A Novel Pseudopodial Component of the Dendritic Cell Anti-Fungal Response: The Fungipod

Fungal pathologies are seen in immunocompromised and healthy humans. C-type lectins expressed on immature dendritic cells (DC) recognize fungi. We report a novel dorsal pseudopodial protrusion, the “fungipod”, formed by DC after contact with yeast cell walls. These structures have a convoluted cell-proximal end and a smooth distal end. They persist for hours, exhibit noticeable growth and total 13.7±5.6 µm long and 1.8±0.67 µm wide at the contact. Fungipods contain clathrin and an actin core surrounded by a sheath of cortactin. The actin cytoskeleton, but not microtubules, is required for fungipod integrity and growth. An apparent rearward flow (225±55 nm/second) exists from the zymosan contact site into the distal fungipod. The phagocytic receptor Dectin-1 is not required for fungipod formation, but CD206 (Mannose Receptor) is the generative receptor for these protrusions. The human pathogen Candida parapsilosis induces DC fungipod formation strongly, but the response is species specific since the related fungal pathogens Candida tropicalis and Candida albicans induce very few and no fungipods, respectively. Our findings show that fungipods are dynamic actin-driven cellular structures involved in fungal recognition by DC. They may promote yeast particle phagocytosis by DC and are a specific response to large (i.e., 5 µm) particulate ligands. Our work also highlights the importance of this novel protrusive structure to innate immune recognition of medically significant Candida yeasts in a species specific fashion

Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer

Introduction: The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, namely CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Over-expression of cyclin D-1 protein, however, confers tamoxifen resistance but not a tamoxifen-induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein over-expression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we examined a selected marker for this event. Method: Array comparative genomic hybridization analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients who were randomly assigned to either tamoxifen or no adjuvant treatment. The protein expression was also compared with gene expression data in a subset of 56 breast cancer samples. Results: Cortactin and FADD (Fas-associated death domain) over-expression was linked to CCND1 amplification, determined by fluorescence in situ hybridization, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1 (checkpoint kinase 1), was associated with an impaired tamoxifen response, and interestingly with low proliferative breast cancer of low grade. For Pak1 (p21-activated kinase 1) and cyclin D-1 the protein expression corresponded to the gene expression data. Conclusions: The results indicate that many 11q13 associated gene products are over-expressed in conjunction with cyclin D-1 but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response

Arp2/3 Complex Regulates Asymmetric Division and Cytokinesis in Mouse Oocytes

Mammalian oocyte meiotic maturation involves oocyte polarization and a unique asymmetric division, but until now, the underlying mechanisms have been poorly understood. Arp2/3 complex has been shown to regulate actin nucleation and is widely involved in a diverse range of processes such as cell locomotion, phagocytosis and the establishment of cell polarity. Whether Arp2/3 complex participates in oocyte polarization and asymmetric division is unknown. The present study investigated the expression and functions of Arp2/3 complex during mouse oocyte meiotic maturation. Immunofluorescent staining showed that the Arp2/3 complex was restricted to the cortex, with a thickened cap above the meiotic apparatus, and that this localization pattern was depended on actin. Disruption of Arp2/3 complex by a newly-found specific inhibitor CK666, as well as by Arpc2 and Arpc3 RNAi, resulted in a range of effects. These included the failure of asymmetric division, spindle migration, and the formation and completion of oocyte cytokinesis. The formation of the actin cap and cortical granule-free domain (CGFD) was also disrupted, which further confirmed the disruption of spindle migration. Our data suggest that the Arp2/3 complex probably regulates oocyte polarization through its effect on spindle migration, asymmetric division and cytokinesis during mouse oocyte meiotic maturation

Soccer and homosexuality: the conflicts that lie within the affective game of the coach-adolescent athlete relationship

Discussions regarding homosexuality within a sports context are mediated by emotional nuances, especially in the world of soccer, where practitioners are required to have attributes such as strength, masculinity and aggressiveness. As a consequence, this work aimed to analyze the symbolic representation of homosexual relationships between adolescent soccer players and their coaches; and, furthermore, to understand the intention behind homoerotic relationships that are established between members of the management team and its players. In this study, researchers used the life history methodology, with participation from three adolescent athletes, ages 14, 15 and 16, and three former athletes, ages 26, 28 and 45, who we called speakers. Based on the collection and analysis of research participants’ testimonies, homosexual relations were found to have occurred between athletes and coaches, or between athletes and other members of the management team, as a part of a “social contract” that is exclusively linked to their professional objectives. These relationships appear to be purely objective; authentic affective links are absent, due apparently to the transient nature of the athletes in these groups. Too, this context is usually marked by the athlete’s physical and emotional vulnerability, and the agreements he makes within this context are accompanied with moral dilemmas, because such adolescents idealize the coach as a paternal archetype.“Futebol e homossexualidade: Os conflitos que se encontram dentro do jogo afetivo da relação treinador-atleta adolescente.” As discussões a respeito da homossexualidade no contexto esportivo são mediadas por nuanças emocionais, especialmente no mundo do futebol que exige de seus praticantes atributos de força, virilidade e agressividade. Por este motivo este trabalho teve como objetivos diagnosticar existência de relações homossexuais entre atletas adolescentes da modalidade de futebol e seus técnicos e sua representação simbólica e ainda, compreender a intencionalidade das relações homoafetivas que se estabelecem entre componentes da equipe diretiva e os jogadores. Esta pesquisa é de natureza qualitativa e a técnica adotada foi a “história de vida” e a participação de três atletas adolescentes em atividade, com idade de 14, 15 e 16 anos e três ex-atletas profissionais, com idades 26, 28 e 45 anos serviram de base metodológica. A partir da análise e tratamento dos depoimentos verificou-se que ocorreram relações homossexuais nas categorias de base envolvendo técnico e atleta, ou com outros membros da equipe diretiva, como parte dos contratos sociais, ligados exclusivamente a objetivos profissionais. Estas relações parecem ser puramente objetais, não parecendo existir vínculos afetivos duradouros, aparentemente, devido à natureza transitória de atletas nesses grupos. Também, nesses ambientes, muitas vezes marcados pela vulnerabilidade física e emocional dos atletas, os acertos para as relações homossexuais são permeadas por dilemas morais, tendo em vista que os atletas adolescentes idealizam o treinador como o arquétipo paterno ideal.“El fútbol y la homosexualidad: Los conflictos que se encuentran dentro del juego afectivo de la relación atleta-entrenador de los adolescentes.” Las discusiones sobre la homosexualidad en contexto deportivo están mediadas por matices emocionales, sobre todo en el mundo del fútbol que exige a sus jugadores atributos como la fuerza, la virilidad y los jugadores. En este estudio, los investigadores utilizaron la metodología de la historia de vida, con la participación de tres atletas adolescentes, con 14, 15 y 16 años, y tres ex atletas con 26, 28 y 45 años, que llamamos ‘oradores’. Basado en la recogida y análisis de testimonios de participantes en la investigación, se encontró que las relaciones homosexuales que se han producido entre los atletas y entrenadores, o entre atletas y otros miembros del equipo de gestión, son como parte de un “contrato social” que está vinculado exclusivamente a sus objetivos profesionales. Estas relaciones parecen ser solamente como un objeto; porque a veces no hay vínculos afectivos auténticos, debido aparentemente a la naturaleza transitoria de los atletas en estos grupos. Demasiado, este contexto es generalmente marcado por la vulnerabilidad física y emocional del deportista, y los acuerdos que hace dentro de este contexto se acompañan con dilemas morales, debido a que tales adolescentes idealizan el entrenador como un arquetipo paterno. la agresividad. Por lo tanto, este estudio tuvo como objetivo diagnosticar la existencia de relaciones homosexuales entre adolescentes atletas de fútbol y sus entrenadores y la representación simbólica de estas relaciones. También comprender la intencionalidad de las relaciones homoafetivas que se intercambian entre algunos componentes del equipo directivo y(undefined

Treatment of myofascial trigger points in common shoulder disorders by physical therapy: A randomized controlled trial [ISRCTN75722066]

Contains fulltext : 52454.pdf (publisher's version ) (Open Access

Too Big to Fail — U.S. Banks’ Regulatory Alchemy: Converting an Obscure Agency Footnote into an “At Will” Nullification of Dodd-Frank’s Regulation of the Multi-Trillion Dollar Financial Swaps Market

The multi-trillion-dollar market for, what was at that time wholly unregulated, over-the-counter derivatives (“swaps”) is widely viewed as a principal cause of the 2008 worldwide financial meltdown. The Dodd-Frank Act, signed into law on July 21, 2010, was expressly considered by Congress to be a remedy for this troublesome deregulatory problem. The legislation required the swaps market to comply with a host of business conduct and anti-competitive protections, including that the swaps market be fully transparent to U.S. financial regulators, collateralized, and capitalized. The statute also expressly provides that it would cover foreign subsidiaries of big U.S. financial institutions if their swaps trading could adversely impact the U.S. economy or represent the use of extraterritorial trades as an attempt to “evade” Dodd-Frank. In July 2013, the CFTC promulgated an 80-page, triple-columned, and single-spaced “guidance” implementing Dodd-Frank’s extraterritorial reach, i.e., that manner in which Dodd-Frank would apply to swaps transactions executed outside the United States. The key point of that guidance was that swaps trading within the “guaranteed” foreign subsidiaries of U.S. bank holding company swaps dealers were subject to all of Dodd-Frank’s swaps regulations wherever in the world those subsidiaries’ swaps were executed. At that time, the standardized industry swaps agreement contemplated that, inter alia, U.S. bank holding company swaps dealers’ foreign subsidiaries would be “guaranteed” by their corporate parent, as was true since 1992. In August 2013, without notifying the CFTC, the principal U.S. bank holding company swaps dealer trade association privately circulated to its members standard contractual language that would, for the first time, “deguarantee” their foreign subsidiaries. By relying only on the obscure footnote 563 of the CFTC guidance’s 662 footnotes, the trade association assured its swaps dealer members that the newly deguaranteed foreign subsidiaries could (if they so chose) no longer be subject to Dodd-Frank. As a result, it has been reported (and it also has been understood by many experts within the swaps industry) that a substantial portion of the U.S. swaps market has shifted from the large U.S. bank holding companies swaps dealers and their U.S. affiliates to their newly deguaranteed “foreign” subsidiaries, with the attendant claim by these huge big U.S. bank swaps dealers that Dodd-Frank swaps regulation would not apply to these transactions. The CFTC also soon discovered that these huge U.S. bank holding company swaps dealers were “arranging, negotiating, and executing” (“ANE”) these swaps in the United States with U.S. bank personnel and, only after execution in the U.S., were these swaps formally “assigned” to the U.S. banks’ newly “deguaranteed” foreign subsidiaries with the accompanying claim that these swaps, even though executed in the U.S., were not covered by Dodd-Frank. In October 2016, the CFTC proposed a rule that would have closed the “deguarantee” and “ANE” loopholes completely. However, because it usually takes at least a year to finalize a “proposed” rule, this proposed rule closing the loopholes in question was not finalized prior to the inauguration of President Trump. All indications are that it will never be finalized during a Trump Administration. Thus, in the shadow of the recent tenth anniversary of the Lehman failure, there is an understanding among many market regulators and swaps trading experts that large portions of the swaps market have moved from U.S. bank holding company swaps dealers and their U.S. affiliates to their newly deguaranteed foreign affiliates where Dodd- Frank swaps regulation is not being followed. However, what has not moved abroad is the very real obligation of the lender of last resort to rescue these U.S. swaps dealer bank holding companies if they fail because of poorly regulated swaps in their deguaranteed foreign subsidiaries, i.e., the U.S. taxpayer. While relief is unlikely to be forthcoming from the Trump Administration or the Republican-controlled Senate, some other means will have to be found to avert another multi-trillion-dollar bank bailout and/or a financial calamity caused by poorly regulated swaps on the books of big U.S. banks. This paper notes that the relevant statutory framework affords state attorneys general and state financial regulators the right to bring so-called “parens patriae” actions in federal district court to enforce, inter alia, Dodd- Frank on behalf of a state’s citizens. That kind of litigation to enforce the statute’s extraterritorial provisions is now badly needed

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

Controls on subaerial erosion rates in Antarctica

Erosion rates offer insight on landscape development and the relative importance of chemical and physical processes of weathering. Minimal chemical weathering makes Antarctica an ideal location in which to compare the physical weathering of carbonate rocks to other lithologies. Here we report the first cosmogenic nuclide-derived erosion rates for carbonate rocks in Antarctica. Carbonate samples collected in the southernmost Ellsworth Mountains reflect a 36Cl erosion rate of 0.22 ± 0.02 mm/ka. This erosion rate is consistent with other reported Antarctic erosion rates, but is lower than 36Cl erosion rates derived from other arid regions in the world. These results are integrated with a continent-wide reanalysis of 28 erosion rate studies (>200 measurements), which comprise numerous rock types and other cosmogenic nuclides. By combining cosmogenic nuclide-derived erosion rates across studies, the larger trends provide insight into factors (e.g. lithology, glacial history, and availability of abrasive material) affecting subaerial erosion rates in Antarctica. Statistical analysis of the compiled data set shows differences based on lithology, with sandstone having the largest range of erosion rates. The compiled data also reveals higher erosion rates in areas with a large potential sediment supply, like the Dry Valleys. Samples collected from boulders yield lower erosion rates than those collected from bedrock, likely due to a combination of physical processes that affect boulders and bedrock differently, and glacial history, which can affect the apparent cosmogenic-nuclide derived erosion rate