Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells.

Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell-mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1⁺ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases.

Characterization of lower-limbs inter-segment coordination during the take-off extension in ski jumping.

Take-off, the most important phase in ski jumping, has been primarily studied in terms of spatio-temporal parameters; little is known about its motor control aspects. This study aims to assess the inter-segment coordination of the shank-thigh and thigh-sacrum pairs using the continuous relative phase (CRP). In total 87 jumps were recorded from 33 athletes with an inertial sensor-based system. The CRP curves indicated that the thighs lead the shanks during the first part of take-off extension and that the shanks rotated faster at the take-off extension end. The thighs and sacrum first rotated synchronously, with the sacrum then taking lead, with finally the thighs rotating faster. Five characteristic features were extracted from the CRP and their relationship with jump length was tested. Three features of the shank-thigh pair and one of the thigh-sacrum pair reported a significant association with jump length. It was observed that athletes who achieved longer jumps had their thighs leading their shanks during a longer time, with these athletes also having a more symmetric movement between thighs and sacrum. This study shows that inter-segment coordination during the take-off extension is related to performance and further studies are necessary to contrast its importance with other ski jumping aspects.

Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible?. Plattenepithelkarzinom des Larynx mit subglottischer Ausdehnung: ist ein Larynxerhalt möglich ?

PURPOSE: Squamous cell carcinoma of larynx with subglottic extension (sSCC) is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of larynx preservation in sSCC patients. PATIENTS AND METHODS: Between 1996 and 2012, 197 patients with sSCC were treated at our institution and included in the analysis. Stage III-IV tumors accounted for 76 %. Patients received surgery (62 %), radiotherapy (RT) (18 %), or induction chemotherapy (CT) (20 %) as front-line therapy. RESULTS: The 5-year actuarial overall survival (OS), locoregional control (LRC), and distant control rate were 59 % (95 % CI 51-68), 83 % (95 % CI 77-89), and 88 % (95 % CI 83-93), respectively, with a median follow-up of 54.4 months. There was no difference in OS and LRC according to front-line treatments or between primary subglottic cancer and glottosupraglottic cancers with subglottic extension. In the multivariate analysis, age > 60 years and positive N stage were the only predictors for OS (HR 2, 95 % CI 1.2-3.6; HR1.9, 95 % CI 1-3.5, respectively). A lower LRC was observed for T3 patients receiving a larynx preservation protocol as compared with those receiving a front-line surgery (HR 14.1, 95 % CI 2.5-136.7; p = 0.02); however, no difference of ultimate LRC was observed according to the first therapy when including T3 patients who underwent salvage laryngectomy (p = 0.6). In patients receiving a larynx preservation protocol, the 5-year larynx-preservation rate was 55 % (95 % CI 43-68), with 36 % in T3 patients. The 5-year larynx preservation rate was 81 % (95 % CI 65-96) and 35 % (95 % CI 20-51) for patients who received RT or induction CT as a front-line treatment, respectively. CONCLUSION: Outcomes of sSCC are comparable with other laryngeal cancers when managed with modern therapeutic options. Larynx-preservation protocols could be a suitable option in T1-T2 (RT or chemo-RT) and selected T3 sSCC patients (induction CT).

Bailey Avenue extension, dedication, September 4, 1986

Program from the dedication ceremony of the Bailey Avenue Extension from the RISE Program : "Revitalize Iowa's Sound Economy" program for the construction and improvement of Iowa's roads.

Mapping the transcription start points of the Staphylococcus aureus eap, emp, and vwb promoters reveals a conserved octanucleotide sequence that is essential for expression of these genes.

Mapping the transcription start points of the eap, emp, and vwb promoters revealed a conserved octanucleotide sequence (COS). Deleting this sequence abolished the expression of eap, emp, and vwb. However, electrophoretic mobility shift assays gave no evidence that this sequence was a binding site for SarA or SaeR, known regulators of eap and emp.

An Essential Role for Insulin and IGF1 Receptors in Regulating Sertoli Cell Proliferation, Testis Size, and FSH Action in Mice.

Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs). Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete. To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r), or both receptors specifically in the GC lineage or in SCs. Whereas ablation of insulin/IGF signaling appears dispensable for GCs and spermatogenesis, adult testes of mice lacking both Insr and Igf1r in SCs (SC-Insr;Igf1r) displayed a 75% reduction in testis size and daily sperm production as a result of a reduced proliferation rate of immature SCs during the late fetal and early neonatal testicular period. In addition, in vivo analyses revealed that FSH requires the insulin/IGF signaling pathway to mediate its proliferative effects on immature SCs. Collectively, these results emphasize the essential role played by growth factors of the insulin family in regulating the final number of SCs, testis size, and daily sperm output. They also indicate that the insulin/IGF signaling pathway is required for FSH-mediated SC proliferation.

Strigolactone Promotes Degradation of DWARF14, an α/β Hydrolase Essential for Strigolactone Signaling in Arabidopsis.

Strigolactones (SLs) are phytohormones that play a central role in regulating shoot branching. SL perception and signaling involves the F-box protein MAX2 and the hydrolase DWARF14 (D14), proposed to act as an SL receptor. We used strong loss-of-function alleles of the Arabidopsis thaliana D14 gene to characterize D14 function from early axillary bud development through to lateral shoot outgrowth and demonstrated a role of this gene in the control of flowering time. Our data show that D14 distribution in vivo overlaps with that reported for MAX2 at both the tissue and subcellular levels, allowing physical interactions between these proteins. Our grafting studies indicate that neither D14 mRNA nor the protein move over a long range upwards in the plant. Like MAX2, D14 is required locally in the aerial part of the plant to suppress shoot branching. We also identified a mechanism of SL-induced, MAX2-dependent proteasome-mediated degradation of D14. This negative feedback loop would cause a substantial drop in SL perception, which would effectively limit SL signaling duration and intensity.

Regulation of epithelial-mesenchymal IL-1 signaling by PPARbeta/delta is essential for skin homeostasis and wound healing.

Skin morphogenesis, maintenance, and healing after wounding require complex epithelial-mesenchymal interactions. In this study, we show that for skin homeostasis, interleukin-1 (IL-1) produced by keratinocytes activates peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARbeta/delta stimulates production of the secreted IL-1 receptor antagonist, which leads to an autocrine decrease in IL-1 signaling pathways and consequently decreases production of secreted mitogenic factors by the fibroblasts. This fibroblast PPARbeta/delta regulation of the IL-1 signaling is required for proper wound healing and can regulate tumor as well as normal human keratinocyte cell proliferation. Together, these findings provide evidence for a novel homeostatic control of keratinocyte proliferation and differentiation mediated via PPARbeta/delta regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARbeta/delta, other epithelial-mesenchymal interactions may also be regulated in a similar manner.

Instrumental leadership: An extension of the Full-Range Leadership Theory

From a theoretical perspective, an extension to the Full Range leadership Theory (FRLT) seems needed. In this paper, we explain why instrumental leadership--a class of leadership includes leader behaviors focusing on task and strategic aspects that are neither values nor exchange oriented--can fulfill this extension. Instrument leadership is composed of four factors: environmental monitoring, strategy formulation and implementation, path-goal facilitation and outcome monitoring; these aspects of leadership are currently not included in any of the FRLT's nine leadership scales (as measured by the MLQ--Multifactor Leadership Questionnaire). We present results from two empirical studies using very large samples from a wide array of countries (N > 3,000) to examine the factorial, discriminant and criterion-related validity of the instrumental leadership scales. We find support for a four-factor instrumental leadership model, which explains incremental variance in leader outcomes in over and above transactional and transformational leadership.

The Iowa State Capitol Grounds 1913 Extension and Reconstruction Project, October 2012

The Capitol grounds have been evolving through planned and unplanned actions for more than 150 years. The 1857 Constitutio established Des Moines as the capital. The commissioners appointed to choose a site decided on land donated by Wilson Alexander Scott and Harrison Lyon. Located on the east side of the Des Moines River, on a gently rising hill, the site for the Iowa State Capitol began with fewer than 10 acres. The Old Brick Capitol was built in the center of that 10-acre plot, and the area to the north was used as a public park until work began on the present day Capitol. In 1884, the two-year process of moving from the Old Brick Capitol to the new Capitol began. The state commissioned John Weidenman to design the first formal decoration of the grounds. Weidenman’s plans for the west approach to the Capitol included planting statues, and walkways. The State held some additional land but not necessarily land adjacent to the Capitol. In 1909, legislation was passed, and in 1913, the Thirty-Fifth General Assembly enacted controversial legislation to acquire additional land. A commission was formed to locate a purposed monument honoring the long-serving U.S. Senator William B. Allison. E.L. Masqueray was hired as the architect expert focusing on the selection of a proper site for the proposed Allison Memorial. Masqueray’s plan detailed the placement of buildings and potential monuments. Growth of the Capitol Complex, as known today, began.

ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis.

The GTPases Rab3a and Rab27a and their effectors Granuphilin/Slp4 and Noc2 are essential regulators of neuroendocrine secretion. Chronic exposure of pancreatic beta-cells to supraphysiological glucose levels decreased selectively the expression of these proteins. This glucotoxic effect was mimicked by cAMP-raising agents and blocked by PKA inhibitors. We demonstrate that the transcriptional repressor ICER, which is induced in a PKA-dependent manner by chronic hyperglycemia and cAMP-raising agents, is responsible for the decline of the four genes. ICER overexpression diminished the level of Granuphilin, Noc2, Rab3a and Rab27a by binding to cAMP responsive elements located in the promoters of these genes and inhibited exocytosis of beta-cells in response to secretagogues. Moreover, the loss in the expression of the genes of the secretory machinery caused by glucose and cAMP-raising agents was prevented by an antisense construct that reduces ICER levels. We propose that induction of inappropriate ICER levels lead to defects in the secretory process of pancreatic beta-cells possibly contributing, in conjunction with other known deleterious effects of hyperglycemia, to defective insulin release in type 2 diabetes.

An essential role for the stalk region of CD8 beta in the coreceptor function of CD8.

The CD8alphabeta heterodimer is integral to the selection of the class I-restricted lineage in the thymus; however, the contribution of the CD8beta chain to coreceptor function is poorly understood. To understand whether the CD8beta membrane proximal stalk region played a role in coreceptor function, we substituted it with the corresponding sequence from the CD8alpha polypeptide and expressed the hybrid molecule in transgenic mice in place of endogenous CD8beta. Although the stalk-swapped CD8beta was expressed on the cell surface as a disulfide-bonded heterodimer at equivalent levels of expression to an endogenous CD8beta molecule, it failed to restore selection of CD8(+) class I MHC-restricted T cells and it altered the response of peripheral T cells. Thus, the stalk region of the CD8beta polypeptide has an essential role in ensuring functionality of the CD8alphabeta heterodimer and its replacement compromises the interaction of CD8 with peptide-MHC complexes.

Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis.

The treatment of advanced prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new cancer treatments. The Foxm1 transcription factor is highly up-regulated in tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific Probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40 large T antigen to induce PCa, loss of Foxm1 decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with a decrease in tumor cell proliferation and the down-regulation of genes critical for cell proliferation and tumor metastasis, including Cdc25b, Cyclin B1, Plk-1, Lox, and Versican. In addition, tumor-associated angiogenesis was decreased, coinciding with reduced Vegf-A expression. The mRNA and protein levels of 11β-Hsd2, an enzyme playing an important role in tumor cell proliferation, were down-regulated in Foxm1-deficient PCa tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11β-Hsd2 promoter through the -892/-879 region, indicating that 11β-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF) tumor suppressor caused a robust epithelial hyperplasia, but was insufficient to induce progression from hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for prostate cancer chemotherapy.