Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Construction of an alignment diagram model for predicting calculous obstructive pyonephrosis before PNL.

Background: To develop a model for the accurate prediction of calculous obstructive pyonephrosis prior to percutaneous nephrolithotomy (PNL), leading to early local anaesthesia microchannel nephrostomy for drainage of pyonephrosis. Methods: By comparing the differences in baseline clinical indicators between the pyonephrosis group and nonpyonephrosis groups, independent risk factors were screened out, and a diagnostic alignment diagram model for predicting calculus obstructive pyonephrosis before PNL was established. Results: Multivariate regression analysis showed that preoperative blood neutrophil count (Neu), serum creatinine level (Scr), serum albumin level (Alb), urine nitrite (UN), hydronephrosis density (HD) and fever history within one month (HFWOM) were independent risk factors for calculous obstructive pyonephrosis. The AUC value of the receiver operating characteristic (ROC) curve was 0.929. The calibration curves showed that the predictive model was well corrected and that the predictive model had strong consistency. Decision analysis curves showed good clinical efficacy of the model. Conclusion: The alignment diagram model accurately predicts patients with preoperative calculous obstructive pyonephrosis in the PNL and provides an evidence-based basis for early renal microchannel nephrostomy.

Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy.

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

Deciphering feedback regulation of prostaglandin F2α in blood stasis syndrome using nitrogen-doped porous transition metal carbides.

Blood stasis syndrome (BSS) has persistent health risks; however, its pathogenesis remains elusive. This obscurity may result in missed opportunities for early intervention, increased susceptibility to chronic diseases, and reduced accuracy and efficacy of treatments. Metabolomics, employing the matrix-assisted laser desorption/ionization (MALDI) strategy, presents distinct advantages in biomarker discovery and unraveling molecular mechanisms. Nonetheless, the challenge is to develop efficient matrices for high-sensitivity and high-throughput analysis of diverse potential biomarkers in complex biosamples. This work utilized nitrogen-doped porous transition metal carbides and nitrides (NP-MXene) as a MALDI matrix to delve into the molecular mechanisms underlying BSS pathogenesis. Structural optimization yielded heightened peak sensitivity (by 1.49-fold) and increased peak numbers (by 1.16-fold) in clinical biosamples. Validation with animal models and clinical serum biosamples revealed significant differences in metabolic fingerprints between BSS and control groups, achieving an overall diagnostic efficacy of 0.905 (95% CI, 0.76-0.979). Prostaglandin F2α was identified as a potential biomarker (diagnostics efficiency of 0.711, specificity = 0.7, sensitivity = 0.6), and pathway enrichment analysis disclosed disruptions in arachidonic acid metabolism in BSS. This innovative approach not only advances comprehension of BSS pathogenesis, but also provides valuable insights for personalized treatment and diagnostic precision.

Task Offloading Strategy for Unmanned Aerial Vehicle Power Inspection Based on Deep Reinforcement Learning.

With the ongoing advancement of electric power Internet of Things (IoT), traditional power inspection methods face challenges such as low efficiency and high risk. Unmanned aerial vehicles (UAVs) have emerged as a more efficient solution for inspecting power facilities due to their high maneuverability, excellent line-of-sight communication capabilities, and strong adaptability. However, UAVs typically grapple with limited computational power and energy resources, which constrain their effectiveness in handling computationally intensive and latency-sensitive inspection tasks. In response to this issue, we propose a UAV task offloading strategy based on deep reinforcement learning (DRL), which is designed for power inspection scenarios consisting of mobile edge computing (MEC) servers and multiple UAVs. Firstly, we propose an innovative UAV-Edge server collaborative computing architecture to fully exploit the mobility of UAVs and the high-performance computing capabilities of MEC servers. Secondly, we established a computational model concerning energy consumption and task processing latency in the UAV power inspection system, enhancing our understanding of the trade-offs involved in UAV offloading strategies. Finally, we formalize the task offloading problem as a multi-objective optimization issue and simultaneously model it as a Markov Decision Process (MDP). Subsequently, we proposed a task offloading algorithm based on a Deep Deterministic Policy Gradient (OTDDPG) to obtain the optimal task offloading strategy for UAVs. The simulation results demonstrated that this approach outperforms baseline methods with significant improvements in task processing latency and energy consumption.

A 10-year retrospective study of antibacterial-induced thrombocytopenia in a women and children hospital using China Hospital Pharmacovigilance System and Visual Basic for Applications.

AIMS: We aimed to investigate antibacterial-induced thrombocytopenia using the China Hospital Pharmacovigilance System (CHPS) in conjunction with Visual Basic for Applications (VBA). METHODS: Between September 2011 and December 2022, a 2-phase workflow was employed to identify antibacterial-induced thrombocytopenia, including preliminary screening in phase (I) conducted by CHPS algorithms and causality assessment by trained pharmacists in phase (II) using VBA. The incidence of thrombocytopenia in each antibacterial was calculated, and comparisons were performed between paediatric and adult patients. RESULTS: CHPS algorithms identified 4080 cases from 485 238 admissions (including 223 735 admissions receiving at least 1 antibacterial treatment). After ruling out cases with chemotherapy and abnormal platelet count at admission, 3832 cases were available. Using VBA, pharmacists identified 1039 cases (1246 antibacterial treatments, 28 agents) as potential thrombocytopenia instances (κ = 0.89), with an incidence of 0.46%. All antibacterial treatments correlated temporally with thrombocytopenia. Carbapenems (meropenem 1.77%), glycopeptides (vancomycin 1.55%) and lincosamides (clindamycin 0.44%) were prominent causal groups. The highest incidences of thrombocytopenia in the cephalosporins and penicillins groups were ceftazidime (2.04%) and piperacillin/tazobactam (1.24%), respectively. Among all antibacterial treatments, clindamycin showed the shortest time to onset (TTO), and erythromycin showed the longest TTO. Paediatric patients exhibited a longer TTO (61 vs. 29 h), extended time to nadir (83 vs. 37 h), lower platelet nadir count values (110 vs. 92 × 109/L), and a higher severe case proportion (12.37 vs. 3.86%) when compared with adults. CONCLUSION: Different antibacterial agents exhibit varying incidences of thrombocytopenia, with notable disparities between adults and children in the characteristics of thrombocytopenia.

A Transportable Atomic Gravimeter with Constraint-Structured Active Vibration Isolation.

Many efforts have been taken in recent years to push atomic gravimeters toward practical applications. We demonstrate an atomic gravimeter named NIM-AGRb2 that is transportable and suitable for high-precision gravity measurements. Constraint-structured active vibration isolation (CS-AVI) is used to reduce the ground vibration noise. The constraint structure in CS-AVI ensures that the isolation platform only has vertical translation, with all other degrees of freedom (DoFs) being constrained. Therefore, the stability of active vibration isolation is enhanced. With the implementation of CS-AVI, the sensitivity of NIM-AGRb2 reached as low as 20.5 µGal/Hz1/2. The short-term sensitivity could be further reduced to 10.8 µGal/Hz1/2 in a seismologic observation station. Moreover, we evaluated the system noise of the gravimeter, and the results were consistent with our observations.

Evaluation of first-line and salvage therapies for unresectable malignant mesothelioma: A systematic review and network meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) of systemic therapies for unresectable malignant mesothelioma have reported conflicting results. It is crucial and urgent to find optimal treatment options for this malignancy, which currently has a poor prognosis. METHODS: Databases PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences were searched until February 29, 2024. The main outcomes of interest were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). RESULTS: We analyzed 16 RCTs with a total of 5018 patients. Among first-line therapies, nivolumab and ipilimumab significantly increased OS and resulted in fewer grade ≥3 TRAEs. Bevacizumab plus chemotherapy significantly increased PFS. Among salvage therapies, ramucirumab and chemotherapy was associated with the best OS and PFS, but resulted in more grade ≥3 TRAEs. Subgroup analysis by histologic types suggested that in first-line settings, bevacizumab and chemotherapy increase OS the most for epithelioid type, while the nivolumab plus ipilimumab treatment increases OS the most for non-epithelioid type. In salvage therapies, ramucirumab and chemotherapy increase OS for both epithelioid and non-epithelioid types. CONCLUSION: Nivolumab plus ipilimumab was associated with the best OS among first-line treatments. Ramucirumab and chemotherapy was associated with the best clinical outcomes in salvage settings. Treatment for malignant mesothelioma should be tailored based on different clinicopathological characteristics.

EGFR Oncogenic Mutations in NSCLC Impair Macrophage Phagocytosis and Mediate Innate Immune Evasion Through Up-Regulation of CD47.

INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.

Uncommon de novo EGFRT790M-Mutant NSCLC characterized with unique genetic Features: Clinical response and acquired resistance to the third-generation EGFR-TKIs treatment.

INTRODUCTION: The literature on de novo EGFRT790M-mutant patients diagnosed with lung cancer is limited, and there is currently no consensus concerning the most effective treatment protocols. This study aimed to investigate the genomic characteristics of de novoEGFRT790M-mutant non-small cell lung cancer (NSCLC) and provide insights into its clinical response and resistance mechanism to third-generation EGFR-TKIs. METHODS: Next-generation sequencing was utilized to screen a substantial cohort of 4,228 treatment-naïve patients from the Mygene genomic database to identifythe de novo EGFR-T790M mutation. Meanwhile, we recruited 83 individuals diagnosed with lung cancer who harbored de novo EGFRT790M mutation in the real world. In addition, 166 patients who acquired EGFR-T790M mutation after becoming resistant to first- or second-generation EGFR-TKIs were included as a comparison cohort. RESULTS: De novo EGFRT790M mutation identified by next-generation sequencing is rare (∼1.3 %) in Chinese lung cancer patients. The relative variant allele frequency (VAF) of de novo EGFRT790M mutation was either comparable to or significantly lower than those of EGFR-activating mutations. Patients with de novo-T790M mutations exhibited less favorable clinical outcomes when administered third-generation EGFR-TKIs as first-line therapy thanthose with 19del mutationsdue to a high overlap rate in EGFR p.L858R mutation. In patients with a de novo EGFRT790M mutation, no correlation was observed between T790M clonality and treatment outcomes with third-generation EGFR-TKIs. In contrast, the sub-clonality of the T790M mutation detrimentally affected the third-generation EGFR-TKI treatment efficacy in patients with acquired T790M mutation. Potential resistance mechanisms of third-generation EGFR TKIs in NSCLC patients with de novo or acquired EGFRT790M mutations included EGFR p.C797S in cis or EGFR p.E709X mutation, as well as activation of bypass pathways. CONCLUSIONS: The present study characterized the uncommon but unique de novo EGFRT790M-mutant NSCLC and laid a foundation for designing future clinical trials in the setting of uncommon EGFR mutation.

Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice.

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

BASALT refines binning from metagenomic data and increases resolution of genome-resolved metagenomic analysis.

Metagenomic binning is an essential technique for genome-resolved characterization of uncultured microorganisms in various ecosystems but hampered by the low efficiency of binning tools in adequately recovering metagenome-assembled genomes (MAGs). Here, we introduce BASALT (Binning Across a Series of Assemblies Toolkit) for binning and refinement of short- and long-read sequencing data. BASALT employs multiple binners with multiple thresholds to produce initial bins, then utilizes neural networks to identify core sequences to remove redundant bins and refine non-redundant bins. Using the same assemblies generated from Critical Assessment of Metagenome Interpretation (CAMI) datasets, BASALT produces up to twice as many MAGs as VAMB, DASTool, or metaWRAP. Processing assemblies from a lake sediment dataset, BASALT produces ~30% more MAGs than metaWRAP, including 21 unique class-level prokaryotic lineages. Functional annotations reveal that BASALT can retrieve 47.6% more non-redundant opening-reading frames than metaWRAP. These results highlight the robust handling of metagenomic sequencing data of BASALT.

TR4 worsen urosepsis by regulating GSDMD.

BACKGROUND: Urosepsis is a life-threatening organ disease in which pathogenic microorganisms in the urine enter the blood through the vessels, causing an imbalance in the immune response to infection. The aim of this study was to elucidate the role of testicular orphan receptor 4 (TR4) in urosepsis. METHODS: The role of TR4 in the progression and prognosis of urosepsis was confirmed by analyzing data from online databases and clinical human samples. To mimic urosepsis, we injected E. coli bacteria into the renal pelvis of mice to create a urosepsis model. Hematoxylin and eosin staining was used to observe histopathological changes in urosepsis. The effects of the upregulation or downregulation of TR4 on macrophage pyroptosis were verified in vitro. Chromatin immunoprecipitation assay was used to verify the effect of TR4 on Gasdermin D (GSDMD) transcription. RESULTS: TR4 was more highly expressed in the nonsurviving group than in the surviving group. Furthermore, overexpressing TR4 promoted inflammatory cytokine expression, and knocking down TR4 attenuated inflammatory cytokine expression. Mechanistically, TR4 promoted pyroptosis by regulating the expression of GSDMD in urosepsis. Furthermore, we also found that TR4 knockdown protected mice from urosepsis induced by the E. coli. CONCLUSIONS: TR4 functions as a key regulator of urosepsis by mediating pyroptosis, which regulates GSDMD expression. Targeting TR4 may be a potential strategy for urosepsis treatment.

Prediction performance comparison of biomarkers for response to immune checkpoint inhibitors in advanced non-small cell lung cancer.

BACKGROUND: The aim of the present study was to compare the predictive accuracy of PD-L1 immunohistochemistry (IHC), tissue or blood tumor mutation burden (tTMB, bTMB), gene expression profile (GEP), driver gene mutation, and combined biomarkers for immunotherapy response of advanced non-small cell lung cancer (NSCLC). METHODS: In part 1, clinical trials involved with predictive biomarker exploration for immunotherapy in advanced NSCLC were included. The area under the curve (AUC) of the summary receiver operating characteristic (SROC), sensitivity, specificity, likelihood ratio and predictive value of the biomarkers were evaluated. In part 2, public datasets of immune checkpoint inhibitor (ICI)-treated NSCLC involved with biomarkers were curated (N = 871). Odds ratio (OR) of the positive versus negative biomarker group for objective response rate (ORR) was measured. RESULTS: In part 1, the AUC of combined biomarkers (0.75) was higher than PD-L1 (0.64), tTMB (0.64), bTMB (0.68), GEP (0.67), and driver gene mutation (0.51). Combined biomarkers also had higher specificity, positive likelihood ratio and positive predictive value than single biomarkers. In part 2, the OR of combined biomarkers of PD-L1 plus TMB (PD-L1 cutoff 1%, 0.14; cutoff 50% 0.13) was lower than that of PD-L1 (cutoff 1%, 0.33; cutoff 50% 0.24), tTMB (0.28), bTMB (0.48), EGFR mutation (0.17) and KRAS mutation (0.47), for distinguishing ORR of patients after immunotherapy. Furthermore, positive PD-L1, tTMB-high, wild-type EGFR, and positive PD-L1 plus TMB were associated with prolonged progression-free survival (PFS). CONCLUSION: Combined biomarkers have superior predictive accuracy than single biomarkers for immunotherapy response of NSCLC. Further investigation is warranted to select optimal biomarkers for various clinical settings.

Metabolomics unveils the exacerbating role of arachidonic acid metabolism in atherosclerosis.

Atherosclerosis is a complex vascular disorder characterized by the deposition of lipids, inflammatory cascades, and plaque formation in arterial walls. A thorough understanding of its causes and progression is necessary to develop effective diagnostic and therapeutic strategies. Recent breakthroughs in metabolomics have provided valuable insights into the molecular mechanisms and genetic factors involved in atherosclerosis, leading to innovative approaches for preventing and treating the disease. In our study, we analyzed clinical serum samples from both atherosclerosis patients and animal models using laser desorption ionization mass spectrometry. By employing methods such as orthogonal partial least-squares discrimination analysis (OPLS-DA), heatmaps, and volcano plots, we can accurately classify atherosclerosis (AUC = 0.892) and identify key molecules associated with the disease. Specifically, we observed elevated levels of arachidonic acid and its metabolite, leukotriene B4, in atherosclerosis. By inhibiting arachidonic acid and monitoring its downstream metabolites, we discovered the crucial role of this metabolic pathway in regulating atherosclerosis. Metabolomic research provides detailed insights into the metabolic networks involved in atherosclerosis development and reveals the close connection between abnormal metabolism and the disease. These studies offer new possibilities for precise diagnosis, treatment, and monitoring of disease progression, as well as evaluating the effectiveness of therapeutic interventions.

Long-Chain Bio-Based Nylon 514 Salt: Crystal Structure, Phase Transformation, and Polymerization.

Nylon 514 is one of the new long-chain bio-based nylon materials; its raw material, 1,5-pentanediamine (PDA), is prepared by biological techniques, using biomass as the raw material. The high-performance monomer of nylon 514, 1,5-pentanediamine-tetradecanedioate (PDA-TDA) salt, was obtained through efficient crystallization methods. Here, two crystal forms of PDA-TDA, anhydrous and dihydrate, were identified and studied in this paper. From the characterization data, their crystal structures and thermal behaviors were investigated. Lattice energy was calculated to gain further insight into the relationship between thermal stability and crystal structures. The contribution of hydrogen bonds and other intermolecular interactions to the crystal structure stability have been quantified according to detailed Hirshfeld and IRI analyses. Additionally, the transformation mechanism of the anhydrate and dihydrate was established through a series of well-designed stability experiments, in which the temperature and water activity play a significant role in the structural stability of crystalline forms. Eventually, we obtained nylon 514 products with good thermal stability and low absorption using stable dihydrate powders as monomers. The properties of nylon 514 products prepared by different polymerization methods were also compared.

Solid-state fermentation of corn straw using synthetic microbiome to produce fermented feed: The feed quality and conversion mechanism.

Straw is a typical biomass resource which can be converted into high nutritional value feed via microbial fermentation. The degradation and conversion of straw using a synthetic microbial community (SMC-8) was functionally investigated to characterise its nitrogen conversion and carbon metabolism. Four species of bacteria were found to utilise >20 % of the inorganic nitrogen within 15 h, and the ratio of the diameter of fungal transparent circles (D) to the diameter of the colony (d) of the four fungal species was >1. Solid-state fermentation of corn straw increased the total amino acid (AA) content by 41.69 %. The absolute digestibility of fermented corn straw dry weight (DW) and true protein was 34.34 % and 45.29 %, respectively. Comprehensive analysis of functional proteins revealed that Aspergillus niger, Trichoderma viride, Cladosporium cladosporioides, Bacillus subtilis and Acinetobacter johnsonii produce a complex enzyme system during corn straw fermentation, which plays a key role in the degradation of lignocellulose. This study provided a new insight in utilizing corn straw.

Prognostic and chemotherapeutic response prediction by proliferation essential gene signature: Investigating POLE2 in bladder cancer progression and cisplatin resistance.

Background: Bladder cancer (BLCA) is the most common genitourinary malignancy. Proliferation essential genes (PEGs) are crucial to the survival of cancer cells. This study aimed to build a PEG signature to predict BLCA prognosis and treatment efficacy. Methods: BLCA PEGs and differentially expressed PEGs were identified using DepMap and TCGA-BLCA datasets, respectively. Based on the prognostic analysis of the differentially expressed PEGs, a PEG model was constructed. Subsequently, we analyzed the relationship between the PEG signature and prognosis of BLCA patients as well as their response to chemotherapy. Finally, we performed random forest analysis to target and functional experiments to validate the most significant PEG which is associated with BLCA progression. CCK-8, invasion, migration, and chemosensitivity assays were performed to assess effects of gene knockdown on BLCA cell proliferation, invasion and migration abilities, and cisplatin chemosensitivity. Results: We screened 10 prognostic PEGs from 201 differentially expressed PEGs and used them to construct a PEG signature model. Patients with high PEG signature score (PEGs-high) exhibited worse OS and lower sensitivity to chemotherapy than those with PEGs-low. We also found significant correlations between the PEG score and previously defined BLCA molecular subtypes. This suggests that the PEG score may effectively predict the molecular subtypes which have distinct clinical outcomes. Random forest analysis revealed that POLE2 (DNA polymerase epsilon subunit 2) was the most significant PEG differentiating BLCA tissue and normal tissue. Bioinformatic analysis and an immunohistochemistry staining assay confirmed that POLE2 was significantly up-regulated in tumor tissues and was associated with poor survival in BLCA patients. Moreover, POLE2 knockdown inhibited the ability of cell clone formation, proliferation, invasion, immigration and IC50 of cisplatin. Conclusion: The PEG signature acts as a potential predictor for prognosis and chemotherapy response in BLCA patients. POLE2 is a key PEG and plays a remarkable role in promoting the malignant progression and cisplatin resistance of BLCA.

TPN10475 Constrains Effector T Lymphocytes Activation and Attenuates Experimental Autoimmune Encephalomyelitis Pathogenesis by Facilitating TGF-ß Signal Transduction.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by immune cells, in which auto-reactive CD4+ T cells have been implicated as a major driver in the pathogenesis of the disease. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS and its possible mechanisms. TPN10475 effectively resisted the reduction of TGF-ß signal transduction induced by TCR stimulation, suppressed the activation and function of effector CD4+ T cells in vitro, and restricted the differentiation of pathogenic Th1 and Th17 cells. It was also found to negatively regulate the inflammatory response in EAE by reducing the peripheral activation drive of auto-reactive helper T lymphocytes, inhibiting the migration of inflammatory cells into the CNS to attenuate EAE. The above results suggested that the upregulation of TGF-ß signal transduction may provide new ideas for the study of MS pathogenesis and have positive implications for the development of drugs for the treatment of autoimmune diseases.