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Introduction & Objective: Allergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest. As these PAMPs are recognized by specialized pattern recognition receptors (PRRs), this study aims at investigating the roles of intracellular PRRs and the inflammasome regulator NLRP3. Methods: We established a physiologically relevant intranasal and adjuvant-free sensitization procedure to study BP-induced systemic and local lung inflammation. Results: Strikingly, BP-sensitized Nlrp3-deficient mice showed significantly lower IgE levels, Th2-associated cytokines, cell infiltration into the lung, mucin production and epithelial thickening than their wild-type counterparts, which appears to be independent of inflammasome formation. Intriguingly, bone-marrow chimera revealed that expression of NLRP3 in the hematopoietic system is required to trigger an allergic response. Conclusion: Overall, this study identifies NLRP3 as an important driver of BP-induced allergic immune responses.
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Administração Intranasal , Alérgenos , Betula , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pólen , Animais , Camundongos , Alérgenos/imunologia , Betula/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Inflamassomos/metabolismo , Inflamassomos/imunologia , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Extratos Vegetais/farmacologia , Pólen/imunologia , Masculino , FemininoRESUMO
The American Pediatric Surgical Association (APSA) Practice Committee endorsed by the Board of Governors presents a Position Statement on the role of locum tenens in the practice of pediatric surgery. The Practice Committee also presents a set of guidelines for locum tenens practice. These recommendations highlight safe practice and quality care that protects the patient as well as the pediatric surgeon by offering best practice standards, defining optimal resources and establishing parameters by which hospitals and locum tenens agencies should abide. These guidelines are intended to foster discussion and contract negotiation as well as inform decision making for a) pediatric surgeons considering locum tenens opportunities, b) host organizations (hospitals and practices) seeking the coverage of a pediatric surgeon, and c) locum tenens companies vetting both surgeons and hospitals for appropriateness of such coverage. This Position Statement and foundational set of guidelines align with APSA's Vision (all children receive the highest quality surgical care) and Mission (to provide the best surgical care to our patients and families by supporting an inclusive community through education, discovery and advocacy).
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Polydimethylsiloxane (PDMS) organogel sponges were prepared and studied in order to understand the role of pore size in an elastomeric network on the ability to uptake and release organic solvents. PDMS organogel sponges have been produced according to sugar leaching techniques by adding two sugar templates of different forms and grain sizes (a sugar cube template and a powdered sugar template), in order to obtain materials differing in porosity, pore size distribution, and solvent absorption and liquid retention capability. These materials were compared to PDMS organogel slabs that do not contain pores. The sponges were characterized by Fourier-transform infrared spectroscopy with attenuated total reflectance (FTIR-ATR) and compared with PDMS slabs that do not contain pores. Scanning electron microscopy (SEM) provided information about their morphology. X-ray micro-tomography (XMT) allowed us to ascertain how the form of the sugar templating agent influences the porosity of the systems: when templated with sugar cubes, the porosity was 77% and the mean size of the pores was ca. 300 µm; when templated with powdered sugar, the porosity decreased to ca. 10% and the mean pore size was reduced to ca. 75 µm. These materials, porous organic polymers (POPs), can absorb many solvents in different proportions as a function of their polarity. Absorption capacity, as measured by swelling with eight solvents covering a wide range of polarities, was investigated. Rheology data established that solvent absorption did not have an appreciable impact on the gel-like properties of the sponges, suggesting their potential for applications in cultural heritage conservation. Application tests were conducted on the surfaces of two different lab mock-ups that simulate real painted works of art. They demonstrated further that PDMS sponges are a potential innovative support for controlled and selective cleaning of works of art surfaces.
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N-9-Fluorenylmethyloxycarbonyl (Fmoc)- and C-tertiary butyl (t-Bu)-protected glutamate (L-2), bearing a phenanthroline moiety at the side residue, forms 1D supramolecular assemblies via H-bonding as well as undergoing π-stacking interactions to afford crystals or gels that depend on the shape-complementarity of coexisting alcohols, as demonstrated by structural analyses on these assemblies by means of single-crystal X-ray diffractometry and supplemented with small- and wide-angle X-ray scattering data. Moreover, the rheological measurements on the gels help to define a model for when gels and crystals are expected and found. These observations and conclusions highlight an important, but not very appreciated, aspect of solute-solvent interactions within supramolecular assemblies that can allow the constituent-aggregating molecules in some systems to exhibit high selectivity toward the structures of their solvents. The consequences of this selectivity, as demonstrated here by single-crystal and powder X-ray diffraction data, can lead to self-assembled structures which alter completely the bulk phase properties and morphology of the materials. In that regard, rheological measurements have helped to develop a model to explain when gels and phase-separated mixtures of crystals and solvents are expected.
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INTRODUCTION: This study evaluated North American pediatric surgeons' opinions and knowledge of business and economics in medicine and their perceptions of trends in their healthcare delivery environment. METHODS: We conducted an elective online survey of 1119 American Pediatric Surgical Association members. Over 8 mo, we iteratively developed the survey focused on four areas: opinion, knowledge, current practice environment, and trends in practice environment over the past 5 y. RESULTS: We received 227 (20.3%) complete surveys from pediatric surgeons. One hundred ninety four (85.5%) perceive healthcare as a business and most (85.9%) believe healthcare decisions may affect patients' out-of-pocket expenses. More than half (51.1%) of surgeons believe it has become more challenging to perform emergent cases and most believe staff quality has decreased for elective (56.4%) and emergent (63.0%) cases over the past 5 y. CONCLUSIONS: Pediatric surgeons recognize that medicine is a business and have concerns regarding the decreasing quality of operating room staff and the increasing difficulty providing surgical care over the last 5 y.
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Especialidades Cirúrgicas , Cirurgiões , Criança , Humanos , Estados Unidos , Inquéritos e Questionários , Gastos em Saúde , ComércioRESUMO
The ion transport properties of ionomers comprised of polydimethylsiloxanes with amidinium or imidazolinium attached side chains and alkyldithiocarbamate anions (where alkyl is hexyl or octadecyl) have been investigated in chloroform solutions principally and as neat liquids. The influence of modifying the molecular weights of the polydimethylsiloxanes, the frequency of their amidininium or imidazolinium side groups, and temperature on the conductivity have been explored. When a solvent more polar than chloroform, syn-tetrachloroethane, was employed, a large increase in the ionic conductivity was found despite there being an increase in the viscosity of the solution. At least in these two solvents, polarity is more important in determining the conductivity than the viscosity. When normalized for ion content, Walden plots of the ionomer solutions at different ionomer concentrations approached values found for 1 M aqueous KCl. As neat liquids, the amidinium and imidazolinium hexyldithiocarbamate ionomers exceeded the values associated with the "superionic" region of the Walden plot (i.e., above the conductivity values for 1 M aqueous KCl). As ion content and polymer molecular weight increased, larger decoupling between bulk viscosity and ionic conductivity was noted, probably as a result of changes in the dynamic fragility of the ionomers.
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The progressive accumulation of misfolded α-synuclein (α-syn) in the brain is widely considered to be causal for the debilitating clinical manifestations of synucleinopathies including, most notably, Parkinson's disease (PD). Immunotherapies, both active and passive, against α-syn have been developed and are promising novel treatment strategies for such disorders. To increase the potency and specificity of PD vaccination, we created the 'Win the Skin Immune System Trick' (WISIT) vaccine platform designed to target skin-resident dendritic cells, inducing superior B and T cell responses. Of the six tested WISIT candidates, all elicited higher immune responses compared to conventional, aluminum adjuvanted peptide-carrier conjugate PD vaccines, in BALB/c mice. WISIT-induced antibodies displayed higher selectivity for α-syn aggregates than those induced by conventional vaccines. Additionally, antibodies induced by two selected candidates were shown to inhibit α-syn aggregation in a dose-dependent manner in vitro. To determine if α-syn fibril formation could also be inhibited in vivo, WISIT candidate type 1 (CW-type 1) was tested in an established synucleinopathy seeding model and demonstrated reduced propagation of synucleinopathy in vivo. Our studies provide proof-of-concept for the efficacy of the WISIT vaccine technology platform and support further preclinical and clinical development of this vaccine candidate.
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Ionomers, polysiloxanes with imidazolinium dithiocarbamate side chains, have been synthesized in situ from three uncharged components-a polysiloxane with imidazole side chains, CS2, and hexylamine or octadecylamine. Their structural and dynamic properties are compared over a temperature range of 0-50 °C with those of the analogous ionomers in which the polysiloxanes have amidinium side chains. The results, primarily from differential scanning calorimetry, powder X-ray diffraction measurements, and rheology show that the small structural (and smaller electronic) differences between the cyclic 5-membered ring imidazolinium and acyclic amidinium groups have marked effects on the bulk properties of the ionomers. These include their shear strengths and the manner in which the microcrystalline portions of the ionomers with dithiooctadecylcarbamate anions are packed. Thus, it is possible to finely tune the natures of the ionomers from one polysiloxane by changing temperature, the chain length of the alkylamine, and the nature of the base attached to the polysiloxane chain. Why these changes occur to the various properties is discussed.
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Patients with spinal cord injury (SCI) frequently develop infections that may affect quality of life, be life-threatening, and impair their neurological recovery in the acute and subacute injury phases. Therefore, identifying patients with SCI at risk for developing infections in this stage is of utmost importance. We determined the systemic levels of immune cell populations, cytokines, chemokines, and growth factors in 81 patients with traumatic SCI at 4 weeks after injury and compared them with those of 26 age-matched healthy control subjects. Patients who developed infections between 4 and 16 weeks after injury exhibited higher numbers of neutrophils and eosinophils, as well as lower numbers of lymphocytes and eotaxin-1 (CCL11) levels. Accordingly, lasso logistic regression showed that incomplete lesions (American Spinal Injury Association Impairment Scale [AIS] C and D grades), the levels of eotaxin-1, and the number of lymphocytes, basophils, and monocytes are predictive of lower odds for infections. On the other hand, the number of neutrophils and eosinophils as well as, in a lesser extent, the levels of IP-10 (CXCL10), MCP-1 (CCL2), BDNF [brain-derived neurotrophic factor], and vascular endothelial growth factor [VEGF]-A, are predictors of increased susceptibility for developing infections. Overall, our results point to systemic immune disbalance after SCI as predictors of infection in a period when infections may greatly interfere with neurological and functional recovery and suggest new pathways and players to further explore novel therapeutic strategies.
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Traumatismos da Medula Espinal , Fator A de Crescimento do Endotélio Vascular , Humanos , Qualidade de Vida , Recuperação de Função Fisiológica , Eosinófilos , Medula EspinalRESUMO
In ACTIVE, abaloparatide increased areal BMD (aBMD) of the hip and femoral neck vs teriparatide and placebo in women with osteoporosis. Previously, 3D-processing of dual X-ray absorptiometry (DXA) scans of a subgroup of ACTIVE subjects showed similar increases in trabecular volumetric BMD (Tb.vBMD) and greater increases in cortical vBMD (Ct.vBMD) of the total hip with abaloparatide vs teriparatide. The current analyses from this subgroup describe 2D- and 3D-DXA data for hip subregions. Randomly selected subjects from ACTIVE (nâ¯=â¯250/treatment group) who received 18 mo of placebo, abaloparatide 80 µg, or open-label teriparatide 20 µg by daily subcutaneous injection underwent hip DXA at baseline, and mo 6 and 18 of treatment. Areal BMD of the femoral neck, trochanter, and femoral shaft was determined using standard 2D-DXA and 3D-SHAPER software to retrospectively evaluate changes from baseline in volumetric parameters of these 3 hip subregions, including trabecular and cortical segmentation. Changes in biomechanical parameters cross-sectional moment of inertia (CSMI), section modulus (Z), and buckling ratio were also evaluated. Femoral neck, trochanter, and shaft aBMD increased in the abaloparatide and teriparatide groups at mo 6 and 18 vs placebo, with greater increases for abaloparatide vs teriparatide at the femoral neck at mo 6 and the shaft at mo 6 and 18. All 3 subregions showed similar significant increases in Tb.vBMD with abaloparatide and teriparatide vs placebo, whereas Ct.vBMD of all 3 subregions showed greater increases after 18 mo of abaloparatide vs teriparatide. Biomechanical parameters improved in all subregions with abaloparatide and teriparatide vs placebo, with greater improvements in CSMI and Z of the femoral neck and lower shaft after 6 and 18 mo of abaloparatide vs teriparatide. Differential femoral neck and shaft Ct.vBMD responses may explain the greater increases in CSMI and Z of those subregions with abaloparatide vs teriparatide.
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Osteoporose Pós-Menopausa , Absorciometria de Fóton , Densidade Óssea/fisiologia , Estudos Transversais , Feminino , Humanos , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo , Estudos Retrospectivos , Teriparatida/farmacologia , Teriparatida/uso terapêuticoRESUMO
BACKGROUND: Treatment of degenerating tendons still presents a major challenge, since the aetiology of tendinopathies remains poorly understood. Besides mechanical overuse, further known predisposing factors include rheumatoid arthritis, diabetes, obesity or smoking all of which combine with a systemic inflammation. METHODS: To determine whether the systemic inflammation accompanying these conditions contributes to the onset of tendinopathy, we studied the effect of a systemic inflammation induced by an allergic episode on tendon properties. To this end, we induced an allergic response in mice by exposing them to a timothy grass pollen allergen and subsequently analysed both their flexor and Achilles tendons. Additionally, we analysed data from a health survey comprising data from more than 10.000 persons for an association between the occurrence of an allergy and tendinopathy. FINDINGS: Biomechanical testing and histological analysis revealed that tendons from allergic mice not only showed a significant reduction of both elastic modulus and tensile stress, but also alterations of the tendon matrix. Moreover, treatment of 3D tendon-like constructs with sera from allergic mice resulted in a matrix-remodelling expression profile and the expression of macrophage-associated markers and matrix metalloproteinase 2 (MMP2) was increased in allergic Achilles tendons. Data from the human health study revealed that persons suffering from an allergy have an increased propensity to develop a tendinopathy. INTERPRETATION: Our study demonstrates that the presence of a systemic inflammation accompanying an allergic condition negatively impacts on tendon structure and function. FUNDING: This study was financially supported by the Fund for the Advancement of Scientific Research at Paracelsus Medical University (PMU-FFF E-15/22/115-LEK), by the Land Salzburg, the Salzburger Landeskliniken (SALK, the Health Care Provider of the University Hospitals Landeskrankenhaus and Christian Doppler Klinik), the Paracelsus Medical University, Salzburg and by unrestricted grants from Bayer, AstraZeneca, Sanofi-Aventis, Boehringer-Ingelheim.
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Tendão do Calcâneo , Hipersensibilidade , Tendinopatia , Tendão do Calcâneo/patologia , Animais , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/patologia , Inflamação/patologia , Metaloproteinase 2 da Matriz , Camundongos , Tendinopatia/etiologia , Tendinopatia/patologiaRESUMO
BACKGROUND: The 2020 Pediatric Surgery (PS) fellowship selection process was heavily impacted by the COVID-19 pandemic. A review of lessons learned can help determine best practices for the future. The purpose of the study was to analyze the virtual interview experience and assess opportunities to improve the post-pandemic fellowship recruitment process. STUDY DESIGN: Using a 28-question survey of Program Directors (PDs) of PS fellowships as well as a 44-question survey of applicants to PS fellowships in the US and Canada, we gathered information on the recruitment process during the COVID-19 pandemic (2020). Dichotomous, multiple choice and open-ended questions about the changes in process, platforms used, format, comparison to on-site interviews and overall satisfaction were used for objective and subjective feedback. RESULTS: A 95% participation rate was recorded for the PD survey. 24 out of 55 programs (44%) changed their on-site interviews to virtual format due to the pandemic. Most PDs described their overall impression of virtual interviews as satisfactory (66%, 16/24) and did not have an impact on the applicant's success in the match (35/54; 65%). About 50% of PDs preferred to have on-site interviews with virtual screening in the future. While the participation rate from applicants was much less (26 of 70), responses confirmed our survey results. Majority preferred on-site interviews (17/26), 6 of which preferred virtual screening followed by on-site interviews. CONCLUSION: Components of virtual screening and interviews were found to have benefits financially and from both time and stress perspectives, and thus might survive past the pandemic. LEVELS OF EVIDENCE LEVEL IV: .
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COVID-19 , Internato e Residência , Especialidades Cirúrgicas , COVID-19/epidemiologia , Criança , Bolsas de Estudo , Humanos , Pandemias , Inquéritos e QuestionáriosRESUMO
BACKGROUND: One of the most competitive surgical sub-specialty fellowships remains Pediatric Surgery (PS), which requires candidates to develop a strong and research-oriented curriculum vitae. Although some objective factors of matriculation are known, factors for the interview selection and ranking per the program directors (PDs) have not been reviewed in over a decade. METHODS: A web-based survey of US and Canadian PS program directors (PDs) (n = 58) was used to evaluate a comprehensive list of factors in the selection criteria for PS fellowships. A mix of dichotomous, ranking, five-point Likert scale, and open-ended questions evaluated applicant characteristics, ABSITE scores, research productivity, interview day, and rank order criteria. RESULTS: Fifty-five programs responded to the survey for a 95% participation rate. PDs desired an average of two years in dedicated research and weighted first authorship and total number of publications heavily. Only 38% of programs used an ABSITE score cutoff for offering interviews; however, the majority agreed that an overall upward trend was important. Quality letters of recommendation, especially from known colleagues, carried weight when deciding to offer interviews. Interview performance, being a team player, observed interpersonal interactions, perceived operative skills and patient care, and leadership were some of the notable factors when finalizing rank lists. CONCLUSIONS: A multitude of factors define a successful matriculant, including quality of letters of recommendation, quality and quantity of publications, supportive phone calls, observed interactions, interview performance, perceptions of being team player with leadership skills as well as perceptions of good operative skills and patient care. LEVEL OF EVIDENCE: Type II. TYPE OF STUDY: Prognostic (retrospective).
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Internato e Residência , Especialidades Cirúrgicas , Canadá , Criança , Bolsas de Estudo , Humanos , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
This study highlights an unmet need in osteoporosis management, suggesting that beyond bone mineral density and fracture history, gender, fracture type, and age should be considered for fracture risk assessment. Following fragility fracture, men, patients with a spine or hip fracture, and those aged ≥ 65 have a higher disease burden. INTRODUCTION: The objective of this study was to characterize osteoporosis-related fracture incidence and identify predictors of subsequent fractures and mortality. METHODS: This retrospective cohort study, conducted within Kaiser Permanente Southern California, included patients aged ≥ 50 years with qualifying fractures from 1/1/2007 to 12/31/2016, identified from diagnosis/procedure codes. Rates for fracture incidence, mortality, and resource utilization in the year post-fracture are reported. Associations between index fracture types and demographic/clinical characteristics, and mortality, subsequent fracture, and rehospitalization outcomes were estimated. RESULTS: Of 63,755 eligible patients, 66.7% were ≥ 65 years and 69.1% female. Index fractures included nonhip/nonspine (64.4%), hip (25.3%), and spine (10.3%). Age-adjusted subsequent fracture rate/100 person-years was higher for those with an index spine (14.5) versus hip fracture (6.3). Hospitalization rate/100 person-years was highest for patients ≥ 65 (31.8) and for spine fractures (43.5). Men (vs women) had higher age-adjusted rates of hospitalization (19.4; 17.7), emergency room visits (73.8; 66.3), and use of rehabilitation services (31.7; 27.2). The 30-day age-adjusted mortality rate/100 person-years was 46.7, 32.4, and 15.5 for spine, hip, and nonspine/nonhip fractures. The 1-year age-adjusted mortality rate/100 person-years was 14.7 for spine and 15.6 for hip fractures. In multivariable analyses, spine and hip fractures (vs nonhip/nonspine fractures) were significant predictors of 1-year mortality, all-cause and osteoporosis-related hospitalization, and nursing home use (all P-values < 0.0001). CONCLUSION: Morbidity is high in the year following a fragility fracture and men, patients with a spine or hip fracture, and those aged ≥ 65 have a greater disease burden.
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Prestação Integrada de Cuidados de Saúde , Fraturas do Quadril , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Feminino , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/etiologia , Fraturas do Quadril/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/epidemiologia , Fraturas por Osteoporose/complicações , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/terapia , Estudos Retrospectivos , Fraturas da Coluna Vertebral/etiologiaRESUMO
Three structurally related gelators, each containing octadecyl chains, an α-diketo group at the 9,10 positions, and each with a different N-amide group-isobutyl (DIBA), isopentyl (DIPA) or N-(2-(dimethylamino)ethyl) (DMEA)-have been synthesized. Their neat structures as well as the thermal mechanical, and photophysical properties in their gel states with various liquids have been investigated. The gelator networks of DIBA and DIPA in octane, hexylbenzene and silicone oil consist of bundles of fibers. These gels are partially thixotropic and mechanically, thermally (to above their melting or silicone oil gelation temperatures), and photophysically stable. They are mechanically and thermally stronger than the gels formed with DMEA, the gelator with a tertiary amine group. The lone pair of electrons of the tertiary amine group leads to an intra-molecular or inter-molecular charge-transfer interaction, depending on whether the sample is a solution, sol, or gel. Neat, solid DMEA does not undergo the charge-transfer process because its amino and diketo groups are separated spatially by a large distance in the crystalline state and cannot diffuse into proximity. However, the solution of DIPA upon the addition of triethylamine becomes unstable over time at room temperature in the dark or (more rapidly) when irradiated, which initiates the aforementioned charge-transfer processes. The eventual reaction of the gelators in the presence of a tertiary amine group is ascribed to electron transfer from the lone-pair on nitrogen to an α-diketo group, followed by proton transfer to an oxygen atom on the anion radical of the α-diketo group from a methyl or methylene group attached to the nitrogen atom of the cation radical. Finally, the formation of an α-diketyl radical leads to irreversible electronic and structural changes that are observed over time.
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Besides their role as a storage for neutral lipids and sterols, there is increasing evidence that lipid droplets (LDs) are involved in cellular detoxification. LDs are in close contact to a broad variety of organelles where protein- and lipid exchange is mediated. Mitochondria as a main driver of the aging process produce reactive oxygen species (ROS), which damage several cellular components. LDs as highly dynamic organelles mediate a potent detoxification mechanism by taking up toxic lipids and proteins. A stimulation of LDs induced by the simultaneously overexpression of Lro1p and Dga1p (both encoding acyltransferases) prolongs the chronological as well as the replicative lifespan of yeast cells. The increased number of LDs reduces mitochondrial fragmentation as well as mitochondrial ROS production, both phenotypes that are signs of aging. Strains with an altered LD content or morphology as in the sei1∆ or lro1∆ mutant lead to a reduced replicative lifespan. In a yeast strain defective for the LON protease Pim1p, which showed an enhanced ROS production, increased doubling time and an altered mitochondrial morphology, a LRO1 overexpression resulted in a partially reversion of this "premature aging" phenotype.
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Nanomaterials have found extensive interest in the development of novel vaccines, as adjuvants and/or carriers in vaccination platforms. Conjugation of protein antigens at the particle surface by non-covalent adsorption is the most widely used approach in licensed particulate vaccines. Hence, it is essential to understand proteins' structural integrity at the material interface in order to develop safe-by-design nanovaccines. In this study, we utilized two model proteins, the wild-type allergen Bet v 1 and its hypoallergenic fold variant (BM4), to compare SiO2 nanoparticles with Alhydrogel® as particulate systems. A set of biophysical and functional assays including circular dichroism spectroscopy and proteolytic degradation was used to examine the antigens' structural integrity at the material interface. Conjugation of both biomolecules to the particulate systems decreased their proteolytic stability. However, we observed qualitative and quantitative differences in antigen processing concomitant with differences in their fold stability. These changes further led to an alteration in IgE epitope recognition. Here, we propose a toolbox of biophysical and functional in vitro assays for the suitability assessment of nanomaterials in the early stages of vaccine development. These tools will aid in safe-by-design innovations and allow fine-tuning the properties of nanoparticle candidates to shape a specific immune response.
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Alérgenos/imunologia , Antígenos de Plantas/imunologia , Epitopos/imunologia , Ativação Linfocitária/imunologia , Nanopartículas/química , Dióxido de Silício/química , Vacinas/imunologia , Alérgenos/química , Humanos , Hidrogéis , Imunoglobulina E/imunologia , Hipersensibilidade Respiratória/imunologia , Linfócitos T/imunologiaRESUMO
The number of osteoporosis-related fractures in the United States is no longer declining. Existing risk-based assessment tools focus on long-term risk. Payers and prescribers need additional tools to identify patients at risk for imminent fracture. We developed and validated a predictive model for secondary osteoporosis fractures in the year following an index fracture using administrative medical and pharmacy claims from the Optum Research Database and Symphony Health, PatientSource. Patients ≥50 years with a case-qualifying fracture identified using a validated claims-based algorithm were included. Logistic regression models were created with binary outcome of a second fracture versus no second fracture within a year of index fracture, with the goal of predicting second fracture occurrence. In the Optum Research Database, 197,104 patients were identified with a case-qualifying fracture (43% commercial, 57% Medicare Advantage). Using Symphony data, 1,852,818 met the inclusion/exclusion criteria. Average patient age was 70.09 (SD = 11.09) and 71.28 (SD = 14.24) years in the Optum Research Database and Symphony data, respectively. With the exception of history of falls (41.26% vs 18.74%) and opioid use (62.80% vs 46.78%), which were both higher in the Optum Research Database, the two populations were mostly comparable. A history of falls and steroid use, which were previously associated with increased fracture risk, continue to play an important role in secondary fractures. Conditions associated with bone health (liver disease), or those requiring medications that impact bone health (respiratory disease), and cardiovascular disease and stroke-which may share etiology or risk factors with osteoporosis fractures-were also predictors of imminent fractures. The model highlights the importance of assessment of patient characteristics beyond bone density, including patient comorbidities and concomitant medications associated with increased fall and fracture risk, in alignment with recently issued clinical guidelines for osteoporosis treatment.