The impact of phenotypic heterogeneity of tumour cells on treatment and relapse dynamics

Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.Author summary The individual cells within a cancer cell population are not all equal. The heterogeneity among them can strongly affect disease progression and treatment success. Recent diagnostic advances allow measuring how the characteristics of this heterogeneity change over time. To match these advances, we developed deterministic and stochastic trait-based models that capture important characteristics of the intratumour heterogeneity and allow to evaluate different treatment types that either do or do not interact with this heterogeneity. We focus on growth rate as the decisive characteristic of the intratumour heterogeneity. We find that by shifting the trait distribution of the cancer cell population, the growth rate-dependent treatment delays an eventual relapse compared to the growth rate-independent treatment. As a downside, however, we observe a refuge effect where slower-growing subpopulations are less affected by the growth rate-dependent treatment, which may decrease the likelihood of successful therapy. We find that navigating along this trade-off may be achieved by sequentially combining both treatment types, which agrees qualitatively with current clinical practice. Interestingly, even rather large intervals between treatment changes allow for close-to-optimal treatment results, which again hints towards a practical applicability.Competing Interest StatementMB performed contract research for Affimed, Amgen and Regeneron, served on the advisory board of Amgen and Incyte, and in the speaker bureau of Amgen, Janssen, Pfizer and Roche

Actuation and stiffening in fluid-driven soft robots using low-melting-point material

Soft material robots offer a number of advantages over traditional rigid robots in applications including humanrobot interaction, rehabilitation and surgery. These robots can navigate around obstacles, elongate, squeeze through narrow openings or be squeezed - and they are considered to be inherently safe. The ability to stiffen compliant soft actuators has been achieved by embedding various mechanisms that are generally decoupled from the actuation principle. Miniaturisation becomes challenging due to space limitations which can in turn result in diminution of stiffening effects. Here, we propose to hydraulically actuate soft manipulators with lowmelting- point material and, at the same time, be able to switch between a soft and stiff state. Instead of allocating an additional stiffening chamber within the soft robot, one chamber only is used for actuation and stiffening. Low Melting Point Alloy is integrated into the actuation chamber of a single-compartment soft robotic manipulator and the interfaced robotic syringe pump. Temperature change is enabled through embedded nichrome wires. Our experimental results show higher stiffness factors, from 9-12 opposing the motion of curvature, than those previously found for jamming mechanisms incorporated in separate additional chambers, in the range of 2-8 for the same motion

Editorial: Influence of environmental variability on climate change impacts in marine ecosystems

multiple drivers, environmental variability, Climate change, marine heatwaves, stressmemory, Ecological memory, Thermal performance curves, acclimatio

Shoot and Root Traits Contribute to Drought Resistance in Recombinant Inbred Lines of MD 23–24 × SEA 5 of Common Bean

Drought is the major abiotic stress factor limiting yield of common bean (Phaseolus vulgaris L.) in smallholder systems in Latin America and eastern and southern Africa; where it is a main source of protein in the daily diet. Identification of shoot and root traits associated with drought resistance contributes to improving the process of designing bean genotypes adapted to drought. Field and greenhouse studies were conducted at the International Center for Tropical Agriculture (CIAT), Palmira, Colombia to determine the relationship between grain yield and different shoot and root traits using a recombinant inbred lines (RILs) population (MD23–24 × SEA 5) of common bean. The main objectives of this study were to identify: (i) specific shoot and root morpho-physiological traits that contribute to improved resistance to drought and that could be useful as selection criteria in breeding beans for drought resistance; and (ii) superior genotypes with desirable shoot and root traits that could serve as parents in breeding programs that are aimed at improving drought resistance. A set of 121 bean genotypes (111 RILs, 2 parents, 8 checks) belonging to the Mesoamerican gene pool and one cowpea variety were evaluated under field conditions with two levels of water supply (irrigated and rainfed) over three seasons. To complement field studies, a greenhouse study was conducted using plastic cylinders with soil inserted into PVC pipes, to determine the relationship between grain yield obtained under field conditions with different root traits measured under greenhouse conditions. Resistance to drought stress was positively associated with a deeper and vigorous root system, better shoot growth, and superior mobilization of photosynthates to pod and seed production. The drought resistant lines differed in their root characteristics, some of them with a vigorous and deeper root system while others with a moderate to shallow root system. Among the shoot traits measured, pod harvest index, and seed number per area could serve as useful selection criteria for assessing sink strength and for genetic improvement of drought resistance in common bean

Heat tolerance in common bean derived from interspecific crosses

Many Countries could experience unprecedented heat stress because of global climate change (Battisti and Naylor,2009). Heat sensitivity in common bean is a major limiting factor that can reduce yield, quality, and lead to restricted geographic adaptation (Beebeetal.,2011). Interspecific lines developed with crosses between P.vulgaris and P. acutifolius were evaluated for their tolerance to heat stress. Results from field and greenhouse evaluation confirmed that Phaseolus acutifolius is an important and useful genetic resource for improving heat tolerance in common bean. Results from genomic analysis indicated the introgression of P. acutifolious genes into interspecific INB line that was used as apparent for developing heat tolerant SEF lines

Effect of intermittent drought on phenotypic traits of F5 RIL Andean intra-gene cross population (BRB 191 X SEQ 1027) of common bean

Drought is a major constraint to common bean ( Phaseolus vulgaris L.) production in East Africa, where irrigation for the crop is very uncommon. The objective of this study was to identify drought tolerant lines and phenotypic traits underlying drought tolerance among 128 F5 recombinant inbred lines (RILs), derived from intra gene pool population, between drought tolerant BRB 191 (source of bc-3) and SEQ 1027. The population was evaluated with eight experimental checks that included BAT 477, CAL 96, DAB 441, DAB 494, and Diacol Calima, NABE 4, SCR 9 and SEQ 1003. A total of 20 phenological, morphological and physiological shoot traits were evaluated, under drought and non-stress conditions, in the field for 2 years (2014 and 2015) at Kawanda in Uganda. New sources of drought tolerance, and previously identified sources of drought tolerance in common bean (BAT 477, DAB 441 and DAB 494), were confirmed based on their superior geometric means and low drought susceptibility. Drought stress in the field significantly affected all measured traits, except harvest index and stem dry weight reduction (P<0.001). Drought significantly reduced yield, yield components and pod harvest index (P<0.01). However, chlorophyll content, canopy temperature, stem dry mass reduction, and 100 seed weight remained stable under season by genotype by water regime treatment interactions (S x G x T). The stability of these traits highlighted their usefulness in selecting for drought tolerance across different environments. Furthermore, pod partitioning index (PPI), harvest index (HI), chlorophyll content and stem dry weight reduction also remained stable under G x T effects. Significant correlations (P<0.001) were maintained between HI and PPI with seed yield under drought stress in field conditions, indicating that photosynthate remobilisation increases yield under drought stress conditions.La s\ue9cheresse est une contrainte major \ue0 la production du haricot commun ( Phaseolus vulgaris L.) en Afrique de l\u2019Est, o\uf9 l\u2019irrigation pour la culture est tr\ue8s rare. L\u2019objectif de cette \ue9tude a \ue9t\ue9 d\u2019identifier les lign\ue9es tol\ue9rantes \ue0 la s\ue9cheresse et les traits ph\ue9notypiques contr\uf4lant la tol\ue9rance \ue0 la s\ue9cheresse parmi les 128 F5 de lign\ue9es consanguines recombinantes, d\ue9riv\ue9es d\u2019une population intra-g\ue8ne de la r\ue9gion andine, entre la lign\ue9e tol\ue9rante \ue0 la s\ue9cheresse BRB191 (source du bc-3) et SEQ 1027. La population a \ue9t\ue9 \ue9valu\ue9e avec huit contr\uf4les exp\ue9rimentaux comprenant BAT 477, CAL 96, DAB 441, DAB 494, et Diacol calima, NABE 4, SCR 9 et SEQ 1003. Un total de 20 traits phr\ue9nologiques, morphologiques et physiologiques a \ue9t\ue9 \ue9valu\ue9, sous les conditions de stress hydrique, dans le champ pour 2 ans (2014 et 2015) \ue0 Kwanda en Uganda. De nouvelles sources de tol\ue9rance, et des sources de tol\ue9rance pr\ue9c\ue9demment identifi\ue9es dans le haricot commun (BAT 477, DAB 441 et DAB 494), ont \ue9t\ue9 confirm\ue9es sur la base des moyens de sup\ue9riorit\ue9 g\ue9om\ue9triques et de susceptibilit\ue9 de faible s\ue8cheresse. Le stress hydrique dans le champ a significativement affect\ue9 tous les traits mesur\ue9s, \ue0 l\u2019exception de l\u2019indice de r\ue9colte et la r\ue9duction du poids sec de la tige (P<0,001). La s\ue9cheresse a significativement r\ue9duit le rendement, les composantes du rendement et l\u2019indice de la r\ue9colte de la gousse (P<0.01). Toutefois, la temp\ue9rature de la canop\ue9e, la r\ue9duction du poids sec de la tige, et le poids de 100 graines sont rest\ue9s stables sous le traitement de l\u2019interaction entre la saison x g\ue9notype x r\ue9gime d\u2019eau de m\ueame que l\u2019interaction entre le g\ue9notype x le traitement (G X T) (P<0,001). La stabilit\ue9 de ces traits a montr\ue9 leur utilit\ue9 dans la s\ue9lection pour la tol\ue9rance \ue0 la s\ue9cheresse \ue0 travers les diff\ue9rents environnements. De plus, l\u2019indice du partitionnement de la gousse (PPI), l\u2019indice de r\ue9colte (HI), la teneur en chlorophylle et la r\ue9duction du poids sec de la tige sont rest\ue9s \ue9galement stables sous les effets de G x T. Des corr\ue9lations significatives (P<0,001) ont \ue9t\ue9 maintenues entre HI et PPI avec le rendement en graine sous le stress hydrique dans les conditions de champ, indiquant la viabilit\ue9 de la remobilisation de la photosynthate dans l\u2019augmentation du rendement potentiel sous les conditions de stress hydrique

Nested reconfigurable robots: theory, design, and realization

Rather than the conventional classification method, we propose to divide modular and reconfigurable robots into intra-, inter-, and nested reconfigurations. We suggest designing the robot with nested reconfigurability, which utilizes individual robots with intra-reconfigurability capable of combining with other homogeneous/heterogeneous robots (inter-reconfigurability). The objective of this approach is to generate more complex morphologies for performing specific tasks that are far from the capabilities of a single module or to respond to programmable assembly requirements. In this paper, we discuss the theory, concept, and initial mechanical design of Hinged-Tetro, a self-reconfigurable module conceived for the study of nested reconfiguration. Hinged-Tetro is a mobile robot that uses the principle of hinged dissection of polyominoes to transform itself into any of the seven one-sided tetrominoes in a straightforward way. The robot can also combine with other modules for shaping complex structures or giving rise to a robot with new capabilities. Finally, the validation experiments verify the nested reconfigurability of Hinged-Tetro. Extensive tests and analyses of intra-reconfiguration are provided in terms of energy and time consumptions. Experiments using two robots validate the inter-reconfigurability of the proposed module