Spatial distribution and environmental correlations of Culex pipiens pallens (Diptera: Culicidae) in Haidian district, Beijing.

Culex pipiens pallens Coquillett, 1898 (Diptera: Culicidae) was the dominant health threat to mosquito species in Beijing, and it is important to unravel the spatial distribution and environmental correlations of Cx. pipiens pallens in Beijing. 3S technology methods and spatial statistics were used to clarify the distribution pattern. Subsequently, linear and spatial regression were performed to detect the environmental factors linked with the density of Cx. pipiens pallens. The same "middle peak" spatial distribution pattern was observed for Cx. pipiens pallens density at the community, subdistrict, and loop area levels in our study area. In addition, there were various correlated environmental factors at the community and subdistrict scales. At the community scale, the summary values of the Modified Normalized Difference Water Index (MNDWI) in 2 km buffer zone (MNDWI_2K) were negatively correlated, and the summary values of Normalized Difference Built-up Index (NDBI) in 800 m buffer zone (NDBI_800) was positively correlated to the Cx. pipiens pallens density. However, the summary values of Normalized Difference Vegetation Index and Nighttime Light Index significantly affected Cx. pipiens pallens density at the subdistrict scale. Our findings provide insight into the spatial distribution pattern of Cx. pipiens pallens density and its associated environmental risk factors at different spatial scales in the Haidian district of Beijing for the first time. The results could be used to predict the Cx. pipiens pallens density as well as the risk of lymphatic filariasis (LF) infection, which would help implement prevention and control measures to prevent future risks of biting and LF transmission in Beijing.

Personalized transcriptome signatures in a cardiomyopathy stem cell biobank.

BACKGROUND: There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines. METHODS: We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility. RESULTS: We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. ADCY5 was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment. CONCLUSIONS: We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for ADCY5 in cardiomyopathy.

Correction: Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication.

[This corrects the article DOI: 10.1371/journal.ppat.1006851.].

M6PR interacts with the HA2 subunit of influenza A virus to facilitate the fusion of viral and endosomal membranes.

Influenza A virus (IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membranes. In this study, we identified cation-dependent mannose-6-phosphate receptor (M6PR) as a crucial host factor for the replication of IAV. We found that siRNA knockdown of M6PR expression significantly reduced the growth titers of different subtypes of IAV, and that the inhibitory effect of M6PR siRNA treatment on IAV growth was overcome by the complement of exogenously expressed M6PR. When A549 cells were treated with siRNA targeting M6PR, the nuclear accumulation of viral nucleoprotein (NP) was dramatically inhibited at early timepoints post-infection, indicating that M6PR engages in the early stage of the IAV replication cycle. By investigating the role of M6PR in the individual entry and post-entry steps of IAV replication, we found that the downregulation of M6PR expression had no effect on attachment, internalization, early endosome trafficking, or late endosome acidification. However, we found that M6PR expression was critical for the fusion of viral envelope and late endosomal membranes. Of note, M6PR interacted with the hemagglutinin (HA) protein of IAV, and further studies showed that the lumenal domain of M6PR and the ectodomain of HA2 mediated the interaction and directly promoted the fusion of the viral and late endosomal membranes, thereby facilitating IAV replication. Together, our findings highlight the importance of the M6PR-HA interaction in the fusion of viral and late endosomal membranes during IAV replication.

NGLY1 mutations cause protein aggregation in human neurons.

Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1's activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.

ABTB1 facilitates the replication of influenza A virus by counteracting TRIM4-mediated degradation of viral NP protein.

Influenza A viruses (IAVs) continue to cause tremendous economic losses to the global animal industry and respiratory diseases and deaths among humans. The nuclear import of the vRNP complex, composed of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), polymerase acidic protein (PA), nucleoprotein (NP), and viral RNA, is essential for the efficient replication of IAV. Host factors involved in this process can be targeted for the development of countermeasures against IAV infection. Here, we found that Ankyrin Repeat and BTB Domain Containing 1 (ABTB1) promotes the replication of IAV, and positively regulates the nuclear import of the vRNP complex. ABTB1 did not interact directly with NP, indicating that ABTB1 plays an indirect role in facilitating the nuclear import of the vRNP complex. Immunoprecipitation and mass spectrometry revealed that Tripartite Motif Containing 4 (TRIM4) interacts with ABTB1. We found that TRIM4 relies on its E3 ubiquitin ligase activity to inhibit the replication of IAV by targeting and degrading NP within the incoming vRNP complex as well as the newly synthesized NP. ABTB1 interacted with TRIM4, leading to TRIM4 degradation through the proteasome system. Notably, ABTB1-mediated degradation of TRIM4 blocked the effect of TRIM4 on NP stability, and largely counteracted the inhibitory effect of TRIM4 on IAV replication. Our findings define a novel role for ABTB1 in aiding the nuclear import of the vRNP complex of IAV by counteracting the destabilizing effect of TRIM4 on the viral NP protein.

Adjuvant Lipoic acid Injection in Sepsis treatment in China (ALIS study): protocol for a randomised, single-blind, placebo-controlled trial.

INTRODUCTION: Sepsis is a life-threatening immune disorder resulting from an dysregulated host response to infection. Adjuvant therapy is a valuable complement to sepsis treatment. Lipoic acid has shown potential in attenuating sepsis-induced immune dysfunction and organ injury in vivo and in vitro studies. However, clinical evidence of lipoic acid injection in sepsis treatment is lacking. Hence, we devised a randomised controlled trial to evaluate the efficacy and safety of lipoic acid injection in improving the prognosis of sepsis or septic shock patients. METHODS AND ANALYSIS: A total of 352 sepsis patients are planned to be recruited from intensive care units (ICUs) at eight tertiary hospitals in China for this trial. Eligible participants will undergo randomisation in a 1:1 ratio, allocating them to either the control group or the experimental group. Both groups received routine care, with the experimental group also receiving lipoic acid injection and the control group receiving placebo. The primary efficacy endpoint is 28-day all-cause mortality. The secondary efficacy endpoints are as follows: ICU and hospital mortality, ICU and hospital stay, new acute kidney injury in ICU, demand and duration of life support, Sequential Organ Failure Assessment (SOFA)/Acute Physiology and Chronic Health Evaluation II (APACHE II) and changes from baseline (ΔSOFA/ΔApache II), arterial blood lactate (LAC) and changes from baseline (ΔLAC), blood procalcitonin, high-sensitivity C-reactive protein, interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and changes from baseline on day 1 (D1), D3, D5 and D7. Clinical safety will be assessed through analysis of adverse events. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Maoming People's Hospital (approval no. PJ2020MI-019-01). Informed consent will be obtained from the participants or representatives. The findings will be disseminated through academic conferences or journal publications. TRIAL REGISTRATION: ChiCTR2000039023.

Advanced Cell Therapies for Glioblastoma.

The sheer ubiquity of Gioblastoma (GBM) cases would lead you to believe that there should have been many opportunities for the discovery of treatments to successfully render it into remission. Unfortunately, its persistent commonality is due in large part to the fact that it is the most treatment-resistant tumors in adults. That completely changes the treatment plan of attack. Long established and accepted treatment therapies such as surgical resection, radiation, and aggressive chemotherapy, (and any combination thereof) have only confirmed that the disease lives up to its treatment-resistant reputation. To add to the seemingly insurmountable task of finding a cure, GBM has also proven to be a very stubborn and formidable opponent to newer immunotherapies. Across the board, regardless of the therapy combination, the five-year survival rate of GBM patients is still very poor at a heartbreaking 5.6%. Obviously, the present situation cannot be tolerated or deemed acceptable. The grave situation calls for researchers to be more innovative and find more efficient strategies to discover new and successful strategies to treat GBM. Inspired by researchers worldwide attempting to control GBM, we provide in this review a comprehensive overview of the many diverse cell therapies currently being used to treat GBM. An overview of the treatments include: CAR T cells, CAR NK cells, gamma-delta T cells, NKT cells, dendritic cells, macrophages, as well stem cell-based strategies. To give you the complete picture, we will discuss the efficacy, safety, and developmental stages, the mechanisms of action and the challenges of each of these therapies and detail their potential to be the next-generation immunotherapeutic to eliminate this dreadful disease.

Influenza A virus use of BinCARD1 to facilitate the binding of viral NP to importin α7 is counteracted by TBK1-p62 axis-mediated autophagy.

As a major component of the viral ribonucleoprotein (vRNP) complex in influenza A virus (IAV), nucleoprotein (NP) interacts with isoforms of importin α family members, leading to the import of itself  and vRNP complex into the nucleus, a process pivotal in the replication cycle of IAV. In this study, we found that BinCARD1, an isoform of Bcl10-interacting protein with CARD (BinCARD), was leveraged by IAV for efficient viral replication. BinCARD1 promoted the nuclear import of the vRNP complex and newly synthesized NP and thus enhanced vRNP complex activity. Moreover, we found that BinCARD1 interacted with NP to promote NP binding to importin α7, an adaptor in the host nuclear import pathway. However, we also found that BinCARD1 promoted RIG-I-mediated innate immune signaling by mediating Lys63-linked polyubiquitination of TRAF3, and that TBK1 appeared to degrade BinCARD1. We showed that BinCARD1 was polyubiquitinated at residue K103 through a Lys63 linkage, which was recognized by the TBK1-p62 axis for autophagic degradation. Overall, our data demonstrate that IAV leverages BinCARD1 as an important host factor that promotes viral replication, and two mechanisms in the host defense system are triggered-innate immune signaling and autophagic degradation-to mitigate the promoting effect of BinCARD1 on the life cycle of IAV.

Identification of the key genes controlling stomach adenocarcinoma stem cell characteristics via an analysis of stemness indices.

Background: In-depth research on tumors has shown that cancer stem cells (CSCs) play a crucial role in tumorigenesis. However, the mechanisms underlying the growth and maintenance of CSCs in stomach adenocarcinoma (STAD) are unclear. This study sought to investigate the expression of stem cell-related genes in STAD. Methods: We identified key genes related to STAD stem cell characteristics by combining gene expression data obtained from The Cancer Genome Atlas to define a messenger ribonucleic acid expression-based stemness index (mRNAsi) based on mRNA expression. The correlations between the mRNAsi and STAD clinical characteristics, including age, tumor grade, pathological stage, and survival status, were explored. Additionally, a weighted gene co-expression network analysis was conducted to identify relevant modules and key genes. The expression verification and functional analysis of the key genes was carried out using multiple databases, including the TIMER (https://cistrome.shinyapps.io/timer/), and Gene Expression Profiling Integrative Analysis, and Gene Expression Omnibus databases. Results: The mRNAsi score was closely related to the clinical characteristics of STAD, including age, tumor grade, pathological stage, and survival status. Similarly, the mRNAsi score was significantly higher in STAD tissues than normal tissues, and the score decreased with tumor stage. The higher the mRNAsi score, the higher the overall survival rate. We screened a module of interest and found a strong correlation between 19 key genes. Among these 19 key genes, 16 had previously been shown to be closely related to STAD survival. The functional analysis showed that these key genes were linked to cell-cycle events, such as chromosome separation, mitosis, and microtubule movement. Conclusions: We identified 19 key genes that play an important role in the maintenance of STAD stem cells. Among these genes, 16 play a role in predicting the prognosis of STAD patients. The cell-cycle pathway was the most important signaling pathway for the key genes associated with STAD stem cells. These findings may provide a new rationale for screening therapeutic targets and the characterization of STAD stem cells.

Formation and transformation of reactive species in the Fe2+/peroxydisulfate/Cl- system.

The influence of Cl- on the formation mechanism of active components is often neglected in the Fe2+/peroxydisulfate (PDS) system containing a large amount of ferryl ion reactive specie (Fe(Ⅳ)). In the current investigation, the effects of Cl- concentration on the removal of methyl phenyl sulfoxide (PMSO), the formation of methyl phenyl sulfone (PMSO2), the transformation of reactive species and oxidation products were investigated under different reaction conditions that included Fe2+ dosage, PDS dosage, and pH0. The results showed that Cl- complexing Fe2+ increased the formation path of sulfate radical (SO4·-) in the Fe2+/PDS system. Fe2+ dosage and pH0 value affected the content and morphology of Fe2+-Cl- complex, thus affecting the composition of reactive species. According to the experiment of free radical steady-state concentration, it was found that low concentration of Cl- reacted with SO4·- and increased the steady-state concentration of chlorine radicals (8.09 × 10-13 M [·Cl]ss at 1.41 mM Cl-), while at high concentration of Cl-, the contents of SO4·-, hydroxyl radical (·OH) and dichloride anion radicals (Cl2·-) increased and the contents of Fe(Ⅳ) and ·Cl decreased. ·Cl had strong reactivity with PMSO, and PMSO and its oxidation products were chlorinated under the combined action of ·Cl and Cl2·-. This work reveals the reaction mechanism and environmental application risks of Fe2+/PDS technology and lays the groundwork for subsequent industrial application of Fe2+/PDS system.

PIAS1-mediated SUMOylation of influenza A virus PB2 restricts viral replication and virulence.

Host defense systems employ posttranslational modifications to protect against invading pathogens. Here, we found that protein inhibitor of activated STAT 1 (PIAS1) interacts with the nucleoprotein (NP), polymerase basic protein 1 (PB1), and polymerase basic protein 2 (PB2) of influenza A virus (IAV). Lentiviral-mediated stable overexpression of PIAS1 dramatically suppressed the replication of IAV, whereas siRNA knockdown or CRISPR/Cas9 knockout of PIAS1 expression significantly increased virus growth. The expression of PIAS1 was significantly induced upon IAV infection in both cell culture and mice, and PIAS1 was involved in the overall increase in cellular SUMOylation induced by IAV infection. We found that PIAS1 inhibited the activity of the viral RNP complex, whereas the C351S or W372A mutant of PIAS1, which lacks the SUMO E3 ligase activity, lost the ability to suppress the activity of the viral RNP complex. Notably, the SUMO E3 ligase activity of PIAS1 catalyzed robust SUMOylation of PB2, but had no role in PB1 SUMOylation and a minimal role in NP SUMOylation. Moreover, PIAS1-mediated SUMOylation remarkably reduced the stability of IAV PB2. When tested in vivo, we found that the downregulation of Pias1 expression in mice enhanced the growth and virulence of IAV. Together, our findings define PIAS1 as a restriction factor for the replication and pathogenesis of IAV.

Mass Spectrometric Behavior and Molecular Mechanisms of Fermented Deoxyanthocyanidins to Alleviate Ulcerative Colitis Based on Network Pharmacology.

Aims: Ulcerative colitis (UC) is a type of chronic idiopathic inflammatory bowel disease with a multifactorial pathogenesis and limited treatment options. The aim of the present study is to investigate the hydrogen deuterium exchange mass spectrometry (HDX-MS) behaviors of fermented deoxyanthocyanidins and their molecular mechanisms to alleviate UC by using quantum chemistry and network pharmacology. Methods: Tandem MS indicated at least two fragmentation pathways through which deuterated vinylphenol-deoxyanthocyanidins could generate different product ions. Quantum calculations were conducted to determine the transition states of the relevant molecules and analyze their optimized configuration, vibrational characteristics, intrinsic reaction coordinates, and corresponding energies. The potential targets of deoxyanthocyanidins in UC were screened from a public database. The R package was used for Gene Ontology (GO) and KEGG pathway analyses, and the protein-protein interactions (PPIs) of the targets were assessed using Search Tool for the Retrieval of Interacting Genes (STRING). Finally, molecular docking was implemented to analyze the binding energies and action modes of the target compounds through the online tool CB-Dock. Results: Quantum calculations indicated two potential fragmentation pathways involving the six-membered ring and dihydrogen cooperative transfer reactions of the vinylphenol-deoxyanthocyanidins. A total of 146 and 57 intersecting targets of natural and fermented deoxyanthocyanidins were separately screened out from the UC database and significant overlaps in GO terms and KEGG pathways were noted. Three shared hub targets (i.e., PTGS2, ESR1, and EGFR) were selected from the two PPI networks by STRING. Molecular docking results showed that all deoxyanthocyanidins have a good binding potential with the hub target proteins and that fermented deoxyanthocyanidins have lower binding energies and more stable conformations compared with natural ones. Conclusions: Deoxyanthocyanidins may provide anti-inflammatory, antioxidative, and immune system regulatory effects to suppress UC progression. It is proposed for the first time that fermentation of deoxyanthocyanidins can help adjust the structure of the intestinal microbiota and increase the biological activity of the natural compounds against UC. Furthermore, HDX-MS is a helpful strategy to analyze deoxyanthocyanidin metabolites with unknown structures.

Patient-derived gene and protein expression signatures of NGLY1 deficiency.

N-Glycanase 1 (NGLY1) deficiency is a rare and complex genetic disorder. Although recent studies have shed light on the molecular underpinnings of NGLY1 deficiency, a systematic characterization of gene and protein expression changes in patient-derived cells has been lacking. Here, we performed RNA-sequencing and mass spectrometry to determine the transcriptomes and proteomes of 66 cell lines representing four different cell types derived from 14 NGLY1 deficient patients and 17 controls. Although NGLY1 protein levels were up to 9.5-fold downregulated in patients compared with parents, residual and likely non-functional NGLY1 protein was detectable in all patient-derived lymphoblastoid cell lines. Consistent with the role of NGLY1 as a regulator of the transcription factor Nrf1, we observed a cell type-independent downregulation of proteasomal genes in NGLY1 deficient cells. In contrast, genes involved in ribosome biogenesis and mRNA processing were upregulated in multiple cell types. In addition, we observed cell type-specific effects. For example, genes and proteins involved in glutathione synthesis, such as the glutamate-cysteine ligase subunits GCLC and GCLM, were downregulated specifically in lymphoblastoid cells. We provide a web application that enables access to all results generated in this study at https://apps.embl.de/ngly1browser. This resource will guide future studies of NGLY1 deficiency in directions that are most relevant to patients.

Clinical Effects of Jiawei Danggui Beimu Kushen Pills in the Treatment of Prostate Cancer and Their Influence on the Expression of Serum Prostate Specific Antigen.

OBJECTIVE: To observe the clinical effects of Jiawei Danggui Beimu Kushen pills in treating prostate cancer and their influence on the expression of serum prostate specific antigen. METHODS: A total of 234 prostate cancer patients were selected and randomly divided into observation group and control group, with 117 cases in each group. The control group was given oral bicalutamide tablets, while the observation group was treated with Jiawei Danggui Beimu Kushen pills on the basis of the control group. The treatment efficacy, IPSS score, TCM syndrome score, VAS score, quality-of-life score, and immune function of the two groups were compared before and after treatment. The serum PSA and f-PSA levels of patients before treatment and after 30 days, 90 days, and 180 days of treatment in the two groups were compared. The five-year cumulative survival rate and the incidence of adverse reactions were compared between the two groups. RESULTS: After treatment, the total effective rate of the observation group was 88.03% (103/117), which was higher than that of the control group 69.23% (81/117); the difference was statistically significant (P < 0.05). After treatment, the IPSS score, TCM syndrome score, and VAS score of the two groups were reduced, and those in the observation group were lower than those in the control group; the difference was statistically significant (P < 0.05). After treatment, the quality-of-life scores of the two groups increased, and the observation group was higher than the control group; the difference was statistically significant (P < 0.05). Before treatment, there was no significant difference in serum PSA levels and f-PSA levels when comparing between the two groups of patients (P > 0.05). With the increase of treatment time, the two index levels of the two groups were gradually decreased. After 180 days of treatment, the two index levels of the two groups of patients were significantly lower than those before treatment, and the two index levels of the observation group were significantly lower than those of the control group; the difference was statistically significant (P < 0.05). After treatment, the levels of IgM and IgA in the two groups were decreased, and the level of IgG was increased. The difference between the two groups in the levels of each index before and after treatment was statistically significant (P < 0.05), and the difference between the two groups in the levels of each index after treatment was also statistically significant (P < 0.05). The five-year cumulative survival rate of the observation group was 69.23%, and the five-year cumulative survival rate of the control group was 46.15% (P < 0.05). There was no statistically significant difference between the two groups in the incidence of dizziness, fatigue, and gastrointestinal reactions (P > 0.05), but the difference in the incidence of dysuria as well as dysuria and hematuria was statistically significant (P < 0.05). CONCLUSION: Jiawei Danggui Beimu Kushen pills are effective in treating prostate cancer, which can effectively reduce the patients' IPSS score and TCM syndrome scores, relieve the pain, and improve the quality of life of patients. They also have a potential role in regulating serum PSA levels, clearing tumor lesions, reducing postoperative complications, and improving related symptoms.

CircRNA pappalysin 1 facilitates prostate cancer development through miR-515-5p/FKBP1A axis.

The role of circular RNA (circRNA) pappalysin 1 (circ-PAPPA; hsa_circ_0088233) in prostate cancer (PCa) cells was explored in the current study. Circ-PAPPA abundance was markedly enhanced in PCa. Circ-PAPPA interference restrained cell viability, proliferation, motility and glycolysis while elevated the apoptosis rate of PCa cells. Circ-PAPPA negatively regulated microRNA-515-5p (miR-515-5p) abundance. MiR-515-5p silencing largely diminished circ-PAPPA knockdown-mediated effects in PCa cells. MiR-515-5p directly bound to FKBP prolyl isomerase 1A (FKBP1A). MiR-515-5p overexpression-mediated impacts were partly counteracted by FKBP1A overexpression. Circ-PAPPA silencing reduced FKBP1A protein level partly by elevating miR-515-5p expression. Circ-PAPPA knockdown significantly restrained the tumour growth in vivo. Circ-PAPPA elevated the malignant phenotypes of PCa cells by sequestering miR-515-5p to induce the expression of FKBP1A.

Retrospective study of the clinicopathological characteristics and prognosis of elderly patients with oropharyngeal squamous cell carcinoma.

OBJECTIVE: Oropharyngeal squamous cell carcinoma (OPSCC) is a malignant tumor that occurs at the tongue base, soft palate, palatine tonsil, and pharyngeal wall. Few studies of OPSCC have been performed in elderly patients. METHODS: Patients with human papilloma virus (HPV)-related OPSCC were extracted from the Head and Neck with HPV Status Database of the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016. We identified 355 patients with HPV-positive status, and we retrospectively evaluated elderly (≥65 years) and younger (30-64 years) patient groups to compare the differences. RESULTS: Of the 355 patients who were diagnosed with HPV-related OPSCC, 113 constituted the elderly group. Comparing the elderly group with the younger group, the 3-year HPV-positive overall survival (OS) rates were 62.4% and 70.2%, respectively, and the 5-year OS rates were 50.4% and 59.2%, respectively. Cox regression analysis demonstrated that tumor (T) stage and chemotherapy were prognostic factors for OS. CONCLUSION: Elderly patients with OPSCC had different clinicopathological characteristics. T stage and chemotherapy should be priorities when evaluating the OS of elderly patients with OPSCC.

Lipidomic alteration of plasma in cured COVID-19 patients using ultra high-performance liquid chromatography with high-resolution mass spectrometry.

BACKGROUND: The pandemic of novel coronavirus disease 2019 (COVID-19) has become a serious public health crisis worldwide. The symptoms of COVID-19 vary from mild to severe among different age groups, but the physiological changes related to COVID-19 are barely understood. METHODS: In the present study, a high-resolution mass spectrometry (HRMS)-based lipidomic strategy was used to characterize the endogenous plasma lipids for cured COVID-19 patients with different ages and symptoms. These patients were further divided into two groups: those with severe symptoms or who were elderly and relatively young patients with mild symptoms. In addition, automated lipidomic identification and alignment was conducted by LipidSearch software. Multivariate and univariate analyses were used for differential comparison. RESULTS: Nearly 500 lipid compounds were identified in each cured COVID-19 group through LipidSearch software. At the level of lipid subclasses, patients with severe symptoms or elderly patients displayed dramatic changes in plasma lipidomic alterations, such as increased triglycerides and decreased cholesteryl esters (ChE). Some of these differential lipids might also have essential biological functions. Furthermore, the differential analysis of plasma lipids among groups was performed to provide potential prognostic indicators, and the change in signaling pathways. CONCLUSIONS: Dyslipidemia was observed in cured COVID-19 patients due to the viral infection and medical treatment, and the discharged patients should continue to undergo consolidation therapy. This work provides valuable knowledge about plasma lipid markers and potential therapeutic targets of COVID-19 and essential resources for further research on the pathogenesis of COVID-19.

Viral RNA-binding ability conferred by SUMOylation at PB1 K612 of influenza A virus is essential for viral pathogenesis and transmission.

Posttranslational modifications, such as SUMOylation, play specific roles in the life cycle of invading pathogens. However, the effect of SUMOylation on the adaptation, pathogenesis, and transmission of influenza A virus (IAV) remains largely unknown. Here, we found that a conserved lysine residue at position 612 (K612) of the polymerase basic protein 1 (PB1) of IAV is a bona fide SUMOylation site. SUMOylation of PB1 at K612 had no effect on the stability or cellular localization of PB1, but was critical for viral ribonucleoprotein (vRNP) complex activity and virus replication in vitro. When tested in vivo, we found that the virulence of SUMOylation-defective PB1/K612R mutant IAVs was highly attenuated in mice. Moreover, the airborne transmission of a 2009 pandemic H1N1 PB1/K612R mutant virus was impaired in ferrets, resulting in reversion to wild-type PB1 K612. Mechanistically, SUMOylation at K612 was essential for PB1 to act as the enzymatic core of the viral polymerase by preserving its ability to bind viral RNA. Our study reveals an essential role for PB1 K612 SUMOylation in the pathogenesis and transmission of IAVs, which can be targeted for the design of anti-influenza therapies.

Mass spectrometric behaviors and molecular mechanisms of Amadori compounds between acute lung injury and diabetes based on network pharmacology.

BACKGROUND: With its complex pathogenesis and high mortality, acute lung injury (ALI) is closely associated with a poor prognosis in critically ill patients. The present study used network pharmacology to investigate the mass spectrometry (MS) behaviors and molecular mechanisms of Amadori compounds acting on ALI and diabetes. METHODS: Two typical Amadori compounds (Fru-Trp and Glc(α1,4)-Fru-Trp) were used to study the fragmentation mechanisms by tandem MS in negative and positive-ion modes. The potential targets of Amadori compounds on ALI were screened from a public database. R package was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and the protein-protein interactions (PPIs) of the targets were evaluated by Search Tool for the Retrieval of Interacting Genes (STRING). Finally, molecular docking was implemented to analyze the binding energies and action modes of the target compounds through the online tool CB-Dock. RESULTS: In relation the common precursor ions of the Amadori compounds, the sodium adducting cations provided the most abundant fragmentation information in c for analyzing their chemical structures. 103 and 109 intersecting targets of glucose-Amadori and maltose-Amadori, respectively, were separately identified in the ALI database, and significant overlaps between the GO terms and KEGG pathways were noted. Three shared hub targets (i.e., vascular endothelial growth factor A, caspase-3, and proto-oncogene tyrosine-protein kinase) were selected from the 2 PPI networks by STRING. The molecular docking results showed that the Amadori compounds had good binding potential to the hub target proteins, and that Amadori compounds had lower binding energies and more stable conformations than their corresponding carbohydrates. CONCLUSIONS: As the endogenous compounds in diabetes, Amadori compounds may act on and activate a wide range of protein receptors, which may also produce bi-directional regulatory effects that influence ALI progression. Thus, the risk factors of diabetes in the progression of ALI should be carefully assessed, and the molecular mechanisms of Amadori compounds in animal models for ALI should be further verified.