A study of Smad4, Smad6 and Smad7 in Surgically Resected Samples of Pancreatic Ductal Adenocarcinoma and Their Correlation with Clinicopathological Parameters and Patient Survival

<p>Abstract</p> <p>Background</p> <p>Smad4 is the common mediator of the tumor suppressive functions of TGF-beta. Smad6 and Smad7 are the antagonists of the TGF-beta pathway. This study investigates the differential protein expressions of Smad4, Smad6 and Smad7 in tumor as compared to normal tissue of pancreatic ductal adenocarcinoma (PDAC) and compares them with clinicopathological parameters and patient survival.</p> <p>Results</p> <p>There was a significant difference in protein expressions of Smad4 (p = 0.0001), Smad6 (p = 0.0015) and Smad7 (p = 0.0005) protein in tumor as compared to paired normal samples. Loss of Smad7 expression correlated significantly with tumor size (r = 0.421, p < 0.036) and margin status (r = 0.431; p < .032). Patients with moderate to high Smad4 protein expression had a better survival (median survival = 14.600 ± 2.112 months) than patients with absent or weak Smad4 protein expression (median survival = 7.150 ± 0.662). In addition, advanced disease stage correlated significantly with poor prognosis.</p> <p>Conclusion</p> <p>Loss of Smad4 significantly correlated with poor survival of PDAC patients. In the cases where Smad4 is expressed, Smad6 inhibition is possibly a novel mechanism for Smad4 inactivation. Smad7 has a role in pathobiology of PDAC. Further investigation in the roles of Smad6 and Smad7 would help in the identification of novel therapeutic targets for PDAC.</p

K-Decompositions and 3d Gauge Theories

This paper combines several new constructions in mathematics and physics. Mathematically, we study framed flat PGL(K,C)-connections on a large class of 3-manifolds M with boundary. We define a space L_K(M) of framed flat connections on the boundary of M that extend to M. Our goal is to understand an open part of L_K(M) as a Lagrangian in the symplectic space of framed flat connections on the boundary, and as a K_2-Lagrangian, meaning that the K_2-avatar of the symplectic form restricts to zero. We construct an open part of L_K(M) from data assigned to a hypersimplicial K-decomposition of an ideal triangulation of M, generalizing Thurston's gluing equations in 3d hyperbolic geometry, and combining them with the cluster coordinates for framed flat PGL(K)-connections on surfaces. Using a canonical map from the complex of configurations of decorated flags to the Bloch complex, we prove that any generic component of L_K(M) is K_2-isotropic if the boundary satisfies some topological constraints (Theorem 4.2). In some cases this implies that L_K(M) is K_2-Lagrangian. For general M, we extend a classic result of Neumann-Zagier on symplectic properties of PGL(2) gluing equations to reduce the K_2-Lagrangian property to a combinatorial claim. Physically, we use the symplectic properties of K-decompositions to construct 3d N=2 superconformal field theories T_K[M] corresponding (conjecturally) to the compactification of K M5-branes on M. This extends known constructions for K=2. Just as for K=2, the theories T_K[M] are described as IR fixed points of abelian Chern-Simons-matter theories. Changes of triangulation (2-3 moves) lead to abelian mirror symmetries that are all generated by the elementary duality between N_f=1 SQED and the XYZ model. In the large K limit, we find evidence that the degrees of freedom of T_K[M] grow cubically in K.Comment: 121 pages + 2 appendices, 80 figures; Version 2: reorganized mathematical perspective, swapped Sections 3 and

Dietary calcium and zinc deficiency risks are decreasing but remain prevalent

Globally, more than 800 million people are undernourished while >2 billion people have one or more chronic micronutrient deficiencies (MNDs). More than 6% of global mortality and morbidity burdens are associated with undernourishment and MNDs. Here we show that, in 2011, 3.5 and 1.1 billion people were at risk of calcium (Ca) and zinc (Zn) deficiency respectively due to inadequate dietary supply. The global mean dietary supply of Ca and Zn in 2011 was 684 ± 211 and 16 ± 3 mg capita−1 d−1 (±SD) respectively. Between 1992 and 2011, global risk of deficiency of Ca and Zn decreased from 76 to 51%, and 22 to 16%, respectively. Approximately 90% of those at risk of Ca and Zn deficiency in 2011 were in Africa and Asia. To our knowledge, these are the first global estimates of dietary Ca deficiency risks based on food supply. We conclude that continuing to reduce Ca and Zn deficiency risks through dietary diversification and food and agricultural interventions including fortification, crop breeding and use of micronutrient fertilisers will remain a significant challenge

Subjects with Knee Osteoarthritis Exhibit Widespread Hyperalgesia to Pressure and Cold

Hyperalgesia to mechanical and thermal stimuli are characteristics of a range of disorders such as tennis elbow, whiplash and fibromyalgia. This study evaluated the presence of local and widespread mechanical and thermal hyperalgesia in individuals with knee osteoarthritis, compared to healthy control subjects. Twenty-three subjects with knee osteoarthritis and 23 healthy controls, matched for age, gender and body mass index, were recruited for the study. Volunteers with any additional chronic pain conditions were excluded. Pain thresholds to pressure, cold and heat were tested at the knee, ipsilateral heel and ipsilateral elbow, in randomized order, using standardised methodology. Significant between-groups differences for pressure pain and cold pain thresholds were found with osteoarthritic subjects demonstrating significantly increased sensitivity to both pressure (p = .018) and cold (p = .003) stimuli, compared with controls. A similar pattern of results extended to the pain-free ipsilateral ankle and elbow indicating widespread pressure and cold hyperalgesia. No significant differences were found between groups for heat pain threshold, although correlations showed that subjects with greater sensitivity to pressure pain were also likely to be more sensitive to both cold pain and heat pain. This study found widespread elevated pain thresholds in subjects with painful knee osteoarthritis, suggesting that altered nociceptive system processing may play a role in ongoing arthritic pain for some patients

BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells

A dopaminergic switch for fear to safety transitions

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signalling when a better than expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signalling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. By contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioural roles for different dopamine neuron projections in fear extinction learning

Avian Pathogenic Escherichia coli (APEC) Infection Alters Bone Marrow Transcriptome in Chickens

Avian pathogenic Escherichia coli (APEC) is a major cause of disease impacting animal health. The bone marrow is the reservoir of immature immune cells; however, it has not been examined to date for gene expression related to developmental changes (cell differentiation, maturation, programming) after APEC infection. Here, we study gene expression in the bone marrow between infected and non-infected animals, and between infected animals with mild (resistant) versus severe (susceptible) pathology, at two times post-infection. We sequenced 24 bone marrow RNA libraries generated from the six different treatment groups with four replicates each, and obtained an average of 22 million single-end, 100-bp reads per library. Genes were detected as differentially expressed (DE) between APEC treatments (mild pathology, severe pathology, and mock-challenged) at a given time point, or DE between 1 and 5 days post-infection (dpi) within the same treatment group. Results demonstrate that many immune cells, genes and related pathways are key contributors to the different responses to APEC infection between susceptible and resistant birds and between susceptible and non-challenged birds, at both times post-infection. In susceptible birds, lymphocyte differentiation, proliferation, and maturation were greatly impaired, while the innate and adaptive immune responses, including dendritic cells, monocytes and killer cell activity, TLR- and NOD-like receptor signaling, as well as T helper cells and many cytokine activities, were markedly enhanced. The resistant birds’ immune system, however, was similar to that of non-challenged birds. The DE genes in the immune cells and identified signaling models are representative of activation and resolution of infection in susceptible birds at both post-infection days. These novel results characterizing transcriptomic response to APEC infection reveal that there is combinatorial activity of multiple genes controlling myeloid cells, and B and T cell lymphopoiesis, as well as immune responses occurring in the bone marrow in these early stages of response to infection

Precocious Metamorphosis in the Juvenile Hormone–Deficient Mutant of the Silkworm, Bombyx mori

Insect molting and metamorphosis are intricately governed by two hormones, ecdysteroids and juvenile hormones (JHs). JHs prevent precocious metamorphosis and allow the larva to undergo multiple rounds of molting until it attains the proper size for metamorphosis. In the silkworm, Bombyx mori, several “moltinism” mutations have been identified that exhibit variations in the number of larval molts; however, none of them have been characterized molecularly. Here we report the identification and characterization of the gene responsible for the dimolting (mod) mutant that undergoes precocious metamorphosis with fewer larval–larval molts. We show that the mod mutation results in complete loss of JHs in the larval hemolymph and that the mutant phenotype can be rescued by topical application of a JH analog. We performed positional cloning of mod and found a null mutation in the cytochrome P450 gene CYP15C1 in the mod allele. We also demonstrated that CYP15C1 is specifically expressed in the corpus allatum, an endocrine organ that synthesizes and secretes JHs. Furthermore, a biochemical experiment showed that CYP15C1 epoxidizes farnesoic acid to JH acid in a highly stereospecific manner. Precocious metamorphosis of mod larvae was rescued when the wild-type allele of CYP15C1 was expressed in transgenic mod larvae using the GAL4/UAS system. Our data therefore reveal that CYP15C1 is the gene responsible for the mod mutation and is essential for JH biosynthesis. Remarkably, precocious larval–pupal transition in mod larvae does not occur in the first or second instar, suggesting that authentic epoxidized JHs are not essential in very young larvae of B. mori. Our identification of a JH–deficient mutant in this model insect will lead to a greater understanding of the molecular basis of the hormonal control of development and metamorphosis

Interleukin-17 regulation: an attractive therapeutic approach for asthma

Interleukin (IL)-17 is recognized to play a critical role in numerous immune and inflammatory responses by regulating the expression of various inflammatory mediators, which include cytokines, chemokines, and adhesion molecules. There is growing evidence that IL-17 is involved in the pathogenesis of asthma. IL-17 orchestrates the neutrophilic influx into the airways and also enhances T-helper 2 (Th2) cell-mediated eosinophilic airway inflammation in asthma. Recent studies have demonstrated that not only inhibitor of IL-17 per se but also diverse regulators of IL-17 expression reduce antigen-induced airway inflammation, bronchial hyperresponsiveness, and Th2 cytokine levels in animal models of asthma. This review will summarize the role of IL-17 in the context of allergic airway inflammation and discuss the therapeutic potential of various strategies targeting IL-17 for asthma