Induced effect of zinc oxide nanoparticles on human acute myeloid leukemia cell apoptosis by regulating mitochondrial division.

Zinc oxide nanoparticles (ZnO NPs) have exhibited excellent anti-tumor properties; the present study aimed to elucidate the underlying mechanism of ZnO NPs induced apoptosis in acute myeloid leukemia (AML) cells by regulating mitochondrial division. THP-1 cells, an AML cell line, were first incubated with different concentrations of ZnO NPs for 24 hr. Next, the expression of Drp-1, Bcl-2, Bax mRNA, and protein was detected, and the effects of ZnO NPs on the levels of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), apoptosis, and ATP generation in THP-1 cells were measured. Moreover, the effect of Drp-1 inhibitor Mdivi-1 and ZnO NPs on THP-1 cells was also detected. The results showed that the THP-1 cells survival rate decreased with the increment of ZnO NPs concentration and incubation time in a dose- and time-dependent manner. ZnO NPs can reduce the cell Δψm and ATP levels, induce ROS production, and increase the levels of mitochondrial division and apoptosis. In contrast, the apoptotic level was significantly reduced after intervention of Drp-1 inhibitor, suggesting that ZnO NPs can induce the apoptosis of THP-1 cells by regulating mitochondrial division. Overall, ZnO NPs may provide a new basis and idea for treating human acute myeloid leukemia in clinical practice.

Changes in resting-state cerebral blood flow and its connectivity in patients with focal to bilateral tonic-clonic seizures.

Arterial spin labeling (ASL) is an important tool for understanding cerebral perfusion in epilepsy patients. The aim of this study was to explore patterns of change in cerebral blood flow (CBF) and CBF connectivity in patients with focal to bilateral tonic-clonic seizures (FBTCS). High-resolution three-dimensional (3-D) T1-weighted and 3-D pseudo-continuous ASL magnetic resonance imaging (MRI) was collected from 32 patients with FBTCS and 16 healthy volunteers using a 3.0 T MRI scanner. Cerebral blood flow and its connectivity were compared between the FBTCS and control group. Correlation analysis was used to explore relationships of CBF and its connectivity changes with clinical parameters. Cerebral blood flow data of spatial standardization and normalization were used to improve statistical power. Patients with FBTCS exhibited increased CBF in the bilateral thalamus, caudate nucleus, olfactory cortex, and gyrus rectus, but decreased CBF in the bilateral supplementary motor areas (SMA) and middle cingulate cortex (MCC). Patients with FBTCS showed significant positive correlation between CBF and gray matter volume (GMV) in bilateral SMA and MCC. No significant correlations between CBF and clinical parameters were found among FBTCS patients. The anterior cingulate cortex (ACC) showed positive CBF connectivity with the bilateral SMA and MCC, and these CBF connectivity measures differed significantly between groups (cluster-level, FWE-corrected, P < 0.001). These findings suggest that patients with FBTCS have changes in cerebral CBF and CBF connectivity, which may relate to the underlying neuropathology of FBTCS.

A drug-biomarker interaction model to predict the key targets of Scutellaria barbata D. Don in adverse-risk acute myeloid leukaemia.

A poor prognosis, relapse and resistance are burning issues during adverse-risk acute myeloid leukaemia (AML) treatment. As a natural medicine, Scutellaria barbata D. Don (SBD) has shown impressive antitumour activity in various cancers. Thus, SBD may become a potential drug in adverse-risk AML treatment. This study aimed to screen the key targets of SBD in adverse-risk AML using the drug-biomarker interaction model through bioinformatics and network pharmacology methods. First, the adverse-risk AML-related critical biomarkers and targets of SBD active ingredient were obtained from The Cancer Genome Atlas database and several pharmacophore matching databases. Next, the protein-protein interaction network was constructed, and topological analysis and pathway enrichment were used to screen key targets and main pathways of intervention of SBD in adverse-risk AML. Finally, molecular docking was implemented for key target verification. The results suggest that luteolin and quercetin are the main active components of SBD against adverse-risk AML, and affected drug resistance, apoptosis, immune regulation and angiogenesis through the core targets AKT1, MAPK1, IL6, EGFR, SRC, VEGFA and TP53. We hope the proposed drug-biomarker interaction model provides an effective strategy for the research and development of antitumour drugs.

Regulatory roles of differentially expressed MicroRNAs in metabolic processes in negative Lens-induced myopia Guinea pigs.

BACKGROUND: Myopia is one of the most common vision defects worldwide. microRNAs can regulate the target gene expression, influencing the development of diseases. RESULTS: To investigate the alterations of microRNA profiling in negative lens-induced myopia (NLIM) guinea pigs and to explore the regulatory role of microRNAs in the occurrence and the development of myopia, we first established the NLIM guinea pig model after induction for 2 weeks. Further, we isolated sclera to purify total messenger RNA (mRNA) in both NLIM and NLIM fellow sclera. Using next generation sequencing technique and bioinformatics analysis, we identified the differentially expressed microRNAs in NLIM guinea pigs, performed the bioinformatics annotation for the differentially expressed microRNAs, and validated the expression of differentially expressed microRNAs. As a result, we successfully established an NLIM model in guinea pigs, identified 27 differentially expressed microRNAs in NLIM guinea pig sclera, including 10 upregulated and 17 downregulated microRNAs. The KEGG annotation showed the main signaling pathways were closely associated with PPAR signaling, pyruvate and propanoate metabolisms, and TGF-beta signaling pathways. CONCLUSIONS: Our findings indicate that the development of myopia is mainly involved in the disorder of metabolic processes in NLIM guinea pigs. The PPAR signaling, pyruvate and propanoate metabolism pathways may play roles in the development of myopia.

Temporal Proteomic Analysis of Pancreatic ß-Cells in Response to Lipotoxicity and Glucolipotoxicity.

Chronic hyperlipidemia causes the dysfunction of pancreatic ß-cells, such as apoptosis and impaired insulin secretion, which are aggravated in the presence of hyperglycemia. The underlying mechanisms, such as endoplasmic reticulum (ER) stress, oxidative stress and metabolic disorders, have been reported before; however, the time sequence of these molecular events is not fully understood. Here, using isobaric labeling-based mass spectrometry, we investigated the dynamic proteomes of INS-1 cells exposed to high palmitate in the absence and presence of high glucose. Using bioinformatics analysis of differentially expressed proteins, including the time-course expression pattern, protein-protein interaction, gene set enrichment and KEGG pathway analysis, we analyzed the dynamic features of previously reported and newly identified lipotoxicity- and glucolipotoxicity-related molecular events in more detail. Our temporal data highlight cholesterol metabolism occurring at 4 h, earlier than fatty acid metabolism that started at 8 h and likely acting as an early toxic event highly associated with ER stress induced by palmitate. Interestingly, we found that the proliferation of INS-1 cells was significantly increased at 48 h by combined treatment of palmitate and glucose. Moreover, benefit from the time-course quantitative data, we identified and validated two new molecular targets: Setd8 for cell replication and Rhob for apoptosis, demonstrating that our temporal dataset serves as a valuable resource to identify potential candidates for mechanistic studies of lipotoxicity and glucolipotoxicity in pancreatic ß-cells.

RNA-binding protein DDX1 is responsible for fatty acid-mediated repression of insulin translation.

The molecular mechanism in pancreatic ß cells underlying hyperlipidemia and insulin insufficiency remains unclear. Here, we find that the fatty acid-induced decrease in insulin levels occurs due to a decrease in insulin translation. Since regulation at the translational level is generally mediated through RNA-binding proteins, using RNA antisense purification coupled with mass spectrometry, we identify a novel insulin mRNA-binding protein, namely, DDX1, that is sensitive to palmitate treatment. Notably, the knockdown or overexpression of DDX1 affects insulin translation, and the knockdown of DDX1 eliminates the palmitate-induced repression of insulin translation. Molecular mechanism studies show that palmitate treatment causes DDX1 phosphorylation at S295 and dissociates DDX1 from insulin mRNA, thereby leading to the suppression of insulin translation. In addition, DDX1 may interact with the translation initiation factors eIF3A and eIF4B to regulate translation. In high-fat diet mice, the inhibition of insulin translation happens at an early prediabetic stage before the elevation of glucose levels. We speculate that the DDX1-mediated repression of insulin translation worsens the situation of insulin resistance and contributes to the elevation of blood glucose levels in obese animals.

DDX1 regulates alternative splicing and insulin secretion in pancreatic ß cells.

DEAD-box helicase 1 (DDX1) is a multifunction protein involved in diverse cellular processes including transcription, viral replication, mRNA/miRNA processing, and tRNA splicing. Here, we report a novel function of DDX1 in mRNA alternative splicing in pancreatic ß cells. By performing integrated data analysis of high-throughput RNA sequencing (RNA-Seq), and cross-linking and immunoprecipitation coupled with deep sequencing (CLIP-Seq), we identify hundreds of alternative splicing genes that are targeted by DDX1. These DDX1-targeted alternative splicing genes are mainly associated with calcium ion binding, high voltage-gated calcium channel, and transmembrane transporter. Functionally, silencing DDX1 impairs calcium influx and insulin secretion in the pancreatic ß cells. These results reveal an important role for DDX1 in the regulation of gene alternative splicing and insulin secretion in pancreatic ß cells.

Association of TGFBR2 rs6785358 Polymorphism with Increased Risk of Congenital Ventricular Septal Defect in a Chinese Population.

Transforming growth factor beta receptor 2 (TGFBR2) plays a central role in normal heart development, and we investigated whether TGFBR2 polymorphism confers the risk of congenital ventricular septal defect (CVSD). The case-control study included 115 CVSD children and 188 healthy children in a Chinese population. TGFBR2 rs6785358 polymorphism was genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Enzyme-linked immunoassay (ELISA) was used to detect serum TGFBR2 levels. The genotype and allele frequency of TGFBR2 rs6785358 were significantly higher in the CVSD group than in the controls (all P < 0.05). The G allele carriers were associated with increased CVSD risk compared with the A allele carriers in CVSD group (OR 3.503, 95 % CI 2.670-4.596). Stratified analysis by gender revealed that the TGFBR2 rs6785358 genotype and allele frequency were significantly different between the CVSD case and controls, in both the male subgroup and the female subgroup (all P < 0.001). The G allele carriers were more susceptible to CVSD risk than the A allele carriers in both the male subgroup (OR 9.096, 95 % CI 5.398-15.33) and the female subgroup (OR 3.148, 95 % CI 1.764-5.618). Logistic regression analysis revealed that age, gender and genotype were associated with the risk of CVSD (all P < 0.05). The study findings revealed that TGFBR2 rs6785358 polymorphism contributes to CVSD susceptibility, and the G allele may increase the risk of CVSD.

Vitamin D receptor gene polymorphisms and multiple myeloma: a meta-analysis.

Vitamin D acts through the vitamin D receptor (VDR), and vitamin D level decreases in multiple myeloma (MM) patients. Single nucleotide polymorphisms in VDR alter its functions to affect the vitamin D status. This raises the question of whether VDR gene polymorphisms are associated with MM risk, which has been investigated in case‒control studies, but the results have been inconsistent. This meta-analysis aimed to investigate the relationship between VDR gene polymorphisms and MM risk. The PubMed, Web of Science, Medline, Embase, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal (VIP), Wanfang Databases (WANFANG) were searched from inception to June 1, 2023, without language restriction or publication preference. Pooled odds ratio (OR) and 95% confidence interval (CI) for each variable were calculated. Leave-one-out sensitivity analysis was performed to determine the source of heterogeneity. Publication bias was assessed using Begg' and Egger's tests, and the trim-and-fill method was used to compensate for publication bias. The correlation meta-analysis was conducted using Comprehensive Meta-Analysis 3.0 and STATA 12.0 software. All the included studies were based on Asian populations and involved four VDR gene polymorphisms, TaqI (rs731236), ApaI (rs7975232), BsmI (rs1544410) and FokI (rs2228570). The results showed that TaqI (C vs. T: OR = 1.487, 95% CI 1.052, 2.104, P = 0.025; CC + CT vs. TT: OR = 1.830, 95% CI 1.138, 2.944, P = 0.013), ApaI (T vs. G: OR = 1.292, 95% CI 1.101, 1.517, P = 0.002; TT vs. GG: OR = 1.600, 95% CI 1.106, 2.314, P = 0.013; TG vs. GG: OR 1.305, 95% CI 1.050, 1.622; P = 0.016; TT + TG vs. GG: OR = 1.353, 95% CI 1.103, 1.662, P = 0.004), BsmI (GG vs. AA: OR = 1.918, 95% CI 1.293, 2.844, P = 0.001; GA vs. AA: OR = 1.333, 95% CI 1.058, 1.679, P = 0.015; G vs. A: OR = 1.398, 95% CI 1.180, 1.657, P = 0.000; GG vs. AA + GA: OR = 1.686, 95% CI 1.174, 2.423, P = 0.005), and FokI (T vs. C: OR = 1.687, 95% CI 1.474, 1.931, P = 0.000; TT vs. CC: OR = 2.829, 95% CI 2.066, 3.872, P = 0.000; TC vs. CC: OR = 1.579, 95% CI 1.304, 1.913, P = 0.000, TT + TC vs. CC: OR = 1.771, 95% CI 1.477, 2.125, P = 0.000; TT vs. CC + TC: OR = 2.409, 95% CI 1.814, 3.200, P = 0.000) are associated with MM risk. VDR gene polymorphisms including ApaI, BsmI, TaqI, and FokI are associated with MM risk in Asian populations. Additional studies with large sample sizes and different ethnicities are needed.

Acupuncture in Multiple Myeloma Peripheral Neuropathy: A Systematic Review.

Background: Peripheral neuropathy (PN) is a prevalent complication of multiple myeloma (MM), due to the disease itself or its treatment. Despite extensive research, the optimal treatment for multiple myeloma peripheral neuropathy (MMPN) remains unclear. Clinical practice has shown the potential efficacy of acupuncture in managing MMPN. This study aimed to conduct a comprehensive analysis of the literature to assess the effectiveness and safety of acupuncture as a treatment for MMPN. Methods: The PubMed, Web of Science, MEDLINE, Cochrane Library, and Embase databases were comprehensively searched from inception to November 1, 2023 to identify relevant studies pertaining to the use of acupuncture to treat MMPN. Results: A total of five studies, encompassing 97 patients diagnosed with drug-related PN, were ultimately included in this analysis. The literature lacks any reports pertaining to the utilization of acupuncture for disease-related PN. ST36, LI4, SP6, and EX-LE-10 were found to be the most frequently chosen acupoints. Following acupuncture treatment, there was a consistent reduction in scores on the Visual Analogue Scale (VAS), Neuropathic Pain Scale (NPS), Brief Pain Inventory-Short Form (BPI-SF), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) among MMPN patients. The results of Nerve Conduction Velocity (NCV) tests yielded conflicting results. No severe adverse effects were reported. Conclusion: The use of acupuncture for disease-related PN has not been studied to date. Acupuncture is safe for drug-related PN and is helpful for relieving pain. But uncertainty exists regarding the efficacy of this approach because there is substantial heterogeneity with respect to acupuncture treatment regimens, and more high-quality studies on this topic are warranted.

Zinc Oxide Nanoparticles Trigger Autophagy in the Human Multiple Myeloma Cell Line RPMI8226: an In Vitro Study.

Multiple myeloma (MM) is a malignant clonal proliferative plasma cell tumor. Zinc oxide nanoparticles (ZnO NPs) are used for antibacterial and antitumor applications in the biomedical field. This study investigated the autophagy-induced effects of ZnO NPs on the MM cell line RPMI8226 and the underlying mechanism. After RPMI8226 cells were exposed to various concentrations of ZnO NPs, the cell survival rate, morphological changes, lactate dehydrogenase (LDH) levels, cell cycle arrest, and autophagic vacuoles were monitored. Moreover, we investigated the expression of Beclin 1 (Becn1), autophagy-related gene 5 (Atg5), and Atg12 at the mRNA and protein levels, as well as the level of light chain 3 (LC3). The results showed that ZnO NPs could effectively inhibit the proliferation and promote the death of RPMI8226 cells in vitro in a dose- and time-dependent manner. ZnO NPs increased LDH levels, enhanced monodansylcadaverine (MDC) fluorescence intensity, and induced cell cycle arrest at the G2/M phases in RPMI8226 cells. Moreover, ZnO NPs significantly increased the expression of Becn1, Atg5, and Atg12 at the mRNA and protein levels and stimulated the production of LC3. We further validated the results using the autophagy inhibitor 3-methyladenine (3­MA). Overall, we observed that ZnO NPs can trigger autophagy signaling in RPMI8226 cells, which may be a potential therapeutic approach for MM.

Long non-coding RNA LncCplx2 regulates glucose homeostasis and pancreatic ß cell function.

OBJECTIVE: Numerous studies have highlighted the role of clock genes in diabetes disease and pancreatic ß cell functions. However, whether rhythmic long non-coding RNAs involve in this process is unknown. METHODS: RNA-seq and 3' rapid amplification of cDNA ends (RACE)-PCR were used to identify the rat LncCplx2 in pancreatic ß cells. The subcellular analysis with qRT-PCR and RNA-Scope were used to assess the localization of LncCplx2. The effects of LncCplx2 overexpression or knockout (KO) on the regulation of pancreatic ß cell functions were assessed in vitro and in vivo. RNA-seq, immunoblotting (IB), Immunoprecipitation (IP), RNA pull-down, and chromatin immunoprecipitation (ChIP)-PCR assays were employed to explore the regulatory mechanisms through LncRNA-protein interaction. Metabolism cage was used to measure the circadian behaviors. RESULTS: We first demonstrate that LncCplx2 is a conserved nuclear long non-coding RNA and enriched in pancreatic islets, which is driven by core clock transcription factor BMAL1. LncCplx2 is downregulated in the diabetic islets and repressed by high glucose, which regulates the insulin secretion in vitro and ex vivo. Furthermore, LncCplx2 KO mice exhibit diabetic phenotypes, such as high blood glucose and impaired glucose tolerance. Notably, LncCplx2 deficiency has significant effects on circadian behavior, including prolonged period duration, decreased locomotor activity, and reduced metabolic rates. Mechanistically, LncCplx2 recruits EZH2, a core subunit of polycomb repression complex 2 (PRC2), to the promoter of target genes, thereby silencing circadian gene expression, which leads to phase shifts and amplitude changes in insulin secretion and cell cycle genes. CONCLUSIONS: Our results propose LncCplx2 as an unanticipated transcriptional regulator in a circadian system and suggest a more integral mechanism for the coordination of circadian rhythms and glucose homeostasis.

FGF7 enhances the expression of ACE2 in human islet organoids aggravating SARS-CoV-2 infection.

The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in ß cells. This upregulation increases both insulin secretion and susceptibility of ß cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.

A proximity labeling strategy enables proteomic analysis of inter-organelle membrane contacts.

Inter-organelle membrane contacts are highly dynamic and act as central hubs for many biological processes, but the protein compositions remain largely unknown due to the lack of efficient tools. Here, we developed BiFCPL to analyze the contact proteome in living cells by a bimolecular fluorescence complementation (BiFC)-based proximity labeling (PL) strategy. BiFCPL was applied to study mitochondria-endoplasmic reticulum contacts (MERCs) and mitochondria-lipid droplet (LD) contacts. We identified 403 highly confident MERC proteins, including many transiently resident proteins and potential tethers. Moreover, we demonstrated that mitochondria-LD contacts are sensitive to nutrient status. A comparative proteomic analysis revealed that 60 proteins are up- or downregulated at contact sites under metabolic challenge. We verified that SQLE, an enzyme for cholesterol synthesis, accumulates at mitochondria-LD contact sites probably to utilize local ATP for cholesterol synthesis. This work provides an efficient method to identify key proteins at inter-organelle membrane contacts in living cells.

Effective Connectivity Analysis and Classification of Action Observation From Different Perspectives: An fMRI Study.

OBJECTIVE: Analyzing the effective connectivity characteristics of brain networks in the process of action observation is helpful for understanding the neurodynamic mechanisms during action observation. METHOD: In this study, functional magnetic resonance imaging (fMRI) images were obtained from 20 participants who performed hand-object interaction observation tasks from the first-person perspective (1PP) and third-person perspective (3PP). On the basis of a meta-analysis, 11 key brain regions were extracted as nodes to build an action observation network. The weighted and directional connections between all of the nodes were investigated using partial directional coherence (PDC) analysis in five narrow frequency bands. RESULTS: The statistical analysis indicated that the ultra-low frequency band ( ≤ 0.04 Hz) exhibited significant activation compared with other frequency bands for both 1PP and 3PP. In addition, it was found that 3PP induced significantly stronger brain activation than 1PP in the ultra-low frequency band. Moreover, this study attempted to classify fMRI data corresponding to different perspectives using brain network features. A comparative analysis revealed that the weighted and binary PDC matrix methods achieved classification accuracies of 86.3% and 80.8%, respectively. SIGNIFICANCE: The weighted PDC analysis exhibits a more comprehensive understanding of neural mechanisms during action observation in different visual perspectives. It also has potential applications value in human-computer interaction in the future.

Zinc oxide nanoparticles induce toxicity in diffuse large B-cell lymphoma cell line U2932 via activating PINK1/Parkin-mediated mitophagy.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. Zinc oxide (ZnO) nanoparticles have excellent anti-tumor properties in the biomedical field. The present study aimed to explore the underlying mechanism by which ZnO nanoparticles induce toxicity in DLBCL cells (U2932) via the PINK1/Parkin-mediated mitophagy pathway. After U2932 cells were exposed to various concentrations of ZnO nanoparticles, the cell survival rate, reactive oxygen species (ROS) generation, cell cycle arrest, and changes in the expression of PINK1, Parkin, P62, and LC3 were monitored. Moreover, we investigated monodansylcadaverine (MDC) fluorescence intensity and autophagosome and further validated the results using the autophagy inhibitor 3-methyladenine (3-MA). The results showed that ZnO nanoparticles could effectively inhibit the proliferation of U2932 cells and induce cell cycle arrest at the G0/G1 phases. Moreover, ZnO nanoparticles significantly increased ROS production, MDC fluorescence intensity, autophagosome formation, and the expression of PINK1, Parkin, and LC3, and decreased the expression of P62 in U2932 cells. In contrast, the autophagy level was reduced after the intervention of the 3-MA. Overall, ZnO nanoparticles can trigger PINK1/Parkin-mediated mitophagy signaling in U2932 cells, which may be a potential therapeutic approach for DLBCL.

Single particle tracking reveals SARS-CoV-2 regulating and utilizing dynamic filopodia for viral invasion.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry mechanism has been explored, little is known about how SARS-CoV-2 regulates the subcellular structural remodeling to invade multiple organs and cell types. Here, we unveil how SARS-CoV-2 boosts and utilizes filopodia to enter the target cells by real-time imaging. Using SARS-CoV-2 single virus-like particle (VLP) tracking in live cells and sparse deconvolution algorithm, we uncover that VLPs utilize filopodia to reach the entry site in two patterns, "surfing" and "grabbing", which avoid the virus from randomly searching on the plasma membrane. Moreover, combining mechanical simulation, we elucidate that the formation of virus-induced filopodia and the retraction speed of filopodia depend on cytoskeleton dynamics and friction resistance at the substrate surface caused by loading-virus gravity, respectively. Further, we discover that the entry process of SARS-CoV-2 via filopodia depends on Cdc42 activity and actin-associated proteins fascin, formin, and Arp2/3. Together, our results highlight that the spatial-temporal regulation of actin cytoskeleton by SARS-CoV-2 infection makes filopodia as a highway for virus entry and potentiates it as an antiviral target.

High Expression of ACOT2 Predicts Worse Overall Survival and Abnormal Lipid Metabolism: A Potential Target for Acute Myeloid Leukemia.

Acyl-CoA thioesterase (ACOT) plays a considerable role in lipid metabolism, which is closely related to the occurrence and development of cancer, nevertheless, its role has not been fully elucidated in acute myeloid leukemia (AML). To explore the role of ACOT2 in AML and to provide a potential therapeutic target for AML, the expression pattern of ACOT was investigated based on the TNMplot, Gene Expression Profiling Interactive Analysis (GEPIA), and Cancer Cell Line Encyclopedia (CCLE) database, and diagnostic value, prognostic value, and clinical phenotype of ACOT were explored based on data from The Cancer Genome Atlas (TCGA). Functional annotation and enrichment analysis of the common targets between ACOT2 coexpressed and AML-related genes were further performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses. The protein-protein interaction (PPI) network of ACOT2 coexpressed genes and functional ACOT2-related metabolites association network were constructed based on GeneMANIA and Human Metabolome Database. Among ACOTs, ACOT2 was highly expressed in AML compared to normal control subjects according to TNMplot, GEPIA, and CCLE database, which was significantly associated with poor overall survival (OS) in AML (P=0.003). Moreover, ACOT2 exhibited excellent diagnostic efficiency for AML (AUC: 1.000) and related to French-American-British (FAB) classification and cytogenetics. GO, KEGG, and GSEA analyses of 71 common targets between ACOT2 coexpressed and AML-related genes revealed that ACOT2 is closely related to ACOT1, ACOT4, enoyl-acyl carrier protein reductase, mitochondrial (MECR), puromycin-sensitive aminopeptidase (NPEPPS), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and long-chain fatty acid-CoA ligase 1 (ACSL1) in PPI network, and plays a significant role in lipid metabolism, that is, involved in fatty acid elongation and biosynthesis of unsaturated fatty acids. Collectively, the increase of ACOT2 may be an important characteristic of worse OS and abnormal lipid metabolism, suggesting that ACOT2 may become a potential therapeutic target for AML.

Clinical significance and potential mechanism of heat shock factor 1 in acute myeloid leukemia.

BACKGROUND: Heat shock factor 1 (HSF1) is now considered to have the potential to be used as a prognostic biomarker in cancers. However, its clinical significance and potential function in acute myeloid leukemia (AML) remain underexplored. METHODS: In this study, the expression pattern and clinical significance of HSF1 in AML were examined by integrating data from databases including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), Vizome, Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO). Linkedomics was applied to collect HSF1-related genes in AML. GeneMANIA was applied to outline HSF1-related functional networks. CancerSEA analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) were performed to mine the potential mechanism of HSF1 in leukemogenesis. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to explore the correlation between HSF1 and infiltrating immune cells in AML. RESULTS: HSF1 expression was elevated in AML compared to healthy controls and indicate a poor overall survival. HSF1 expression was significantly correlated with patients age, associated with patient survival in subgroup of bone marrow blasts (%) >20. Functional analyses indicated that HSF1 plays a role in the metastatic status of AML, and is involved in inflammation-related pathways and biological processes. HSF1 expression was significantly correlated with the immune infiltration of nature killer cells and T cell population. CONCLUSION: HSF1 plays a vital role in the molecular network of AML pathogenesis, and has the potential to be a biomarker for prognosis prediction.

Nutritional assessment of patients with aplastic anemia: comparison of four nutritional screening tools.

Introduction: Introduction: nutritional status can affect the treatment of hospitalized patients, and malnutrition can even lead to death. However, the nutritional status of patients with aplastic anemia (AA) is unclear. Objective: to assess the nutritional status of aplastic anemia patients with body mass index (BMI) ≥ 24 kg/m2 (high BMI group) and BMI < 24 kg/m2 (low BMI group), and to compare the consistency between different nutritional screening tools. Methods: patients with aplastic anemia hospitalized from January 2016 to December 2020 were collected. We used the combined index generated by Nutritional Risk Index (NRI), Prognostic Nutritional Index (PNI), Control Nutritional Status (CONUT) and Instant Nutritional Assessment (INA) to assess nutritional status of patients with aplastic anemia. Kappa index was used to measure the consistency between different nutritional screening tools. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of different nutritional screening tools. Results: one hundred and ninety-five patients with aplastic anemia were enrolled. The overall prevalence of malnutrition calculated by the combined index in patients with aplastic anemia was 51.3 %. The malnutrition rates of patients in the low BMI group and high BMI group were 60.9 % and 38.8 %, respectively. The malnutrition rates of very severe aplastic anemia (VSAA) patients, severe aplastic anemia (SAA) patients and ordinary patients were 76 %, 63.8 % and 45.1 %, respectively. Compared with the combined index, NRI had the highest consistency and area under the curve. Conclusions: the nutritional status of patients with aplastic anemia was very poor; the more serious the disease, the worse the nutritional status. Although the malnutrition rate in the low-BMI group was higher than in the high BMI group, the nutritional status of overweight or obese patients can not be ignored. NRI is the best tool for assessing the nutritional status of patients with aplastic anemia.

Introducción: Introducción: el estado nutricional puede afectar el tratamiento de los pacientes hospitalizados y la malnutrición puede incluso causar la muerte. Sin embargo, el estado nutricional de los pacientes con anemia aplásica (AA) no está claro. Objetivo: evaluar el estado nutricional de pacientes con anemia aplásica con índice de masa corporal (IMC) ≥ 24 kg/m2 (grupo de IMC mayor) e IMC < 24 kg/m2 (grupo de IMC inferior), y comparar la consistencia entre diferentes herramientas de cribado nutricional. Métodos: se recogieron datos de pacientes con anemia aplásica hospitalizados entre enero de 2016 y diciembre de 2020. El estado nutricional de los pacientes con anemia aplásica se evaluó utilizando un índice compuesto por el índice de riesgo nutricional (NRI), el índice de pronóstico nutricional (PNI), el índice de estado nutricional controlado (CONUT) y la evaluación nutricional instantánea (INA). El índice Kappa se utilizó para medir la coherencia entre los diferentes instrumentos de detección nutricional. Las curvas de características operativas de los sujetos (ROC) se utilizaron para evaluar el valor diagnóstico de las diferentes herramientas de detección nutricional. Resultados: un total de 195 pacientes con anemia aplásica fueron incluidos en el estudio. La prevalencia global de desnutrición calculada por el índice combinado en pacientes con anemia aplásica fue del 51,3 %. Las tasas de desnutrición de los pacientes en el grupo de bajo IMC y el grupo de alto IMC fueron 60,9 % y 38,8 %, respectivamente. Las tasas de desnutrición en pacientes con anemia aplásica muy grave (VSAA), anemia aplásica grave (SAA) y pacientes comunes fueron del 76 %, 63,8 % y 45,1 %, respectivamente. En comparación con el índice compuesto, NRI tiene la mayor consistencia y área bajo la curva. Conclusiones: el estado nutricional de los pacientes con anemia aplásica es muy deficiente; a mayor gravedad de la enfermedad, peor estado nutricional. Aunque la tasa de malnutrición en el grupo con bajo IMC es mayor que en el grupo con alto IMC, no se puede pasar por alto el estado nutricional de los pacientes con sobrepeso u obesidad. El NRI es la mejor herramienta para evaluar el estado nutricional de los pacientes con anemia aplásica.