Abstract
We present cosmological parameter constraints from a joint analysis of three cosmological probes: the tomographic cosmic shear signal in ∼450 deg2 of data from the Kilo Degree Survey (KiDS), ...the galaxy-matter cross-correlation signal of galaxies from the Galaxies And Mass Assembly (GAMA) survey determined with KiDS weak lensing, and the angular correlation function of the same GAMA galaxies. We use fast power spectrum estimators that are based on simple integrals over the real-space correlation functions, and show that they are practically unbiased over relevant angular frequency ranges. We test our full pipeline on numerical simulations that are tailored to KiDS and retrieve the input cosmology. By fitting different combinations of power spectra, we demonstrate that the three probes are internally consistent. For all probes combined, we obtain $S_8\equiv \sigma _8 \sqrt{\Omega _{\rm m}/0.3}=0.800_{-0.027}^{+0.029}$, consistent with Planck and the fiducial KiDS-450 cosmic shear correlation function results. Marginalizing over wide priors on the mean of the tomographic redshift distributions yields consistent results for S8 with an increase of $28\, {per \,cent}$ in the error. The combination of probes results in a 26 per cent reduction in uncertainties of S8 over using the cosmic shear power spectra alone. The main gain from these additional probes comes through their constraining power on nuisance parameters, such as the galaxy intrinsic alignment amplitude or potential shifts in the redshift distributions, which are up to a factor of 2 better constrained compared to using cosmic shear alone, demonstrating the value of large-scale structure probe combination.
Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro ...and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA-GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.
Familial occurrence of testicular cancer suggests a genetic predisposition to the disease. A genetic susceptibility may also be reflected by the occurrence of bilateral testicular neoplasms and the ...high rates of urogenital developmental anomalies in families prone to testicular cancer. In this study, the proportion of familial testicular cancer cases was analysed retrospectively in a single-centre population of 693 testicular cancer patients treated between 1977 and 1997 and the relative risk (RR) for first-degree relatives of patients was estimated. In addition, the existence of bilateral testicular neoplasms and urogenital developmental anomalies in familial testicular cancer patients was evaluated. 24 of the 693 patients (3.5%) had a first-degree relative with testicular cancer. These 24 cases belonged to 17 families; in 7 of these 17 families both affected first-degree family members were part of the study population of 693 patients. Consequently, the 693 studied patients belonged to a total of 686 families. Thus, the actual proportion of familial testicular cancer was 2.5% (17 of 686 families). The familial cases consisted of 11 brother pairs, including 2 pairs of identical twins and 1 pair which also had two affected cousins, and 6 father–son pairs (in total 36 cases, 12 treated elsewhere). Estimates of the RR to first-degree relatives showed a 9- to 13-fold increased RR to brothers (
P<0.001) and a 2-fold increased RR to fathers (
P=non-significant (n.s)) of testicular cancer patients. Among the 36 patients with familial testicular cancer, 2 (5.6%) had bilateral testicular cancer, 4 (11.1%) had undescended testis, 3 (8.3%) had inguinal hernia, and 1 (2.8%) showed renal hypoplasia. The present data on familial occurrence of testicular cancer may lend support to a role of genetic factors in the aetiology of testicular cancer.
The
activities of fungal CYP51 inhibitors VT-1161 and VT-1129 were determined for
(
= 34) and
(
= 50).
isolates were screened for FKS gene mutations. All isolates were resistant clinically and/or
to ...at least one standard antifungal compound. VT-1161 and VT-1129 MICs for all isolates were at least 5-fold below achievable human plasma levels for VT-1161. VT-1161 and VT-1129 are promising for the treatment of resistant
and
infections.
Summary Background The deep inferior epigastric artery perforator (DIEP) flap is the first choice for autologous breast reconstruction. The aim of this retrospective cohort study was to analyse the ...recipient- and donor-site complications and compare them between unilateral and bilateral DIEP flap breast reconstructions. Methods Between January 2010 and December 2014, 530 DIEP flap reconstructions were performed in 426 consecutive patients in three Dutch hospitals. Major and minor complications were categorised into recipient- and donor-site complications. Post-operative flap re-explorations were recorded. Results Of the total 530 DIEP flap reconstructions performed (322 unilateral, 104 bilateral), recipient-site complications were major in 9.8% and minor in 20.2%. The patients developed fat necrosis (unilateral 14.0% vs. bilateral 7.7%; OR 1.950; 95% CI 1.071–3.550; p = 0.027) and infection (unilateral 5.6% vs. bilateral 1.9%; OR 3.020; 95% CI 1.007–9.052; p = 0.039) at the recipient site significantly more frequently in the unilateral DIEP flap reconstructions. The donor-site complications were major in 0.9% and minor in 19.5% of the cases. Body mass index (BMI) was significantly associated with complications (donor site: OR 1.137; 95% CI 1.075–1.201; p < 0.001, recipient site: OR 1.073; 95% CI 1.009–1.142; p = 0.026). Flap re-explorations were performed in 5.7% ( n = 30) of the cases. Total flap loss occurred in 3.0% ( n = 16) of the cases. Conclusions Bilateral DIEP flap breast reconstructions can be performed with the same percentage of complications and re-explorations as unilateral reconstructions and even result in less fat necrosis and infection at the recipient site. Higher BMIs are significantly associated with recipient- and donor-site complications.
Impaired response inhibition is commonly present in individuals with attention-deficit/hyperactivity disorder (ADHD) and their unaffected relatives, suggesting impaired response inhibition as a ...candidate endophenotype in ADHD. Therefore, we explored whether behavioral and neural correlates of response inhibition are related to polygenic risk scores for ADHD (PRS-ADHD). We obtained functional magnetic resonance imaging of neural activity and behavioral measures during a stop-signal task in the NeuroIMAGE cohort, where inattention and hyperactivity-impulsivity symptoms were assessed with the Conners Parent Rating Scales. Our sample consisted of 178 ADHD cases, 103 unaffected siblings, and 173 controls (total
N
= 454; 8–29 years), for whom genome-wide genotyping was available. PRS-ADHD was constructed using the PRSice-2 software. We found PRS-ADHD to be associated with ADHD symptom severity, a slower and more variable response to Go-stimuli, and altered brain activation during response inhibition in several regions of the bilateral fronto-striatal network. Mean reaction time and intra-individual reaction time variability mediated the association of PRS-ADHD with ADHD symptoms (total, inattention, hyperactivity-impulsivity), and activity in the left temporal pole and anterior parahippocampal gyrus during failed inhibition mediated the relationship of PRS-ADHD with hyperactivity-impulsivity. Our findings indicate that PRS-ADHD are related to ADHD severity on a spectrum of clinical, sub-threshold, and normal levels; more importantly, we show a shared genetic etiology of ADHD and behavioral and neural correlates of response inhibition. Given the modest sample size of our study, future studies with higher power are warranted to explore mediation effects, suggesting that genetic liability to ADHD may adversely affect attention regulation on the behavioral level and point to a possible response inhibition-related mechanistic pathway from PRS-ADHD to hyperactivity-impulsivity.
Aims During the first days after harvest of Lolium perenne L., N remobilized from roots and stubble forms the main N source for regrowth. Low N uptake from the soil during this period may lead to N ...loss if N fertilizer is applied too soon. Furthermore, temporary N deprivation has been found to stimulate root growth. We therefore hypothesized that a strategic delay in N application after harvest may improve N-use efficiency of L. perenne grassland by increasing root biomass and reducing N loss. Methods In a laboratory and field experiment with L. perenne, we delayed N fertilizer application after harvest for 0,3,6,9 and 12 days, repeated this for up to six harvest cycles, and determined effects on herbage yield, herbage N uptake and root biomass. Results In both experiments, delaying N application for up to 12 days had no significant effect on root biomass or total herbage N uptake, but it significantly reduced total herbage yield in the laboratory experiment. Total yield tended to be highest when N application was delayed for 3 days. Two growth periods in the field experiment showed significantly higher N uptake when N application was delayed, possibly due to rainfallinduced N losses in the treatments with shorter delay. Conclusions Our results do not provide evidence that delaying N application improves N-use efficiency of L. perenne grassland by increasing root biomass. However, strategic timing of N fertilizer application based on rainfall forecasts could contribute to improve N-use efficiency by reducing N losses from leaching and denitrification.
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