DNA from multiple viral species is associated with Alzheimer's disease risk.

INTRODUCTION: Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer's disease (AD) risk by independent lines of evidence. We explored this association by comparing the frequencies of viral species identified in a large sample of AD cases and controls. METHODS: DNA sequence reads that did not align to the human genome in sequences were mapped to viral reference sequences, quantified, and then were tested for association with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets. RESULTS: Several viruses were significant predictors of AD according to the machine learning classifiers. Subsequent regression analyses showed that herpes simplex type 1 (HSV-1) (odds ratio [OR] = 3.71, p = 8.03 × 10-4) and human papillomavirus 71 (HPV-71; OR = 3.56, p = 0.02), were significantly associated with AD after Bonferroni correction. The phylogenetic-related cluster of Herpesviridae was significantly associated with AD in several strata of the data (p < 0.01). DISCUSSION: Our results support the hypothesis that viral infection, especially HSV-1, is associated with AD risk.

A DNA methylation signature for the prediction of tumour recurrence in stage II colorectal cancer.

BACKGROUND: A major challenge in stage II colorectal carcinoma is to identify patients with increased risk of recurrence. Biomarkers that distinguish patients with poor prognosis from patients without recurrence are currently lacking. This study aims to develop a robust DNA methylation classifier that allows the prediction of recurrence and chemotherapy benefit in patients with stage II colorectal cancer. We performed a genome-wide DNA methylation capture sequencing in 243 stage II colorectal carcinoma samples and identified a relapse-specific DNA methylation signature consisting of eight CpG sites. METHODS: Two hundred and forty-three patients with stage II CRC were enrolled in this study. In order to select differential methylation sites among recurrence and non-recurrence stage II CRC samples, DNA methylation profiles of 62 tumour samples including 31 recurrence and 31 nonrecurrence samples were analysed using the Agilent SureSelectXT Human Methyl-Seq, a comprehensive target enrichment system to analyse CpG methylation. Pyrosequencing was applied to quantify the methylation level of candidate DNA methylation sites in 243 patients. Least absolute shrinkage and selection operator (LASSO) method was employed to build the disease recurrence prediction classifier. RESULTS: We identified a relapse-related DNA methylation signature consisting of eight CpG sites in stage II CRC by DNA methylation capture sequencing. The classifier showed significantly higher prognostic accuracy than any clinicopathological risk factors. The Kaplan-Meier survival curve showed an association of high-risk score with poor prognosis. In multivariate analysis, the signature was the most significant prognosis factor, with an HR of 2.80 (95% CI, 1.71-4.58, P < 0.001). The signature could identify patients who are suitable candidates for adjuvant chemotherapy. CONCLUSIONS: An eight-CpG DNA methylation signature is a reliable prognostic and predictive tool for disease recurrence in patients with stage II CRC.

Vascular Endothelial Growth Factor A VEGFA Inhibition: An Effective Treatment Strategy for Psoriasis.

Psoriasis is an inflammatory skin disease mediated by the immune system and characterized by an inflammatory ring, also known as an epithelial immune microenvironment (EIME). The interaction between the epithelial tissue of the skin and the immune system has a crucial role in the immune cycle of psoriasis. Although the formation of new blood vessels in skin lesions provides energy support for the proliferation of epidermal keratinocytes, the role of angiogenesis in psoriasis has not been extensively studied. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis that has an important role in the development of psoriasis. VEGFA promotes angiogenesis and directly stimulates epidermal keratinocytes and infiltrating immune cells, thus contributing to the progression of psoriasis. Measuring VEGFA levels to identify angiogenic characteristics in psoriasis patients may be a predictive biomarker for disease severity and response to anti-angiogenic therapy. Clinical data have shown that anti-angiogenic therapy can improve skin lesions in psoriasis patients. Therefore, this study aimed to uncover the underestimated role of blood vessels in psoriasis, explore the relationship between VEGFA and keratinocytes in the EIME, and inspire innovative drug therapies for the treatment of psoriasis.

Efficient Solar-osmotic Power Generation from Bioinspired Anti-fouling 2D WS2 Composite Membranes.

Nanofluidic reverse electrodialysis provides an attractive way to harvest osmotic energy. However, most attention was paid to monotonous membrane structure optimization to promote selective ion transport, while the role of external fields and relevant mechanisms are rarely explored. Here, we demonstrate a Kevlar-toughened tungsten disulfide (WS2 ) composite membrane with bioinspired serosa-mimetic structures as an efficient osmotic energy generator coupling light. As a result, the output power could be up to 16.43 W m-2 under irradiation, outperforming traditional two-dimensional (2D) membranes. Both the experiment and simulation uncover that the generated photothermal and photoelectronic effects could synergistically promote the confined ion transport process. In addition, this membrane also possesses great anti-fouling properties, endowing its practical application. This work paves new avenues for sustainable power generation by coupling solar energy.

Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease.

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ɛ2/ɛ3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-ß 42 level, suggesting this APOE ɛ2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

Theoretical analysis of the absorption of CO2 and CO on pristine and Al-doped C3B.

CO2 and CO, the by-products of fossil fuels; one of them is a major cause of global warming and the other endangers the nervous and cardiovascular systems of humans. Therefore, real-time monitoring towards those harmful gases is of practical significance. Nano-structured materials have attracted the attention of scholars for their enormous potential for harmful gas detection. In this work, the adsorption and sensing behavior of C3B and Al-doped C3B monolayers for these two typical hazardous gases were investigated theoretically. The most stable doping model was obtained, and the adsorption process for CO and CO2 was simulated based on this model. The adsorption system shows that the gas molecules are all deformed and that the charge transfer and adsorption energy are significantly increased. Moreover, the adsorption mechanism was investigated by analyzing the electronic behavior of the adsorbent, and the physical adsorption between the hazardous gas and the adsorbent was more favorable for desorption. The good adsorption performance and sensing mechanism suggest that the CO/CO2 sensor prepared using Al-C3B has great potential for application. Our work may provide some guidance for the application of toxic gas monitoring and adsorption.

HIF1α promotes tumor chemoresistance via recruiting GDF15-producing TAMs in colorectal cancer.

Chemoresistance is a tremendous challenge to efficacy of systemic chemotherapy which is the preferred treatment for the advanced CRC patients. More tumor-associated macrophages (TAMs) are recruited into the CRC tumor under chemotherapy, which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we present that activated HIF1α signaling in CRC cells under chemotherapy drives the expression of HMGB1to promotes macrophage infiltration and in turn chemoresistance development. Chemotherapeutic treatment with 5-FU leads to increased recruitment of macrophages into tumors, which display tumor-protective alternative activation. Mechanistically, tumor HIF1α signaling activated by chemo-induced ROS drives the transcription of HMGB1 to promote more macrophage infiltration into CRC tumor. Furthermore, high levels of GDF15 produced by TAMs impair the chemosensitity of tumor cells via enhancing fatty acids ß-oxidation. Together, our current study reveals a new insight into the cross-talking between tumor cells and immune cells, and provides novel drug targets for clinic treatments for CRC.

Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.

INTRODUCTION: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent. METHODS: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O. RESULTS: Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L variant (rs28709356 C>T; minor allele frequency = 0.002; P = 7.3 × 10-5 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10-5 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10-5 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03). DISCUSSION: Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.

Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease.

INTRODUCTION: The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. METHODS: We conducted a genome-wide association study for AD among 2096 ɛ2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele-specific induced pluripotent stem cell (iPSC)-derived neurons and astrocytes and in 224 neuropathologically examined human brains. RESULTS: PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10-7 ) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10-27 ). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10-4 ) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10-7 ). DISCUSSION: PP2A may be linked to classical complement activation leading to AD-related tau pathology.

Metallic Two-Dimensional MoS2 Composites as High-Performance Osmotic Energy Conversion Membranes.

Molybdenum disulfide (MoS2) has shown large promise in harvesting osmotic energy. However, the current investigations generally focus on proof-of-concept nanoscale single-pore devices with a semiconductor phase structure. Exploration of the application viability of MoS2 in a more robust macroscopic-scale two-dimensional (2D) nanofluidic membrane and acquisition of fundamentals of how the phase structure influences the power generation process are highly demanded. Here, we demonstrate that robust and stable composite membranes made up of 2D metallic MoS2 can act as high-performance osmotic power generators. Both experiment and simulation reveal that the higher electron density of metallic MoS2 increases the affinity of cations to the surface, which renders the system excellent ion selectivity and high ionic flux and greatly promotes transmembrane ion diffusion. When natural river water and seawater are mixed, the power density can achieve about 6.7 W m-2. This work shows the great potential of metallic MoS2 in nanofluidic energy devices.

Neutralization Reaction Assisted Chemical-Potential-Driven Ion Transport through Layered Titanium Carbides Membrane for Energy Harvesting.

Chemical potential energy harvesting from the concentration gradient has been largely improved recently due to the development of nanofluidic energy conversion systems. However, the reported systems mainly focus on improving the membrane's performance but neglect the forms of concentration gradient. Here, we demonstrate the chemical reaction assisted chemical-potential-driven directional ion transport through layered titanium carbides membranes for energy harvesting. The MXene membrane with negatively charged nanochannels shows excellent cation selectivity and could reach 1.1 W/m2 for a 500-fold salinity gradient. By adopting the traditional neutralization reaction, HCl/KOH as the acid-base pair (ABP), the power density can reach 7.89 W/m2 with 1 M ABP due to the maintained transmembrane proton gradient. Besides, the membrane's excellent acid-base stability renders the power density stable for ∼192 h without obvious damping. This work provides new inspiration for industrial waste treatment issues and would be worth exploring its potential applications in extreme environments.

Improved Ion Transport and High Energy Conversion through Hydrogel Membrane with 3D Interconnected Nanopores.

To mimic and use the functions of the ion transport system that are central to biological processes, bioinspired ion-selective membranes are developed and show great potential in a variety of fields. However, the practical applications of them are now limited due to low pore density, low conductivity, or scale-up difficulty. Herein, we demonstrate a 2-hydroxyethyl methacrylate phosphate (HEMAP) hydrogel membrane with 3D interconnected nanopores and space charged through simple photopolymerization. The HEMAP hydrogel membrane exhibits high conductance and outstanding ion selectivity, and the membrane-based osmotic power generator shows the excellent output power density up to 5.38 W/m2. Both experimentally and theoretically, the 3D interconnected structure is revealed to play a key role in enhancing charge-governed ion transport and energy conversion. This work highlights the advantages of 3D interconnected nanopores in ion diffusion and shows the potential of our designed hydrogel membrane in osmotic energy conversion, water desalination, and sensors.

Better understanding of acute gouty attack using CT perfusion in a rabbit model.

OBJECTIVE: To assess hemodynamic changes related to acute gouty knee arthritis in a rabbit with CT perfusion (CTP) METHODS: Forty-two rabbits were randomly separated into two groups: the treated group of 30 and the control group of 12. The right knee was injected with monosodium urate solution and polymyxin in the treated group and saline and polymyxin in the control group. At 2, 16, 32, 48, 60, and 72 h after injection, five rabbits from the treated group and two rabbits from the control group were selected for CTP. At each time point, blood flow (BF), blood volume (BV), and clearance rate (CL) were measured, and microvessel density (MVD) was evaluated with a microscope. RESULTS: In the treated group, BF, BV, CL, and MVD were significantly higher than in the control group (p < 0.001). Differences within paired comparison of BV, BF, CL, and MVD were all significant (all p < 0.001). Peak time of BV, BF, and MVD was 32 h and 48 h for CL. After multivariate stepwise linear regression analysis, BV was linearly associated with MVD and vice versa, which also applied to BF with MVD and BF with CL, separately. The ascending rate of MVD was the highest among that of all parameters; so was the descending rate of CL. CONCLUSION: CTP in this rabbit knee model accurately detected hemodynamic changes during a gouty attack. KEY POINTS: • Acute gouty arthritis can be evaluated with CTP in a rabbit knee model. • Following injection of MSU crystals, producing an acute gouty attack, CTP successfully assessed hemodynamic changes. • The ascending rate of MVD was the highest among that of all parameters; so was the descending rate of CL.

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease.

INTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood. METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10-10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10-10). DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

CCR6 promotes tumor angiogenesis via the AKT/NF-κB/VEGF pathway in colorectal cancer.

Chemokines and chemokine receptors play an important role in tumorigenesis. Angiogenesis is a vital part of the occurrence, development and metastasis of cancer. CCR6 is an important factor during tumor progression; however, its function in tumor angiogenesis is not fully understood. In our study, we found that CCR6 was significantly overexpressed in colorectal cancer (CRC) tissues and predicted a poor prognosis in CRC patients. We then verified the function of CCR6 on tumor angiogenesis in vivo and in vitro. We observed that silencing CCR6 could decrease angiogenesis by inhibiting the proliferation and migration of human umbilical vein endothelial cells (HUVECs), whereas overexpression of CCR6 can promote angiogenesis. Additionally, we investigated the molecular mechanisms and demonstrated that activation of the AKT/NF-κB pathway maybe involved in CCR6-mediated tumor angiogenesis, which was able to promote the secretion of vascular endothelial growth factor A (VEGF-A). In conclusion, CCR6 facilitates tumor angiogenesis via the AKT/NF-κB/VEGF pathway in colorectal cancer. CCR6 inhibition may be a novel option for anti-vascular treatment in CRC.

Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3ß/ß-catenin pathways.

BACKGROUND: Metastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood. METHODS: Herein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo. RESULTS: We found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3ß/ß-catenin pathway in a CXCR2-dependent manner. The silencing of Snail and ß-catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model. CONCLUSION: In conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients.

Photoreconfigurable polymers for biomedical applications: chemistry and macromolecular engineering.

Stimuli-responsive polymers play an important role in many biomedical technologies. Light responsive polymers are particularly desirable because the parameters of irradiated light and diverse photoactive chemistries produce a large number of combinations between functional materials and associated stimuli. This Review summarizes recent advances in utilizing photoactive chemistries in macromolecules for prospective use in biomedical applications. Special focus is granted to selection criterion when choosing photofunctional groups. Synthetic strategies to incorporate these functionalities into polymers and networks with different topologies are also highlighted herein. Prospective applications of these materials are discussed including programmable matrices for controlled release, dynamic scaffolds for tissue engineering, and functional coatings for medical devices. The article concludes by summarizing the state of the art in photoresponsive polymers for biomedical applications including current challenges and future opportunities.

Toxic effects and mechanisms of cationic blue SD-GSL on Chlorella vulgaris before and after the biological decolorization process.

Biodegradation is regarded as an efficient way to decolorize azo dyes. However, the changes in the algal toxicity of azo dyes during biodecolorization are still unclear. In this study, the physiological responses of Chlorella vulgaris to the hydrophobic and hydrophilic components of cationic blue SD-GSL (a typical monoazo dye) and its biodecolorization products were investigated. The toxicity of each component to Chlorella vulgaris and the sources of the toxicity were analyzed. The cationic blue SD-GSL components inhibited the algal cell division and superoxide dismutase (SOD) activity at all concentrations, and inhibited the synthesis of chlorophyll-a (Chl-a) at concentrations >100 mg/L, whereas increased the malondialdehyde (MDA) content. The hydrophobic and hydrophilic components of its biodecolorization products had enhanced inhibition rates on cell density (10.7% and 15.6%, respectively), Chl-a content (31.2% and 8.4%, respectively), and SOD activity (13.5% and 1.9%, respectively) of Chlorella vulgaris, and further stimulated an increase in MDA content (4.4% and 7.0%, respectively), indicating that the biodecolorization products were more toxic than the pristine dye. Moreover, the toxic effect of hydrophobic components on Chlorella vulgaris was stronger than that of hydrophilic components. The sensitivity sequence of Chlorella vulgaris to the toxicity of cationic blue SD-GSL and its biodecolorization product components was: Chl-a synthesis > SOD activity > cell division. SUVA analysis and 3D-EEM analysis revealed that the enhanced algal toxicity of the biodecolorization products of cationic blue SD-GSL was attributed to the aromatic compounds, which were mainly concentrated in the hydrophobic components. UPLC-Q-TOF-MS was used to verify dye biodecolorization byproducts. The information obtained from this study helps to understand the decolorization products toxicities of the biologically treated azo dyes, thereby providing new insights into the environmental safety of textile wastewater after traditional biological treatment.

HeadDiff: Exploring Rotation Uncertainty With Diffusion Models for Head Pose Estimation.

In this paper, we propose a probabilistic regression diffusion model for head pose estimation, dubbed HeadDiff, which typically addresses the rotation uncertainty, especially when faces are captured in wild conditions. Unlike conventional image-to-pose methods which cannot explicitly establish the rotational manifold of head poses, our HeadDiff aims to ensure the pose rotation via the diffusion process and in parallel, refine the mapping process iteratively. Specifically, we initially formulate the head pose estimation problem as a reverse diffusion process, defining a paradigm for progressive denoising on the manifold, which explores the uncertainty by decomposing the large gap into intermediate steps. Moreover, our HeadDiff is equipped with an isotropic Gaussian distribution by encoding the incoherence information in our rotation representation. Finally, we learn the facial relationship of nearest neighbors with a cycle-consistent constraint for robust pose estimation versus diverse shape variations. Experimental results on multiple datasets demonstrate that our proposed method outperforms existing state-of-the-art techniques without auxiliary data.

Cordycepin Ameliorates Psoriasis-Like Skin Lesion by Regulating p53/MDM2 Feedback Loop.

Apoptosis is a natural physiological process of programmed cell death. It is essential for maintaining the homeostasis of the body and the immune system. The dysfunction of apoptosis can lead to the development of autoimmune diseases. In psoriasis, the dysfunction of keratinocyte proliferation manifests as an impairment of apoptosis. Cordycepin is the major active component in cordyceps militaris and has pharmacological effects, including regulation of apoptosis. The pharmacological mechanism of Cordycepin in psoriasis remains unclear. In this study, bioinformatics analysis revealed that the mechanism may be associated with the p53 apoptotic pathway. Further, we confirmed in the experiments that cordycepin inhibited the interleukin (IL)-17A-induced proliferation of HaCaT cells and down-regulated the expression of proliferating cell nuclear antigen (PCNA) and Ki-67. Regulating the expression of apoptotic proteins BAX, Bcl-2, and p53 promote apoptosis. Further investigation of the upstream pathway of apoptosis revealed that cordycepin could normalize the abnormal p53-mouse double minute 2 (MDM2) feedback loop. In vivo results showed that the cordycepin gel could effectively improve imiquimod (IMQ)-induced psoriasis-like skin lesions in mice, and the p53-MDM2 pathway was verified at the protein level. In conclusion, the anti-psoriasis effect of Cordycepin and its potential mechanism have not been discussed in detail. However, our work supports the idea that Cordycepin can be further developed as an Active Pharmaceutical Ingredient (API) for the treatment of psoriasis.