Lipid droplets in the nervous system: involvement in cell metabolic homeostasis.

Lipid droplets serve as primary storage organelles for neutral lipids in neurons, glial cells, and other cells in the nervous system. Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum. Previously, lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis; however, recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system. In addition to their role in regulating cell metabolism, lipid droplets play a protective role in various cellular stress responses. Furthermore, lipid droplets exhibit specific functions in neurons and glial cells. Dysregulation of lipid droplet formation leads to cellular dysfunction, metabolic abnormalities, and nervous system diseases. This review aims to provide an overview of the role of lipid droplets in the nervous system, covering topics such as biogenesis, cellular specificity, and functions. Additionally, it will explore the association between lipid droplets and neurodegenerative disorders. Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

4-Nitrophenol at environmentally relevant concentrations mediates reproductive toxicity in Caenorhabditis elegans via metabolic disorders-induced estrogen signaling pathway.

4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.

Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future.

Müller glia, as prominent glial cells within the retina, plays a significant role in maintaining retinal homeostasis in both healthy and diseased states. In lower vertebrates like zebrafish, these cells assume responsibility for spontaneous retinal regeneration, wherein endogenous Müller glia undergo proliferation, transform into Müller glia-derived progenitor cells, and subsequently regenerate the entire retina with restored functionality. Conversely, Müller glia in the mouse and human retina exhibit limited neural reprogramming. Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders. Müller glia reprogramming in mice has been accomplished with remarkable success, through various technologies. Advancements in molecular, genetic, epigenetic, morphological, and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice. Nevertheless, there remain issues that hinder improving reprogramming efficiency and maturity. Thus, understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency, and for developing novel Müller glia reprogramming strategies. This review describes recent progress in relatively successful Müller glia reprogramming strategies. It also provides a basis for developing new Müller glia reprogramming strategies in mice, including epigenetic remodeling, metabolic modulation, immune regulation, chemical small-molecules regulation, extracellular matrix remodeling, and cell-cell fusion, to achieve Müller glia reprogramming in mice.

Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis.

JOURNAL/nrgr/04.03/01300535-202502000-00029/figure1/v/2024-05-28T214302Z/r/image-tiff Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis. Human-induced pluripotent stem cell-derived neural stem cell exosomes (hiPSC-NSC-Exos) have shown potential for brain injury repair in central nervous system diseases. In this study, we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism. Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits, enhanced blood-brain barrier integrity, and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage. Additionally, hiPSC-NSC-Exos decreased immune cell infiltration, activated astrocytes, and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α post-intracerebral hemorrhage, thereby improving the inflammatory microenvironment. RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion, thereby improving blood-brain barrier integrity. Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects. In summary, our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity, in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury.

JOURNAL/nrgr/04.03/01300535-202502000-00032/figure1/v/2024-05-28T214302Z/r/image-tiff Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury. Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction. However, the mechanisms involved remain unclear. In this study, we found that after spinal cord injury, resting microglia (M0) were polarized into pro-inflammatory phenotypes (MG1 and MG3), while resting astrocytes were polarized into reactive and scar-forming phenotypes. The expression of growth arrest-specific 6 (Gas6) and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury. In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia, and even inhibited the cross-regulation between them. We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway. This, in turn, inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways. In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord, thereby promoting tissue repair and motor function recovery. Overall, Gas6 may play a role in the treatment of spinal cord injury. It can inhibit the inflammatory pathway of microglia and polarization of astrocytes, attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment, and thereby alleviate local inflammation and reduce scar formation in the spinal cord.

Impaired arginine/ornithine metabolism drives severe HFMD by promoting cytokine storm.

Introduction: The Hand, Foot and Mouth Disease (HFMD), caused by enterovirus 71 infection, is a global public health emergency. Severe HFMD poses a significant threat to the life and well-being of children. Numerous studies have indicated that the occurrence of severe HFMD is associated with cytokine storm. However, the precise molecular mechanism underlying cytokine storm development remains elusive, and there are currently no safe and effective treatments available for severe HFMD in children. Methods: In this study, we established a mouse model of severe HFMD to investigate the molecular mechanisms driving cytokine storm. We specifically analyzed metabolic disturbances, focusing on arginine/ornithine metabolism, and assessed the potential therapeutic effects of spermine, an ornithine metabolite. Results: Our results identified disturbances in arginine/ornithine metabolism as a pivotal factor driving cytokine storm onset in severe HFMD cases. Additionally, we discovered that spermine effectively mitigated the inflammatory injury phenotype observed in mice with severe HFMD. Discussion: In conclusion, our findings provide novel insights into the molecular mechanisms underlying severe HFMD from a metabolic perspective while offering a promising new strategy for its safe and effective treatment.

Development and validation of a prediction model for mortality in critically ill COVID-19 patients.

Background: Early prediction of prognosis may help early treatment measures to reduce mortality in critically ill coronavirus disease (COVID-19) patients. The study aimed to develop a mortality prediction model for critically ill COVID-19 patients. Methods: This retrospective study analyzed the clinical data of critically ill COVID-19 patients in an intensive care unit between April and June 2022. Propensity matching scores were used to reduce the effect of confounding factors. A predictive model was built using logistic regression analysis and visualized using a nomogram. Calibration and receiver operating characteristic (ROC) curves were used to estimate the accuracy and predictive value of the model. Decision curve analysis (DCA) was used to examine the value of the model for clinical interventions. Results: In total, 137 critically ill COVID-19 patients were enrolled; 84 survived, and 53 died. Univariate and multivariate logistic regression analyses revealed that aspartate aminotransferase (AST), creatinine, and myoglobin levels were independent prognostic factors. We constructed logistic regression prediction models using the seven least absolute shrinkage and selection operator regression-selected variables (hematocrit, red blood cell distribution width-standard deviation, procalcitonin, AST, creatinine, potassium, and myoglobin; Model 1) and three independent factor variables (Model 2). The calibration curves suggested that the actual predictions of the two models were similar to the ideal predictions. The ROC curve indicated that both models had good predictive power, and Model 1 had better predictive power than Model 2. The DCA results suggested that the model intervention was beneficial to patients and patients benefited more from Model 1 than from Model 2. Conclusion: The predictive model constructed using characteristic variables screened using LASSO regression can accurately predict the prognosis of critically ill COVID-19 patients. This model can assist clinicians in implementing early interventions. External validation by prospective large-sample studies is required.

Influence of Long Non-Coding RNAs on Human Oocyte Development.

Recent research findings have highlighted the pivotal roles played by lncRNAs in both normal human development and disease pathogenesis. LncRNAs are expressed in oocytes and early embryos, and their expression levels change dynamically once the embryonic genome is activated during early human embryonic development. Abnormal expression of lncRNAs was found in follicular fluid, granulosa cells and oocytes of patients, and these lncRNAs were related to cell proliferation and apoptosis, nuclear maturation and follicle development. The expression levels of some lncRNAs in cumulus cells demonstrate correlations with the quality of oocytes and early embryos. This paper aims to present a comprehensive overview of the influence of LncRNAs on the developmental process of human oocytes as well as their involvement in certain infertility-related diseases.

Cytochrome P450 Enzyme Design by Constraining the Catalytic Pocket in a Diffusion Model.

Although cytochrome P450 enzymes are the most versatile biocatalysts in nature, there is insufficient comprehension of the molecular mechanism underlying their functional innovation process. Here, by combining ancestral sequence reconstruction, reverse mutation assay, and progressive forward accumulation, we identified 5 founder residues in the catalytic pocket of flavone 6-hydroxylase (F6H) and proposed a "3-point fixation" model to elucidate the functional innovation mechanisms of P450s in nature. According to this design principle of catalytic pocket, we further developed a de novo diffusion model (P450Diffusion) to generate artificial P450s. Ultimately, among the 17 non-natural P450s we generated, 10 designs exhibited significant F6H activity and 6 exhibited a 1.3- to 3.5-fold increase in catalytic capacity compared to the natural CYP706X1. This work not only explores the design principle of catalytic pockets of P450s, but also provides an insight into the artificial design of P450 enzymes with desired functions.

Validation of Yeo's index in assessing severity of rheumatic mitral stenosis in mixed valve lesions.

Introduction: Yeo's Index, product of the mitral leaflet separation index and dimensionless index, is a novel measure of the severity of rheumatic mitral stenosis (MS). We assess Yeo's index in patients with rheumatic MS with or without mixed valve disease. Methods: In a retrospective cohort study, Yeo's index was measured in 237 cases of rheumatic MS - 124 in a transthoracic echocardiography validation cohort using mitral valve area (MVA) by pressure half-time and planimetry as comparator and 113 in a transesophageal echocardiography (TEE) validation cohort using TEE three-dimensional MVA as comparator. Patients were considered to have mixed valve disease if they had MS and concomitant mitral regurgitation or aortic valve disease. Results: There were 113 patients with isolated MS and 124 patients with mixed valve disease. Overall, Yeo's index ≤ 0.26 cm showed 93.0 % sensitivity and 87.5 % specificity for identifying severe MS (MVA ≤ 1.5 cm2). In isolated MS, Yeo's index ≤ 0.26 cm showed sensitivity of 94.6 % and specificity of 90.0 % for identifying severe MS, while in mixed valve disease sensitivity was 90.6 % and specificity 86.7 %. Overall, Yeo's index ≤ 0.15 cm showed 83.6 % sensitivity and 94.3 % specificity for very severe MS (MVA ≤ 1.0 cm2). In isolated MS, the threshold of ≤0.15 cm showed sensitivity of 84.4 % and specificity of 92.6 % for very severe MS, while in mixed valve disease sensitivity was 81.3 % and specificity 95.3 %. The presence of atrial fibrillation did not influence the performance of Yeo's index. Conclusion: Yeo's Index accurately differentiates severity of rheumatic MS with or without mixed valve disease.

Changes in the rumen development, rumen fermentation, and rumen microbiota community in weaned calves during steviol glycosides treatment.

Early weaning leads to weaning stress in calves, which hinders healthy growth and development. As an excellent sweetener applied in food, steviol glycosides (STE) has also been shown to exhibit positive biological activity in monogastric animals. Therefore, this study aimed to evaluate the impact of incorporating STE as a dietary supplement on rumen development, fermentation, and microbiota of rumen in weaned calves. This study selected 24 healthy Holstein bull calves and randomly allocated them into two groups (CON and STE). The results indicated that supplementation STE group improved rumen development in weaned calves, as demonstrated by a marked increase in the weight of the rumen, as well as the length and surface area of the rumen papilla. Compared with the CON group, the concentrations of total volatile fatty acids (TVFA), propionate, butyrate, and valerate were higher in the STE group. Moreover, STE treatment increased the relative abundance of Firmicutes and Actinobacteria at the phylum level. At the genus level, the STE group showed a significantly increased relative abundance of Succiniclasticum, Lachnospiraceae_NK3A20_group, and Olsenella, and a decreased relative abundance of Acinetobacter compared to the CON group. Pusillimonas, Lachnospiraceae_NK3A20_group, Olsenella, and Succiniclasticum were significantly enriched in rumen chyme after supplementation with STE, as demonstrated by LEfSe analysis. Overall, our findings revealed that rumen bacterial communities altered in response to the dietary supplementation with STE, and some bacterial taxa in these communities may have positive effects on rumen development during this period.

Class-Irrelevant Feature Removal for Few-Shot Image Classification.

Most existing few-shot image classification methods employ global pooling to aggregate class-relevant local features in a data-drive manner. Due to the difficulty and inaccuracy in locating class-relevant regions in complex scenarios, as well as the large semantic diversity of local features, the class-irrelevant information could reduce the robustness of the representations obtained by performing global pooling. Meanwhile, the scarcity of labeled images exacerbates the difficulties of data-hungry deep models in identifying class-relevant regions. These issues severely limit deep models' few-shot learning ability. In this work, we propose to remove the class-irrelevant information by making local features class relevant, thus bypassing the big challenge of identifying which local features are class irrelevant. The resulting class-irrelevant feature removal (CIFR) method consists of three phases. First, we employ the masked image modeling strategy to build an understanding of images' internal structures that generalizes well. Second, we design a semantic-complementary feature propagation module to make local features class relevant. Third, we introduce a weighted dense-connected similarity measure, based on which a loss function is raised to fine-tune the entire pipeline, with the aim of further enhancing the semantic consistency of the class-relevant local features. Visualization results show that CIFR achieves the removal of class-irrelevant information by making local features related to classes. Comparison results on four benchmark datasets indicate that CIFR yields very promising performance.

Projective Synchronization of Discrete-Time Variable-Order Fractional Neural Networks With Time-Varying Delays.

This article is committed to studying projective synchronization and complete synchronization (CS) issues for one kind of discrete-time variable-order fractional neural networks (DVFNNs) with time-varying delays. First, two new variable-order fractional (VF) inequalities are built by relying on nabla Laplace transform and some properties of Mittag-Leffler function, which are extensions of constant-order fractional (CF) inequalities. Moreover, the VF Halanay inequality in discrete-time sense is strictly proved. Subsequently, some sufficient projective synchronization and CS criteria are derived by virtue of VF inequalities and hybrid controllers. Finally, we exploit numerical simulation examples to verify the validity of the derived results, and a practical application of the obtained results in image encryption is also discussed.

The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation.

The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. We used gene co-essentiality analysis to identify an unappreciated relationship between TSC22D2, WNK1, and NRBP1 in regulating cell volume homeostasis. All of these genes have paralogs and are functionally buffered for osmo-sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK, and NRBP family members physically associate into biomolecular condensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans revealed that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is accompanied by rapid IDR length expansion in WNK-family kinases. Our study reveals that TSC22D, WNK, and NRBP genes evolved in metazoans to co-regulate rapid cell volume changes in response to osmolarity.

Hypersensitive MR Angiography for Diagnosis of Ischemic Stroke and Reperfusion Subarachnoid Hemorrhage.

Stroke is an acute injury of the central nervous system caused by the disorders of cerebral blood circulation, which has become one of the major causes of disability and death. Hemorrhage, particularly subarachnoid hemorrhage (SAH), is one of the poorest prognostic factors in stroke, which is related to the thrombolytic therapy, and has been considered very dangerous. In this context, the MR angiography with high sensitivity and resolution has been developed based on biocompatible paramagnetic ultrasmall NaGdF4 nanoprobes. Owing to the appropriate hydrodynamic diameter, the nanoprobe can be confined inside the blood vessels and it only extravasates at the vascular injury site when the bleeding occurs. Relying on this property, the three-dimensional (3D) anatomic structures of artery occlusion of stroke rat can be precisely visualized; reperfusion-related SAH has been successfully visualized and identified. Benefiting from the long blood half-life of the nanoprobe, the observation window of MR angiography can last for the whole period of reperfusion, thereby monitoring the probable SAH in real time during thrombolytic therapy. More importantly, through reconstruction of multiparametric MRI, the arterial occlusion, cerebral ischemic region, and SAH can be simultaneously visualized in vivo in a 3D manner for the first time. Therefore, the current study provides a novel approach for both noninvasive 3D vascular visualization and hemorrhage alert, which possesses great prospects for clinical translation.

Significantly Enhanced Mechanical, Thermal, and Ablative Properties of the Lightweight Carbon Fabric/Phenol-Formaldehyde Resin/Siloxane Aerogels Ternary Interpenetrating Network.

Lightweight ablative thermal protection materials (TPMs), which can resist long-term ablation in an oxidizing atmosphere, are urgently required for aerospace vehicles. Herein, carbon fabric/phenol-formaldehyde resin/siloxane aerogels (CF/PFA/SiA) nanocomposite with interpenetrating network multiscale structure was developed via simple and efficient sol-gel followed by atmospheric pressure drying. The ternary networks structurally interpenetrating in macro-, micron-, and the nanoscales, chemically cross-linking at the molecular scale, and silica layer generated by in situ heating synergistically bring about low density (∼0.3 g cm-3), enhanced mechanical properties, thermal stability, and oxidation resistance, and a low thermal conductivity of 81 mW m-1 K-1. More intriguingly, good thermal protection with near-zero surface recession at 1300 °C for 300 s and remarkable thermal insulation with a back-side temperature below 60 °C at 20 mm thickness. The interpenetrating network strategy can be extended to other porous components with excellent high-temperature properties, such as ZrO2 and SiC, which will facilitate the improvement of lightweight ablative TPMs. Moreover, it may open a new avenue for fabricating multifunctional binary, ternary, and even multiple interpenetrating network materials.

Antimony-Platinum Modulated Contact Enabling Majority Carrier Polarity Selection on a Monolayer Tungsten Diselenide Channel.

We develop a novel metal contact approach using an antimony (Sb)-platinum (Pt) bilayer to mitigate Fermi-level pinning in 2D transition metal dichalcogenide channels. This strategy allows for control over the transport polarity in monolayer WSe2 devices. By adjustment of the Sb interfacial layer thickness from 10 to 30 nm, the effective work function of the contact/WSe2 interface can be tuned from 4.42 eV (p-type) to 4.19 eV (n-type), enabling selectable n-/p-FET operation in enhancement mode. The shift in effective work function is linked to Sb-Se bond formation and an emerging n-doping effect. This work demonstrates high-performance n- and p-FETs with a single WSe2 channel through Sb-Pt contact modulation. After oxide encapsulation, the maximum current density at |VD| = 1 V reaches 170 µA/µm for p-FET and 165 µA/µm for n-FET. This approach shows promise for cost-effective CMOS transistor applications using a single channel material and metal contact scheme.

Stimulating Electron Delocalization of Lanthanide Elements through High-Entropy Confinement to Promote Electrocatalytic Water Splitting.

High-entropy alloys (HEAs) have aroused extensive attention in the field of catalysis. However, due to the integration of multiple active sites in HEA, it exhibits excessive adsorption behavior resulting in difficult desorption of active species from the catalyst surfaces, which hinders the catalytic efficiency. Therefore, adjusting the adsorption strength of the active site in HEA to enhance the catalytic activity is of great importance. By introducing rare-earth (RE) elements into the high-entropy alloy, the delocalization of 4f electrons can be achieved through the interaction between the multimetal active site and RE, which benefits to regulate the adsorption strength of the HEA surface. Herein, the RE Ce-modified hexagonal-close-packed PtRuFeCoNiZn-Ce/C HEAs are synthesized and showed an excellent electrocatalytic activity for hydrogen evolution reaction and oxygen evolution reaction with ultralow overpotentials of 4, 7 and 156, 132 mV, respectively, to reach 10 mA cm-2 in 0.5 M H2SO4 and 1.0 M KOH solutions, and the assembled water electrolysis cell only requires a voltage of 1.43 V to reach 10 mA cm-2, which is much better than the performance of PtRuFeCoNiZn/C. Combined with the results of in situ attenuated total reflection infrared spectroscopy and density functional theory (DFT), the fundamental reasons for the improvement of catalyst activity come from two aspects: (i) local lattice distortion of HEA caused by the introduction of RE with large atomic radius induces 4f orbital electron delocalization of RE elements and enhances electron exchange between RE and active sites. (ii) The electronegativity difference between the RE element and the active site forms a surface dipole in HEA, which optimizes the adsorption of the active intermediate by the HEA surface site. This study provides an insightful idea for the rational design of high-performance HEA- and RE-based electrocatalysts.