Identification of PANoptosis-related predictors for prognosis and tumor microenvironment by multiomics analysis in glioma.

PANoptosis is a newly described inflammatory programmed cell death, that highlights coordination between pyroptosis, apoptosis and necroptosis. However, the functions of PANoptosis-related genes in glioma progression still remain to be explored. This study aims to identify PANoptosis-related predictors that may be utilized for prognosis prediction and development of new therapeutic targets. Firstly, bulk and single-cell RNA-seq (scRNA-seq) data of glioma patients were extracted from TCGA, CGGA and GEO database. Genetic analysis indicates a considerably high mutation frequency of PANoptosis-related genes (PANRGs) in glioma. Consensus clustering was applied to reveal different subtypes of glioma based on PANRGs. Two PANoptosis subtypes with distinct prognostic and TME characteristics were identified. Then, with LASSO-Cox regression analysis, four PANoptosis-related predictors (MYBL2, TUBA1C, C21orf62 and KCNIP2) were determined from bulk and scRNA-seq analysis. Predictive PANRG score model was established with these predictors and its correlation with tumor microenvironment (TME) was investigated. The results showed that patients with low PANRG score, had higher infiltration of anti-tumor immune cells, higher MSI score and lower TIDE score, which are more likely to benefit from immunotherapy. Further analysis identified 16 potential drugs associated with PANoptosis-related predictors. Moreover, the expression levels of four PANoptosis-related predictors were examined in clinical samples and the results were consistent with those analyzed in the database. Besides, we also confirmed the biological functions of two oncogenic predictors (MYBL2 and TUBA1C) by cell experiments, which revealed that knockdown of MYBL2 or TUBA1C could significantly inhibit the proliferation and migration of glioma cells. These findings highlight the prognostic value and biological functions of PANRGs in glioma, which may provide valuable insights for individualized treatment.

Serum metabolomic profiles in BALB/c mice induced by Babesia microti infection.

Introduction: The protozoan parasite Babesia microti is the primary cause of human babesiosis. This parasite invades and multiplies inside red blood cells (RBCs), and infections differ significantly based on the age and immune competency of the host. The aim of this study was to investigate the use of serum metabolic profiling to identify systemic metabolic variations between B. microti-infected mice and noninfected controls. Methods: A serum metabolomics analysis of BALB/c mice that had been intraperitoneally injected with 107 B. microti-infected RBCs was performed. Serum samples from the early infected group (2 days postinfection), the acutely infected group (9 days postinfection), and the noninfected group were collected and evaluated using a liquid chromatography-mass spectrometry (LC-MS) platform. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) identified metabolomic profiles that differentiated the B. microti-infected and noninfected groups. Results: Our results confirm that the serum metabolome is significantly influenced by acute B. microti infection and show that infection results in dysregulation of metabolic pathways and perturbation of metabolites. Acutely infected mice displayed perturbations in metabolites associated with taurine and hypotaurine metabolism, histidine metabolism, and arachidonic acid metabolism. Taurocholic acid, anserine, and arachidonic acid may be potential candidates as serological biomarkers for diagnosing B. microti infection at the acute stage. These metabolites could be further examined for their role in disease complexity. Discussion: Our findings demonstrate that the acute stage of B. microti infection induces abnormalities in the metabolites present in mouse serum and provide new insight into the mechanisms involved in systemic metabolic changes that occur during B. microti infection.

Critical pore size for micropore filling in coal samples with different rank coals.

The objectives of this study were to explore the occurrence and migration of coalbed methane in coals of different ranks and reveal the microscopic reservoir space and the mechanism of coalbed methane. To meet these objectives, this study selected six coal samples of different coal ranks for low-pressure N2 adsorption experiments, explored the critical pore filling characteristics of packed N2 molecules in the coals, and analyzed the low-pressure N2 adsorption/desorption experimental isotherms using the DFT method and DA equation based on the micropore filling theory. Finally, the critical filling pressure and pore size range for micropore filling were determined, and the analysis results were verified by combining the Langmuir, DA, and BET equations. The results showed that, from low to high coal rank, the N2 adsorption/desorption isotherms of the coal samples transition from type Ⅱ to type Ⅰ. The proportion of N2 molecules in low-rank coals in the form of micropore filling and monolayer adsorption was higher than that in high-rank coals. The critical pressure and critical pore size for micropore filling exhibited U-shaped correlations with the coal rank. Low-rank coals (lignite and long flame coal) were gradually filled in the relative pressure range P/P0 ≈ 1E-4-0.03, and medium- and high-rank coals (gas coal, 1/3 coking coal, lean coal, and anthracite) were filled in the relative pressure range P/P0 ≈ 1E-4-0.01; the corresponding critical pore size ranges were 1.7-2.19 and 1.61-2.00 nm, respectively.

Deltex E3 ubiquitin ligase 3 inhibits colorectal cancer cell growth and regulates cell cycle progression via upregulating E2F transcription factor 1.

BACKGROUND: The mortality rate of colorectal cancer (CRC) remains high in developing countries. Interventions that can inhibit the proliferation of tumor cells represent promising strategies in CRC treatment. Deltex E3 ubiquitin ligase 3 (DTX3) plays an essential role in tumor development and may predict the outcome of cancer patients. This study aimed to investigate the regulatory mechanisms of DTX3 in CRC progression. METHODS AND RESULTS: The expression of DTX3 was significantly downregulated in CRC tissues relative to normal colorectal tissues. DTX3 overexpression inhibited, while DTX3 knockout promoted the colony-forming capacity and proliferation of CRC cells. E2F transcription factor 1 (E2F1) is a key mediator of cell cycle progression that participates in the progression, metastasis, and chemoresistance of CRC. Further analysis revealed that DTX3 regulated the transcriptional activity of E2F1 in CRC cells. The transcription by E2F1 was significantly reduced with the increase in the cellular level of DTX3, while DTX3 knockout exerted an opposite effect. DTX3 knockout also increased the expression of E2F1 target genes involved in cell cycle progression, CDC2 and Cyclin D3, while PD 0332991, an inhibitor of E2F1 transcription, inhibited the expression of both proteins. CONCLUSIONS: In conclusion, DTX3 regulated CRC cell growth via regulating E2F1 and its downstream genes. These findings support further exploration of DTX3 as a potential therapeutic target for CRC.

Genome sequencing of biocontrol strain Bacillus amyloliquefaciens Bam1 and further analysis of its heavy metal resistance mechanism.

Plant growth-promoting rhizobacteria (PGPR) or Biocontrol strains inevitably encounter heavy metal excess stress during the product's processing and application. Bacillus amyloliquefaciens Bam1 was a potential biocontrol strain with strong heavy metal resistant ability. To understand its heavy metal resistance mechanism, the complete genome of Bam1 had been sequenced, and the comparative genomic analysis of Bam1 and FZB42, an industrialized PGPR and biocontrol strain with relatively lower heavy metal tolerance, was conducted. The comparative genomic analysis of Bam1 and the other nine B. amyloliquefaciens strains as well as one Bacillus velezensis (genetically and physiologically very close to B. amyloliquefaciens) was also performed. Our results showed that the complete genome size of Bam1 was 3.95 Mb, 4219 coding sequences were predicted, and it possessed the highest number of unique genes among the eleven analyzed strains. Nine genes related to heavy metal resistance were detected within the twelve DNA islands of Bam1, while only two of them were detected within the seventeen DNA islands of FZB42. When compared with B. amyloliquefaciens type strain DSM7, Bam1 lacked contig L, whereas FZB42 lacked contig D and I, as well as just possessed contig B with a very small size. Our results could also deduce that Bam1 promoted its essential heavy metal resistance mainly by decreasing the import and increasing the export of heavy metals with the corresponding homeostasis systems, which are regulated by different metalloregulators. While Bam1 promoted its non-essential heavy metal resistance mainly by the activation of some specific or non-specific exporters responding to different heavy metals. The variation of the genes related to heavy metal resistance and the other differences of the genomes, including the different number and arrangement of contigs, as well as the number of the heavy metal resistant genes in Prophages and Genomic islands, led to the significant different resistance of Bam1 and FZB42 to heavy metals.

COVID-19 information overload and generation Z's social media discontinuance intention during the pandemic lockdown.

While previous research highlights the benefits of social media in times of a pandemic, this research focuses on the potential dark side of social media use among Generation Z (Gen Z) in the UK during the COVID-19 pandemic lockdown between March and May 2020. The study reveals that COVID-19 information overload through social media had a negative impact on Gen Z social media users' psychological well-being. Moreover, perceived information overload heightened both social media fatigue and fear of COVID-19, which, in turn, increased users' social media discontinuance intention. In addition, considering that social media is the predominant method of maintaining connectivity with others for Gen Z users during the lockdown, the fear of missing out (FoMO) buffered the impact of social media fatigue and fear of COVID-19 on Gen Z users' social media discontinuance intention. Our research adds a hitherto underexplored perspective to the impact of the COVID-19 pandemic on young people's mental health. We offer a series of practical suggestions for social media users, social media platform providers, and health officials, institutions, and organizations in the effective and sustainable use of social media during the global COVID-19 pandemic and in the post-pandemic time.

ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer that tests negative for PR, ER and excess HER2 protein. TNBC has a greater progression potential with poorer prognosis, compared with other types of breast cancer. Endothelial cell-specific molecule 1 (ESM1), also known as endocan, is overexpressed in various cancers including breast cancer and may play an important role in cancer progression. METHODS: The online resource of The Cancer Genome Atlas (TCGA) was used for analyzing the expression alteration of ESM1 in breast cancer patient tissues. We examined the changes of various malignant behaviors of TNBC cell and in vivo tumor growth after inhibiting or overexpressing ESM1 in two human TNBC cell lines, MDA-MB-468 and MDA-MB-231. When ESM1 was knocked down or overexpressed in TNBC cell, AKT and p65 phosphorylation and Cyclin D1 expression were analyzed by western blotting. The ESM1-overexpressing TNBC cell was treated with MK-2206 and BAY-117082 at various concentrations. RESULTS: Our analyses show that ESM1 is overexpressed in TNBC cell lines as well as patient tissues, which is correlated to poor prognosis. Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases in vitro proliferation, migration and invasion of TNBC cell and knockdown of ESM1 inhibits in vivo TNBC tumor growth. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating an Akt-dependent NF-κB/Cyclin D1 pathway. CONCLUSIONS: Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases in vitro migration, proliferation and invasion of TNBC cell and knockdown of ESM1 inhibits in vivo tumor growth of TNBC in the xenograft mouse model. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating the Akt-dependent NF-κB/CyclinD1 pathway. Our findings expand the knowledge about the molecular mechanisms underlying TNBC progression and provide rationale for using ESM1 as a therapeutic target or prognostic marker for TNBC.

Dirhodium(II)-catalyzed [3 + 2] cycloaddition of N-arylaminocyclopropane with alkyne derivatives.

Dirhodium(II) complex-catalyzed [3 + 2] reactions between N-arylaminocyclopropanes and alkyne derivatives are described. The cycloaddition products proved to be versatile synthetic intermediates. trans-Cyclic ß-amino acids and derivatives thereof can be conveniently synthesized using this cycloaddition protocol.

New insights into meningitic Escherichia coli infection of brain microvascular endothelial cells from quantitative proteomics analysis.

BACKGROUND: Bacterial meningitis remains a big threat to the integrity of the central nervous system (CNS), despite the advancements in antimicrobial reagents. Escherichia coli is a bacterial pathogen that can disrupt the CNS function, especially in neonates. E. coli meningitis occurs after bacteria invade the brain microvascular endothelial cells (BMECs) that form a direct and essential barrier restricting the entry of circulating microbes and toxins to the brain. Previous studies have reported on several cellular proteins that function during meningitic E. coli infections; however, more comprehensive investigations to elucidate the potential targets involved in E. coli meningitis are essential to better understand this disease and discover new treatments for it. METHODS: The isobaric tags for relative and absolute quantification (iTRAQ) approach coupled with LC-MS/MS were applied to compare and characterize the different proteomic profiles of BMECs in response to meningitic or non-meningitic E. coli strains. KEGG and gene ontology annotations, ingenuity pathways analysis, and functional experiments were combined to identify the key host molecules involved in the meningitic E. coli-induced tight junction breakdown and neuroinflammatory responses. RESULTS: A total of 13 cellular proteins were found to be differentially expressed by meningitic E. coli strains PCN033 and RS218, including one that was also affected by HB101, a non-meningitic E. coli strain. Through bioinformatics analysis, we identified the macrophage migration inhibitory factor (MIF), granzyme A, NF-κB signaling, and mitogen-activated protein kinase (MAPK) pathways as being biologically involved in the meningitic E. coli-induced tight junction breakdown and neuroinflammation. Functionally, we showed that MIF facilitated meningitic E. coli-induced production of cytokines and chemokines and also helped to disrupt the blood-brain barrier by decreasing the expression of tight junction proteins like ZO-1, occludin. Moreover, we demonstrated the significant activation of NF-κB and MAPK signaling in BMECs in response to meningitic E. coli strains, which dominantly determined the generation of the proinflammatory cytokines including IL-6, IL-8, TNF-α, and IL-1ß. CONCLUSIONS: Our work identified 12 host cellular targets that are affected by meningitic E. coli strains and revealed MIF to be an important contributor to meningitic E. coli-induced cytokine production and tight junction disruption, and also the NF-κB and MAPK signaling pathways that are mainly involved in the infection-induced cytokines production. Characterization of these distinct proteins and pathways in BMECs will facilitate further elucidation of meningitis-causing mechanisms in humans and animals, thereby enabling the development of novel preventative and therapeutic strategies against infection with meningitic E. coli.

Differential transcription profiles of long non-coding RNAs in primary human brain microvascular endothelial cells in response to meningitic Escherichia coli.

Accumulating studies have indicated the influence of long non-coding RNAs (lncRNAs) on various biological processes as well as disease development and progression. However, the lncRNAs involved in bacterial meningitis and their regulatory effects are largely unknown. By RNA-sequencing, the transcriptional profiles of host lncRNAs in primary human brain microvascular endothelial cells (hBMECs) in response to meningitic Escherichia coli were demonstrated. Here, 25,257 lncRNAs were identified, including 24,645 annotated lncRNAs and 612 newly found ones. A total of 895 lncRNAs exhibited significant differences upon infection, among which 382 were upregulated and 513 were downregulated (≥2-fold, p < 0.05). Via bioinformatic analysis, the features of these lncRNAs, their possible functions, and the potential regulatory relationships between lncRNAs and mRNAs were predicted. Moreover, we compared the transcriptional specificity of these differential lncRNAs among hBMECs, human astrocyte cell U251, and human umbilical vein endothelial cells, and demonstrated the novel regulatory effects of proinflammatory cytokines on these differential lncRNAs. To our knowledge, this is the first time the transcriptional profiles of host lncRNAs involved in E. coli-induced meningitis have been reported, which shall provide novel insight into the regulatory mechanisms behind bacterial meningitis involving lncRNAs, and contribute to better prevention and therapy of CNS infection.

EGFR transactivation contributes to neuroinflammation in Streptococcus suis meningitis.

BACKGROUND: Streptococcus suis serotype 2 (SS2) is an important zoonotic bacterial pathogen in both humans and animals, which can cause high morbidity and mortality. Meningitis is one of the major clinical manifestations of SS2 infection. However, the specific process of SS2 meningitis and its molecular mechanisms remain unclear. Epidermal growth factor receptor (EGFR) has been reported to initiate transduction of intracellular signals and regulate host inflammatory responses. Whether and how EGFR contributes to the development of S. suis meningitis are currently unknown. METHODS: The tyrosine phosphorylation of cellular proteins, the transactivation of EGFR, as well as its dimerization, and the associated signal transduction pathways were investigated by immunoprecipitation and western blotting. Real-time quantitative PCR was used to investigate the transcriptional level of the ErbB family members, EGFR-related ligands, cytokines, and chemokines. The secretion of cytokines and chemokines in the serum and brain were detected by Q-Plex™ Chemiluminescent ELISA. RESULTS: We found an important role of EGFR in SS2 strain SC19-induced meningitis. SC19 increasingly adhered to human brain microvascular endothelial cells (hBMEC) and caused inflammatory lesions in the brain tissues, with significant induction and secretion of proinflammatory cytokines and chemokines in the serum and brains. SC19 infection of hBMEC induced tyrosine phosphorylation of cellular EGFR in a ligand-dependent manner involving the EGF-like ligand HB-EGF, amphiregulin (AREG), and epiregulin (EREG) and led to heterodimerization of EGFR/ErbB3. The EGFR transactivation did not participate in SS2 strain SC19 adhesion of hBMEC, as well as in bacterial colonization in vivo. However, its transactivation contributed to the bacterial-induced neuroinflammation, via triggering the MAPK-ERK1/2 and NF-κB signaling pathways in hBMEC that promote the production of proinflammatory cytokines and chemokines. CONCLUSIONS: We investigated for the first time the tyrosine phosphorylation of cellular proteins in response to SS2 strain SC19 infection of hBMEC and demonstrated the contribution of EGFR to SS2-induced neuroinflammation. These observations propose a novel mechanism involving EGFR in SS2-mediated inflammatory responses in the brain, and therefore, EGFR might be an important host target for further investigation and prevention of neuroinflammation caused by SS2 strains.

Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier.

Escherichia coli is the most common Gram-negative bacterium that possesses the ability to cause neonatal meningitis, which develops as circulating bacteria penetrate the blood-brain barrier (BBB). However, whether meningitic E. coli could induce disruption of the BBB and the underlying mechanisms are poorly understood. Our current work highlight for the first time the participation of VEGFA and Snail-1, as well as the potential mechanisms, in meningitic E. coli induced disruption of the BBB. Here, we characterized a meningitis-causing E. coli PCN033, and demonstrated that PCN033 invasion could increase the BBB permeability through downregulating and remodeling the tight junction proteins (TJ proteins). This process required the PCN033 infection-induced upregulation of VEGFA and Snail-1, which involves the activation of TLR2-MAPK-ERK1/2 signaling cascade. Moreover, production of proinflammatory cytokines and chemokines in response to infection also promoted the upregulation of VEGFA and Snail-1, therefore further mediating the BBB disruption. Our observations reported here directly support the involvement of VEGFA and Snail-1 in meningitic E. coli induced BBB disruption, and VEGFA and Snail-1 would therefore represent the essential host targets for future prevention of clinical E. coli meningitis.

[Evaluation of absolute alcohol treatment for renal cyst with percutaneous puncture and catheterization under ultrasonographic guidance].

OBJECTIVE: To evaluate the effect of absolute alcohol treatment for renal cyst with percutaneous puncture and catheterization. METHODS: This report presented 64 cases of renal cysts, 34 cases were treated with percutaneous puncture (A group) and 30 cases with percutaneous catheterization (B group). According to the size, the cysts were divided into 2 groups, more than 6 cm in diameter and less than 6 cm in diameter. RESULTS: All the patients were followed up for 3 - 12 months by CT or B ultrasonography. Striking difference of the therapeutic results were existed when cystS were more than 6 cm in diameter. CONCLUSION: Percutaneous catheterization is applicable to the sclerosing treatment of renal cyst whose diameter is more than 6 cm.