Merging logical models: An application in Acute Myeloid Leukemia modeling.

Gene regulatory network (GRNs) models provide mechanistic understanding of the gene regulations and interactions that control various aspects of cellular behaviors. While researchers have constructed GRNs to model specific sets of gene regulations or interactions, little work has been made to integrate or merge these models into larger, more comprehensive ones that could encompass more genes, and improve the accuracy of predicting biological processes. Here, we present a workflow for merging logical GRN models, which requires sequential steps including model standardization, reproducing, merging and evaluations, and demonstrate its application in acute myeloid leukemia (AML) study. We demonstrate the feasibility and benefits of model merging by integrating two pairs of published models. Our integrated models were able to retain similar accuracy of the original publications, while increasing the coverage and explainability of the biological system. This approach highlights the integration of logical models in advancing system biology and enhancing the understanding of complex diseases. Author summary: In our study, we tackle the challenges of integrating gene regulatory network (GRN) models to enhance our understanding of complex biological systems. GRNs are essential tools for understanding how genes regulate various cellular behaviors, but individual models often focus on specific sets of genes or interactions. We present a novel workflow that merges these individual logical GRN models into more comprehensive ones, providing a broader view of gene regulation. We applied this workflow to Acute Myeloid Leukemia (AML), a highly aggressive form of blood cancer. AML is challenging to treat due to its genetic complexity and the frequent occurrence of treatment-resistant mutations. Our integrated models retain the accuracy of the original models while offering improved coverage of the biological processes. This approach offers valuable insights into the disease's underlying mechanisms through a combination of models that describe different aspects of AML. We envision that the proposed workflow will improve predictions, generate deeper insights, and improve our understanding and treatment of complex diseases like AML.

Towards optimized methodological parameters for maximizing the behavioral effects of transcranial direct current stimulation.

Introduction: Transcranial direct current stimulation (tDCS) administers low-intensity direct current electrical stimulation to brain regions via electrodes arranged on the surface of the scalp. The core promise of tDCS is its ability to modulate brain activity and affect performance on diverse cognitive functions (affording causal inferences regarding regional brain activity and behavior), but the optimal methodological parameters for maximizing behavioral effects remain to be elucidated. Here we sought to examine the effects of 10 stimulation and experimental design factors across a series of five cognitive domains: motor performance, visual search, working memory, vigilance, and response inhibition. The objective was to identify a set of optimal parameter settings that consistently and reliably maximized the behavioral effects of tDCS within each cognitive domain. Methods: We surveyed tDCS effects on these various cognitive functions in healthy young adults, ultimately resulting in 721 effects across 106 published reports. Hierarchical Bayesian meta-regression models were fit to characterize how (and to what extent) these design parameters differentially predict the likelihood of positive/negative behavioral outcomes. Results: Consistent with many previous meta-analyses of tDCS effects, extensive variability was observed across tasks and measured outcomes. Consequently, most design parameters did not confer consistent advantages or disadvantages to behavioral effects-a domain-general model suggested an advantage to using within-subjects designs (versus between-subjects) and the tendency for cathodal stimulation (relative to anodal stimulation) to produce reduced behavioral effects, but these associations were scarcely-evident in domain-specific models. Discussion: These findings highlight the urgent need for tDCS studies to more systematically probe the effects of these parameters on behavior to fulfill the promise of identifying causal links between brain function and cognition.

The Educational Function of English Children's Movies From the Perspective of Multiculturalism Under Deep Learning and Artificial Intelligence.

In children's learning subjects, English courses has its relative particularity compared with Chinese courses and the mathematics. Children's English teaching is often inefficient because of the lack of students' timely consolidation after class. Given this, the present work starts with the analysis of the current situation of children's learning, and introduces the film-assisted English teaching. In the specific teaching links, English teaching is carried out in a three-dimensional teaching mode. Before that, topics of the films are selected for the English teaching, and the films are edited and processed. Initially, the present work expounds the English children's films and their educational functions. Then, children can obtain teaching effect from the films. An English questionnaire is designed to analyze the application effect of English films in children's English teaching. The results show that the film teaching mode improves children's learning interest and motivation, and English film teaching can stimulate students' learning interest. Students are also more active to participate in teaching activities, thus improving their language skills. Under the teaching in the scenes of films, students can perceive the functions of language in certain contexts. Comprehensible language input promotes students' English listening ability and oral expression ability. The films can intuitively show the humanistic style, historical geography, cultures, and customs of English countries, and then cultivate students' western cultural literacy. Practice has proved that the method proposed here can achieve good teaching effect, and it provides certain references for children's English education.

Novel gRNA design pipeline to develop broad-spectrum CRISPR/Cas9 gRNAs for safe targeting of the HIV-1 quasispecies in patients.

The CRISPR/Cas9 system has been proposed as a cure strategy for HIV. However, few published guide RNAs (gRNAs) are predicted to cleave the majority of HIV-1 viral quasispecies (vQS) observed within and among patients. We report the design of a novel pipeline to identify gRNAs that target HIV across a large number of infected individuals. Next generation sequencing (NGS) of LTRs from 269 HIV-1-infected samples in the Drexel CARES Cohort was used to select gRNAs with predicted broad-spectrum activity. In silico, D-LTR-P4-227913 (package of the top 4 gRNAs) accounted for all detectable genetic variation within the vQS of the 269 samples and the Los Alamos National Laboratory HIV database. In silico secondary structure analyses from NGS indicated extensive TAR stem-loop malformations predicted to inactivate proviral transcription, which was confirmed by reduced viral gene expression in TZM-bl or P4R5 cells. Similarly, a high sensitivity in vitro CRISPR/Cas9 cleavage assay showed that the top-ranked gRNA was the most effective at cleaving patient-derived HIV-1 LTRs from five patients. Furthermore, the D-LTR-P4-227913 was predicted to cleave a median of 96.1% of patient-derived sequences from other HIV subtypes. These results demonstrate that the gRNAs possess broad-spectrum cutting activity and could contribute to an HIV cure.

Functional Studies of CCAAT/Enhancer Binding Protein Site Located Downstream of the Transcriptional Start Site.

Previous studies have identified a CCAAT/enhancer binding protein (C/EBP) site located downstream of the transcriptional start site (DS3). The role of the DS3 element with respect to HIV-1 transactivation by Tat and viral replication has not been characterized. We have demonstrated that DS3 was a functional C/EBPß binding site and mutation of this site to the C/EBP knockout DS3-9C variant showed lower HIV-1 long terminal repeat (LTR) transactivation by C/EBPß. However, it was able to exhibit similar or even higher transcription levels by Tat compared to the parental LTR. C/EBPß and Tat together further enhanced the transcription level of the parental LAI-LTR and DS3-9C LTR, with higher levels in the DS3-9C LTR. HIV molecular clone viruses carrying the DS3-9C variant LTR demonstrated a decreased replication capacity and delayed rate of replication. These results suggest that DS3 plays a role in virus transcriptional initiation and provides new insight into C/EBP regulation of HIV-1.

Facet Engineered Interface Design of Plasmonic Metal and Cocatalyst on BiOCl Nanoplates for Enhanced Visible Photocatalytic Oxygen Evolution.

Integration of plasmonic metal and cocatalyst with semiconductor is a promising approach to simultaneously optimize the generation, transfer, and consumption of photoinduced charge carriers for high-performance photocatalysis. The photocatalytic activities of the designed hybrid structures are greatly determined by the efficiencies of charge transfer across the interfaces between different components. In this paper, interface design of Ag-BiOCl-PdOx hybrid photocatalysts is demonstrated based on the choice of suitable BiOCl facets in depositing plasmonic Ag and PdOx cocatalyst, respectively. It is found that the selective deposition of Ag and PdOx on BiOCl(110) planes realizes the superior photocatalytic activity in O2 evolution compared with the samples with other Ag and PdOx deposition locations. The reason was the superior hole transfer abilities of Ag-(110)BiOCl and BiOCl(110)-PdOx interfaces in comparison with those of Ag-(001)BiOCl and BiOCl(001)-PdOx interfaces. Two effects are proposed to contribute to this enhancement: (1) stronger electronic coupling at the BiOCl(110)-based interfaces resulted from the thinner contact barrier layer and (2) the shortest average hole diffuse distance realized by Ag and PdOx on BiOCl(110) planes. This work represents a step toward the interface design of high-performance photocatalyst through facet engineering.

cAMP Signaling Enhances HIV-1 Long Terminal Repeat (LTR)-directed Transcription and Viral Replication in Bone Marrow Progenitor Cells.

CD34+ hematopoietic progenitor cells have been shown to be susceptible to HIV-1 infection, possibly due to a low-level expression of CXCR4, a coreceptor for HIV-1 entry. Given these observations, we have explored the impact of forskolin on cell surface expression of CXCR4 in a cell line model (TF-1). The elevation of intracellular cyclic adenosine monophosphate (cAMP) by forskolin through adenylyl cyclase (AC) resulted in transcriptional upregulation of CXCR4 with a concomitant increase in replication of the CXCR4-utilizing HIV-1 strain IIIB. Transient expression analyses also demonstrated an increase in CXCR4-, CCR5-, and CXCR4-/CCR5-utilizing HIV-1 (LAI, YU2, and 89.6, respectively) promoter activity. Studies also implicated the protein kinase A (PKA) pathway and the downstream transcription factor CREB-1 in interfacing with cAMP response elements located in the CXCR4 and viral promoter. These observations suggest that the cAMP signaling pathway may serve as a regulator of CXCR4 levels and concomitantly of HIV-1 replication in bone marrow (BM) progenitor cells.

Contrast-enhanced Spectral Mammography: Modality-Specific Artifacts and Other Factors Which May Interfere with Image Quality.

RATIONALE AND OBJECTIVES: Contrast-enhanced spectral mammography (CESM) uses full field digital mammography with the added benefit of intravenous contrast administration to significantly reduce false-positive and false-negative results and improve specificity while maintaining high sensitivity. For CESM to fulfill its purpose, one should be aware of possible artifacts and other factors which may interfere with image quality, and attention should be taken to minimize these factors. MATERIALS AND METHODS: This pictorial demonstration will depict types of artifacts detected and other factors that interfere with image acquisition in our practice since CESM implementation. RESULTS: Many of the artifacts and other factors we have encountered while using CESM have simple solutions to resolve them. CONCLUSION: The illustrated artifacts and other factors interfering with image quality will serve as a useful reference to anyone using CESM.

Modeling Bone Marrow Progenitor Cell Differentiation and Susceptibility to HIV-1 Infection.

Human immunodeficiency virus type 1 (HIV-1) infection of the monocytic lineage is involved in the pathologic events associated with AIDS and HIV-1-associated dementia (HAD). Hematopoietic progenitor cells (HPCs) within the bone marrow are refractile to HIV-1 infection, while their progeny of the monocyte-macrophage lineage are susceptible. Previous studies, using phorbol-myristate-acetate (PMA) as a differentiating agent, have suggested that the CD34+/CD38+ TF-1 cell line may be used as one model to study the differentiation processes of HPCs. In the present study, medium that has been conditioned by PMA-treated TF-1 cells but is devoid of any traces of PMA, was utilized to induce differentiation of TF-1 cells. The conditioned medium (CM) from this bone marrow-derived cell population is enriched with respect to numerous cytokines and induces differentiation and activation of TF-1 cells, as indicated by changes in the expression of CD34, CD38, and CD69 cell surface molecules. Furthermore, treatment with CM was also shown to induce the expression of CCR5 and CXCR4, while maintaining the expression of CD4, which was ultimately correlated with increased susceptibility to HIV-1. Additionally, the activation of the TF-1 cells was shown to lead to increased LTR activity, with specificity protein (Sp) and nuclear factor kappa-light-chain-enhancer of activated B cells) NF-κB factors playing a crucial role in HIV-1 long terminal repeat (LTR)-mediated transcription and possibly overall TF-1 permissivity. Interleukin (IL)-1ß, which is elevated in the CM, recapitulates some of the CM effects. In summary, these studies suggest that the TF-1 cell line could serve as a model to study the susceptibility of bone marrow progenitor cells to HIV-1 infection.

Impact of Tat Genetic Variation on HIV-1 Disease.

The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation within tat of different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability within tat may impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.

Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment.

The long terminal repeat (LTR) regulates gene expression of HIV-1 by interacting with multiple host and viral factors. Cross-sectional studies in the pre-HAART era demonstrated that single nucleotide polymorphisms (SNPs) in peripheral blood-derived LTRs (a C-to-T change at position 3 of C/EBP site I (3T) and at position 5 of Sp site III (5T)) increased in frequency as disease severity increased. Additionally, the 3T variant correlated with HIV-1-associated dementia. LTR sequences derived by longitudinal sampling of peripheral blood from a single patient in the DrexelMed HIV/AIDS Genetic Analysis Cohort resulted in the detection of the 3T and 5T co-selected SNPs before the onset of neurologic impairment, demonstrating that these SNPs may be useful in predicting HIV-associated neurological complications. The relative fitness of the LTRs containing the 3T and/or 5T co-selected SNPs as they evolve in their native patient-derived LTR backbone structure demonstrated a spectrum of basal and Tat-mediated transcriptional activities using the IIIB-derived Tat and colinear Tat derived from the same molecular clone containing the 3T/5T LTR SNP. In silico predictions utilizing colinear envelope sequence suggested that the patient's virus evolved from an X4 to an R5 swarm prior to the development of neurological complications and more advanced HIV disease. These results suggest that the HIV-1 genomic swarm may evolve during the course of disease in response to selective pressures that lead to changes in prevalence of specific polymorphisms in the LTR, env, and/or tat that could predict the onset of neurological disease and result in alterations in viral function.

Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency virus type 1 subtype C LTR.

Human immunodeficiency virus type 1 (HIV-1) subtype C, which is most predominant in sub-Saharan Africa as well as in Asia and India, is the most prevalent subtype worldwide. A large number of transcription factor families have been shown to be involved in regulating HIV-1 gene expression in T lymphocytes and cells of the monocyte-macrophage lineage. Among these, proteins of the CCAAT/enhancer binding protein (C/EBP) family are of particular importance in regulating HIV-1 gene expression within cells of the monocytic lineage during the course of hematologic development and cellular activation. Few studies have examined the role of C/EBPs in long terminal repeat (LTR)-directed viral gene expression of HIV-1 subtypes other than subtype B. Within subtype B viruses, two functional C/EBP sites located upstream of the TATA box are required for efficient viral replication in cells of the monocyte-macrophage lineage. We report the identification of three putative subtype C C/EBP sites, upstream site 1 and 2 (C-US1 and C-US2) and downstream site 1 (C-DS1). C-US1 and C-DS1 were shown to form specific DNA-protein complexes with members of the C/EBP family (C/EBPα, ß, and δ). Functionally, within the U-937 monocytic cell line, subtype B and C LTRs were shown to be equally responsive to C/EBPß-2, although the basal activity of subtype C LTRs appeared to be higher. Furthermore, the synergistic interaction between C/EBPß-2 and Tat with the subtype C LTR was also observed in U-937 cells as previously demonstrated with the subtype B LTR.