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  • 1
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    Gene therapy restores vision and delays degeneration in the CNGB1-/- mouse model of retinitis pigmentosa (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-28
    Description: Retinitis pigmentosa (RP) is a group of genetically heterogeneous, severe retinal diseases commonly leading to legal blindness. Mutations in the CNGB1a subunit of the rod cyclic nucleotide-gated (CNG) channel have been found to cause RP in patients. Here, we demonstrate the efficacy of gene therapy as a potential treatment for RP by means of recombinant adeno-associated viral (AAV) vectors in the CNGB1 knockout (CNGB1 –/– ) mouse model. To enable efficient packaging and rod-specific expression of the relatively large CNGB1a cDNA (~4 kb), we used an AAV expression cassette with a short rod-specific promoter and short regulatory elements. After injection of therapeutic AAVs into the subretinal space of 2-week-old CNGB1 –/– mice, we assessed the restoration of the visual system by analyzing (i) CNG channel expression and localization, (ii) retinal function and morphology and (iii) vision-guided behavior. We found that the treatment not only led to expression of full-length CNGB1a, but also restored normal levels of the previously degraded CNGA1 subunit of the rod CNG channel. Both proteins co-localized in rod outer segments and formed regular CNG channel complexes within the treated area of the CNGB1 –/– retina, leading to significant morphological preservation and a delay of retinal degeneration. In the electroretinographic analysis, we also observed restoration of rod-driven light responses. Finally, treated CNGB1 –/– mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this work provides a proof-of-concept for the treatment of rod channelopathy-associated RP by AAV-mediated gene replacement.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    The Mitochondrial Atp8 Mutation Induces Mitochondrial ROS Generation, Secretory Dysfunction, and {beta}-Cell Mass Adaptation in Conplastic B6-mtFVB Mice (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-22
    Description: Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic phenotypes. In this study, we used conplastic mouse strains to characterize the impact of a mtDNA mutation in the Atp8 gene on β-cell function, reactive oxygen species (ROS) generation, β-cell mass, and glucose metabolism in response to high-fat diet (HFD). In comparison with B6-mt AKR controls, the B6-mt FVB strain carries a point mutation of the mtDNA-coded Atp8 gene (ATP synthase), leading to a fragmentated mitochondrial phenotype. Isolated pancreatic islets from 3-month-old B6-mt FVB mice showed increased mitochondrial generation of ROS, reduced cellular ATP levels, reduced glucose-induced insulin secretion, higher susceptibility to palmitate stress, and pathological morphology of mitochondria. ROS generation in β-cells was not affected by changes of the ambient glucose concentrations. Feeding a HFD for 3 months resulted in impaired glucose tolerance in B6-mt FVB mice but not in B6-mt AKR controls. In B6-mt FVB animals, glucose intolerance positively correlated with gain of body weight. Serum insulin levels and β-cell mass significantly increased in B6-mt FVB mice after a 3-month HFD. The data indicate that the mutation in the Atp8 gene induces mitochondrial dysfunction in β-cells with concomitant impairment of secretory responsiveness. This mitochondrial dysfunction induced a higher susceptibility to metabolic stressors, although this effect appeared not strictly linked to nutrient-induced ROS generation. The Atp8 gene mutation caused mitochondrial dysfunction, apparently stimulating an adaptive increase of β-cell mass in response to HFD, whereas mitochondrial ROS might have had an supportive role.
    Print ISSN: 0013-7227
    Topics: Medicine
    Published by Oxford University Press on behalf of The Endocrine Society.
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  • 3
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    Niche of harmful alga Aureococcus anophagefferens revealed through ecogenomics [Environmental Sciences] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-03-16
    Description: Harmful algal blooms (HABs) cause significant economic and ecological damage worldwide. Despite considerable efforts, a comprehensive understanding of the factors that promote these blooms has been lacking, because the biochemical pathways that facilitate their dominance relative to other phytoplankton within specific environments have not been identified. Here, biogeochemical measurements showed that the harmful alga Aureococcus anophagefferens outcompeted co-occurring phytoplankton in estuaries with elevated levels of dissolved organic matter and turbidity and low levels of dissolved inorganic nitrogen. We subsequently sequenced the genome of A. anophagefferens and compared its gene complement with those of six competing phytoplankton species identified through metaproteomics. Using an ecogenomic approach, we specifically focused on gene sets that may facilitate dominance within the environmental conditions present during blooms. A. anophagefferens possesses a larger genome (56 Mbp) and has more genes involved in light harvesting, organic carbon and nitrogen use, and encoding selenium- and metal-requiring enzymes than competing phytoplankton. Genes for the synthesis of microbial deterrents likely permit the proliferation of this species, with reduced mortality losses during blooms. Collectively, these findings suggest that anthropogenic activities resulting in elevated levels of turbidity, organic matter, and metals have opened a niche within coastal ecosystems that ideally suits the unique genetic capacity of A. anophagefferens and thus, has facilitated the proliferation of this and potentially other HABs.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Highly Controlled Gas/Liquid Processes in a Continuous Lab-Scale Device (2013)
    Wiley-Blackwell
    Details
    Publication Date: 2013-05-14
    Description: The use of reactive gases for syntheses on small laboratory scale is often avoided due to safety concerns so that expensive alternatives are required. The recent development of gas-permeable membrane-based reactors offers new options for safe handling of these gases in a continuous-flow system. A prototype of a gas/liquid system was built to introduce gas in the microreactor. An integrated gas flow controller and inline FTIR analysis were used to safely handle the gas. With the system, the carboxylation of a Grignard reagent with carbon dioxide was chosen as a nonhazardous model reaction to validate the prototype reactor. Gas-permeable membrane-based reactors offer safe handling of gases in a continuous-flow system. A prototype of a gas/liquid system was constructed to introduce gas in a microreactor. An integrated gas flow controller and inline FTIR analysis were used to safely handle the gas. Carboxylation of a Grignard reagent with CO 2 served as a nonhazardous model reaction.
    Print ISSN: 0930-7516
    Electronic ISSN: 1521-4125
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Published by Wiley-Blackwell
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  • 5
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    A Novel Immunofluorescence Flow Cytometry Technique Detects the Expansion of Brown Tides Caused by Aureoumbra lagunensis to the Caribbean Sea [Environmental Microbiology] (2014)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2014-07-23
    Description: During the past 3 decades, brown tides caused by the pelagophytes Aureococcus anophagefferens and Aureoumbra lagunensis have caused ecological and economic damage to coastal ecosystems across the globe. While blooms of A. lagunensis had previously been confined to Texas, in 2012, an expansive brown tide occurred on Florida's East Coast, causing widespread disruption within the Indian River and Mosquito Lagoons and generating renewed interest in this organism. A major impediment to detailed investigations of A. lagunensis in an ecosystem setting has been the absence of a rapid and reliable method for cell quantification. The combination of their small size (3 to 5 μm) and nondescript extracellular features makes identification and enumeration of these cells with conventional methods a challenge. Here we report the development of an immunological-based flow cytometry method that uses a fluorescently labeled antibody developed against A. lagunensis . This method is species specific, sensitive (detection limit of 1.5 x 10 3 cells ml –1 ), precise (1% relative standard deviation of replicated samples), and accurate (108% ± 8% recovery of spiked samples) over a wide range of cell concentrations. Furthermore, this method effectively quantifies A. lagunensis in both glutaraldehyde- and formalin-preserved samples, yields a high throughput of samples (~35 samples h –1 ), and is cost-effective, making it an ideal tool for managers and scientists. This method successfully documented the recurrence of a brown tide bloom in Florida in 2013. Bloom densities were highest in June (〉2.0 x 10 6 cells ml –1 ) and spanned 〉60 km from the Ponce de Leon inlet in the northern Mosquito Lagoon south to Titusville in the Indian River Lagoon. Low levels of A. lagunensis cells were found 〉250 km south of this region. This method also quickly and accurately identified A. lagunensis as the causative agent of a 2013 brown tide bloom in Guantanamo Bay, Cuba, and thus should prove useful for both quantifying the dynamics of ongoing blooms of A. lagunensis as well as documenting new outbreaks of this harmful alga.
    Print ISSN: 0099-2240
    Electronic ISSN: 1098-5336
    Topics: Biology
    Published by The American Society for Microbiology (ASM)
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  • 6
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    Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5) (2012)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2012-06-23
    Description: Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2 . We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.
    Keywords: Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 7
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    CpG islands and GC content dictate nucleosome depletion in a transcription-independent manner at mammalian promoters [RESEARCH] (2012)
    Cold Spring Harbor Laboratory Press
    Details
    Publication Date: 2012-12-02
    Description: One clear hallmark of mammalian promoters is the presence of CpG islands (CGIs) at more than two-thirds of genes, whereas TATA boxes are only present at a minority of promoters. Using genome-wide approaches, we show that GC content and CGIs are major promoter elements in mammalian cells, able to govern open chromatin conformation and support paused transcription. First, we define three classes of promoters with distinct transcriptional directionality and pausing properties that correlate with their GC content. We further analyze the direct influence of GC content on nucleosome positioning and depletion and show that CpG content and CGI width correlate with nucleosome depletion both in vivo and in vitro. We also show that transcription is not essential for nucleosome exclusion but influences both a weak +1 and a well-positioned nucleosome at CGI borders. Altogether our data support the idea that CGIs have become an essential feature of promoter structure defining novel regulatory properties in mammals.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
    Published by Cold Spring Harbor Laboratory Press
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  • 8
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    Test results of the Data Handling Processor for the DEPFET Pixel Vertex Detector (2013)
    Institute of Physics Publishing (IOP)
    Details
    Publication Date: 2013-01-19
    Description: In the new Belle II detector, which is currently under construction at the SuperKEKB accelerator, a two layer pixel detector will be introduced to improve the vertex reconstruction in a ultra high luminosity environment. The pixel detector will be produced using the DEPFET technology. A new ASIC (Data Handling Processor or DHP) designed to steer the readout process, pre-process and compress the raw data has been developed. The DHP will be directly bump bonded to the balcony of the all-silicon DEPFET module. The current chip prototype has been produced in CMOS 90 nm. Its test results, including the data processing quality, the signal integrity of the gigabit transmission lines will be presented here. For the final chip, which will be produced using CMOS 65 nm, single event upset (SEU) cross sections were measured. An additional chip, containing memory blocks to be tested, was submitted and produced using this technology.
    Electronic ISSN: 1748-0221
    Topics: Physics
    Published by Institute of Physics Publishing (IOP)
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  • 9
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    Higher maternal education is associated with favourable growth of young children in different countries (2013)
    BMJ Publishing Group
    Details
    Publication Date: 2013-06-08
    Description: Background Childhood growth affects long-term health and could contribute to health inequalities that persist throughout life. Methods We compared growth data of 4-year-old to 6-year-old children born 1997–2002 in UK (n=15 168), Sweden (n=6749) and rural China (n=10 327). SD scores (SDS) were calculated against the WHO Growth Standard. Obesity and overweight were defined by the International Obesity Taskforce cut-offs, and stunting, underweight and thinness by height, weight or body mass index (BMI)〈–2 SDS. Associations with maternal education were standardised by calculating the Slope Index of Inequality (SII). Results Mean SDS height, weight and BMI in the UK (–0.01, 0.42, 0.62, respectively) and Sweden (0.45, 0.59, 0.45) were higher than in China (–0.98, –0.82, –0.29). Higher maternal education was consistently associated with taller offspring height SDS (SII: UK 0.25; Sweden 0.17; China 1.06). Underweight and stunting were less common in the UK (prevalence: 0.6% and 2.2%, respectively) and Sweden (0.3% and 0.6%) than in China (9.5% and 16.4%), where these outcomes were inversely associated with maternal education (SII: –25.8% and –12.7%). Obesity prevalence in the UK, Sweden and China was 4.8%, 3.7% and 0.4%, respectively. Maternal education was inversely associated with offspring obesity in the UK (SII: –3.3%) and Sweden (–2.8%), but not in China (+0.3%). Conclusions Higher maternal education was associated with more favourable growth in young children: lower obesity and overweight in the UK and Sweden, and lower stunting and underweight in rural China. Public health strategies to optimise growth in early childhood need to acknowledge socioeconomic factors, but possibly with a different emphasis in different settings.
    Keywords: Health service research, Health education, Obesity (public health), Health promotion
    Print ISSN: 0143-005X
    Electronic ISSN: 1470-2738
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 10
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    Cascade energy transfer versus charge separation in ladder-type oligo(p-phenylene)/ZnO hybrid structures for light-emitting applications (2014)
    American Institute of Physics (AIP)
    Details
    Publication Date: 2014-12-09
    Description: Usability of inorganic/organic semiconductor hybrid structures for light-emitting applications can be intrinsically limited by an unfavorable interfacial energy level alignment causing charge separation and nonradiative deactivation. Introducing cascaded energy transfer funneling away the excitation energy from the interface by transfer to a secondary acceptor molecule enables us to overcome this issue. We demonstrate a substantial recovery of the light output along with high inorganic-to-organic exciton conversion rates up to room temperature.
    Print ISSN: 0003-6951
    Electronic ISSN: 1077-3118
    Topics: Physics
    Published by American Institute of Physics (AIP)
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