 and 21.3%, respectively, as compared with LX. Ensuring more soil water extraction post-anthesis by increasing roots in the 20-60 cm soil profile, improving root morphology traits, and alleviating root senescence in the topsoil during mid-grain filling stage will assist in selecting wheat varieties with high yield and WUE.

Nitrogen supply modulates nitrogen remobilization and nitrogen use of wheat under supplemental irrigation in the North China Plain.

Excessive nitrogen (N) input and irrigation exacerbate N leaching in winter wheat production in the North China Plain (NCP). To explore the optimal N for better N remobilization and higher N utilization of wheat under water-saving irrigation will be conductive to less environmental contamination. A field experiment was conducted at 300 (N300), 240 (N240), 180 (N180), and 0 (N0) kg N ha-1 of N application under supplemental irrigation (SI) that brought the relative soil water content (RSWC) to 70% at jointing and 65% at anthesis. Compared with N0, N180 improved the free amino acid content in the flag leaf and grain after anthesis, dry matter and plant N accumulation at maturity, N translocation amount of vegetable organs and its contribution to grain from anthesis to maturity. Compared to N240 and N300, N180 increased the N translocation efficiency of vegetable organs, and reduced the soil NO3-N residue in the 60-180 cm soil layer, which contributing to no significant reduction in grain yield and grain protein yield, but higher grain N recovery efficiency (GREN), N recovery efficiency (REN), and N partial factor productivity (PFPN). Positive relationships were found between leaf N translocation efficiency and grain yield, grain protein yield, PFPN, GREN, and REN. Therefore, N180 is appropriate to obtain a steady grain yield over 7.5 t ha-1 for at least 2 years under SI based on RSWC in the NCP.

Visuoauditory Associative Memory Established with Cholecystokinin Under Anesthesia Is Retrieved in Behavioral Contexts.

Plastic change in neuronal connectivity is the foundation of memory encoding. It is not clear whether the changes during anesthesia can alter subsequent behavior. Here, we demonstrated that in male rodents under anesthesia, a visual stimulus (VS) was associated with electrical stimulation of the auditory cortex or natural auditory stimulus in the presence of cholecystokinin (CCK), which guided the animals' behavior in a two-choice auditory task. Auditory neurons became responsive to the VS after the pairings. Moreover, high-frequency stimulation of axon terminals of entorhinal CCK neurons in the auditory cortex enabled LTP of the visual response in the auditory cortex. Such pairing during anesthesia also generated VS-induced freezing in an auditory fear conditioning task. Finally, we verified that direct inputs from the entorhinal CCK neurons and the visual cortex enabled the above neural plasticity in the auditory cortex. Our findings suggest that CCK-enabled visuoauditory association during anesthesia can be translated to the subsequent behavior action.SIGNIFICANCE STATEMENT Our study provides strong evidence for the hypothesis that cholecystokinin plays an essential role in the formation of cross-modal associative memory. Moreover, we demonstrated that an entorhinal-neocortical circuit underlies such neural plasticity, which will be helpful to understand the mechanisms of memory formation and retrieval in the brain.

Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.

[Protective effect of grape seed proanthocyanidin on spermatogenesis following testicular torsion/detorsion in mice].

OBJECTIVE: To investigate the protective effect of grape seed proanthocyanidin (GSP) on spermatogenesis following testicular torsion/detorsion in mice. METHODS: Twenty-four healthy male Kunming mice, aged 8 weeks and weighing 25 - 27 g, were randomly divided into a control, a torsion and a treatment group, each containing 8 animals. The unilateral testicular torsion/detorsion model was established in the treatment and torsion groups. Thirty minutes before detorsion, the animals of the treatment group were injected intraperitoneally with 50 mg/kg GSP, and those of the torsion group with normal saline at the same dose, both for 3 days postoperatively. On the 4th day after surgery, ipsilateral orchiectomy were performed to detect histopathological changes, the levels of superoxide dismutase (SOD) and malondialdehyde (MDA), and the apoptotic index (AI) of germ cells in all the mice. RESULTS: Compared with the torsion group, the treated mice showed significantly increased Johnsen score (5.00 +/- 1.85 vs 7.38 +/- 0.92, P < 0.05), seminiferous tubule diameter ([176.50 +/- 1.60]microm vs [178.75 +/- 1.58] microm, P > 0.05), spermatogenic cell layers (3.75 +/- 1.03 vs 5.75 +/- 0.71, P < 0.05) and SOD activity ([29.04 +/- 4.46] U/mg prot vs [52.67 +/- 3.57] U/mg prot, P < 0.05), but remarkably reduced level of MDA ([4.63 +/- 0.05] nmol/mg prot vs [2.91 +/- 0.04] nmol/mg prot, P < 0.05) and AI of germ cells ([40.50 +/- 1.60]% vs [16.25 +/- 1.67] %, P < 0.05). CONCLUSION: Grape seed proanthocyanidin has a protective effect against spermatogenic injury in mice, the mechanisms of which may be related to its actions of scavenging oxygen free radicals, inhibiting lipid peroxidation and improving the antioxidant ability of the body.