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Autophagy, the intracellular lysosomal degradation process plays a pivotal role in podocyte homeostasis in diabetic kidney disease (DKD). Lysosomal function, autophagic activity, and their actions were investigated in vitro and in vivo. We found that LC3-II- and p62-positive vacuoles accumulated in podocytes of patients with DKD. Moreover, we found that advanced glycation end products (AGEs) could increase the protein expression of LC3-II and p62 in a dose- and time-dependent manner in cultured podocytes. However, the mRNA expression of LC3B, Beclin-1 or ATG7, as well as the protein level of Beclin-1 or ATG7 did not change significantly in the AGE-treated cells compared with that in control groups, suggesting that AGEs did not induce autophagy. In addition, AGEs led to an increase in the number of autophagosomes but not autolysosomes, accompanied with a failure in lysosomal turnover of LC3-II or p62, indicating that the degradation of autophagic vacuoles was blocked. Furthermore, we observed a dramatic decrease in the enzymatic activities, and the degradation of DQ-ovalbumin was significantly suppressed after podocytes were treated with AGEs. Plasma-irregular lysosomal-associated membrane protein 1 granules accompanied with the diffusion of cathepsin D expression and acridine orange redistribution were observed in AGE-treated podocytes, indicating that the lysosomal membrane permeability was triggered. Interestingly, we also found that AGEs-induced autophagic inhibition and podocyte injury were mimicked by the specific lysosomotropic agent, l -leucyl- l -leucine methyl ester. The exacerbated apoptosis and Rac-1-dependent actin-cytoskeletal disorganization were alleviated by an improvement in the lysosomal-dependent autophagic pathway by resveratrol plus vitamin E treatment in AGE-treated podocytes. However, the rescued effects were reversed by the addition of leupeptin, a lysosomal inhibitor. It suggests that restoring lysosomal function to activate autophagy may contribute to the development of new therapeutic strategies for DKD.

Background The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown. Methods Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior. Results The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats. Conclusions These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.

The widely distributed Dendrobium has been studied for a long history, due to its important economic values in both medicine and ornamental. In recent years, some species of Dendrobium and other orchids had been reported on genomic sequences, using the next-generation sequencing technology. And the chloroplast genomes of many Dendrobium species were also revealed. The chromosomes of most Dendrobium species belong to mini-chromosomes, and showed 2n = 38. Only a few of genetic studies were reported in Dendrobium. After revealing of genomic sequences, the techniques of transcriptomics, proteomics and metabolomics could be employed on Dendrobium easily. Some other molecular biological techniques, such as gene cloning, gene editing, genetic transformation and molecular marker developing, had also been applied on the basic research of Dendrobium, successively. As medicinal plants, insights into the biosynthesis of some medicinal components were the most important. As ornamental plants, regulation of flower related characteristics was the most important. More, knowledge of growth and development, environmental interaction, evolutionary analysis, breeding of new cultivars, propagation, and identification of species and herbs were also required for commercial usage. All of these studies were improved using genomic sequences and related technologies. To answer some key scientific issues in Dendrobium, quality formation, flowering, self-incompatibility and seed germination would be the focus of future research. And genome related technologies and studies would be helpful.

Pollen tube reception involves a pollen tube-synergid interaction that controls the discharge of sperm cells into the embryo sac during plant fertilization. Despite its importance in the sexual reproduction of plants, little is known about the role of gene regulation in this process. We report here that the pollen-expressed transcription factors MYB97, MYB101 and MYB120 probably control genes whose encoded proteins play important roles in Arabidopsis thaliana pollen tube reception. They share a high amino acid sequence identity and are expressed mainly in mature pollen grains and pollen tubes. None of the single or double mutants of these three genes exhibited any visible defective phenotype. Although the myb97 myb101 myb120 triple mutant was not defective in pollen development, pollen germination, pollen tube growth or tube guidance, the pollen tubes of the triple mutants exhibited uncontrolled growth and failed to discharge their sperm cells after entering the embryo sac. In addition, the myb97 myb101 myb120 triple mutation significantly affected the expression of a group of pollen-expressed genes in mature pollen grains. All these results indicate that MYB97, MYB101 and MYB120 participate in pollen tube reception, possibly by controlling the expression of downstream genes.

Objectives Building upon the minimization random grouping algorithm designed by Pocock and Simon, this study proposes a randomization algorithm based on the minimization of expected balance distribution differences. This approach aims to balance key covariates and other potential confounding factors. Methods A global difference algorithm based on expected balance distribution was proposed upon analysis of the limitations of the local range algorithm used in traditional minimization randomization for imbalance calculation. The study implemented three algorithms using R 4.3.2 and conducted three experiments through Monte Carlo simulations, In Experiment One, the sample size was fixed, while the number of control factors varied. In Experiment Two, the control factors and their levels were fixed, and the sample sizes varied. Imbalance performance was compared the imbalance performance across groups and control factors. Additionally, in Experiment Three, a real-data analysis was conducted to assess the applicability of the new design in clinical trials. Results In Experiment One, the Expected Balance Distribution and Minimized Variations(EBDMV) consistently outperformed the minimum sufficient balance and the traditional minimization method in terms of the sample size difference between the groups (e.g., 0.716 vs. 15.55 vs. 0.574). Additionally, the P -values distribution was more concentrated, approaching 1. When the number of control factors was increased to 10, the minimum P -value of the traditional method was individually less than 0.05, whereas the minimum P -value of the expected balance distribution and minimized variations(EBDMV) remained greater than 0.05, indicating that the latter method exhibited stronger stability and adaptability. In Experiment Two, the EBDMV also demonstrated higher performance in terms of the sample size difference between groups (e.g., 0.708 vs. 7 vs. 0.726). Furthermore, as the sample size increased, the P -value approached 1, demonstrating greater stability. The results of Experiment Three were consistent with the simulated data. The EBDMV method generally outperformed the traditional minimization method in terms of sample size difference between groups (e.g., 1.08 vs. 9.652 vs. 0.968) and exhibited a more centralized distribution of P -values. Conclusions When the number of control factors is high and the sample size is small, the EBDMV method demonstrates significantly superior balance in both inter-group distributions and control factor balance compared to the traditional minimization method.

Muscle genetic defects can lead to impaired movement, respiratory failure, and other severe symptoms. The development of curative therapies is challenging due to the need for the delivery of gene-editing tools into skeletal muscle cells throughout the body. Here, we use muscular fusogens (Myomaker and Myomerger) to engineer muscle-specific virus-like particles (MuVLPs) for the systemic delivery of gene-editing tools. We demonstrate that MuVLPs can be loaded with diverse payloads, including EGFP, Cre and Cas9/sgRNA ribonucleoproteins (Cas9 RNPs), and can be delivered into skeletal muscle cells via targeted membrane fusion. Systemic administration of MuVLPs carrying Cas9 RNPs enables skeletal muscle-specific gene editing, which excised the exon containing a premature terminator codon mutation in a mouse model for Duchenne muscular dystrophy (DMD). This treatment restores dystrophin expression in various skeletal muscle tissues, including the diaphragm, quadriceps, tibialis anterior, gastrocnemius, and triceps. As a result, the treated mice exhibit a significantly increased capacity for exercise and endurance. This study established a platform for precise gene editing in skeletal muscle tissues. Genetic muscle diseases are difficult to treat due to challenges in delivering gene editors to muscles throughout the body. Here, authors engineer muscle-specific virus-like particles that fuse with skeletal muscle cells to deliver CRISPR tools and restore dystrophin in a DMD model.

Environmental factors are essential input variables for susceptibility assessment models of mountain geohazards. However, the existing literature provides a limited understanding of the relative contribution of these factors to the occurrence of geohazards with a warming climate, posing tremendous challenges for risk management in mountainous areas. Ya'an city is susceptible to hazards because of its steep terrain, abundant precipitation and active seismic activity. In this regard, we utilise the GeoDetector model to extract critical environmental factors affecting the spatial patterns of mountain geohazards (i.e., landslide, debris flow and rockfall) in Southwest China. The analysis indicates that the factors with the highest explanatory power for the spatial distribution of landslides, debris flows, and rockfalls are soil property, extreme precipitation and extreme temperature, respectively. Notably, we revealed the synergistic effects among factors given their larger q-value than individual ones. We further explored the responses of mountain geohazards to climate change, including the rising temperature and precipitation, because the frequent occurrence of mountain geohazards is closely related to a warming climate. The variation in snow water equivalent caused by antecedent snowfall and snowdrifts acts as a crucial indicator for geohazards, highlighting the significance of snow and wind observations in meteorological nowcasting and disaster prewarning. We disclose the phenomenon of the geohazard hysteresis to the precipitation peak resulting from the top–down (i.e., precipitation-runoff and surface-deep soil moisture) peak shifts. Our work is expected to enhance the precision of susceptibility assessment models and the reliability of short-term forecasts for mountain geohazards.

Posterior cingulate cortex (area 23, A23) in human and monkeys is a critical component of the default mode network and is involved in many diseases such as Alzheimer’s disease, autism, depression, attention deficit hyperactivity disorder and schizophrenia. However, A23 has not yet identified in rodents, and this makes modeling related circuits and diseases in rodents very difficult. Using a comparative approach, molecular markers and unique connectional patterns this study has uncovered the location and extent of possible rodent equivalent (A23~) of the primate A23. A23 ~ but not adjoining areas in the rodents displays strong reciprocal connections with anteromedial thalamic nucleus. Rodent A23 ~ reciprocally connects with the medial pulvinar and claustrum as well as with anterior cingulate, granular retrosplenial, medial orbitofrontal, postrhinal, and visual and auditory association cortices. Rodent A23 ~ projects to dorsal striatum, ventral lateral geniculate nucleus, zona incerta, pretectal nucleus, superior colliculus, periaqueductal gray, and brainstem. All these findings support the versatility of A23 in the integration and modulation of multimodal sensory information underlying spatial processing, episodic memory, self-reflection, attention, value assessment and many adaptive behaviors. Additionally, this study also suggests that the rodents could be used to model monkey and human A23 in future structural, functional, pathological, and neuromodulation studies.

Substituted piperidine‐2,6‐diones are privileged scaffolds in numerous bioactive molecules and their facile and practical preparation still remains unsolved. In this paper, a facile and practical approach for the construction of α‐substituted and α,α‐/α,β‐disubstituted piperidine‐2,6‐diones from abundant methyl acetates and acrylamides under transition‐metal free condition was disclosed. It features mild reaction condition, operational simplicity, and excellent functional group tolerance, delivering a wide range of piperidine‐2,6‐diones in moderate to good yield. Furthermore, the application potential was further demonstrated by reaction scale‐up (5 kilo‐gram scale) and bio‐active molecule synthesis (Aminoglutethimide and Niraparib). Additional control experiments revealed that the radical process could be excluded from this reaction and a michael addition/intramolecular imidation cascade sequence was proposed based on the control experiments. All these results demonstrated its significant application potential both in academic and industrial production. KOtBu‐promoted facile and practical synthesis of various substituted piperidine‐2,6‐diones between methyl acetates and acrylamides via a Michael addition/intramolecular imidation cascade sequence has been disclosed. And reaction scale‐up, further transformation of representative products, and preparation of bioactive molecules (e. g. Aminoglutethimide and Niraparib) were achieved in good yield using this newly developed method.

Objectives We aimed to investigate the value of performing gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) radiomics for preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) based on multiple sequences. Methods We randomly allocated 165 patients with HCC who underwent partial hepatectomy to training and validation sets. Stepwise regression and the least absolute shrinkage and selection operator algorithm were used to select significant variables. A clinicoradiological model, radiomics model, and combined model were constructed using multivariate logistic regression. The performance of the models was evaluated, and a nomogram risk-prediction model was built based on the combined model. A concordance index and calibration curve were used to evaluate the discrimination and calibration of the nomogram model. Results The tumour margin, peritumoural hypointensity, and seven radiomics features were selected to build the combined model. The combined model outperformed the radiomics model and the clinicoradiological model and had the highest sensitivity (90.89%) in the validation set. The areas under the receiver operating characteristic curve were 0.826, 0.755, and 0.708 for the combined, radiomics, and clinicoradiological models, respectively. The nomogram model based on the combined model exhibited good discrimination (concordance index = 0.79) and calibration. Conclusions The combined model based on radiomics features of Gd-EOB-DTPA enhanced MRI, tumour margin, and peritumoural hypointensity was valuable for predicting HCC microvascular invasion. The nomogram based on the combined model can intuitively show the probabilities of MVI.