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At least 1,513 records · Page 84

Modelling breast cancer requires identification and correction of a critical cell lineage-dependent transduction bias

When trying to explore the biology and etiology of human cancers, clinically relevant human culture models are essential. Current breast tumour models, such as those from oncogenically transformed primary breast cells, produce predominantly basal-like properties, whereas the more common phenotype expressed by the vast majority of breast tumours are luminal. Reasons for this puzzling, yet important phenomenon, are not understood. We show here that luminal epithelial cells are significantly more resistant to viral transduction than their myoepithelial counterparts. Here, we suggest that this is a significant barrier to generating luminal cell lines and experimental tumours in vivo and to accurate interpretation of results. We show that the resistance is due to lower affinity of luminal cells for virus attachment, which can be overcome by pretreating cells—or virus—with neuraminidase. We present an analytical method for quantifying transductional differences between cell types and an optimized protocol for transducing unsorted primary human breast cells in context.

59 BASIC BIOLOGICAL SCIENCES↗

Global leaf trait estimates biased due to plasticity in the shade

The study of leaf functional trait relationships, the so-called leaf economics spectrum , is based on the assumption of high-light conditions (as experienced by sunlit leaves). Owing to the exponential decrease of light availability through canopies, however, the vast majority of the world's vegetation exists in at least partial shade. Plant functional traits vary in direct dependence of light availability, with different traits varying to different degrees, sometimes in conflict with expectations from the economic spectrum. This means that the derived trait relationships of the global leaf economic spectrum are probably dependent on the extent to which observed data in existing large-scale plant databases represent high-light conditions. Here, using an extensive worldwide database of within-canopy gradients of key physiological, structural and chemical traits, along with three different global trait databases we show that: (1) accounting for light-driven trait plasticity can reveal novel trait relationships, particularly for highly plastic traits (for example, the relationship between net assimilation rate per area (A a ) and leaf mass per area (LMA)); and (2) a large proportion of leaf traits in current global plant databases reported as measured in full sun were probably measured in the shade. Our results show that even though the majority of leaves exist in the shade, along with a large proportion of observations, our current understanding is too focused on conditions in the sun.

59 BASIC BIOLOGICAL SCIENCES↗

Exchange-biasing topological charges by antiferromagnetism

Geometric Hall effect is induced by the emergent gauge field experienced by the carriers adiabatically passing through certain real-space topological spin textures, which is a probe to non-trivial spin textures, such as magnetic skyrmions. We report experimental indications of spin-texture topological charges induced in heterostructures of a topological insulator (Bi,Sb) 2 Te 3 coupled to an antiferromagnet MnTe. Through a seeding effect, the pinned spins at the interface leads to a tunable modification of the averaged real-space topological charge. This effect experimentally manifests as a modification of the field-dependent geometric Hall effect when the system is field-cooled along different directions. This heterostructure represents a platform for manipulating magnetic topological transitions using antiferromagnetic order.

36 MATERIALS SCIENCE↗

Biased localization of actin binding proteins by actin filament conformation

The assembly of actin filaments into distinct cytoskeletal structures plays a critical role in cell physiology, but how proteins localize differentially to these structures within a shared cytoplasm remains unclear. Here, we show that the actin-binding domains of accessory proteins can be sensitive to filament conformational changes. Using a combination of live cell imaging and in vitro single molecule binding measurements, we show that tandem calponin homology domains (CH1–CH2) can be mutated to preferentially bind actin networks at the front or rear of motile cells. We demonstrate that the binding kinetics of CH1–CH2 domain mutants varies as actin filament conformation is altered by perturbations that include stabilizing drugs and other binding proteins. These findings suggest that conformational changes of actin filaments in cells could help to direct accessory binding proteins to different actin cytoskeletal structures through a biophysical feedback loop.

42 ENGINEERING↗

Bias free multiobjective active learning for materials design and discovery

The design rules for materials are clear for applications with a single objective. For most applications, however, there are often multiple, sometimes competing objectives where there is no single best material and the design rules change to finding the set of Pareto optimal materials. In this work, we leverage an active learning algorithm that directly uses the Pareto dominance relation to compute the set of Pareto optimal materials with desirable accuracy. We apply our algorithm to de novo polymer design with a prohibitively large search space. Using molecular simulations, we compute key descriptors for dispersant applications and drastically reduce the number of materials that need to be evaluated to reconstruct the Pareto front with a desired confidence. This work showcases how simulation and machine learning techniques can be coupled to discover materials within a design space that would be intractable using conventional screening approaches.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

The interplay of DNA repair context with target sequence predictably biases Cas9-generated mutations

Abstract Repair of double-stranded breaks generated by CRISPR/Cas9 is highly dependent on the flanking DNA sequence. To learn about interactions between DNA repair and target sequence, we measure frequencies of over 236,000 distinct Cas9-generated mutational outcomes at over 2800 synthetic target sequences in 18 DNA repair deficient mouse embryonic stem cells lines. We classify the outcomes in an unbiased way, finding a specialised role forPrkdc(DNA-PKcs protein) andPolmin creating 1 bp insertions matching the nucleotide on the protospacer-adjacent motif side of the break, a variable involvement ofNbnandPolqin the creation of different deletion outcomes, and uni-directional deletions dependent on both end-protection and end-resection. Using our dataset, we build predictive models of the mutagenic outcomes of Cas9 scission that outperform the current standards. This work improves our understanding of DNA repair gene function, and provides avenues for more precise modulation of Cas9-generated mutations.

Science & Technology - Other Topics↗

Structural complexity biases vegetation greenness measures

Vegetation ‘greenness’ characterized by spectral vegetation indices (VIs) is an integrative measure of vegetation leaf abundance, biochemical properties and pigment composition. Surprisingly, satellite observations reveal that several major VIs over the US Corn Belt are higher than those over the Amazon rainforest, despite the forests having a greater leaf area. This contradicting pattern underscores the pressing need to understand the underlying drivers and their impacts to prevent misinterpretations. Here we show that macroscale shadows cast by complex forest structures result in lower greenness measures compared with those cast by structurally simple and homogeneous crops. The shadow-induced contradictory pattern of VIs is inevitable because most Earth-observing satellites do not view the Earth in the solar direction and thus view shadows due to the sun–sensor geometry. The shadow impacts have important implications for the interpretation of VIs and solar-induced chlorophyll fluorescence as measures of global vegetation changes. For instance, a land-conversion process from forests to crops over the Amazon shows notable increases in VIs despite a decrease in leaf area. In conclusion, our findings highlight the importance of considering shadow impacts to accurately interpret remotely sensed VIs and solar-induced chlorophyll fluorescence for assessing global vegetation and its changes.

60 APPLIED LIFE SCIENCES↗

Experimental energy resolution of a paracentric hemispherical deflector analyzer for different entry positions and bias

A specially designed hemispherical deflector analyzer (HDA) with 5-element input lens having a movable entry position R{sub 0} suitable for electron energy analysis in atomic collisions was constructed and tested. The energy resolution of the HDA was experimentally determined for three different entry positions R{sub 0}= 84, 100, 112 mm as a function of the nominal entry potential V(R{sub 0}) under pre-retardation conditions. The resolution for the (conventional) entry at the mean radius R{sub 0}= 100 mm was found to be a factor of 1.6-2 times worse than the resolution for the two (paracentric) positions R{sub 0}= 84 and 112 mm at particular values of V(R{sub 0}). These results provide the first experimental verification and a proof of principle of the utility of such a paracentric HDA, while demonstrating its advantages over the conventional HDA: greater dispersion with reduced angular aberrations resulting in better energy resolution without the use of any additional fringing field correction electrodes. Supporting simulations of the entire lens plus HDA spectrometer are also provided and mostly found to be within 20%-30% of experimental values. The paracentric HDA is expected to provide a lower cost and/or more compact alternative to the conventional HDA particularly useful in modern applications utilizing a position sensitive detector.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗