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"Vogel, Val"
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Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes
Bardet-Biedl syndrome (BBS) is a heterogeneous disorder characterized by obesity, retinopathy, polydactyly, and congenital anomalies. The incidence of hypertension and diabetes are also increased in BBS patients. Mutation of 16 genes independently causes BBS, and seven BBS proteins form the BBSome that promotes ciliary membrane elongation. BBS3 (ARL6), an ADP ribosylation factor-like small GTPase, is not part of the BBSome complex. The in vivo function of BBS3 is largely unknown. Here we developed a Bbs3 knockout model and demonstrate that Bbs3–/– mice develop BBS-associated phenotypes, including retinal degeneration, male infertility, and increased body fat. Interestingly, Bbs3–/– mice develop some unique phenotypes not seen in other BBS knockout models: no overt obesity, severe hydrocephalus, and elevated blood pressure (shared by some but not all BBS gene knockout mice). We found that endogenous BBS3 and the BBSome physically interact and depend on each other for their ciliary localization. This finding explains the phenotypic similarity between Bbs3–/– mice and BBSome subunit knockout mice. Loss of Bbs3 does not affect BBSome formation but disrupts normal localization of melanin concentrating hormone receptor 1 to ciliary membranes and affects retrograde transport of Smoothened inside cilia. We also show that the endogenous BBSome and BBS3 associate with membranes and the membrane association of the BBSome and BBS3 are not interdependent. Differences between BBS mouse models suggest nonoverlapping functions to individual BBS protein.
Journal Article
A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment
Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.
Journal Article
Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species
Background: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. Results: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. Conclusions: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.
Journal Article
Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model
Hydrocephalus is a neurological disorder characterized by expansion of the ventricles. In a mouse model, the authors identified a role for neural progenitors and for platelet-derived growth factor signaling in the pathogenesis of neonatal hydrocephalus. Targeting this pathway reduced ventricular volume, pointing to a new therapeutic target for this condition.
Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor α (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or NG2)
+
PDGFR-α
+
neural progenitors. Targeting this pathway with lithium treatment rescued NG2
+
PDGFR-α
+
progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.
Journal Article
XCO2 in an emission hot-spot region: the COCCON Paris campaign 2015
Providing timely information on urban greenhouse gas (GHG) emissions and their trends to stakeholders relies on reliable measurements of atmospheric concentrations and the understanding of how local emissions and atmospheric transport influence these observations. Portable Fourier transform infrared (FTIR) spectrometers were deployed at five stations in the Paris metropolitan area to provide column-averaged concentrations of CO 2 (XCO 2) during a field campaign in spring of 2015, as part of the Col-laborative Carbon Column Observing Network (COCCON). Here, we describe and analyze the variations of XCO 2 observed at different sites and how they changed over time. We find that observations upwind and downwind of the city centre differ significantly in their XCO 2 concentrations, while the overall variability of the daily cycle is similar, i.e. increasing during night-time with a strong decrease (typically 2-3 ppm) during the afternoon. An atmospheric transport model framework (CHIMERE-CAMS) was used to simulate XCO 2 and predict the same behaviour seen in the observations, which supports key findings , e.g. that even in a densely populated region like Paris (over 12 million people), biospheric uptake of CO 2 can be of major influence on daily XCO 2 variations. Despite a general offset between modelled and observed XCO 2 , the model correctly predicts the impact of the meteorological parameters (e.g. wind direction and speed) on the concentration gradients between different stations. When analyzing local gradients of XCO 2 for upwind and downwind station pairs, those local gradients are found to be less sensitive to changes in XCO 2 boundary conditions and biogenic fluxes within the domain and we find the model-data agreement further improves. Our modelling framework indicates that the local XCO 2 gradient between the stations is dominated by the fossil fuel CO 2 signal of the Paris metropolitan area. This further highlights the potential usefulness of XCO 2 observations to help optimize future urban GHG emission estimates.
Journal Article
Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer
Purpose
Radium Ra 223 dichloride (radium-223, Xofigo®) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision.
Methods
An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined.
Results
The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway.
Conclusions
These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care.
Journal Article
Genome sequencing and analysis of the model grass Brachypodium distachyon
Three subfamilies of grasses, the Ehrhartoideae, Panicoideae and Pooideae, provide the bulk of human nutrition and are poised to become major sources of renewable energy. Here we describe the genome sequence of the wild grass Brachypodium distachyon (Brachypodium), which is, to our knowledge, the first member of the Pooideae subfamily to be sequenced. Comparison of the Brachypodium, rice and sorghum genomes shows a precise history of genome evolution across a broad diversity of the grasses, and establishes a template for analysis of the large genomes of economically important pooid grasses such as wheat. The high-quality genome sequence, coupled with ease of cultivation and transformation, small size and rapid life cycle, will help Brachypodium reach its potential as an important model system for developing new energy and food crops.
Journal Article
Recreating Stable Brachypodium hybridum Allotetraploids by Uniting the Divergent Genomes of B. distachyon and B. stacei
Brachypodium hybridum (2n = 30) is a natural allopolyploid with highly divergent subgenomes derived from two extant diploid species, B. distachyon (2n = 10) and B. stacei (2n = 20) that differ in chromosome evolution and number. We created synthetic B. hybridum allotetraploids by hybridizing various lines of B. distachyon and B. stacei. The initial amphihaploid F1 interspecific hybrids were obtained at low frequencies when B. distachyon was used as the maternal parent (0.15% or 0.245% depending on the line used) and were sterile. No hybrids were obtained from reciprocal crosses or when autotetraploids of the parental species were crossed. Colchicine treatment was used to double the genome of the F1 amphihaploid lines leading to allotetraploids. The genome-doubled F1 plants produced a few S1 (first selfed generation) seeds after self-pollination. S1 plants from one parental combination (Bd3-1xBsta5) were fertile and gave rise to further generations whereas those of another parental combination (Bd21xABR114) were sterile, illustrating the importance of the parental lineages crossed. The synthetic allotetraploids were stable and resembled the natural B. hybridum at the phenotypic, cytogenetic and genomic levels. The successful creation of synthetic B. hybridum offers the possibility to study changes in genome structure and regulation at the earliest stages of allopolyploid formation in comparison with the parental species and natural B. hybridum.
Journal Article
Abnormal development of NG2.sup.+PDGFR-α.sup.+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model
Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor a (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or [NG2.sup.+]PDGFR-[α.sup.+] neural progenitors. Targeting this pathway with lithium treatment rescued [NG2.sup.+]PDGFR-[α.sup.+] progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.
Journal Article