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The Diligencia basin in the Orocopia Mountains of southeastern California has been one of the primary areas used to test the hypothesis of more than 300 km of dextral slip along the combined San Andreas/San Gabriel fault system. The Orocopia Mountains have also been the focus of research on deposition, deformation, metamorphism, uplift and exposure of the Orocopia Schist, which resulted from fl at-slab subduction during the latest Cretaceous/Paleogene Laramide orogeny. The uppermost Oligocene/Lower Miocene Diligencia Formation consists of more than 1500 m of nonmarine strata, including basalt fl ows and intrusions dated at 24-21 Ma. The base of the Diligencia Formation sits nonconformably on Proterozoic augen gneiss and related units along the southern basin boundary, where low-gradient alluvial fans extended into playa-lacustrine environments to the northeast. The northern basal conglomerate of the Diligencia Formation, which was derived from granitic rocks in the Hayfield Mountains to the north, sits unconformably on the Eocene Maniobra Formation. The northern basal conglomerate is overlain by more than 300 m of mostly red sandstone, conglomerate, mudrock and tuff. The basal conglomerate thins and fines westward; paleocurrent measurements suggest deposition on alluvial fans derived from the northeast, an interpretation consistent with a NW-SE-trending normal fault (present orientation) as the controlling structure of the half graben formed during early Diligencia deposition. This fault is hereby named the Diligencia fault, and is interpreted as a SW-dipping normal fault, antithetic to the Orocopia Mountains detachment and related faults. Deposition of the upper Diligencia Formation was infl uenced by a NE-dipping normal fault, synthetic with, and closer to, the exposed detachment faults. The Diligencia Formation is nonconformable on Mesozoic granitoids in the northwest part of the basin. Palinspastic restoration of the Orocopia Mountain area includes the following phases, each of which corresponds with microplate-capture events along the southern California continental margin: (1) Reversal of 240 km of dextral slip on the San Andreas fault (including the Punchbowl and other fault strands) in order to align the San Francisquito-Fenner-Orocopia Mountains detachment-fault system at 6 Ma. (2) Reversal of N-S shortening and 90° of clockwise rotation of the Diligencia basin and Orocopia Mountains, and 40 km of dextral slip on the San Gabriel fault between 12 and 6 Ma. (3) Reversal of 40° of clockwise rotation of the San Gabriel block (including Soledad basin and Sierra Pelona) and 30 km of dextral slip on the Canton fault between 18 and 12 Ma. These palinspastic restorations result in a coherent set of SW-NE-trending normal faults, basins (including Diligenica basin) and antiformal structures consistent with NW-SE-directed crustal extension from 24 to 18 Ma, likely resulting from the unstable configuration of the Mendocino triple junction. © 2014 Geological Society of America.

AbstractBackgroundNeuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.MethodsThe potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ1–42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide.Results3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.ConclusionsOur data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

The identification of the factors triggering continental environmental changes at the Permian–Triassic transition is of general interest as they allow a better understanding of the most controversial mass extinction of the Phanerozoic. This study investigates the environmental response to external forcings on continental successions at the south‐east‐margin of the Central European Basin System in Germany. Studies from this area are scarce, and its evolution is poorly understood. This work integrates high‐resolution core‐logging and quantitative sedimentary petrography of Middle Permian–Early Triassic successions recovered from the wells Obernsees‐1 and Lindau‐1. The sedimentological investigation reveals major vertical variations in the depositional settings marked by changes in grain‐size trends and facies associations: (i) the progradation of mass flow/fluvial fans over sandflat environments denotes the Guadalupian–Lopingian; (ii) sabkha to shallow‐marine conditions occur during the uppermost Permian; (iii) the onset of braided fluvial sequences marks the Permian–Triassic boundary; (iv) changes in fluvial style, reflecting increased river sinuosity, and aeolian deposition characterize the remaining Triassic. Environmental changes are accentuated by variations in sediment composition. Proximal deposits (for example, alluvial fan) are lithic arkoses, while more distal associations reveal arkosic composition. Detrital modes point to: (i) a high‐grade metamorphic source feeding the drainage of Lindau‐1 (metamorphic index, MI 441–500); and (ii) a mixed low‐grade and high‐grade metamorphic source (MI 277–395) feeding the Permian of Obernsees‐1, passing upward to high‐grade metamorphic (MI 441–500) and subordinate granitoid sources. Compositional signatures and environmental changes suggest distinct drainage evolutions regulated by upstream climate and tectonic controls. The higher plutonic clast content coeval to the onset of fluvial sedimentation and coarse‐grained influxes reflects local tectonic perturbations attributed to the Early Triassic reactivation of Variscan faults. The evidence of perennial fluvial systems during the lowermost Triassic reflects wetter climate conditions in the upstream catchment area, which contradicts the common view of increased aridity at the Permian–Triassic boundary. [ABSTRACT FROM AUTHOR]

Abstract Background Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD. Methods The potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ1–42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide. Results 3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment. Conclusions Our data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.