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IntroductionDendrolimus punctatus, a major pest endemic to the native Pinus massoniana forests in China, displays major outbreak characteristics and causes severe destructiveness. In the context of global climate change, this study aims to investigate the effects of climatic variations on the distribution of D. punctatus and its host, P. massoniana. MethodsWe predict their potential suitable distribution areas in the future, thereby offering a theoretical basis for monitoring and controlling D. punctatus, as well as conserving P. massoniana forest resources. By utilizing existing distribution data on D. punctatus and P. massoniana, coupled with relevant climatic variables, this study employs an optimized maximum entropy (MaxEnt) model for predictions. With feature combinations set as linear and product (LP) and the regularization multiplier at 0.1, the model strikes an optimal balance between complexity and accuracy.ResultsThe results indicate that the primary climatic factors influencing the distribution of D. punctatus and P. massoniana include the minimum temperature of the coldest month, annual temperature range, and annual precipitation. Under the influence of climate change, the distribution areas of P. massoniana and its pests exhibit a high degree of similarity, primarily concentrated in the region south of the Qinling−Huaihe line in China. In various climate scenarios, the suitable habitat areas for these two species may expand to varying degrees, exhibiting a tendency to shift toward higher latitude regions. Particularly under the high emission scenario (SSP5-8.5), D. punctatus is projected to expand northwards at the fastest rate. DiscussionBy 2050, its migration direction is expected to closely align with that of P. massoniana, indicating that the pine forests will continue to be affected by the pest. These findings provide crucial empirical references for region-specific prevention of D. punctatus infestations and for the rational utilization and management of P. massoniana resources.

The extraction of species-specific calls from passive acoustic recordings is a common preliminary step in ecological analysis. But for many species, especially those occupying noisy, acoustically variable habitats, the call extraction process remains largely manual, a time-consuming, and increasingly unsustainable process. Deep neural networks have been shown to provide excellent performance in a range of acoustic classification applications. We take as an example the recognition of four songs of one of the rarest mammals in the world, the western black-crested gibbon (Nomascus concolors).The process of recognition in this paper which includes distributed BIC ambient sound segmentation based on the OpenPAI platform; DNN-based western black-crested gibbon song enhancement processing; data pre-processing, labeling samples; proposed DNN + ResNet34 + CBAM + GRU + Attention recognition model; comparing other classical neural network models.Our best model converts acoustic recordings into spectrogram images on the mel frequency scale and uses these images to train convolutional neural networks.Our proposed model proved to be very accurate in predicting the segmented western black-crested gibbon songs with an accuracy of 99.8%, and almost a few western black-crested gibbon songs were incorrectly identified when all segmented data were recognized. In the four consecutive years of the acoustic monitoring system deployed in the Ailao Mountain National Nature Reserve, the western black-crested gibbon was most active near the monitoring site from March to August each year, and least active in January and February. Based on call sound intensity analysis, we monitored a total of two different western black-crested gibbon groups (G1 and G2) during the monitoring cycle. We demonstrate that passive acoustic monitoring combined with CNN classifiers is an effective tool for the remote detection of one of the rarest and most threatened species in the world.

Sampling and 14C detection of biomass are now essential steps to ensure the accuracy of the 14C method, but they require additional time and economic investment. When there are multiple types of biomass fuels, it is not possible to guarantee the uniformity of sampling. The 14C activity of biomass fuels exhibits variability, and this value significantly impacts the precision of the 14C method. Therefore, this study aims to investigate the influencing factors of 14C activity in biomass fuels. It also provides predicted values of 14C activity for different types of biomass fuels for each year from 2020 to 2030. Additionally, this study discusses the potential blending ratio measurement errors that may arise due to the uncertainties of the predicted values. The reduction in the 14C activity of biomass fuels can occur due to the utilization of fossil fuels, human activities, and the photosynthesis mode of C3 plants. This study presents a prediction method for determining the reduction factor. The other component of the prediction methodology involves determining the original 14C activity of biomass fuels. The 14C activity of the annual biomass is equal to the 14CO2 activity (the 14C activity of CO2) of the surrounding environment, and it experiences a decline of 0.355 pMC/year. The 14C activity has ranges of five types of perennial biomass fuels, including wood chips and branches, bark, leaves, wasted furniture, and abandoned building wood, for the time period between 2020 and 2030, are 97.34~102.84, 96.35~106.27, 96.35~102.64, 111.00~118.60, and 111.32~129.47 pMC, respectively. Based on these, this study introduces a new formula for calculating blending ratios, which enhances the current methodology. The calculation errors of blending ratios caused by the uncertainties of the predicted values are generally negligible, with the exception of wasted furniture and construction wood. The annual decrease in the blending ratio calculation error, caused by the uncertainty associated with the predicted value, can be observed. This study aims to reduce the implementation time and economic cost of the 14C method while ensuring the accuracy of biomass blending ratio detection.

Microglia/macrophages make up the largest population of tumor-infiltrating cells. Numerous studies have demonstrated that glioma-associated microglia/macrophages (GAMs) could promote the malignant progression of gliomas in various pathways. However, the primary function of GAMs in glioma remains inconclusive. First, by the CIBERSORT algorithm, we evaluated the content of microglia/macrophages in glioma tissues by bioinformatic analysis of omic data from thousands of glioma samples. Subsequently, we analyzed and confirmed the significant relationship between GAMs and the malignant phenotype of glioma, including survival time, IDH mutation status, and time of symptom onset. Afterward, Epithelial-Mesenchymal Transition (EMT) was identified by Gene Set Enrichment Analysis (GSEA) from numerous biological processes as the most relevant mechanism of malignant progression to GAMs. Moreover, a series of clinical samples were detected, including normal brain and various-grade glioma tissues. The results not only showed that GAMs were significantly associated with gliomas and their malignancy but also that GAMs were highly correlated with the degree of EMT in gliomas. In addition, we isolated GAMs from glioma samples and constructed co-culture models (in vitro) to demonstrate the promotion of the EMT process in glioma cells by GAMs. In conclusion, our study clarified that GAMs exert oncogenic effects with EMT in gliomas, suggesting the possibility of GAMs as immunotherapeutic targets.

Alzheimer’s disease (AD) and vascular dementia (VD) are the two most common forms of dementia, share similar symptoms, and are sometimes difficult to distinguish. To investigate the potential mechanisms by which they differ, we identified differentially expressed genes in blood and brain samples from patients with these diseases, and performed weighted gene co-expression network analysis and other bioinformatics analyses. Weighted gene co-expression network analysis resulted in mining of different modules based on differences in gene expression between these two diseases. Enrichment analysis and generation of a protein-protein interaction network were used to identify core pathways for each disease. Modules were significantly involved in cAMP and AMPK signaling pathway, which may be regulated cell death in AD and VD. Genes of cAMP and neurotrophin signaling pathways, including ATP1A3, PP2A, NCEH1, ITPR1, CAMKK2, and HDAC1, were identified as key markers. Using the least absolute shrinkage and selection operator method, a diagnostic model for AD and VD was generated and verified through analysis of gene expression in blood of patients. Furthermore, single sample gene set enrichment analysis was used to characterize immune cell infiltration into brain tissue. That results showed that infiltration of DCs and pDCs cells was increased, and infiltration of B cells and TFH cells was decreased in the brain tissues of patients with AD and VD. In summary, classification based on target genes showed good diagnostic efficiency, and filled the gap in the diagnostic field or optimizes the existing diagnostic model, which could be used to distinguish between AD and VD.

In order to utilize a wider range of low-grade syngas, the syngas biomethanation was studied in this work with respect to the gas–liquid mass transfer and the reactor start-up strategy. Two reactors, a continuous stirred tank (CSTR) and a bubble column with gas recirculation (BCR-C), were used in the experiment by feeding an artificial syngas of 20% H2, 50% CO, and 30% CO2 into the reactors at 55 °C. The results showed that the CH4 productivity was slightly increased by reducing the gas retention time (GRT), but was significantly improved by increasing the stirring speed in the CSTR and the gas circulation rate in the BCR-C. The best syngas biomethanation performance of the CSTR with a CH4 productivity of 22.20 mmol·Lr−1·day−1 and a yield of 49.01% was achieved at a GRT of 0.833 h and a stirring speed of 300 rpm, while for the BCR-C, the best performance with a CH4 productivity of 61.96 mmol·Lr−1·day−1 and a yield of 87.57% was achieved at a GRT of 0.625 h and a gas circulation rate of 40 L·Lr−1·h−1. The gas–liquid mass transfer capability provided by gas circulation is far superior to mechanical stirring, leading to a much better performance of low-grade syngas biomethanation in the BCR-C. Feeding H2/CO2 during the startup stage of the reactor can effectively stimulate the growth and metabolism of microorganisms, and create a better metabolic environment for subsequent low-grade syngas biomethanation. In addition, during the thermophilic biomethanation of syngas, Methanothermobacter is the dominant genus.

Abstract Background High-grade serous ovarian cancer (HGSC), the most common ovarian carcinoma type, is associated with the highest mortality rate among all gynecological malignancies. As chemoresistance has been demonstrated as the major challenge in improving the prognosis of HGSC patients, we here aimed to identify microRNA (miRNA) biomarkers for predicting platinum resistance and further explore their functions in HGSC. Results We developed and applied our network vulnerability-based and knowledge-guided bioinformatics model first time for the study of drug-resistance in cancer. Four miRNA biomarkers (miR-454-3p, miR-98-5p, miR-183-5p and miR-22-3p) were identified with potential in stratifying platinum-sensitive and platinum-resistant HGSC patients and predicting prognostic outcome. Among them, miR-454-3p and miR-183-5p were newly discovered to be closely implicated in platinum resistance in HGSC. Functional analyses highlighted crucial roles of the four miRNA biomarkers in platinum resistance through mediating transcriptional regulation, cell proliferation and apoptosis. Moreover, expression patterns of the miRNA biomarkers were validated in both platinum-sensitive and platinum-resistant ovarian cancer cells. Conclusions With bioinformatics modeling and analysis, we identified and confirmed four novel putative miRNA biomarkers, miR-454-3p, miR-98-5p, miR-183-5p and miR-22-3p that could serve as indicators of resistance to platinum-based chemotherapy, thereby contributing to the improvement of chemotherapeutic efficiency and optimization of personalized treatments in HGSC.

In this work, the forms of potassium and chlorine from oxy-fuel co-combustion of lignite coal and corn stover under atmospheric pressure were investigated. In order to check transitional stage, the feedstocks were combusted stepwise, first by pyrolysis to form coke under N2 environment and later by coke combustion into the ash at 850 °C in O2/CO2 atmosphere. The results show that an increase in blend ratio from 15% to 40% results in an increase in water-soluble potassium in the feedstock and the ashes from 0.15% to 0.4% and 0.015% to 0.038 % in weight respectively. The water-soluble potassium is present mainly as KCl and K2SO4. For ammonium acetate soluble potassium, a similar trend to water-soluble potassium is presented but with a much lower content of potassium. The bound potassium in the fuel matrix exists, likely in the form of AlKSi2O6. Chlorides are present mainly in the form of KCl which is the dominant water-soluble compound. Keywords: Co-combustion (biomas & coal), Oxyfuel combustion, Chemical fractionation, Phase-mineral identifications

BackgroundTreatment for recurrent glioblastoma is poor, and there is a need for better therapies. Here we retrospectively assessed the efficacy and toxicity of temozolomide plus apatinib, an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 in recurrent glioblastoma.Materials and MethodsA retrospective analysis of patients with recurrent glioblastoma who underwent apatinib plus temozolomide treatment was performed. Apatinib was given at 500 mg once daily. Temozolomide was administered at 200 mg/m2/d on days 1–5 or 50 mg/m2/d continuous daily according to whether they had experienced temozolomide maintenance treatment before. The main clinical data collected included tumor characteristics, status of MGMT promoter, and IDH mutation, number of relapse, response, survival, adverse reactions, and salvage therapies.ResultsFrom April 2016 to August 2019, thirty-one patients were identified. The objective response rate was 26.3%, and the disease control rate was 84.2%. The progression-free survival (PFS) at 6 months and overall survival (OS) at 12 months were 44.6 and 30.2%. The median PFS and OS were 4.9 and 8.2 months, respectively. Two patients achieved long PFS of 30.9 and 38.7+ months. The median survival time after progression of the patients with or without salvage bevacizumab was 5.1 versus 1.2 months. The most common grade 3 or 4 toxicities were hypertension (5.8%), decreased appetite (5.8%), and thrombocytopenia (4.3%), most of which were resolved after symptomatic treatment or dose reduction.ConclusionApatinib plus temozolomide is an effective salvage regimen with manageable toxicities for recurrent glioblastoma and could not reduce the sensitivity to bevacizumab.

Amino acid network (AAN) models empower us to gain insights into protein structures and functions by describing a protein 3D structure as a graph, where nodes represent residues and edges as amino acid interactions. Here, we present the ANCA, an interactive Web server for Amino Acids Network Construction and Analysis based on a single structure or a set of structures from the Protein Data Bank. The main purpose of ANCA is to provide a portal for three types of an environment-dependent residue contact energy (ERCE)-based network model, including amino acid contact energy network (AACEN), node-weighted amino acid contact energy network (NACEN), and edge-weighted amino acid contact energy network (EACEN). For comparison, the C-alpha distance-based network model is also included, which can be extended to protein–DNA/RNA complexes. Then, the analyses of different types of AANs were performed and compared from node, edge, and network levels. The network and corresponding structure can be visualized directly in the browser. The ANCA enables researchers to investigate diverse concerns in the framework of AAN, such as the interpretation of allosteric regulation and functional residues. The ANCA portal, together with an extensive help, is available at http://sysbio.suda.edu.cn/anca/.

Objective: Central neurocytomas (CNs) are rare, and this has resulted in a paucity of information and a lack of clarity regarding their optimal management. This study aimed to explore individual treatment strategies for CNs and the benefits of these strategies for patients.Methods: This single-center study retrospectively analyzed data from 67 patients with CNs who underwent surgery. Based on the extent of resection, patients were divided into complete and incomplete resection groups. The patients were followed, and overall survival (OS) and progression-free survival (PFS) were determined.Results: Of 55 patients (82.1%) who underwent complete resections, 24 received radiotherapy (24/55, 43.6%). Of 12 patients who underwent incomplete resections, 9 (9/12, 75.0%) received radiotherapy. The OS (p = 0.003) and PFS (p = 0.006) intervals were significantly longer in the complete resection group than in the incomplete resection group. Postoperative radiotherapy did not affect OS (p = 0.129) or PFS (p = 0.233) in the complete resection group. In the incomplete resection group, postoperative adjuvant radiotherapy prolonged patient survival significantly (p = 0.021). PFS was significantly longer among patients who underwent complete resection without radiotherapy than in those who underwent incomplete resection followed by radiotherapy (p = 0.034). Functional dependence on admission, which was defined as a Karnofsky Performance Status score

Objective(s): Increasing evidence suggests that Alzheimer’s disease (AD) is associated with diabetes. Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist and anti-diabetic agent, may improve symptoms of AD. However, the underlying therapeutic potential of it has not been fully elucidated. Materials and Methods: Rats were divided into four groups: control group, sham operated group, Streptozotocin (STZ) group, rosiglitazone (RGZ) group. Particularly, the STZ-induced rat model was established by intracerebroventricular injection (3 mg/kg) on the first and third day. The water maze behavioral test was performed to evaluate spatial reference learning and memory of the rats. Aβ1-40 and Aβ1-42 levels were measured by ELISA method. To determine APP-derived fragment, BACE1 and Aβ degrading enzymes levels, such as NEP and IDE, as well as Aβ transportation protein level, such as LRP1, RAGE, Abca1 and APOE , which were analyzed by Western blot. Immunohistochemistry was used to observe the change of Aβ1-40 and Aβ1-42 in hippocampus. Results: Chronic treatment with RGZ could reduce the Aβ level and improved spatial memory performance in STZ-induced rat model. However, RGZ modified the expression of specific transport proteins monitoring Aβ clearance, such as ATP-binding cassette transporter 1 (ABCA1), lipoprotein receptor-related protein 1 (LRP1), and the advanced glycation end product-specific receptor (RAGE) rather than change levels of Aβ degrading enzymes, such as IDE and NEP, nor affect APP processing. Conclusion: As a potential therapeutic strategy, rosiglitazone might exert anti-AD effect not by alteration of APP processing pathway and Aβ degradation directly, but through promotion of Aβ clearance indeed.

Cancer stem-like cells (CSCs) is a cell population in glioma with capacity of self-renewal and is critical in glioma tumorigenesis. Parallels between CSCs and normal stem cells suggest that CSCs give rise to tumors. Oncogenic roles of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) have been reported to play a crucial role in glioma tumorigenesis. Herein, we focus on mechanistic contributions of downstream molecules to maintaining stemness of glioma stem-like cells (GSCs). Transcriptional factor, NF-κB, co-locates with MELK/EZH2 complex. Clinically, we observe that the proportion of MELK/EZH2/NF-κB complex is elevated in high-grade gliomas, which is associated with poor prognosis in patients and correlates negatively with survival. We describe the interaction between these three proteins. Specifically, MELK induces EZH2 phosphorylation, which subsequently binds to and methylates NF-κB, leading to tumor proliferation and persistence of stemness. Furthermore, the interaction between MELK/EZH2 complex and NF-κB preferentially occurs in GSCs compared with non-stem-like tumor cells. Conversely, loss of this signaling dramatically suppresses the self-renewal capability of GSCs. In conclusion, our findings suggest that the GSCs depend on EZH2 phosphorylation to maintain the immature status and promote self-proliferation through NF-κB methylation, and represent a novel therapeutic target in this difficult to treat malignancy.

The circulating fluidized bed (CFB) boiler is a mainstream technology of biomass combustion generation in China. The high flue gas flow rate and relatively low combustion temperature of CFB make the deposition process different from that of a grate furnace. The dynamic deposition process of biomass ash needs further research, especially in industrial CFB boilers. In this study, a temperature-controlled ash deposit probe was used to sample the deposits in a 12 MW CFB boiler. Through the analysis of multiple deposit samples with different deposition times, the changes in micromorphology and chemical composition of the deposits in each deposition stage can be observed more distinctively. The initial deposits mainly consist of particles smaller than 2 μm, caused by thermophoretic deposition. The second stage is the condensation of alkali metal. Different from the condensation of KCl reported by most previous literatures, KOH is found in deposits in place of KCl. Then, it reacts with SO2, O2 and H2O to form K2SO4. In the third stage, the higher outer layer temperature of deposits reduces the condensation rate of KOH significantly. Meanwhile, the rougher surface of deposits allowed more calcium salts in fly ash to deposit through inertial impact. Thus, the elemental composition of deposits surface shows an overall trend of K decreasing and Ca increasing.

The raw material requirements for the indirect liquefaction of biomass are strict. In particular, the ratio of H2/CO must be greater than or equal to 1. However, traditional biomass gasification has problems that include a low H2/CO ratio and low carbon conversion rates. This study proposes a three-stage gasification optimization model in which pyrolysis products are separated before being put through a second gasification step. The optimized model simulation used MATLAB software and the experiments were carried out in a biomass, high-temperature entrained-flow bed. The results demonstrate that, compared to traditional mixing gasification, three-stage gasification can effectively increase the H2 content in syngas. The H2 content can reach 42.3%, which is 4.6% higher than in traditional gasification. Additionally, this process can increase the H2/CO ratio to 1.23, which is 43% higher than the ratio 0.86 in traditional gasification. This also could provide raw materials for the indirect liquefaction of syngas. Thus, three-stage gasification can eliminate the need for intermediate steps such as steam reforming and adding external H2. Experiments indicated that the best gasification conditions were a first gasification time of 0.6s and a gasification temperature of 1100 °C, under which the H2/CO ratio reached a maximum of 1.2.

Rice straw, which is a typical agricultural residue in China, was pyrolyzed in a horizontal tube reactor connected with a Fourier transform infrared (FTIR) analyzer at temperatures ranging from 500 to 900 °C to research the release mechanism of fuel-N into NOx and N2O precursors. The concentrations of gaseous nitrogen components were monitored online. NH3, HCN, HNCO, as well as NO were identified components. A high dependency between the gaseous products and temperature was found. NH3 and HNCO preferred to be formed at lower temperatures and HCN tended to form at higher temperatures. It is worth noting that NO was also an important product. X-ray photoelectron spectroscopy (XPS) was performed to analyze the nitrogen species in rice straw. The result showed that amino-N (N-A) was the main form of nitrogen which accounted for 88.85%. Pyrrolic-N (N-5) was also identified and occupied the rest. Then nitrogen modeling compounds, glycine and pyrrole, were appropriately selected based on the results of XPS to well understand the nitrogen release mechanism during pyrolysis of rice straw. The formation routes of all the nitrogen gaseous components were confirmed. NH3, HNCO and NO were originated from the decomposition of amino-N. While both amino-N and pyrrolic-N produced HCN. NO was not detected during the pyrolysis of pyrrole and a little NO was found during the pyrolysis of glycine. Hence, it can be deduced that the large amount of NO formed during the pyrolysis of rice straw was due to the direct oxidization reaction of –NH and –OH, the latter is abundant in the raw material. In order to provide evidence for this deduction, cellulose was added to increase the amount of –OH and co-pyrolysis of cellulose and glycine was conducted. The effect of –OH on the formation of NO was confirmed. Then, the release mechanism of fuel-N into NOx and N2O precursors during rice straw pyrolysis was concluded based on the experimental results.

Although a bone tumor, significant differences in the extent of bone invasion exist in skull base chordoma, which directly affect the extent of surgical resection, and have an impact on its prognosis. However, the underlying mechanism of the phenomenon is not clearly understood. Therefore, we used an iTRAQ-based quantitative proteomics strategy to identify potential molecular signatures, and to find predictive markers of discrepancy in bone invasion of clivus chordoma. According to bone invasive classification criteria, 35 specimens of clivus chordoma were calssified to be either endophytic type (Type I) or exophytic type (Type II). An initial screening of six specimens of endophytic type and six of exophytic was performed, and 250 differentially expressed proteins were identified. Through the GO and IPA analysis, we found evidence that the expression of inflammatory activity-associated proteins up-regulated in endophytic type, whereas the expression of cell motility-associated proteins up-regulated in exophytic ones. Moreover, TGFβ1 and mTOR signal pathway seemed to be related with bone invasion. Thus, TGFβ1, PI3K, Akt, mTOR, and PTEN were validated in the following 23 samples by immune histochemistry and Western blot. The expression levels of TGFβ1 and PTEN were significantly lower in the endophytic type than in the exophytic ones. It was found that TGFβ1 may play an important role in its bone invasion. The mechanisms may be related with conducting an increased inflammatory cell response and a decline in cytoskeletal protein expression. PTEN is confirmed to be associated with the degree of bone invasion. The PI3K/AKT/mTOR signaling pathway might be associated with the bone invasion, but still needs a larger sample size to be verified These results, for the first time, not only demonstrate the biological changes that occur in different growth patterns from the perspective of proteomics, but also provide novel markers that may help to reveal the mechanisms behind clivus chordomas.

The ε4 allele of the gene that encodes apolipoprotein E (APOE4) is the greatest genetic risk factor for Alzheimer's disease (AD), while APOE2 reduces AD risk, compared to APOE3. The mechanism(s) underlying the effects of APOE on AD pathology remains unclear. In vivo , dendritic spine density is lower in APOE4-targeted replacement (APOE-TR) mice compared with APOE2- and APOE3-TR mice. To investigate whether this apoE4-induced decrease in spine density results from alterations in the formation or the loss of dendritic spines, the effects of neuron age and apoE isoform on the total number and subclasses of spines were examined in long-term wild-type neurons co-cultured with glia from APOE2-, APOE3- and APOE4-TR mice. Dendritic spine density and maturation were evaluated by immunocytochemistry via the presence of drebrin (an actin-binding protein) with GluN1 (NMDA receptor subunit) and GluA2 (AMPA receptor subunit) clusters. ApoE isoform effects were analyzed via a method previously established that identifies phases of spine formation (day-in-vitro, DIV10–18), maintenance (DIV18–21) and loss (DIV21–26). In the formation phase, apoE4 delayed total spine formation. During the maintenance phase, the density of GluN1 + GluA2 spines did not change with apoE2, while the density of these spines decreased with apoE4 compared to apoE3, primarily due to the loss of GluA2 in spines. During the loss phase, total spine density was lower in neurons with apoE4 compared to apoE3. Thus, apoE4 delays total spine formation and may induce early synaptic dysfunction via impaired regulation of GluA2 in spines.

Apolipoprotein E (apoE) and apoE/amyloid-β (Aβ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type, apoE−/− mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology, apoE−/− mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice with apoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβ pathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβ pathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve.