The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation

<p>Abstract</p> <p>Background</p> <p>Activated microglia are a feature of the host response to neurodegeneration in Parkinson's disease (PD) and are thought to contribute to disease progression. Recent evidence suggests that extracellular α-synuclein (eSNCA) may play an important role in the pathogenesis of PD and that this may be mediated by a microglial response.</p> <p>Methods</p> <p>We wished to discover whether the host response to eSNCA would be sufficient to induce significant cytokine production. <it>In vitro </it>cultured BV-2 microglia were used to determine the basic inflammatory response to eSNCA. <it>In vivo</it>, 8-week old Biozzi mice were subjected to a single intranigral injection of either 3 μg SNCA, lipopolysaccharide (LPS) or serum protein (BSA) and allowed to recover for 24 hours. A second cohort of animals were peripherally challenged with LPS (0.5 mg/kg) 6 hours prior to tissue collection. Inflammation was studied by quantitative real-time PCR for a number of pro-inflammatory genes and immunohistochemistry for microglial activation, endothelial activation and cell death.</p> <p>Results</p> <p><it>In vitro </it>data showed a robust microglial response to SNCA, including a positive NFĸB response and the production of pro-inflammatory cytokines. Direct injection of SNCA into the substantia nigra resulted in the upregulation of mRNA expression of proinflammatory cytokines, the expression of endothelial markers of inflammation and microglial activation. However, these results were significantly different to those obtained after direct injection of LPS. By contrast, when the animals were injected intracerebrally with SNCA and subsequently challenged with systemic LPS, the level of production of IL-1β in the substantia nigra became comparable to that induced by the direct injection of LPS into the brain. The injection of albumin into the nigra with a peripheral LPS challenge did not provoke the production of a significant inflammatory response. Direct injection of LPS into the substantia nigra also induces cell death in a more robust manner than direct injection of either SNCA or BSA.</p> <p>Conclusion</p> <p>These results suggest that the presence of eSNCA protein 'primes' microglia, making them susceptible to environmental proinflammatory challenge. For this reason, we hypothesise that where 'inflammation' contributes to the disease progression in PD, it does so in a punctuate manner (on-off) as a result of systemic events.</p

Quantum oscillations of nitrogen atoms in uranium nitride

The vibrational excitations of crystalline solids corresponding to acoustic or optic one phonon modes appear as sharp features in measurements such as neutron spectroscopy. In contrast, many-phonon excitations generally produce a complicated, weak, and featureless response. Here we present time-of-flight neutron scattering measurements for the binary solid uranium nitride (UN), showing well-defined, equally-spaced, high energy vibrational modes in addition to the usual phonons. The spectrum is that of a single atom, isotropic quantum harmonic oscillator and characterizes independent motions of light nitrogen atoms, each found in an octahedral cage of heavy uranium atoms. This is an unexpected and beautiful experimental realization of one of the fundamental, exactly-solvable problems in quantum mechanics. There are also practical implications, as the oscillator modes must be accounted for in the design of generation IV nuclear reactors that plan to use UN as a fuel.Comment: 25 pages, 10 figures, submitted to Nature Communications, supplementary information adde

The Expression of ERCC1, RRM1, and BRCA1 in Breast Cancer According to the Immunohistochemical Phenotypes

We studied the expression of BRCA1, ERCC1, and RRM1 which play an important role in DNA repair systems in breast cancer. Immunohistochemical staining for EGFR, BRCA1, ERCC1, and RRM1 were performed by using a tissue microarray made from 230 breast cancer patients. Patients were classified into luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) types according to ER, PR, and HER-2 expression. The expression of ERCC1, RRM1, and BRCA1 were correlated (P < 0.05). The expression level of ERCC1 was the lowest in TNBC type (P = 0.031), ERCC1 negativity was more prominent in TNBC and luminal B groups than luminal A and HER-2 groups (P = 0.013). Cases with EGFR overexpression showed high expression of RRM1 and BRCA1 (P = 0.046, and 0.004, respectively). In conclusion, the expression of ERCC1 is particularly lower in TNBCs than other types of breast cancers

Development and Validation of the Behavioral Tendencies Questionnaire

At a fundamental level, taxonomy of behavior and behavioral tendencies can be described in terms of approach, avoid, or equivocate (i.e., neither approach nor avoid). While there are numerous theories of personality, temperament, and character, few seem to take advantage of parsimonious taxonomy. The present study sought to implement this taxonomy by creating a questionnaire based on a categorization of behavioral temperaments/tendencies first identified in Buddhist accounts over fifteen hundred years ago. Items were developed using historical and contemporary texts of the behavioral temperaments, described as “Greedy/Faithful”, “Aversive/Discerning”, and “Deluded/Speculative”. To both maintain this categorical typology and benefit from the advantageous properties of forced-choice response format (e.g., reduction of response biases), binary pairwise preferences for items were modeled using Latent Class Analysis (LCA). One sample (n1 = 394) was used to estimate the item parameters, and the second sample (n2 = 504) was used to classify the participants using the established parameters and cross-validate the classification against multiple other measures. The cross-validated measure exhibited good nomothetic span (construct-consistent relationships with related measures) that seemed to corroborate the ideas present in the original Buddhist source documents. The final 13-block questionnaire created from the best performing items (the Behavioral Tendencies Questionnaire or BTQ) is a psychometrically valid questionnaire that is historically consistent, based in behavioral tendencies, and promises practical and clinical utility particularly in settings that teach and study meditation practices such as Mindfulness Based Stress Reduction (MBSR)

Granular cell tumors of the urinary bladder

BACKGROUND: Granular cell tumors (GCTs) are extremely rare lesions of the urinary bladder with only nine cases being reported in world literature of which one was malignant. Generally believed to be of neural origin based on histochemical, immunohistochemical, and ultrastructural studies; they mostly follow a clinically benign course but are commonly mistaken for malignant tumors since they are solid looking, ulcerated tumors with ill-defined margins. MATERIALS AND METHODS: We herein report two cases of GCTs, one benign and one malignant, presenting with gross hematuria in a 14- and a 47-year-old female, respectively. RESULTS: Histopathology revealed characteristic GCTs with positive immunostaining for neural marker (S-100) and negative immunostaining for epithelial (cytokeratin, Cam 5.2, AE/A13), neuroendocrine (neuron specific enolase, chromogranin A, and synaptophysin) and sarcoma (desmin, vimentin) markers. The benign tumor was successfully managed conservatively with transurethral resection alone while for the malignant tumor, radical cystectomy, hysterectomy with bilateral salpingo-oophorectomy, anterior vaginectomy, plus lymph node dissection was done. Both cases show long-term disease free survival. CONCLUSION: We recommend careful pathologic assessment for establishing the appropriate diagnosis and either a conservative or aggressive surgical treatment for benign or localized malignant GCT of the urinary bladder, respectively

Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients

The RPS6KB1 gene is amplified and overexpressed in approximately 10% of breast carcinomas and has been found associated with poor prognosis. We studied the prognostic significance of P70 S6 kinase protein (PS6K) overexpression in a series of 452 node-negative premenopausal early-stage breast cancer patients (median follow-up: 10.8 years). Immunohistochemistry was used to assess PS6K expression in the primary tumour, which had previously been analysed for a panel of established prognostic factors in breast cancer. In a univariate analysis, PS6K overexpression was associated with worse distant disease-free survival as well as impaired locoregional control (HR 1.80, P 0.025 and HR 2.50, P 0.006, respectively). In a multivariate analysis including other prognostic factors, PS6K overexpression remained an independent predictor for poor locoregional control (RR 2.67, P 0.003). To our knowledge, P70 S6 kinase protein is the first oncogenic marker that has prognostic impact on locoregional control and therefore may have clinical implications in determining the local treatment strategy in early-stage breast cancer patients

The 2dF galaxy redshift survey: near-infrared galaxy luminosity functions

We combine the Two Micron All Sky Survey (2MASS) Extended Source Catalogue and the 2dF Galaxy Redshift Survey to produce an infrared selected galaxy catalogue with 17 173 measured redshifts. We use this extensive data set to estimate the galaxy luminosity functions in the J- and KS-bands. The luminosity functions are fairly well fitted by Schechter functions with parameters MJ*−5 log h=−22.36±0.02, αJ=−0.93±0.04, ΦJ*=0.0104±0.0016 h3 Mpc3 in the J-band and MKS*−5 log h=−23.44±0.03, αKS=−0.96±0.05, ΦKS*=0.0108±0.0016 h3 Mpc3 in the KS-band (2MASS Kron magnitudes). These parameters are derived assuming a cosmological model with Ω0=0.3 and Λ0=0.7. With data sets of this size, systematic rather than random errors are the dominant source of uncertainty in the determination of the luminosity function. We carry out a careful investigation of possible systematic effects in our data. The surface brightness distribution of the sample shows no evidence that significant numbers of low surface brightness or compact galaxies are missed by the survey. We estimate the present-day distributions of bJ−KS and J−KS colours as a function of the absolute magnitude and use models of the galaxy stellar populations, constrained by the observed optical and infrared colours, to infer the galaxy stellar mass function. Integrated over all galaxy masses, this yields a total mass fraction in stars (in units of the critical mass density) of Ωstarsh =(1.6±0.24)×103 for a Kennicutt initial mass function (IMF) and Ωstarsh =(2.9±0.43)×103 for a Salpeter IMF. These values are consistent with those inferred from observational estimates of the total star formation history of the Universe provided that dust extinction corrections are modest

Female labour market outcomes and the impact of maternity leave policies

ABSTRACT: This paper shows how family policies aimed at reconciling the pressures of family and work generate substantial variation in labour market outcomes across developed countries. We use a life-cycle model of female labour supply and savings behaviour, calibrated to the US economy, to assess the effect of introducing to the US a maternity leave policy similar to Scandinavian-type policies. We focus on the impact on gender differences in participation and in wages. We distinguish between the effect of the job protection offered by maternity leave and the effect of income replacement. Job protection leads to substantial increases in participation of mothers with children under 6, but with little long term effects. The effects on wages are minimal, with negative selection effects offsetting the reduced human capital depreciation. Income replacement has a limited impact on participation or wages.Virginia Sánchez-Marcos thanks the Spanish Ministry of Science and Technology for Grant ECO2009-09614 and RecerCaixa for financial support

The 2dF Galaxy Redshift Survey: correlation functions, peculiar velocities and the matter density of the Universe

We present a detailed analysis of the two-point correlation function, ξ(σ, π), from the 2dF Galaxy Redshift Survey (2dFGRS). The large size of the catalogue, which contains ∼220 000 redshifts, allows us to make high-precision measurements of various properties of the galaxy clustering pattern. The effective redshift at which our estimates are made is zs≈ 0.15, and similarly the effective luminosity, Ls≈ 1.4L*. We estimate the redshift-space correlation function, ξ(s), from which we measure the redshift-space clustering length, s0= 6.82 ± 0.28 h−1 Mpc. We also estimate the projected correlation function, Ξ(σ), and the real-space correlation function, ξ(r), which can be fit by a power law (r/r0), with r0= 5.05 ± 0.26 h−1 Mpc, γr= 1.67 ± 0.03. For r≳ 20 h−1 Mpc, ξ drops below a power law as, for instance, is expected in the popular Λ cold dark matter model. The ratio of amplitudes of the real- and redshift-space correlation functions on scales of 8–30 h−1 Mpc gives an estimate of the redshift-space distortion parameter β. The quadrupole moment of ξ(σ, π) on scales 30–40 h−1 Mpc provides another estimate of β. We also estimate the distribution function of pairwise peculiar velocities, ƒ(v), including rigorously the significant effect due to the infall velocities, and we find that the distribution is well fit by an exponential form. The accuracy of our ξ(σ, π) measurement is sufficient to constrain a model, which simultaneously fits the shape and amplitude of ξ(r) and the two redshift-space distortion effects parametrized by β and velocity dispersion, a. We find β= 0.49 ± 0.09 and a= 506 ± 52 km s−1, although the best-fitting values are strongly correlated. We measure the variation of the peculiar velocity dispersion with projected separation, a(σ), and find that the shape is consistent with models and simulations. This is the first time that β and ƒ(v) have been estimated from a self-consistent model of galaxy velocities. Using the constraints on bias from recent estimates, and taking account of redshift evolution, we conclude that β (L=L*, z= 0) = 0.47 ± 0.08, and that the present-day matter density of the Universe, Ωm≈ 0.3, consistent with other 2dFGRS estimates and independent analyses