PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.

Linking megathrust earthquakes to brittle deformation in a fossil accretionary complex

Seismological data from recent subduction earthquakes suggest that megathrust earthquakes induce transient stress changes in the upper plate that shift accretionary wedges into an unstable state. These stress changes have, however, never been linked to geological structures preserved in fossil accretionary complexes. The importance of coseismically induced wedge failure has therefore remained largely elusive. Here we show that brittle faulting and vein formation in the palaeo-accretionary complex of the European Alps record stress changes generated by subduction-related earthquakes. Early veins formed at shallow levels by bedding-parallel shear during coseismic compression of the outer wedge. In contrast, subsequent vein formation occurred by normal faulting and extensional fracturing at deeper levels in response to coseismic extension of the inner wedge. Our study demonstrates how mineral veins can be used to reveal the dynamics of outer and inner wedges, which respond in opposite ways to megathrust earthquakes by compressional and extensional faulting, respectively.

Finite element analysis predicts experimental failure patterns in vertebral bodies loaded via intervertebral discs up to large deformation

Vertebral compression fracture is a common medical problem in osteoporotic individuals. The quantitative computed tomography (QCT)-based finite element (FE) method may be used to predict vertebral strength in vivo, but needs to be validated with experimental tests. The aim of this study was to validate a nonlinear anatomy specific QCT-based FE model by using a novel testing setup. Thirty-seven human thoracolumbar vertebral bone slices were prepared by removing cortical endplates and posterior elements. The slices were scanned with QCT and the volumetric bone mineral density (vBMD) was computed with the standard clinical approach. A novel experimental setup was designed to induce a realistic failure in the vertebral slices in vitro. Rotation of the loading plate was allowed by means of a ball joint. To minimize device compliance, the specimen deformation was measured directly on the loading plate with three sensors. A nonlinear FE model was generated from the calibrated QCT images and computed vertebral stiffness and strength were compared to those measured during the experiments. In agreement with clinical observations, most of the vertebrae underwent an anterior wedge-shape fracture. As expected, the FE method predicted both stiffness and strength better than vBMD (R2 improved from 0.27 to 0.49 and from 0.34 to 0.79, respectively). Despite the lack of fitting parameters, the linear regression of the FE prediction for strength was close to the 1:1 relation (slope and intercept close to one (0.86 kN) and to zero (0.72 kN), respectively). In conclusion, a nonlinear FE model was successfully validated through a novel experimental technique for generating wedge-shape fractures in human thoracolumbar vertebrae.

Relating orogen width to shortening, erosion, and exhumation during Alpine collision

We investigate along-strike width changes of the thickened, accreted lower plate (TALP) in the Central and in the Eastern Alps. We set the width of the TALP in relation to the inferred amount of collisional shortening and exhumation along six orogen-scale cross sections. Taking the present-day, along-strike gradients in the amount of collisional shortening to represent the temporal evolution of the collisional wedge, it may be concluded that the cross-sectional area of the TALP diminishes during ongoing shortening, indicating that the erosional flux outpaced the accretionary flux. Higher amounts of collisional shortening systematically coincide with smaller widths of the TALP and dramatic increases of the reconstructed eroded rock column. Higher amounts of shortening also coincide with larger amplitudes of orogen-scale, upright folds, with higher exhumation and with higher exhumation rates. Hence, erosion did play a major role in reducing by >30 km the vertical crustal thickness in order to accommodate and allow shortening by folding. Long-term climate differences cannot explain alternating changes of width by a factor of almost 2 along straight segments of the orogen on length scales less than 200 km, as observed from the western Central Alps to the easternmost Eastern Alps. Sedimentary or paleontological evidences supporting such paleo-climatic differences are lacking, suggesting that erosional processes did not directly control the width of the orogen.

Structural, metamorphic and geochronological relations between the Zanskar Shear Zone and the Miyar Shear Zone (NW Indian Himalaya): Evidence for two distinct tectonic structures and implications for the evolution of the High Himalayan Crystalline of Zanskar

The geologic structures and metamorphic zonation of the northwestern Indian Himalaya contrast significantly with those in the central and eastern parts of the range, where the high-grade metamorphic rocks of the High Himalayan Crystalline (HHC) thrust southward over the weakly metamorphosed sediments of the Lesser Himalaya along the Main Central Thrust (MCT). Indeed, the hanging wall of the MCT in the NW Himalaya mainly consists of the greenschist facies metasediments of the Chamba zone, whereas HHC high-grade rocks are exposed more internally in the range as a large-scale dome called the Gianbul dome. This Gianbul dome is bounded by two oppositely directed shear zones, the NE-dipping Zanskar Shear Zone (ZSZ) on the northern flank and the SW-dipping Miyar Shear Zone (MSZ) on the southern limb. Current models for the emplacement of the HHC in NW India as a dome structure differ mainly in terms of the roles played by both the ZSZ and the MSZ during the tectonothermal evolution of the HHC. In both the channel flow model and wedge extrusion model, the ZSZ acts as a backstop normal fault along which the high-grade metamorphic rocks of the HHC of Zanskar are exhumed. In contrast, the recently proposed tectonic wedging model argues that the ZSZ and the MSZ correspond to one single detachment system that operates as a subhorizontal backthrust off of the MCT. Thus, the kinematic evolution of the two shear zones, the ZSZ and the MSZ, and their structural, metamorphic and chronological relations appear to be diagnostic features for discriminating the different models. In this paper, structural, metamorphic and geochronological data demonstrate that the MSZ and the ZSZ experienced two distinct kinematic evolutions. As such, the data presented in this paper rule out the hypothesis that the MSZ and the ZSZ constitute one single detachment system, as postulated by the tectonic wedging model. Structural, metamorphic and geochronological data are used to present an alternative tectonic model for the large-scale doming in the NW Indian Himalaya involving early NE-directed tectonics, weakness in the upper crust, reduced erosion at the orogenic front and rapid exhumation along both the ZSZ and the MSZ.

The tectonometamorphic evolution of the Sesia–Dent Blanche nappes (internal Western Alps): review and synthesis

This study reviews and synthesizes the present knowledge on the Sesia–Dent Blanche nappes, the highest tectonic elements in the Western Alps (Switzerland and Italy), which comprise pieces of pre-Alpine basement and Mesozoic cover. All of the available data are integrated in a crustal-scale kinematic model with the aim to reconstruct the Alpine tectono-metamorphic evolution of the Sesia–Dent Blanche nappes. Although major uncertainties remain in the pre-Alpine geometry, the basement and cover sequences of the Sesia–Dent Blanche nappes are seen as part of a thinned continental crust derived from the Adriatic margin. The earliest stages of the Alpine evolution are interpreted as recording late Cretaceous subduction of the Adria-derived Sesia–Dent Blanche nappes below the South-Alpine domain. During this subduction, several sheets of crustal material were stacked and separated by shear zones that rework remnants of their Mesozoic cover. The recently described Roisan-Cignana Shear Zone of the Dent Blanche Tectonic System represents such a shear zone, indicating that the Sesia–Dent Blanche nappes represent a stack of several individual nappes. During the subsequent subduction of the Piemonte–Liguria Ocean large-scale folding of the nappe stack (including the Roisan-Cignana Shear Zone) took place under greenschist facies conditions, which indicates partial exhumation of the Dent Blanche Tectonic System. The entrance of the Briançonnais micro-continent within the subduction zone led to a drastic change in the deformation pattern of the Alpine belt, with rapid exhumation of the eclogite-facies ophiolite bearing units and thrust propagation towards the foreland. Slab breakoff probably was responsible for allowing partial melting in the mantle and Oligocene intrusions into the most internal parts of the Sesia–Dent Blanche nappes. Finally, indentation of the Adriatic plate into the orogenic wedge resulted in the formation of the Vanzone back-fold, which marks the end of the pervasive ductile deformation within the Sesia–Dent Blanche nappes during the earliest Miocene.

The Initial Slope of the Variogram, Foundation of the Trabecular Bone Score, Is Not or Poorly Associated With Vertebral Strength

Trabecular bone score (TBS) rests on the textural analysis of DXA to reflect the decay in trabecular structure characterising osteoporosis. Yet, its discriminative power in fracture studies remains incomprehensible as prior biomechanical tests found no correlation with vertebral strength. To verify this result possibly due to an unrealistic set-up and to cover a wide range of loading scenarios, the data from three previous biomechanical studies using different experimental settings was used. They involved the compressive failure of 62 human lumbar vertebrae loaded 1) via intervertebral discs to mimic the in vivo situation (“full vertebra”), 2) via the classical endplate embedding (“vertebral body”) or 3) via a ball joint to induce anterior wedge failure (“vertebral section”). HR-pQCT scans acquired prior testing were used to simulate anterior-posterior DXA from which areal bone mineral density (aBMD) and the initial slope of the variogram (ISV), the early definition of TBS, were evaluated. Finally, the relation of aBMD and ISV with failure load (Fexp) and apparent failure stress (σexp) was assessed and their relative contribution to a multi-linear model was quantified via ANOVA. We found that, unlike aBMD, ISV did not significantly correlate with Fexp and σexp, except for the “vertebral body” case (r2 = 0.396, p = 0.028). Aside from the “vertebra section” set-up where it explained only 6.4% of σexp (p = 0.037), it brought no significant improvement to aBMD. These results indicate that ISV, a replica of TBS, is a poor surrogate for vertebral strength no matter the testing set-up, which supports the prior observations and raises a fortiori the question of the deterministic factors underlying the statistical relationship between TBS and vertebral fracture risk.

The behaviour of incompatible elements during hydrous melting of metasomatized peridotite at 4–6 GPa and 1000 °C–1200 °C

Trace element behavior during hydrous melting of a metasomatized garnet–peridotite was examined at pressures of 4–6 GPa and temperatures of 1000 °C–1200 °C, conditions appropriate for fluid penetrating the mantle wedge atop the subducting slab. Experiments were performed in a rocking multi-anvil apparatus using a diamond-trap setup. The compositions of the fluid and melt phases were measured using the cryogenic LA-ICP-MS technique. The water-saturated solidus of the K-lherzolite composition is located between 900 °C and 1000 °C at 4 GPa and between 1000 °C and 1100 °C at 5 and 6 GPa. The partition coefficients between fluid or melt and clinopyroxene reveal an asymmetric MREE trough with a minimum at Dy. The clinopyroxene in equilibrium with aqueous fluids is characterized by DUfluid–cpx > DThfluid–cpx while DUmelt–cpx tends to be similar to DThmelt–cpx. The partition coefficients between fluid or melt and garnet reveal very strong light to heavy REE fractionation, DLa/DLu from 95 (hydrous melt) to 1600 (aqueous fluid). The LILE are highly incompatible with partition coefficients > 50. The behavior of HFSE are decoupled, with DZr,Hf close to 1 while DNb,Ta > 10. Garnet is characterized by DUmelt/fluid–garnet < DThmelt/fluid–garnet. A comparison of our experimental partitioning results for trivalent cations as well as the results from the literature and the calculations carried out using the lattice strain model adapted to the presence of water in the bulk system indicates that H2O in the fluid or melt phase has a prominent effect on trace element partitioning. Garnet in mantle rocks in equilibrium with an aqueous fluid is characterized by significantly higher Do(3 +) for REE in the X site of the garnet compared with the partitioning values of the optimal cation in garnet in equilibrium with hydrous melts. Our data show for the first time that the change in the nature of the mobile phase (fluid vs. melt) does affect the affinities of trace elements into the garnet crystal at conditions below the second critical endpoint of the system. The same also applies for clinopyroxene, although this is less clear. Consequently, our new data allow for refinements in predictive modeling of element transfer from the slab to the mantle wedge and of possible compositions of metasomatized mantle that sources OIB magmatism.

Fluid-related inclusions in Alpine high-pressure peridotite reveal trace element recycling during subduction-zone dehydration of serpentinized mantle (Cima di Gagnone, Swiss Alps).

Serpentinites release at sub-arc depths volatiles and several fluid-mobile trace elements found in arc magmas. Constraining element uptake in these rocks and defining the trace element composition of fluids released upon serpentinite dehydration can improve our understanding of mass transfer across subduction zones and to volcanic arcs. The eclogite-facies garnet metaperidotite and chlorite harzburgite bodies embedded in paragneiss of the subduction melange from Cima di Gagnone derive from serpentinized peridotite protoliths and are unique examples of ultramafic rocks that experienced subduction metasomatism and devolatilization. In these rocks, metamorphic olivine and garnet trap polyphase inclusions representing the fluid released during high-pressure breakdown of antigorite and chlorite. Combining major element mapping and laser-ablation ICP-MS bulk inclusion analysis, we characterize the mineral content of polyphase inclusions and quantify the fluid composition. Silicates, Cl-bearing phases, sulphides, carbonates, and oxides document post-entrapment mineral growth in the inclusions starting immediately after fluid entrapment. Compositional data reveal the presence of two different fluid types. The first (type A) records a fluid prominently enriched in fluid-mobile elements, with Cl, Cs, Pb, As, Sb concentrations up to 10(3) PM (primitive mantle), similar to 10(2) PM Tit Ba, while Rb, B, Sr, Li, U concentrations are of the order of 10(1) PM, and alkalis are similar to 2 PM. The second fluid (type B) has considerably lower fluid-mobile element enrichments, but its enrichment patterns are comparable to type A fluid. Our data reveal multistage fluid uptake in these peridotite bodies, including selective element enrichment during seafloor alteration, followed by fluid-rock interaction along with subduction metamorphism in the plate interface melange. Here, infiltration of sediment-equilibrated fluid produced significant enrichment of the serpentinites in As, Sb, B, Pb, an enriched trace element pattern that was then transferred to the fluid released at greater depth upon serpentine dehydration (type A fluid). The type B fluid hosted by garnet may record the composition of the chlorite breakdown fluid released at even greater depth. The Gagnone study-case demonstrates that serpentinized peridotites acquire water and fluid-mobile elements during ocean floor hydration and through exchange with sediment-equilibrated fluids in the early subduction stages. Subsequent antigorite devolatilization at subarc depths delivers aqueous fluids to the mantle wedge that can be prominently enriched in sediment-derived components, potentially triggering arc magmatism without the need of concomitant dehydration/melting of metasediments or altered oceanic crust.

106: Synthetic preimplantation factor (sPIF*) promotes neuroprotection by modulating PKA/PKC kinases

OBJECTIVE: Survivors of premature birth suffer from long term disabilities. Synthetic PreImplantation Factor (sPIF*) modulates inflammatory responses and reverses neuroinflammation. Proteinkinase A (PKA) and protein kinase C (PKC) are crucial signaling molecules. PKA up-regulates IL-10 and brain-derived neurotrophic factor (BDNF) expression, which exert neuroprotective effects. Anti-apoptotic phosphorylation of Bad is mediated by PKA. PKC phosphorylates GAP-43, a marker for neuronal plasticity and structural recovery. We explored sPIF protective role in neuronal (N2a) cells and in a rat model of encephalopathy of prematurity. *proprietary. STUDY DESIGN: Cells were subjected to LPS and treated with sPIF or scrambled sPIF. Neonatal rats (postnatal day 3: P3) were subjected to LPS, ligation of carotid artery, and hypoxia (8% O2, 65min; n¼ 30). sPIF (0.75mg/kg twice daily) was injected (P6-13) and brains harvested at P13. sPIF’s potential and mechanisms were evaluated using immunohistochemistry, ELISA, Western Blot, and qRT-PCR. Data were analyzed using two-tailed Student’s t-test. P<0.05 wasconsidered statistically significant. RESULTS: In vitro sPIF increased PKA/PKC activity in time dependent manner (Fig. 1A). sPIF induced higher IL-10, BDNF, and GAP-43 and lower CASP3, BAD, and TNF-a mRNA levels (Fig. 1B,C). sPIF increased pGap-43/Gap-43 and decreased pBad/Bad ratio while decreasing Bad (Fig. 1 D,E). In brain tissue sPIF treatment resulted in rescued neuronal number (NeuN positive cells) and reduced apoptosis (Casp-3 positive cells) with decreased glial (Iba-1 positive cells) activation (Fig. 2A,B). The Iba-1 morphology changed from predominantly amoeboid to ramified state. Additionally sPIF increased IL-10 mRNA levels (Fig. 2C) and pGap-43/Gap-43 ratio (Fig. 2D). CONCLUSION: sPIF modulates PKA/PKC pathways reducing apoptosis and inflammatory responses while increasing neuronal plasticity and survival. The identified PKA/PKC regulatory axis strengthens the potential of sPIF in reducing the burden of prematurity.

Biochemical MRI predicts hip osteoarthritis in an experimental ovine femoroacetabular impingement model

BACKGROUND Cam-type femoroacetabular impingement (FAI) resulting from an abnormal nonspherical femoral head shape leads to chondrolabral damage and is considered a cause of early osteoarthritis. A previously developed experimental ovine FAI model induces a cam-type impingement that results in localized chondrolabral damage, replicating the patterns found in the human hip. Biochemical MRI modalities such as T2 and T2* may allow for evaluation of the cartilage biochemistry long before cartilage loss occurs and, for that reason, may be a worthwhile avenue of inquiry. QUESTIONS/PURPOSES We asked: (1) Does the histological grading of degenerated cartilage correlate with T2 or T2* values in this ovine FAI model? (2) How accurately can zones of degenerated cartilage be predicted with T2 or T2* MRI in this model? METHODS A cam-type FAI was induced in eight Swiss alpine sheep by performing a closing wedge intertrochanteric varus osteotomy. After ambulation of 10 to 14 weeks, the sheep were euthanized and a 3-T MRI of the hip was performed. T2 and T2* values were measured at six locations on the acetabulum and compared with the histological damage pattern using the Mankin score. This is an established histological scoring system to quantify cartilage degeneration. Both T2 and T2* values are determined by cartilage water content and its collagen fiber network. Of those, the T2* mapping is a more modern sequence with technical advantages (eg, shorter acquisition time). Correlation of the Mankin score and the T2 and T2* values, respectively, was evaluated using the Spearman's rank correlation coefficient. We used a hierarchical cluster analysis to calculate the positive and negative predictive values of T2 and T2* to predict advanced cartilage degeneration (Mankin ≥ 3). RESULTS We found a negative correlation between the Mankin score and both the T2 (p < 0.001, r = -0.79) and T2* values (p < 0.001, r = -0.90). For the T2 MRI technique, we found a positive predictive value of 100% (95% confidence interval [CI], 79%-100%) and a negative predictive value of 84% (95% CI, 67%-95%). For the T2* technique, we found a positive predictive value of 100% (95% CI, 79%-100%) and a negative predictive value of 94% (95% CI, 79%-99%). CONCLUSIONS T2 and T2* MRI modalities can reliably detect early cartilage degeneration in the experimental ovine FAI model. CLINICAL RELEVANCE T2 and T2* MRI modalities have the potential to allow for monitoring the natural course of osteoarthrosis noninvasively and to evaluate the results of surgical treatments targeted to joint preservation.

Surgical Technique: Reverse Periacetabular Osteotomy

Acetabular retroversion is the result of an externally rotated hemipelvis rather than a focal overgrowth of the anterior wall and/or hypoplasia of the posterior wall. Acetabular retroversion is a cause of pincer impingement which, if left untreated, can lead to hip pain and osteoarthritis. The causal surgical treatment in hips with acetabular retroversion is acetabular reorientation with a reverse periacetabular osteotomy (PAO). Indication is based on a positive correlation among symptoms (typically groin pain), physical findings on examination (positive anterior impingement test and decreased flexion and internal rotation), and radiographic signs for acetabular retroversion. These include a positive crossover, posterior wall, and ischial spine sign. A reverse PAO is performed with four osteotomies and a controlled fracture. Unlike reorientation of the acetabular fragment in dysplastic hips, correction for acetabular retroversion is achieved by a combined extension and internal rotation of the acetabular fragment. Typically, a small supra-acetabular wedge resection is required to allow sufficient extension of the fragment. The quality of acetabular reorientation is evaluated by intraoperative AP pelvic radiographs. In addition, intraoperative testing of range of motion following acetabular reorientation is mandatory. An arthrotomy and offset correction of the femoral head-neck area is indicated in hips with decreased internal rotation following acetabular reorientation. In a 10-year follow-up study of reverse PAO, a favorable outcome with preservation of all native joints was found. Correct acetabular orientation and, if necessary, a concomitant offset correction were the keys of successful outcome.

Effects of Forskolin on Trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons

Trefoil factor 1 (TFF1) belongs to a family of secreted peptides that are mainly expressed in the gastrointestinal tract. Notably, TFF1 has been suggested to operate as a neuropeptide, however, its specific cellular expression, regulation and function remain largely unknown. We have previously shown that TFF1 is expressed in developing and adult rat ventral mesencephalic tyrosine hydroxylase-immunoreactive (TH-ir) dopaminergic neurons. Here, we investigated the expression of TFF1 in rat ventral mesencephalic dopaminergic neurons (embryonic day 14) grown in culture for 5, 7 or 10 days in the absence (controls) or presence of either glial cell line-derived neurotrophic factor (GDNF), Forskolin or the combination. No TFF1-ir cells were identified at day 5 and only a few at day 7, whereas TH was markedly expressed at both time points. At day 10, several TFF1-ir cells were detected, and their numbers were significantly increased after the addition of GDNF (2.2-fold) or Forskolin (4.1-fold) compared to controls. Furthermore, the combination of GDNF and Forskolin had an additive effect and increased the number of TFF1-ir cells by 5.6-fold compared to controls. TFF1 expression was restricted to neuronal cells, and the percentage of TH/TFF1 co-expressing cells was increased to the same extent in GDNF and Forskolin-treated cultures (4-fold) as compared to controls. Interestingly, the combination of GDNF and Forskolin resulted in a significantly increased co-expression (8-fold) of TH/TFF1, which could indicate that GDNF and Forskolin targeted different subpopulations of TH/TFF1 neurons. Short-term treatment with Forskolin resulted in an increased number of TFF1-ir cells, and this effect was significantly reduced by the MEK1 inhibitor PD98059 or the protein kinase A (PKA) inhibitor H89, suggesting that Forskolin induced TFF1 expression through diverse signaling pathways. In conclusion, distinct populations of cultured dopaminergic neurons express TFF1, and their numbers can be increased by factors known to influence survival and differentiation of dopaminergic cells.

Focused fluid transfer through the mantle above subduction zones

Volcanic arcs above subduction zones are enriched in volatiles and fluid-mobile elements with respect to mid-oceanic ridge basalts. There is general consensus that this particular subduction zone signature is generated by fluid-induced extraction of these elements from subducted oceanic crust and its sedimentary cover. However, how these fluids are transferred through the mantle wedge to the locus of partial melting and what modification the fluids will experience is unresolved. Here we investigate the interaction of slab fluids with the mantle wedge through a series of high-pressure experiments. We explore two end-member processes of focused and porous reactive flow of hydrous slab melts through the mantle. Transfer by porous flow leads to the formation of hydrous minerals that sequester fluid-mobile elements and residual fluids characterized by trace element patterns inconsistent with typical arc lavas. In contrast, no hydrous minerals are formed in the reaction zone of experiments mimicking focused flow, and the typical trace element signature acquired during fluid extraction from the slab is preserved, indicating that this is an efficient process for element transfer through the mantle wedge.

Volcanic terrain and the possible periglacial formation of "excess ice" at the mid-latitudes of Utopia Planitia, Mars

At the mid-latitudes of Utopia Planitia (UP), Mars, a suite of spatially-associated landforms exhibit geomorphological traits that, on Earth, would be consistent with periglacial processes and the possible freeze-thaw cycling of water. The suite comprises small-sized polygonally-patterned ground, polygon-junction and -margin pits, and scalloped, rimless depressions. Typically, the landforms incise a dark-toned terrain that is thought to be ice-rich. Here, we investigate the dark-toned terrain by using high resolution images from the HiRISE as well as near-infrared spectral-data from the OMEGA and CRISM. The terrain displays erosional characteristics consistent with a sedimentary nature and near-infrared spectra characterised by a blue slope similar to that of weathered basaltic-tephra. We also describe volcanic terrain that is dark-toned and periglacially-modified in the Kamchatka mountain-range of eastern Russia. The terrain is characterised by weathered tephra inter-bedded with snow, ice-wedge polygons and near-surface excess ice. The excess ice forms in the pore space of the tephra as the result of snow-melt infiltration and, subsequently, in-situ freezing. Based on this possible analogue, we construct a three-stage mechanism that explains the possible ice-enrichment of a broad expanse of dark-toned terrain at the mid-latitudes of UP: (1) the dark-toned terrain accumulates and forms via the regional deposition of sediments sourced from explosive volcanism; (2) the volcanic sediments are blanketed by atmospherically-precipitated (H2O) snow, ice or an admixture of the two, either concurrent with the volcanic-events or between discrete events; and, (3) under the influence of high obliquity or explosive volcanism, boundary conditions tolerant of thaw evolve and this, in turn, permits the migration, cycling and eventual formation of excess ice in the volcanic sediments. Over time, and through episodic iterations of this scenario, excess ice forms to decametres of depth. (C) 2015 Elsevier B.V. All rights reserved.