Effects of Nonuniform Fiber Geometries on the Microstructural Fracture Behavior of Ceramic Matrix Composites

Microstructural fracture behavior of a ceramic matrix composite (CMC) with nonuniformly distributed fibers is studied in the presentation. A comprehensive numerical analysis package to study the effect of nonuniform fiber dimensions and locations on the microstructural fracture behavior is developed. The package starts with an optimization algorithm for generating representative volume element (RVE) models that are statistically equivalent to experimental measurements. Experimentally measured statistical data are used as constraints while the optimization algorithm is running. Virtual springs are utilized between any adjacent fibers to nonuniformly distribute the coated fibers in the RVE model. The virtual spring with the optimization algorithm can efficiently generate multiple RVEs that are statistically identical to each other. Smeared crack approach (SCA) is implemented to consider the fracture behavior of the CMC material in a mesh-objective manner. The RVEs are subjected to tension as well as the shear loading conditions. SCA is capable of predicting different fracture patterns, uniquely defined by not only the fiber arrangement but also the specific loading type. In addition, global stress-strain curves show that the microstructural fracture behavior of the RVEs is highly dependent on the fiber distributions

Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

PPM1A Controls Diabetic Gene Programming through Directly Dephosphorylating PPAR?? at Ser273

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipose tissue biology. In obesity, phosphorylation of PPAR gamma at Ser273 (pSer273) by cyclin-dependent kinase 5 (CDK5)/extracellular signal-regulated kinase (ERK) orchestrates diabetic gene reprogramming via dysregulation of specific gene expression. Although many recent studies have focused on the development of non-classical agonist drugs that inhibit the phosphorylation of PPAR gamma at Ser273, the molecular mechanism of PPAR gamma dephosphorylation at Ser273 is not well characterized. Here, we report that protein phosphatase Mg2+/Mn2+-dependent 1A (PPM1A) is a novel PPAR gamma phosphatase that directly dephosphorylates Ser273 and restores diabetic gene expression which is dysregulated by pSer273. The expression of PPM1A significantly decreases in two models of insulin resistance: diet-induced obese (DIO) mice and db/db mice, in which it negatively correlates with pSer273. Transcriptomic analysis using microarray and genotype-tissue expression (GTEx) data in humans shows positive correlations between PPM1A and most of the genes that are dysregulated by pSer273. These findings suggest that PPM1A dephosphorylates PPAR gamma at Ser273 and represents a potential target for the treatment of obesity-linked metabolic disorders

Current advances in combining stem cell and gene therapy for neurodegenerative diseases

Neuronal death is the common final pathologic pathway of various neurodegenerative diseases (NDs). Although central nervous system has little regenerative potential, it is expected that damaged neural tissue can be recovered by exogenous supplementation of stem cells; however, stem cell therapy cannot modulate specific causes of NDs, such as accumulation of extracellular amyloid peptides in Alzheimer’s disease. In contrast, gene therapy can deliver therapeutic genes to specific ND targets. Therefore, combining stem cell and gene therapy would have dual treatment mechanisms (regenerating damaged neural tissue and modifying specific causes of NDs) and lead to better clinical outcomes. In this review, we discuss various therapeutic genes that can be used to develop stem cell gene therapy for various NDs and the techniques for how therapeutic genes can be integrated into stem cells

Atrophic Gastritis: A Related Factor for Osteoporosis in Elderly Women

Purpose Osteoporosis poses a great threat to the aging society. Hypochlorhydric or achlorhydric conditions are risk factors for osteoporosis. Atrophic gastritis also decreases gastric acid production; however, the role of atrophic gastritis as a related factor for osteoporosis is unclear. We investigated the relationship between atrophic gastritis and osteoporosis in postmenopausal women over 60 years of age. Subjects and Methods A total of 401 postmenopausal women were included in this cross-sectional study, which was conducted during their medical check-ups. Bone mineral densitometry was measured using a dual energy X-ray absorptiometry. Atrophic gastritis was defined endoscopically if gastric mucosa in the antrum and the body were found to be atrophied and thinned and submucosal vessels could be well visualized. Results: The proportion of people with atrophic gastritis was higher in the osteoporotic group than in the group without osteoporosis. A linear relationship was observed in the proportion of atrophic gastritis according to the categories of normal, osteopenia, and osteoporosis at the lumbar spine (p for trend = 0.039) and femur (p for trend = 0.001). A multiple logistic regression analysis revealed that the presence of atrophic gastritis was associated with an increased odds of osteoporosis after adjusting for age, body mass index, triglyceride, high-density lipoprotein cholesterol, alcohol consumption, and smoking status (odds ratio 1.89, 95% confidence interval 1.15–3.11). Conclusions: Atrophic gastritis is associated with an increased likelihood of osteoporosis in Korean elderly women

Impact of Diabetes on Oncologic Outcome of Colorectal Cancer Patients: Colon vs. Rectal Cancer

Background: To evaluate the impact of diabetes on outcomes in colorectal cancer patients and to examine whether this association varies by the location of tumor (colon vs. rectum). Patients and methods This study includes 4,131 stage I-III colorectal cancer patients, treated between 1995 and 2007 (12.5% diabetic, 53% colon, 47% rectal) in South Korea. Cox proportional hazards modeling was used to determine the prognostic influence of DM on survival endpoints. Results: Colorectal cancer patients with DM had significantly worse disease-free survival (DFS) [hazard ratio (HR) 1.17, 95% confidence interval (CI): 1.00–1.37] compared with patients without DM. When considering colon and rectal cancer independently, DM was significantly associated with worse overall survival (OS) (HR: 1.46, 95% CI: 1.11–1.92), DFS (HR: 1.45, 95% CI: 1.15–1.84) and recurrence-free survival (RFS) (HR: 1.32, 95% CI: 0.98–1.76) in colon cancer patients. No association for OS, DFS or RFS was observed in rectal cancer patients. There was significant interaction of location of tumor (colon vs. rectal cancer) with DM on OS (P = 0.009) and DFS (P = 0.007). Conclusions: This study suggests that DM negatively impacts survival outcomes of patients with colon cancer but not rectal cancer

Funding structures for Build-to-Suit developments in Brazil: advantages and risks

Empreendimentos build-to-suit são aqueles em que o locador desenvolve um imóvel sob medida para o locatário, que o ocupará pelo prazo previsto em contrato. Dadas as peculiaridades desse tipo de contrato no contexto do real estate, o objetivo deste artigo é analisar as diferentes origens de recursos (fontes de funding) e a forma como eles são empregados (estruturas de funding) para desenvolver os empreendimentos, e discutir as vantagens e riscos dessas estruturas de funding do ponto de vista do empreendedor, que também é o locador. De forma a desenvolver este estudo e formatar as estruturas de funding apresentadas, parte-se de uma revisão das\ud práticas atuais do mercado imobiliário brasileiro (através de notícias veiculadas\ud na mídia e de prospectos de negócios realizados), da literatura brasileira sobre o tema e do conhecimento gerado no Grupo de Real Estate da Escola Politécnica da USP. De maneira a verificar a validade legal das soluções, é realizada uma checagem com\ud base na legislação brasileira e nas normas da Comissão de Valores Mobiliários.\ud Considera-se fontes de funding aquelas tratadas (1) como equity: capital próprio do empreendedor, capital de parceiros (e sócios) no empreendimento na forma de dinheiro ou imóveis (notadamente, o terreno onde será construído o empreendimento), ou investimento de Fundo de Investimento Imobiliário (FII); e (2) como dívida: financiamento bancário, securitização dos recebíveis de aluguéis com CRI ou debêntures. As estruturas de funding apresentadas serão combinações dessas fontes. A análise evidencia que estruturas com financiamento por securitização e emissão de CRI são as mais adequadas de forma geral para os negócios, assim como o investimento completo por FII para negócios de maior porte e nos quais o FII é proprietário direto do empreendimento. \ud Palavras-chave: real estate, build-to-suit, locação, funding, project financeBuild-to-suit real estate assets are tailor made developments for the tenant purposes, who occupies and operates the property for the duration agreed. Given the peculiarities of these contracts and the specificities of the property, this article aims at analyzing the sources of capital and how these funds are mixed and structured for the developments. The article discusses the risks and benefits of each of these funding\ud structures assuming the role of developer. In order to do this study and establish the funding structures shown, the research starts with a review of the current practices in Brazilian real estate market (based on press releases and prospects of deals), of local research papers, and will use the knowledge created at the Real Estate Research Group at Escola Politécnica at Universidade de São Paulo. Since it’s necessary to validate\ud the solutions proposed, Brazilian laws and Comissão de Valores Mobiliários (CVM) norms\ud are reviewed. Funding sources considered will be treated as (1) equity: developers own funds, partnership (via capital or real state – mainly land – investment), or Fundo de Investimento Imobiliário (Brazilian investment structure comparable to REITs); or as (2) debt: banks traditional credit lines, securitization of receivables with CRI emissions\ud , and debt bond emissions. The funding structures presented are mixes of these sources. The analysis shows that the structures best suited for this purpose are those with debt by securitization with CRI emissions, along with the complete investment by a FII but only with large emissions and having the FII as the sole owner of the real estate. \ud Keywords: real estate, build-to-suit, rent, funding, project financ

Aerosol delivery of kinase-deficient Akt1 attenuates Clara cell injury induced by naphthalene in the lungs of dual luciferase mice

Conventional lung cancer therapies are associated with poor survival rates; therefore, new approaches such as gene therapy are required for treating cancer. Gene therapies for treating lung cancer patients can involve several approaches. Among these, aerosol gene delivery is a potentially more effective approach. In this study, Akt1 kinase-deficient (KD) and wild-type (WT) Akt1 were delivered to the lungs of CMV-LucR-cMyc-IRES-LucF dual reporter mice through a nose only inhalation system using glucosylated polyethylenimine and naphthalene was administrated to the mice via intraperitoneal injection. Aerosol delivery of Akt1 WT and naphthalene treatment increased protein levels of downstream substrates of Akt signaling pathway while aerosol delivery of Akt1 KD did not. Our results showed that naphthalene affected extracellular signal-regulated kinase (ERK) protein levels, ERK-related signaling, and induced Clara cell injury. However, Clara cell injury induced by naphthalene was considerably attenuated in mice exposed to Akt1 KD. Furthermore, a dual luciferase activity assay showed that aerosol delivery of Akt1 WT and naphthalene treatment enhanced cap-dependent protein translation, while reduced cap-dependent protein translation was observed after delivering Akt1 KD. These studies demonstrated that our aerosol delivery is compatible for in vivo gene delivery