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Abstract Seismic tomography of Earth's mantle images abundant slab remnants, often located in close proximity to active subduction systems. The impact of such remnants on the dynamics of subduction remains underexplored. Here, we use simulations of multi‐material free subduction in a 3‐D spherical shell geometry to examine the interaction between visco‐plastic slabs and remnants that are positioned above, within and below the mantle transition zone. Depending on their size, negatively buoyant remnants can set up mantle flow of similar strength and length scales as that due to active subduction. As such, we find that remnants located within a few hundred km from a slab tip can locally enhance sinking by up to a factor 2. Remnant location influences trench motion: the trench advances toward a remnant positioned in the mantle wedge region, whereas remnants in the sub‐slab region enhance trench retreat. These motions aid in rotating the subducting slab and remnant toward each other, reducing the distance between them, and further enhancing the positive interaction of their mantle flow fields. In this process, the trench develops along‐strike variations in shape that are dependent on the remnant's location. Slab‐remnant interactions may explain the poor correlation between subducting plate velocities and subducting plate age found in recent plate tectonic reconstructions. Our results imply that slab‐remnant interactions affect the evolution of subducting slabs and trench geometry. Remnant‐induced downwelling may also anchor and sustain subduction systems, facilitate subduction initiation, and contribute to plate reorganization events.

Abstract The effects of sphericity are regularly neglected in numerical and laboratory studies that examine the factors controlling subduction dynamics. Most existing studies have been executed in a Cartesian domain, with the small number of simulations undertaken in a spherical shell incorporating plates with an oversimplified rheology, limiting their applicability. Here, we simulate free‐subduction of composite visco‐plastic plates in 3‐D Cartesian and spherical shell domains, to examine the role of sphericity in dictating the dynamics of subduction, and highlight the limitations of Cartesian models. We identify two irreconcilable differences between Cartesian and spherical models, which limit the suitability of Cartesian‐based studies: (a) the presence of sidewall boundaries in Cartesian models, which modify the flow regime; and (b) the reduction of space with depth in spherical shells, alongside the radial gravity direction, which cannot be captured in Cartesian domains. Although Cartesian models generally predict comparable subduction regimes and slab morphologies to their spherical counterparts, there are significant quantitative discrepancies. We find that simulations in Cartesian domains that exceed Earth's dimensions overestimate trench retreat. Conversely, due to boundary effects, simulations in smaller Cartesian domains overestimate the variation of trench curvature driven by plate width. Importantly, spherical models consistently predict higher sinking velocities and a reduction in slab width with depth, particularly for wider subduction systems, enhancing along‐strike slab buckling and trench curvature. Results imply that sphericity must be considered for understanding the dynamics of Earth's wider subduction systems, and is already a significant factor for slabs of width 2,400 km.

Abstract Many of the factors expected to control the dynamics and evolution of Earth's subduction zones are under‐explored in an Earth‐like spherical geometry. Here, we simulate multi‐material free‐subduction of a complex rheology slab in a 3‐D spherical shell domain, to investigate the effect of plate age (simulated by covarying plate thickness and density) and width on the evolution of subduction systems. We find that the first‐order predictions of our spherical cases are generally consistent with existing Cartesian studies: (a) as subducting plate age increases, slabs retreat more and subduct at a shallower dip angle, due to increased bending resistance and sinking rates; and (b) wider slabs can develop along‐strike variations in trench curvature due to toroidal flow at slab edges, trending toward a “W”‐shaped trench with increasing slab width. We find, however, that these along‐strike variations are restricted to older, stronger, retreating slabs: Younger slabs that drive minimal trench motion remain relatively straight along the length of the subduction zone. We summarize our results into a regime diagram, which highlights how slab age modulates the effect of slab width, and present examples of the evolutionary history of subduction zones that are consistent with our model predictions.

Abstract Several of Earth's intra‐plate volcanic provinces lie on or adjacent to continental lithosphere. Although many are believed to mark the surface expression of mantle plumes, our limited understanding of how buoyant plumes interact with heterogeneous continental lithosphere prevents further progress in identifying mechanisms at the root of continental volcanism. In this study, using a suite of 3‐D geodynamical models, we demonstrate that the magmatic expression of plumes in continental settings is complex and strongly sensitive to the location of plume impingement, differing substantially from that expected beneath more homogeneous oceanic lithosphere. Within Earth's continents, thick cratonic roots locally limit decompression melting. However, they deflect plume conduits during their ascent, with plume material channeled along gradients in lithospheric thickness, activating magmatism away from the plume conduit, sometimes simultaneously at locations more than a thousand kilometres apart. This magmatism regularly concentrates at lithospheric steps, where it may be difficult to distinguish from that arising through edge‐driven convection. At times, the flow field associated with the plume enhances melting at these steps long before plume material enters the melting zone, implying that differentiating geochemical signatures will be absent. Beneath regions of thinner lithosphere, plume‐related flow can force material downwards at lithospheric steps, shutting off pre‐existing edge‐related magmatism. Additionally, variations in lithospheric structure can induce internal destabilization of ponding plume material, driving intricate magmatic patterns at the surface. Our analysis highlights the challenges associated with linking continental magmatism to underlying mantle dynamics, motivating an inter‐disciplinary approach in future studies.

Abstract Several of Earth's intraplate volcanic provinces are hard to reconcile with the mantle plume hypothesis. Instead, they exhibit characteristics that are more compatible with shallower processes that involve the interplay between uppermost mantle flow and the base of Earth's heterogeneous lithosphere. The mechanisms most commonly invoked are edge‐driven convection (EDC) and shear‐driven upwelling (SDU), both of which act to focus upwelling flow and the associated decompression melting adjacent to steps in lithospheric thickness. In this study, we undertake a systematic numerical investigation, in both 2‐D and 3‐D, to quantify the sensitivity of EDC, SDU, and the associated melting to key controlling parameters. Our simulations demonstrate that the spatio‐temporal characteristics of EDC are sensitive to the geometry and material properties of the lithospheric step, in addition to the magnitude and depth‐dependence of upper‐mantle viscosity. These simulations also indicate that asthenospheric shear can either enhance or reduce upwelling velocities and the associated melting, depending upon the magnitude and orientation of flow relative to the lithospheric step. When combined, such sensitivities explain why step changes in lithospheric thickness, which are common along cratonic edges and passive margins, only produce volcanism at isolated points in space and time. Our predicted trends of melt production suggest that, in the absence of potential interactions with mantle plumes, EDC and SDU are viable mechanisms only for Earth's shorter‐lived, lower‐volume intraplate volcanic provinces.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of non‐small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5‐year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine‐specific demethylase 1 (LSD1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD. Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD1 as a novel therapeutic option for treating LUAD. The reversible LSD1 inhibitor HCI‐2509 significantly reduced cell growth with an IC50 of 0.3–5 μmin vitro, which was linked to an enhancement of histone 3 lysine methylation. Most importantly, growth arrest, as well as inhibition of the invasion capacities, was independent of the underlying driver mutations. Subsequent expression profiling revealed that the cell cycle and replication machinery were prominently affected after LSD1 inhibition. In addition, our data provide evidence that LSD1 blockade significantly interferes with EGFR downstream signaling. Finally, our in vitro results were confirmed by preclinical therapeutic approaches, including the use of two autochthonous transgenic LUAD mouse models driven by either EGFR or KRAS mutations. Importantly, LSD1 inhibition resulted in significantly lower tumor formation and a strong reduction in tumor progression, which were independent of the underlying mutational background of the mouse models. Hence, our findings provide substantial evidence indicating that tumor growth of LUAD can be markedly decreased by HCI‐2509 treatment, suggesting its use as a single agent maintenance therapy or combined therapeutical application in novel concerted drug approaches.

We report herein the case of a 57-year-old lady who had two concomittant lesions, an inflammatory myofibroblastic tumor in the trachea, and severe granulomatous lesions in the adjacent hilar lymph nodes. While these two lesions shared histological and some immunohistochemical features lesions. They differed in terms of ALK-1 expression, which was positive in the tracheal tumor and negative in the lymph nodes. The discussion of the case circles around putative pathophysiological links between the lesions. The authors favor the idea that the lymph nodes present a sarcoid-like granulomatous reaction to the inflammatory myofibroblastic tumor in the trachea over a coexistence of two independent entities. However, no conclusive evidence for this interpretation can be presented based on the existing literature.

Cardiovascular shock due to verapamil intoxication is often refractory to standard resuscitation methods. Recommended therapy includes prevention of further absorption of the drug, inotropic therapy, calcium gluconate, and hyperinsulinemia/euglycemia therapy. Often further measures are needed such as ventricular pacing or mechanical circulatory support. Still, mortality remains high. Levosimendan, an inotropic agent, that enhances myofilament response to calcium, increases myocardial contraction and could therefore be beneficial in verapamil intoxication. Here, we report the case of a 60-year-old patient with clinically severe verapamil poisoning who presented with shock, bradycardia, and sopor. Standard therapy including high-dose inotropes failed to ameliorate the signs of intoxication. But additional therapy with levosimendan led to rapid improvement. Based on this observation, the literature is reviewed focusing on utilization of levosimendan in the treatment of calcium channel blocker overdose. We suggest to consider levosimendan as additional treatment option in patients with cardiovascular shock due to verapamil intoxication that are refractory to standard management.

Abstract Background Several protective factors have been identified for mental health (MH) resilience in adolescent offspring of depressed parents. However, it is unclear if these effects persist into adulthood. Methods Depressed parents and their offspring (N = 188) from the Early Prediction of Adolescent Depression study were assessed four times (mean offspring ages 12.39, 13.77, 14.82, and 23.41). Mental health resilience was examined using residual scores (better‐than‐expected mood‐, behaviour‐, or anxiety‐related MH at mean age 23 given risk exposure), and categorically as sustained good MH across adolescence and young adulthood. Results Only 9.2% of young adults demonstrated sustained good MH. Parents of resilient individuals showed lower comorbidity (anxiety, antisocial behaviour and harmful drinking) and higher depression remission. Considering adolescent protective factors, weak evidence was observed of associations of mood‐resilience with adolescent peer‐relationship quality (β = −0.20, 95%CI:−0.36, −0.04); friendship quality (β = −0.14, 95%CI:−0.31, 0.02); risk adjustment (β = −0.16, 95%CI:‐0.34, 0.03) and dysfunctional attitudes (β = 0.18, 95%CI:0.01, 0.35). There was weak evidence of behavioural‐resilience association with parent positive expressed emotion (β = −0.15, 95%CI:−0.31, 0.02) and offspring exercise (β = −0.37, 95%CI:−0.77, 0.03). No adolescent protective factors showed an association with anxiety‐resilience. For sustained good MH, there was weak evidence of an association with inhibitory control (OR = 0.39, 95%CI:0.14, 1.07). Strong evidence was observed for associations between young adult‐reported peer relationship quality and mood‐resilience (β = −0.35, 95%CI:−0.53, −0.17), behavioural‐resilience (β = −0.33, 95%CI:−0.51, −0.14) and anxiety‐resilience (β = −0.34, 95%CI:−0.53, −0.14), while weak evidence was observed of an association of social activities with anxiety‐resilience (β = −0.51, 95%CI:−0.97, −0.06). Conclusions We found limited evidence for the long‐lasting effects of adolescent protective factors on adult MH resilience. Social factors remained protective into young adulthood, while family factors did not. Early preventative intervention might not be sufficient to maintain good long‐term MH, and young people will likely require more prolonged support.