Creation of memory-memory entanglement in a metropolitan quantum network.

Towards realizing the future quantum internet1,2, a pivotal milestone entails the transition from two-node proof-of-principle experiments conducted in laboratories to comprehensive multi-node set-ups on large scales. Here we report the creation of memory-memory entanglement in a multi-node quantum network over a metropolitan area. We use three independent memory nodes, each of which is equipped with an atomic ensemble quantum memory3 that has telecom conversion, together with a photonic server where detection of a single photon heralds the success of entanglement generation. The memory nodes are maximally separated apart for 12.5 kilometres. We actively stabilize the phase variance owing to fibre links and control lasers. We demonstrate concurrent entanglement generation between any two memory nodes. The memory lifetime is longer than the round-trip communication time. Our work provides a metropolitan-scale testbed for the evaluation and exploration of multi-node quantum network protocols and starts a stage of quantum internet research.

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

Karyotype and LTR-RTs analysis provide insights into oak genomic evolution.

BACKGROUND: Whole-genome duplication and long terminal repeat retrotransposons (LTR-RTs) amplification in organisms are essential factors that affect speciation, local adaptation, and diversification of organisms. Understanding the karyotype projection and LTR-RTs amplification could contribute to untangling evolutionary history. This study compared the karyotype and LTR-RTs evolution in the genomes of eight oaks, a dominant lineage in Northern Hemisphere forests. RESULTS: Karyotype projections showed that chromosomal evolution was relatively conservative in oaks, especially on chromosomes 1 and 7. Modern oak chromosomes formed through multiple fusions, fissions, and rearrangements after an ancestral triplication event. Species-specific chromosomal rearrangements revealed fragments preserved through natural selection and adaptive evolution. A total of 441,449 full-length LTR-RTs were identified from eight oak genomes, and the number of LTR-RTs for oaks from section Cyclobalanopsis was larger than in other sections. Recent amplification of the species-specific LTR-RTs lineages resulted in significant variation in the abundance and composition of LTR-RTs among oaks. The LTR-RTs insertion suppresses gene expression, and the suppressed intensity in gene regions was larger than in promoter regions. Some centromere and rearrangement regions indicated high-density peaks of LTR/Copia and LTR/Gypsy. Different centromeric regional repeat units (32, 78, 79 bp) were detected on different Q. glauca chromosomes. CONCLUSION: Chromosome fusions and arm exchanges contribute to the formation of oak karyotypes. The composition and abundance of LTR-RTs are affected by its recent amplification. LTR-RTs random retrotransposition suppresses gene expression and is enriched in centromere and chromosomal rearrangement regions. This study provides novel insights into the evolutionary history of oak karyotypes and the organization, amplification, and function of LTR-RTs.

Ensemble species distribution modeling and multilocus phylogeography provide insight into the spatial genetic patterns and distribution dynamics of a keystone forest species, Quercus glauca.

BACKGROUND: Forests are essential for maintaining species diversity, stabilizing local and global climate, and providing ecosystem services. Exploring the impact of paleogeographic events and climate change on the genetic structure and distribution dynamics of forest keystone species could help predict responses to future climate change. In this study, we combined an ensemble species distribution model (eSDM) and multilocus phylogeography to investigate the spatial genetic patterns and distribution change of Quercus glauca Thunb, a keystone of East Asian subtropical evergreen broad-leaved forest. RESULTS: A total of 781 samples were collected from 77 populations, largely covering the natural distribution of Q. glauca. The eSDM showed that the suitable habitat experienced a significant expansion after the last glacial maximum (LGM) but will recede in the future under a general climate warming scenario. The distribution centroid will migrate toward the northeast as the climate warms. Using nuclear SSR data, two distinct lineages split between east and west were detected. Within-group genetic differentiation was higher in the West than in the East. Based on the identified 58 haplotypes, no clear phylogeographic structure was found. Populations in the Nanling Mountains, Wuyi Mountains, and the southwest region were found to have high genetic diversity. CONCLUSIONS: A significant negative correlation between habitat stability and heterozygosity might be explained by the mixing of different lineages in the expansion region after LGM and/or hybridization between Q. glauca and closely related species. The Nanling Mountains may be important for organisms as a dispersal corridor in the west-east direction and as a refugium during the glacial period. This study provided new insights into spatial genetic patterns and distribution dynamics of Q. glauca.

Molecular and genetic regulation of petal number variation.

Floral forms with an increased number of petals, also known as double-flower phenotypes, have been selected and conserved in many domesticated plants, particularly in ornamentals, because of their great economic value. The molecular and genetic mechanisms that control this trait are therefore of great interest, not only for scientists, but also for breeders. In this review, we summarize current knowledge of the gene regulatory networks of flower initiation and development and known mutations that lead to variation of petal number in many species. In addition to the well-accepted miR172/AP2-like module, for which many questions remain unanswered, we also discuss other pathways in which mutations also lead to the formation of extra petals, such as those involved in meristem maintenance, hormone signalling, epigenetic regulation, and responses to environmental signals. We discuss how the concept of 'natural mutants' and recent advances in genomics and genome editing make it possible to explore the molecular mechanisms underlying double-flower formation, and how such knowledge could contribute to the future breeding and selection of this trait in more crops.

Evolution of FLOWERING LOCUS T-like genes in angiosperms: a core Lamiales-specific diversification.

Plant life history is determined by two transitions, germination and flowering time, in which the phosphatidylethanolamine-binding proteins (PEBPs) FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1) play key regulatory roles. Compared with the highly conserved TFL1-like genes, FT-like genes vary significantly in copy numbers in gymnosperms, and monocots within the angiosperms, while sporadic duplications can be observed in eudicots. Here, via a systematic analysis of the PEBPs in angiosperms with a special focus on 12 representative species featuring high-quality genomes in the order Lamiales, we identified a successive lineage-specific but systematic expansion of FT-like genes in the families of core Lamiales. The first expansion event generated FT1-like genes mainly via a core Lamiales-specific whole-genome duplication (cL-WGD), while a likely random duplication produced the FT2-like genes in the lineages containing Scrophulariaceae and the rest of the core Lamiales. Both FT1- and FT2-like genes were further amplified tandemly in some families. These expanded FT-like genes featured highly diverged expression patterns and structural variation, indicating functional diversification. Intriguingly, some core Lamiales contained the relict MOTHER OF FT AND TFL1 like 2 (MFT2) that probably expanded in the common ancestor of angiosperms. Our data showcase the highly dynamic lineage-specific expansion of the FT-like genes, and thus provide important and fresh evolutionary insights into the gene regulatory network underpinning flowering time diversity in Lamiales and, more generally, in angiosperms.

Vertical transmission of microbiomes into embryo culture media and its association with assisted reproductive outcomes.

RESEARCH QUESTION: Can microbes vertically transmit from semen and follicular fluid to embryo culture media during assisted reproductive technology (ART) treatment? DESIGN: Spent embryo culture media (SECM), seminal fluid and follicular fluid samples were collected from 61 couples with infertility undergoing ART treatment at the Prince of Wales Hospital, Hong Kong SAR, China. Metagenomic analysis was conducted using 16s rRNA sequencing to identify the source of microbes in SECM, correlation between the semen microbiome and male infertility, and correlation between the follicular fluid microbiome and female infertility. RESULTS: Microbial vertical transmission into SECM was reported in 82.5% of cases, and semen was the main source of contamination in conventional IVF cases. The increased abundances of Staphylococcus spp. and Streptococcus anginosus in semen had negative impacts on total motility and sperm count, respectively (P < 0.001). Significant increases in abundance of the genera Prophyromonas, Neisseria and Facklamia were observed in follicular fluid in women with anovulation, uterine factor infertility and unexplained infertility, respectively (P < 0.01). No significant correlation was found between the bacteria identified in all sample types and ART outcomes, including fertilization rate, embryo development, number of available embryos, and clinical pregnancy rate. CONCLUSION: Embryo culture media can be contaminated during ART treatment, not only by seminal microbes but also by follicular fluid and other sources of microbes. Strong correlations were found between specific microbial taxa in semen and sperm quality, and between the follicular fluid microbiome and the aetiology of female infertility. However, no significant association was found between the microbiomes of SECM, semen and follicular fluid and ART outcomes.

Streptomyces albipurpureus sp. nov., a novel actinobacterium with antimicrobial activity isolated from the rhizospheric soil of Fritillaria cirrhosa D. Don.

A novel actinobacterium, designated strain CWNU-1T, was isolated from the rhizospheric soil of Fritillaria cirrhosa D. Don and examined using a polyphasic taxonomic approach. The organism developed pale blue aerial mycelia that was simply branched and terminated in open or closed coils of three or more volutions on International Streptomyces Project 3 agar. Spores were ellipsoidal to cylindrical with wrinkled surfaces. The strain showed high 16S rRNA gene sequence similarity to Streptomyces kurssanovii NBRC 13192T (98.8 %), Streptomyces xantholiticus NBRC 13354T (98.7 %) and Streptomyces peucetius JCM 9920T (98.6 %). The phylogenetic result based on 16S rRNA gene and genome sequences clearly demonstrated that strain CWNU-1T formed an independent phylogenetic lineage. On the basis of orthologous average nucleotide identity, CWNU-1T was most closely related to Streptomyces inusitatus NBRC 13601T with 79.3 % identity. The results of the digital DNA-DNA hybridization analysis also indicated low levels of relatedness with other species, as the highest value was observed with S. inusitatus NBRC 13601T (25.3 %). With reference to phenotypic characteristics, phylogenetic data, orthologous average nucleotide identity and digital DNA-DNA hybridization results, strain CWNU-1T was readily distinguished from its most closely related strains and classified as representing a novel species, for which the name Streptomyces albipurpureus sp. nov. is proposed. The type strain is CWNU-1T (=CGMCC 4.7758T=MCCC 1K07402T=JCM 35391T).

Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

PURPOSE: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity. DESIGN: We randomly assigned women with a serum 25(OH)D concentration < 75 nmol/L to receive 1600 IU/d (intervention group) or 400 IU/d (control group) of vitamin D3 for two months at 24-28 weeks' gestation. The primary outcome was gestational CVH marks (lipids, inflammatory cytokines, endothelial function). RESULTS: There were 1537 participants divided into the intervention (N = 766) and control groups (N = 771). No baseline differences existed among study groups in CVH markers. At the two-month visit, the intervention group's HDL-C levels (2.01 ± 0.39 VS 1.96 ± 0.39 mmol/L) were significantly higher than those of the control group, while the hs-CRP levels were significantly lower (3.28 ± 2.02 VS 3.64 ± 2.42 mg/L). Subgroup analysis found that HDL-C, TC, hs-CRP, E-Selectin, and SBP were improved in the intervention group among women with GDM or overweight/obesity, and the improvement was not found in women without GDM or overweight/obesity. Vitamin D supplementation significantly decreased the mean triglyceride-glucose index at the two-month visit in women with GDM. CONCLUSIONS: Vitamin D supplementation at mid-gestation might optimize the gestational CVH status for pregnant women, particularly the women with GDM or obesity, which is advantageous for later-life primary prevention of CVD. CLINICAL TRIAL REGISTRATION: The Chinese Clinical Trial Registry (ChiCTR2100051914, 10/9/2021, Prospective registered, https://www.chictr.org.cn/showproj.aspx?proj=134700 ).

PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy.

Hypoxia-ischemia (HI) is one of the main causes of neonatal brain injury. Mitophagy has been implicated in the degradation of damaged mitochondria and cell survival following neonatal brain HI injury. Pleckstrin homology-like domain family A member 1 (PHLDA1) plays vital roles in the progression of various disorders including the regulation of oxidative stress, the immune responses and apoptosis. In the present study we investigated the role of PHLDA1 in HI-induced neuronal injury and further explored the mechanisms underlying PHLDA1-regulated mitophagy in vivo and in vitro. HI model was established in newborn rats by ligation of the left common carotid artery plus exposure to an oxygen-deficient chamber with 8% O2 and 92% N2. In vitro studies were conducted in primary hippocampal neurons subjected to oxygen and glucose deprivation/-reoxygenation (OGD/R). We showed that the expression of PHLDA1 was significantly upregulated in the hippocampus of HI newborn rats and in OGD/R-treated primary neurons. Knockdown of PHLDA1 in neonatal rats via lentiviral vector not only significantly ameliorated HI-induced hippocampal neuronal injury but also markedly improved long-term cognitive function outcomes, whereas overexpression of PHLDA1 in neonatal rats via lentiviral vector aggravated these outcomes. PHLDA1 knockdown in primary neurons significantly reversed the reduction of cell viability and increase in intracellular reactive oxygen species (ROS) levels, and attenuated OGD-induced mitochondrial dysfunction, whereas overexpression of PHLDA1 decreased these parameters. In OGD/R-treated primary hippocampal neurons, we revealed that PHLDA1 knockdown enhanced mitophagy by activating FUNDC1, which was abolished by FUNDC1 knockdown or pretreatment with mitophagy inhibitor Mdivi-1 (25 µM). Notably, pretreatment with Mdivi-1 or the knockdown of FUNDC1 not only increased brain infarct volume, but also abolished the neuroprotective effect of PHLDA1 knockdown in HI newborn rats. Together, these results demonstrate that PHLDA1 contributes to neonatal HI-induced brain injury via inhibition of FUNDC1-mediated neuronal mitophagy.

E3 ubiquitin ligase UBR5 modulates circadian rhythm by facilitating the ubiquitination and degradation of the key clock transcription factor BMAL1.

The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila, could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila. PER2-luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification level, offering potential insights into the modulation of the dysregulated circadian rhythm.

A comparative study of 18F-PSMA-1007 PET/CT and pelvic MRI in newly diagnosed prostate cancer.

PURPOSE: To evaluate the difference in the diagnostic efficacy of 18F-PSMA-1007 PET/CT and pelvic MRI in primary prostate cancer, as well as the correlation between the two methods and histopathological parameters and serum PSA levels. METHODS: A total of 41 patients with suspected prostate cancer who underwent 18F-PSMA-1007 PET/CT imaging in our department from 2018 to 2023 were retrospectively collected. All patients underwent 18F-PSMA-1007 PET/CT and MRI scans. The sensitivity, PPV and diagnostic accuracy of MRI and 18F-PSMA-1007 PET/CT in the diagnosis of prostate cancer were calculated after comparing the results of MRI and 18F-PSMA-1007 PET/CT with biopsy. The Spearman test was used to calculate the correlation between 18F-PSMA-1007 PET/CT, MRI parameters, histopathological indicators, and serum PSA levels. RESULTS: Compared with histopathological results, the sensitivity, PPV and diagnostic accuracy of 18F-PSMA-1007 PET/CT in the diagnosis of prostate cancer were 95.1%, 100.0% and 95.1%, respectively. The sensitivity, PPV and diagnostic accuracy of MRI in the diagnosis of prostate cancer were 82.9%, 100.0% and 82.9%, respectively. There was a mild to moderately positive correlation between Gleason (Gs) score, Ki-67 index, serum PSA level and 18F-PSMA-1007 PET/CT parameters (p < 0.05). There was a moderately negative correlation between the expression of AMACR (P504S) and 18F-PSMA-1007 PET/CT parameters (p < 0.05). The serum PSA level and the Gs score were moderately positively correlated with the MRI parameters (p < 0.05). There was no correlation between histopathological parameters and MRI parameters (p > 0.05). CONCLUSION: Compared with MRI, 18F-PSMA-1007 PET/CT has higher sensitivity and diagnostic accuracy in the detection of malignant prostate tumors. In addition, the Ki-67 index and AMACR (P504S) expression were only correlated with 18F-PSMA-1007 PET/CT parameters. Gs score and serum PSA level were correlated with 18F-PSMA-1007 PET/CT and MRI parameters. 18F-PSMA-1007 PET/CT examination can provide certain reference values for the clinical diagnosis, evaluation, and treatment of malignant prostate tumors.

Rsad2 mediates Bisphenol A-induced actin cytoskeletal disruption in mouse spermatocytes.

Bisphenol A (BPA) is widely exposed in populations worldwide and has negative effects on spermatogenesis both in animals and humans. The homeostasis of the actin cytoskeleton in the spermatogenic epithelium is crucial for spermatogenesis. Actin cytoskeleton destruction in the seminiferous epithelium is one of the important reasons for BPA-induced spermatogenesis disorder. However, the underlying molecular mechanisms remain largely unexplored. Herein, we explored the role and mechanism of Rsad2, an interferon-stimulated gene in BPA-induced actin cytoskeleton disorder in mouse GC-2 spermatocyte cell lines. After BPA exposure, the actin cytoskeleton was dramatically disrupted and the cell morphology was markedly altered accompanied by a significant increase in Rsad2 expression both in mRNA and protein levels in GC-2 cells. Furthermore, the phalloidin intensities and cell morphology were restored obviously when interfering with the expression of Rsad2 in BPA-treated GC-2 cells. In addition, we observed a significant decrease in intracellular ATP levels after BPA treatment, while the ATP level was obviously upregulated when knocking down the expression of Rsad2 in BPA-treated cells compared to cells treated with BPA alone. Moreover, Rsad2 relocated to mitochondria after BPA exposure in GC-2 cells. BPA promoted Rsad2 expression by activating type I IFN-signaling in GC-2 cells. In summary, Rsad2 mediated BPA-induced actin cytoskeletal disruption in GC-2 cells, which provided data to reveal the mechanism of BPA-induced male reproductive toxicity.

Polystyrene nanoplastics exposure triggers spermatogenic cell senescence via the Sirt1/ROS axis.

Polystyrene nanoplastics (PS-NPs) have been reported to accumulate in the testes and constitute a new threat to reproductive health. However, the exact effects of PS-NPs exposure on testicular cells and the underlying mechanisms remain largely unknown. The C57BL/6 male mice were orally administered with PS-NPs (80 nm) at different dosages (0, 10, and 40 mg/kg/day) for 60 days, and GC-1 cells were treated with PS-NPs in this study. Enlarged seminiferous tubule lumens and a loose and vacuolated layer of spermatogenic cells were observed in PS-NPs-exposed mice. Spermatogenic cells which may be one of the target cells for this reproductive damage, were decreased in the mice from PS-NPs group. PS-NPs caused spermatogenic cells to undergo senescence, manifested as elevated SA-ß-galactosidase activity and activated senescence-related signaling p53-p21/Rb-p16 pathways, and induced cell cycle arrest. Mechanistically, Gene Ontology (GO) enrichment suggested the key role of reactive oxygen species (ROS) in PS-NPs-induced spermatogenic cell senescence, and this result was confirmed by measuring ROS levels. Moreover, ROS inhibition partially attenuated the senescence phenotype of spermatogenic cells and DNA damage. Using the male health atlas (MHA) database, Sirt1 was filtrated as the critical molecule in the regulation of testicular senescence. PS-NPs induced overexpression of the main ROS generator Nox2, downregulated Sirt1, increased p53 and acetylated p53 in vivo and in vitro, whereas these disturbances were partially restored by pterostilbene. In addition, pterostilbene intervention significantly alleviated the PS-NPs-induced spermatogenic cell senescence and attenuated ROS burst. Collectively, our study reveals that PS-NPs exposure can trigger spermatogenic cell senescence mediated by p53-p21/Rb-p16 signaling by regulating the Sirt1/ROS axis. Importantly, pterostilbene intervention may be a promising strategy to alleviate this damage.

Vortioxetine for depression in adults: A systematic review and dose-response meta-analysis of randomized controlled trials.

AIM: Major depressive disorder (MDD) is a prevalent psychiatric condition and vortioxetine offers promising antidepressant effects due to its unique pharmacological profile. However, the dose-response relationships of vortioxetine for MDD is not well established. We aimed to conduct dose-response meta-analyses to fill this gap. METHODS: We systematically searched multiple electronic databases for randomized controlled trials of vortioxetine for MDD, with the last search conducted on 08 February, 2024. The dose-response relationship was evaluated using a one-stage random-effects dose-response meta-analysis with restricted cubic spline model. The primary outcome was efficacy (mean change in depression scale score), with secondary outcomes including response, dropout for any reasons (acceptability), dropout for adverse events (tolerability), and any adverse events (safety). RESULTS: The dose-response meta-analysis comprised 16 studies, with 4,294 participants allocated to the vortioxetine group and 2,299 participants allocated to the placebo group. The estimated 50% effective dose was 4.37 mg/day, and the near-maximal effective dose (95% effective dose) was 17.93 mg/day. Visual inspection of the dose-efficacy curve suggests that a plateau possibly had not been reached yet at 20 mg/day. Acceptability, tolerability and safety decreased as the dose increased. Subgroup analysis indicated that no significant differences were observed in acceptability, tolerability and safety among the dosage groups. CONCLUSIONS: Vortioxetine may potentially provide additional therapeutic benefits when exceeding the current licensed dosage without significantly impacting safety. Conducting clinical trials exceeding the current approved dosage appears necessary to fully comprehend its efficacy and risk.

Isoalantolactone exerts anti-melanoma effects via inhibiting PI3K/AKT/mTOR and STAT3 signaling in cell and mouse models.

BACKGROUND AND AIM: Although the anti-cancer activity of isoalantolactone (IATL) has been extensively studied, the anti-melanoma effects of IATL are still unknown. Here, we have investigated the anti-melanoma effects and mechanism of action of IATL. MTT and crystal violet staining assays were performed to detect the inhibitory effect of IATL on melanoma cell viability. Apoptosis and cell cycle arrest induced by IATL were examined using flow cytometry. The molecular mechanism of IATL was explored by Western blotting, confocal microscope analysis, molecular docking, and cellular thermal shift assay (CETSA). A B16F10 allograft mouse model was constructed to determine the anti-melanoma effects of IATL in vivo. The results showed that IATL exerted anti-melanoma effects in vitro and in vivo. IATL induced cytoprotective autophagy in melanoma cells by inhibiting the PI3K/AKT/mTOR signaling. Moreover, IATL inhibited STAT3 activation both in melanoma cells and allograft tumors not only by binding to the SH2 domain of STAT3 but also by suppressing the activity of its upstream kinase Src. These findings demonstrate that IATL exerts anti-melanoma effects via inhibiting the STAT3 and PI3K/AKT/mTOR signaling pathways, and provides a pharmacological basis for developing IATL as a novel phytotherapeutic agent for treating melanoma clinically.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. METHOD: We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. RESULT: Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. CONCLUSION: The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

A new cassane diterpenoid from the seed of Caesalpinia sappan.

In this study, a previously undescribed cassane diterpenoid, named caesalpinin JF (1), along with two known cassane diterpenoids caesanine C (2) and tomocinol B (3), was isolated from 95% EtOH extract of the seeds of Caesalpinia sappan Linn. Additionally, three known compounds including pulcherrin R (4), syringaresinol-4'-O-ß-D-glucopyranoside (5) and kaempferol (6) were also identified. The structures of the isolated compounds were elucidated by comprehensive 1D and 2D NMR spectroscopic analyses. Additionally, electronic circular dichroism (ECD) calculation was used to identify the absolute structure of compound 1. Among the isolated compounds, compound 1 displayed a potent anti-neuroinflammation with an IC50 value of 9.87 ± 1.71 µM.

Social frailty and the incidence of motoric cognitive risk syndrome in older adults.

INTRODUCTION: Various associations between social factors and motoric cognitive risk syndrome (MCR) have been reported. However, whether social frailty (integrated from multiple social factors) is associated with MCR is still unclear. METHODS: We included 4657 individuals without MCR at Round 1 of the NHATS as the discovery sample, and 3075 newly recruited individuals from Round 5 of the NHATS as the independent validation sample. Social frailty was assessed by five social items. MCR was defined as the presence of both subjective cognitive complaints and slow gait speed in individuals without dementia or mobility disability. RESULTS: Compared with normal individuals, those with social frailty had higher risk of incident MCR (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.34-1.84). Each additional unfavorable social item was associated with an increased risk of MCR (HR: 1.32, 95% CI: 1.22-1.43). DISCUSSION: Social frailty was associated with an increased risk of incident MCR in older adults. HIGHLIGHTS: Various associations between social factors and motoric cognitive risk syndrome (MCR) have been reported. Social frailty that integrated from multiple social factors was associated with an increased risk of incident MCR. Social frailty should be included in the early screening of individuals to identify those at higher risk of MCR.

The effects of environmental factors on the synthesis of water-soluble Monascus red pigments via submerged fermentation: a review.

Monascus pigments (MPs) have been used as natural food pigments for many years. There is a high demand for Monascus red pigments (MRPs) to enhance color and for antibacterial and cancer prevention therapies in food and medicine. Most MRPs are not water soluble, and the yield of water-soluble MRPs is naturally low. On the other hand, water-soluble MRP is more cost effective for application in industrial mass production. Therefore, it is important to improve the yield of water-soluble MRPs. Environmental factors have a significant influence on the synthesis of water-soluble MRPs, which is crucial for the development of industrial production of water-soluble MRPs. This review introduces the biosynthetic pathways of water-soluble MRPs and summarizes the effects of environmental factors on the yield of water-soluble MRPs. Acetyl coenzyme A (acetyl-CoA) is a precursor for MPs synthesis. Carbon and nitrogen sources and the carbon/nitrogen ratio can impact MP production by regulating the metabolic pathway of acetyl-CoA. Optimization of fermentation conditions to change the morphology of Monascus can stimulate the synthesis of MPs. The appropriate choice of nitrogen sources and pH values can promote the synthesis of MRPs from MPs. Additives such as metal ions and non-ionic surfactants can affect the fluidity of Monascus cell membrane and promote the transformation of MRPs into water-soluble MRPs. This review will lay the foundation for the industrial production of water-soluble MRPs. © 2024 Society of Chemical Industry.