Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide

Child Protective Service Referrals Involving Exposure to Domestic Violence: Prevalence, Associated Maltreatment Types, and Likelihood of Formal Case Openings

Childhood exposure to domestic violence (CEDV) is widely understood as potentially harmful to children. Accordingly, many child welfare systems in the United States construe CEDV as maltreatment when the exposure results in harm or threatened harm to the child. The purpose of the current study was to investigate substantiated child welfare referrals directly related to CEDV to better understand the prevalence and patterns of CEDV-related maltreatment and how child welfare workers respond under the “harm or threatened harm” standard. Data were drawn from 23,704 substantiated referrals between 2009 and 2013 in a large Midwestern child welfare system. Approximately 20% of substantiated referrals were CEDV related. A plurality of CEDV-related referrals included both a male caregiver and female caregiver who were co-substantiated for maltreatment. The most common maltreatment types substantiated for these referrals were neglect based rather than abuse based, and just under a quarter (23%) of CEDV-related referrals were formally opened for services. Referrals involving co-occurring substance abuse were most likely to be opened for services based on predicted probabilities derived from multilevel modeling. Implications for policy and practice are considered

Sustainable Drag Reduction in Turbulent Taylor-Couette Flows by Depositing Sprayable Superhydrophobic Surfaces

We demonstrate a reduction in the measured inner wall shear stress in moderately turbulent Taylor-Couette flows by depositing sprayable superhydrophobic microstructures on the inner rotor surface. The magnitude of reduction becomes progressively larger as the Reynolds number increases up to a value of 22% at Re=8.0×10[superscript 4]. We show that the mean skin friction coefficient C[subscript f] in the presence of the superhydrophobic coating can be fitted to a modified Prandtl–von Karman–type relationship of the form (C[subscript f]/2)[[superscript -1/2] = Mln (Re(C[subscript f]/2)[[superscript 1/2]) + N + (b/Δr)Re(C[subscript f]/2)[superscript 1/2] from which we extract an effective slip length of b ≈ 19  μm. The dimensionless effective slip length b[superscript +] = b/δ[subscript ν], where δ[subscript ν] is the viscous length scale, is the key parameter that governs the drag reduction and is shown to scale as b[[superscript +] ~ Re[superscript 1/2] in the limit of high Re.United States. Office of Naval Research (Contract 3002453814

Renewed investigations at Taung; 90 years after the discovery of Australopithecus africanus

2015 marked the 90th anniversary of the description of the first fossil ofAustralopithecus africanus, commonly known as the Taung Child, which was unearthed during blasting at the Buxton-Norlim Limeworks (referred to as the BNL) 15 km SE of the town of Taung, South Africa. Subsequently, this site has been recognized as a UNESCOWorld Heritage site on the basis of its importance to southern African palaeoanthropology. Some other sites such as Equus Cave and Black Earth Cave have also been investigated; but the latter not since the 1940s. These sites indicate that the complex of palaeontological and archaeological localities at the BNL preserve a time sequence spanning the Pliocene to the Holocene. The relationship of these various sites and how they fit into the sequence of formation of tufa, landscapes and caves at the limeworks have also not been investigated or discussed in detail since Peabody’s efforts in the 1940s. In this contribution we mark the 90th anniversary of the discovery and description of the Taung Child by providing a critical review of previous work at Taung based on our recent preliminary work at the site. This includes a reassessment of the Taung Child Type Site, as well as renewed excavations at Equus Cave and the lesser-known locality and little-investigated Black Earth Cave. Preliminary results suggest that much of our previous understandings of the BNL’s formational history and site formation processes need to be reassessed. Only through detailed analysis on the BNLas a whole can we understand this complex depositional environment.Australian Research Council Future Fellowship grant FT120100399 Palaeontological Scientific Trust (PAST) National Geographic grants (8774-10 and 3212)JNC2016https://www.wits.ac.za/esi/palaeontologia-africana

Interfacial-Redox-Induced Tuning of Superconductivity in YBa2Cu3O7-δ.

Solid-state ionic approaches for modifying ion distributions in getter/oxide heterostructures offer exciting potentials to control material properties. Here, we report a simple, scalable approach allowing for manipulation of the superconducting transition in optimally doped YBa2Cu3O7-δ (YBCO) films via a chemically driven ionic migration mechanism. Using a thin Gd capping layer of up to 20 nm deposited onto 100 nm thick epitaxial YBCO films, oxygen is found to leach from deep within the YBCO. Progressive reduction of the superconducting transition is observed, with complete suppression possible for a sufficiently thick Gd layer. These effects arise from the combined impact of redox-driven electron doping and modification of the YBCO microstructure due to oxygen migration and depletion. This work demonstrates an effective step toward total ionic tuning of superconductivity in oxides, an interface-induced effect that goes well into the quasi-bulk regime, opening-up possibilities for electric field manipulation

Electronic Medical Record Inaccuracies: Multicenter Analysis of Challenges with Modified Lung Cancer Screening Criteria.

The National Comprehensive Cancer Network expanded their lung cancer screening (LCS) criteria to comprise one additional clinical risk factor, including chronic obstructive pulmonary disease (COPD). The electronic medical record (EMR) is a source of clinical information that could identify high-risk populations for LCS, including a diagnosis of COPD; however, an unsubstantiated COPD diagnosis in the EMR may lead to inappropriate LCS referrals. We aimed to detect the prevalence of unsubstantiated COPD diagnosis in the EMR for LCS referrals, to determine the efficacy of utilizing the EMR as an accurate population-based eligibility screening trigger using modified clinical criteria. We performed a multicenter review of all individuals referred to three LCS programs from 2012 to 2015. Each individual\u27s EMR was searched for COPD diagnostic terms and the presence of a diagnostic pulmonary functionality test (PFT). An unsubstantiated COPD diagnosis was defined by an individual\u27s EMR containing a COPD term with no PFTs present, or the presence of PFTs without evidence of obstruction. A total of 2834 referred individuals were identified, of which 30% (840/2834) had a COPD term present in their EMR. Of these, 68% (571/840) were considered unsubstantiated diagnoses: 86% (489/571) due to absent PFTs and 14% (82/571) due to PFTs demonstrating no evidence of postbronchodilation obstruction. A large proportion of individuals referred for LCS may have an unsubstantiated COPD diagnosis within their EMR. Thus, utilizing the EMR as a population-based eligibility screening tool, employing expanded criteria, may lead to individuals being referred, potentially, inappropriately for LCS

Intestinal GUCY2C prevents TGF-β secretion coordinating desmoplasia and hyperproliferation in colorectal cancer.

Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-β secretion, activating fibroblasts through TGF-β type I receptors and Smad3 phosphorylation. In turn, activating TGF-β signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through cMET-dependent signaling. Elimination of GUCY2C signaling in mice (Gucy2c(-/-)) produces intestinal desmoplasia, with increased reactive myofibroblasts, which is suppressed by anti-TGF-β antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-β and HGF. In that context, GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. The recent regulatory approval of oral GUCY2C ligands to treat chronic gastrointestinal disorders underscores the potential therapeutic opportunity for oral GUCY2C hormone replacement to prevent remodeling of the microenvironment essential for colorectal tumorigenesis