Co-regulation and synteny of GFM2 and NSA2 links ribosomal function in mitochondria and the cytosol with chronic kidney disease.

BACKGROUND: We previously reported aberrant expression of the cytosolic ribosomal biogenesis factor Nop-7-associated 2 (NSA2) in diabetic nephropathy, the latter also known to involve mitochondrial dysfunction, however the connections between NSA2, mitochondria and renal disease were unclear. In the current paper, we show that NSA2 expression is co-regulated with the GTP-dependent ribosome recycling factor mitochondrial 2 (GFM2) and provide a molecular link between cytosolic and mitochondrial ribosomal biogenesis with mitochondrial dysfunction in chronic kidney disease (CKD). METHODS: Human renal tubular cells (HK-2) were cultured (+/- zinc, or 5mM/20mM glucose). mRNA levels were quantified using real-time qPCR. Transcriptomics data were retrieved and analysed from Nakagawa chronic kidney disease (CKD) Dataset (GSE66494) and Kidney Precision Medicine Project (KPMP) ( https://atlas.kpmp.org/ ). Protein levels were determined by immunofluorescence and Western blotting. Cellular respiration was measured using Agilent Seahorse XF Analyzer. Data were analysed using one-way ANOVA, Students' t-test and Pearson correlation. RESULTS: The NSA2 gene, on human chromosome 5q13 was next to GFM2. The two genes were syntenic on opposite strands and orientation in multiple species. Their common 381 bp 5' region contained multiple transcription factor binding sites (TFBS) including the zinc-responsive transcription factor MTF1. NSA2 and GFM2 mRNAs showed a dose-dependent increase to zinc in-vitro and were highly expressed in proximal tubular cells in renal biopsies. CKD patients showed higher renal NSA2/GFM2 expression. In HK-2 cells, hyperglycaemia led to increased expression of both genes. The total cellular protein content remained unchanged, but GFM2 upregulation resulted in increased levels of several mitochondrial oxidative phosphorylation (OXPHOS) subunits. Furthermore, increased GFM2 expression, via transient transfection or hyperglycemia, correlated with decrease cellular respiration. CONCLUSION: The highly conserved synteny of NSA2 and GFM2, their shared 5' region, and co-expression in-vitro and in CKD, shows they are co-regulated. Increased GFM2 affects mitochondrial function with a disconnect between an increase in certain mitochondrial respiratory proteins but a decrease in cellular respiration. These data link the regulation of 2 highly conserved genes, NSA2 and GFM2, connected to ribosomes in two different cellular compartments, cytosol and mitochondria, to kidney disease and shows that their dysregulation may be involved in mitochondrial dysfunction.

Correlation Analysis of Characteristics of Intestinal Microbiota and Cytokine Levels in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome.

Objective: The aim of this study was to analyze the relationship between the characteristics of the intestinal microbiota and cytokine levels in individuals with different degrees of obstructive sleep apnea-hypopnea syndrome (OSAHS) as well as to investigate intestinal microbiota imbalances in patients with OSAHS and the associated mechanisms. Methods: Based on their sleep apnea hypopnea index (AHI), a total of 37 adults were assigned to a control group, a mild OSAHS group, or a moderate-to-severe OSAHS group. Fecal samples were collected to characterize the intestinal microbiota using metagenomic next-generation sequencing (mNGS), while blood samples were collected to detect levels of interleukin-17a (IL-17a), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in each group. Results: 1. There was no significant difference in the Shannon index among the three groups (P > 0.05). The three groups showed significant difference in the relative abundance of Faecalibacterium prausnitzii and Bifidobacterium adolescentis (with F values of 3.955 and 7.24, respectively, P < 0.05), while showed no significant difference in the relative abundance of B. pseudocatenulatum, Bifidobacterium longum, Klebsiella pneumoniae, and Haemophilus parainfluenzae (P > 0.05). 2. The three groups showed significant difference in the expression of serum IL-17A and TNF-α levels (with F values of 18.119 and 10.691, respectively, P < 0.05), while showed no significant difference in the expression of IL-10, IL-6, and CRP levels (P > 0.05). 3. Multiple linear regression analysis revealed that the relative abundance of F. prausnitzii was correlated with changes in BMI and AHI (with ß values of 2.585 and -0.157, respectively, P < 0.05), while the relative abundance of B. adolescentis was correlated with changes in IL-17a (with ß value of -0.161, P < 0.05). Conclusion: The study revealed a significant correlation between intestinal microbiota abundance and cytokine levels, suggesting that gut microbiota disruption in OSAHS patients may be linked to systemic chronic inflammation.

Spying with a pilot's eye: Using eye tracking to investigate pilots' attention allocation and workload during helicopter autorotative gliding.

Flight safety in helicopters is a critical aspect of overall aircraft operational safety management, particularly during engine failures requiring autorotative glide, which makes it extremely challenging for the pilot to land the helicopter successfully. In this study, we evaluated the workload and attention allocation of helicopter pilots under such circumstances. In the experiment, a helicopter flight simulator was used to simulate level flight followed by autorotative glide, with the two phases divided into time segments for data collection. First, the data were visualized using heat maps and saccade sequence diagrams, while changes in eye movement metrics (such as peak value and standard deviation) were statistically analyzed. Finally, the criteria through the inter-criteria correlation (CRITIC) method was used to calculate the weight coefficient for each area of interest. This evaluation system was further applied to analyze and compare the changes in eye-movement data and attention to areas of interest during the two phases. The results revealed a shorter fixation duration, but a greater fixation number during the autorotative glide phase. Further, the mean pupil diameter changed over a larger range than during level flight (in level flight, the mean was 5.229 mm, while the standard deviation was 0.059 mm; in autorotative glide the corresponding values were 5.326 mm and 0.126 mm, respectively). For the tachometer, the weight coefficient matched the color of the heat map (2.7 % and colorless during level flight, but 23.8 % and red during autorotative glide), while those for the airspeed indicator and forward view differed significantly between the two phases. This discrepancy stemmed from the fact that during autorotative glide, the pilots prioritized monitoring aircraft rotation speed and attitude, with a particular focus on the forward view, rotor speed, and airspeed, resulting in a more concentrated attention distribution compared to that achieved during level flight. These results confirmed a significant increase in pilot workload during autorotative glide landing, while a shift was observed from low-frequency long gaze time during level flight to high-frequency short gaze time during autorotative glide. Furthermore, the pilots allocated 81 % of their attention to the tachometer, airspeed indicator, and forward views. Adopting this strategy can improve pilots' landing success and provide flight students with valuable training advice to prevent landing failures when helicopters lose power.

Impaired phase separation and nucleolar functions in hiPSC models of SNORD118-related ribosomopathies.

Ribosomopathies arise from the disruptions in ribosome biogenesis within the nucleolus, which is organized via liquid-liquid phase separation (LLPS). The roles of LLPS in ribosomopathies remain poorly understood. Here, we generated human induced pluripotent stem cell (hiPSC) models of ribosomopathy caused by mutations in small nucleolar RNA (snoRNA) gene SNORD118. Mutant hiPSC-derived neural progenitor cells (NPCs) or neural crest cells (NCCs) exhibited ribosomopathy hallmark cellular defects resulting in reduced organoid growth, recapitulating developmental delay in patients. SNORD118 mutations in NPCs disrupted nucleolar morphology and LLPS properties coupled with impaired ribosome biogenesis and a translational downregulation of fibrillarin (FBL), the key LLPS effector acting via the intrinsically disordered region (IDR) motif. IDR-depleted FBL failed to rescue NPC defects, whereas a chimeric FBL with swapped IDR motif from an unrelated protein mitigated ribosomopathy and organoid growth defects. Thus, SNORD118 human iPSC models revealed aberrant phase separation and nucleolar functions as potential pathogenic mechanisms in ribosomopathies.

Investigation of Deoxynivalenol Contamination in Local Area and Evaluation of Its Multiple Intestinal Toxicity.

Deoxynivalenol (DON) is a mycotoxin produced by Fusarium fungi widespread in wheat, corn, barley and other grain crops, posing the potential for being toxic to human and animal health, especially in the small intestine, which is the primary target organ for defense against the invasion of toxins. This study firstly investigated DON contamination in a local area of a wheat production district in China. Subsequently, the mechanism of DON toxicity was analyzed through cellular molecular biology combining with intestinal flora and gene transcription analysis; the results indicated that DON exposure can decrease IPEC-J2 cell viability and antioxidant capacity, stimulate the secretion and expression of proinflammatory factors, destroy the gut microbiota and affect normal functions of the body. It is illustrated that DON could induce intestinal damage through structural damage, functional injury and even intestinal internal environment disturbance, and, also, these intestinal toxicity effects are intrinsically interrelated. This study may provide multifaceted information for the treatment of intestinal injury induced by DON.

High expression of PDCD11 in colorectal cancer and its correlation with the prognosis and immune cell infiltration.

Objective: To undertake a comprehensive assay of PDCD11 expression in colorectal cancer (CRC) and its association with prognosis and immune cell infiltration (ICIN) utilizing bioinformatics tools. Methods: The PDCD11 expression in CRC and pan-cancer was quantified through datasets from TCGA and GEO databases, and the assay was conducted through R software and the GEPIA database. Moreover, mRNA and protein expression data of PDCD11 were attained from the HPA database. It was attempted to establish protein-protein interaction networks of PDCD11 via the STRING and GeneMANIA databases. The association of PDCD11 expression with CRC staging was evaluated through R software, while its association with CRC and pan-cancer prognosis was figured out via the GEPIA database. Furthermore, the relationship of PDCD11 expression with ICIN was assayed using R software and the TIMER database. Additionally, the influences of PDCD11 knockdown on the proliferation, apoptosis, and migration of colon cancer RKO cell lines was evaluated. Results: PDCD11 exhibited elevated expression in CRC and various other malignancies, potentially indicating a promotive role in cancer progression. Overexpression of PDCD11 was found to correlate with attenuated overall survival in CRC and other malignancies. Moreover, PDCD11 demonstrated promising predictive capabilities for distinguishing between tumor and non-tumor tissues. The positive association of high PDCD11 expression with the infiltration of neutrophils, dendritic cells, CD8+ T cells, CD4+ T cells, and macrophages, as well as with the expression of immune checkpoint molecules CTLA4 and PD-1 was noteworthy. Lentivirus-mediated PDCD11 knockdown suppressed RKO cell proliferation, colony formation, and migration, while triggered apoptosis in these cells. Conclusion: The outcomes unveiled the noticeable function of PDCD11 in CRC and various other malignancies, emphasizing its potential as a prognostic biomarker and therapeutic target.

Could Ocular Glands Be Infected by SARS-CoV-2?

The aim of the study was to investigate the expression levels of ACE2 in ocular glands and to investigate the effect of S protein on them. Male C57BL/6J mice were used for the experiments. The expression levels of ACE2 are highest in the Meibomian glands, followed by the conjunctiva, the cornea, and the lacrimal glands. Co-immunoprecipitation assays confirmed direct binding between ACE2 and S protein in ocular surface epithelia and Meibomian glands. CD45+ cell infiltration was found in the S protein treatment group, which was accompanied by upregulation of inflammation-related cytokines. There was also prominent cell apoptosis in the S protein treatment group. In conclusion, not only the cornea and the conjunctiva, but also the Meibomian glands express ACE2, and S protein could induce ocular surface epithelial cell and Meibomian gland cell inflammation and apoptosis.

Association of heavy metals exposure with lower blood pressure in the population aged 8-17 years: a cross-sectional study based on NHANES.

Background: The existing evidence regarding the joint effect of heavy metals on blood pressure (BP) in children and adolescents is insufficient. Furthermore, the impact of factors such as body weight, fish consumption, and age on their association remains unclear. Methods: The study utilized original data from the National Health and Nutrition Examination Survey, encompassing 2,224 children and adolescents with complete information on 12 urinary metals (barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, tungsten, uranium, mercury and arsenic), BP, and core covariates. Various statistical methods, including weighted multiple logistic regression, linear regression, and Weighted Quantile Sum regression (WQS), were employed to evaluate the impact of mixed metal exposure on BP. Sensitivity analysis was conducted to confirm the primary analytical findings. Results: The findings revealed that children and adolescents with low-level exposure to lead (0.40 µg/L, 95%CI: 0.37, 0.42), mercury (0.38 µg/L, 95%CI: 0.35, 0.42) and molybdenum (73.66 µg/L, 95%CI: 70.65, 76.66) exhibited reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP). Conversely, barium (2.39 µg/L, 95%CI: 2.25, 2.54) showed a positive association with increased SBP. A 25th percentile increase in the WQS index is significantly associated with a decrease in SBP of 0.67 mmHg (95%CI, -1.24, -0.10) and a decrease in DBP of 0.59 mmHg (95% CI, -1.06, -0.12), which remains statistically significant even after adjusting for weight. Furthermore, among individuals who consume fish, heavy metals have a more significant influence on SBP. A 25 percentile increase in the WQS index is significantly associated with a decrease of 3.30 mmHg (95% CI, -4.73, -1.87) in SBP, primarily attributed to mercury (27.61%), cadmium (27.49%), cesium (17.98%), thallium (8.49%). The study also identified a declining trend in SBP among children aged 10-17, whereas children aged 11-18 exhibited lower levels of systolic and diastolic blood pressure, along with a reduced risk of hypertension. Conclusion: Some heavy metals demonstrate an inverse association with the BP of children and adolescents, particularly notable in groups with fish consumption and older children and adolescents. Future studies are warranted to validate these findings and delve deeper into the interplay of heavy metals.

Depression outcome in women with recurrent spontaneous abortion: A systematic review and meta-analysis.

BACKGROUND: It is widely recognized that depression is highly prevalent among women experiencing recurrent spontaneous abortion (RSA), exerting detrimental effects on both the individual and the family. OBJECTIVE: To assess the depression risk and associated factors among women with RSA. DATA SOURCES: Our search strategy encompassed PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure (CNKI), and WANFANG. The research was conducted in May 2022. We included both randomized and nonrandomized studies that reported the prevalence of depression among women with RSA. DATA EXTRACTION AND SYNTHESIS: Two independent evaluators reviewed the titles and abstracts, assessed the full-text papers, extracted data from the included studies, and evaluated their quality using the Newcastle-Ottawa Scale (NOS). We performed random-effects meta-analyses to pool the data. Odds ratios (ORs) and standardized mean differences (SMDs) were combined based on effect sizes for binary and continuous outcomes. MAIN OUTCOMES: To conduct a meta-analysis to understand the risk of depression in women with RSA who were not treated with psychiatric medications, as well as an analysis of potential factors for depressive symptoms. RESULTS: Out of the initially identified 527 papers, a total of 20 studies (N = 13087) that fulfilled the inclusion criteria were selected. Compared to healthy controls, patients with RSA had a significantly higher risk of depression (OR: 4.26, 95 % confidence interval [CI]: 2.44-7.41; SMD: 0.89, 95 % CI: 0.51-1.26). The occurrence of depression among RSA patients was found to be significantly associated with several factors including the severity of depressive symptoms (OR: 3.82, 95 % CI: 2.22-6.59), number of spontaneous miscarriages (SMD: 0.59, 95 % CI: 0.01-1.18), history of therapeutic termination of pregnancy (SMD: 0.20, 95 % CI: 0.09-0.32), history of live birth (SMD: -0.32, 95 % CI: -0.49--0.15), and duration of marriage (SMD: 0.15, 95 % CI: 0.02-0.27). CONCLUSIONS: In clinical practice, it is crucial to provide appropriate psychological interventions for women undergoing RSA. These individuals face a significantly heightened risk of depression, which exhibits strong correlations with various demographic factors such as the severity of depressive symptoms, history of both spontaneous miscarriages and therapeutic termination of pregnancy, number of live births, and duration of marriage. Consequently, women who are suffering RSA deserves more assistance and emotional support.

DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson's disease.

The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson's disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. L-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.

miRNA-seq analysis of high glucose induced osteoblasts provides insight into the mechanism underlying diabetic osteoporosis.

The present study aims to explore the etiology of Diabetic osteoporosis (DOP), a chronic complication associated with diabetes mellitus. Specifically, the research seeks to identify potential miRNA biomarkers of DOP and investigated role in regulating osteoblasts. To achieve this, an animal model of DOP was established through the administration of a high-sugar and high-fat diet, and then injection of streptozotocin. Bone microarchitecture and histopathology analysis were analyzed. Rat calvarial osteoblasts (ROBs) were stimulated with high glucose (HG). MiRNA profiles of the stimulated osteoblasts were compared to control osteoblasts using sequencing. Proliferation and mineralization abilities were assessed using MTT assay, alkaline phosphatase, and alizarin red staining. Expression levels of OGN, Runx2, and ALP were determined through qRT-PCR and Western blot. MiRNA-sequencing results revealed increased miRNA-702-5p levels. Luciferase reporter gene was utilized to study the correlation between miR-702-5p and OGN. High glucose impaired cell proliferation and mineralization in vitro by inhibiting OGN, Runx2, and ALP expressions. Interference with miR-702-5p decreased OGN, Runx2, and ALP levels, which were restored by OGN overexpression. Additionally, downregulation of OGN and Runx2 in DOP rat femurs was confirmed. Therefore, the miRNA-702-5p/OGN/Runx2 signaling axis may play a role in DOP, and could be diagnostic biomarker and therapeutic target for not only DOP but also other forms of osteoporosis.

The combined effect of handgrip strength and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly: A cohort study.

OBJECTIVE: The aim of this study was to investigate the combined effect of handgrip strength (HGS) and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly people. METHODS: The data was used from the China Health and Retirement Longitudinal Study (CHARLS). Middle-aged and older adults who participated in surveys between 2011 and 2018 were included in the study. They were divided into 4 different types of obesity phenotypes based on obesity and metabolic status: metabolically healthy non-overweight/obesity (MHNO), metabolically healthy overweight/obesity (MHO), metabolically abnormal non-overweight/obesity (MANO), and metabolically abnormal overweight/obesity (MAO). The HGS level was divided into low and high groups according to the median values. Cox proportional risk regression model was used to analyze the joint effect of HGS and obesity phenotype on the risk of stroke among participants. RESULTS: A total of 7904 participants aged 58.89±9.08 years were included in this study. After adjusting for potential confounders, high HGS&MHO (HR=1.86, 95 % CI=1.12-3.09), high HGS&MANO (HR=2.01, 95 %CI=1.42-2.86), high HGS&MAO (HR=2.01, 95 % CI=1.37-2.93), low HGS&MHNO (HR=1.57, 95 % CI=1.00-2.46), low HGS&MHO (HR=2.09, 95 % CI=1.29-3.38), low HGS&MANO (HR=2.02, 95 % CI=1.35-3.03), and low HGS&MAO (HR=2.48, 95 % CI=1.72-3.58) group had significantly higher risks of stroke than the high HGS&MHNO group. CONCLUSION: The coexistence of metabolically unhealthy and low HGS can synergistically increase the risk of stroke in Chinese middle-aged and elderly people.

SDH, a novel diarylheptane compound, alleviates dextran sulfate sodium (DSS)-induced colitis by reducing Th1/Th2/Th17 induction and regulating the gut microbiota in mice.

Ulcerative colitis, a chronic inflammatory condition affecting the rectum and colon to varying degrees, is linked to a dysregulated immune response and the microbiota. Sodium (aS,9R)-3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) emerges as a novel diarylheptane compound aimed at treating inflammatory bowel diseases. However, the mechanisms by which SDH modulates these conditions remain largely unknown. In this study, we assessed SDH's impact on the clinical progression of dextran sodium sulfate (DSS)-induced ulcerative colitis. Our results demonstrated that SDH significantly mitigated the symptoms of DSS-induced colitis, reflected in reduced disease activity index scores, alleviation of weight loss, shortening of the colorectum, and reduction in spleen swelling. Notably, SDH decreased the proportion of Th1/Th2/Th17 cells and normalized inflammatory cytokine levels in the colon. Furthermore, SDH treatment modified the gut microbial composition in mice with colitis, notably decreasing Bacteroidetes and Proteobacteria populations while substantially increasing Firmicutes, Actinobacteria, and Patescibacteria. In conclusion, our findings suggest that SDH may protect the colon from DSS-induced colitis through the regulation of Th1/Th2/Th17 cells and gut microbiota, offering novel insights into SDH's therapeutic potential.

A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization.

Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway.

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 µM for Hela cells and 3.78 µM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

Ferrielectricity controlled widely-tunable magnetoelectric coupling in van der Waals multiferroics.

The discovery of various primary ferroic phases in atomically-thin van der Waals crystals have created a new two-dimensional wonderland for exploring and manipulating exotic quantum phases. It may also bring technical breakthroughs in device applications, as evident by prototypical functionalities of giant tunneling magnetoresistance, gate-tunable ferromagnetism and non-volatile ferroelectric memory etc. However, two-dimensional multiferroics with effective magnetoelectric coupling, which ultimately decides the future of multiferroic-based information technology, has not been realized yet. Here, we show that an unconventional magnetoelectric coupling mechanism interlocked with heterogeneous ferrielectric transitions emerges at the two-dimensional limit in van der Waals multiferroic CuCrP2S6 with inherent antiferromagnetism and antiferroelectricity. Distinct from the homogeneous antiferroelectric bulk, thin-layer CuCrP2S6 under external electric field makes layer-dependent heterogeneous ferrielectric transitions, minimizing the depolarization effect introduced by the rearrangements of Cu+ ions within the ferromagnetic van der Waals cages of CrS6 and P2S6 octahedrons. The resulting ferrielectric phases are characterized by substantially reduced interlayer magnetic coupling energy of nearly 50% with a moderate electric field of 0.3 V nm-1, producing widely-tunable magnetoelectric coupling which can be further engineered by asymmetrical electrode work functions.

Patulin Biodegradation Mechanism Study in Pichia guilliermondii S15-8 Based on PgSDR-A5D9S1.

Patulin contamination has become a bottleneck problem in the safe production of fruit products, although biodegradation technology shows potential application value in patulin control. In the present study, the patulin biodegradation mechanism in a probiotic yeast, Pichia guilliermondii S15-8, was investigated. Firstly, the short-chain dehydrogenase PgSDR encoded by gene A5D9S1 was identified as a patulin degradation enzyme, through RNA sequencing and verification by qRT-PCR. Subsequently, the exogenous expression system of the degradation protein PgSDR-A5D9S1 in E. coli was successfully constructed and demonstrated a more significant patulin tolerance and degradation ability. Furthermore, the structure of PgSDR-A5D9S1 and its active binding sites with patulin were predicted via molecular docking analysis. In addition, the heat-excited protein HSF1 was predicted as the transcription factor regulating the patulin degradation protein PgSDR-A5D9S1, which may provide clues for the further analysis of the molecular regulation mechanism of patulin degradation. This study provides a theoretical basis and technical support for the industrial application of biodegradable functional strains.

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

An ALNS-based approach for the traffic-police-routine-patrol-vehicle assignment problem in resource allocation analysis of traffic crashes.

OBJECTIVES: Imbalances between limited police resource allocations and the timely handling of road traffic crashes are prevalent. To optimize resource allocations and route choices for traffic police routine patrol vehicle (RPV) assignments, a dynamic crash handling response model was developed. METHODS: This approach was characterized by two objective functions: the minimum waiting time and the minimum number of RPVs. In particular, an adaptive large neighborhood search (ALNS) was designed to solve the model. Then, the proposed ALNS-based approach was examined using comprehensive traffic and crash data from Ningbo, China. RESULTS: Finally, a sensitivity analysis was conducted to evaluate the bi-objective of the proposed model and simultaneously demonstrate the efficiency of the obtained solutions. Two resolution methods, the global static resolution mode, and real-time dynamic resolution mode, were applied to explore the optimal solution. CONCLUSIONS: The results show that the optimal allocation scheme for traffic police is 13 RPVs based on the global static resolution mode. Specifically, the average waiting time for traffic crash handling can be reduced to 5.5 min, with 53.8% less than 5.0 min and 90.0% less than 10.0 min.

Efficient Modulation of Schottky to Ohmic Contact in MoSi2N4/M3C2 (M = Zn, Cd, Hg) van der Waals Heterostructures.

A strong Fermi level pinning (FLP) effect can induce a large Schottky barrier in metal/semiconductor contacts; reducing the Schottky barrier height (SBH) to form an Ohmic contact (OhC) is a critical problem in designing high-performance electronic devices. Herein, we report the interfacial electronic features and efficient modulation of the Schottky contact (ShC) to OhC for MoSi2N4/M3C2 (M = Zn, Cd, Hg) van der Waals heterostructures (vdWHs). We find that the MoSi2N4/M3C2 vdWHs can form a p-type ShC with small SBH with the calculated pinning factor S ≈ 0.8 for MoSi2N4/M3C2 contacts. These results indicate that the FLP effect can be effectively suppressed in MoSi2N4 contact with M3C2. Moreover, the interfacial properties and SBH of MoSi2N4/Zn3C2 vdWHs can be effectively modulated by a perpendicular electric field and biaxial strain. In particular, an efficient OhC can be achieved in MoSi2N4/Zn3C2 vdWHs by applying a positive electric field of 0.5 V/Å and strain of ±8%.