138 research outputs found

    KAJIAN SPASIAL KEBUTUHAN AIR BERSIH DI KECAMATAN PINELENG, KABUPATEN MINAHASA

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    Salah satu faktor penting dalam keberlangsungan pembangunan di suatu wilayah perkotaan adalah ketersediaan sumber daya alam yang mencukupi guna memenuhi segala kebutuhan masyarakatnya.Salah satu sumber daya alam yang memiliki peran vital di wilayah perkotaan adalah sumber daya air bersih. Yang menjadi fokus dari penelitian ini yakni mengkaji fungsi spasial wilayah Kecamatan Pineleng, memproyeksi kebutuhan air bersih dalam jangka waktu 10 tahun kedepan (2013-2023), serta mengetahui rasio ketersediaan sumber air (kapasitas produksi) terhadap proyeksi kebutuhan air selama 10 tahun kedepan. Lingkup dari penelitian ini adalah Kecamatan Pineleng, Kabupaten Minahasa.Metode penelitian ini adalah deskriptif kuantitatif-kualitatif dengan menggunakan analisis spasial GIS dan analisis proyeksi geometrik.Analisis spasial GIS mencakup kajian tentang kelerengan, topografi, perkembangan kawasan terbangun dan tidak terbangun, pola pemanfaatan lahan, dan kajian sumber air.Sedangkan analisis proyeksi geometrik mencakup proyeksi tentang kependudukan 10 tahun kedepan, proyeksi kebutuhan sektor domestik, dan proyeksi kebutuhan sektor non domestik.Berdasarkan hasil penelitian dapat disimpulkan bahwa secara spasial Kecamatan Pineleng terletak pada kelerengan 15-25 % dan terletak pada ketinggian 77-429 mdpl.kemudian untuk proyeksi kebutuhan air domestik dan non domestik selama 10 tahun mendatang mencapai 38,963 liter/detik atau meningkat sebesar 34,10 %. Kemudian total ketersediaan air bersih dari seluruh sumber air di Kecamatan Pineleng sebesar 154,45 l/dtk. Sedangkan untuk rasio ketersediaan sumber air dengan proyeksi kebutuhan air diperoleh hasil bahwa sumber air di Kecamatan Pineleng masih dapat memenuhi kebutuhan masyarakatnya dalam kurun waktu lebih dari 10 tahun kedepan.   Kata kunci : Kajian spasial, kebutuhan air bersih, Kecamatan Pinelen

    De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

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    Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability

    Characterization of Oligomers of Heterogeneous Size as Precursors of Amyloid Fibril Nucleation of an SH3 Domain: An Experimental Kinetics Study

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    Correction: Characterization of Oligomers of Heterogeneous Size as Precursors of Amyloid Fibril Nucleation of an SH3 Domain: An Experimental Kinetics Study. PLoS ONE 9(1): 10.1371/annotation/dbb84118-9ada-43e4-8734-8f8322be1a59. doi: 10.1371/annotation/dbb84118-9ada-43e4-8734-8f8322be1a59Understanding the earliest molecular events during nucleation of the amyloid aggregation cascade is of fundamental significance to prevent amyloid related disorders. We report here an experimental kinetic analysis of the amyloid aggregation of the N47A mutant of the α-spectrin SH3 domain (N47A Spc-SH3) under mild acid conditions, where it is governed by rapid formation of amyloid nuclei. The initial rates of formation of amyloid structures, monitored by thioflavine T fluorescence at different protein concentrations, agree quantitatively with high-order kinetics, suggesting an oligomerization pre-equilibrium preceding the rate-limiting step of amyloid nucleation. The curves of native state depletion also follow high-order irreversible kinetics. The analysis is consistent with the existence of low-populated and heterogeneous oligomeric precursors of fibrillation that form by association of partially unfolded protein monomers. An increase in NaCl concentration accelerates fibrillation but reduces the apparent order of the nucleation kinetics; and a double mutant (K43A, N47A) Spc-SH3 domain, largely unfolded under native conditions and prone to oligomerize, fibrillates with apparent first order kinetics. On the light of these observations, we propose a simple kinetic model for the nucleation event, in which the monomer conformational unfolding and the oligomerization of an amyloidogenic intermediate are rapidly pre-equilibrated. A conformational change of the polypeptide chains within any of the oligomers, irrespective of their size, is the rate-limiting step leading to the amyloid nuclei. This model is able to explain quantitatively the initial rates of aggregation and the observed variations in the apparent order of the kinetics and, more importantly, provides crucial thermodynamic magnitudes of the processes preceding the nucleation. This kinetic approach is simple to use and may be of general applicability to characterize the amyloidogenic intermediates and oligomeric precursors of other disease-related proteins.This work was financed by the Andalucía Government (grant FQM-02838), the Spanish Ministry of Science and Innovation (grant BIO2009-07317), and the European Regional Development Fund of the European Union. D. Ruzafa is recipient of a research fellowship from the F.P.U. program of the Spanish Ministry of Education. L. Varela is financed by the G.R.E.I.B. program of the University of Granada

    RNA Aptamers Generated against Oligomeric AÎČ40 Recognize Common Amyloid Aptatopes with Low Specificity but High Sensitivity

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    Aptamers are useful molecular recognition tools in research, diagnostics, and therapy. Despite promising results in other fields, aptamer use has remained scarce in amyloid research, including Alzheimer's disease (AD). AD is a progressive neurodegenerative disease believed to be caused by neurotoxic amyloid ÎČ-protein (AÎČ) oligomers. AÎČ oligomers therefore are an attractive target for development of diagnostic and therapeutic reagents. We used covalently-stabilized oligomers of the 40-residue form of AÎČ (AÎČ40) for aptamer selection. Despite gradually increasing the stringency of selection conditions, the selected aptamers did not recognize AÎČ40 oligomers but reacted with fibrils of AÎČ40, AÎČ42, and several other amyloidogenic proteins. Aptamer reactivity with amyloid fibrils showed some degree of protein-sequence dependency. Significant fibril binding also was found for the naĂŻve library and could not be eliminated by counter-selection using AÎČ40 fibrils, suggesting that aptamer binding to amyloid fibrils was RNA-sequence-independent. Aptamer binding depended on fibrillogenesis and showed a lag phase. Interestingly, aptamers detected fibril formation with ≄15-fold higher sensitivity than thioflavin T (ThT), revealing substantial ÎČ-sheet and fibril formation undetected by ThT. The data suggest that under physiologic conditions, aptamers for oligomeric forms of amyloidogenic proteins cannot be selected due to high, non-specific affinity of oligonucleotides for amyloid fibrils. Nevertheless, the high sensitivity, whereby aptamers detect ÎČ-sheet formation, suggests that they can serve as superior amyloid recognition tools

    Assessment of spatial variability of multiple ecosystem services in grasslands of different intensities

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    Grasslands provide multiple Ecosystem Services (ES) such as forage provision, carbon sequestration or habitat provision. Knowledge about the trade-offs between these ES is of great importance for grassland management. Yet, the outcome of different management strategies on ES provision is highly uncertain due to spatial variability. We aim to characterize the provision (level and spatial variability) of grassland ES under various management strategies. To do so, we combine empirical data for multiple ES with spatially explicit census data on land use intensities. We analyzed the variations of five ES (forage provision, climate regulation, pollination, biodiversity conservation and outdoor recreation) using data from biodiversity fieldwork, experimental plots for carbon as well as social network data from Flickr. These data were used to calculate the distribution of modelled individual and multiple ES values from different grassland management types in a Swiss case study region using spatial explicit information for 17,383 grassland parcels. Our results show that (1) management regime and intensity levels play an important role in ES provision but their impact depends on the ES. In general, extensive management, especially in pastures, favors all ES but forage provision, whereas intensive management favors only forage provision and outdoor recreation; (2) ES potential provision varies between parcels under the same management due to the influence of environmental drivers, related to topography and landscape structure; (3) there is a trade-offs between forage provision and other ES at the cantonal level but a synergy between forage provision and biodiversity conservation within the grassland categories, due to the negative impact of elevation on both ES. Information about multiple ES provision is key to support effective agri-environmental measures and information about the spatial variability can prevent uncertain outputs of decision-making processes

    ICAR: endoscopic skull‐base surgery

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    Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

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    Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

    Distinguishing closely related amyloid precursors using an RNA aptamer

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    Although amyloid fibrils assembled in vitro commonly involve a single protein, fibrils formed in vivo can contain multiple protein sequences. The amyloidogenic protein human ?2-microglobulin (h?2m) can co-polymerize with its N-terminally truncated variant (?N6) in vitro to form hetero-polymeric fibrils that differ from their homo-polymeric counterparts. Discrimination between the different assembly precursors, for example by binding of a biomolecule to one species in a mixture of conformers, offers an opportunity to alter the course of co-assembly and the properties of the fibrils formed. Here, using h?2m and its amyloidogenic counterpart, ??6, we describe selection of a 2'F-modified RNA aptamer able to distinguish between these very similar proteins. SELEX with a N30 RNA pool yielded an aptamer (B6) that binds h?2m with an EC50 of ?200 nM. NMR spectroscopy was used to assign the (1)H-(15)N HSQC spectrum of the B6-h?2m complex, revealing that the aptamer binds to the face of h?2m containing the A, B, E, and D ?-strands. In contrast, binding of B6 to ?N6 is weak and less specific. Kinetic analysis of the effect of B6 on co-polymerization of h?2m and ?N6 revealed that the aptamer alters the kinetics of co-polymerization of the two proteins. The results reveal the potential of RNA aptamers as tools for elucidating the mechanisms of co-assembly in amyloid formation and as reagents able to discriminate between very similar protein conformers with different amyloid propensity
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