Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion.

High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.

The WOX9-WUS modules are indispensable for the maintenance of stem cell homeostasis in Arabidopsis thaliana.

The dynamic balance between the self-renewal and differentiation of stem cells in plants is precisely regulated by a series of developmental regulated genes that exhibit spatiotemporal-specific expression patterns. Several studies have demonstrated that the WOX family transcription factors play critical roles in maintaining the identity of stem cells in Arabidopsis thaliana. In this study, we obtained amiR-WOX9 transgenic plants, which displayed terminating prematurely of shoot apical meristem (SAM) development, along with alterations in inflorescence meristem and flower development. The phenotype of amiR-WOX9 plants exhibited similarities to that of wus-101 mutant, characterized by a stop-and-go growth pattern. It was also found that the expression of WUS in amiR-WOX9 lines was decreased significantly, while in UBQ10::WOX9-GFP transgenic plants, the WUS expression was increased significantly despite no substantial alteration in meristem size compared to Col. Therefore, these data substantiated the indispensable role of WOX9 in maintaining the proper expression of WUS. Further investigations unveiled the direct binding of WOX9 to the WUS promoter via the TAAT motif, thereby activating its expression. It was also found that WUS recognized identical the same TAAT motif cis-elements in its own promoter, thereby repress self-expression. Next, we successfully identified a physical interaction between WOX9 and WUS, and verified that it was harmful to the expression of WUS. Finally, our experimental findings demonstrate that WOX9 was responsible for the direct activating of WUS, which however was interfered by the ways of WUS binding its own promoter and the interaction of WUS and WOX9, thereby ensuring the appropriate expression pattern of WUS and then the stem cell stability. This study contributes to an enhanced comprehension of the regulatory network of the WOX9-WUS module in maintaining the equilibrium of the SAM.

STAMENLESS1 activates SUPERWOMAN 1 and FLORAL ORGAN NUMBER 1 to control floral organ identities and meristem fate in rice.

Floral patterns are unique to rice and contribute significantly to its reproductive success. SL1 encodes a C2H2 transcription factor that plays a critical role in flower development in rice, but the molecular mechanism regulated by it remains poorly understood. Here, we describe interactions of the SL1 with floral homeotic genes, SPW1, and DL in specifying floral organ identities and floral meristem fate. First, the sl1 spw1 double mutant exhibited a stamen-to-pistil transition similar to that of sl1, spw1, suggesting that SL1 and SPW1 may located in the same pathway regulating stamen development. Expression analysis revealed that SL1 is located upstream of SPW1 to maintain its high level of expression and that SPW1, in turn, activates the B-class genes OsMADS2 and OsMADS4 to suppress DL expression indirectly. Secondly, sl1 dl displayed a severe loss of floral meristem determinacy and produced amorphous tissues in the third/fourth whorl. Expression analysis revealed that the meristem identity gene OSH1 was ectopically expressed in sl1 dl in the fourth whorl, suggesting that SL1 and DL synergistically terminate the floral meristem fate. Another meristem identity gene, FON1, was significantly decreased in expression in sl1 background mutants, suggesting that SL1 may directly activate its expression to regulate floral meristem fate. Finally, molecular evidence supported the direct genomic binding of SL1 to SPW1 and FON1 and the subsequent activation of their expression. In conclusion, we present a model to illustrate the roles of SL1, SPW1, and DL in floral organ specification and regulation of floral meristem fate in rice.

The APC/CTAD1-WIDE LEAF 1-NARROW LEAF 1 pathway controls leaf width in rice.

Leaf morphology is one of the most important features of the ideal plant architecture. However, the genetic and molecular mechanisms controlling this feature in crops remain largely unknown. Here, we characterized the rice (Oryza sativa) wide leaf 1 (wl1) mutant, which has wider leaves than the wild-type due to more vascular bundles and greater distance between small vascular bundles. WL1 encodes a Cys-2/His-2-type zinc finger protein that interacts with Tillering and Dwarf 1 (TAD1), a co-activator of the anaphase-promoting complex/cyclosome (APC/C) (a multi-subunit E3 ligase). The APC/CTAD1 complex degrades WL1 via the ubiquitin-26S proteasome degradation pathway. Loss-of-function of TAD1 resulted in plants with narrow leaves due to reduced vascular bundle numbers and distance between the small vascular bundles. Interestingly, we found that WL1 negatively regulated the expression of a narrow leaf gene, NARROW LEAF 1 (NAL1), by recruiting the co-repressor TOPLESS-RELATED PROTEIN and directly binding to the NAL1 regulatory region to inhibit its expression by reducing the chromatin histone acetylation. Furthermore, biochemical and genetic analyses revealed that TAD1, WL1, and NAL1 operated in a common pathway to control the leaf width. Our study establishes an important framework for understanding the APC/CTAD1-WL1-NAL1 pathway-mediated control of leaf width in rice, and provides insights for improving crop plant architecture.

Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19-associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin, a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.

Full-length EFOP3 and EFOP4 proteins are essential for pollen intine development in Arabidopsis thaliana.

Pollen development is critical to plant reproduction, but the underlying regulatory molecular mechanisms have not been fully elucidated. The Arabidopsis (Arabidopsis thaliana) EFR3 OF PLANT 3 (EFOP3) and EFR3 OF PLANT 4 (EFOP4) genes encode members of the Armadillo (ARM) repeat superfamily that play key roles in pollen development. Herein, we demonstrate that EFOP3 and EFOP4 are co-expressed in pollen at anther stages 10-12, but loss-of-function of both EFOP3 and EFOP4 leads to male gametophyte sterility, irregular intine, and shriveled pollen grains at anther stage 12. We further established that full-length EFOP3 and EFOP4 specifically localize to the plasma membrane, and the integrity of these proteins is essential for pollen development. We observed uneven intine, less organized cellulose and reduced pectin content in mutant pollen compared with the wild-type. These, together with the misexpression of several genes related to cell wall metabolism in efop3-/- efop4+/- mutants, suggest that EFOP3 and EFOP4 may indirectly regulate the expression of these genes to affect intine formation, thus controlling Arabidopsis pollen fertility in a functionally redundant manner. Moreover, transcriptome analysis showed that the absence of EFOP3 and EFOP4 function affects multiple pollen development pathways. These results enhance our understanding of EFOPs proteins and their role in pollen development.

Improving Quantitative Analysis with Cross Instrument-Sparse Bayesian Learning (CI-SBL) Raman Spectroscopy Analysis Algorithm.

Qualitative and quantitative analysis of Raman spectroscopy is a widely used nondestructive analytical technique in many fields. It utilizes the Raman scattering effect of lasers to obtain molecular vibration information on samples. By comparison with the Raman spectra of standard substances, qualitative and quantitative analyses can be achieved on unknown samples. However, current Raman spectroscopy analysis algorithms still have many drawbacks. They struggled to handle quantitative analysis between different instruments. Their prediction accuracy for concentration is generally low, with poor robustness. Therefore, this study addresses these deficiencies by designing the cross instrument-sparse Bayesian learning (CI-SBL) Raman spectroscopy analysis algorithm. CI-SBL can facilitate spectroscopic analysis between different instruments through the cross instrument module. CI-SBL converts data from portable instruments into data from scientific instruments, with high similarity between the converted spectrum and the spectrum from the scientific instruments reaching 98.6%. The similarity between the raw portable instrument spectrum and the scientific instrument spectrum is often lower than 90%. The cross instrument effect of the CI-SBL is remarkable. Moreover, CI-SBL employs sparse Bayesian learning (SBL) as the core module for analysis. Through multiple iterations, the SBL algorithm effectively identified various components within mixtures. In experiments, CI-SBL can achieve a qualitative accuracy of 100% for the majority of binary and multicomponent mixtures. On the other hand, the previous Raman spectroscopy analysis algorithms predominantly yield a qualitative accuracy below 80% for the same data. Additionally, CI-SBL incorporates a quantitative module to calculate the concentration of each component within the mixed samples. In the experiment, the quantification error for all substances was below 3%, with the majority of the substances exhibiting an error of approximately 1%. These experimental results illustrate that CI-SBL significantly enhances the accuracy of qualitative judgment of mixture spectra and the prediction of mixture concentrations compared with previous Raman spectroscopy analysis algorithms. Furthermore, the cross instrument module of CI-SBL allows for a flexible handling of data acquired from different instruments.

Maize actin depolymerizing factor 1 (ZmADF1) negatively regulates pollen development.

The normal development of pollen grains and the completion of double fertilization in embryos are crucial for both the sexual reproduction of angiosperms and grain production. Actin depolymerizing factor (ADF) regulates growth, development, and responses to biotic and abiotic stress by binding to actin in plants. In this study, the function of the ZmADF1 gene was validated through bioinformatic analysis, subcellular localization, overexpression in maize and Arabidopsis, and knockout via CRISPR/Cas9. The amino acid sequence of ZmADF1 exhibited high conservation and a similar tertiary structure to that of ADF homologs. Subcellular localization analysis revealed that ZmADF1 is localized mainly to the nucleus and cytoplasm. The ZmADF1 gene was specifically expressed in maize pollen, and overexpression of the ZmADF1 gene decreased the number of pollen grains in the anthers of transgenic Arabidopsis plants. The germination rate of pollen and the empty seed shell rate in the fruit pods of the overexpressing plants were significantly greater than those in the wild-type (WT) plants. In maize, the pollen viability of the knockout lines was significantly greater than that of both the WT and the overexpressing lines. Our results confirmed that the ZmADF1 gene was specifically expressed in pollen and negatively regulated pollen quantity, vigor, germination rate, and seed setting rate. This study provides insights into ADF gene function and possible pathways for improving high-yield maize breeding.

Hierarchically Porous Carbon Rods Derived from Metal-Organic Frameworks for Aqueous Zinc-Ion Hybrid Capacitors.

Aqueous zinc-ion hybrid capacitors (ZIHCs), as ideal candidates for high energy-power supply systems, are restricted by unsatisfied energy density and poor cycling durability for further applications. The construction of a surface-functionalized carbon cathode is an effective strategy for improving the performance of ZIHCs. Herein, a high-performance ZIHC is achieved using oxygen-rich hierarchically porous carbon rods (MDPC-X) prepared by the pyrolysis of a metal-organic framework (MOF) assisted by KOH activation. The MDPC-X samples displayed high electric double-layer capacitance (EDLC) and pseudocapacitance owing to their oxygen-rich surfaces, abundant electroactive sites, and short ions/electron transfer lengths. The surface oxygen functional groups for the reversible chemical adsorption/desorption of Zn2+ are identified using ex situ X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). Consequently, the as-assembled ZIHC exhibited a high capacity of 323.4 F g-1 (161.7 mA h g-1) at 0.5 A g-1 and a retention of 147 F g-1 (73.5 mA h g-1) at an ultrahigh current density of 50 A g-1, corresponding to high energy and power densities of 145.5 W h kg-1 and 45 kW kg-1, respectively. Furthermore, an excellent cycling life with 96.5% of capacity retention is also maintained after 10 000 cycles at 10 A g-1, demonstrating its promising potential for applications.

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

SQLE-a promising prognostic biomarker in cervical cancer: implications for tumor malignant behavior, cholesterol synthesis, epithelial-mesenchymal transition, and immune infiltration.

BACKGROUND: Cervical cancer, encompassing squamous cell carcinoma and endocervical adenocarcinoma (CESC), presents a considerable risk to the well-being of women. Recent studies have reported that squalene epoxidase (SQLE) is overexpressed in several cancers, which contributes to cancer development. METHODS: RNA sequencing data for SQLE were obtained from The Cancer Genome Atlas. In vitro experiments, including colorimetry, colony formation, Transwell, RT-qPCR, and Western blotting were performed. Furthermore, a transplanted CESC nude mouse model was constructed to validate the tumorigenic activity of SQLE in vivo. Associations among the SQLE expression profiles, differentially expressed genes (DEGs), immune infiltration, and chemosensitivity were examined. The prognostic value of genetic changes and DNA methylation in SQLE were also assessed. RESULTS: SQLE mRNA expression was significantly increased in CESC. ROC analysis revealed the strong diagnostic ability of SQLE toward CESC. Patients with high SQLE expression experienced shorter overall survival. The promotional effects of SQLE on cancer cell proliferation, metastasis, cholesterol synthesis, and EMT were emphasized. DEGs functional enrichment analysis revealed the signaling pathways and biological processes. Notably, a connection existed between the SQLE expression and the presence of immune cells as well as the activation of immune checkpoints. Increased SQLE expressions exhibited increased chemotherapeutic responses. SQLE methylation status was significantly associated with CESC prognosis. CONCLUSION: SQLE significantly affects CESC prognosis, malignant behavior, cholesterol synthesis, EMT, and immune infiltration; thereby offering diagnostic and indicator roles in CESC. Thus, SQLE can be a novel therapeutic target in CESC treatment.

Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation.

Major depressive disorder (MDD) is a global health burden characterized by persistent low mood, deprivation of pleasure, recurrent thoughts of death, and physical and cognitive deficits. The current understanding of the pathophysiology of MDD is lacking, resulting in few rapid and effective antidepressant therapies. Recent studies have pointed to the sigma-1 (σ-1) receptor as a potential rapid antidepressant target; σ-1 agonists have shown promise in a variety of preclinical depression models. Hypidone hydrochloride (YL-0919), an independently developed antidepressant by our institute with faster onset of action and low rate of side effects, has recently emerged as a highly selective σ-1 receptor agonist; however, its underlying astrocyte-specific mechanism is unknown. In this study, we investigated the effect of YL-0919 treatment on gene expression in the prefrontal cortex of depressive-like mice by single-cell RNA sequencing. Furthermore, we knocked down σ-1 receptors on astrocytes in the medial prefrontal cortex of mice to explore the effects of YL-0919 on depressive-like behavior and neuroinflammation in mice. Our results demonstrated that astrocyte-specific knockdown of σ-1 receptor resulted in depressive-like behavior in mice, which was reversed by YL-0919 administration. In addition, astrocytic σ-1 receptor deficiency led to activation of the NF-κB inflammatory pathway, and crosstalk between reactive astrocytes and activated microglia amplified neuroinflammation, exacerbating stress-induced neuronal apoptosis. Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs.

The Role of Neuromodulation and Potential Mechanism in Regulating Heterotopic Ossification.

Heterotopic ossification (HO) is a pathological process characterized by the aberrant formation of bone in muscles and soft tissues. It is commonly triggered by traumatic brain injury, spinal cord injury, and burns. Despite a wide range of evidence underscoring the significance of neurogenic signals in proper bone remodeling, a clear understanding of HO induced by nerve injury remains rudimentary. Recent studies suggest that injury to the nervous system can activate various signaling pathways, such as TGF-ß, leading to neurogenic HO through the release of neurotrophins. These pathophysiological changes lay a robust groundwork for the prevention and treatment of HO. In this review, we collected evidence to elucidate the mechanisms underlying the pathogenesis of HO related to nerve injury, aiming to enhance our understanding of how neurological repair processes can culminate in HO.

Nanocomposite Hydrogel Bioinks for 3D Bioprinting of Tumor Models.

In vitro tumor models were successfully constructed by 3D bioprinting; however, bioinks with proper viscosity, good biocompatibility, and tunable biophysical and biochemical properties are highly desirable for tumor models that closely recapitulated the main features of native tumors. Here, we developed a nanocomposite hydrogel bioink that was used to construct ovarian and colon cancer models by 3D bioprinting. The nanocomposite bioink was composed of aldehyde-modified cellulose nanocrystals (aCNCs), aldehyde-modified hyaluronic acid (aHA), and gelatin. The hydrogels possessed tunable gelation time, mechanical properties, and printability by controlling the ratio between aCNCs and gelatin. In addition, ovarian and colorectal cancer cells embedded in hydrogels showed high survival rates and rapid growth. By the combination of 3D bioprinting, ovarian and colorectal tumor models were constructed in vitro and used for drug screening. The results showed that gemcitabine had therapeutic effects on ovarian tumor cells. However, the ovarian tumor model showed drug resistance for oxaliplatin treatment.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol.

BACKGROUND: Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported. METHODS: The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet. RESULTS: We identified 2 PCSK9 mutations-E144K and C378W-in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus-mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum. CONCLUSIONS: Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.

Polyoxometalate Cluster-Guided Dynamic Nucleation and Hierarchical Growth of Branched WO3 Nanofibers with Ultrafine Pt Nanoparticles for Advanced Gas Sensing.

In the food industry, 2,3-butanedione is a significant volatile organic compound valued for its unique aroma and flavor. Real-time detection of its concentration during food preparation is crucial for ensuring optimal taste and food safety. However, accurately detecting low concentrations of 2,3-butanedione requires highly sensitive sensing materials. Herein, we present a novel synthesis of branched WO3 nanofibers decorated with ultrafine Pt nanoparticles (Pt NPs-WO3 NFs), templated by polyoxometalate (POM) clusters, through a combination of electrospinning and thermal oxidation strategies for advanced gas sensing applications. This Pt NPs-WO3 NFs-based sensor exhibits impressive sensitivity (Ra/Rg = 2.25 vs 500 ppb), a low detection limit of 10 ppb, high selectivity, excellent repeatability, and stable performance over a period of 25 days. Using POM clusters as templates offers significant advantages over the traditional WCl6 salt in synthesizing WO3 NFs with smooth surfaces. Specifically, the POM clusters guide the dynamic nucleation and hierarchical growth of branched NFs, enhancing the concentration of oxygen vacancies and increasing the number of active adsorption sites. Furthermore, the uniform dispersion of ultrafine Pt NPs (≈ 4 nm) within the WO3 NFs further enhances the catalytic activation of 2,3-butanedione, significantly improving the gas sensing performance. This study introduces an efficient method to synthesize Pt NPs-WO3 NFs with potential for manufacturing advanced nanostructured sensing materials using POM clusters as templates, paving the way for high-performance gas sensing technologies.

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus.

Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.

Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels.

Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

Optimal design and analysis of a space lightweight mirror with a directionally oriented 2.5D-CVT structure.

Reflective mirrors are the key imaging components of space-borne telescopes, which require a high lightweight ratio integrated with excellent optical properties. In this context, a novel, to our knowledge, 2.5D centroidal Voronoi tessellation (CVT) generation methodology is proposed for designing and optimizing a lightweight mirror structure. Firstly, the initial designs are obtained combining global sensitivity factor mapping and local distribution optimization. Then, the optimal model is selected through multi-objective optimization and decision making. Subsequently, the FEA (finite element analysis) results indicate that, under the same mass, the proposed design exhibits better optomechanical performance. Finally, in practical applications, the approach presented in this paper outperforms the traditional design for each technological requirement, including a 62% reduction in RMS and a higher lightweight ratio. This method offers a kind of novel design and optimization process for space-based optomechanical lightweight structures.