Utilizing profile hidden Markov model databases for discovering viruses from metagenomic data: a comprehensive review.

Profile hidden Markov models (pHMMs) are able to achieve high sensitivity in remote homology search, making them popular choices for detecting novel or highly diverged viruses in metagenomic data. However, many existing pHMM databases have different design focuses, making it difficult for users to decide the proper one to use. In this review, we provide a thorough evaluation and comparison for multiple commonly used profile HMM databases for viral sequence discovery in metagenomic data. We characterized the databases by comparing their sizes, their taxonomic coverage, and the properties of their models using quantitative metrics. Subsequently, we assessed their performance in virus identification across multiple application scenarios, utilizing both simulated and real metagenomic data. We aim to offer researchers a thorough and critical assessment of the strengths and limitations of different databases. Furthermore, based on the experimental results obtained from the simulated and real metagenomic data, we provided practical suggestions for users to optimize their use of pHMM databases, thus enhancing the quality and reliability of their findings in the field of viral metagenomics.

Reprogramming roadmap reveals route to human induced trophoblast stem cells.

The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development1-6. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas7. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.

Towards more accurate microbial source tracking via non-negative matrix factorization (NMF).

MOTIVATION: The microbiome of a sampled habitat often consists of microbial communities from various sources, including potential contaminants. Microbial source tracking (MST) can be used to discern the contribution of each source to the observed microbiome data, thus enabling the identification and tracking of microbial communities within a sample. Therefore, MST has various applications, from monitoring microbial contamination in clinical labs to tracing the source of pollution in environmental samples. Despite promising results in MST development, there is still room for improvement, particularly for applications where precise quantification of each source's contribution is critical. RESULTS: In this study, we introduce a novel tool called SourceID-NMF towards more precise microbial source tracking. SourceID-NMF utilizes a non-negative matrix factorization (NMF) algorithm to trace the microbial sources contributing to a target sample. By leveraging the taxa abundance in both available sources and the target sample, SourceID-NMF estimates the proportion of available sources present in the target sample. To evaluate the performance of SourceID-NMF, we conducted a series of benchmarking experiments using simulated and real data. The simulated experiments mimic realistic yet challenging scenarios for identifying highly similar sources, irrelevant sources, unknown sources, low abundance sources, and noise sources. The results demonstrate the superior accuracy of SourceID-NMF over existing methods. Particularly, SourceID-NMF accurately estimated the proportion of irrelevant and unknown sources while other tools either over- or under-estimated them. In addition, the noise sources experiment also demonstrated the robustness of SourceID-NMF for MST. AVAILABILITY AND IMPLEMENTATION: SourceID-NMF is available online at https://github.com/ZiyiHuang0708/SourceID-NMF.

A novel tRNA-derived fragment tRF-3023b suppresses inflammation in RAW264.7 cells by targeting Cul4a through NF-κB signaling.

The role of transfer RNA (tRNA)-derived fragment (tRF) in various diseases has been established. However, the effect of tRF-3023b on inflammation remains unclear. Inflammation was imitated in RAW264.7 cells by adding Lipopolysaccharide (LPS). Cells were first divided into control, LPS, and LPS + Bulleyaconitine A (BLA) groups. The contents of TNF-α, IL-6, and MCP-1 were quantified using ELISA. The levels of cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), and the phosphorylation of nuclear factor-kappa B (NF-κB)-P65 (p-P65) were detected by Western blotting. RNA sequencing was utilized to find differentially expressed tRFs (DE-tRFs) among three groups. The levels of various tRFs were checked by quantitative real-time PCR (qRT-PCR). Cell cycle and apoptosis were checked by flow cytometry. Dluciferase reporter assay was applied to predict and confirm the interaction between tRF-3023b and Cullin 4A (Cul4a), subsequently RNA pull-down followed by mass spectrometry analysis were conducted. BLA treatment decreased the contents of TNF-α, IL-6, MCP-1, and the expression levels of COX2, iNOS, p-P65. We found 6 DE-tRFs in LPS + BLA group compared to LPS group, tRF-3023b was high expression in control and BLA groups, and the lowest in LPS group. Cul4a was a direct target of tRF-3023b. tRF-3023b mimic affected the cell cycle distribution, promoted cells apoptosis, and suppressed the TNF-α, IL-6, MCP-1, COX2, iNOS and p-P65. The suppression of Cul4a affected the cell cycle distribution, resulted in an increase of cell apoptosis while a decrease of TNF-α, IL-6, MCP-1, COX2, iNOS and p-P65. Furthermore, Cul4a overexpression reversed the effect of tRF-3023b mimic. Cul4a knockdown reversed the effect of tRF-3023b inhibitor. Our study positions tRF-3023b as a compelling candidate, through its interaction with Cul4a, the underlying mechanism on inflammation maybe related to NF-κB pathway. The study provides a basis for exploring new therapeutic strategies for inflammation.

Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Automated prediction of isthmus areas in scar-related atrial tachycardias using artificial intelligence.

INTRODUCTION: Ablation of scar-related reentrant atrial tachycardia (SRRAT) involves identification and ablation of a critical isthmus. A graph convolutional network (GCN) is a machine learning structure that is well-suited to analyze the irregularly-structured data obtained in mapping procedures and may be used to identify potential isthmuses. METHODS: Electroanatomic maps from 29 SRRATs were collected, and custom electrogram features assessing key tissue and wavefront properties were calculated for each point. Isthmuses were labeled off-line. Training data was used to determine the optimal GCN parameters and train the final model. Putative isthmus points were predicted in the training and test populations and grouped into proposed isthmus areas based on density and distance thresholds. The primary outcome was the distance between the centroids of the true and closest proposed isthmus areas. RESULTS: A total of 193 821 points were collected. Thirty isthmuses were detected in 29 tachycardias among 25 patients (median age 65.0, 5 women). The median (IQR) distance between true and the closest proposed isthmus area centroids was 8.2 (3.5, 14.4) mm in the training and 7.3 (2.8, 16.1) mm in the test group. The mean overlap in areas, measured by the Dice coefficient, was 11.5 ± 3.2% in the training group and 13.9 ± 4.6% in the test group. CONCLUSION: A GCN can be trained to identify isthmus areas in SRRATs and may help identify critical ablation targets.

Functional brain activity is highly associated with cortical myelination in neonates.

Functional organization of the human cerebral cortex is highly constrained by underlying brain structures, but how functional activity is associated with different brain structures during development is not clear, especially at the neonatal stage. Since long-range functional connectivity is far from mature in the dynamically developing neonatal brain, it is of great scientific significance to investigate the relationship between different structural and functional features at the local level. To this end, for the first time, correlation and regression analyses were performed to examine the relationship between cortical morphology, cortical myelination, age, and local brain functional activity, as well as functional connectivity strength using high-resolution structural and resting-state functional MRI data of 177 neonates (29-44 postmenopausal weeks, 98 male and 79 female) from both static and dynamic perspectives. We found that cortical myelination was most strongly associated with local brain functional activity across the cerebral cortex than other cortical structural features while controlling the age effect. These findings suggest the crucial role of cortical myelination in local brain functional development at birth, providing valuable insights into the fundamental biological basis of functional activity at this early developmental stage.

Activity flow mapping over probabilistic functional connectivity.

Emerging evidence indicates that activity flow over resting-state network topology allows the prediction of task activations. However, previous studies have mainly adopted static, linear functional connectivity (FC) estimates as activity flow routes. It is unclear whether an intrinsic network topology that captures the dynamic nature of FC can be a better representation of activity flow routes. Moreover, the effects of between- versus within-network connections and tight versus loose (using rest baseline) task contrasts on the prediction of task-evoked activity across brain systems remain largely unknown. In this study, we first propose a probabilistic FC estimation derived from a dynamic framework as a new activity flow route. Subsequently, activity flow mapping was tested using between- and within-network connections separately for each region as well as using a set of tight task contrasts. Our results showed that probabilistic FC routes substantially improved individual-level activity flow prediction. Although it provided better group-level prediction, the multiple regression approach was more dependent on the length of data points at the individual-level prediction. Regardless of FC type, we consistently observed that between-network connections showed a relatively higher prediction performance in higher-order cognitive control than in primary sensorimotor systems. Furthermore, cognitive control systems exhibit a remarkable increase in prediction accuracy with tight task contrasts and a decrease in sensorimotor systems. This work demonstrates that probabilistic FC estimates are promising routes for activity flow mapping and also uncovers divergent influences of connectional topology and task contrasts on activity flow prediction across brain systems with different functional hierarchies.

Prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

BACKGROUND: Tissue-resident CD8+T cells (CD103+CD8+T cells) are the essential effector cell population of anti-tumor immune response in tissue regional immunity. And we have reported that IL-33 can promote the proliferation and effector function of tissue-resident CD103+CD8+T cells. As of now, the immunolocalization and the prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) still remain to be illustrated. METHODS: In our present study, we used the tissue microarrays of HCC and ICC, the multicolor immunohistochemistry (mIHC), and imaging analysis to characterize the tissue-resident CD8+T cells in HCC and ICC tissues. The prognostic values and clinical associations were also analyzed. We also studied the biological functions and the cell-cell communication between tumor-infiltrating CD103+CD8+T cells and other cell types in HCC and ICC based on the published single-cell RNA sequencing (scRNA-seq) data. RESULTS: Our work unveiled the expressions of CD8 and CD103 and immunolocalization of tissue-resident CD8+T cells in human HCC and ICC. Elevated CD8+T cells indicated a better overall survival (OS) rate, implying that tumor-infiltrating CD8+T cells in HCC and ICC could serve as an independent prognostic factor. Moreover, the number of CD103+CD8+T cells was increased in HCC and ICC tissues compared with adjacent normal tissues. HCC patients defined as CD8highCD103high had a better OS, and the CD8lowCD103low group tended to have a poorer prognosis in ICC. Evaluation of the CD103+CD8+T-cell ratio in CD8+T cells could also be a prognostic predictor for HCC and ICC patients. A higher ratio of CD103+CD8+T cells over total CD8+T cells in HCC tissues was negatively and significantly associated with the advanced pathological stage. The percentage of higher numbers of CD103+CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In contrast, the higher ratio of CD103+CD8+T cells over total CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In addition, single-cell transcriptomics revealed that CD103+CD8+T cells were enriched in genes associated with T-cell activation, proliferation, cytokine function, and T-cell exhaustion. CONCLUSION: The CD103+ tumor-specific T cells signified an important prognostic marker with improved OS, and the evaluation of the tissue-resident CD103+CD8+T cells might be helpful in assessing the on-treatment response of liver cancer.

Comprehensive evaluation of the risk system for heavy metals in the rehabilitated saline-alkali land.

A comprehensive assessment of the heavy metal system in the rehabilitated saline-alkali land holds significant importance, as the in-situ remediation process utilizing amendments substantially alters the initial physicochemical properties of the soil, which could lead to the migration or reactivation of previously stabilized heavy metals. In this context, the present study aims to evaluate the heavy metal content and health risk within the improved saline-alkali soil-plant system. Moreover, a comprehensive evaluation based on the TOPSIS-RSR method is carried out to accurately gauge the soil health status. The findings indicate that the modification process has an impact on the concentrations of heavy metals in the soil and crops, causing either an increase or decrease. However, the level of heavy metal pollution in the improved saline-alkali soil and rape remains within safe limits. The results of the migration of heavy metals after amendment application indicated that the migration of heavy metals in the soil was influenced by the properties of the heavy metals, the composition of the amendment, and leaching. Furthermore, the total non-carcinogenic hazard quotients in the soil and rape were within the safe threshold for all populations. The findings provided novel insights into the status and risk assessment of the pollution of improved saline-alkali soil.

Light transmission mechanisms in a SMF-capillary fiber-SMF structure and its application to bi-directional liquid level measurement.

Capillary fiber (CF) has been extensively investigated in a singlemode fiber (SMF)-CF-SMF (SCS) sensing structure since multiple light guiding mechanisms can be easily excited by simply tuning the air core diameter (cladding diameter) and length of the CF. Understanding the light guiding principles in an SCS structure is essential for improved implementation of a CF based fiber sensor. In this work, light guiding principles in a relatively large air core diameter (≥ 20 µm) and long length of CF (> 1 mm) are investigated theoretically and experimentally. It is found that both multimode interference (MMI) and Anti-Resonant Reflecting Optical Waveguide (ARROW) light guiding mechanisms are excited in the SCS structure in the transmission configuration. However, MMI dips are not observed in the spectrum for the air core diameters of CF smaller than 50 µm in the experiment due to large transmission loss in small air core CFs. Further experimental results demonstrate that a CF with a bigger air core diameter shows a higher sensitivity to curvature, and the highest sensitivity of -16.15 nm/m-1 is achieved when an CF-100 was used. In addition, a SMF-CF-20-CF-30-SMF (SCCS) structure is proposed for high sensitivity bi-direction liquid level measurement for the first time, to the best of our knowledge. Two types of ARROW dips (Dip-20 and Dip-30) are simultaneously excited in transmission, hence both liquid level and liquid flow direction can be detected by tracing the dip strength changes of Dip-20 and Dip-30, respectively.

Construction of multiple anti-resonant light guidance mechanisms in a hollow-core fiber structure for simultaneous measurement of multiple parameters.

The construction of multiple light guidance mechanisms in a hollow-core fiber (HCF) structure is a popular way to realize the simultaneous measurement of multiple parameters. In this work, a partial coating method to excite multiple anti-resonant light guidance mechanisms (ARLGMs) in an HCF structure for the simultaneous measurement of multiple parameters is proposed. As an example, a double ARLGM based on a partially polyimide (PI)-coated HCF structure for the simultaneous measurement of relative humidity (RH) and temperature is demonstrated theoretically and experimentally. The dip (dip II) produced by the PI-coated HCF section shifts linearly with surrounding RH changes with a sensitivity of circa 58.6 ± 0.77 pm/%RH, while the dip (dip I) produced by the bare HCF section (with an air coating layer) is insensitive to RH changes. In addition, both types of dips have linear responses to temperature variations, with similar sensitivities of ∼ 17 pm/°C. Hence, the proposed sensor structure can be used as an RH sensor that is also capable of compensating for local temperature fluctuations. More importantly, the simultaneous measurement of multiple parameters (such as biomarkers) is possible using the proposed method provided the proper sensing materials are partially coated onto the HCF surface.

Anti-L1 antibody-bound HPV16 pseudovirus is degraded intracellularly via TRIM21/proteasomal pathway.

BACKGROUND: Persistent HPV16 infection is the leading risk factor for developing cervical cancer. Anti-L1 antibodies against HPV16 produced in HPV16 infections play diverse roles in the clearance of virus infection and prevention of persistence. It has been implicated that the cervicovaginal squamous epithelial cells actually express TRIM21 and that some HPV16 particles could escape leaky endosomal compartment into the cytosol and that Fc receptor TRIM21 directly neutralize infection by targeting antibody-opsonized viruses for proteasomal degradation. We explored whether anti-L1 antibody opsonized HPV16 pseudovirus (PsV) entered into the cytosol could be neutralized by TRIM21-mediated activation of a proteasomal pathway to reduce the chance of persistent HPV16 infection. METHODS: HPV16 PsV were generated and extracted in HEK 293FT cells co-transfected with pcDNA3.1-eGFP and p16sheLL plasmids according to the standard protocol. The HPV16 PsV with capsid protein L1 was characterized by fluorescence microscopy and western blot, and the HPV16 PsV titer and anti-L1-bound PsV entry efficiency were detected by flow cytometry. The expressions of transcription factors (TF) and cytokines elicited by the TRIM21-activated proteasomal pathway were confirmed by dual-luciferase reporter assay and RT-qPCR. The changes in HPV16 PsV load with or without inhibitors in the infected HEK 293FT cells were determinated by qPCR. RESULTS: Simultaneous transfection with pcDNA3.1-eGFP and p16sheLL plasmids into the HEK 293FT cells resulted in the self-assembly of HPV16 PsV with capsid protein L1. Both HPV16 PsV and anti-L1-bound HPV16 PsV could infect HEK 293FT cells. Anti-L1-bound PsV up-regulated TRIM21 mediated-activation of proteasome and increased expressions of TF and cytokines in the infected cells where HPV16 PsV load reduced by ~ 1000-fold in the presence of anti-L1 antibody, but inhibition of proteasomal activity increased HPV16 PsV load. CONCLUSION: Our preliminary results indicate that anti-L1 antibody entered with HPV16 PsV into the cells could mediate degradation of HPV16 PsV by TRIM21-activated proteasomal pathway intracellularly, giving anti-capsid protein L1 antibody a role in host defense of persistent HPV16 infection.

Synthesis of spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones through gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered indoles.

A variety of functionalized spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones were prepared in good to excellent yields through a gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered C2-substituted indoles. This reaction features a broad substrate scope, good functional group tolerance, and easy gram-scale preparation and transformations. Furthermore, biological activity studies showed that most of the obtained spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinone scaffolds showed potential as good anti-inflammatory agents.

Association of somatic mutations in BRCA2 BRC domain with chemotherapy sensitivity and survival in high grade serous ovarian cancer.

BACKGROUND: Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer (HGSOC). METHODS: We identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: 21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P = 0.000), PFS (43 vs 14 months, p = 0.000) and OS (56 vs 31 months, P = 0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P = 0.044), PFS (21 vs 14 months, P = 0.049) and OS (38 vs 31 months, P = 0.037), compared to those without any mutation. CONCLUSIONS: Somatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC.

A Novel Epidemic Model Base on Pulse Charging in Wireless Rechargeable Sensor Networks.

As wireless rechargeable sensor networks (WRSNs) are gradually being widely accepted and recognized, the security issues of WRSNs have also become the focus of research discussion. In the existing WRSNs research, few people introduced the idea of pulse charging. Taking into account the utilization rate of nodes' energy, this paper proposes a novel pulse infectious disease model (SIALS-P), which is composed of susceptible, infected, anti-malware and low-energy susceptible states under pulse charging, to deal with the security issues of WRSNs. In each periodic pulse point, some parts of low energy states (LS nodes, LI nodes) will be converted into the normal energy states (S nodes, I nodes) to control the number of susceptible nodes and infected nodes. This paper first analyzes the local stability of the SIALS-P model by Floquet theory. Then, a suitable comparison system is given by comparing theorem to analyze the stability of malware-free T-period solution and the persistence of malware transmission. Additionally, the optimal control of the proposed model is analyzed. Finally, the comparative simulation analysis regarding the proposed model, the non-charging model and the continuous charging model is given, and the effects of parameters on the basic reproduction number of the three models are shown. Meanwhile, the sensitivity of each parameter and the optimal control theory is further verified.

Resourcing, annotating, and analysing synthetic peptides of SARS-CoV-2 for immunopeptidomics and other immunological studies.

SARS-CoV-2 has caused a significant ongoing pandemic worldwide. A number of studies have examined the T cell mediated immune responses against SARS-CoV-2, identifying potential T cell epitopes derived from the SARS-CoV-2 proteome. Such studies will aid in identifying targets for vaccination and immune monitoring. In this study, we applied tandem mass spectrometry and proteomic techniques to a library of ∼40,000 synthetic peptides, in order to generate a large dataset of SARS-CoV-2 derived peptide MS/MS spectra. On this basis, we built an online knowledgebase, termed virusMS (https://virusms.erc.monash.edu/), to document, annotate and analyse these synthetic peptides and their spectral information. VirusMS incorporates a user-friendly interface to facilitate searching, browsing and downloading the database content. Detailed annotations of the peptides, including experimental information, peptide modifications, predicted peptide-HLA (human leukocyte antigen) binding affinities, and peptide MS/MS spectral data, are provided in virusMS.

Time-varying effects of FOXA1 on breast cancer prognosis.

PURPOSE: Results of previous studies on the associations between Forkhead box A1 (FOXA1) expression in breast cancer tissues and the prognosis varied depending on the follow-up durations. The present study would investigate whether there is a time-varying effect of FOXA1 in breast cancer tissues on the prognosis. METHODS: FOXA1 expressions were evaluated in 1041 primary invasive breast tumors with tissue microarrays by immunohistochemistry. Cox models with restricted cubic splines and Kaplan-Meier survival analysis were used to examine the associations between FOXA1 and the prognosis. Flexible parametric models were applied to explore the time-varying effect of FOXA1. RESULTS: Overall, the association between FOXA1 expression and the prognosis was not significant but varied on the time of follow-up. Compared to FOXA1 ≤ 270 of H-score, the hazard ratios (HRs) of death for those with 271-285 of FOXA1 expression increased from 0.35 (95% CI 0.14-0.86) at 6 months after diagnosis to 2.88 (95% CI 1.35-6.15) at 120 months with a crossover at around 36 months. Similar patterns were also observed for FOXA1 > 285 of H-score and for progression free survival (PFS). Moreover, when allowed both FOXA1 and estrogen receptor (ER) to change over time in the model (considering that ER had a similar time-varying effect), these time-varying effects remained for FOXA1 on both overall survival (OS) (P < 0.01) and PFS (P = 0.01) but were attenuated for ER (P = 0.13 for OS). CONCLUSIONS: This study revealed an independent time-varying effect of FOXA1 on breast cancer prognosis, which would provide an insight into the roles of FOXA1 as a marker of breast cancer prognosis and may help optimize the medication strategies.

NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the ß-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition.

Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of ß-catenin was reversed by proteasome inhibitor via the ß-catenin/ GSK3ß signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the ß-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.

Modelling and Analysis of the Epidemic Model under Pulse Charging in Wireless Rechargeable Sensor Networks.

With the development of wireless sensor networks (WSNs), energy constraints and network security have become the main problems. This paper discusses the dynamic of the Susceptible, Infected, Low-energy, Susceptible model under pulse charging (SILS-P) in wireless rechargeable sensor networks. After the construction of the model, the local stability and global stability of the malware-free T-period solution of the model are analyzed, and the threshold R0 is obtained. Then, using the comparison theorem and Floquet theorem, we obtain the relationship between R0 and the stability. In order to make the conclusion more intuitive, we use simulation to reveal the impact of parameters on R0. In addition, the paper discusses the continuous charging model, and reveals its dynamic by simulation. Finally, the paper compares three charging strategies: pulse charging, continuous charging and non-charging and obtains the relationship between their threshold values and system parameters.