Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro

Age-related neuronal dysfunction can be overcome by circulating factors present inyoung blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declineswith age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Giventhat age increases susceptibility to stroke, we hypothesized that GDF-11 may be directlyprotective to neurons following ischemia. Primary cortical neurons were isolated fromE18 Wistar rat embryos and cultured for 7–10 days. Neurons were deprived of oxygenand glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactatedehydrogenase, propidium iodide or CellToxTMgreen cytotoxicity assays. 40 ng/mLGDF-11 administration during 2 h OGD significantly increased neuronal death following24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 hOGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did notalter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatmenthad increased neuronal death which remained raised at 24 h. Co-treatment of 1µMSB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicityafter 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFβ) did not increaseneuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity wasalso exhibited following neuronal exposure to hydrogen peroxide. These results revealfor the first time that GDF-11 is neurotoxic to primary neurons in the acute phase ofsimulated stroke through primarily ALK4 receptor signaling

Placental capillary pericytes release excess extracellular vesicles under hypoxic conditions inducing a pro-angiogenic profile in term pregnancy

Supplementary data available online at: https://www.sciencedirect.com/science/article/pii/S0006291X2300181X#appsec1Copyright © 2023 The Authors. Pericytes are multifunctional cells wrapped around capillary endothelia, essential for vascular health, development, and blood flow regulation, although their role in human placental chorionic villi has not been fully explored. The second half of normal pregnancy is characterized by a progressive decline in placental and fetal oxygen levels which, by term, comprises a substantial degree of hypoxia. We hypothesized this hypoxia would stimulate pericyte regulation of chorionic villous capillary function. This study's objective was to investigate the role of hypoxia on normal term placental pericytes (PLVP) and their signaling to endothelial cells. First, we confirmed fetoplacental hypoxia at term by a new analysis of umbilical arterial blood oxygen tension of 3,010 healthy singleton neonates sampled at caesarean section and before labor. We then measured the release of cytokines, chemokines, and small extracellular vesicles (PLVPsv), from PLVP cultured at 20%, 8% and 1% O2. As O2 levels decreased, secreted cytokines and chemokines [interleukin-6 (IL-6), interleukin-1α (IL-1α) and vascular endothelial growth factor (VEGF)], and small extracellular vesicle markers, (Alix, Syntenin and CD9) increased significantly in the culture supernatants. When primary human umbilical vein endothelial cells (HUVEC) were cultured with PLVPsv, polygon formation, number, and tube formation length was significantly increased compared to cells not treated with PLVPsv, indicating PLVPsv stimulated angiogenesis. We conclude that adding PLVPsv stimulates angiogenesis and vessel stabilization on neighboring endothelial cells in response to hypoxia in term pregnancy compared to no addition of PLVPsv. Our finding that PLVP can release angiogenic molecules via extracellular vesicles in response to hypoxia may apply to other organ systems.MRC Program Grant (MR/J003360/1); rad Sutherland is supported by the National Health and Medical Research Council of Australia (APP1137776)

Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

<p>Abstract</p> <p>Background</p> <p>BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer.</p> <p>Case Presentation</p> <p>A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat.</p> <p>Conclusions</p> <p>Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.</p

The 2dF Galaxy Redshift Survey: power-spectrum analysis of the final data set and cosmological implications

We present a power-spectrum analysis of the final 2dF Galaxy Redshift Survey (2dFGRS), employing a direct Fourier method. The sample used comprises 221 414 galaxies with measured redshifts. We investigate in detail the modelling of the sample selection, improving on previous treatments in a number of respects. A new angular mask is derived, based on revisions to the photometric calibration. The redshift selection function is determined by dividing the survey according to rest-frame colour, and deducing a self-consistent treatment of k-corrections and evolution for each population. The covariance matrix for the power-spectrum estimates is determined using two different approaches to the construction of mock surveys, which are used to demonstrate that the input cosmological model can be correctly recovered. We discuss in detail the possible differences between the galaxy and mass power spectra, and treat these using simulations, analytic models and a hybrid empirical approach. Based on these investigations, we are confident that the 2dFGRS power spectrum can be used to infer the matter content of the universe. On large scales, our estimated power spectrum shows evidence for the ‘baryon oscillations’ that are predicted in cold dark matter (CDM) models. Fitting to a CDM model, assuming a primordial n_s = 1 spectrum, h = 0.72 and negligible neutrino mass, the preferred parameters are Ω_mh = 0.168 ± 0.016 and a baryon fraction Ωb/Ω_m= 0.185 ± 0.046 (1σ errors). The value of Ω_mh is 1σ lower than the 0.20 ± 0.03 in our 2001 analysis of the partially complete 2dFGRS. This shift is largely due to the signal from the newly sampled regions of space, rather than the refinements in the treatment of observational selection. This analysis therefore implies a density significantly below the standard Ω_m = 0.3: in combination with cosmic microwave background (CMB) data from the Wilkinson Microwave Anisotropy Probe (WMAP), we infer Ω_m = 0.231 ± 0.021

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

Evolution of Linked Avirulence Effectors in Leptosphaeria maculans Is Affected by Genomic Environment and Exposure to Resistance Genes in Host Plants

Brassica napus (canola) cultivars and isolates of the blackleg fungus, Leptosphaeria maculans interact in a ‘gene for gene’ manner whereby plant resistance (R) genes are complementary to pathogen avirulence (Avr) genes. Avirulence genes encode proteins that belong to a class of pathogen molecules known as effectors, which includes small secreted proteins that play a role in disease. In Australia in 2003 canola cultivars with the Rlm1 resistance gene suffered a breakdown of disease resistance, resulting in severe yield losses. This was associated with a large increase in the frequency of virulence alleles of the complementary avirulence gene, AvrLm1, in fungal populations. Surprisingly, the frequency of virulence alleles of AvrLm6 (complementary to Rlm6) also increased dramatically, even though the cultivars did not contain Rlm6. In the L. maculans genome, AvrLm1 and AvrLm6 are linked along with five other genes in a region interspersed with transposable elements that have been degenerated by Repeat-Induced Point (RIP) mutations. Analyses of 295 Australian isolates showed deletions, RIP mutations and/or non-RIP derived amino acid substitutions in the predicted proteins encoded by these seven genes. The degree of RIP mutations within single copy sequences in this region was proportional to their proximity to the degenerated transposable elements. The RIP alleles were monophyletic and were present only in isolates collected after resistance conferred by Rlm1 broke down, whereas deletion alleles belonged to several polyphyletic lineages and were present before and after the resistance breakdown. Thus, genomic environment and exposure to resistance genes in B. napus has affected the evolution of these linked avirulence genes in L. maculans

Multiple Translocation of the AVR-Pita Effector Gene among Chromosomes of the Rice Blast Fungus Magnaporthe oryzae and Related Species

Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens) and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2) is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation