Amplification of seismic energy in steep topography plays an important role controlling the location of earthquake-induced landslides. Alpine mountains represent extreme topography, therefore large ...amplification may be anticipated, however suitable data needed to probe the limits of topographic effects in these demanding locations are rare. Here we present new ambient vibration data from seismic stations on the summit and ridge of one of the tallest freestanding mountains in the Swiss Alps – the Matterhorn – comparing these to a nearby local reference. Results show elevated spectral power at mountain stations between 0.4 and 1 Hz, and directional site-to-reference spectral amplitude ratios up to 14, which we attribute in part to topographic resonance. We used ambient vibration modal analysis and numerical eigenfrequency modeling to identify the fundamental mode of the Matterhorn at 0.42 Hz, as well as evidence for a second, mutually-perpendicular mode at a similar frequency. We identified high modal damping ratios of ∼20% for these modes, which we ascribe to radiative energy loss. A short campaign measurement at another mountain of comparable shape but smaller scale showed similar modal properties with a higher fundamental frequency of 1.8 Hz and peak spectral ratios of 6. Tracking of resonant frequencies over one year at the Matterhorn revealed no measurable seasonal variations related to near-surface environmental changes (e.g. temperature, ice). Our results demonstrate large spectral amplifications linked to resonance of high-relief mountain landforms, which is likely to be a widespread effect making such areas more prone to co-seismic rock damage and landslides.
•We identified resonant modes of two mountains based on ambient seismic data.•Analyzed spectral, polarization and modal attributes plus eigenfrequency models.•The larger of these sites, the Matterhorn, has a fundamental frequency of 0.42 Hz.•Both sites exhibit large site-to-reference spectral ratios and high modal damping.•Spectral amplification and fundamental frequency were consistent over time.
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•Eighteen N-substituted N-arylsulfonamido d-valines were synthesized and considered for both therapeutic application and medicinal imaging.•Most of these compounds proved to be ...nanomolar inhibitors particularly for gelatinases MMP-2 and MMP-9.•Generally, the compounds are less potent inhibitors of collagenases (MMP-8 and MMP-13) and macrophage elastase (MMP-12)•Linking a terminal fluoroalkyltriazole moiety at the P1′ substituent did not significantly lower the inhibition potential, but opens an opportunity for 18F-labeling and PET imaging.•Linking a fluorescein moiety (P2′ substituent) at the sulfonamide nitrogen via a triethyleneglycol spacer led to a highly potent probe for fluorescence imaging.
To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N-substituted N-arylsulfonamido d-valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-ylphenyl}sulfonyl)-d-valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1′ substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2′ substituent) were almost as active as the lead structure 1, making the latter derivative a suitable fluorescence imaging tool.
The relation between caregiver follow-in utterances with verbs presented in different states of dyadic engagement and later child expressive verb vocabulary in children with autism spectrum disorder ...(ASD) was examined in 29 toddlers with ASD and their caregivers. Caregiver verb input in follow-in utterances presented during higher order supported joint engagement (HSJE) accounted for a significant, large amount of variance in later child verb vocabulary;
R
2
= .26. This relation remained significant when controlling for early verb vocabulary or verb input in lower support engagement states. Other types of talk in follow-in utterances in HSJE did not correlate with later verb vocabulary. These findings are an important step towards identifying interactional contexts that facilitate verb learning in children with ASD.
We examined differences between children with autism spectrum disorder and typically developing children over an 8-month period in: (a) longitudinal associations between expressive and receptive ...vocabulary and (b) the extent to which caregiver utterances provided within an “optimal” engagement state mediated the pathway from early expressive to later receptive vocabulary. In total, 59 children (28–53 months at Time 1) comprised the autism spectrum disorder group and 46 children (8–24 months at Time 1) comprised the typically developing group. Groups were matched on initial vocabulary sizes. Results showed that the association between early expressive and later receptive vocabulary was moderated by group. A moderated mediation effect was also found, indicating linguistic input provided within an optimal engagement state only mediated associations for the autism spectrum disorder group.
Twin Lakes, located on the Confederated Tribes of the Colville Indian Reservation in eastern Washington, USA, include North Twin Lake (NT) and South Twin Lake (ST). The mesotrophic, dimictic lakes ...are important recreational fishing sites for both warm-water bass and cold-water trout. To improve summertime cold-water habitat for trout in NT, dissolved oxygen (DO) addition to the hypolimnion, using liquid oxygen as an oxygen gas source, started in 2009. This study assessed mercury (Hg) in the water column, zooplankton and fish, and related water quality parameters, in Twin Lakes from 2009 to 2012. Because methylmercury (MeHg) buildup in lake bottom water is commonly associated with hypolimnetic anoxia, hypolimnetic oxygenation was hypothesized to reduce Hg in bottom waters and biota in NT relative to ST. Oxygen addition led to significantly higher DO (mean hypolimnetic DO: 2–8mg/L versus <1mg/L) and lower MeHg (peak mean hypolimnetic MeHg: 0.05–0.2ng/L versus 0.15–0.4ng/L) in North Twin. In North Twin, years with higher DO (2009 and 2011) exhibited lower MeHg in bottom waters and lower total Hg in zooplankton, inferring a positive linkage between oxygen addition and lower bioaccumulation. However, when comparing between the two lakes, Hg levels were significantly higher in zooplankton (total Hg range: 100–200 versus 50–100μg/kg dry weight) and trout (spring 2010 stocking cohort of eastern brook trout mean total Hg: 74.9 versus 49.9μg/kg wet weight) in NT relative to ST. Lower Hg bioaccumulation in ST compared to NT may be related to bloom dilution in chlorophyll-rich bottom waters, a vertical disconnect between the location of zooplankton and MeHg in the water column, and high binding affinity between sulfide and MeHg in bottom waters.
•Oxygen addition correlated with lower mercury bioaccumulation in North Twin.•However, mercury levels in zooplankton and fish were lower in non-oxygenated South Twin.•South Twin was a naturally low bioaccumulating ecosystem.•Bloom dilution and zooplankton exclusion explain low bioaccumulation in South Twin.
Matrix metalloproteinases (MMPs) are emerging as pivotal fine-tuners of cell function in tissue homeostasis and in various pathologies, in particular inflammation. In vivo monitoring of the activity ...of specific MMPs, therefore, provides high potential for assessing disease progression and tissue function, and manipulation of MMP activity in tissues and whole organisms may further provide a mode of controlling pathological processes. We describe here the synthesis of novel fluorinated and nonfluorinated analogues of a secondary sulfonamide-based lead structure, compound 2, and test their efficacy as in vivo inhibitors and tracers of the gelatinases, MMP-2 and MMP-9. Using a murine neuroinflammatory model, we show that compound 2 is a highly effective in vivo inhibitor of both MMP-2 and MMP-9 activity with little or no adverse effects even after long-term daily oral administration. A fluorescein-labeled derivative compound 17 shows direct binding to activated gelatinases surrounding inflammatory cuffs in the neuroinflammation model and to pancreatic β-cells in the islets of Langerhans, colocalizing with MMP-2 and MMP-9 activity as detected using in situ zymography techniques. These results demonstrate that compound 2 derivatives have potential as in vivo imaging tools and for future development for specific MMP-2 versus MMP-9 probes. Our chemical modifications mainly target the residues directed toward the S1′ and S2′ pockets and, thereby, provide new information on the structure–activity relationships of this inhibitor type.
Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and ...identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10
) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
The association between kidney disease and cancer is multifaceted and complex. Persons with chronic kidney disease (CKD) have an increased incidence of cancer, and both cancer and cancer treatments ...can cause impaired kidney function. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. In addition, the oncology treatment landscape is changing rapidly, and data on tolerability of novel therapies in patients with CKD are often lacking. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and research priorities are described.
Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the ...PDF and HTML versions of the Article.
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