Quantitative proteomic analyses in combination with genetics provide powerful tools in developmental cell signalling research.
is one of the most widely used genetic models for studying development ...and disease. Here we combined quantitative proteomics with genetic selection to determine changes in the proteome upon depletion of Heartless (Htl) Fibroblast-Growth Factor (FGF) receptor signalling in
embryos at the gastrula stage. We present a robust, single generation SILAC (stable isotope labelling with amino acids in cell culture) protocol for labelling proteins in early embryos. For the selection of homozygously mutant embryos at the pre-gastrula stage, we developed an independent genetic marker. Our analyses detected quantitative changes in the global proteome of
mutant embryos during gastrulation. We identified distinct classes of downregulated and upregulated proteins, and network analyses indicate functionally related groups of proteins in each class. In addition, we identified changes in the abundance of phosphopeptides. In summary, our quantitative proteomic analysis reveals global changes in metabolic, nucleoplasmic, cytoskeletal and transport proteins in
mutant embryos.
The Drosophila argonaute2 (ago2) gene plays a major role in siRNA mediated RNA silencing pathways. Unlike mammalian Argonaute proteins, the Drosophila protein has an unusual amino-terminal domain ...made up largely of multiple copies of glutamine-rich repeats (GRRs). We report here that the ago2 locus produces an alternative transcript that encodes a putative short isoform without this amino-terminal domain. Several ago2 mutations previously reported to be null alleles only abolish expression of the long, GRR-containing isoform. Analysis of drop out (dop) mutations had previously suggested that variations in GRR copy number result in defects in RNAi and embryonic development. However, we find that dop mutations genetically complement transcript-null alleles of ago2 and that ago2 alleles with variant GRR copy numbers support normal development. In addition, we show that the assembly of the central RNAi machinery, the RISC (RNA induced silencing complex), is unimpaired in embryos when GRR copy number is altered. In fact, we find that GRR copy number is highly variable in natural D. melanogaster populations as well as in laboratory strains. Finally, while many other insects share an extensive, glutamine-rich Ago2 amino-terminal domain, its primary sequence varies drastically between species. Our data indicate that GRR variation does not modulate an essential function of Ago2 and that the amino-terminal domain of Ago2 is subject to rapid evolution.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In segmented markets for heterogeneous goods, prices reflect a mixture of demand for characteristics, bargaining power and market segmentation. This article integrates bargaining into the search ...model to investigate bargaining for housing across investors and owner‐occupiers when the investment housing segment is also subject to a rental property discount. It provides a framework for empirically identifying separate price effects of property type and bargaining power. We exploit homestead exemption information to empirically identify sellers and buyers as investors or owner‐occupiers. Data from Orange County, Florida, over 2000–2012 show a greater rental discount when controlling for investor bargaining power than when estimated in the conventional manner. In addition, investor relative bargaining power is not the same when selling to an owner‐occupier as when buying from an owner‐occupier. The results are robust across market phases and across neighborhoods.
Full text
Available for:
FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Key Points
Brutsaert and Parlange made landmark contributions to groundwater theory
Hydraulic groundwater theory is basis of applications in hydrology
Applications from drought analysis to climate ...impact
Based on a literature overview, this paper summarizes the impact and legacy of the contributions of Wilfried Brutsaert and Jean‐Yves Parlange (Cornell University) with respect to the current state‐of‐the‐art understanding in hydraulic groundwater theory. Forming the basis of many applications in catchment hydrology, ranging from drought flow analysis to surface water‐groundwater interactions, hydraulic groundwater theory simplifies the description of water flow in unconfined riparian and perched aquifers through assumptions attributed to Dupuit and Forchheimer. Boussinesq (1877) derived a general equation to study flow dynamics of unconfined aquifers in uniformly sloping hillslopes, resulting in a remarkably accurate and applicable family of results, though often challenging to solve due to its nonlinear form. Under certain conditions, the Boussinesq equation can be solved analytically allowing compact representation of soil and geomorphological controls on unconfined aquifer storage and release dynamics. The Boussinesq equation has been extended to account for flow divergence/convergence as well as for nonuniform bedrock slope (concave/convex). The extended Boussinesq equation has been favorably compared to numerical solutions of the three‐dimensional Richards equation, confirming its validity under certain geometric conditions. Analytical solutions of the linearized original and extended Boussinesq equations led to the formulation of similarity indices for baseflow recession analysis, including scaling rules, to predict the moments of baseflow response. Validation of theoretical recession parameters on real‐world streamflow data is complicated due to limited measurement accuracy, changing boundary conditions, and the strong coupling between the saturated aquifer with the overlying unsaturated zone. However, recent advances are shown to have mitigated several of these issues. The extended Boussinesq equation has been successfully applied to represent baseflow dynamics in catchment‐scale hydrological models, and it is currently considered to represent lateral redistribution of groundwater in land surface schemes applied in global circulation models. From the review, it is clear that Wilfried Brutsaert and Jean‐Yves Parlange stimulated a body of research that has led to several fundamental discoveries and practical applications with important contributions in hydrological modeling.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Foreclosures lead to lower house prices in the short run. However, whether or not foreclosures also have long-run or legacy price effects has not been addressed extensively. Do neighborhoods with a ...greater number of past foreclosures exhibit long lasting house price discounts? This paper examines both transitory and legacy foreclosure price effects. We use almost 20 years of data from one of the epicenters of the foreclosure crisis: Orange County, Florida. We measure the number of recent and past foreclosures within narrowly defined neighborhoods for each house sold during 2016–2019:Q2. We compare transaction prices with different numbers of recent and past foreclosures, while controlling for differences in observed property characteristics and taking measures to reduce the impact of unobserved heterogeneity. We find that greater numbers of recent and past foreclosures are associated with lower house prices. We find strong transitory effects consistent with the existing literature. We also find significant but modest legacy effects on surrounding prices. These long-run discounts are about 0.41 percent to 0.79 percent in Orange County, Florida.
Full text
Available for:
CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To compare bone marrow-sparing intensity-modulated pelvic radiotherapy (BMS-IMRT) with conventional (four-field box and anteroposterior-posteroanterior AP-PA) techniques in the treatment of cervical ...cancer.
The data from 7 cervical cancer patients treated with concurrent chemotherapy and IMRT without BMS were analyzed and compared with data using four-field box and AP-PA techniques. All plans were normalized to cover the planning target volume with the 99% isodose line. The clinical target volume consisted of the pelvic and presacral lymph nodes, uterus and cervix, upper vagina, and parametrial tissue. Normal tissues included bowel, bladder, and pelvic bone marrow (PBM), which comprised the lumbosacral spine and ilium and the ischium, pubis, and proximal femora (lower pelvis bone marrow). Dose-volume histograms for the planning target volume and normal tissues were compared for BMS-IMRT vs. four-field box and AP-PA plans.
BMS-IMRT was superior to the four-field box technique in reducing the dose to the PBM, small bowel, rectum, and bladder. Compared with AP-PA plans, BMS-IMRT reduced the PBM volume receiving a dose >16.4 Gy. BMS-IMRT reduced the volume of ilium, lower pelvis bone marrow, and bowel receiving a dose >27.7, >18.7, and >21.1 Gy, respectively, but increased dose below these thresholds compared with the AP-PA plans. BMS-IMRT reduced the volume of lumbosacral spine bone marrow, rectum, small bowel, and bladder at all dose levels in all 7 patients.
BMS-IMRT reduced irradiation of PBM compared with the four-field box technique. Compared with the AP-PA technique, BMS-IMRT reduced lumbosacral spine bone marrow irradiation and reduced the volume of PBM irradiated to high doses. Therefore BMS-IMRT might reduce acute hematologic toxicity compared with conventional techniques.
Full text
Available for:
GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Abstract Background Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up. Objective To ...assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. Design, setting, and participants A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993–1999, a total of 42 376 men aged 54–74 yr were randomized to a screening arm (S-arm) ( n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen PSA level cut-off ≥3.0 ng/ml as biopsy indication) or a control arm (C-arm) ( n = 21 166; no intervention). Outcome measurements and statistical analysis Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55–74 yr at randomization and separately in the predefined age group of 55–69 yr. Results and limitations After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 21.0% were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55–69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55–74 yr; p = 0.042) and 31.6% (age: 55–69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70–74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55–69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55–74 yr, and 392 and 24, respectively, for age group 65–69 yr. Given the slow natural history of the disease, follow-up might be too short. Conclusions Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55–69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with ...locoregionally advanced cervical cancer.
In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m
weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS.
In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval CI, 64.9%-84.3%) and 84% (95% CI, 76%-92.9%), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ
P = .048) and in the combined cohort (13% vs 35%, χ
P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group.
PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.
PDF
