Geminal-atom catalysis for cross-coupling.

Single-atom catalysts (SACs) have well-defined active sites, making them of potential interest for organic synthesis1-4. However, the architecture of these mononuclear metal species stabilized on solid supports may not be optimal for catalysing complex molecular transformations owing to restricted spatial environment and electronic quantum states5,6. Here we report a class of heterogeneous geminal-atom catalysts (GACs), which pair single-atom sites in specific coordination and spatial proximity. Regularly separated nitrogen anchoring groups with delocalized π-bonding nature in a polymeric carbon nitride (PCN) host7 permit the coordination of Cu geminal sites with a ground-state separation of about 4 Å at high metal density8. The adaptable coordination of individual Cu sites in GACs enables a cooperative bridge-coupling pathway through dynamic Cu-Cu bonding for diverse C-X (X = C, N, O, S) cross-couplings with a low activation barrier. In situ characterization and quantum-theoretical studies show that such a dynamic process for cross-coupling is triggered by the adsorption of two different reactants at geminal metal sites, rendering homo-coupling unfeasible. These intrinsic advantages of GACs enable the assembly of heterocycles with several coordination sites, sterically congested scaffolds and pharmaceuticals with highly specific and stable activity. Scale-up experiments and translation to continuous flow suggest broad applicability for the manufacturing of fine chemicals.

Constructing molecule-metal relay catalysis over heterophase metallene for high-performance rechargeable zinc-nitrate/ethanol batteries.

Zinc-nitrate batteries can integrate energy supply, ammonia electrosynthesis, and sewage disposal into one electrochemical device. However, current zinc-nitrate batteries still severely suffer from the limited energy density and poor rechargeability. Here, we report the synthesis of tetraphenylporphyrin (tpp)-modified heterophase (amorphous/crystalline) rhodium-copper alloy metallenes (RhCu M-tpp). Using RhCu M-tpp as a bifunctional catalyst for nitrate reduction reaction (NO3RR) and ethanol oxidation reaction in neutral solution, a highly rechargeable and low-overpotential zinc-nitrate/ethanol battery is successfully constructed, which exhibits outstanding energy density of 117364.6 Wh kg-1cat, superior rate capability, excellent cycling stability of ~400 cycles, and potential ammonium acetate production. Ex/in situ experimental studies and theoretical calculations reveal that there is a molecule-metal relay catalysis in NO3RR over RhCu M-tpp that significantly facilitates the ammonia selectivity and reaction kinetics via a low energy barrier pathway. This work provides an effective design strategy of multifunctional metal-based catalysts toward the high-performance zinc-based hybrid energy systems.

1T'-transition metal dichalcogenide monolayers stabilized on 4H-Au nanowires for ultrasensitive SERS detection.

Unconventional 1T'-phase transition metal dichalcogenides (TMDs) have aroused tremendous research interest due to their unique phase-dependent physicochemical properties and applications. However, due to the metastable nature of 1T'-TMDs, the controlled synthesis of 1T'-TMD monolayers (MLs) with high phase purity and stability still remains a challenge. Here we report that 4H-Au nanowires (NWs), when used as templates, can induce the quasi-epitaxial growth of high-phase-purity and stable 1T'-TMD MLs, including WS2, WSe2, MoS2 and MoSe2, via a facile and rapid wet-chemical method. The as-synthesized 4H-Au@1T'-TMD core-shell NWs can be used for ultrasensitive surface-enhanced Raman scattering (SERS) detection. For instance, the 4H-Au@1T'-WS2 NWs have achieved attomole-level SERS detections of Rhodamine 6G and a variety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins. This work provides insights into the preparation of high-phase-purity and stable 1T'-TMD MLs on metal substrates or templates, showing great potential in various promising applications.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Individualized prediction of anxiety and depressive symptoms using gray matter volume in a non-clinical population.

Machine learning is an emerging tool in clinical psychology and neuroscience for the individualized prediction of psychiatric symptoms. However, its application in non-clinical populations is still in its infancy. Given the widespread morphological changes observed in psychiatric disorders, our study applies five supervised machine learning regression algorithms-ridge regression, support vector regression, partial least squares regression, least absolute shrinkage and selection operator regression, and Elastic-Net regression-to predict anxiety and depressive symptom scores. We base these predictions on the whole-brain gray matter volume in a large non-clinical sample (n = 425). Our results demonstrate that machine learning algorithms can effectively predict individual variability in anxiety and depressive symptoms, as measured by the Mood and Anxiety Symptoms Questionnaire. The most discriminative features contributing to the prediction models were primarily located in the prefrontal-parietal, temporal, visual, and sub-cortical regions (e.g. amygdala, hippocampus, and putamen). These regions showed distinct patterns for anxious arousal and high positive affect in three of the five models (partial least squares regression, support vector regression, and ridge regression). Importantly, these predictions were consistent across genders and robust to demographic variability (e.g. age, parental education, etc.). Our findings offer critical insights into the distinct brain morphological patterns underlying specific components of anxiety and depressive symptoms, supporting the existing tripartite theory from a neuroimaging perspective.

Characteristic Plasmon Energies for 2D In2Se3 Phase Identification at Nanoscale.

Two-dimensional (2D) materials with competing polymorphs offer remarkable potential to switch the associated 2D functionalities for novel device applications. Probing their phase transition and competition mechanisms requires nanoscale characterization techniques that can sensitively detect the nucleation of secondary phases down to single-layer thickness. Here we demonstrate nanoscale phase identification on 2D In2Se3 polymorphs, utilizing their distinct plasmon energies that can be distinguished by electron energy-loss spectroscopy (EELS). The characteristic plasmon energies of In2Se3 polymorphs have been validated by first-principles calculations, and also been successfully applied to reveal phase transitions using in situ EELS. Correlating with in situ X-ray diffraction, we further derive a subtle difference in the valence electron density of In2Se3 polymorphs, consistent with their disparate electronic properties. The nanometer resolution and independence of orientation make plasmon-energy mapping a versatile technique for nanoscale phase identification on 2D materials.

Orbital-Selectivity-Induced Robust Quantum Anomalous Hall Effect in Hund's Metals MgFeP.

Ferromagnetic (FM) states with high Curie temperatures (Tc) and strong spin-orbit coupling (SOC) are indispensable for the long-sought room-temperature quantum anomalous Hall (QAH) effects. Here, we propose a two-dimensional (2D) iron-based monolayer MgFeP that exhibits a notably high FM Tc (about 1525 K) along with exceptional structural stabilities. The unique multiorbital nature in MgFeP, where localized dx2-y2 and dxz/yz orbitals coexist with itinerant dxy and dz2 orbitals, renders the monolayer a Hund's metal and in an orbital-selective Mott phase (OSMP). This OSMP triggers an FM double exchange mechanism, rationalizing the high Tc in the Hund's metal. This material transitions to a QAH insulator upon consideration of the SOC effect. By leveraging orbital selectivity, the QAH band gap can be enlarged by more than two times (to 137 meV). Our findings showcase Hund's metals as a promising material platform for realizing high-performance quantum topological electronic devices.

Happy people are always similar: The evidence from brain morphological and functional inter-subject correlations.

A fundamental question in the study of happiness is whether there is neural evidence to support a well-known hypothesis that happy people are always similar while unfortunate people have their own misfortunes. To investigate this, we employed several happiness-related questionnaires to identify potential components of happiness, and further investigated and confirmed their associations with personality, mood, aggressive behaviors, and amygdala reactivity to fearful faces within a substantial sample size of college students (n = 570). Additionally, we examined the functional and morphological similarities and differences among happy individuals using the inter-subject representational similarity analysis (IS-RSA). IS-RSA emphasizes the geometric properties in a high-dimensional space constructed by brain or behavioral patterns and focuses on individual subjects. Our behavioral findings unveiled two factors of happiness: individual and social, both of which mediated the effect of personality traits on individual aggression. Subsequently, mood mediated the impact of happiness on aggressive behaviors across two subgroup splits. Functional imaging data revealed that individuals with higher levels of happiness exhibited reduced amygdala reactivity to fearful faces, as evidenced by a conventional face-matching task (n = 104). Moreover, IS-RSA demonstrated that these participants manifested similar neural activation patterns when processing fearful faces within the visual pathway, but not within the emotional network (e.g., amygdala). Morphological observations (n = 425) indicated that individuals with similar high happiness levels exhibited comparable gray matter volume patterns within several networks, including the default mode network, fronto-parietal network, visual network, and attention network. Collectively, these findings offer early neural evidence supporting the proposition that happy individuals may share common neural characteristics.

Facet-Dependent Surface Restructuring on Nickel (Oxy)hydroxides: A Self-Activation Process for Enhanced Oxygen Evolution Reaction.

Unraveling the catalyst surface structure and behavior during reactions is essential for both mechanistic understanding and performance optimization. Here we report a phenomenon of facet-dependent surface restructuring intrinsic to ß-Ni(OH)2 catalysts during oxygen evolution reaction (OER), discovered by the correlative ex situ and operando characterization. The ex situ study after OER reveals ß-Ni(OH)2 restructuring at the edge facets to form nanoporous Ni1-xO, which is Ni deficient containing Ni3+ species. Operando liquid transmission electron microscopy (TEM) and Raman spectroscopy further identify the active role of the intermediate ß-NiOOH phase in both the OER catalysis and Ni1-xO formation, pinpointing the complete surface restructuring pathway. Such surface restructuring is shown to effectively increase the exposed active sites, accelerate Ni oxidation kinetics, and optimize *OH intermediate bonding energy toward fast OER kinetics, which leads to an extraordinary activity enhancement of ∼16-fold. Facilitated by such a self-activation process, the specially prepared ß-Ni(OH)2 with larger edge facets exhibits a 470-fold current enhancement than that of the benchmark IrO2, demonstrating a promising way to optimize metal-(oxy)hydroxide-based catalysts.

Engineered bone marrow mesenchymal stem cell-derived exosomes loaded with miR302 through the cardiomyocyte specific peptide can reduce myocardial ischemia and reperfusion (I/R) injury.

BACKGROUND: MicroRNA (miRNA)-based therapies have shown great potential in myocardial repair following myocardial infarction (MI). MicroRNA-302 (miR302) has been reported to exert a protective effect on MI. However, miRNAs are easily degraded and ineffective in penetrating cells, which limit their clinical applications. Exosomes, which are small bioactive molecules, have been considered as an ideal vehicle for miRNAs delivery due to their cell penetration, low immunogenicity and excellent stability potential. Herein, we explored cardiomyocyte-targeting exosomes as vehicles for delivery of miR302 into cardiomyocyte to potentially treat MI. METHODS: To generate an efficient exosomal delivery system that can target cardiomyocytes, we engineered exosomes with cardiomyocyte specific peptide (CMP, WLSEAGPVVTVRALRGTGSW). Afterwards, the engineered exosomes were characterized and identified using transmission electron microscope (TEM) and Nanoparticle Tracking Analysis (NTA). Later on, the miR302 mimics were loaded into the engineered exosomes via electroporation technique. Subsequently, the effect of the engineered exosomes on myocardial ischemia and reperfusion (I/R) injury was evaluated in vitro and in vivo, including MTT, ELISA, real-time quantitative polymerase chain reaction (PCR), western blot, TUNNEL staining, echocardiogram and hematoxylin and eosin (HE) staining. RESULTS: Results of in vitro experimentation showed that DSPE-PEG-CMP-EXO could be more efficiently internalized by H9C2 cells than unmodified exosomes (blank-exosomes). Importantly, compared with the DSPE-PEG-CMP-EXO group, DSPE-PEG-CMP-miR302-EXO significantly upregulated the expression of miR302, while exosomes loaded with miR302 could enhance proliferation of H9C2 cells. Western blot results showed that the DSPE-PEG-CMP-miR302-EXO significantly increased the protein level of Ki67 and Yap, which suggests that DSPE-PEG-CMP-miR302-EXO enhanced the activity of Yap, the principal downstream effector of Hippo pathway. In vivo, DSPE-PEG-CMP-miR302-EXO improved cardiac function, attenuated myocardial apoptosis and inflammatory response, as well as reduced infarct size significantly. CONCLUSION: In conclusion, our findings suggest that CMP-engineered exosomes loaded with miR302 was internalized by H9C2 cells, an in vitro model for cardiomyocytes coupled with potential enhancement of the therapeutic effects on myocardial I/R injury.

FURION: modeling of FEL pulses propagation in dispersive soft X-ray beamline systems.

Modern X-ray free-electron lasers (XFELs) can generate pulses with durations ranging from femtoseconds to attoseconds. The numerical evaluation of ultra-short XFEL pulses through beamline systems is a critical process of beamline system design. However, the bandwidth of such ultra-short XFEL pulses is often non-negligible, and the propagation cannot be simply approximated using the central wavelength, especially in dispersive beamline systems. We developed a numerical model which is called Fourier optics based Ultrashort x-Ray pulse propagatION tool (FURION). This model can not only be used to simulate dispersive beamline systems but also to evaluate non-dispersive beamline systems. The FURION model utilizes Fresnel integral and angular spectrum integral to perform ultra-short XFEL pulse propagation in free space. We also present the method for XFEL pulse propagation through different types of dispersive gratings, which are commonly used in soft X-ray beamline systems. By using FURION, a start-to-end simulation of the FEL-1 beamline system at Shenzhen superconducting soft X-ray free electron laser (S3FEL) is carried out. This model can also be used to evaluate gratings-based spectrometers, beam splitters, pulse compressors, and pulse stretchers. This work provides valuable insights into the start-to-end simulation of X-ray beamline systems.

The novel peptide PFAP1 promotes primordial follicle activation by binding to MCM5.

Premature ovarian failure (POF) is a complication of ovarian dysfunction resulting from the depletion or dysfunction of primordial follicles (PFs) in the ovaries. However, residual follicles that have the potential to be activated are present in POF or aged women. Little is known about the mechanisms by which the remaining dormant PFs in POF patients are activated. Using mass spectrometry, we screened differentially generated peptides extracted from the ovarian cortical tissue biopsies of patients with or without POF, during which we identified PFAP1, a peptide that significantly promoted the activation of PFs in the ovaries of 3 dpp mice in vitro. PFAP1 reversed age-related fertility damage in vivo to a certain extent, promoted estrogen (E2) and anti-mullerian hormone (AMH) production (p < .05), and decreased the levels of follicle-stimulating hormone (FSH) (p < .05). In newborn mouse ovaries, PFAP1 could bind to the protein minichromosome maintenance protein 5 (MCM5) and inhibit its ubiquitination and degradation. In addition, PFAP1 promoted the proliferation of GCs, probably by regulating the function and production of MCM5. In conclusion, PFAP1 could promote the activation of PFs in the ovaries of newborn mice, partially restore the ovarian function of aged mice, and increase the proliferation of primary granulosa cells (GCs) by regulating the function of MCM5. PFAP1 is a promising novel peptide that may be developed into a new therapeutic agent for POF and other ovarian diseases.

Electroacupuncture Alleviates Obesity and Insulin Resistance via the GLP-1-VTADA Reward Circuit.

INTRODUCTION: We investigated the effects of electroacupuncture (EA) on improving obesity and insulin resistance (IR) in high-fat diet-induced (HFDI) obese rats by modulating the nucleus tractus solitarius (NTS) glucagon-like peptide-1 (GLP-1)-ventral tegmental area (VTA) dopamine (DA) neural reward circuit, thereby uncovering a possible central mechanism underlying EA's actions in improving obesity and IR. METHODS: We randomly allocated 45 Wistar male rats to five groups (normal, model, EA, chemogenetic activation, chemogenetic suppression + EA), with 9 rats in each group. All interventions were conducted within 8 weeks after the model was established. We tested rats for obesity phenotypes included body mass, Lee's index, 24-h food intake, and glucose-metabolism parameters. We observed protein and gene expression for GLP-1 in the NTS and tyrosine hydroxylase in the VTA by Western blotting and real-time polymerase chain reaction, as well as their localization by immunofluorescence. We also determined the DA content in the VTA using high-performance liquid chromatography. RESULTS: Obese rats exhibited marked hyperphagia, accompanied by increased excitability of DA neurons in the VTA region and reduced insulin sensitivity. After EA treatment, obese rats showed augmented excitability of NTS GLP-1 and suppression of VTADA neurons with a diminution in food intake, showing results similar to those in the chemogenetic activation group. After EA treatment and while inhibiting GLP-1 neurons by chemogenetics, the effect of EA on activating GLP-1 neurons and inhibiting VTADA was partially abrogated. The effects of improving obesity and insulin sensitivity were likewise also suppressed. CONCLUSION: EA effectively activated GLP-1 neurons in the NTS, thereby inhibited the expression of DA in the VTA and improved obesity and insulin sensitivity in HFDI-obese rats.

Solvent-regulated self-assembled carbon nitride for photocatalytic reduction of U(VI) in water.

Manufacturing high-performance and reusable materials from radioactive uranium-containing wastewater remains a significant challenge. Herein, a supramolecular self-assembly strategy was proposed, using melamine and cyanuric acid as precursors and using intermolecular hydrogen bond force to form carbon nitride (CN-D) in different solvents through a single thermal polymerization strategy. Supramolecular self-assembly method is a promising strategy to synthesize a novel carbon nitride with molecular regulatory properties. In addition, 98% of U(VI) in wastewater can be removed by using CN-D for 60 min under visible light. After five cycles of recycling, more than 95% of U(VI) can still be reduced, indicating that it has good recyclability and reusability. This study not only provides an efficient photocatalytic method of uranium reduction, but also provides a new method for self-assembly synthesis.

Convolutional autoencoder based on latent subspace projection for anomaly detection.

Image anomaly detection (AD) is widely researched on many occasions in computer vision tasks. High-dimensional data, such as image data, with noise and complex background is still challenging to detect anomalies under the situation that imbalanced or incomplete data are available. Some deep learning methods can be trained in an unsupervised way and map the original input into low-dimensional manifolds to predict larger differences in anomalies according to normal ones by dimension reduction. However, training a single low-dimension latent space is limited to present the low-dimensional features due to the fact that the noise and irreverent features are mapped into this space, resulting in that the manifolds are not discriminative for detecting anomalies. To address this problem, a new autoencoder framework is proposed in this study with two trainable mutually orthogonal complementary subspaces in the latent space, by latent subspace projection (LSP) mechanism, which is named as LSP-CAE. Specifically, latent subspace projection is used to train the latent image subspace (LIS) and the latent kernel subspace (LKS) in the latent space of the autoencoder-like model respectively, which can enhance learning power of different features from the input instance. The features of normal data are projected into the latent image subspace, while the latent kernel subspace is trained to extract the irrelevant information according to normal features by end-to-end training. To verify the generality and effectiveness of the proposed method, we replace the convolutional network with the fully-connected network contucted in the real-world medical datasets. The anomaly score based on projection norms in two subspace is used to evaluate the anomalies in the testing. Consequently, our proposed method can achieve the best performance according to four public datasets in comparison of the state-of-the-art methods.

Diverticular peroral endoscopic myotomy (D-POEM) for symptomatic oesophageal diverticulum: a multicentre cohort study with a minimum follow-up of 3 years.

OBJECTIVE: To evaluate the medium- and long-term outcomes of diverticular peroral endoscopic myotomy (D-POEM) for symptomatic oesophageal diverticulum. METHODS: Consecutive patients with symptomatic oesophageal diverticulum who underwent D-POEM from 1st May 2016 to 1st April 2020 in 6 centres were extracted and researched. Symptoms assessed by the modified Eckardt score were registered pre- and post-D-POEM at 1, 6, 12, 24 and 36 months. RESULTS: A total of 34 patients with Zenker's diverticulum (ZD, n = 12), mid-oesophageal diverticulum (MED, n = 12), and epiphrenic diverticulum (ED, n = 10) were included. Complete septotomy was achieved in a mean of 39.15 min, with 100% technical success. No severe intraoperative or postoperative complications were observed. Five patients exhibited subcutaneous emphysema, while 1 had mucosal injury. The mean Eckardt score was 8.59 preoperatively and 2.56 at 1 month, 2.09 at 6 months, 2.21 at 12 months, 2.15 at 24 months, and 2.21 at 36 months postoperatively. The total clinical success rates at 1, 6, 12, 24 and 36 months postoperatively were 97.1%, 97.1%, 94.1%, 91.2%, and 88.2%, respectively. With a median follow-up of 47.2 months, four patients suffered symptom relapse, with a total clinical success rate of 88.2%. A long disease duration, a high Eckardt score, and coexistence of achalasia were identified as risk factors for symptomatic recurrence by multivariable Cox analysis. CONCLUSIONS: D-POEM is an effective and durable treatment for patients with symptomatic oesophageal diverticulum.

Serum alpha 1 antitrypsin potent act as an early diagnostic biomarker for cardiac amyloidosis.

Cardiac amyloidosis is a refractory cardiomyopathy with a poor prognosis and lacks effective treatments. N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T are poor prognostic factors for myocardial amyloidosis. However, NT-proBNP and troponin also serve as markers of heart failure and myocardial infarction, lacking specificity. Whether abnormal elevation of alpha-1 antitrypsin in myocardial amyloidosis also predicts the poor prognosis of patients remains unknown. We conducted a retrospective single-center case-control study to analyze the serological and physical examination data of 83 cardiac amyloidosis patients and 68 healthy controls matched by gender and age. We aimed to explore the onset and prognostic factors of cardiac amyloidosis. The serum alpha-1 antitrypsin level (169.78 ± 39.59 mg/dl) in patients with cardiac amyloidosis was significantly higher than that in the normal control (125.92 ± 18.26 mg/dl). Logistic regression results showed that alpha-1 antitrypsin, free sialic acid, high-density lipoprotein cholesterol, apolipoprotein A/B ratio, and homocysteine were predictors of cardiac amyloidosis. Multivariable logistic regression showed that only alpha 1 antitrypsin was an independent risk factor for cardiac amyloidosis. Receiver operating characteristic curve analysis based on the Mayo stage and troponin level showed the cut-off value of 140.55 mg/dl for alpha-1 antitrypsin in predicting cardiac amyloidosis with 81.7% sensitivity and 83.9% specificity. Elevated alpha-1 antitrypsin levels may be an early diagnostic biomarker for cardiac amyloidosis.

Nuclear poly(A) binding protein 1 (PABPN1) mediates zygotic genome activation-dependent maternal mRNA clearance during mouse early embryonic development.

An embryo starts its life with maternal mRNA clearance, which is crucial for embryonic development. The elimination of maternal transcripts occurs by the joint action of two pathways: the maternally encoded mRNA decay pathway (M-decay) and the zygotic genome activation (ZGA)-dependent pathway (Z-decay). However, zygotic factors triggering maternal mRNA decay in early mammalian embryos remain largely unknown. In this study, we identified the zygotically encoded nuclear poly(A) binding protein 1 (PABPN1) as a factor required for maternal mRNA turnover, with a previously undescribed cytoplasmic function. Cytoplasmic PABPN1 docks on 3'-uridylated transcripts, downstream of terminal uridylyl transferases TUT4 and TUT7, and recruits 3'-5' exoribonuclease DIS3L2 to its targets, facilitating maternal mRNA decay. Pabpn1-knockout in mice resulted in preimplantation stage mortality due to early developmental arrest at the morula stage. Maternal mRNAs to be eliminated via the Z-decay pathway failed to be removed from Pabpn1-depleted embryos. Furthermore, PABPN1-mediated Z-decay is essential for major ZGA and regulates the expression of cell fate-determining factors in mouse preimplantation embryos. This study revealed an unforeseen cytoplasmic function of PABPN1 coupled with early embryonic development, characterized the presence of a zygotic destabilizer of maternal mRNA, and elucidated the Z-decay process mechanisms, which potentially contribute to human fertility.

USP16-mediated histone H2A lysine-119 deubiquitination during oocyte maturation is a prerequisite for zygotic genome activation.

Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and intimately related to changes in chromatin structure and histone modifications. H2AK119ub1, an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by PRC1 and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated using chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes and was enriched at the TSSs of maternal genes, but was promptly declined after meiotic resumption at genome-wide including the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase for H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, or meiotic maturation. However, oocytes lacking USP16 have defects when undergoing zygotic genome activation or gaining developmental competence after fertilization, potentially associated with high levels of maternal H2AK119ub1 deposition on the zygotic genomes. Taken together, H2AK119ub1 level is declined during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.

Exploring the mechanism of dendrobine in treating metabolic associated fatty liver disease based on network pharmacology and experimental validation.

BACKGROUND: This study investigates the therapeutic mechanisms of dendrobine, a primary bioactive compound in Dendrobium nobile, for Metabolic Associated Fatty Liver Disease (MASLD) management. Utilizing network pharmacology combined with experimental validation, the clinical effectiveness of dendrobine in MASLD treatment was assessed and analyzed. RESULTS: The study demonstrates significant improvement in liver function among MASLD patients treated with Dendrobium nobile. Network pharmacology identified key targets such as Peroxisome Proliferator-Activated Receptor Gamma (PPARG), Interleukin 6 (IL6), Tumor Necrosis Factor (TNF), Interleukin 1 Beta (IL1B), and AKT Serine/Threonine Kinase 1 (AKT1), with molecular docking confirming their interactions. Additionally, dendrobine significantly reduced ALT and AST levels in palmitic acid-treated HepG2 cells, indicating hepatoprotective properties and amelioration of oxidative stress through decreased Malondialdehyde (MDA) levels and increased Superoxide Dismutase (SOD) levels. CONCLUSION: Dendrobine mitigates liver damage in MASLD through modulating inflammatory and immune responses and affecting lipid metabolism, potentially by downregulating inflammatory mediators like TNF, IL6, IL1B, and inhibiting AKT1 and Signal Transducer and Activator of Transcription 3 (STAT3). This study provides a theoretical basis for the application of dendrobine in MASLD treatment, highlighting its potential as a therapeutic agent.