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The Greatwall-family protein kinase Rim15 is associated with the nutrient starvation response, whereas its role in oxidative stress responses remains unclear. Here, acetic acid and peroxide were used as two oxidative stress elicitors. The antioxidant indicator assay under acetic acid stress revealed the impaired growth in rim15 Δ related to the regulation of antioxidant systems. Comparative transcriptome analysis revealed that differentially expressed genes (DEGs) are predicted to be mostly regulated by oxidative stress-responsive transcriptional factor Yap1. Among the DEGs, acetic acid stress-induced genes were found, and YAP1 disruption also inhibited their induction. The deletion of Rim15 or the Rim15 kinase domain in yap1 Δ did not further decrease the gene expression, suggesting that Rim15 functions together with Yap1 in regulating acetic acid stress-induced genes, which requires Rim15 kinase activity. Additionally, Rim15 regulated H 2 O 2 stress tolerance through partially similar but special mechanisms in that Rim15 kinase activity impacted acetic acid and H 2 O 2 stress tolerance in different degrees, indicating the different mechanisms underlying Rim15-mediated redox regulation against different stressors. These results benefit the better understanding of stress signaling pathways related to Rim15. Given that Rim15 and some of its target genes are conserved across eukaryotes, these results also provide a basis for studies of oxidative stress-related processes in other organisms.

We developed a visible-light-driven expanded EDA complex profile for the synthesis of aza-arenes via aza-6π electrocyclization of 2-styrylanilines with aromatic aldehydes. This protocol relies on the EDA complexes of AlCl 3 with imine to induce the absorption red-shift to visible light from ultraviolet light. An array of 2,3-disubstituted quinolines were constructed smoothly after excitation with blue-light-emitting diodes at room temperature. In addition, the resultant product, used as a cell permeable lipid droplet-specific probe, shows a low working concentration, a short staining time, and functionality in living and fixed cells.

Objective： To observe roproductive hormone levels in varicocele patients during a cycle (6 years) of Wu Yun Liu Qi, and explore whether the cycle had effect on the roproductive hormone levels. Methods： Data of roproductive hormone levels in varicocele patients from 2015 to 2020 were analyzed retrospectively. FSH、LH、T、PRL、E2 levels and T/E2 ratio were compared among the six years. According to Chinese sexagenary cycle heavenly stems and earthly branches of each year from 2015 to 2020 its yunqi characteristics were determined. Results: Totally data of 848 cases of varicocele patients were collected from 2015 to 2020. Among which, in 2015 (Yiwei year) there were 57 cases, in 2016 (Bingshen year) 83 cases, in 2017 (Dingyou year ) 133 cases, in 2018(Wuxu year) 156 cases, in 2019(Sihai year) 274 cases, and in 2020(Gengzi year) 145 cases. The levels of FSH、LH、PRL、T were not diferrent statistically from the six years except individual year. However, the level of E2 in 2016 when the Yunqi was Shao Yang Xiang Huo Si Tian and Jue Yin Feng Mu Zai Quan obviously higher than other years excpet 2018( All P< 0.05). And T/E2 ratio was lower in 2016 than other years except 2018 and 2020( All P< 0.05). Conclusions: Shi Xiang factors of Wu Yun Liu Qi had effect on roproductive hormone levels in varicocele patients, showing by higher E2 level in Yinshen year when the Shi Xiang factors may have bad effect on human fertility.

This study investigated the differences in excretion kinetics of three alkaloids and their four metabolites from Simiao Pills in normal and type 2 diabetic rats. The diabetes model was established in rats by injection of streptozotocin, and the alkaloids in urine, feces, and bile of normal and diabetic rats were detected by LC-MS/MS to explore the effect of diabetes on alkaloid excretion of Simiao Pills. The results showed that 72 h after intragastric administration of the extract of Simiao Pills, feces were the main excretion route of alkaloids from Simiao Pills. The total excretion rates of magnoflorine and berberine in normal rats were 4.87% and 56.54%, which decreased to 2.35% and 35.53% in diabetic rats, which had statistical significance(P&lt;0.05). The total excretion rates of phellodendrine, magnoflorine, and berberine in the urine of diabetic rats decreased significantly, which were 53.57%, 60.84%, and 52.78% of those in normal rats, respectively. After 12 h of intragastric administration, the excretion rate of berberine in the bile of diabetic rats increased significantly, which was 253.33% of that of normal rats. In the condition of diabetes, the excretion rate of berberine metabolite, thalifendine significantly decreased in urine and feces, but significantly increased in bile. The total excretion rates of jateorrhizine and palmatine in the urine increased significantly, and t&#95;(1/2) and K&#95;e changed significantly. The results showed that diabetes affected the in vivo process of alkaloids from Simiao Pills, reducing their excretion in the form of prototype drug, affecting the biotransformation of berberine, and ultimately increasing the exposure of alkaloids in vivo, which would be conducive to the hypoglycemic effect of alkaloids. This study provides references for the clinical application and drug development of Simiao Pills in diabetes.

The development of functionally distinct catalysts for enantioselective synthesis is a prominent yet challenging goal of synthetic chemistry. In this work, we report a family of chiral N -heterocyclic carbene (NHC)-ligated boryl radicals as catalysts that enable catalytic asymmetric radical cycloisomerization reactions. The radical catalysts can be generated from easily prepared NHC-borane complexes, and the broad availability of the chiral NHC component provides substantial benefits for stereochemical control. Mechanistic studies support a catalytic cycle comprising a sequence of boryl radical addition, hydrogen atom transfer, cyclization, and elimination of the boryl radical catalyst, wherein the chiral NHC subunit determines the enantioselectivity of the radical cyclization. This catalysis allows asymmetric construction of valuable chiral heterocyclic products from simple starting materials.

Understanding the mechanisms behind porcine primordial germ cell like cells (pPGCLCs) development, differentiation, and gametogenesis is crucial in the treatment of infertility. In this study, SOX9 + skin derived stem cells (SOX9 + SDSCs) were isolated from fetal porcine skin and a high-purity SOX9 + SDSCs population was obtained. The SOX9 + SDSCs were induced to transdifferentiate into PGCLCs during 8 days of cultured. The results of RNA-seq, western blot and immunofluorescence staining verified SDSCs have the potential to transdifferentiate into PGCLCs from aspects of transcription factor activation, germ layer differentiation, energy metabolism, and epigenetic changes. Both adherent and suspended cells were collected. The adherent cells were found to be very similar to early porcine primordial germ cells (pPGCs). The suspended cells resembled late stage pPGCs and had a potential to enter meiotic process. This SDSCs culture-induced in vitro model is expected to provide suitable donor cells for stem cell transplantation in the future., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Zearalenone (ZEN) is well known as a kind of endocrine disruptor whose exposure is capable of causing reproductive toxicity in animals. Cyanidin-3- O -glucoside (C3G) is a derivative of cyanidin and owns multiple biofunctions, and prior efforts have suggested that C3G has therapeutic actions for reproductive diseases. In this article, a ZEN exposure model during primordial follicle assembly was constructed using the in vitro culture platform of neonatal mouse ovaries. We investigated the protective effect of C3G on ZEN-induced ovarian toxicity during primordial follicle assembly in mice, as well as its potential mechanism. Interestingly, we observed that C3G could effectively protect the ovary from ZEN damage, mainly by restoring primordial follicle assembly, which upregulated the expression of LHX8 and SOHLH1 proteins and relieved ZEN-induced DNA damage. Next, to explore the mechanism by which C3G rescued ZEN-induced injury, we performed RNA sequencing (RNA-seq). The bioinformatic analysis illustrated that the rescue pathway of C3G was associated with p53-Gadd45a signaling and cell cycle. Then, western blotting and flow cytometry results revealed that C3G restored the expression levels of cyclin-dependent kinase 6 (CDK6) and cyclin D2 (CCND2) and regulated the ovarian cell cycle to normal. In conclusion, our findings manifested that C3G could alleviate ZEN-induced primordial follicle assembly impairment by restoring the cell cycle involved in p53-GADD45a signaling.

Background: Triple-negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA-Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear., Methods: In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142-regulated mouse double minute 2 (MDM2)-binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays., Results: In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up-regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142-mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib., Conclusions: Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Traditional plastic products have caused serious environmental pollution due to difficulty to be degraded in the natural environment. In the recent years, biodegradable plastics are receiving increasing attention due to advantages in natural degradability and environmental friendliness. Biodegradable plastics have potential to be used in food, agriculture, industry, medicine and other fields. However, the high production cost of such plastics is the bottleneck that limits their commercialization and application. Yeasts, including budding yeast and non-conventional yeasts, are widely studied to produce biodegradable plastics and their organic acid monomers. Compared to bacteria, yeast strains are more tolerable to multiple stress conditions including low pH and high temperature, and also have other advantages such as generally regarded as safe, and no phage infection. In addition, synthetic biology and metabolic engineering of yeast have enabled its rapid and efficient engineering for bioproduction using various renewable feedstocks, especially lignocellulosic biomass. This review focuses on the recent progress in biosynthesis technology and strategies of monomeric organic acids for biodegradable polymers, including polylactic acid (PLA), polyhydroxyalkanoate (PHA), polybutylene succinate (PBS), and polybutylene adipate terephthalate (PBAT) using yeast cell factories. Improving the performance of yeast as a cell factory and strategies to improve yeast acid stress tolerance are also discussed. In addition, the critical challenges and future prospects for the production of biodegradable plastic monomer using yeast are also discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury., (© 2023. Springer Nature Limited.)

Zearalenone (ZEN) is a widespread and transgenerational toxicant that can cause serious reproductive health risks, which poses a potential threat to global agricultural production and human health; its estrogenic activity can lead to reproductive toxicity through the induction of granulosa cell apoptosis. Herein, comparative transcriptome analysis, single-cell transcriptome analysis, and weighted gene co-expression network analysis (WGCNA) combined with gene knockout in vivo and RNA interference in vitro were used to comprehensively describe the damage caused by ZEN exposure on ovarian granulosa cells. Comparative transcriptome analysis and WGCNA suggested that the tumor necrosis factor (TNF)-α-mediated mitogen-activated protein kinase 7 (MAP2K7)/ AKT serine/threonine kinase 2 (AKT2) axis was disordered after ZEN exposure in porcine granulosa cells (pGCs) and mouse granulosa cells (mGCs). In vivo gene knockout and in vitro RNA interference verified that TNF-α-mediated MAP2K7/AKT2 was the guiding signal in ZEN-induced apoptosis in pGCs and mGCs. Moreover, single-cell transcriptome analysis showed that ZEN exposure could induce changes in the TNF signaling pathway in offspring. Overall, we concluded that the TNF-α-mediated MAP2K7/AKT2 axis was the main signaling pathway of ZEN-induced apoptosis in pGCs and mGCs. This work provides new insights into the mechanism of ZEN toxicity and provides new potential therapeutic targets for the loss of livestock and human reproductive health caused by ZEN., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.

Realizing the dual emission of fluorescence-phosphorescence in a single system is an extremely important topic in the fields of biological imaging, sensing, and information encryption. However, the phosphorescence process is usually in an inherently "dark state" at room temperature due to the involvement of spin-forbidden transition and the rapid non-radiative decay rate of the triplet state. In this work, we achieved luminescent harvesting of the dark phosphorescence processes by coupling singlet-triplet molecular emitters with a rationally designed plasmonic cavity. The achieved Purcell enhancement effect of over 1000-fold allows for overcoming the triplet forbidden transitions, enabling radiation enhancement with selectable emission wavelengths. Spectral results and theoretical simulations indicate that the fluorescence-phosphorescence peak position can be intelligently tailored in a broad range of wavelengths, from visible to near-infrared. Our study sheds new light on plasmonic tailoring of molecular emission behavior, which is crucial for advancing research on plasmon-tailored fluorescence-phosphorescence spectroscopy in optoelectronics and biomedicine.

The development and utilization of coastal saline-alkali lands hold significant importance in mitigating the shortage of cultivated land resources in China, enhancing the agro-ecological environment in coastal saline and alkaline areas, and ensuring national food security. We set up both pot and field trials (randomized block design) at Xinxiang experimental station of Institute of Crop Science, Chinese Academy of Agricultural Sciences (ICS-CAAS) and Dongying Yellow River Delta Modern Agricultural Research Base in Shandong Province in 2021 and 2022, respectively. The experimental materials, Jiliang 1 and Jiliang 2, underwent seed dressing with GKI composites at concentrations of 2.5 and 5 mL·kg -1 . These composites, which contained the main components of gibberellin, kinetin, and indole butyric acid, were denoted as GKI2.5 and GKI5.0, respectively. The control plots (CK) received water seed dressing. The aim was to assess the regulatory effects of GKI on salt tolerance and grain sorghum yield. Compared to CK, the GKI2.5 and GKI5.0 seed dressing treatments significantly enhanced the growth and development of the two grain sorghum varieties, increased antioxidant enzyme activity and soluble protein content of sorghum leaves, while reducing leaf malondialdehyde content. Moreover, the GKI treatments increased leaf net photosynthetic rate. Under field conditions, yields of Jiliang 1 and Jiliang 2 were enhanced by an average of 17.1% and 19.1%, respectively. In conclusion, GKI seed dressing treatment effectively promoted the growth and development of sorghum under salt stress. It enhanced the antioxidant and osmoregulatory capacities of leaves, reduced the level of membrane lipid peroxidation, and improved net photosynthetic rate of leaves, which together improved the salt tolerance and sorghum yield.

Streptococcosis disease caused by Streptococcus agalactiae (Group B Streptococcus, GBS) results in a huge economic loss of tilapia culture. It is urgent to find new antimicrobial agents against streptococcosis. In this study, 20 medicinal plants were evaluated in vitro and in vivo to obtain medicinal plants and potential bioactive compounds against GBS infection. The results showed that the ethanol extracts of 20 medicinal plants had low or no antibacterial properties in vitro, with a minimal inhibitory concentration ≥256 mg/L. Interestingly, in vivo tests showed that 7 medicinal plants could significantly inhibit GBS infection in tilapia, and Sophora flavescens (SF) had the strongest anti-GBS activity in tilapia, reaching 92.68%. SF could significantly reduce the bacterial loads of GBS in different tissues (liver, spleen and brain) of tilapia after treated with different tested concentrations (12.5, 25.0, 50.0 and 100.0 mg/kg) for 24 h. Moreover, 50 mg/kg SF could significantly improve the survival rate of GBS-infected tilapia by inhibiting GBS replication. Furthermore, the expression of antioxidant gene cat, immune-related gene c-type lysozyme and anti-inflammatory cytokine il-10 in liver tissue of GBS-infected tilapia significantly increased after treated with SF for 24 h. Meanwhile, SF significantly reduced the expression of immune-related gene myd88 and pro-inflammatory cytokines il-8 and il-1β in liver tissue of GBS-infected tilapia. The negative and positive models of UPLC-QE-MS, respectively, identified 27 and 57 components of SF. The major components of SF extract in the negative model were α, α-trehalose, DL-malic acid, D- (-)-fructose and xanthohumol, while in the positive model were oxymatrine, formononetin, (-)-maackiain and xanthohumol. Interestingly, oxymatrine and xanthohumol could significantly inhibit GBS infection in tilapia. Taken together, these results suggest that SF can inhibit GBS infection in tilapia, and it has potential for the development of anti-GBS agents., (© 2023 John Wiley & Sons Ltd.)

Six degrees-of-freedom (6-DoF) video provides telepresence by enabling users to move around in the captured scene with a wide field of regard. Compared to methods requiring sophisticated camera setups, the image-based rendering method based on photogrammetry can work with images captured with any poses, which is more suitable for casual users. However, existing image-based rendering methods are based on perspective images. When used to reconstruct 6-DoF views, it often requires capturing hundreds of images, making data capture a tedious and time-consuming process. In contrast to traditional perspective images, 360° images capture the entire surrounding view in a single shot, thus, providing a faster capturing process for 6-DoF view reconstruction. This article presents a novel method to provide 6-DoF experiences over a wide area using an unstructured collection of 360° panoramas captured by a conventional 360° camera. Our method consists of 360° data capturing, novel depth estimation to produce a high-quality spherical depth panorama, and high-fidelity free-viewpoint generation. We compared our method against state-of-the-art methods, using data captured in various environments. Our method shows better visual quality and robustness in the tested scenes.

With the rapid development of underground space utilization, the excavation of new tunnels with ultra-shallow under crossing buildings using the drilling and blasting method is gradually increasing. The blasting vibration will undoubtedly affect the surrounding buildings. Reducing the impact of blasting vibration on ground buildings has become an important technical challenge faced by tunnel blasting technicians. The inlet end of the Xi'an-Chengdu High-Speed Railway Xiannvyan Tunnel passes below a village through an ultra-shallow buried section; as a result, blasting vibration control is a major concern. A design scheme for a 0.6 m footage in tunnel was proposed and verified through field tests. A 0.8 m footage scheme and 1.8 m footage millisecond interference vibration reduction scheme were proposed, respectively. Based on the HHT analysis, by comparing the surface vibration velocities and instantaneous energy obtained from the millisecond delay detonation of cutting holes and the detonation of different charging schemes, we found that the free surface, mass of single dynamite charges, and tunnel burial depth had significant influences on the surface vibration.

Heavy metal ions, which are over-emitted from industrial production, pose a major threat to the ecological environment and human beings. Among the present detection technologies, achieving rapid and on-site detection of contaminants remains a challenge. Herein, capillaries with three-dimensional (3D) hot spot constructures are fabricated to achieve repaid and ultrasensitive mercury ion (Hg 2+ ) detection in water based on surface-enhanced Raman scattering (SERS). The 4-mercapto pyridine (4-Mpy) serves as the Raman reporter with high selectivity, enabling the detection of Hg 2+ by changes in adsorption configuration at the trace level. Under optimized conditions, the SERS response of 4-Mpy for Hg 2+ exhibits good linearity, ranging from 1 pM to 0.1 μM in a few minutes, and the detection limit of 0.2 pM is much lower than the maximum Hg 2+ concentration of 10 nM allowed in drinking water, as defined by the US Environmental Protection Agency (EPA). Simultaneously, combined with the theoretical simulation and experimental results, the above results indicate that the SERS substrates possess outstanding performances in specificity, recovery rate and stability, which may hold great potential for achieving rapid and on-site environmental pollutant detection using a portable Raman spectrometer.

Celastrol has been identified as a potential candidate for anticancer drug development. In this study, 28 novel celastrol derivatives with C-6 sulfhydryl substitution and 20-substitution were designed and synthesized, and their antiproliferative activity against human cancer cells and non-malignant human cells was evaluated, with cisplatin and celastrol being used as controls. The results showed that most of the derivatives had enhanced in vitro anticancer activity compared to the parent compound celastrol. Specifically, derivative 2f demonstrated the most potent inhibitory potential and selectivity against HOS with an IC 50 value of 0.82 μM. Our study provides new insights into the structure-activity relationship of celastrol and suggests that compound 2f may be a promising drug candidate for the treatment of osteosarcoma., (© 2023 John Wiley & Sons Ltd.)

Aflatoxins B1 (AFB1), a type I carcinogen widely present in the environment, not only poses a danger to animal husbandry, but also poses a potential threat to human reproductive health, but its mechanism is still unclear. To address this question, multi-omics were performed on porcine Sertoli cells and mice testis. The data suggest that AFB1 induced testicular damage manifested as decreased expression of GJA1, ZO1 and OCCLUDIN in mice (p < 0.01) and inhibition of porcine Sertoli cell proliferation. Transcriptomic analysis suggested changes in noncoding RNA expression profiles that affect the cell cycle-related Ras/PI3K/Akt signaling pathway after AFB1 exposure both in mice and pigs. Specifically, AFB1 caused abnormal cell cycle of testis with the characterization of decreased expressions of CCNA1, CCNB1 and CDK1 (p < 0.01). Flow cytometry revealed that the G2/M phase was significantly increased after AFB1 exposure. Meanwhile, AFB1 downregulated the expressions of Ras, PI3K and AKT both in porcine Sertoli cell (p < 0.01) and mice testis (p < 0.01). Metabolome analysis verified the alterations in the PI3K/Akt signaling pathway (p < 0.05). Moreover, the joint analysis of metabolome and microbiome found that the changes of metabolites were correlated with the expression of flora. In conclusion, we have demonstrated that AFB1 impairs testicular development via the cell cycle-related Ras/PI3K/Akt signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite aging is closely linked to increased aneuploidy in the oocytes, the mechanism of how aging affects aneuploidy remains largely elusive. Here, we applied single-cell parallel methylation and transcriptome sequencing (scM&T-seq) data from the aging mouse oocyte model to decode the genomic landscape of oocyte aging. We found a decline in oocyte quality in aging mice, as manifested by a significantly lower rate of first polar body exclusion (P < 0.05), and dramatically increasing aneuploidy rate (P < 0.01). Simultaneously, scM&T data suggested that a large number of differential expression genes (DEGs) and differential methylation regions (DMRs) were obtained. Next, we identified strong association of spindle assembly and mitochondrial transmembrane transport during oocyte aging. Moreover, we verified the DEGs related to spindle assembly (such as Naip1, Aspm, Racgap1, Zfp207) by real-time quantitative PCR (RT-qPCR) and checked the mitochondrial dysfunction by JC-1 staining. Pearson correlation analysis found that receptors for mitochondrial function were strongly positively correlated with abnormal spindle assembly (P < 0.05). In conclusion, these results suggested that the mitochondrial dysfunction and abnormal spindle assembly of aging oocytes ultimately may lead to increased oocyte aneuploidy., (© 2023. The Author(s).)

Coloring line art images based on the colors of reference images is a crucial stage in animation production, which is time-consuming and tedious. This paper proposes a deep architecture to automatically color line art videos with the same color style as the given reference images. Our framework consists of a color transform network and a temporal refinement network based on 3U-net. The color transform network takes the target line art images as well as the line art and color images of the reference images as input and generates corresponding target color images. To cope with the large differences between each target line art image and the reference color images, we propose a distance attention layer that utilizes non-local similarity matching to determine the region correspondences between the target image and the reference images and transforms the local color information from the references to the target. To ensure global color style consistency, we further incorporate Adaptive Instance Normalization (AdaIN) with the transformation parameters obtained from a multiple-layer AdaIN that describes the global color style of the references extracted by an embedder network. The temporal refinement network learns spatiotemporal features through 3D convolutions to ensure the temporal color consistency of the results. Our model can achieve even better coloring results by fine-tuning the parameters with only a small number of samples when dealing with an animation of a new style. To evaluate our method, we build a line art coloring dataset. Experiments show that our method achieves the best performance on line art video coloring compared to the current state-of-the-art methods.

Background: Cattle (Bos taurus) are a major large livestock, however, compared with other species, the transcriptional specificity of bovine oocyte development has not been emphasised., Results: To reveal the unique transcriptional signatures of bovine oocyte development, we used integrated multispecies comparative analysis and weighted gene co-expression network analysis (WGCNA) to perform bioinformatic analysis of the germinal follicle (GV) and second meiosis (MII) gene expression profile from cattle, sheep, pigs and mice. We found that the expression levels of most genes were down-regulated from GV to MII in all species. Next, the multispecies comparative analysis showed more genes involved in the regulation of cAMP signalling during bovine oocyte development. Moreover, the green module identified by WGCNA was closely related to bovine oocyte development. Finally, integrated multispecies comparative analysis and WGCNA picked up 61 bovine-specific signature genes that participate in metabolic regulation and steroid hormone biosynthesis., Conclusion: In a short, this study provides new insights into the regulation of cattle oocyte development from a cross-species comparison., (© 2023. The Author(s).)

Glutamate (Glu) is the major excitatory transmitter in the nervous system. Impairment of its vesicular release by β-amyloid (Aβ) oligomers is thought to participate in pathological processes leading to Alzheimer's disease. However, it remains unclear whether soluble Aβ 42 oligomers affect intravesicular amounts of Glu or their release in the brain, or both. Measurements made in this work on single Glu varicosities with an amperometric nanowire Glu biosensor revealed that soluble Aβ 42 oligomers first caused a dramatic increase in vesicular Glu storage and stimulation-induced release, accompanied by a high level of parallel spontaneous exocytosis, ultimately resulting in the depletion of intravesicular Glu content and greatly reduced release. Molecular biology tools and mouse models of Aβ amyloidosis have further established that the transient hyperexcitation observed during the primary pathological stage is mediated by an altered behavior of VGLUT1 responsible for transporting Glu into synaptic vesicles. Thereafter, an overexpression of Vps10p-tail-interactor-1a, a protein that maintains spontaneous release of neurotransmitters by selective interaction with t-SNAREs, resulted in a depletion of intravesicular Glu content, triggering advanced-stage neuronal malfunction. These findings are expected to open perspectives for remediating Aβ 42 -induced neuronal hyperactivity and neuronal degeneration.

Triple-negative breast cancer (TNBC), although highly lethal, lacks validated therapeutic targets. Here, we report that U2 snRNP-associated SURP motif-containing protein (U2SURP), a poorly defined member of the serine/arginine rich protein family, was significantly upregulated in TNBC tissues, and its high expression was associated with poor prognosis of TNBC patients. MYC, a frequently amplified oncogene in TNBC tissues, enhanced U2SURP translation through an eIF3D (eukaryotic translation initiation factor 3 subunit D)-dependent mechanism, resulting in the accumulation of U2SURP in TNBC tissues. Functional assays revealed that U2SURP played an important role in facilitating tumorigenesis and metastasis of TNBC cells both in vitro and in vivo. Intriguingly, U2SURP had no significant effects on proliferative, migratory, and invasive potential of normal mammary epithelial cells. Furthermore, we found that U2SURP promoted alternative splicing of spermidine/spermine N1-acetyltransferase 1 (SAT1) pre-mRNA by removal of intron 3, resulting in an increase in the stability of SAT1 mRNA and subsequent protein expression levels. Importantly, spliced SAT1 promoted the oncogenic properties of TNBC cells, and re-expression of SAT1 in U2SURP-depleted cells partially rescued the impaired malignant phenotypes of TNBC cells caused by U2SURP knockdown both in vitro and in mice. Collectively, these findings reveal previously unknown functional and mechanism roles of the MYC-U2SURP-SAT1 signaling axis in TNBC progression and highlight U2SURP as a potential therapy target for TNBC., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Objective: 'Homotherapy for heteropathy' is a theory by which different diseases with similar pathogenesis can be treated with one Chinese formula. We aimed to explore the key components and core targets of Weijing decoction (WJD) in treating various lung diseases, namely, pneumonia, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), pulmonary fibrosis, pulmonary tuberculosis and non-small cell lung cancer (NSCLC), via network pharmacology, molecular docking and some experiments., Significance: This is the first study on the mechanism of WJD in treating various lung diseases by 'homotherapy for heteropathy'. This study is helpful for the transformation of TCM formula and development of new drugs., Methods: Active components and therapeutic targets of WJD were obtained via TCMSP and UniProt databases. Targets of the six pulmonary diseases were harvested from the GeneCards TTD, DisGeNet, UniProt and OMIM databases. Drug-disease intersection targets, corresponding Venn diagrams, herb-component-target networks and protein-protein interaction networks were established. Furthermore, GO biological function and KEGG enrichment analysis were completed. Moreover, the binding activity between main compounds and core targets was measured through molecular docking. Finally, the xenograft NSCLC mouse model was established. Immune responses were evaluated by flow cytometry and mRNA expression levels of critical targets were measured by real-time PCR., Results: JUN, CASP3 and PTGS2 were the most critical targets in six pulmonary diseases. The active compounds beta-sitosterol, tricin and stigmasterol stably bound to many active sites on target proteins. WJD had extensive pharmacological regulation, involving pathways related to cancer, inflammation, infection, hypoxia, immunity and so on., Conclusions: Effects of WJD against various lung diseases involve lots of compounds, targets and pathways. These findings will facilitate further research as well as clinical application of WJD., (© 2023 The Authors.)

Background: Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived tryptophan metabolites and intestinal ischemia/reperfusion (I/R) injury yet to be investigated. This study aimed to evaluate the role of L. murinus-derived tryptophan metabolites in intestinal I/R injury and the underlying molecular mechanism., Methods: Liquid chromatograph mass spectrometry analysis was used to measure the fecal content of tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. Immunofluorescence, quantitative RT-PCR, Western blot, and ELISA were performed to explore the inflammation protective mechanism of tryptophan metabolites in WT and Nrf2-deficient mice undergoing intestinal I/R, hypoxia-reoxygenation (H/R) induced intestinal organoids., Results: By comparing the fecal contents of three L. murinus-derived tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. We found that the high abundance of indole-3-lactic acid (ILA) in the preoperative feces was associated with better postoperative intestinal function, as evidenced by the correlation of fecal metabolites with postoperative gastrointestinal function, serum I-FABP and D-Lactate levels. Furthermore, ILA administration improved epithelial cell damage, accelerated the proliferation of intestinal stem cells, and alleviated the oxidative stress of epithelial cells. Mechanistically, ILA improved the expression of Yes Associated Protein (YAP) and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) after intestinal I/R. The YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of ILA, both in vivo and in vitro. Additionally, we found that ILA failed to protect epithelial cells from oxidative stress in Nrf2 knockout mice under I/R injury., Conclusions: The content of tryptophan metabolite ILA in the preoperative feces of patients is negatively correlated with intestinal function damage under CPB surgery. Administration of ILA alleviates intestinal I/R injury via the regulation of YAP and Nrf2. This study revealed a novel therapeutic metabolite and promising candidate targets for intestinal I/R injury treatment., (© 2023. The Author(s).)

A boryl radical-promoted dehydroxylative alkylation of 3-hydroxy-oxindole derivatives is achieved. The reaction starts from addition of 4-dimethylaminopyridine (DMAP)-boryl radical to the amide carbonyl oxygen atom, which induces a spin-center shift process to promote the C-O bond cleavage. The elimination of a hydroxide anion from a free hydroxy group is also accomplished. Capture of the generated carbon radical with alkenes furnishes a variety of C-3 alkylated oxindoles. This method features a simple operation and broad substrate scope.

Direct C-H amidation of α-ketoesters was accomplished using various organic azides as the amino source through the combination of transient directing group strategy and iridium catalysis. Excellent functional group tolerance and wide substrate scope were explored under simple and mild conditions. Importantly, it was found that the steric hindrance of the ester moiety played a pivotal role for the reaction efficacy. In addition, the reaction could be enlarged to gram scale, and several useful heterocycles were readily constructed via one-step late-stage derivatization.

Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe hemorrhagic fever in humans and is mainly transmitted by ticks. There is no effective vaccine for Crimean-Congo hemorrhagic fever (CCHF) at present. We developed three DNA vaccines encoding CCHFV nucleocapsid protein (NP), glycoprotein N-terminal (Gn) and C-terminal (Gc) fused with lysosome-associated membrane protein 1 (LAMP1) and assessed their immunogenicity and protective efficacy in a human MHC (HLA-A11/DR1) transgenic mouse model. The mice that were vaccinated three times with pVAX-LAMP1-CCHFV-NP induced balanced Th1 and Th2 responses and could most effectively protect mice from CCHFV transcription and entry-competent virus-like particles (tecVLPs) infection. The mice vaccinated with pVAX-LAMP1-CCHFV-Gc mainly elicited specific anti-Gc and neutralizing antibodies and provided a certain protection from CCHFV tecVLPs infection, but the protective efficacy was less than that of pVAX-LAMP1-CCHFV-NP. The mice vaccinated with pVAX-LAMP1-CCHFV-Gn only elicited specific anti-Gn antibodies and could not provide sufficient protection from CCHFV tecVLPs infection. These results suggest that pVAX-LAMP1-CCHFV-NP would be a potential and powerful candidate vaccine for CCHFV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Zhang, Liu, Ye, Zhao, Zhang, Qiang, Zhang, Lei, Jiang, Cheng and Zhang.)

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Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the lack of effective targeted therapies. Transmembrane (TMEM) proteins represent attractive drug targets for cancer therapy, but biological functions of most members of the TMEM family remain unknown. Here, we report for the first time that TMEM63A (transmembrane protein 63A), a poorly characterized TMEM protein with unknown functions in human cancer, functions as a novel oncogene to promote TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung metastasis in vivo . Mechanistic investigations revealed that TMEM63A localizes in endoplasmic reticulum (ER) and lysosome membranes, and interacts with VCP (valosin-containing protein) and its cofactor DERL1 (derlin 1). Furthermore, TMEM63A undergoes autophagy receptor TOLLIP-mediated autophagic degradation and is stabilized by VCP through blocking its lysosomal degradation. Strikingly, TMEM63A in turn stabilizes oncoprotein DERL1 through preventing TOLLIP-mediated autophagic degradation. Notably, pharmacological inhibition of VCP by CB-5083 or knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on TNBC progression both in vitro and in vivo . Collectively, these findings uncover a previously unknown functional and mechanistic role for TMEM63A in TNBC progression and provide a new clue for targeting TMEM63A-driven TNBC tumors by using a VCP inhibitor. Abbreviations: ATG16L1, autophagy related 16 like 1; ATG5, autophagy related 5; ATP5F1B/ATP5B, ATP synthase F1 subunit beta; Baf-A1, bafilomycin A 1 ; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CANX, calnexin; DERL1, derlin 1; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; HSPA8, heat shock protein family A (Hsp70) member 8; IP, immunoprecipitation; LAMP2A, lysosomal associated membrane protein 2; NBR1, NBR1 autophagy cargo receptor; OPTN, optineurin; RT-qPCR, reverse transcription-quantitative PCR; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TMEM63A, transmembrane protein 63A; TNBC, triple-negative breast cancer; TOLLIP, toll interacting protein; VCP, valosin containing protein.

Background: Microtubule-targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges., Methods: Immunoblotting and RT-qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein-protein interaction and protein co-localization., Results: Here, we identified microrchidia family CW-type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR., Conclusions: Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

In order to reveal the complex mechanism governing the mitotic/meiotic switch in female germ cells at epigenomic and genomic levels, we examined the chromatin accessibility (scATAC-seq) and the transcriptional dynamics (scRNA-seq) in germ cells of mouse embryonic ovary between E11.5 to 13.5 at single-cell resolution. Adopting a strict transcription factors (TFs) screening framework that makes it easier to understand the single-cell chromatin signature and a TF interaction algorithm that integrates the transcript levels, chromatin accessibility, and motif scores, we identified 14 TFs potentially regulating the mitotic/meiotic switch, including TCFL5, E2F1, E2F2, E2F6, E2F8, BATF3, SP1, FOS, FOXN3, VEZF1, GBX2, CEBPG, JUND, and TFDP1. Focusing on TCFL5, we constructed Tcfl5 +/- mice which showed significantly reduced fertility and found that decreasing TCFL5 expression in cultured E12.5 ovaries by RNAi impaired meiotic progression from leptotene to zygotene. Bioinformatics analysis of published results of the embryonic germ cell transcriptome and the finding that in these cells central meiotic genes (Stra8, Tcfl5, Sycp3, and E2f2) possess open chromatin status already at the mitotic stage together with other features of TCFL5 (potential capability to interact with core TFs and activate meiotic genes, its progressive activation after preleptotene, binding sites in the promoter region of E2f2 and Sycp3), indicated extensive amplification of transcriptional programs associated to mitotic/meiotic switch with an important contribution of TCFL5. We conclude that the identified TFs, are involved in various stages of the mitotic/meiotic switch in female germ cells, TCFL5 primarily in meiotic progression. Further investigation on these factors might give a significant contribution to unravel the molecular mechanisms of this fundamental process of oogenesis and provide clues about pathologies in women such as primary ovarian insufficiency (POI) due at least in part to meiotic defects., (© 2023. The Author(s).)

Two unusual polyketide-sesquiterpene metabolites, craterodoratins T ( 1 ) and U ( 2 ), along with the known compound craterellin A ( 3 ), were isolated from the higher fungus Craterellus odoratus . The structures of isolated compounds were characterized based on nuclear magnetic resonance (NMR) and mass spectrum (MS) spectroscopic analysis, while the absolute configuration of the compounds was determined by theoretical NMR and electronic circular dichroism (ECD) calculations. Compound 1 possessed a rare structure with two aromatic groups. Compounds 1 and 3 showed immunosuppressive activity with IC 50 values ranging from 5.516 to 19.953 μ M.

Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective therapeutic targets. To identify novel approaches for targeting TNBC, we examined the role of protein phosphatases in TNBC progression and chemoresistance. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B), a poorly defined member of the protein phosphatase 1 regulatory subunits, was aberrantly upregulated in TNBC tissues and predicted poor prognosis. PPP1R14B was degraded mainly through the ubiquitin-proteasome pathway. RPS27A recruited deubiquitinase USP9X to deubiquitinate and stabilize PPP1R14B, resulting in overexpression of PPP1R14B in TNBC tissues. Gain- and loss-of-function assays demonstrated that PPP1R14B promoted TNBC cell proliferation, colony formation, migration, invasion, and resistance to paclitaxel in vitro. PPP1R14B also induced xenograft tumor growth, lung metastasis, and paclitaxel resistance in vivo. Mechanistic investigations revealed that PPP1R14B maintained phosphorylation and stability of oncoprotein stathmin 1 (STMN1), a microtubule-destabilizing phosphoprotein critically involved in cancer progression and paclitaxel resistance, which was dependent on PP1 catalytic subunits α and γ. Importantly, the tumor-suppressive effects of PPP1R14B deficiency could be partially rescued by ectopic expression of wild-type but not phosphorylation-deficient STMN1. Moreover, PPP1R14B decreased STMN1-mediated α-tubulin acetylation, microtubule stability, and promoted cell-cycle progression, leading to resistance of TNBC cells to paclitaxel. Collectively, these findings uncover a functional and mechanistic role of PPP1R14B in TNBC progression and paclitaxel resistance, indicating PPP1R14B is a potential therapeutic target for TNBC., Significance: PPP1R14B upregulation induced by RPS27A/USP9X in TNBC increases STMN1 activity, leading to cancer progression and paclitaxel resistance., (©2022 The Authors; Published by the American Association for Cancer Research.)

Recent works have achieved remarkable performance for action recognition with human skeletal data by utilizing graph convolutional models. Existing models mainly focus on developing graph convolutional operations to encode structural properties of a skeletal graph, whose topology is manually predefined and fixed over all action samples. Some recent works further take sample-dependent relationships among joints into consideration. However, the complex relationships between arbitrary pairwise joints are difficult to learn and the temporal features between frames are not fully exploited by simply using traditional convolutions with small local kernels. In this paper, we propose a motif-based graph convolution method, which makes use of sample-dependent latent relations among non-physically connected joints to impose a high-order locality and assigns different semantic roles to physical neighbors of a joint to encode hierarchical structures. Furthermore, we propose a sparsity-promoting loss function to learn a sparse motif adjacency matrix for latent dependencies in non-physical connections. For extracting effective temporal information, we propose an efficient local temporal block. It adopts partial dense connections to reuse temporal features in local time windows, and enrich a variety of information flow by gradient combination. In addition, we introduce a non-local temporal block to capture global dependencies among frames. Our model can capture local and non-local relationships both spatially and temporally, by integrating the local and non-local temporal blocks into the sparse motif-based graph convolutional networks (SMotif-GCNs). Comprehensive experiments on four large-scale datasets show that our model outperforms the state-of-the-art methods. Our code is publicly available at https://github.com/wenyh1616/SAMotif-GCN.

Rationale: SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic. Methods: In vivo and in vitro SUMOylation assays were used to determine the SUMOylation levels of MORC2. Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation. The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through in vitro and in vivo functional assays. Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms. Results: Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner. MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1). Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28. MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair. At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair. Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs. Conclusions: Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR. We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

ConspectusThe past decades have witnessed tremendous progress on radical reactions. However, in comparison with carbon, nitrogen, oxygen, and other main group element centered radicals, the synthetic chemistry of boron centered radicals was less studied, mainly due to the high electron-deficiency and instability of such 3-center-5-electron species. In the 1980s, Roberts and co-workers found that the coordination of a Lewis base (amines or phosphines) with the boron center could form 4-center-7-electron boryl radicals (Lewis base-boryl radicals, LBRs) that are found to be more stable. However, only limited synthetic applications were developed. In 2008, Curran and co-workers achieved a breakthrough with the discovery of N- heterocyclic carbene (NHC) boryl radicals, which could enable a range of radical reduction and polymerization reactions. Despite these exciting findings, more powerful and valuable synthetic applications of LBRs would be expected, given that the structures and reactivities of LBRs could be easily modulated, which would provide ample opportunities to discover new reactions. In this Account, a summary of our key contributions in LBR-enabled radical borylation reactions and selective activation of inert carbon-heteroatom bonds will be presented.Organoboron compounds have shown versatile applications in chemical society, and their syntheses rely principally on ionic borylation reactions. The development of mechanistically different radical borylation reactions allows synthesizing products that are inaccessible by traditional methods. For this purpose, we progressively developed a series of NHC-boryl radical mediated chemo-, regio-, and stereoselective radical borylation reactions of alkenes and alkynes, by which a wide variety of structurally diverse organoboron molecules were successfully prepared. The synthetic utility of these borylated products was also demonstrated. Furthermore, we disclosed a photoredox protocol for oxidative generation of NHC-boryl radicals, which enabled useful defluoroborylation and arylboration reactions.Selective bond activation is an ideal way to convert simple starting materials to value-added products, while the cleavage of inert chemical bonds, in particular the chemoselectivity control when multiple identical bonds are present in similar chemical environments, remains a long-standing challenge. We envisaged that finely tuning the properties of LBRs might provide a new solution to address this challenge. Recently, we disclosed a 4-dimethylaminopyridine (DMAP)-boryl radical promoted sequential C-F bond functionalization of trifluoroacetic acid derivatives, in which the α-C-F bonds were selectively snipped via a spin-center shift mechanism. This strategy enables facile conversion of abundantly available trifluoroacetic acid to highly valuable mono- and difluorinated molecules. Encouraged by this finding, we further developed a boryl radical enabled three-step sequence to construct all-carbon quaternary centers from a range of trichloromethyl groups, where the three C-Cl bonds were selectively cleaved by the rational choice of suitable boryl radical precursors in each step. Furthermore, a boryl radical promoted dehydroxylative alkylation of α-hydroxy carboxylic acid derivatives was achieved, allowing for the efficient conversion of some biomass platform molecules to high value products.

Influenza is an infectious acute respiratory disease with complications and a high mortality rate; the effective medicines for influenza therapy are limited. "Huanglian" or Coptidis Rhizoma , Coptis chinensis Franch., Ranunculaceae, and "ganjiang" or Zingiberis Rhizoma , Zingiber officinale Roscoe, Zingiberaceae, combination is clinically used for treating respiratory diseases. HPLC was applied for the quantification of berberine hydrochloride (1.101 mg/ml) and 6-gingerol (38.41 μg/ml) in the H 2 O-soluble extract of the herbal formulation. In this study, the effect of "huanglian"- "ganjiang" extract on influenza virus H1N1-induced acute pulmonary inflammation was evaluated, in addition to the investigation of its anti-influenza mechanism in a mouse model. The analyzed herbal combination inhibited the expression of cytokine IL-6 and stimulated the expression of IL-2 in the serum of influenza virus-infected mice. Meanwhile, the herbal combination downregulated the gene and protein expression levels of TLR3, TLR7, MyD88, RIG-I, MAVS, TRAF3, and NF-κB p65, which are key targets of toll-like and RIG-I-like receptor signaling pathways in mice. In addition, the herbal combination could also promote the combination of intracellular autophagosomes and lysosomes in autophagosome-lysosome formation and improve impaired fusion of autophagosomes and lysosomes by influenza virus. This study suggested that the "huanglian"- "ganjiang" extract may be a candidate therapeutic strategy for the treatment of H1N1 influenza., Supplementary Information: The online version contains supplementary material available at 10.1007/s43450-023-00372-z., (© The Author(s) under exclusive licence to Sociedade Brasileira de Farmacognosia 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Master equations under appropriate assumptions are efficient tools for the study of open quantum systems. For many-body systems, subsystems of which locally couple to thermal baths and weakly interact with each other, the local approach provides a more convenient description than the global approach. However, these local master equations are believed to generate inconsistencies with the laws of thermodynamics when intersubsystem interactions exist. Here we develop an alternative local master equation by virtue of similar approximations used in deriving the traditional Gorini-Kossakowski-Lindblad-Sudarshan master equation. In particular, we stick to using eigenstates of each subsystem to construct quantum jump operators, and the secular approximation is also employed to modify the intersubsystem interactions. Our results show that violations of thermodynamic laws will be avoided after correcting intersubsystem interactions. Finally, we study a two-qubit heat transfer model and this further shows the validity of our modified master equation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by high heterogeneity and metabolic dysregulation. Inositol monophosphatase 1(IMPA1) is critical for the metabolism of inositol, which has profound effects on gene expression and other biological processes. Here, we report for the first time that IMPA1 was upregulated in TNBC cell lines and tissues, and enhanced cell colony formation and proliferation in vitro and tumorigenicity in vivo. Additionally, IMPA1 promoted cell motility in vitro and metastatic lung colonization in vivo. Mechanistic investigations by transcriptome sequencing revealed that 4782 genes were differentially expressed between cells with IMPA1 knockdown and control cells. Among the differentially expressed genes after IMPA1 knockdown, five significantly altered genes were verified via qRT-PCR assays. Morerover, we found that the expression profile of those five targets as a gene set was significantly associated with IMPA1 status in TNBC cells. As this gene set was associated with mTOR pathway and epithelial-mesenchymal transition (EMT) process, we further confirmed that IMPA1 induced mTOR activity and EMT process, which at least in part contributed to IMPA1-induced TNBC progression. Collectively, our findings reveal a previously unrecognized role of IMPA1 in TNBC progression and identify IMPA1 as a potential target for TNBC therapy., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Disruption of gamma-amino butyric acid type A receptors (GABA A Rs) synaptic clustering and a decrease in the number of GABA A Rs in the plasma membrane are thought to contribute to alteration of the balance between excitatory and inhibitory neurotransmission, which promotes seizure induction and propagation. The multipass transmembrane protein cleft lip and palate transmembrane protein 1 (Clptm1) controls the forward trafficking of GABA A R, thus decaying miniature inhibitory postsynaptic current (mIPSC) of inhibitory synapses. In this study, using a pentylenetetrazol (PTZ)-induced epilepsy rat model, we found that Clptm1 regulates epileptic seizures by modulating GABA A R-mediated inhibitory synaptic transmission. First, we showed that Clptm1 expression was elevated in the PTZ-induced epileptic rats. Subsequently, we found that downregulation of Clptm1 expression protected against PTZ-induced seizures, which was attributed to an increase in the number of GABA A Rγ2s in the plasma membrane and the amplitude of mIPSC. Taken together, our findings identify a new anti-seizure target that provides a theoretical basis for the development of novel strategies for the prevention and treatment of epilepsy., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Addressing the spread of coronavirus disease 2019 (COVID-19) has highlighted the need for rapid, accurate, and low-cost diagnostic methods that detect specific antigens for SARS-CoV-2 infection. Tests for COVID-19 are based on reverse transcription PCR (RT-PCR), which requires laboratory services and is time-consuming. Here, by targeting the SARS-CoV-2 spike protein, we present a point-of-care SERS detection platform that specifically detects SARS-CoV-2 antigen in one step by captureing substrates and detection probes based on aptamer-specific recognition. Using the pseudovirus, without any pretreatment, the SARS-CoV-2 virus and its variants were detected by a handheld Raman spectrometer within 5 min. The limit of detection (LoD) for the pseudovirus was 124 TU μL -1 (18 fM spike protein), with a linear range of 250-10,000 TU μL -1 . Moreover, this assay can specifically recognize the SARS-CoV-2 antigen without cross reacting with specific antigens of other coronaviruses or influenza A. Therefore, the platform has great potential for application in rapid point-of-care diagnostic assays for SARS-CoV-2.

Considering that research has mainly focussed on how excessive iron supplementation leads to reproductive cytotoxicity, there is a lack of in-depth research on reproductive system disorders caused by iron deficiency. To gain a better understanding of the effects of iron deficiency on the reproductive system, especially spermatogenesis, we first constructed a mouse model of iron deficiency. We employed multi-omic analysis, including transcriptomics, metabolomics, and microbiomics, to comprehensively dissect the impact of iron deficiency on spermatogenesis. Moreover, we verified our findings in detail using western blot, immunofluorescence, immunohistochemistry, qRT-PCR and other techniques. Microbiomic analysis revealed altered gut microbiota in iron-deficient mice, and functional predictive analysis showed that gut microbiota can regulate spermatogenesis. The transcriptomic data indicated that iron deficiency directly alters expression of meiosis-related genes. Transcriptome data also revealed that iron deficiency indirectly regulates spermatogenesis by affecting hormone synthesis, findings confirmed by metabolomic data, western blot and immunofluorescence. Interestingly, competing endogenous RNA networks also play a vital role in regulating spermatogenesis after iron deficiency. Taken together, the data elucidate that iron deficiency impairs spermatogenesis and increases the risk of male infertility by affecting hormone synthesis and promoting gut microbiota imbalance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the relationship of hypertriglyceridemic waist phenotype (HTWP) with initial neurological severity and etiologic subtypes in patients with acute ischemic stroke., Methods: The data for this study were collected from hospitalized patients within 72 h of acute ischemic stroke onset at the Department of Neurology of the Affiliated Hospital of Beihua University from 1 July 2020 to 30 June 2022. The initial neurological severity was assessed by the National Institute of Health Stroke Scale (NIHSS) on the day of admission: NIHSS <6 was defined as mild stroke, and NIHSS ≥6 as moderate to severe stroke. HTWP was defined by fasting serum triglycerides ≥1.7 mmol/L and waist circumference ≥90 cm in men and ≥80 cm in women. Differentiation of etiologic subtypes was based on the method reported in the Trial of Org 10 172 in Acute Stroke Treatment. Multivariate logistic regression analysis was used to analyze the association of HTWP with initial neurological severity and etiologic subtypes., Results: The study included 431 patients. Compared with the normal waist-normal blood triglyceride group, patients with HTWP had reduced risks of moderate to severe stroke [odds ratio (OR): 0.384, 95% confidence interval (CI): 0.170-0.869; P = 0.022]. In addition, the risk of small-artery occlusion stroke was 2.318 times higher in the HTWP group than in the normal triglyceride-normal waist (NWNT) group (OR: 2.318, 95% CI: 1.244-4.319; P = 0.008)., Conclusion: Initial neurological severity was less severe in patients with HTWP, and HTWP was associated with an increased risk of small-artery occlusion stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ren, Qiu, Wu, Dong, Han, Zhang, Kong and Li.)

Rapid dehydration of maize grain is one of the main characteristics of cultivar selection for mechanical grain harvest; however, the dominant driving forces and mechanisms of grain dehydration before physiological maturity remain disputable and obscure. This study compared the grain moisture content and dehydration rate of coated treatment (no surface evaporation) and control grains. Meanwhile, the xylem-mobile dye was infused from stem and cob, and its movement was observed in cob, ear-stalk and stem xylem. The development dynamics of husk, grain and cob were analyzed to determine the mechanism of grain dehydration. The results showed that, from grain formation to 5-10 days before physiological maturity, the main driving force of grain dehydration of the early and middle-maturity maize cultivars was filling, followed by surface evaporation. In the dye movement experiment, the movement of the stem-infused xylem-mobile dye through the pedicel xylem was observed during but not after the grain formation period. Moreover, the cob-infused xylem-mobile dye moved to the ear- stalk and the stem via the xylem. There was a significantly positive correlation between grain filling rate and dehydration rate from grain formation to physiological maturity. According to these results, we proposed that in the grain dehydration phase driven by filling, the surplus water in the grain flows back to the cob via the pedicel xylem, of which some flowed back to the plant via the cob and ear- stalk xylem. This provides a new theoretical basis for selecting and breeding maize cultivars suitable for mechanical grain harvesting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JR declared a shared affiliation with the authors to the handling editor at the time of review, (Copyright © 2022 Zhang, Marasini, Li and Zhang.)