The gut-to-brain axis for toxin-induced defensive responses.

After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.

Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat.

Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns1. Here we uncover the mechanism by which NPY in sympathetic neurons2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY+ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT4-6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.

METTL3 protects METTL14 from STUB1-mediated degradation to maintain m6 A homeostasis.

N6 -Methyladenosine (m6 A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m6 A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.

Fluids and Electrolytes under Confinement in Single-Digit Nanopores.

Confined fluids and electrolyte solutions in nanopores exhibit rich and surprising physics and chemistry that impact the mass transport and energy efficiency in many important natural systems and industrial applications. Existing theories often fail to predict the exotic effects observed in the narrowest of such pores, called single-digit nanopores (SDNs), which have diameters or conduit widths of less than 10 nm, and have only recently become accessible for experimental measurements. What SDNs reveal has been surprising, including a rapidly increasing number of examples such as extraordinarily fast water transport, distorted fluid-phase boundaries, strong ion-correlation and quantum effects, and dielectric anomalies that are not observed in larger pores. Exploiting these effects presents myriad opportunities in both basic and applied research that stand to impact a host of new technologies at the water-energy nexus, from new membranes for precise separations and water purification to new gas permeable materials for water electrolyzers and energy-storage devices. SDNs also present unique opportunities to achieve ultrasensitive and selective chemical sensing at the single-ion and single-molecule limit. In this review article, we summarize the progress on nanofluidics of SDNs, with a focus on the confinement effects that arise in these extremely narrow nanopores. The recent development of precision model systems, transformative experimental tools, and multiscale theories that have played enabling roles in advancing this frontier are reviewed. We also identify new knowledge gaps in our understanding of nanofluidic transport and provide an outlook for the future challenges and opportunities at this rapidly advancing frontier.

MAFF confers vulnerability to cisplatin-based and ionizing radiation treatments by modulating ferroptosis and cell cycle progression in lung adenocarcinoma.

AIMS: Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD. METHODS: CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models. RESULTS: Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments. CONCLUSIONS: MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients.

Nobiletin enhances mitochondrial function by regulating SIRT1/PGC-1α signaling in porcine oocytes during in vitro maturation.

Nobiletin is a natural flavonoid found in citrus fruits with beneficial effects, including anti-inflammatory, anti-cancer and anti-oxidation effects. The aim of this study was to investigate whether nobiletin improves mitochondrial function in porcine oocytes and examine the underlying mechanism. Oocytes enclosed by cumulus cells were cultured in TCM-199 for 44 h with 0.1% dimethyl sulfoxide (control), or supplemented with 5, 10, 25, and 50 µM of nobiletin (Nob5, Nob10, Nob25, and Nob50, respectively). Oocyte maturation rate was significantly enhanced in Nob10 (70.26 ± 0.45%) compared to the other groups (control: 60.12 ± 0.47%; Nob5: 59.44 ± 1.63%; Nob25: 63.15 ± 1.38%; Nob50: 46.57 ± 1.19%). The addition of nobiletin reduced the levels of reactive oxygen species and increased glutathione levels. Moreover, Nob10 promoted mitochondrial biogenesis by upregulating the protein levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α). This resulted in an increase in the number of active mitochondria, mitochondrial DNA copy number, mitochondrial membrane potential, and ATP production, thereby enhancing mitochondrial function. The protein level of p53 decreased, followed by the phosphorylation of B-cell lymphoma 2, suggesting a reduction in mitochondria-mediated apoptosis in the Nob10 group. Additionally, the release of cytochrome c from the mitochondria was significantly diminished along with a decrease in the protein expression of caspase 3. Thus, nobiletin has a great potential to promote the in vitro maturation of porcine oocytes by suppressing oxidative stress and promoting mitochondrial function through the upregulation of the SIRT1/PGC-1α signaling pathway.

Association of the Number of Concurrent Metabolic Syndrome Risk Factors with Textbook Outcomes Following Liver Resection for Patients with Hepatocellular Carcinoma: A Multicenter Study.

BACKGROUND: There is little information regarding the impact of the number of concurrent metabolic syndrome (MetS) risk factors on the textbook outcomes (TO) in patients with hepatocellular carcinoma (HCC) following liver resection. PATIENTS AND METHODS: Data from patients who underwent liver resection between 2015 and 2023 in a multicenter database were retrospectively reviewed (N = 3156). According to the guidelines, MetS risk factors include obesity, hypertension, diabetes, and dyslipidemia. RESULTS: In this study, 2056 (65.1%) patients achieved TO. The incidence of TO was 63.1% in patients with ≥ 1 MetS risk factor, which was lower than that in patients without any MetS risk factors (67.5%, P = 0.011). As the number of MetS risk factors increased, the probability of not achieving TO gradually increased. The non-TO rates in patients with no, 1, 2, and ≥ 3 MetS risk factors were 32.5%, 35.9%, 37.6% and 40.2%, respectively (Ptrend = 0.005). Multivariate logistic regression confirmed that the number of MetS risk factors (0 as a reference; 1, OR 1.220, 95% CI 1.029-1.447, P = 0.022; 2, OR 1.397, 95% CI 1.113-1.755, P = 0.004; ≥ 3, OR 1.647, 95% CI 1.197-2.264, P = 0.002) independently contributed to non-TO in patients with HCC after liver resection. Both the 5-year recurrence-free survival (TO: 50.7% versus non-TO: 43.9%, P < 0.001) and overall survival rates (TO: 71.0% versus non-TO: 58.7%, P < 0.001) of TO patients were significantly better than those of non-TO patients. CONCLUSIONS: Concurrent MetS risk factors can adversely impact TO achievement in patients with HCC after liver resection. The more risk factors patients have, the less likely they are to achieve TO.

Gut microbiota alterations in colorectal adenoma-carcinoma sequence based on 16S rRNA gene sequencing: A systematic review and meta-analysis.

BACKGROUND: Most sporadic colorectal cancers (CRC) develop through the adenoma-carcinoma sequence. While dysbiosis of the intestinal flora contributes to CRC's pathogenesis, precise microbial taxa closely associated with the colorectal adenoma-carcinoma sequence remain elusive. This meta-analysis aimed to summarize the features of intestinal flora in patients with AD and CRC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched for case-control studies comparing the relative abundance of gut microbiota in the feces of patients with AD, CRC, and healthy controls (HC) from inception to January 2024. The weighted mean difference (WMD) with a 95 % confidence interval (CI) was used to display the results. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the entailed literature. Publication bias was evaluated with the Egger's and Begg's tests. RESULTS: Eleven studies were included, involving 477 CRC patients, 628 AD patients, and 864 healthy controls. Compared with HC, the patients with AD had a significantly lower Chao 1 index (WMD = -30.17, 95 % CI [-41.10, -19.23], P < 0.001) and Shannon index (WMD = -0.11 95 % CI [-0.18, -0.04], P = 0.002). Compared with AD, the CRC patients had a significantly higher Chao1 index (WMD = 22.09, 95 % CI [7.59, 36.00], P = 0.003) and Shannon index (WMD = 0.08, 95 % CI [0.00, 0.15], P = 0.037). Enterobacteriaceae (WMD = 0.03 95 % CI [0.00,0.05], P = 0.047; WMD = 0.02 95 % CI [0.00,0.04], P = 0.027) significantly increased in the order of Control-AD-CRC, while that of Blautia (WMD = -0.00 95 % CI [-0.01, -0.00], P = 0.001; WMD = -0.00 95 % CI [-0.00, -0.00], P = 0.002) was reduced. Compared with HC, the relative abundance of Proteobacteria (WMD = 0.05 95 % CI [0.03,0.07], P < 0.001), Fusobacteria (WMD = 0.02 95 % CI [0.00,0.03], P = 0.042), Streptococcaceae (WMD = 0.03 95 % CI [0.01,0.05], P = 0.017), Prevotellaceae (WMD = 0.02 95 % CI [0.00,0.04], P = 0.040), and Escherichia-Shigella (WMD = 0.06 95 % CI [0.01, 0.11], P = 0.021) was enriched in the CRC group. The relative abundance of Alistipes (WMD = 0.00 95 % CI [0.00,0.01], P = 0.032) and Streptococcus (WMD = 0.00 95 % CI [0.00,0.00], P = 0.001) was increased in the AD vs HC. The relative abundance of Firmicutes (WMD = -0.07 95 % CI [-0.12, -0.03], P = 0.003), Bifidobacteria (WMD = -0.03 95 % CI [-0.05, -0.01], P = 0.016), and Klebsiella (WMD = -0.01 95 % CI [-0.01, -0.00], P = 0.001) was decreased in the CRC vs HC. Compared with AD, the relative abundance of Firmicutes (WMD = -0.04 95 % CI [-0.07, -0.02], P = 0.002), Peptostreptococcaceae (WMD = -0.03 95 % CI [-0.05, -0.00], P = 0.021), Lachnospiraceae (WMD = -0.04 95 % CI [-0.08,-0.00], P = 0.037), Ruminococcaceae (WMD = -0.06 95 % CI [-0.09,-0.03], P < 0.001), Faecalibacterium (WMD = -0.01 95 % CI [-0.02, -0.01], P = 0.001), and Lachnoclostridium (WMD = -0.02 95 % CI [-0.03, -0.00], P = 0.040) was decreased in the CRC group, while Proteobacteria (WMD = 0.04 95 % CI [0.02,0.05], P < 0.001) was increased. CONCLUSIONS: The dysbiosis characterized by reduced levels of short-chain fatty acid (SCFA)-producing bacteria, decreased anti-inflammatory bacteria, increased pro-inflammatory bacteria, and an elevation of bacteria with cytotoxic effects damaging to DNA may represent the specific microbial signature of colorectal adenoma/carcinoma. Further research is required to elucidate the mechanisms by which gut dysbiosis leads to the progression from AD to CRC and to explore the potential of specific microbiota markers in clinical treatment and non-invasive screening.

The effects of repeated freezing and thawing on bovine sperm morphometry and function.

Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.

Development of a TLR-Based Model That Can Predict Prognosis, Tumor Microenvironment, and Drug Response for Esophageal Squamous Cell Carcinoma.

The toll-like receptor (TLR) family is an important class of proteins involved in the immune response. However, little is known about the association between TLRs and Esophageal squamous cell cancer (ESCC). We explored differentially expressed genes (DEGs) between ESCC and esophagus tissues in TCGA and GTEx database. By taking the intersection with TLR gene set and using univariate Cox analysis and multivariate Cox regression analysis to discriminate the hub genes, we created a TLR-prognostic model. Our model separated patients with ESCC into high- and low-risk score (RS) groups. Prognostic analysis was performed with Kaplan-Meier curves. The two groups were also compared regarding tumor immune microenvironment and drug sensitivity. Six hub genes (including CD36, LGR4, MAP2K3, NINJ1, PIK3R1, and TRAF3) were screened to construct a TLR-prognostic model. High-RS group had a worse survival (p < 0.01), lower immune checkpoint expression (p < 0.05), immune cell abundance (p < 0.05) and decreased sensitivity to Epirubicin (p < 0.001), 5-fluorouracil (p < 0.0001), Sorafenib (p < 0.01) and Oxaliplatin (p < 0.05). We constructed a TLR-based model, which could be used to assess the prognosis of patients with ESCC, provide new insights into drug treatment for ESCC patients and investigate the TME and drug response.

G-Protein-Coupled Receptor Kinase 2 Inhibition Induces Meiotic Arrest by Disturbing Ca2+ Release in Porcine Oocytes.

G-protein-coupled receptor kinase 2 (GRK2) interacts with Gßγ and Gαq, subunits of G-protein alpha, to regulate cell signalling. The second messenger inositol trisphosphate, produced by activated Gαq, promotes calcium release from the endoplasmic reticulum (ER) and regulates maturation-promoting factor (MPF) activity. This study aimed to investigate the role of GRK2 in MPF activity during the meiotic maturation of porcine oocytes. A specific inhibitor of GRK2 (ßi) was used in this study. The present study showed that GRK2 inhibition increased the percentage of oocyte arrest at the metaphase I (MI) stage (control: 13.84 ± 0.95%; ßi: 31.30 ± 4.18%), which resulted in the reduction of the maturation rate (control: 80.36 ± 1.94%; ßi: 65.40 ± 1.14%). The level of phospho-GRK2 decreased in the treated group, suggesting that GRK2 activity was reduced upon GRK2 inhibition. Furthermore, the addition of ßi decreased Ca2+ release from the ER. The protein levels of cyclin B and cyclin-dependent kinase 1 were higher in the treatment group than those in the control group, indicating that GRK2 inhibition prevented a decrease in MPF activity. Collectively, GRK2 inhibition induced meiotic arrest at the MI stage in porcine oocytes by preventing a decrease in MPF activity, suggesting that GRK2 is essential for oocyte meiotic maturation in pigs.

Inhibition of PKA/CREB1 pathway confers sensitivity to ferroptosis in non-small cell lung cancer.

Ferroptosis is a type of regulated cell death characterized by iron accumulation and lipid peroxidation. The molecular mechanisms underlying ferroptosis regulation in non-small cell lung cancer (NSCLC) are poorly understood. In this study, we found that protein kinase A (PKA) inhibition enhanced ferroptosis susceptibility in NSCLC cells, as evidenced by reduced cell viability and increased lipid peroxidation. We further identified cAMP-responsive element protein 1 (CREB1), a transcription factor and a substrate of PKA, as a key regulator of ferroptosis. Knockdown of CREB1 sensitized NSCLC cells to ferroptosis inducers (FINs) and abolished the effects of PKA inhibitor and agonist, revealing the pivotal role of CREB1 in ferroptosis regulation. Using a high-throughput screening approach and subsequent validation by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, we discovered that CREB1 transcriptionally activated stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. SCD conferred ferroptosis resistance by decreasing the availability of polyunsaturated fatty acids for lipid peroxidation, and its overexpression rescued the effect of CREB1 knockdown on ferroptosis in vitro. Besides, CREB1 knockdown suppressed xenograft tumor growth in the presence of Imidazole Ketone Erastin (IKE), a potent FIN, and this effect was reversed by SCD. Finally, we showed that high expression of CREB1 was associated with poor prognosis in NSCLC patients from public datasets and our institution. Collectively, this study illustrates the effect of PKA/CREB1/SCD axis in regulating ferroptosis of NSCLC, targeting this pathway may provide new strategies for treating NSCLC patients.

AGRN promotes lung adenocarcinoma progression by activating Notch signaling pathway and acts as a therapeutic target.

Lung cancer is the main reason for cancer-associated death globally, and lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer. Recently, AGRN is considered playing an vital role in the development of some cancers. However, the regulatory effects and mechanisms of AGRN in LUAD remain elusive. In this study, we clarified the significant upregulation of AGRN expression in LUAD by single-cell RNA sequencing combined with immunohistochemistry. Besides, we confirmed that LUAD patients with high AGRN expression are more susceptible to lymph node metastases and have a worse prognosis by a retrospective study of 120 LUAD patients. Next, we demonstrated that AGRN directly interact with NOTCH1, which results in the release of the intracellular structural domain of NOTCH1 and the subsequent activation of the NOTCH pathway. Moreover, we also found that AGRN promotes proliferation, migration, invasion, EMT and tumorigenesis of LUAD cells in vitro and in vivo, and that these effects are reversed by blocking the NOTCH pathway. Furthermore, we prepared several antibodies targeting AGRN, and clarify that Anti-AGRN antibody treatment could significantly inhibit proliferation and promote apoptosis of tumor cells. Our study highlights the important role and regulatory mechanism of AGRN in LUAD development and progression, and suggests that antibodies targeting AGRN have therapeutic potential for LUAD. We also provide theoretical and experimental evidence for further development of monoclonal antibodies targeting AGRN.

Understanding the piezocatalytic properties of the BaTiO3(001) surface via density functional theory.

Piezoelectric materials have been reported to possess catalytic activity under mechanical excitation, such as by ultrasonic waves or collisions. Energy band theory (EBT) is often used to explain the piezocatalytic phenomenon caused by the strain-induced charge separation, but the correlation between the piezoelectric polarization and catalytic activity has still not been fully understood in early theoretical studies with the EBT model. To reveal the intrinsic connection between the piezoelectric feature and surface catalytic activity, in this work, we employ first-principles Density Functional Theory (DFT) to investigate the prototype piezocatalyst BaTiO3 (001) surface (BTO). Our simulation shows that the thickness of BTO has a significant impact on the band structure, polarization charge distribution and the surface work function of both positively and negatively polarized sides. As the driving force of piezocatalysis, the electrostatic potential difference (piezopotential) of the two sides shows strong a correlation with the band structure change under the applied strain, which determines the theoretical catalytic activity of BaTiO3 (001) for water splitting. Finally, we reveal the piezoelectric effects on the surface adsorption energy of H and OH species, which provide a new insight into the mechanism of piezocatalysis. Our work provides a new and in-depth physical insight into the fundamental mechanism of piezocatalysis, which may have important implications for the application of piezocatalysts in water treatment and renewable energy technologies.

Exploring the catalytic activity of graphene-based TM-NxC4-x single atom catalysts for the oxygen reduction reaction via density functional theory calculation.

Electrocatalysts for the oxygen reduction reaction (ORR) are extremely crucial for advanced energy conversion technologies, such as fuel cell batteries. A promising ORR catalyst usually should have low overpotentials, rich catalytic sites and low cost. In the past decade, single-atom catalyst (SAC) TM-N4 (TM = Fe, Co, etc.) embedded graphene matrixes have been widely studied for their promising performance and low cost for ORR catalysis, but the effect of coordination on the ORR activity is not fully understood. In this work, we will employ density functional theory (DFT) calculations to systematically investigate the ORR activity of 40 different 3d transition metal single-atom catalysts (SACs) supported on nitrogen-doped graphene supports, ranging from vanadium to zinc. Five different nitrogen coordination configurations (TM-NxC4-x with x = 0, 1, 2, 3, and 4) were studied to reveal how C/N substitution affects the ORR activity. By looking at the stability, free energy diagram, overpotential, and scaling relationship, our calculation showed that partial C substitution can effectively improve the ORR performance of Mn, Co, Ni, and Zn-based SACs. The volcano plot obtained from the scaling relationship indicated that the substitution of N by C could distinctively affect the potential-limiting step in the ORR, which leads to the enhanced or weakened ORR performance. Density of states and d-band center analysis suggested that this coordination-tuned ORR activity can be explained by the shift of the d-band center due to the coordination effect. Finally, four candidates with optimal ORR activity and dynamic stability were proposed from the pool: NiC4, CoNC3, CrN4, and ZnN3C. Our work provides a feasible designing strategy to improve the ORR activity of graphene-based TM-N4 SACs by tuning the coordination environment, which may have potential implication in the high-performance fuel cell development.

Tumor burden score-AFP-albumin-bilirubin grade score predicts the survival of patients with hepatocellular carcinoma after liver resection.

PURPOSE: There is little information regarding the overall survival (OS) predictive ability of the combination of tumor burden score (TBS), α-fetoprotein (AFP), and albumin-bilirubin (ALBI) grade for patients with hepatocellular carcinoma (HCC). Here, we aimed to develop a model including TBS, AFP, and ALBI grade to predict HCC patient OS following liver resection. METHODS: Patients (N = 1556) from six centers were randomly divided 1:1 into training and validation sets. The X-Tile software was used to determine the optimal cutoff values. The time-dependent area under the receiver operating characteristic curve (AUROC) was calculated to assess the prognostic ability of the different models. RESULTS: In the training set, tumor differentiation, TBS, AFP, ALBI grade, and Barcelona Clinic Liver Cancer (BCLC) stage were independently related to OS. According to the coefficient values of TBS, AFP, and ALBI grade, we developed the TBS-AFP-ALBI (TAA) score using a simplified point system (0, 2 for low/high TBS, 0, 1 for low/high AFP and 0,1 for ALBI grade 1/2). Patients were further divided into low TAA (TAA ≤ 1), medium TAA (TAA = 2-3), and high TAA (TAA= 4) groups. TAA scores (low: referent; medium, HR = 1.994, 95% CI = 1.492-2.666; high, HR = 2.413, 95% CI = 1.630-3.573) were independently associated with patient survival in the validation set. The TAA scores showed higher AUROCs than BCLC stage for the prediction of 1-, 3-, and 5-year OS in both the training and validation sets. CONCLUSION: TAA is a simple score that has better OS prediction performance than the BCLC stage in predicting OS for HCC patients after liver resection.

Correlational analysis of physicochemical indexes, microbial communities, and volatile components in light-flavor Daqu from north and south regions of China.

Daqu is of great significance to the brewing process of Baijiu, and there are variations in the light-flavor Baijiu Daqu in different regions. However, few studies have been conducted on light-flavor Daqu from the north and south regions of China. In this study, the physicochemical indices, volatile flavor components, and microbial community structure of two types of Daqu from the north and south regions of China were comparatively analyzed. The study findings reveal that Daqu originating from the southern region of China (HB) exhibits superior moisture content, acidity, starch content, and saccharification power. In contrast, Daqu from the northern region of China (SX) displays higher fermentation, esterification, and liquefaction power. The analysis of the microbial community structure revealed that HB was dominated by Bacillus, Kroppenstedtia, Saccharomycopsis, and Thermoascus, while SX was dominated by Bacillus, Prevotella, and Saccharomycopsis. The analysis detected a total of 47 volatile components in both HB Daqu and SX Daqu. The volatile components of pyrazine were significantly more abundant in HB Daqu than in SX Daqu, while alcohol compounds were more prominent in SX Daqu than in HB Daqu. In addition, the RDA analysis established a correlation between dominant microorganisms and volatile components. Cyanobacteria, Fusobacteriota, Ascomycota, Blastocladiomycota, Basidiomycota, and Mucormyce exhibited positive correlations with a significant proportion of the key volatile compounds. This study establishes a scientific foundation for improving the quality of light-flavor Daqu liquor in different regions of China.

Metformin inhibits human non-small cell lung cancer by regulating AMPK-CEBPB-PDL1 signaling pathway.

Metformin has been found to have inhibitory effects on a variety of tumors. However, its effects on non-small cell lung cancer (NSCLC) remain unclear. We demonstrated that metformin could inhibit the proliferation of A549 and H1299 cells. RNA transcriptome sequencing revealed that PDL1 was significantly downregulated in both cell types following treatment with metformin (P < 0.001). Jaspar analysis and chromatin immunoprecipitation showed that CEBPB could directly bind the promoter region of PDL1. Western blotting showed that protein expression of the isoforms CEBPB-LAP*, CEBPB-LAP, and CEBPB-LIP was significantly upregulated and the LIP/LAP ratio was increased. Gene chip analysis showed that PDL1 was significantly upregulated in A549-CEBPB-LAP cells and significantly downregulated in A549-CEBPB-LIP cells (P < 0.05) compared with CEBPB-NC cells. Dual-luciferase reporter gene assay showed that CEBPB-LAP overexpression could promote transcription of PDL1 and CEBPB-LIP overexpression could inhibit the process. Functional assays showed that the changes in CEBPB isoforms affected the function of NSCLC cells. Western blotting showed that metformin could regulate the function of NSCLC cells via AMPK-CEBPB-PDL1 signaling. Animal experiments showed that tumor growth was significantly inhibited by metformin, and atezolizumab and metformin had a synergistic effect on tumor growth. A total of 1247 patients were retrospectively analyzed, including 166 and 1081 patients in metformin and control groups, respectively. The positive rate of PDL1 was lower than that of the control group (HR = 0.338, 95% CI = 0.235-0.487; P < 0.001). In conclusion, metformin inhibited the proliferation of NSCLC cells and played an anti-tumor role in an AMPK-CEBPB-PDL1 signaling-dependent manner.

Cisplatin resistance-related multi-omics differences and the establishment of machine learning models.

OBJECTIVES: Platinum-based chemotherapies are currently the first-line treatment of non-small cell lung cancer. This study will improve our understanding of the causes of resistance to cisplatin, especially in lung adenocarcinoma (LUAD) and provide a reference for therapeutic decisions in clinical practice. METHODS: Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA) and Zhongshan hospital affiliated to Fudan University (zs-cohort) were used to identify the multi-omics differences related to platinum chemotherapy. Cisplatin-resistant mRNA and miRNA models were constructed by Logistic regression, classification and regression tree and C4.5 decision tree classification algorithm with previous feature selection performed via least absolute shrinkage and selection operator (LASSO). qRT-PCR and western-blotting of A549 and H358 cells, as well as single-cell Seq data of tumor samples were applied to verify the tendency of certain genes. RESULTS: 661 cell lines were divided into three groups according to the IC50 value of cisplatin, and the top 1/3 (220) with a small IC50 value were defined as the sensitive group while the last 1/3 (220) were enrolled in the insensitive group. TP53 was the most common mutation in the insensitive group, in contrast to TTN in the sensitive group. 1348 mRNA, 80 miRNA, and 15 metabolites were differentially expressed between 2 groups (P < 0.05). According to the LASSO penalized logistic modeling, 6 of the 1348 mRNAs, FOXA2, BATF3, SIX1, HOXA1, ZBTB38, IRF5, were selected as the associated features with cisplatin resistance and for the contribution of predictive mRNA model (all of adjusted P-values < 0.001). Three of 6 (BATF3, IRF5, ZBTB38) genes were finally verified in cell level and patients in zs-cohort. CONCLUSIONS: Somatic mutations, mRNA expressions, miRNA expressions, metabolites and methylation were related to the resistance of cisplatin. The models we created could help in the prediction of the reaction and prognosis of patients given platinum-based chemotherapies.

Pseudocapacitance: From Fundamental Understanding to High Power Energy Storage Materials.

There is an urgent global need for electrochemical energy storage that includes materials that can provide simultaneous high power and high energy density. One strategy to achieve this goal is with pseudocapacitive materials that take advantage of reversible surface or near-surface Faradaic reactions to store charge. This allows them to surpass the capacity limitations of electrical double-layer capacitors and the mass transfer limitations of batteries. The past decade has seen tremendous growth in the understanding of pseudocapacitance as well as materials that exhibit this phenomenon. The purpose of this Review is to examine the fundamental development of the concept of pseudocapacitance and how it came to prominence in electrochemical energy storage as well as to describe new classes of materials whose electrochemical energy storage behavior can be described as pseudocapacitive.