Efficacy and safety of neoadjuvant immunotherapy plus chemotherapy followed by adjuvant immunotherapy in resectable non-small cell lung cancer: a meta-analysis of phase 3 clinical trials.

Objective: At present, several important trials have been published show that perioperative immunotherapy combined with chemotherapy can improve the prognosis of patients with resectable non-small cell lung cancer, which further optimizes treatment options. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of perioperative immunotherapy combined with chemotherapy in resectable non-small cell lung cancer. Methods: The following databases were searched for relevant studies: PubMed, EMBASE, Cochrane library (updated 12 October 2023). All randomized trials comparing perioperative immunotherapy combined with chemotherapy versus chemotherapy alone in resectable non-small cell lung cancer were eligible for inclusion. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes and measures included overall survival (OS), event-free survival (EFS), pathological complete response (pCR), major pathological response (MPR), R0 resection rate, rate of underwent surgery and adverse events (AEs). Results: A total of 2912 patients (1453 receiving perioperative immunotherapy plus chemotherapy and 1459 receiving chemotherapy alone) were included in this systematic review and meta-analysis. The result showed that compared with chemotherapy alone, combined therapy significantly improved OS (HR = 0.68;95% CI: 0.56-0.83), EFS (HR = 0.58;95% CI: 0.51-0.65), pCR (OR = 7.53;95% CI: 4.63-12.26), MPR (OR = 5.03;95% CI: 3.40-7.44), R0 resection (OR = 1.58;95% CI: 1.152.18) and rate of underwent surgery (OR = 1.25;95% CI: 1.04-1.49). However, combination therapy was associated with higher risk of severe adverse event (OR = 1.46;95% CI: 1.19-1.78; P=0.0002), grade 3 and higher treatment-related adverse event (TRAE) (OR = 1.25;95% CI: 1.06-1.49; P=0.010), TRAE that led to interruption (OR = 1.90;95% CI: 1.34-2.68; P=0.0003) and immune-related adverse event (OR = 2.78;95% CI: 2.18-3.55; P<0.00001). Significant benefits were observed across most subgroups of EFS and pCR. However, no statistical differences were observed for EFS of never smoked (HR = 0.73;95% CI: 0.51-1.05) and EGFR-mutation positive (HR = 0.35;95% CI: 0.04-3.03). Conclusion: This systematic review and meta-analysis found superior efficacy associated with perioperative immunotherapy plus chemotherapy compared with chemotherapy alone in both tumor regression and prolonged survival in resectable NSCLC, but increased the risk of TRAE, so monitoring for adverse events is warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier (CRD42023476786).

[Clinical analysis of ear symptoms of 40 patients with ANCA-associated vasculitis].

Objective:To analyze the clinical feature, diagnosis and treatment of Anca-associated vasculitis with ear symptoms. Methods:In this retrospective study, we summarized the clinical and laboratory examination, pure tone audiometry, aural immittance measurement, CT scan of temporal bone and treatment of 40 patients in the First Medical Center of the PLA General Hospital. Results:A total of 11 cases（27.5%） had the initial symptom in the ear. The most common symptoms were hearing loss, and the other symptoms included a sense of ear fullness, otorrhea and tinnitus. There were 35 cases with hearing loss: 19 cases with conductive hearing loss（47.5%）, 9 cases with sensorineural hearing loss（22.5%）, and 7 cases with mixed hearing loss（17.5%）. 5 cases had a sense of ear fullness or tinnitus, and the results of the hearing test were normal（12.5%）. All of the 40 patients had multi-system involvement, and respiratory system accounted for the most. All patients had a positive result of Anti-neutrophil cytoplasmic antibody（ANCA）. Treatment included systemic hormonal, immunosuppressive, or biologic therapy. There were 3 cases recovered（7.5%）, 22 cases with alleviated ear symptoms（55.0%）, 6 cases with recurrent hearing loss（15%） and 9 cases had no significant improvement（22.5%）. Conclusion:Conductive deafness（secretory otitis media） can be the first manifestation in the early stage of otitis media with AAV（OMAAV）, later it may turn to binaural mixed deafness. Otolaryngologists need to consider OMAAV diagnosis when diagnosing and treating patients with recurrent secretory otitis media. Multi-system symptom consultation and ANCA examination can help identify. Early systemic medication and the application of immunosuppressants or biological agents can help relieve the ear symptoms.

Recombinant human collagen I/carboxymethyl chitosan hydrogel loaded with long-term released hUCMSCs derived exosomes promotes skin wound repair.

BACKGROUND: Stem cell exosomes are beneficial in accelerating wound repair. However, the therapeutic function is limited due to its rapid clearance in vivo. To improve the functionality of exosomes in cutaneous wound healing, a novel hydrogel was designed and fabricated by recombinant human collagen I and carboxymethyl chitosan loaded with exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs), named as the rhCol I/CMC-Exos hydrogel. METHODS: Exosomes were extracted from hUCMSCs and were characterizated by TEM (Transmission Electron Microscopy), and biomarker detection. The rhCol I hydrogel, rhCol I/carboxymethyl chitosan (rhCol I/CMC) hydrogel and the rhCol I/CMC-Exos hydrogel composites were cross-linked by genipin. These materials were assessed and compared for their physical characteristics, including cross-sectional morphology, porosity, pore distribution, and hydrophilicity. Cell biocompatibility on biomaterials was investigated using scanning electron microscopy and CFDA staining, as well as assessed in vivo through histological examination of major organs in mice. Effects of the hydrogel composite on wound healing were further evaluated by using the full-thickness skin defect mice model. RESULTS: Successful extraction of hUCMSCs-derived exosomes was confirmed by TEM，Western Blotting and flow cytometry. The synthesized rhCol I/CMC-Exos hydrogel composite exhibited cytocompatibility and promoted cell growth in vitro. The rhCol I/CMC-Exos hydrogel showed sustained release of exosomes. In the mice full skin-defects model, the rhCol I/CMC-Exos-treated group showed superior wound healing efficiency, with 15 % faster wound closure compared to controls. Histological examinations revealed thicker dermis formation and more balanced collagen deposition in wounds treated with rhCol I/CMC-Exos hydrogel. Mechanistically, the application of rhCol I/CMC-Exos hydrogel increased fibroblasts proliferation, alleviated inflammation responses as well as promoted angiogenesis, thereby was beneficial in promoting skin wound healing and regeneration. CONCLUSION: Our study, for the first time, introduced recombinant human Collagen I in fabricating a novel hydrogel loaded with hUCMSCs-derived exosomes, which effectively promoted skin wound closure and regeneration, demonstrating a great potential in severe skin wound healing treatment.

What happens when left meets right under equimolar and non-equimolar co-assembly of short peptide stereoisomers?

The co-assembly of different peptide chains usually leads to the formation of intricate architectures and sophisticated functions in biological systems. Although the co-assembly of stereoisomeric peptides represents a facile and flexible strategy for the synthesis of peptide-based nanomaterials with novel structures and potentially interesting properties, there is a lack of a general knowledge on how different isomers pack during assembly. Through the combined use of simulations and experimental observations, we report that heterochiral pairing is preferred to homochiral pairing at the molecular scale but self-sorting dictates beyond the molecular level for the mixtures of the short stereoisomeric ß-sheet peptides I3K (Ile-Ile-Ile-Lys). Furthermore, we demonstrate that flat ß-sheets and fibril morphology are always preferred to twisted ones during heterochiral pairing and subsequent assembly. However, the heterochiral pairing into flat morphology is not always at an equimolar ratio. Instead, a non-equimolar ratio (1:2) is observed for the mixing of homochiral LI3LK and heterochiral LI3DK, whose strand twisting degrees differ greatly. Such a study provides a paradigm for understanding the co-assembly of stereoisomeric peptides at the molecular scale and harnessing their blending for targeted nanostructures.

Apoptosis and pyroptosis in the nasal mucosa of Syrian hamster during SARS-CoV-2 infection and reinfection.

In SARS-CoV-2 infection, it has been observed that viral replication lasts longer in the nasal mucosa than in the lungs, despite the presence of a high viral load at both sites. In hamsters, we found that the nasal mucosa exhibited a mild inflammatory response and minimal pathological injuries, whereas the lungs displayed a significant inflammatory response and severe injuries. The underlying cellular events may be induced by viral infection in three types of cell death: apoptosis, pyroptosis, and necroptosis. Our findings indicate that apoptosis was consistently activated during infection in the nasal mucosa, and the levels of apoptosis were consistent with the viral load. On the other hand, pyroptosis and a few instances of necroptosis were observed only on 7 dpi in the nasal mucosa. In the lungs, however, both pyroptosis and apoptosis were prominently activated on 3 dpi, with lower levels of apoptosis compared to the nasal mucosa. Interestingly, in reinfection, obvious viral load and apoptosis in the nasal mucosa were detected on 3 dpi, while no other forms of cell death were detected. We noted that the inflammatory reactions and pathological injuries in the nasal mucosa were milder, indicating that apoptosis may play a role in promoting lower inflammatory reactions and milder pathological injuries and contribute to the generation of long-term viral replication in the nasal mucosa. Our study provides valuable insights into the differences in cellular mechanisms during SARS-CoV-2 infection and highlights the potential significance of apoptosis regulation in the respiratory mucosa for controlling viral replication.

Controlled Assembly and Disassembly of Higher-Order Peptide Nanotubes.

The controlled peptide self-assembly and disassembly are not only implicated in many cellular processes but also possess huge application potential in a wide range of biotechnology and biomedicine. ß-sheet peptide assemblies possess high kinetic stability, so it is usually hard to disassemble them rapidly. Here, we reported that both the self-assembly and disassembly of a designed short ß-sheet peptide IIIGGHK could be well harnessed through the variations of concentration, pH, and mechanical stirring. Microscopic imaging, neutron scattering, and infrared spectroscopy were used to track the assembly and disassembly processes upon these stimuli, especially the interconversion between thin, left-handed protofibrils and higher-order nanotubes with superstructural right-handedness. The underlying rationale for these controlled disassembly processes mainly lies in the fact that the specific His-His interactions between protofibrils were responsive to these stimuli. By taking advantage of the peptide self-assembly and disassembly, the encapsulation of the hydrophobic drug curcumin and its rapid release upon stimuli were achieved. Additionally, the peptide hydrogels facilitated the differentiation of neural cells while maintaining low cell cytotoxicity. We believe that such dynamic and reversible structural transformation in this work provides a distinctive paradigm for controlling the peptide self-assembly and disassembly, thus laying a foundation for practical applications of peptide assemblies.

Diagnostic value of contrast-enhanced ultrasound in the activity of idiopathic retroperitoneal fibrosis: a retrospective study.

OBJECTIVES: To explore the diagnostic value of contrast-enhanced ultrasound (CEUS) in the disease activity of idiopathic retroperitoneal fibrosis (IRPF). METHODS: This retrospective study included 148 CEUS examinations from 63 patients with IRPF treated in our hospital from April 2016 to September 2021. They were divided into two groups: IRPF active group (69 examinations) and inactive group (79 examinations). Uni- and multivariable analyses were used to identify independent risk factors for IRPF activity. Receiver operating characteristic (ROC) curves were drawn to establish different diagnostic models to evaluate the diagnostic value of IRPF activity. The z test was used to compare the differences of the area under the curves (AUCs). The value of CEUS in evaluating the variation of disease activity over time was also investigated between repeat patient studies. RESULTS: Univariate and multivariate logistic regression analyses revealed the thickness [odds ratio (OR) = 14.125, 95% confidence interval (CI) = 3.017-66.123] was the most significant independent risk factor for IRPF activity (P < 0.01). The best diagnostic model was model 3, which was established by CEUS score combined with thickness. The AUC was 0.944 (95%CI = 0.912-0.977), and the sensitivity and specificity were 89.86% and 86.08%, respectively. The diagnostic performance was not significantly improved after combining clinical symptom (back pain) and laboratory indicators [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]. Compared with before treatment, the CEUS score and thickness were significantly decreased after treatment (x2 = 14.580, P < 0.001 and z = 4.708, P < 0.001, respectively). CONCLUSION: CEUS has good diagnostic value for IRPF disease activity. Key points • Thickness and contrast-enhanced ultrasound score were significantly higher in the active group than those in inactive group (P < 0.001). • With thickness of 4 mm and contrast-enhanced ultrasound 2 score as optimal cut-off values, the sensitivity and specificity were 89.86%, 81.01% and 52.17%, 100.00%, respectively. • During follow-up, when the disease progressed, the change of CEUS score was earlier than the change of thickness.

The Abundant Distribution and Duplication of SARS-CoV-2 in the Cerebrum and Lungs Promote a High Mortality Rate in Transgenic hACE2-C57 Mice.

Patients with COVID-19 have been reported to experience neurological complications, although the main cause of death in these patients was determined to be lung damage. Notably, SARS-CoV-2-induced pathological injuries in brains with a viral presence were also found in all fatal animal cases. Thus, an appropriate animal model that mimics severe infections in the lungs and brain needs to be developed. In this paper, we compared SARS-CoV-2 infection dynamics and pathological injuries between C57BL/6Smoc-Ace2em3(hACE2-flag-Wpre-pA)Smoc transgenic hACE2-C57 mice and Syrian hamsters. Importantly, the greatest viral distribution in mice occurred in the cerebral cortex neuron area, where pathological injuries and cell death were observed. In contrast, in hamsters, viral replication and distribution occurred mainly in the lungs but not in the cerebrum, although obvious ACE2 expression was validated in the cerebrum. Consistent with the spread of the virus, significant increases in IL-1ß and IFN-γ were observed in the lungs of both animals. However, in hACE2-C57 mice, the cerebrum showed noticeable increases in IL-1ß but only mild increases in IFN-γ. Notably, our findings revealed that both the cerebrum and the lungs were prominent infection sites in hACE2 mice infected with SARS-CoV-2 with obvious pathological damage. Furthermore, hamsters exhibited severe interstitial pneumonia from 3 dpi to 5 dpi, followed by gradual recovery. Conversely, all the hACE2-C57 mice experienced severe pathological injuries in the cerebrum and lungs, leading to mortality before 5 dpi. According to these results, transgenic hACE2-C57 mice may be valuable for studying SARS-CoV-2 pathogenesis and clearance in the cerebrum. Additionally, a hamster model could serve as a crucial resource for exploring the mechanisms of recovery from infection at different dosage levels.

Synthesis and Antibacterial Activity of Novel Triazolo[4,3-a]pyrazine Derivatives.

Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A series of novel triazolo[4,3-a]pyrazine derivatives were synthesized and their structures were characterized using various techniques, such as melting point, 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. All the synthesized compounds were evaluated for in vitro antibacterial activity using the microbroth dilution method. Among all the tested compounds, some showed moderate to good antibacterial activities against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli strains. In particular, compound 2e exhibited superior antibacterial activities (MICs: 32 µg/mL against Staphylococcus aureus and 16 µg/mL against Escherichia coli), which was comparable to the first-line antibacterial agent ampicillin. In addition, the structure-activity relationship of the triazolo[4,3-a]pyrazine derivatives was preliminarily investigated.

2-Pyridinecarboxaldehyde-Modified Chitosan-Silver Complexes: Optimized Preparation, Characterization, and Antibacterial Activity.

The widespread prevalence of infectious bacteria is one of the greatest threats to public health, and consequently, there is an urgent need for efficient and broad-spectrum antibacterial materials that are antibiotic-free. In this study, 2-pyridinecarboxaldehyde (PCA) was grafted onto chitosan (CS) and the modified CS coordinated with silver ions to prepare PCA-CS-Ag complexes with antibacterial activity. To obtain complexes with a high silver content, the preparation process was optimized using single-factor experiments and response surface methodology. Under the optimal preparation conditions (an additional amount of silver nitrate (58 mg), a solution pH of 3.9, and a reaction temperature of 69 °C), the silver content of the PCA-CS-Ag complex reached 13.27 mg/g. The structure of the PCA-CS-Ag complex was subsequently verified using ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and thermogravimetric analysis. Furthermore, three possible complexation modes of the PCA-CS-Ag complex were proposed using molecular mechanics calculations. The results of the antibacterial assay in vitro showed that the PCA-CS-Ag complex exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, exerting the synergistic antibacterial effect of modified chitosan and silver ions. Therefore, the PCA-CS-Ag complex is expected to be developed as an effective antibacterial material with promising applications in food films, packaging, medical dressings, and other fields.

TCF12 Activates TGFB2 Expression to Promote the Malignant Progression of Melanoma.

As one of the most common malignant tumors, melanoma is a serious threat to human health. More than half of melanoma patients have a BRAF mutation, and 90% of them have a BRAF(V600E) mutation. There is a targeted therapy for patients using a BRAF(V600E) inhibitor. However, no response to treatment is generally inevitable due to the heterogeneity of melanoma. Coupled with its high metastatic character, melanoma ultimately leads to poor overall survival. This study aimed to explore the possible mechanisms of melanoma metastasis and identify a more effective method for the treatment of melanoma. In this paper, we report that TCF12 expression is higher in melanoma, especially in metastatic tumors, through analyzing data from TCGA. Then, cell proliferation, colony formation, and transwell assays show that the upregulated expression of TCF12 can promote proliferation and metastasis of melanoma cells in vitro. The same result is confirmed in the subcutaneous tumor formation assay. Moreover, TGFB2 is identified as a direct downstream target of TCF12 by RNA-seq, qPCR, immunoblotting, ChIP, and a dual luciferase reporting assay. Interestingly, depletion of TCF12 can sensitize melanoma to BRAF inhibition both in vitro and in vivo. Overall, our results demonstrate that TCF12 promotes melanoma progression and can be a potential tumor therapeutic target.

Effect of Achiral Glycine Residue on the Handedness of Surfactant-Like Short Peptide Self-Assembly Nanofibers.

Surfactant-like short peptides are a kind of ideal model for the study of chiral self-assembly. At present, there are few studies on the chiral self-assembly of multicharged surfactant-like peptides. In this study, we adopted a series of short peptides of Ac-I4KGK-NH2 with different combinations of L-lysine and D-lysine residues as the model molecules. TEM, AFM and SANS results showed that Ac-I4LKGLK-NH2, Ac-I4LKGDK-NH2, and Ac-I4DKGLK-NH2 formed the morphologies of nanofibers, and Ac-I4DKGDK-NH2 formed nanoribbons. All the self-assembled nanofibers, including the intermediate nanofibers of Ac-I4DKGDK-NH2 nanoribbons, showed the chirality of left handedness. Based on the molecular simulation results, it has been demonstrated that the supramolecular chirality was directly dictated by the orientation of single ß strand. The insertion of glycine residue demolished the effect of lysine residues on the single strand conformation due to its high conformational flexibility. The replacement of L-isoleucine with Da-isoleucine also confirmed that the isoleucine residues involved in the ß-sheet determined the supramolecular handedness. This study provides a profound mechanism of the chiral self-assembly of short peptides. We hope that it will improve the regulation of chiral molecular self-assembly with achiral glycine, as well.

Alternative glucose uptake mediated by ß-catenin/RSK1 axis under stress stimuli in mammalian cells.

Cells adapt to stress conditions by increasing glucose uptake as cytoprotective strategy. The efficiency of glucose uptake is determined by the translocation of glucose transporters (GLUTs) from cytosolic vesicles to cellular membranes in many tissues and cells. GLUT translocation is tightly controlled by the activation of Tre-2/BUB2/CDC16 1 domain family 4 (TBC1D4) via its phosphorylation. The mechanisms of glucose uptake under stress conditions remain to be clarified. In this study, we surprisingly found that glucose uptake is apparently increased for the early response to three stress stimuli, glucose starvation and the exposure to lipopolysaccharide (LPS) or deoxynivalenol (DON). The stress-induced glucose uptake was mainly controlled by the increment of ß-catenin level and the activation of RSK1. Mechanistically, ß-catenin directly interacted with RSK1 and TBC1D4, acting as the scaffold protein to recruit activated RSK1 to promote the phosphorylation of TBC1D4. In addition, ß-catenin was further stabilized due to the inhibition of GSK3ß kinase activity which is caused by activated RSK1 phosphorylating GSK3ß at Ser9. In general, this triple protein complex consisting of ß-catenin, phosphorylated RSK1, and TBC1D4 were increased in the early response to these stress signals, and consequently, further promoted the phosphorylation of TBC1D4 to facilitate the translocation of GLUT4 to the cell membrane. Our study revealed that the ß-catenin/RSK1 axis contributed to the increment of glucose uptake for cellular adaption to these stress conditions, shedding new insights into cellular energy utilization under stress.

Disassembling ability of lipopeptide promotes the antibacterial activity.

Lipopeptides have become one of the most potent antibacterial agents, however, there is so far no consensus about the link between their physic-chemical properties and biological activity, in particular their inherent aggregation propensity and antibacterial potency. To this end, we here de novo design a series of lipopeptides (CnH(2n-1)O-(VVKK)2V-NH2), in which an alkyl chain is covalently attached onto the N-terminus of a short cationic peptide sequence with an alternating pattern of hydrophobic VV (Val) and positively charged KK (Lys) motifs. By varying the alkyl chain length (ortho-octanoic acid (C8), lauric acid (C12), and palmitic acid (C16)), the lipopeptides show distinct physicochemical properties and self-assembly behaviors, which have great effect on their antibacterial activities. C8H15O-(VVKK)2V-NH2, which contains the lowest hydrophobicity and surface activity has the lowest antibacterial activity. C12H23O-(VVKK)2V-NH2 and C16H31O-(VVKK)2V-NH2 both have high hydrophobicity and surface activity, and self-assembled into long nanofibers. However, the nanofibers formed by C12H23O-(VVKK)2V-NH2 disassembled by dilution, resulting in its high antibacterial activity via bacterial membrane disruption. Comparatively, the nanofibers formed by C16H31O-(VVKK)2V-NH2 were very stable, which can closely attach on bacterial surface but not permeate bacterial membrane, leading to its low antibacterial activity. Thus, the stability other than the morphologies of lipopeptides' nanostructures contribute to their antibacterial ability. Importantly, this study enhances our understanding of the antibacterial mechanisms of self-assembling lipopeptides that will be helpful in exploring their biomedical applications.

Saturated fatty acids synergizes cadmium to induce macrophages M1 polarization and hepatic inflammation.

Exposure to the toxic metal cadmium (Cd) is a well-established risk factor for hepatic inflammation, but it remains unclear how metabolic components, such as different fatty acids (FAs), interact with Cd to influence this process. Understanding these interactions is essential for identifying potential preventative and therapeutic targets for this disorder. To address this question, we conducted in vitro and in vivo studies to investigate the combinatorial effect of Cd and saturated FAs on hepatic inflammation. Specifically, we assessed the cytotoxicity of Cd on macrophages and their polarization and inflammatory activation upon co-exposure to Cd and saturated FAs. Our results showed that while saturated FAs had minimal impact on the cytotoxicity of Cd on macrophages, they significantly collaborated with Cd in predisposing macrophages towards a pro-inflammatory M1 polarization, thereby promoting inflammatory activation. This joint effect of Cd and saturated FAs resulted in persistent inflammation and hepatic steatohepatitis in vivo. In summary, our study identified macrophage polarization as a novel mechanism by which co-exposure to Cd and saturated lipids induces hepatic inflammation. Our findings suggest that intervening in macrophage polarization may be a potential approach for mitigating the adverse hepatic effects of Cd.

BRAFV600E restructures cellular lactylation to promote anaplastic thyroid cancer proliferation.

Anaplastic thyroid cancer (ATC) is a rare but fatal cancer with BRAF mutation ranging from 30 to 50%. Histone lysine lactylation represents a novel epigenetic mark that translates cellular metabolic signals into transcriptional regulation. It is not clear whether the Warburg effect can promote the proliferation of ATC with BRAFV600E mutation via metabolite-mediated histone lactylation. Our study aimed at illustrating how BRAFV600E restructures the cellular protein lactylation landscape to boost ATC proliferation, and determining whether blockade of protein lactylation can sensitize mutant ATC to BRAFV600E inhibitors. Western blotting was used to evaluate lactylation status. Aerobic glycolysis was intervened by adding cell-permeable ethyl lactate or using metabolic inhibitors. Chromatin immunoprecipitation and RT-qPCR were applied to analyze the expression of growth-related genes. Different chemical inhibitors were used to inhibit BRAFV600E and other enzymes. ATC cell line-derived xenograft model was employed to examine the efficacy of mono and combinatorial therapies. The results showed that aerobic glycolysis in ATC increased global protein lactylation via improving cellular lactate availability. In particular, lactylation on Histone 4 Lysine 12 residue (H4K12La) activated the expression of multiple genes essential for ATC proliferation. Furthermore, oncogenic BRAFV600E boosted glycolytic flux to restructure the cellular lactylation landscape, leading to H4K12La-driven gene transcription and cell cycle deregulation. Accordingly, the blockade of cellular lactylation machinery synergized with BRAFV600E inhibitor to impair ATC progression both in vitro and in vivo. Our results demonstrated an extra beneficial effect of aerobic glycolysis on ATC, revealing a novel metabolism-epigenetics axis suitable for combinatorial therapy with BRAFV600E inhibition.

Astragalus polysaccharide improves the growth, meat quality, antioxidant capacity and bacterial resistance of Furong crucian carp (Furong carp♀ × red crucian carp♂).

To evaluate the functional effects of APS (Astragalus polysaccharide) on Furong crucian carp, APS-supplemented diets (0.00 %, 0.05 %, 0.10 % and 0.15 %) were prepared and utilized in feeding experiment. The results showed that the 0.05 % APS group has the highest weight gain rate and specific growth rate, and the lowest feed coefficient rate. In addition, 0.05 % APS supplement could improve muscle elasticity, adhesiveness and chewiness. Moreover, the 0.15 % APS group had the highest spleen-somatic index and the 0.05 % group had the maximum intestinal villus length. 0.05 % and 0.10 % APS addition significantly increased T-AOC and CAT activities while MDA contents decreased in all APS groups. The plasma TNF-α levels in all APS groups significantly increased (P<0.05), and the 0.05 % group showed the highest TNF-α level in spleen. In APS addition groups, the tlr8, lgp2 and mda5 gene expressions were significantly elevated, while xbp1, caspase-2 and caspase-9 expressions decreased in uninfected and A. hydrophila-infected fish. Finally, higher survival rate and slower disease outbreak rate were observed in APS-supplemented groups after being infected by A. hydrophila. In conclusion, Furong crucian carp fed by APS-supplemented diets possesses elevated weight gain rate and specific growth rate, and improved meat quality, immunity and disease resistance.

Cellular differentiation into hyphae and spores in halophilic archaea.

Several groups of bacteria have complex life cycles involving cellular differentiation and multicellular structures. For example, actinobacteria of the genus Streptomyces form multicellular vegetative hyphae, aerial hyphae, and spores. However, similar life cycles have not yet been described for archaea. Here, we show that several haloarchaea of the family Halobacteriaceae display a life cycle resembling that of Streptomyces bacteria. Strain YIM 93972 (isolated from a salt marsh) undergoes cellular differentiation into mycelia and spores. Other closely related strains are also able to form mycelia, and comparative genomic analyses point to gene signatures (apparent gain or loss of certain genes) that are shared by members of this clade within the Halobacteriaceae. Genomic, transcriptomic and proteomic analyses of non-differentiating mutants suggest that a Cdc48-family ATPase might be involved in cellular differentiation in strain YIM 93972. Additionally, a gene encoding a putative oligopeptide transporter from YIM 93972 can restore the ability to form hyphae in a Streptomyces coelicolor mutant that carries a deletion in a homologous gene cluster (bldKA-bldKE), suggesting functional equivalence. We propose strain YIM 93972 as representative of a new species in a new genus within the family Halobacteriaceae, for which the name Actinoarchaeum halophilum gen. nov., sp. nov. is herewith proposed. Our demonstration of a complex life cycle in a group of haloarchaea adds a new dimension to our understanding of the biological diversity and environmental adaptation of archaea.