Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this ...process by repressing E-cadherin and enhancing vimentin and N-cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic ductal adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT, which translates to increased invasiveness and metastasis. EMT was significantly reduced when MUC1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT-PCR and western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared with cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus, thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.
Considerable evidence suggests that there are significant ethnic/racial differences in the experience of pain among individuals suffering from chronic musculoskeletal conditions. Additionally, low ...levels of vitamin D have been associated with pain severity. Further, vitamin D deficiency is more prevalent in Non-Hispanic Black (NHB) individuals compared to Non-Hispanic Whites (NHW).
The aim of this study was to investigate the associations among race, pain severity, and serum levels of vitamin D in a sample of patients with chronic low back pain (cLBP).
All study participants (n = 155) self-identified their race/ethnicity as either NHB or NHW. Blood samples were collected to assess circulating levels of serum 25- hydroxy vitamin D. Vitamin D levels were categorized as optimal (≥20 ng/mL), insufficient (12-19 ng/mL) or deficient (<12 ng/mL). Participants then self-reported their pain severity using the Brief Pain Inventory - Short Form.
Results showed that a greater proportion of NHB versus NHW participants were categorized as Vitamin D deficient (
(2, N = 155) = 16.79, p < 0.001). An analysis of covariance (ANCOVA) revealed that NHBs reported significantly greater pain severity relative to NHWs (F(1150) = 6.45)
= 0.012. Further, self-reported pain severity significantly differed according to Vitamin D clinical categories (F(2150) = 4.19, p = 0.013). Participants with deficient vitamin D reported significantly greater pain severity in comparison to participants with optimal vitamin D (F(1101) = 7.28,
= 0.008).
The findings suggest that Vitamin D deficiency may be linked to greater pain severity in a sample of individuals with cLBP, especially for those who identify as NHB.
Amyloid fibrils are self-assembled filamentous structures associated with protein deposition conditions including Alzheimer's disease and the transmissible spongiform encephalopathies. Despite the ...immense medical importance of amyloid fibrils, no atomic-resolution structures are available for these materials, because the intact fibrils are insoluble and do not form diffraction-quality 3D crystals. Here we report the high-resolution structure of a peptide fragment of the amyloidogenic protein transthyretin, TTR(105-115), in its fibrillar form, determined by magic angle spinning NMR spectroscopy. The structure resolves not only the backbone fold but also the precise conformation of the side chains. Nearly complete13C and15N resonance assignments for TTR(105-115) formed the basis for the extraction of a set of distance and dihedral angle restraints. A total of 76 self-consistent experimental measurements, including 41 restraints on 19 backbone dihedral angles and 3513C-15N distances between 3 and$6\>\AA$were obtained from 2D and 3D NMR spectra recorded on three fibril samples uniformly$^{13}C, \>^{15}N\!-\!labeled$in consecutive stretches of four amino acids and used to calculate an ensemble of peptide structures. Our results indicate that TTR(105-115) adopts an extended β-strand conformation in the amyloid fibrils such that both the main- and side-chain torsion angles are close to their optimal values. Moreover, the structure of this peptide in the fibrillar form has a degree of long-range order that is generally associated only with crystalline materials. These findings provide an explanation of the unusual stability and characteristic properties of this form of polypeptide assembly.
Os reguladores tem lutado em atribuir culpa pelo colapso hipotecario, as vezes apontando para todos e para ninguem em particular. Muitas instituicoes estavam envolvidas em fazer emprestimos, avaliar ...as dividas e acondiciona-los na forma de titulos. Contudo as empresas de ratings tiveram um papel critico ao dar classificacao do tipo "triple-A" a titulos financiados por hipotecas, um padrao ouro que permitia que investidores como os fundos de pensao e as companhias de seguros os comprassem. Sob o acordo proposto com Andrew M. Cuomo, uma agencia de classificacao cobraria taxas em estagios para varias tarefas analiticas - nao so pela classificacao, que funciona como um tipo de nota para os investidores. Elas tambem divulgarao a cada tres meses todos os negocios que pediram que elas classificassem e todos os que acabaram classificando, fornecendo mais informacao aos investidores do que esta disponivel hoje. No passado, os bancos de investimento afirmaram que fizeram divulgacoes adequadas sobre os riscos oferecidos pelos emprestimos, mas que muitos investidores nao se preocuparam em avaliar cuidadosamente os titulos que estavam comprando. E as firmas de classificacao argumentaram que nao lhes foram fornecidos os relatorios produzidos por companhias como a Clayton. 2008 NoticiasFinancieras - Gazeta Mercantil - All rights reserved
The treatment of cartilage injuries secondary to patellar instability is multifactorial. These factors include the time frame of patellar instability, the pathoanatomic factors, the extent of ...symptoms, and the size and location of the cartilage injury. The chondral or osteochondral injury which occurs with acute patellar instability is managed with either reduction and internal fixation or removal. The treatment of the patellar instability component is controversial in the acute setting, especially when there is no need for an osteochondral surgery. In such cases, patellar dislocations are treated nonoperatively. However, if the patient is indicated for surgery for treatment of osteochondral fracture and intra-operatively the medial patellofemoral ligament (MPFL) remains pathologically lax and presents with a discrete MPFL injury site, there is the option of acute repair. Chondral injury associated with recurrent patellar instability may be subdivided into 2 overlapping groups: (1) chondral damage resulting from the instability episodes (distal medial region of the patellar and/or lateral proximal region of the lateral femoral condyle) and (2) chondrosis secondary to the chronic lateral tracking of the patella (chronic patellar subluxation) from patholaxity of the MPFL (lateral chondrosis to patella and trochlea in addition to the injuries sustained from the actual instability episodes). The treatment is based on the patient's chief complaints and the unique underlying pathoanatomy. Many of these patients will have one or more predisposing factors, such as patella alta, trochlear dysplasia, patholaxity of the MPFL and an excessively lateral position of the tibial tuberosity. Therefore, the key to managing this patient population is to address each patient's specific pathoanatomy, which by definition will include addressing the MPFL patholaxity. The goals are to stabilize the patella, normalize patellofemoral contact area and/or forces, and then restore the articular cartilage based on relevant symptoms. As of this writing, treatment options in the United States include debridement, marrow stimulation, osteochondral auto and allograft, autologous chondrocyte implantation, and the use of particulate articular cartilage.
ABSTRACT
We present the Hubble imaging Probe of Extreme Environments and Clusters (HiPEEC) survey. We fit HST NUV to NIR broad-band and H α fluxes to derive star cluster ages, masses, and extinctions ...and determine the star formation rate (SFR) of six merging galaxies. These systems are excellent laboratories to trace cluster formation under extreme gas physical conditions, rare in the local Universe, but typical for star-forming galaxies at cosmic noon. We detect clusters with ages of 1–500 Myr and masses that exceed 107 M⊙. The recent cluster formation history and their distribution within the host galaxies suggest that systems such as NGC 34, NGC 1614, and NGC 4194 are close to their final coalescing phase, while NGC 3256, NGC 3690, and NGC 6052 are at an earlier/intermediate stage. A Bayesian analysis of the cluster mass function in the age interval 1–100 Myr provides strong evidence in four of the six galaxies that an exponentially truncated power law better describes the observed mass distributions. For two galaxies, the fits are inconclusive due to low number statistics. We determine power-law slopes β ∼ −1.5 to −2.0 and truncation masses, Mc, between 106 and a few times 107 M⊙, among the highest values reported in the literature. Advanced mergers have higher Mc than early/intermediate merger stage galaxies, suggesting rapid changes in the dense gas conditions during the merger. We compare the total stellar mass in clusters to the SFR of the galaxy, finding that these systems are among the most efficient environments to form star clusters in the local Universe.
Today, a large number of different steels are being processed by Additive Manufacturing (AM) methods. The different matrix microstructure components and phases (austenite, ferrite, martensite) and ...the various precipitation phases (intermetallic precipitates, carbides) lend a huge variability in microstructure and properties to this class of alloys. This is true for AM-produced steels just as it is for conventionally-produced steels. However, steels are subjected during AM processing to time-temperature profiles which are very different from the ones encountered in conventional process routes, and hence the resulting microstructures differ strongly as well. This includes a very fine and highly morphologically and crystallographically textured microstructure as a result of high solidification rates as well as non-equilibrium phases in the as-processed state. Such a microstructure, in turn, necessitates additional or adapted post-AM heat treatments and alloy design adjustments. In this review, we give an overview over the different kinds of steels in use in fusion-based AM processes and present their microstructures, their mechanical and corrosion properties, their heat treatments and their intended applications. This includes austenitic, duplex, martensitic and precipitation-hardening stainless steels, TRIP/TWIP steels, maraging and carbon-bearing tool steels and ODS steels. We identify areas with missing information in the literature and assess which properties of AM steels exceed those of conventionally-produced ones, or, conversely, which properties fall behind. We close our review with a short summary of iron-base alloys with functional properties and their application perspectives in Additive Manufacturing.
Background & Aims Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires ...gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. Methods We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. Results Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. Conclusions In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.
The magnitude, consistency, and manner of association between sedentary time and outcomes independent of physical activity remain unclear.
To quantify the association between sedentary time and ...hospitalizations, all-cause mortality, cardiovascular disease, diabetes, and cancer in adults independent of physical activity.
English-language studies in MEDLINE, PubMed, EMBASE, CINAHL, Cochrane Library, Web of Knowledge, and Google Scholar databases were searched through August 2014 with hand-searching of in-text citations and no publication date limitations.
Studies assessing sedentary behavior in adults, adjusted for physical activity and correlated to at least 1 outcome.
Two independent reviewers performed data abstraction and quality assessment, and a third reviewer resolved inconsistencies.
Forty-seven articles met our eligibility criteria. Meta-analyses were performed on outcomes for cardiovascular disease and diabetes (14 studies), cancer (14 studies), and all-cause mortality (13 studies). Prospective cohort designs were used in all but 3 studies; sedentary times were quantified using self-report in all but 1 study. Significant hazard ratio (HR) associations were found with all-cause mortality (HR, 1.240 95% CI, 1.090 to 1.410), cardiovascular disease mortality (HR, 1.179 CI, 1.106 to 1.257), cardiovascular disease incidence (HR, 1.143 CI, 1.002 to 1.729), cancer mortality (HR, 1.173 CI, 1.108 to 1.242), cancer incidence (HR, 1.130 CI, 1.053 to 1.213), and type 2 diabetes incidence (HR, 1.910 CI, 1.642 to 2.222). Hazard ratios associated with sedentary time and outcomes were generally more pronounced at lower levels of physical activity than at higher levels.
There was marked heterogeneity in research designs and the assessment of sedentary time and physical activity.
Prolonged sedentary time was independently associated with deleterious health outcomes regardless of physical activity.
None.
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