The study of source‐to‐sink systems relates long‐term variations in sediment flux to morphogenic evolution of erosional–depositional systems. These variations are caused by an intricate combination of autogenic and allogenic forcing mechanisms that operate on multiple time scales – from individual transport events to large‐scale filling of basins. In order to achieve a better understanding of how these mechanisms influence morphological characteristics on different scales, 29 submodern source‐to‐sink systems have been investigated. The study is based on measurements of morphological parameters from catchments, shelves and slopes derived from a ∼1 km global digital elevation model dataset, in combination with data on basin floor fans, sediment supply, water discharge and deposition rates derived from published literature. By comparing various morphological and sedimentological parameters within and between individual systems, a number of relationships governing system evolution and behaviour are identified. The results suggest that the amount of low‐gradient floodplain area and river channel gradient are good indicators for catchment storage potential. Catchment area and river channel length is also related to shelf area and shelf width, respectively. Similarly to the floodplain area, these parameters are important for long‐term storage of sediment on the shelf platform. Additionally, the basin floor fan area is correlative to the long‐term deposition rate and the slope length. The slope length thus proves to be a useful parameter linking proximal and distal segments in source‐to‐sink systems. The relationships observed in this study provide insight into segment scale development of source‐to‐sink systems, and an understanding of these relationships in modern systems may result in improved knowledge on internal and external development of source‐to‐sink systems over geological time scales. They also allow for the development of a set of semi‐quantitative guidelines that can be used to predict similar relationships in other systems where data from individual system segments are missing or lacking.

Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene, SMN2 that produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by two-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-quinazoline probe, we identified the scavenger decapping enzyme, DcpS as a potential binder. We show that the C5-quinazolines potently inhibit DcpS decapping activity, and that the potency of inhibition correlates with potency for SMN2 promoter induction. Binding of C5-quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m7GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule.

Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of survival motor neuron (SMN) protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh-throughput screening recently identified substituted quinazolines as potent SMN2 inducers. A series of C5-quinazoline derivatives were tested for their ability to increase SMN expression in vivo. Oral administration of three compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. We then examined the effect of these compounds on the progression of disease in SMN lacking exon 7 (SMNDelta7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss. In summary, the C5-quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11 and ameliorates the motor phenotype of SMNDelta7 SMA mice.

Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene ( SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.

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Ground-based hyperspectral imaging combined with terrestrial lidar scanning is a novel technique for outcrop analysis, which has been applied to Early and Late Albian carbonates of the Pozalagua Quarry (Cantabrian Mountains, Spain). An image processing workflow has been developed for differentiating limestone from dolomite, providing additional sedimentary and diagenetic information, and the possibility to quantitatively delineate diagenetic phases in an accurate way. Spectral absorption signatures can be linked to specific sedimentary or diagenetic products, such as recent and palaeokarst, hydrothermal karst, (solution enlarged) fractures and different dolomite types. Some of the spectral signatures are related to iron, manganese, organic matter, clay and/or water content. Ground-truthing accessible parts of the quarry showed that the classification based on hyperspectral image interpretation was very accurate. This technique opens the possibility for quantitative data evaluation on sedimentary and diagenetic features in inaccessible outcrops. This study demonstrates the potential of ground-based imaging spectroscopy to provide information about the chemical-mineralogical distribution in outcrops, which could otherwise not be established using conventional field methods.

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