Cellular and circuit architecture of the lateral septum for reward processing.

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.

Striking the balance: Configurations of causation and effectuation principles for SME performance.

Causation and effectuation are two fundamental decision-making logics that managers use for crucial firm strategic decisions. However, existing research has yet to agree on the relationship between the two logics, supporting both the substitution and complementarity of causation and effectuation in influencing firm performance. This leaves us with a puzzle: How do causation and effectuation combine in balance to improve firm performance? To address the gap, we utilize a fuzzy set qualitative comparative analysis (fsQCA) with data collected from 344 small to medium-sized enterprises (SMEs) in China to uncover the dynamic relationships between the two logics. Our findings indicate that causation or effectuation alone is insufficient to achieve superior firm performance. By distinguishing between four dimensions of effectuation, we identify three types of configurations for high performance: (1) causation with promotion-focused effectuation principles; (2) causation with prevention-focused effectuation principles; (3) causation with hybrid-focused effectuation principles. More importantly, we find that the effectiveness of the configurations depends on the firm development stage. Our findings provide SMEs with practical insights into how to effectively choose their decision-making logic when faced with different firm growth challenges.

Transition between Heavy-Fermion-Strange-Metal and Quantum Spin Liquid in a 4d-Electron Trimer Lattice.

We present experimental evidence that a heavy Fermi surface consisting of itinerant, charge-neutral spinons underpins both heavy-fermion-strange-metal (without f electrons) and quantum-spin-liquid states in the 4d-electron trimer lattice, Ba_{4}Nb_{1-x}Ru_{3+x}O_{12}(|x|<0.20). These two exotic states both exhibit an extraordinarily large entropy, a linear heat capacity extending into the milli-Kelvin regime, a linear thermal conductivity at low temperatures, and separation of charges and spins. Furthermore, the insulating spin liquid is a much better thermal conductor than the heavy-fermion-strange-metal that separately is observed to strongly violate the Wiedemann-Franz law. We propose that at the heart of this 4d system is a universal, heavy spinon Fermi surface that provides a unified framework for explaining the exotic phenomena observed throughout the entire series. The control of such exotic ground states provided by variable Nb concentration offers a new paradigm for studies of correlated quantum matter.

A cascade nanosystem with "Triple-Linkage" effect for enhanced photothermal and activatable metal ion therapy for hepatocellular carcinoma.

Due to the limitations of single-model tumor therapeutic strategies, multimodal combination therapy have become a more favorable option to enhance efficacy by compensating for its deficiencies. However, in nanomaterial-based multimodal therapeutics for tumors, exploiting synergistic interactions and cascade relationships of materials to achieve more effective treatments is still a great challenge. Based on this, we constructed a nanoplatform with a "triple-linkage" effect by cleverly integrating polydopamine (PDA), silver nanoparticles (AgNPs), and glucose oxidase (GOx) to realize enhanced photothermal therapy (PTT) and activatable metal ion therapy (MIT) for hepatocellular carcinoma (HCC) treatment. First, the non-radiative conversion of PDA under light conditions was enhanced by AgNPs, which directly enhanced the photothermal conversion efficiency of PDA. In addition, GOx reduced the synthesis of cellular heat shock proteins by interfering with cellular energy metabolism, thereby enhancing cellular sensitivity to PTT. On the other hand, H2O2, a by-product of GOx-catalyzed glucose, could be used as an activation source to activate non-toxic AgNPs to release cytotoxic Ag+, achieving activatable Ag+-mediated MIT. In conclusion, this nanosystem achieved efficient PTT and MIT for HCC by exploiting the cascade effect among PDA, AgNPs, and GOx, providing a novel idea for the design of multimodal tumor therapeutic systems with cascade regulation.

[Retracted] Effect of microRNA-27b on cisplatin chemotherapy sensitivity of oral squamous cell carcinoma via FZD7 signaling pathway.

[This retracts the article DOI: 10.3892/ol.2019.10347.].

Targeting tumor suppressor p53 for organ fibrosis therapy.

Fibrosis is a reparative and progressive process characterized by abnormal extracellular matrix deposition, contributing to organ dysfunction in chronic diseases. The tumor suppressor p53 (p53), known for its regulatory roles in cell proliferation, apoptosis, aging, and metabolism across diverse tissues, appears to play a pivotal role in aggravating biological processes such as epithelial-mesenchymal transition (EMT), cell apoptosis, and cell senescence. These processes are closely intertwined with the pathogenesis of fibrotic disease. In this review, we briefly introduce the background and specific mechanism of p53, investigate the pathogenesis of fibrosis, and further discuss p53's relationship and role in fibrosis affecting the kidney, liver, lung, and heart. In summary, targeting p53 represents a promising and innovative therapeutic approach for the prevention and treatment of organ fibrosis.

Detoxification and underlying mechanisms towards toxic alkaloids by Traditional Chinese Medicine processing: A comprehensive review.

BACKGROUND: Alkaloids have attracted enduring interest worldwide due to their remarkable therapeutic effects, including analgesic, anti-inflammatory, and anti-tumor properties, thus offering a rich source for lead compound design and new drug discovery. However, some of these alkaloids possess intrinsic toxicity. Processing (Paozhi) is a pre-treatment step before the application of herbal medicines in traditional Chinese medicine (TCM) clinics, which has been employed for centuries to mitigate the toxicity of alkaloid-rich TCMs. PURPOSE: To explore the toxicity phenotypes, chemical basis, mode of action, detoxification processing methods, and underlying mechanisms, we can gain crucial insights into the safe and rational use of these toxic alkaloid-rich herbs. Such insights have the great potential to offer new strategies for drug discovery and development, ultimately improving the quality of life for millions of people. METHODS: Literatures published or early accessed until December 31, 2023, were retrieved from databases including PubMed, Web of Science, and CNKI. The following keywords, such as "toxicity", "alkaloid", "detoxification", "processing", "traditional Chinese medicine", "medicinal plant", and "plant", were used in combination or separately for screening. RESULTS: Toxicity of alkaloids in TCM includes hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, and other forms of toxicity, primarily induced by pyrrolizidines, quinolizidines, isoquinolines, indoles, pyridines, terpenoids, and amines. Factors such as whether the toxic-alkaloid enriched part is limited or heat-sensitive, and whether toxic alkaloids are also therapeutic components, are critical for choosing appropriate detoxification processing methods. Mechanisms of alkaloid detoxification includes physical removal, chemical decomposition or transformation, as well as biological modifications. CONCLUSION: Through this exploration, we review toxic alkaloids and the mechanisms underlying their toxicity, discuss methods to reduce toxicity, and unravel the intricate mechanisms behind detoxification. These offers insights into the quality control of herbs containing toxic alkaloids, safe and rational use of alkaloid-rich TCMs in clinics, new strategies for drug discovery and development, and ultimately helping improve the quality of life for millions of people.

Spatial multi-omics at subcellular resolution via high-throughput in situ pairwise sequencing.

Technology for spatial multi-omics aids the discovery of new insights into cellular functions and disease mechanisms. Here we report the development and applicability of multi-omics in situ pairwise sequencing (MiP-seq), a method for the simultaneous detection of DNAs, RNAs, proteins and biomolecules at subcellular resolution. Compared with other in situ sequencing methods, MiP-seq enhances decoding capacity and reduces sequencing and imaging costs while maintaining the efficacy of detection of gene mutations, allele-specific expression and RNA modifications. MiP-seq can be integrated with in vivo calcium imaging and Raman imaging, which enabled us to generate a spatial multi-omics atlas of mouse brain tissues and to correlate gene expression with neuronal activity and cellular biochemical fingerprints. We also report a sequential dilution strategy for resolving optically crowded signals during in situ sequencing. High-throughput in situ pairwise sequencing may facilitate the multidimensional analysis of molecular and functional maps of tissues.

Cornus officinalis with high pressure wine steaming enhanced anti-hepatic fibrosis: Possible through SIRT3-AMPK axis.

Cornus officinalis, a medicinal and edible plant known for its liver-nourishing properties, has shown promise in inhibiting the activation of hepatic stellate cells (HSCs), crucial indicators of hepatic fibrosis, especially when processed by high pressure wine steaming (HPWS). Herein, this study aims to investigate the regulatory effects of cornus officinalis, both in its raw and HPWS forms, on inflammation and apoptosis in liver fibrosis and their underlying mechanisms. In vivo liver fibrosis models were established by subcutaneous injection of CCl4, while in vitro HSCs were exposed to transforming growth factor-ß (TGF-ß). These findings demonstrated that cornus officinalis with HPWS conspicuously ameliorated histopathological injury, reduced the release of proinflammatory factors, and decreased collagen deposition in CCl4-induced rats compared to its raw form. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) combined with network analysis, we identified that the pharmacological effects of the changed components of cornus officinalis before and after HPWS, primarily centered on the adenosine phosphate (AMP)-activated protein kinase (AMPK) pathway. Of note, cornus officinalis activated AMPK and Sirtuin 3 (SIRT3), promoting the apoptosis of activated HSCs through the caspase cascade by regulating caspase3, caspase6 and caspase9. siRNA experiments showed that cornus officinalis could regulate AMPK activity and its mediated-apoptosis through SIRT3. In conclusion, cornus officinalis exhibited the ability to reduce inflammation and apoptosis, with the SIRT3-AMPK signaling pathway identified as a potential mechanism underlying the synergistic effect of cornus officinalis with HPWS on anti-liver fibrosis.

Traditional Chinese medicine in osteoporosis: from pathogenesis to potential activity.

Osteoporosis characterized by decreased bone density and mass, is a systemic bone disease with the destruction of microstructure and increase in fragility. Osteoporosis is attributed to multiple causes, including aging, inflammation, diabetes mellitus, and other factors induced by the adverse effects of medications. Without treatment, osteoporosis will further progress and bring great trouble to human life. Due to the various causes, the treatment of osteoporosis is mainly aimed at improving bone metabolism, inhibiting bone resorption, and promoting bone formation. Although the currently approved drugs can reduce the risk of fragility fractures in individuals, a single drug has limitations in terms of safety and effectiveness. By contrast, traditional Chinese medicine (TCM), a characteristic discipline in China, including syndrome differentiation, Chinese medicine prescription, and active ingredients, shows unique advantages in the treatment of osteoporosis and has received attention all over the world. Therefore, this review summarized the pathogenic factors, pathogenesis, therapy limitations, and advantages of TCM, aiming at providing new ideas for the prevention and treatment of OP.

Current-sensitive Hall effect in a chiral-orbital-current state.

Chiral orbital currents (COC) underpin a novel colossal magnetoresistance in ferrimagnetic Mn3Si2Te6. Here we report the Hall effect in the COC state which exhibits the following unprecedented features: (1) A sharp, current-sensitive peak in the magnetic field dependence of the Hall resistivity, and (2) A current-sensitive scaling relation between the Hall conductivity σxy and the longitudinal conductivity σxx, namely, σxy ∝ σxxα with α reaching up to 5, which is exceptionally large compared to α ≤ 2 typical of all solids. The novel Hall responses along with a current-sensitive carrier density and a large Hall angle of 15% point to a giant, current-sensitive Hall effect that is unique to the COC state. Here, we show that a magnetic field induced by the fully developed COC combines with the applied magnetic field to exert the greatly enhanced transverse force on charge carriers, which dictates the COC Hall responses.

SIRT3: A potential therapeutic target for liver fibrosis.

Sirtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase located in the mitochondria, which mainly regulates the acetylation of mitochondrial proteins. In addition, SIRT3 is involved in critical biological processes, including oxidative stress, inflammation, DNA damage, and apoptosis, all of which are closely related to the progression of liver disease. Liver fibrosis characterized by the deposition of extracellular matrix is a result of long termed or repeated liver damage, frequently accompanied by damaged hepatocytes, the recruitment of inflammatory cells, and the activation of hepatic stellate cells. Based on the functions and pharmacology of SIRT3, we will review its roles in liver fibrosis from three aspects: First, the main functions and pharmacological effects of SIRT3 were investigated based on its structure. Second, the roles of SIRT3 in major cells in the liver were summarized to reveal its mechanism in developing liver fibrosis. Last, drugs that regulate SIRT3 to prevent and treat liver fibrosis were discussed. In conclusion, exploring the pharmacological effects of SIRT3, especially in the liver, may be a potential strategy for treating liver fibrosis.

Adenine-induced animal model of chronic kidney disease: current applications and future perspectives.

Chronic kidney disease (CKD) with high morbidity and mortality all over the world is characterized by decreased kidney function, a condition which can result from numerous risk factors, including diabetes, hypertension and obesity. Despite significant advances in our understanding of the pathogenesis of CKD, there are still no treatments that can effectively combat CKD, which underscores the urgent need for further study into the pathological mechanisms underlying this condition. In this regard, animal models of CKD are indispensable. This article reviews a widely used animal model of CKD, which is induced by adenine. While a physiologic dose of adenine is beneficial in terms of biological activity, a high dose of adenine is known to induce renal disease in the organism. Following a brief description of the procedure for disease induction by adenine, major mechanisms of adenine-induced CKD are then reviewed, including inflammation, oxidative stress, programmed cell death, metabolic disorders, and fibrillation. Finally, the application and future perspective of this adenine-induced CKD model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given the simplicity and reproducibility of this animal model, it remains a valuable tool for studying the pathological mechanisms of CKD and identifying therapeutic targets to fight CKD.

Regulatory role of PDK1 via integrated gene analysis of mitochondria-immune response in periodontitis.

AIMS: To investigate the association between mitochondrial events and immune response in periodontitis and related regulatory genes. MAIN METHODS: Gene expression profiles in gingival tissues were retrieved from the Gene Expression Omnibus. Mitochondria-immune response-related differentially expressed genes (MIR-DEGs) between the healthy and periodontitis samples were determined. WGCNA, GO, and KEGG were used to investigate the function and the enriched pathways of MIR-DEGs. The correlation between MIR-DEGs expression and clinical probing pocket depth was analyzed. The MIR-DEGs were further identified and verified in animal samples. A periodontitis model was established in C57BL/6 mice with silk ligation. Micro-computed tomography was used to assess alveolar bone loss. Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses further validated the differential expression of the MIR-DEGs. KEY FINDINGS: A total of ten MIR-DEGs (CYP24A1, PRDX4, GLDC, PDK1, BCL2A1, CBR3, ARMCX3, BNIP3, IFI27, and UNG) were identified, the expression of which could effectively distinguish patients with periodontitis from the healthy controls. Enhanced immune response was detected in the periodontitis group with that in the healthy controls, especially in B cells. PDK1 was a critical MIR-DEG correlated with B cell immune response and clinical periodontal probing pocket depth. Both animal and clinical periodontal samples presented higher gene and protein expression of PDK1 than the control samples. Additionally, PDK1 colocalized with B cells in both animal and clinical periodontal tissues. SIGNIFICANCE: Mitochondria participate in the regulation of the immune response in periodontitis. PDK1 may be the key mitochondria-related gene regulating B-cell immune response in periodontitis.

Comparison of Radiofrequency Ablation and Craniotomy Microvascular Decompression for Treatment of Hemifacial Spasm.

BACKGROUND: Hemifacial spasm (HFS) is distinguished by sudden and involuntary spasms of the facial muscles, predominantly on one side of the face. Microvascular decompression (MVD) is an efficacious surgical technique for treating HFS; however, MVD may occasionally lead to noteworthy postoperative complications. Previously, we reported the successful utilization of an innovative awake computed tomography-guided percutaneous puncture of the stylomastoid foramen for administering radiofrequency ablation (RFA) therapy in the treatment of HFS. STUDY DESIGN: Prospective clinical research study. SETTING: Department of Anesthesiology and Pain Medical Center, Ningbo, China. OBJECTIVES: The aim of this study was to compare and contrast the clinical outcomes and adverse reactions associated with attempts to use RFA and MVD to manage primary HFS. METHODS: Three hundred patients received either RFA or MVD treatment (Group R and Group M). We tracked and recorded each patient's cure rate, remission rate, intraoperative and postoperative complications, short-term and long-term therapeutic outcomes, hospitalization duration, hospitalization expenses, and operation time. RESULTS: One hundred and fifty-eight patients were placed in the R group, and 142 patients were sorted into the M group. In the R group, 87.34% of patients showed improvement, 9.49% experienced relief, and 3.16% experienced treatment failure. Similarly, in the M group, 85.92% of patients showed improvement, 10.56% experienced relief, and 3.52% experienced treatment failure. The difference in therapeutic efficacy between the 2 groups was not significant. However, the M group had significantly lower recurrence rates at 3 months, 6 months, and one year post-operation than the R group did. Notably, the M group also experienced a higher rate of postoperative complications. Among the complications reported in the M group were 25 cases of dizziness or headache (17.6%) following the operation, 22 cases of hearing damage, including one case of complete hearing loss on the side involved, and 28 cases of peripheral nerve injury with abnormal skin sensation. Postoperative facial paralysis occurred in 15 patients, including 10 cases of moderate to severe facial paralysis that were relieved to grade II after one year. In comparison, the R group had 40 cases of grade II and 53 cases of grade III, and no cases of more severe facial paralysis were found. There were also 13 cases of peripheral nerve injury, such as local skin numbness and tenderness. Importantly, there were no cases of facial hematoma, intracranial hemorrhage, infection, or any other complications in either group, and no fatalities occurred during the study period. LIMITATIONS: The limitations of this study are the exclusion of transient postoperative complications, the lack of in-person follow-up with patients, and the potential underestimation of certain complications. CONCLUSION: The short-term outcome was found to be comparable between the 2 treatment modalities. Notably, RFA demonstrates both safety and efficacy as a method for managing primary HFS; however, the procedure may lead to mild facial paralysis. In situations during which surgery is contraindicated, especially among elderly or high-risk surgical patients, percutaneous facial nerve RFA at the stylomastoid foramen may be considered as an alternative therapeutic approach.

Three-dimensional chromatin analysis reveals Sp1 as a mediator to program and reprogram HPV-host epigenetic architecture in cervical cancer.

Human papillomavirus (HPV) is predominantly associated with HPV-related cancers, however, the precise mechanisms underlying the HPV-host epigenetic architectures in HPV carcinogenesis remain elusive. Here, we employed high-throughput chromosome conformation capture (Hi-C) to comprehensively map HPV16/18-host chromatin interactions. Our study identified the transcription factor Sp1 as a pivotal mediator in programming HPV-host interactions. By targeting Sp1, the active histone modifications (H3K27ac, H3K4me1, and H3K4me3) and the HPV-host chromatin interactions are reprogrammed, which leads to the downregulation of oncogenes located near the integration sites in both HPV (E6/E7) and the host genome (KLF5/MYC). Additionally, Sp1 inhibition led to the upregulation of immune checkpoint genes by reprogramming histone modifications in host cells. Notably, humanized patient-derived xenograft (PDX-HuHSC-NSG) models demonstrated that Sp1 inhibition promoted anti-PD-1 immunotherapy via remodeling the tumor immune microenvironment in cervical cancer. Moreover, single-cell transcriptomic analysis validated the enrichment of transcription factor Sp1 in epithelial cells of cervical cancer. In summary, our findings elucidate Sp1 as a key mediator involved in the programming and reprogramming of HPV-host epigenetic architecture. Inhibiting Sp1 with plicamycin may represent a promising therapeutic option for HPV-related carcinoma.

Investigation of New Accelerometer Based on Capacitive Micromachined Ultrasonic Transducer (CMUT) with Ring-Perforation Membrane.

Capacitive micromachined ultrasonic transducer (CMUT) has been widely studied due to its excellent resonance characteristics and array integration. This paper presents the first study of the CMUT electrostatic stiffness resonant accelerometer. To improve the sensitivity of the CMUT accelerometer, this paper innovatively proposes the CMUT ring-perforation membrane structure, which effectively improves the acceleration sensitivity by reducing the mechanical stiffness of the elastic membrane. The acceleration sensitivity is 10.9 (Hz/g) in the acceleration range of 0-20 g, which is 100% higher than that of the conventional CMUT structure. This research contributes to the acceleration measurement field of CMUT and can effectively contribute to the breakthrough of vibration acceleration monitoring technology in aerospace, medical equipment, and automotive electronics.

An algorithm for power transmission line fault detection based on improved YOLOv4 model.

In response to the escalating demand for real-time and accurate fault detection in power transmission lines, this paper undertook an optimization of the existing YOLOv4 network. This involved the substitution of the main feature extraction network within the original YOLOv4 model with a lighter EfficientNet network. Additionally, the inclusion of Grouped Convolution modules in the feature pyramid structure replaced conventional convolution operations. The resulting model not only reduced model parameters but also effectively ensured detection accuracy. Moreover, in enhancing the model's reliability, data augmentation techniques were employed to bolster the robustness of the power transmission line fault detection algorithm. This optimization further utilized the DIoU loss function to stabilize target box regression. Comparative experiments demonstrated the improved YOLOv4 model's superior performance in terms of loss function optimization while significantly enhancing detection speed under equivalent configurations. The parameter capacity was reduced by 81%, totaling merely 43.65 million, while the frame rate surged by 85% to achieve 24 frames per second. These experimental findings validate the effectiveness of the algorithm.

The Role of Rv1476 in Regulating Stress Response and Intracellular Survival of Mycobacterium tuberculosis.

The virulence of Mycobacterium tuberculosis (M. tuberculosis) is related to many factors, including intracellular survival, cell wall permeability, and cell envelope proteins. However, the biological function of the M. tuberculosis membrane protein Rv1476 remains unclear. To investigate the potential role played by Rv1476, we constructed an Rv1476 overexpression strain and found that overexpression of Rv1476 enhanced the intracellular survival of M. tuberculosis, while having no impact on the growth rate in vitro. Stress experiments demonstrated that the Rv1476 overexpression strain displayed increased susceptibility to different stresses compared to the wild-type strain. Transcriptome analysis showed that Rv1476 overexpression causes changes in the transcriptome of THP-1 cells, and differential genes are mainly enriched in cell proliferation, fatty acid degradation, cytokine-cytokine receptor interaction, and immune response pathways. Rv1476 overexpression inhibited the expression of some anti-tuberculosis-related genes, such as CCL1, IL15, IL16, ISG15, GBP5, IL23, ATG2A, IFNß, and CSF3. Altogether, we conclude that Rv1476 may play a critical role for M. tuberculosis in macrophage survival.

Self-heating mitochondrion-induced free radical blast for immunogenic cell death stimulation and HCC immunotherapy.

Hepatocellular carcinoma (HCC) is an immunosuppressive tumor associated with high mortality. Photothermal and photodynamic therapies have been applied to induce immunogenic cell death (ICD) in HCC, successfully eliciting immune responses but facing limitations in penetration depth in clinical trials. Here, intrinsic mitochondrial hyperthermia was used to trigger thermosensitive drug release. The mitochondria were further self-heated through 2,4-dinitrophenol uncoupling, dramatically promoting free radical initiation and inducing tumor ICD. The synthesized mitochondrial-targeting TPP-HA-TDV nanoparticles specifically generated free radicals in the mitochondria without external stimulation, and obviously enhanced the release of ICD markers, subsequently evoking immune responses. The results showed that mitochondrial hyperthermia could be an endogenous target for thermosensitive drug release. Furthermore, self-heating mitochondria-induced free radical blast could be an efficient therapeutic for deep-seated tumor therapy.