Modulation of Nitro-fatty acid signaling: prostaglandin reductase-1 is a Nitroalkene reductase

Background: Nitroalkenes are electrophilic anti-inflammatory mediators that signal via Michael addition and are metabolized in vivo. Results: Prostaglandin reductase-1 is identified as a nitroalkene reductase. Conclusion: Prostaglandin reductase-1 reduces fatty acid nitroalkenes to nitroalkanes, inactivating electrophilic reactivity. Significance: A mammalian enzyme is identified that metabolizes fatty acid nitroalkenes in vivo to silence their signaling reactions.Fil: Vitturi, Dario A.. University of Pittsburgh; Estados UnidosFil: Chen, Chen Shan. University of Pittsburgh; Estados UnidosFil: Woodcock, Steven R.. University of Pittsburgh; Estados UnidosFil: Salvatore, Sonia R.. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Koenitzer, Jeffrey R.. University of Pittsburgh; Estados UnidosFil: Stewart, Nicolas A.. University of Pittsburgh; Estados UnidosFil: Wakabayashi, Nobunao. University of Pittsburgh; Estados UnidosFil: Kensler, Thomas W.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Schopfer, Francisco J.. University of Pittsburgh; Estados Unido

Self-oligomerization Regulates Stability of Survival Motor Neuron Protein Isoforms by Sequestering an SCF\u3csup\u3eSlmb\u3c/sup\u3e Degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Changing climate both increases and decreases European river floods

Climate change has led to concerns about increasing river floods resulting from the greater water-holding capacity of a warmer atmosphere. These concerns are reinforced by evidence of increasing economic losses associated with flooding in many parts of the world, including Europe. Any changes in river floods would have lasting implications for the design of flood protection measures and flood risk zoning. However, existing studies have been unable to identify a consistent continental-scale climatic-change signal in flood discharge observations in Europe, because of the limited spatial coverage and number of hydrometric stations. Here we demonstrate clear regional patterns of both increases and decreases in observed river flood discharges in the past five decades in Europe, which are manifestations of a changing climate. Our results—arising from the most complete database of European flooding so far—suggest that: increasing autumn and winter rainfall has resulted in increasing floods in northwestern Europe; decreasing precipitation and increasing evaporation have led to decreasing floods in medium and large catchments in southern Europe; and decreasing snow cover and snowmelt, resulting from warmer temperatures, have led to decreasing floods in eastern Europe. Regional flood discharge trends in Europe range from an increase of about 11 per cent per decade to a decrease of 23 per cent. Notwithstanding the spatial and temporal heterogeneity of the observational record, the flood changes identified here are broadly consistent with climate model projections for the next century, suggesting that climate-driven changes are already happening and supporting calls for the consideration of climate change in flood risk management

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Effects of barefoot and shod running on lower extremity joint loading, a musculoskeletal simulation study

PURPOSE: The aim of the current investigation was to utilize a musculoskeletal simulation based approach, to examine the effects of barefoot and shod running on lower extremity joint loading during the stance phase. METHODS: Twelve male runners, ran over an embedded force plate at 4.0 m/s, in both barefoot and shod conditions. Kinematics of the lower extremities were collected using an eight camera motion capture system. Lower extremity joint loading was also explored using a musculoskeletal simulation and mathematical modelling approach, and differences between footwear conditions were examined using paired samples t-tests. RESULTS: Peak Achilles tendon force was significantly larger (P=0.039) when running barefoot (6.85 BW) compared to shod (6.07 BW). In addition, both medial (P=0.013) and lateral (P=0.007) tibiofemoral instantaneous load rates were significantly larger in the barefoot (medial = 289.17 BW/s & lateral = 179.59 BW/s) in relation to the shod (medial = 167.57 BW/s & lateral = 116.40 BW/s) condition. Finally, the barefoot condition (9.70 BW) was associated with a significantly larger (P=0.037) peak hip force compared to running shod (8.51 BW). CONCLUSIONS: The current investigation indicates that running barefoot may place runners at increased risk from the biomechanical factors linked to the aetiology of chronic lower extremity pathologies. However, future analyses using habitual barefoot runners, are required before more definitive affirmations regarding injury predisposition can be made

An effect of pier pilings on nearshore submarine groundwater discharge from a (partially) confined aquifer

Concurrent bulk ground conductivity mapping and direct measurements of seepage rates were carried out near a pier at Shelter Island, New York, U.S.A. A shallow sediment layer was identified to provide confinement for lower aquifer units. The conductivity and seepage rate data indicate that pilings of the pier apparently pierce this shallow sediment layer, producing a comparatively high seepage rate driven by the hydraulic head of the (partially) confined aquifer, resulting in a substantial increase in submarine groundwater discharge (SGD) near the pier. Seepage rate measurements made close to the pier, which runs perpendicular to the shoreline, cannot be considered representative for the area. At the study site, the magnitude of SGD depends both on the distance from shore and on the distance from the pier, a rmding that confounds the commonly observed patterns of decreasing SGD with increasing distance from shore. This alteration of a groundwater flow pattern is a previously undescribed effect of anthropogenic perturbation in a coastal system