467 research outputs found

    Compact Saloplastic Poly(Acrylic Acid)/Poly(Allylamine) Complexes: Kinetic Control Over Composition, Microstructure, and Mechanical Properties

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    Durable compact polyelectrolyte complexes (CoPECs) with controlled porosity and mechanical properties are prepared by ultracentrifugation. Because thestarting materials, poly(allylamine hydrochloride) (PAH) and poly(acrylic acidsodium salt) (PAA), are weak acids/bases, both composition and morphology are controlled by solution pH. In addition, the nonequilibrium nature of polyelectrolyte complexation can be exploited to provide a range of compositions and porosities under the infl uence of polyelectrolyte addition order and speed, and concentration. Confocal microscopy shows these “saloplastic” materials to be highly porous, where pore formation is attributed to a combination of deswelling of the polyelectrolyte matrix and expansion of small inhomogenities by osmotic pressure. The porosity (15–70%) and the pore size ( < 5 μ m to > 70 μ m) of these materials can be tuned by adjusting the PAA to PAH ratio, the salt concentration, and the pH. The modulus of these CoPECs depends on the ratio of the two polyelectrolytes, with stoichiometric complexes being the stiffest due to optimized charge pairing, which correlates with maximized crosslinking density. Mechanical properties, pore sizes, and pore density of these materials make them well suited to three dimensional supports for tissue engineering applications

    Functional consequences of seven novel mutations in the CYP11B1 Gene: four mutations associated with nonclassic and three mutations causing classic 11 -Hydroxylase Deficiency

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    Context: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. Objective: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. Methods: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. Results: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11β-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. Conclusion: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling i

    On the benefits of rubbing salt in the cut: self-healing of saloplastic PAA/PAH compact polyelectrolyte complexes.

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    The inherent room temperature mending and self-healing properties of saloplastic PAA/PAH CoPECs are studied. After ultracentrifugation of PAA/PAH polyelectrolyte complexes, tough, elastic materials are obtained that undergo self-healing facilitated by salt. At intermediate salt concentrations the CoPECs remain elastic enough to recover their original shape while the chains are mobile enough to repair the cut, thus leading to actual self-healing behavior.journal articleresearch support, non-u.s. gov'tresearch support, u.s. gov't, non-p.h.s.2014 Apr 232014 01 29importe

    Catalytic Saloplastics: Alkaline Phosphatase Immobilized and Stabilized in Compacted Polyelectrolyte Complexes

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    Novel biochemically active compact polyelectrolyte complexes (CoPECs) are obtained through a simple coprecipitation and compaction procedure. As shown for the system composed of poly(acrylic acid) (PAA) and poly(allylamine) (PAH) as polyelectrolytes and alkaline phosphatase (ALP) as enzyme, the enzyme can be firmly immobilized into these materials. The ALP not only remains active in these materials, but the matrix also enhances the specific activity of the enzyme while protecting it from deactivation at higher temperature. The presence of the matrix allows fine control and substantial enhancement of reaction rates by varying the salt concentration of the contacting solution or temperature. The excellent reusability, together with the ease of co-immobilizing other useful components, such as magnetic particles, allowing facile handling of the CoPECs, makes these materials interesting candidates for variable scaffolds for the immobilization of enzymes for small- and large-scale enzyme-catalyzed processes

    On the Benefits of Rubbing Salt in the Cut: Self-Healing of Saloplastic PAA/PAH Compact Polyelectrolyte Complexes

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    The inherent room temperature mending and self-healing properties of saloplastic PAA/PAH CoPECs are studied. After ultracentrifugation of PAA/PAH polyelectrolyte complexes, tough, elastic materials are obtained that undergo self-healing facilitated by salt. At intermediate salt concentrations the CoPECs remain elastic enough to recover their original shape while the chains are mobile enough to repair the cut, thus leading to actual self-healing behavior

    The Q2Q^2-dependence of the generalised Gerasimov-Drell-Hearn integral for the deuteron, proton and neutron

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    The Gerasimov-Drell-Hearn (GDH) sum rule connects the anomalous contribution to the magnetic moment of the target nucleus with an energy-weighted integral of the difference of the helicity-dependent photoabsorption cross sections. The data collected by HERMES with a deuterium target are presented together with a re-analysis of previous measurements on the proton. This provides a measurement of the generalised GDH integral covering simultaneously the nucleon-resonance and the deep inelastic scattering regions. The contribution of the nucleon-resonance region is seen to decrease rapidly with increasing Q2Q^2. The DIS contribution is sizeable over the full measured range, even down to the lowest measured Q2Q^2. As expected, at higher Q2Q^2 the data are found to be in agreement with previous measurements of the first moment of g1g_1. From data on the deuteron and proton, the GDH integral for the neutron has been derived and the proton--neutron difference evaluated. This difference is found to satisfy the fundamental Bjorken sum rule at Q2=5Q^2 = 5 GeV2^2.Comment: 12 pages, 10 figure

    Venous thromboembolism in Cushing syndrome:results from an EuRRECa and Endo-ERN survey

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    Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG’s) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3–30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.</p

    Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis

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    Introduction: Rheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord (UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were evaluated. Methods: The effects of UC-MSCs on the responses of fibroblast-like synoviocytes (FLSs) and T cells in RA patients were explored. The possible molecular mechanism mediating this immunosuppressive effect of UC-MSCs was explored by addition of inhibitors to indoleamine 2,3-dioxygenase (IDO), Nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor beta 1 (TGF-beta 1) and interleukin 10 (IL-10). The therapeutic effects of systemic infusion of human UC-MSCs on collagen-induced arthritis (CIA) in a mouse model were explored. Results: In vitro, UC-MSCs were capable of inhibiting proliferation of FLSs from RA patients, via IL-10, IDO and TGF-beta 1. Furthermore, the invasive behavior and IL-6 secretion of FLSs were also significantly suppressed. On the other hand, UC-MSCs induced hyporesponsiveness of T cells mediated by PGE2, TGF-beta 1 and NO and UC-MSCs could promote the expansion of CD4(+) Foxp3(+) regulatory T cells from RA patients. More importantly, systemic infusion of human UC-MSCs reduced the severity of CIA in a mouse model. Consistently, there were reduced levels of proinflammatory cytokines and chemokines (TNF-alpha, IL-6 and monocyte chemoattractant protein-1) and increased levels of the anti-inflammatory/regulatory cytokine (IL-10) in sera of UC-MSCs treated mice. Moreover, such treatment shifted Th1/Th2 type responses and induced Tregs in CIA. Conclusions: In conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000287517000020&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701RheumatologySCI(E)PubMed64ARTICLE6R2101

    Alternative pathway androgen biosynthesis and human fetal female virilization

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    Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography–tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography–mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
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