Phase Coupled Firing of Prefrontal Parvalbumin Interneuron With High Frequency Oscillations

The prefrontal cortex (PFC) plays a central role in executive functions and inhibitory control over many cognitive behaviors. Dynamic changes in local field potentials (LFPs), such as gamma oscillation, have been hypothesized to be important for attentive behaviors and modulated by local interneurons such as parvalbumin (PV) cells. However, the precise relationships between the firing patterns of PV interneurons and temporal dynamics of PFC activities remains elusive. In this study, by combining in vivo electrophysiological recordings with optogenetics, we investigated the activities of prefrontal PV interneurons and categorized them into three subtypes based on their distinct firing rates under different behavioral states. Interestingly, all the three subtypes of interneurons showed strong phase-locked firing to cortical high frequency oscillations (HFOs), but not to theta or gamma oscillations, despite of behavior states. Moreover, we showed that sustained optogenetic stimulation (over a period of 10 s) of PV interneurons can consequently modulate the activities of local pyramidal neurons. Interestingly, such optogenetic manipulations only showed moderate effects on LFPs in the PFC. We conclude that prefrontal PV interneurons are consist of several subclasses of cells with distinct state-dependent modulation of firing rates, selectively coupled to HFOs

A Parallel Local Reconnection Approach for Tetrahedral Mesh Improvement

AbstractA multi-threaded parallel local reconnection algorithm is proposed for tetrahedral meshes. It defines a feature point within the region involved in each operation, and sorts the features points along a Hilbert curve. The decomposition of this Hilbert curve results in a load-balanced distribution of local operations. Meanwhile, the regions of concurrently executed local operations are separated far away, such that the possibility of interference is reduced to a very low level. Finally, a parallel mesh improver is developed by combining the proposed algorithm with a parallel mesh smoothing algorithm, and its effectiveness and efficiency is verified in various numerical experiments

Adaptive Integration of Partial Label Learning and Negative Learning for Enhanced Noisy Label Learning

There has been significant attention devoted to the effectiveness of various domains, such as semi-supervised learning, contrastive learning, and meta-learning, in enhancing the performance of methods for noisy label learning (NLL) tasks. However, most existing methods still depend on prior assumptions regarding clean samples amidst different sources of noise (\eg, a pre-defined drop rate or a small subset of clean samples). In this paper, we propose a simple yet powerful idea called \textbf{NPN}, which revolutionizes \textbf{N}oisy label learning by integrating \textbf{P}artial label learning (PLL) and \textbf{N}egative learning (NL). Toward this goal, we initially decompose the given label space adaptively into the candidate and complementary labels, thereby establishing the conditions for PLL and NL. We propose two adaptive data-driven paradigms of label disambiguation for PLL: hard disambiguation and soft disambiguation. Furthermore, we generate reliable complementary labels using all non-candidate labels for NL to enhance model robustness through indirect supervision. To maintain label reliability during the later stage of model training, we introduce a consistency regularization term that encourages agreement between the outputs of multiple augmentations. Experiments conducted on both synthetically corrupted and real-world noisy datasets demonstrate the superiority of NPN compared to other state-of-the-art (SOTA) methods. The source code has been made available at {\color{purple}{\url{https://github.com/NUST-Machine-Intelligence-Laboratory/NPN}}}.Comment: accepted by AAAI 202

EFFECTS OF CIJI HUA’AI BAOSHENG FORMULA ON APOPTOSIS CORRELATION FACTORS OF TUMOR CHEMOTHERAPY MODEL MOUSE WITH H22 HEPATOMA CARCINOMA CELLS

Background: Ciji Hua’ai Baosheng Formula (CHBF) is a traditional Chinese empirical formula that can help the tumor patients who received chemotherapy to antagonize the toxin and side-effects so as to improve and prolong the life. This study is to evaluate the effects of Ciji Hua’ai Baosheng Formula on apoptosis correlation factors of transplanted tumor chemotherapy model mouse with H22 hepatoma carcinoma cells through detecting the protein level of serum Bax, Bcl-2, Caspase-3, epidermal growth factor receptor (EGFR) and the protein expression of CyclinD1 in femur bone marrow. Materials and Methods: H22 hepatoma carcinoma cells were cultivated and diluted to 2×107/ml, and a total of 50 specific pathogen-free Kunming mice were injected subcutaneously into the right anterior armpit with H22 hepatoma carcinoma cells, after 7 days, all mice had formed tumors and were used peritoneal injection of Cytoxan (CTX) (200mg/kg) to establish the mouse chemotherapy model with transplanted tumor, then they were randomly divided into 5 groups such as model, positive control (CTX, 0.033g/kg) and three CHBF (117g/kg, 58.5g/kg and 29.25g/kg) groups with 10 mice in each group. They were administered next day after making model. Survival state was observed. After administering for 10 days, pathological tissue structural change was detected by light microscope, blood was collected through pricking eyeball, protein level of serum Bax, Bcl-2, Caspase-3 and EGFR was detected by enzyme-linked immunosorbent assay (ELISA), the protein expression of CyclinD1 in femur bone marrow was detected by immunohistochemisty. Results: Under the light microscope, the deteriorated degree of tumor tissue and the proliferation degree of tumor cells in three CHBF groups were obviously milder than that of model group. The protein content of the pro-apoptotic gene Bax and effective enzyme Caspase-3 in CHBF (58.5g/kg and 29.25g/kg) groups were obviously higher than that of model groups (

Metal ions steer the duality in microbial community recovery from nitrogen enrichment by shaping functional groups

Abstract Atmospheric nitrogen (N) deposition has been substantially reduced due to declines in the reactive N emission in major regions of the world. Nevertheless, the impact of reduced N deposition on soil microbial communities and the mechanisms by which they are regulated remain largely unknown. Here, we examined the effects of N addition and cessation of N addition on plant and soil microbial communities through a 17‐year field experiment in a temperate grassland. We found that extreme N input did not irreversibly disrupt the ecosystem, but ceasing high levels of N addition led to greater resilience in bacterial and fungal communities. Fungi exhibited diminished resilience compared to bacteria due to their heightened reliance on changes in plant communities. Neither bacterial nor fungal diversity fully recovered to their original states. Their sensitivity and resilience were mainly steered by toxic metal ions and soil pH differentially regulating on functional taxa. Specifically, beneficial symbiotic microbes such as N‐fixing bacteria and arbuscular mycorrhizal fungi experienced detrimental effects from toxic metal ions and lower pH, hindering their recovery. The bacterial functional groups involved in carbon decomposition, and ericoid mycorrhizal and saprotrophic fungi were positively influenced by soil metals, and demonstrated gradual recovery. These findings could advance our mechanistic understanding of microbial community dynamics under ongoing global changes, thereby informing management strategies to mitigate the adverse effects of N enrichment on soil function

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1flox(exon3)/+, designated CA-β-catenin) by crossing Ctnnb1flox(exon3)/flox(exon3) mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss

Identification of Novel Potential β-N-Acetyl-D-Hexosaminidase Inhibitors by Virtual Screening, Molecular Dynamics Simulation and MM-PBSA Calculations

Chitinolytic β-N-acetyl-d-hexosaminidases, as a class of chitin hydrolysis enzyme in insects, are a potential species-specific target for developing environmentally-friendly pesticides. Until now, pesticides targeting chitinolytic β-N-acetyl-d-hexosaminidase have not been developed. This study demonstrates a combination of different theoretical methods for investigating the key structural features of this enzyme responsible for pesticide inhibition, thus allowing for the discovery of novel small molecule inhibitors. Firstly, based on the currently reported crystal structure of this protein (OfHex1.pdb), we conducted a pre-screening of a drug-like compound database with 8 × 106 compounds by using the expanded pesticide-likeness criteria, followed by docking-based screening, obtaining 5 top-ranked compounds with favorable docking conformation into OfHex1. Secondly, molecular docking and molecular dynamics simulations are performed for the five complexes and demonstrate that one main hydrophobic pocket formed by residues Trp424, Trp448 and Trp524, which is significant for stabilization of the ligand–receptor complex, and key residues Asp477 and Trp490, are respectively responsible for forming hydrogen-bonding and π–π stacking interactions with the ligands. Finally, the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis indicates that van der Waals interactions are the main driving force for the inhibitor binding that agrees with the fact that the binding pocket of OfHex1 is mainly composed of hydrophobic residues. These results suggest that screening the ZINC database can maximize the identification of potential OfHex1 inhibitors and the computational protocol will be valuable for screening potential inhibitors of the binding mode, which is useful for the future rational design of novel, potent OfHex1-specific pesticides

“Adjust Zang and arouse spirit” electroacupuncture ameliorates cognitive impairment by reducing endoplasmic reticulum stress in db/db mice

IntroductionDiabetic cognitive impairment (DCI) is a chronic complication of the central nervous system (CNS) caused by diabetes that affects learning and memory capacities over time. Recently, acupuncture has been shown to improve cognitive impairment in streptozotocin-induced diabetic rats. However, the effects of electroacupuncture on DCI and its underlying mechanism have not yet been elucidated in detail. MethodsIn this study, we used db/db mice as DCI animal models which showed low cognitive, learning and memory functions. Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. The db/db mice with cognitive impairment were randomly divided into a model group (Mod) and an electroacupuncture treatment group (Acup), while db/m mice were used as a normal control group (Con). First, the mice were subjected to behavioural tests using the Morris water maze (MWM), and body weight, blood glucose, insulin, triglycerides (TG) and total cholesterol (TC) were observed; HE, Nissl, and TUNEL staining were used to observe the morphological changes and neuronal apoptosis in the mice hippocampus; Finally, Western blot and rt-PCR were applied to detect the essential proteins and mRNA of ERS and insulin signalling pathway, as well as the expression levels of Tau and Aβ.ResultsElectroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. Moreover, electroacupuncture attenuated diabetes-induced morphological structure change, neuronal apoptosis in the hippocampus of db/db mice. Our results revealed that electroacupuncture could regulate the expression levels of Tau and Aβ by improving hippocampal ERS levels in db/db mice, inhibiting JNK activation, attenuating IRS1 serine phosphorylation, and restoring normal transduction of the insulin signaling pathway.DiscussionIn summary, ERS and insulin signaling pathway paly causal roles in DCI development. Electroacupuncture can significantly alleviate the pathogenesis of DCI, improve mice's learning and memory ability, and improve cognitive dysfunction. This study adds to our understanding of the effect of acupuncture on DCI and opens the door to further research on DCI

Ivermectin induces apoptosis of esophageal squamous cell carcinoma via mitochondrial pathway

Background: Esophageal squamous cell carcinoma (ESCC) is the most predominant primary malignant tumor among worldwide, especially in China. To date, the successful treatment remains a mainly clinical challenge, it is imperative to develop successful therapeutic agents. Methods: The anti-proliferative effect of ivermectin on ESCC is investigated in cell model and in nude mice model. Cell apoptosis was assessed using flow cytometry, TUNEL assay and western blotting. Mitochondrial dysfunction was determined by reactive oxygen species accumulation, mitochondrial membrane potential and ATP levels. Results: Our results determined that ivermectin significantly inhibited the proliferation of ESCC cells in vitro and in vivo. Furthermore, we found that ivermectin markedly mediated mitochondrial dysfunction and induced apoptosis of ESCC cells, which indicated the anti-proliferative effect of ivermectin on ESCC cells was implicated in mitochondrial apoptotic pathway. Mechanistically, ivermectin significantly triggered ROS accumulation and inhibited the activation of NF-κB signaling pathway and increased the ratio of Bax/Bcl-2. Conclusions: These finding indicated that ivermectin has significant anti-tumour potential for ESSC and may be a potential therapeutic candidate against ESCC

Anxiety Specific Response and Contribution of Active Hippocampal Neural Stem Cells to Chronic Pain Through Wnt/β-Catenin Signaling in Mice

Chronic pain usually results in persistent anxiety, which worsens the life quality of patients and complicates the treatment of pain. Hippocampus is one of the few brain regions in many mammalians species which harbors adult neural stem cells (NSCs), and plays a key role in the development and maintenance of chronic anxiety. Recent studies have suggested a potential involvement of hippocampal neurogenesis in modulating chronic pain. Whether and how hippocampal NSCs are involved in the pain-associated anxiety remains unclear. Here, we report that mice suffering persistent neuropathic pain showed a quick reduction of active NSCs in the ventral dentate gyrus (vDG), which was followed by the decrease of neurogenesis and appearance of anxiety. Wnt/β-catenin signaling, a key pathway in sustaining the active status of NSCs was suppressed in the vDG of mice suffering chronic pain. Depleting β-catenin by inducible Nestin-Cre significantly reduced the number of active NSCs and facilitated anxiety development, while expressing stabilized β-catenin amplified active NSCs and alleviated anxiety, indicating that Wnt activated NSCs is required for anxiety development under chronic pain. Treatment with Fluoxetine, the most widely used anxiolytic in clinic, significantly increased the proliferation of active NSCs and enhanced Wnt signaling. Interestingly, both β-catenin manipulation and Fluoxetine treatment had no significant effects on the pain thresholds. Therefore, our data demonstrated an anxiety-specific response and contribution of activated NSCs to chronic pain through Wnt/β-catenin signaling, which may be targeted for treating chronic pain- or other diseases-associated anxiety