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Abstract Decades of studies at divergent plate margins have revealed networks of magmatic sills at the crust-mantle boundary. However, a lack of direct observations of deep magma motion limits our understanding of magma inflow from the mantle into the lower crust and the mechanism of sill formation. Here, satellite geodesy reveals rift-scale deformation caused by magma inflow in the deep crust in the Afar rift (East Africa). Simultaneous inflation of four sills, laterally separated by 10s of km and at depths ranging 9–28 km, caused uplift across a ~ 100-km-wide zone, suggesting the sills are linked to a common mantle source. Our results show the supply of magma into the lower crust is temporally episodic, occurring across a network of sills. This process reflects inherent instability of melt migration through porous mantle flow and may be the fundamental process that builds the thick igneous crust beneath magmatic rifts and rifted margins globally.

Abstract Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1 R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1 R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.

The authors revealed novel roles of catalytic residues and divalent metal ions for hsTOP3B, the human RNA topoisomerase, and demonstrated the structural elements that kinetically modulate the DNA and RNA topoisomerase activities of TOP3B.

Human Bloom’s syndrome (BLM) helicase has a role in DNA repair, and BLM deficiency in humans is associated with chromosomal abnormalities. Here the authors employ solution biophysical assays to show BLM maintains a balance for disruption and stabilization of oligonucleotide-based D-loops. Interaction with the Topoisomerase IIIalpha-RMI1-RMI2 complex orients the activity toward D-loop disruption.

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.

Continuous continental rift zones evolve from enigmatic interactions between individual propagating rift segments. Here, the authors document progressive focusing of tectonic and magmatic activity caused by interactions between the Kenyan and Ethiopian rift segments of the East African Rift.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Unbiased identification of proteins from pathogens that are exposed to a host can provide insight into host–pathogen interaction. Here, the authors use an enzymatic tagging method and mass spectrometry to identify rapidly evolvingNematocida microsporidia proteins when infecting C. elegans.

Our understanding of melt production during early continental breakup remains poorly constrained. Using the Afar triple junction as an example, Gallacher et al. generate a 3D velocity model suggesting that melt production is highest during early continental breakup due to localised thinning of the crust.