Inhibition of colorectal cancer in Alzheimer's disease is mediated by gut microbiota via induction of inflammatory tolerance.

Epidemiological studies have revealed an inverse relationship between the incidence of Alzheimer's disease (AD) and various cancers, including colorectal cancer (CRC). We aimed to determine whether the incidence of CRC is reduced in AD-like mice and whether gut microbiota confers resistance to tumorigenesis through inducing inflammatory tolerance using 16S ribosomal RNA gene sequencing and fecal microbiota transplantation (FMT). AD-like mice experienced a significantly decreased incidence of CRC tumorigenesis induced by azoxymethane-dextran sodium sulfate as evidenced by suppressed intestinal inflammation compared with control mice. However, FMT from age-matched control mice reversed the inhibitory effects on the tumorigenesis of CRC and inflammatory response in AD-like mice. The key bacterial genera in gut microbiota, including Prevotella, were increased in both the AD-like mice and in patients with amnestic mild cognitive impairment (aMCI) but were decreased in patients with CRC. Pretreatment with low-dose Prevotella-derived lipopolysaccharides (LPS) induced inflammatory tolerance both in vivo and in vitro and inhibited CRC tumorigenesis in mice. Imbalanced gut microbiota increased intestinal barrier permeability, which facilitated LPS absorption from the gut into the blood, causing cognitive decline in AD-like mice and patients with aMCI. These data reveal that intestinal Prevotella-derived LPS exerts a resistant effect to CRC tumorigenesis via inducing inflammatory tolerance in the presence of AD. These findings provide biological evidence demonstrating the inverse relationship between the incidence of AD and CRC.

Thermodynamics-Guided High-Throughput Discovery of Eutectic High-Entropy Alloys for Rapid Solidification.

Excellent castability, significantly refined microstructure, and good mechanical properties make eutectic high-entropy alloys (EHEAs) a natural fit for rapid solidification processes, e.g., additive manufacturing. Previous investigations have focused on developing EHEAs through trial and error and mixing known binary eutectic materials. However, eutectic compositions obtained from near-equilibrium conditions do not guarantee a fully eutectic microstructure under rapid solidifications. In this work, a thermodynamically guided high-throughput framework is proposed to design EHEAs for rapid solidification. Empirical formulas derived from past experimental observations and thermodynamic computations are applied and considered phase growth kinetics under rapid solidification (skewed phase diagram). The designed alloy candidate, Co25.6Fe17.9Ni22.4Cr19.1Ta8.9Al6.1 (wt.%), contains nanostructured eutectic lamellar and shows a high Vickers hardness of 675 Hv. In addition to this specific composition, the alloy design toolbox enables the development of new EHEAs for rapid solidification without the limitation of previous knowledge.

Substantially enhanced homogeneous plastic flow in hierarchically nanodomained amorphous alloys.

To alleviate the mechanical instability of major shear bands in metallic glasses at room temperature, topologically heterogeneous structures were introduced to encourage the multiplication of mild shear bands. Different from the former attention on topological structures, here we present a compositional design approach to build nanoscale chemical heterogeneity to enhance homogeneous plastic flow upon both compression and tension. The idea is realized in a Ti-Zr-Nb-Si-XX/Mg-Zn-Ca-YY hierarchically nanodomained amorphous alloy, where XX and YY denote other elements. The alloy shows ~2% elastic strain and undergoes highly homogeneous plastic flow of ~40% strain (with strain hardening) in compression, surpassing those of mono- and hetero-structured metallic glasses. Furthermore, dynamic atomic intermixing occurs between the nanodomains during plastic flow, preventing possible interface failure. Our design of chemically distinct nanodomains and the dynamic atomic intermixing at the interface opens up an avenue for the development of amorphous materials with ultrahigh strength and large plasticity.

Alzheimer's risk factor FERMT2 promotes the progression of colorectal carcinoma via Wnt/ß-catenin signaling pathway and contributes to the negative correlation between Alzheimer and cancer.

Increasing evidence from epidemiological studies indicate that Alzheimer's disease (AD) has a negative relationship with the incidence of cancers. Whether the Alzheimer's genetic risk factor, named as fermitin family homolog-2 (FERMT2), plays a pivotal part in the progressive process of colorectal carcinoma (CRC) yet remains unclear. This study revealed that FERMT2 was upregulated in CRC tissues which predicted an unfavorable outcome of CRC using the PrognoScan web tool. FERMT2 was co-expressed with a variety of genes have been linked with CRC occurrence and implicated in the infiltration of immune cell in CRC tissues. Overexpressing FERMT2 promoted CRC progression with upregulation of Wnt/ß-catenin signaling. Knockdown of FERMT2 suppressed the cell multiplication, colony formation rate, migration and invasion, along with the epithelial to mesenchymal transition (EMT) with downregulation Wnt/ß-catenin proteins in cells of CRC, while overexpressing ß-catenin reversed the inhibitory effects of silencing FERMT2 on the migration or invasion of CRC cells. Furthermore, Aß1-42 treated HT22 cells induced downregulation of FERMT2 and inhibited the migration, invasion and EMT in co-cultured CT26 cells through Wnt/ß-catenin signaling. Our results revealed that the downregulated FERMT2 gene during AD is prominently activated in CRC, which promotes its progression via Wnt/ß-catenin pathway.

Massive interstitial solid solution alloys achieve near-theoretical strength.

Interstitials, e.g., C, N, and O, are attractive alloying elements as small atoms on interstitial sites create strong lattice distortions and hence substantially strengthen metals. However, brittle ceramics such as oxides and carbides usually form, instead of solid solutions, when the interstitial content exceeds a critical yet low value (e.g., 2 at.%). Here we introduce a class of massive interstitial solid solution (MISS) alloys by using a highly distorted substitutional host lattice, which enables solution of massive amounts of interstitials as an additional principal element class, without forming ceramic phases. For a TiNbZr-O-C-N MISS model system, the content of interstitial O reaches 12 at.%, with no oxides formed. The alloy reveals an ultrahigh compressive yield strength of 4.2 GPa, approaching the theoretical limit, and large deformability (65% strain) at ambient temperature, without localized shear deformation. The MISS concept thus offers a new avenue in the development of metallic materials with excellent mechanical properties.

Reactive wear protection through strong and deformable oxide nanocomposite surfaces.

Wear-related energy and material loss cost over 2500 Billion Euro per year. Traditional wisdom suggests that high-strength materials reveal low wear rates, yet, their plastic deformation mechanisms also influence their wear performance. High strength and homogeneous deformation behavior, which allow accommodating plastic strain without cracking or localized brittle fracture, are crucial for developing wear-resistant metals. Here, we present an approach to achieve superior wear resistance via in-situ formation of a strong and deformable oxide nanocomposite surface during wear, by reaction of the metal surface with its oxidative environment, a principle that we refer to as 'reactive wear protection'. We design a TiNbZr-Ag alloy that forms an amorphous-crystalline oxidic nanocomposite surface layer upon dry sliding. The strong (2.4 GPa yield strength) and deformable (homogeneous deformation to 20% strain) nanocomposite surface reduces the wear rate of the TiNbZr-Ag alloy by an order of magnitude. The reactive wear protection strategy offers a pathway for designing ultra-wear resistant alloys, where otherwise brittle oxides are turned to be strong and deformable for improving wear resistance.

Decreased lncRNA SNHG16 Accelerates Oxidative Stress Induced Pathological Angiogenesis in Human Retinal Microvascular Endothelial Cells by Regulating miR-195/mfn2 Axis.

BACKGROUND: This study was performed to identify the alterations of Long non-coding RNAs (lncRNAs) induced by oxidative stress and investigate the functional roles of SNHG16 in the pathological angiogenesis by human retinal microvascular endothelial cells (HMRECs). METHODS: The expression profiles of lncRNAs and mRNAs induced by oxidative stress were identified by RNA-Seq, and the dysregulation of 16 lncRNAs including SNHG16 was verified in H2O2-treated human umbilical vein endothelial cells (HUVECs). Luciferase reporter assay and RIP analysis were used to investigate the binding relationship of SNHG16 to miR-195. RESULTS: We confirmed that over-expression of SNGH16 attenuated H2O2-induced angiogenesis by HMRECs. In addition, SNHG16 was significantly decreased, whereas miR-195, a predictive target of SNHG16, was upregulated in H2O2;, HG, and AGE-treated HMRECs. The binding relationship of SNHG16 to miR-195 was subsequently verified by luciferase reporter assay and RIP analysis. SNHG16 cotransfection abolished miR-195-mediated repression on mitofusin 2 (mfn2) protein level and counteracted the inductive effect of miR-195 on angiogenesis by HMRECs. CONCLUSION: These results indicated that decreased SNHG16 accelerates oxidative stress-induced pathological angiogenesis in HMRECs by regulating the miR-195/mfn2 axis, providing a potential target for diabetic retinopathy (DR) therapy.

Nanoglass-Nanocrystal Composite-a Novel Material Class for Enhanced Strength-Plasticity Synergy.

The properties of a material can be engineered by manipulating its atomic and chemical architecture. Nanoglasses which have been recently invented and comprise nanosized glassy particles separated by amorphous interfaces, have shown promising properties. A potential way to exploit the structural benefits of nanoglasses and of nanocrystalline materials is to optimize the composition to obtain crystals forming within the glassy particles. Here, a metastable Fe-10 at% Sc nanoglass is synthesized. A complex hierarchical microstructure is evidenced experimentally at the atomic scale. This bulk material comprises grains of a Fe90 Sc10 amorphous matrix separated by an amorphous interfacial network enriched and likely stabilized by hydrogen, and property-enhancing pure-Fe nanocrystals self-assembled within the matrix. This composite structure leads a yield strength above 2.5 GPa with an exceptional quasi-homogeneous plastic flow of more than 60% in compression. This work opens new pathways to design materials with even superior properties.

[Research progress on the epigenetic mechanisms of inverse relationship between Alzheimer's disease and cancer onset].

Alzheimer's disease (AD) is currently the most prevalent neurodegenerative disease in the aging population. It is characterized by massive deposition of extracellular ß-amyloid peptide and formation of intracellular neurofibrillary tangles. Cancer is also an age-related disease. Some epidemiological studies have shown an inverse relationship between AD and the onset of various types of cancers, that is, the risk of cancer in patients with AD is reduced, and vice versa. Epigenetic mechanisms play important roles in the development of AD and cancer. In this article, we will review the recent research advances on the epigenetic mechanisms of AD and cancer onset, and provide new ideas for rethinking the relevance of AD and cancer with a "holistic concept".

Crystal-Glass High-Entropy Nanocomposites with Near Theoretical Compressive Strength and Large Deformability.

High-entropy alloys (HEAs) and metallic glasses (MGs) are two material classes based on the massive mixing of multiple-principal elements. HEAs are single or multiphase crystalline solid solutions with high ductility. MGs with amorphous structure have superior strength but usually poor ductility. Here, the stacking fault energy in the high-entropy nanotwinned crystalline phase and the glass-forming-ability in the MG phase of the same material are controlled, realizing a novel nanocomposite with near theoretical yield strength (G/24, where G is the shear modulus of a material) and homogeneous plastic strain above 45% in compression. The mutually compatible flow behavior of the MG phase and the dislocation flux in the crystals enable homogeneous plastic co-deformation of the two regions. This crystal-glass high-entropy nanocomposite design concept provides a new approach to developing advanced materials with an outstanding combination of strength and ductility.

Increased miR-34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS-JNK-p53 pathway in Alzheimer's Disease.

Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR-34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR-34c in AD remain to be investigated. The expression of miR-34c was detected by RT-qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR-34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR-34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR-34c was mediated by ROS-JNK-p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3'-untranslated region (3'-UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR-34c in the HT-22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR-34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR-34c mediated synaptic and memory deficits by targeting SYT1 through ROS-JNK-p53 pathway and the miR-34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.