The Focal Nature of Darier's Disease Lesions: Calcium Pumps, Stress, and Mutation?

Haploinsufficiency of the ATP2A2 gene product, SERCA2, underlies most cases of Darier's disease. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2) is an intracellular Ca2+ pump that replenishes ER Ca2+, and it seems likely that the disease manifests in stress-induced lesions because SERCA levels become limiting as extra demands are made on the pump in times of stress. However, Müller and colleagues (2006) present a radical new proposal invoking somatic mutation as the basis for Darier lesions. Using a novel animal model for depleted keratinocyte SERCA-gated Ca2+ stores, the authors show that keratinocytes from Darier-like lesions retain their distinctive phenotype after culture, suggesting heritable defects. Mechanistically linking stress, calcium levels, mutation, and disease pathogenesis is complicated, and the proposal is likely to be controversial. However, recent reports of age- and stress-dependent tumor formation in the mouse model for SERCA2 haploinsufficiency (ATP2A2 heterozygous mouse) support the proposal that deficiency in SERCA-gated ER Ca2+ replenishment may be linked to mutation accumulation

Insights into the subsurface structure of the Caloris basin, Mercury, from assessments of mechanical layering and changes in long-wavelength topography

The volcanic plains that fill the Caloris basin, the largest recognized impact basin on Mercury, are deformed by many graben and wrinkle ridges, among which the multitude of radial graben of Pantheon Fossae allow us to resolve variations in the depth extent of associated faulting. Displacement profiles and displacement-to-length scaling both indicate that faults near the basin center are confined to a ~ 4-km-thick mechanical layer, whereas faults far from the center penetrate more deeply. The fault scaling also indicates that the graben formed in mechanically strong material, which we identify with dry basalt-like plains. These plains were also affected by changes in long-wavelength topography, including undulations with wavelengths of up to 1300 km and amplitudes of 2.5 to 3 km. Geographic correlation of the depth extent of faulting with topographic variations allows a first-order interpretation of the subsurface structure and mechanical stratigraphy in the basin. Further, crosscutting and superposition relationships among plains, faults, craters, and topography indicate that development of long-wavelength topographic variations followed plains emplacement, faulting, and much of the cratering within the Caloris basin. As several examples of these topographic undulations are also found outside the basin, our results on the scale, structural style, and relative timing of the topographic changes have regional applicability and may be the surface expression of global-scale interior processes on Mercury

Insights into the subsurface structure of the Caloris basin, Mercury, from assessments of mechanical layering and changes in long-wavelength topography

The volcanic plains that fill the Caloris basin, the largest recognized impact basin on Mercury, are deformed by many graben and wrinkle ridges, among which the multitude of radial graben of Pantheon Fossae allow us to resolve variations in the depth extent of associated faulting. Displacement profiles and displacement-to-length scaling both indicate that faults near the basin center are confined to a ~ 4-km-thick mechanical layer, whereas faults far from the center penetrate more deeply. The fault scaling also indicates that the graben formed in mechanically strong material, which we identify with dry basalt-like plains. These plains were also affected by changes in long-wavelength topography, including undulations with wavelengths of up to 1300 km and amplitudes of 2.5 to 3 km. Geographic correlation of the depth extent of faulting with topographic variations allows a first-order interpretation of the subsurface structure and mechanical stratigraphy in the basin. Further, crosscutting and superposition relationships among plains, faults, craters, and topography indicate that development of long-wavelength topographic variations followed plains emplacement, faulting, and much of the cratering within the Caloris basin. As several examples of these topographic undulations are also found outside the basin, our results on the scale, structural style, and relative timing of the topographic changes have regional applicability and may be the surface expression of global-scale interior processes on Mercury

Deformation Associated with Ghost Craters and Basins in Volcanic Smooth Plains on Mercury: Strain Analysis and Implications for Plains Evolution

Since its insertion into orbit about Mercury in March 2011, the MESSENGER spacecraft has imaged most previously unseen regions of the planet in unprecedented detail, revealing extensive regions of contiguous smooth plains at high northern latitudes and surrounding the Caloris basin. These smooth plains, thought to be emplaced by flood volcanism, are populated with several hundred ghost craters and basins, nearly to completely buried impact features having rims for which the surface expressions are now primarily rings of deformational landforms. Associated with some ghost craters are interior groups of graben displaying mostly polygonal patterns. The origin of these graben is not yet fully understood, but comparison with numerical models suggests that the majority of such features are the result of stresses from local thermal contraction. In this paper, we highlight a previously unreported category of ghost craters, quantify extensional strains across graben-bearing ghost craters, and make use of graben geometries to gain insights into the subsurface geology of smooth plains areas. In particular, the style and mechanisms of graben development imply that flooding of impact craters and basins led to substantial pooling of lavas, to thicknesses of ∼1.5 km. In addition, surface strains derived from groups of graben are generally in agreement with theoretically and numerically derived strains for thermal contraction

The Distribution and Origin of Smooth Plains on Mercury

Orbital images from the MESSENGER spacecraft show that ~27% of Mercury's surface is covered by smooth plains, the majority (greater than 65%) of which are interpreted to be volcanic in origin. Most smooth plains share the spectral characteristics of Mercury's northern smooth plains, suggesting they also share their magnesian alkali-basalt-like composition. A smaller fraction of smooth plains interpreted to be volcanic in nature have a lower reflectance and shallower spectral slope, suggesting more ultramafic compositions, an inference that implies high temperatures and high degrees of partial melting in magma source regions persisted through most of the duration of smooth plains formation. The knobby and hummocky plains surrounding the Caloris basin, known as Odin-type plains, occupy an additional 2% of Mercury’s surface. The morphology of these plains and their color and stratigraphic relationships suggest that they formed as Caloris ejecta, although such an origin is in conflict with a straightforward interpretation of crater size-frequency distributions. If some fraction is volcanic, this added area would substantially increase the abundance of relatively young effusive deposits inferred to have more mafic compositions. Smooth plains are widespread on Mercury, but they are more heavily concentrated in the north and in the hemisphere surrounding Caloris. No simple relationship between plains distribution and crustal thickness or radioactive element distribution is observed. A likely volcanic origin for some older terrain on Mercury suggests that the uneven distribution of smooth plains may indicate differences in the emplacement age of large-scale volcanic deposits rather than differences in crustal formational process

Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms

AKT1 Loss Correlates with Episomal HPV16 in Vulval Intraepithelial Neoplasia

Anogenital malignancy has a significant association with high-risk mucosal alpha-human papillomaviruses (alpha-PV), particularly HPV 16 and 18 whereas extragenital SCC has been linked to the presence of cutaneous beta and gamma–HPV types. Vulval skin may be colonised by both mucosal and cutaneous (beta-, mu-, nu- and gamma-) PV types, but there are few systematic studies investigating their presence and their relative contributions to vulval malignancy. Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers. Mucosal HPV types can increase AKT phosphorylation and activity whereas cutaneous HPV types down-regulate AKT1 expression, probably to weaken the cornified envelope to promote viral release. We assessed the presence of mucosal and cutaneous HPV in vulval malignancy and its relationship to AKT1 expression in order to establish the corresponding HPV and AKT1 profile of normal vulval skin, vulval intraepithelial neoplasia (VIN) and vulval squamous cell carcinoma (vSCC). We show that HPV16 is the principle HPV type present in VIN, there were few detectable beta types present and AKT1 loss was not associated with the presence of these cutaneous HPV. We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis. AKT1 loss in our VIN cohort correlated with presence of high copy number, episomal HPV16. Maintained AKT1 expression correlated with low copy number, an increased frequency of integration and increased HPV16E7 expression, a finding we replicated in another untyped cohort of vSCC. Since expression of E7 reflects tumour progression, these findings suggest that AKT1 loss associated with episomal HPV16 may have positive prognostic implications in vulval malignancy