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AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis in mammals and is an attractive target for drug discovery against diabetes, obesity and other diseases. The AMPK homologue in Saccharomyces cerevisiae, known as SNF1, is essential for responses to glucose starvation as well as for other cellular processes, although SNF1 seems to be activated by a ligand other than AMP1. Here we report the crystal structure at 2.6 Å resolution of the heterotrimer core of SNF1. The ligand-binding site in the γ-subunit (Snf4) has clear structural differences from that of the Schizosaccharomyces pombe enzyme, although our crystallographic data indicate that AMP can also bind to Snf4. The glycogen-binding domain in the β-subunit (Sip2) interacts with Snf4 in the heterotrimer but should still be able to bind carbohydrates. Our structure is supported by a large body of biochemical and genetic data on this complex. Most significantly, the structure reveals that part of the regulatory sequence in the α-subunit (Snf1) is sequestered by Snf4, demonstrating a direct interaction between the α- and γ-subunits and indicating that our structure may represent the heterotrimer core of SNF1 in its activated state.

The European Aerosol Research Lidar Network, EARLINET, was founded in 2000 as a research project for establishing a quantitative, comprehensive, and statistically significant database for the horizontal, vertical, and temporal distribution of aerosols on a continental scale. Since then EARLINET has continued to provide the most extensive collection of ground-based data for the aerosol vertical distribution over Europe. This paper gives an overview of the network's main developments since 2000 and introduces the dedicated EARLINET special issue, which reports on the present innovative and comprehensive technical solutions and scientific results related to the use of advanced lidar remote sensing techniques for the study of aerosol properties as developed within the network in the last 13 years. Since 2000, EARLINET has developed greatly in terms of number of stations and spatial distribution: from 17 stations in 10 countries in 2000 to 27 stations in 16 countries in 2013. EARLINET has developed greatly also in terms of technological advances with the spread of advanced multiwavelength Raman lidar stations in Europe. The developments for the quality assurance strategy, the optimization of instruments and data processing, and the dissemination of data have contributed to a significant improvement of the network towards a more sustainable observing system, with an increase in the observing capability and a reduction of operational costs. Consequently, EARLINET data have already been extensively used for many climatological studies, long-range transport events, Saharan dust outbreaks, plumes from volcanic eruptions, and for model evaluation and satellite data validation and integration. Future plans are aimed at continuous measurements and near-real-time data delivery in close cooperation with other ground-based networks, such as in the ACTRIS (Aerosols, Clouds, and Trace gases Research InfraStructure Network) www.actris.net, and with the modeling and satellite community, linking the research community with the operational world, with the aim of establishing of the atmospheric part of the European component of the integrated global observing system.

In this paper we describe the EARLINET Single Calculus Chain (SCC), a tool for the automatic analysis of lidar measurements. The development of this tool started in the framework of EARLINET-ASOS (European Aerosol Research Lidar Network – Advanced Sustainable Observation System); it was extended within ACTRIS (Aerosol, Clouds and Trace gases Research InfraStructure Network), and it is continuing within ACTRIS-2. The main idea was to develop a data processing chain that allows all EARLINET stations to retrieve, in a fully automatic way, the aerosol backscatter and extinction profiles starting from the raw lidar data of the lidar systems they operate. The calculus subsystem of the SCC is composed of two modules: a pre-processor module which handles the raw lidar data and corrects them for instrumental effects and an optical processing module for the retrieval of aerosol optical products from the pre-processed data. All input parameters needed to perform the lidar analysis are stored in a database to keep track of all changes which may occur for any EARLINET lidar system over the time. The two calculus modules are coordinated and synchronized by an additional module (daemon) which makes the whole analysis process fully automatic. The end user can interact with the SCC via a user-friendly web interface. All SCC modules are developed using open-source and freely available software packages. The final products retrieved by the SCC fulfill all requirements of the EARLINET quality assurance programs on both instrumental and algorithm levels. Moreover, the manpower needed to provide aerosol optical products is greatly reduced and thus the near-real-time availability of lidar data is improved. The high-quality of the SCC products is proven by the good agreement between the SCC analysis, and the corresponding independent manual retrievals. Finally, the ability of the SCC to provide high-quality aerosol optical products is demonstrated for an EARLINET intense observation period.

Forward genetic screens remain at the forefront of biology as an unbiased approach for discovering and elucidating gene function at the organismal and molecular level. Past mutagenesis screens targeting maternal-effect genes identified a broad spectrum of phenotypes ranging from defects in oocyte development to embryonic patterning. However, earlier vertebrate screens did not reach saturation, anticipated classes of phenotypes were not uncovered, and technological limitations made it difficult to pinpoint the causal gene. In this study, we performed a chemically-induced maternal-effect mutagenesis screen in zebrafish and identified eight distinct mutants specifically affecting the cleavage stage of development and one cleavage stage mutant that is also male sterile. The cleavage-stage phenotypes fell into three separate classes: developmental arrest proximal to the mid blastula transition (MBT), irregular cleavage, and cytokinesis mutants. We mapped each mutation to narrow genetic intervals and determined the molecular basis for two of the developmental arrest mutants, and a mutation causing male sterility and a maternal-effect mutant phenotype. One developmental arrest mutant gene encodes a maternal specific Stem Loop Binding Protein, which is required to maintain maternal histone levels. The other developmental arrest mutant encodes a maternal-specific subunit of the Minichromosome Maintenance Protein Complex, which is essential for maintaining normal chromosome integrity in the early blastomeres. Finally, we identify a hypomorphic allele of Polo-like kinase-1 (Plk-1), which results in a male sterile and maternal-effect phenotype. Collectively, these mutants expand our molecular-genetic understanding of the maternal regulation of early embryonic development in vertebrates.

During the eruption of Eyjafjallajökull in April–May 2010 multi-wavelength Raman lidar measurements were performed at the CNR-IMAA Atmospheric Observatory (CIAO), whenever weather conditions permitted observations. A methodology both for volcanic layer identification and accurate aerosol typing has been developed. This methodology relies on the multi-wavelength Raman lidar measurements and the support of long-term lidar measurements performed at CIAO since 2000. The aerosol mask for lidar measurements performed at CIAO during the 2010 Eyjafjallajökull eruption has been obtained. Volcanic aerosol layers were observed in different periods: 19–22 April, 27–29 April, 8–9 May, 13–14 May and 18–19 May. A maximum aerosol optical depth of about 0.12–0.13 was observed on 20 April, 22:00 UTC and 13 May, 20:30 UTC. Volcanic particles were detected at low altitudes, in the free troposphere and in the upper troposphere. Occurrences of volcanic particles within the PBL were detected on 21–22 April and 13 May. A Saharan dust event was observed on 13–14 May: dust and volcanic particles were simultaneously detected at CIAO at separated different altitudes as well as mixed within the same layer. Lidar ratios at 355 and 532 nm, the Ångström exponent at 355/532 nm, the backscatter-related Ångström exponent at 532/1064 nm and the particle linear depolarization ratio at 532 nm measured inside the detected volcanic layers are discussed. The dependence of these quantities on relative humidity has been investigated by using co-located microwave profiler measurements. The measured values of these intensive parameters indicate the presence of volcanic sulfates/continental mixed aerosol in the volcanic aerosol layers observed at CIAO. In correspondence of the maxima observed in the volcanic aerosol load on 19–20 April and 13 May, different values of intensive parameters were observed. Apart from the occurrence of sulfate aerosol, these values indicate also the presence of some ash which is affected by the aging during transport over Europe.

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower order and higher order RRBs. Individuals displaying lower order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. In rodents, lower order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs, while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A activation RRB expression, whereas blockades generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less, but show promise as potential targets for regulating RRBs. Increasing 5-HT3 has not been shown to affect RRBs. 5-HT6 activation can increase RRBs, and blocking 5-HT6 activity decreases RRBs. Lastly, either increasing or blocking 5-HT7 activity can reduce RRBs.

According to our experience, the treatment with remineralising mousse based on biomimetic nanohydroxyapatite has the advantage of being easily implemented by all patients as it is economical and absolutely noninvasive. The following case report reports the results obtained from the use of a mousse based on biomimetic nanohydroxyapatite for the treatment of incisor and molar hypomineralisation. This case report illustrates the case of a 4-year-old patient who was diagnosed with MIH and was subjected to remineralising treatments at home for six months, at alternating periods. Throughout the observation period, the painful perception of the lesions was detected through an assessment scale, and the clinical appearance was documented photographically. One year after the diagnosis, all the elements involved no longer showed any symptoms.

Early embryos must rapidly generate large numbers of cells to form an organism. Many species accomplish this through a series of rapid, reductive, and transcriptionally silent cleavage divisions. Previous work has demonstrated that the number of divisions before both cell cycle elongation and zygotic genome activation (ZGA) is regulated by the ratio of nuclear content to cytoplasm (N/C). To understand how the N/C ratio affects the timing of ZGA, we directly assayed the behavior of several previously identified N/C ratio–dependent genes using the MS2-MCP reporter system in living Drosophila embryos with altered ploidy and cell cycle durations. For every gene that we examined, we found that nascent RNA output per cycle is delayed in haploid embryos. Moreover, we found that the N/C ratio influences transcription through three overlapping modes of action. For some genes (knirps, fushi tarazu, and snail), the effect of ploidy can be primarily attributed to changes in cell cycle duration. However, additional N/C ratio–mediated mechanisms contribute significantly to transcription delays for other genes. For giant and bottleneck, the kinetics of transcription activation are significantly disrupted in haploids, while for frühstart and Krüppel, the N/C ratio controls the probability of transcription initiation. Our data demonstrate that the regulatory elements of N/C ratio–dependent genes respond directly to the N/C ratio through multiple modes of regulation.

Since its establishment in 2000, EARLINET (European Aerosol Research Lidar NETwork) has provided, through its database, quantitative aerosol properties, such as aerosol backscatter and aerosol extinction coefficients, the latter only for stations able to retrieve it independently (from Raman or high-spectral-resolution lidars). These coefficients are stored in terms of vertical profiles, and the EARLINET database also includes the details of the range resolution of the vertical profiles. In fact, the algorithms used in the lidar data analysis often alter the spectral content of the data, mainly acting as low-pass filters to reduce the high-frequency noise. Data filtering is described by the digital signal processing (DSP) theory as a convolution sum: each filtered signal output at a given range is the result of a linear combination of several signal input data samples (relative to different ranges from the lidar receiver), and this could be seen as a loss of range resolution of the output signal. Low-pass filtering always introduces distortions in the lidar profile shape. Thus, both the removal of high frequency, i.e., the removal of details up to a certain spatial extension, and the spatial distortion produce a reduction of the range resolution. This paper discusses the determination of the effective resolution (ERes) of the vertical profiles of aerosol properties retrieved from lidar data. Large attention has been dedicated to providing an assessment of the impact of low-pass filtering on the effective range resolution in the retrieval procedure.

During early development, animal embryos depend on maternally deposited RNA until zygotic genes become transcriptionally active. Before this maternal-to-zygotic transition, many species execute rapid and synchronous cell divisions without growth phases or cell cycle checkpoints. The coordinated onset of transcription, cell cycle lengthening, and cell cycle checkpoints comprise the midblastula transition (MBT). A long-standing model in the frog, Xenopus laevis , posits that MBT timing is controlled by a maternally loaded inhibitory factor that is titrated against the exponentially increasing amount of DNA. To identify MBT regulators, we developed an assay using Xenopus egg extract that recapitulates the activation of transcription only above the DNA-to-cytoplasm ratio found in embryos at the MBT. We used this system to biochemically purify factors responsible for inhibiting transcription below the threshold DNA-to-cytoplasm ratio. This unbiased approach identified histones H3 and H4 as concentration-dependent inhibitory factors. Addition or depletion of H3/H4 from the extract quantitatively shifted the amount of DNA required for transcriptional activation in vitro. Moreover, reduction of H3 protein in embryos induced premature transcriptional activation and cell cycle lengthening, and the addition of H3/H4 shortened post-MBT cell cycles. Our observations support a model for MBT regulation by DNA-based titration and suggest that depletion of free histones regulates the MBT. More broadly, our work shows how a constant concentration DNA binding molecule can effectively measure the amount of cytoplasm per genome to coordinate division, growth, and development. Significance Embryos depend on maternally deposited RNA until zygotic transcription activates. In many species, genome activation coincides with cell cycle lengthening and cellular motility, which collectively comprise the midblastula transition (MBT). A long-standing model is that MBT onset is controlled by titration of a maternally loaded inhibitor against exponentially increasing DNA. To identify MBT inhibitors, we developed an assay using Xenopus egg extract that recapitulates transcriptional activation only above a DNA-to-cytoplasm ratio similar to MBT embryos and identified histones H3 and H4 as inhibitors. Changing histone levels quantitatively shifts the DNA concentration required for transcription in vitro and alters the onset of both zygotic transcription and cell cycle lengthening in vivo. Our work strongly supports histones as a titrated MBT inhibitor.