Tiburon Associates (United States)

Abstract Intra-tumour heterogeneity (ITH) and cellular plasticity contribute to therapy resistance. Single-cell transcriptomics is the gold standard for assessing ITH, but this approach remains costly and slow. Here, we show that distinct melanoma transcriptomic states exhibit unique cellular morphologies, and introduce ORIGAMI, a scalable flow cytometry assay leveraging cell surface area (S) and volume (V) measurements to resolve melanoma cell state diversity and to track therapy-induced transitions. MAPK- and CDK4/6-targeted therapies induce predictable shifts in cell geometry: drug-tolerant persister cancer cells increase cell surface area along a de-differentiation trajectory and/or increase volume while acquiring senescent-like features. Using ORIGAMI-guided screening, we identified brefeldin A (BFA) and other ER-Golgi modulators as agents that reduce surface area, promote differentiation, and sensitize melanoma cells to targeted therapies. Therapy-induced high-volume cells exhibit lysosomal scaling and increased sensitivity to nigericin, a natural polyether related to the lysosomal iron sequestering compounds and ferroptosis inducers salinomycin and narasin. Nigericin and BFA combined with MEK- and CDK4/6-inhibitors are highly potent in vitro across cell states and genotypes, and significantly extend survival in NRAS-mutant melanoma patient-derived xenografts without overt toxicity. Moreover, this combination induces hallmarks of immunogenic cell death and enhances anti–PD-1 efficacy in immunotherapy-refractory preclinical models. Beyond melanoma, the combination shows broad anti-tumour activity across a large panel of cancer lines derived from varied tissues. These findings establish a generalizable, geometry-based framework to monitor ITH, anticipate plasticity, and inform genotype-agnostic combination strategies that negate non-genetic adaptive resistance while potentiating immunotherapy.

Abstract The five Mw≥7.8 continental transform earthquakes since 2000 all nucleated on branch faults. This includes the 2001 Mw 7.8 Kokoxili, 2002 Mw 7.9 Denali, 2008 Mw 7.9 Wenchuan, 2016 Mw 7.8 Kaikōura, and 2023 Mw 7.8 Pazarcık events. A branch or splay is typically an immature fault that connects to the transform at an oblique angle and can have a different rake and dip than the transform. The branch faults ruptured for at least 25 km before they joined the transforms, which then ruptured an additional 250–450 km, in all but one case (Pazarcık) unilaterally. Branch fault nucleation is also likely for the 1939 M 7.8 Erzincan earthquake, possible for the 1906 Mw∼7.8 and 1857 Mw∼7.9 San Andreas earthquakes, but not for the 1990 Mw 7.7 Luzon, 2013 Mw 7.7 Balochistan, and 2023 Mw 7.7 Elbistan events. Here, we argue that because fault continuity and cataclastite within the fault damage zone develop through cumulative fault slip, mature transforms are pathways for dynamic rupture. Once a rupture enters the transform from the branch fault, flash shear heating causes pore fluid pressurization and sudden weakening in the cataclastite, resulting in very low dynamic friction. But the static friction on transforms is high, and so they are usually far from failure, which could be why they tend to be aseismic between, or at least for centuries after, great events. This could explain why the largest continental transform earthquakes either begin on a branch fault or nucleate along the transform at locations where the damage zone is absent or the fault continuity is disrupted by bends or echelons, as in the 1999 Mw 7.6 İzmit earthquake. Recognition of branch fault nucleation could be used to strengthen earthquake early warning in regions such as California, New Zealand, and Türkiye with transform faults.

Abstract Finite-element models of neotectonics require transform faults to rupture seismically even where preseismic shear stresses are low, presumably by dynamic-weakening mechanisms. A long-standing objection is that, if a rupture initiated at an asperity with high static friction stresses, which then transitioned to low dynamic-weakening stresses, local stress drop would be near total and on the order of 80 MPa, which is 4×–40× greater than observed. But the 5 Mw ≥ 7.8 transform earthquakes since 2000 initially ruptured on the branch faults of small net slip (Stein and Bird, 2024). If the slip initiates on a branch fault with different slip physics and no dynamic weakening, this solves the stress-drop problem. We propose that most large shallow earthquakes are hybrid ruptures, which begin on branch faults of small slip with high shear stresses, and then continue propagating on a connected dynamically weakened fault of large slip, even where shear stresses are low. One prediction of this model is that most large shallow ruptures should be unilateral. We test this prediction against the 100 largest (m ≥ 6.49) shallow continental strike-slip earthquakes 1977–2022, using information from the Global Centroid Moment Tensor and International Seismological Centre catalogs. The differences in time and location between the epicenter and the epicentroid define a horizontal “migration” velocity vector for the evolving centroid of each rupture. Early aftershock locations are summarized by a five-parameter elliptical model. Using the geometric relations between these (and mapped traces of active faults) and guided by a symmetrical decision table, we classified 55 ruptures as apparently unilateral, 30 as bilateral, and 15 as ambiguous. Our finding that a majority (55%–70%) of these ruptures are unilateral permits the interpretation that a majority of ruptures are hybrids, both in terms of geometry (branch fault to transform) and in terms of the physics of their fault slip.

A. C. van Trigt's 1853 doctoral thesis, De Speculo Oculi or De Oogspiegel, is generally recognized to contain the first ever published images of the interior of living human eyes. One of its 12 images is recognized and often reproduced as the first published. Others, showing physiological processes such as retinal venous pulsations and arteriolar light reflexes, and pathological processes such as retinal detachment and retinitis pigmentosa, are scarcely ever noted in the literature. Although van Trigt is widely recognized for this accomplishment, virtually nothing has been written about him or his thesis. This article describes his life, his artistic talent and diverse interests, and his thesis with its rarely credited original ophthalmoscopic observations and illustrations.

The nuclear ribosomal internal transcribed spacer (ITS) region is the most commonly chosen genetic marker for the molecular identification of fungi in environmental sequencing and molecular ecology studies. Several analytical issues complicate such efforts, one of which is the formation of chimeric—artificially joined—DNA sequences during PCR amplification or sequence assembly. Several software tools are currently available for chimera detection, but rely to various degrees on the presence of a chimera-free reference dataset for optimal performance. However, no such dataset is available for use with the fungal ITS region. This study introduces a comprehensive, automatically updated reference dataset for fungal ITS sequences based on the UNITE database for the molecular identification of fungi. This dataset supports chimera detection throughout the fungal kingdom and for full-length ITS sequences as well as partial (ITS1 or ITS2 only) datasets. The performance of the dataset on a large set of artificial chimeras was above 99.5%, and we subsequently used the dataset to remove nearly 1,000 compromised fungal ITS sequences from public circulation. The dataset is available at http://unite.ut.ee/repository.php and is subject to web-based third-party curation.