Developing a soft tissue surrogate for use in photoelastic testing

An improved skin tissue substitute for use in photoelastic testing is required to enable investigation of the mechanics of needle insertion into soft tissue. Current tissue substitutes are mainly used in large scale testing and can neglect the small scale mechanical properties of soft tissue. A series of experiments on konjac glucomannan are performed to characterise its mechanical properties, and the results are compared to published results from similar experiments on skin tissue. The optical properties of the gel, such as its strain optic coefficient, are also assessed using a grey field polariscope (GFP2500). A concentration of 1.5% konjac to water produced a viscoelastic gel whose mechanical response closely matches published data for skin. A strain optic coefficient was recorded and found ideal for the planned testing with a GFP2500. Overall konjac glucomannan was found to be a potential soft tissue surrogate for use in small scale photoelastic testing

Interpreting selection when individuals interact

A useful interpretation of quantitative genetic models of evolutionary change is that they (i) define a set of phenotypes that have a causal effect on fitness and on which selection acts, and (ii) define a set of breeding values that change as a correlated response to that selection because they covary with the phenotypes. When the expression of one trait causes variation in other traits then there are multiple paths by which a trait can cause fitness variation. Because of this, there are multiple ways in which selection can be defined, and still be consistent with a causal effect of traits on fitness. We use this result to show that genetical theories of natural/kin selection ignore causation and because of this we suggest they shed little light on the nature of selection. When traits expressed by an individual are affected by traits of their social partners (indirect genetic effects), we suggest a causal partitioning that allows selection to be cast in terms of Hamilton's costs and benefits. We show that previous attempts to understand Hamilton's rule in the context of indirect genetic effects either lack generality, or do not adequately describe all the ways in which an individual's actions constitute a cost to the individual or a benefit to its social partner(s). Our results allow us to explore Hamilton's rule in a multitrait setting. We show that evolution always increases inclusive fitness, and when the traits are measured in units of generalised genetic distance evolutionary change in the traits is in the direction in which inclusive fitness increases the fastest. However, we show that Hamilton's rule only holds in a multitrait context when the suite of traits are at equilibrium. When they are out of equilibrium, the conditions for altruism to evolve may be more or less stringent depending on genetic architecture and how costs and benefits are defined.</p

On the asymptotic magnitude of subsets of Euclidean space

Magnitude is a canonical invariant of finite metric spaces which has its origins in category theory; it is analogous to cardinality of finite sets. Here, by approximating certain compact subsets of Euclidean space with finite subsets, the magnitudes of line segments, circles and Cantor sets are defined and calculated. It is observed that asymptotically these satisfy the inclusion-exclusion principle, relating them to intrinsic volumes of polyconvex sets.Comment: 23 pages. Version 2: updated to reflect more recent work, in particular, the approximation method is now known to calculate (rather than merely define) the magnitude; also minor alterations such as references adde

Hypoxia‐responsive prodrug of ATR inhibitor, AZD6738, selectively eradicates treatment‐resistant cancer cells

Targeted therapy remains the future of anti‐cancer drug development, owing to the lack of specificity of current treatments which lead to damage in healthy normal tissues. ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility. Here, ICT10336 is reported, a newly developed hypoxia‐responsive prodrug of ATR inhibitor, AZD6738, which is hypoxia‐activated and specifically releases AZD6738 only in hypoxic conditions, in vitro. This hypoxia‐selective release of AZD6738 inhibited ATR activation (T1989 and S428 phosphorylation) and subsequently abrogated HIF1a‐mediated adaptation of hypoxic cancers cells, thus selectively inducing cell death in 2D and 3D cancer models. Importantly, in normal tissues, ICT10336 is demonstrated to be metabolically stable and less toxic to normal cells than its active parent agent, AZD6738. In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor‐targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index

Cancer-specific glycosylation of CD13 impacts its detection and activity in preclinical cancer tissues

Harnessing the differences between cancer and non-cancer tissues presents new opportunities for selective targeting by anti-cancer drugs. CD13, a heavily glycosylated protein, is one example with significant unmet clinical potential in cancer drug discovery. Despite its high expression and activity in cancers, CD13 is also expressed in many normal tissues. Here, we report differential tissue glycosylation of CD13 across tissues and demonstrate for the first time that the nature and pattern of glycosylation of CD13 in preclinical cancer tissues are distinct compared to normal tissues. We identify cancer-specific O-glycosylation of CD13, which selectively blocks its detection in cancer models but not in normal tissues. In addition, the metabolism activity of cancer-expressed CD13 was observed to be critically dependent on its unique glycosylation. Thus, our data demonstrate the existence of discrete cancer-specific CD13 glycoforms and propose cancer-specific CD13 glycoforms as a clinically useful target for effective cancer-targeted therapy

The DNA repair kinase ATM regulates CD13 expression and cell migration

Classically, ATM is known for its role in sensing double-strand DNA breaks, and subsequently signaling for their repair. Non-canonical roles of ATM include transcriptional silencing, ferroptosis, autophagy and angiogenesis. Angiogenesis mediated by ATM signaling has been shown to be VEGF-independent via p38 signaling. Independently, p38 signaling has been shown to upregulate metalloproteinase expression, including MMP-2 and MMP-9, though it is unclear if this is linked to ATM. Here, we demonstrate ATM regulates aminopeptidase-N (CD13/APN/ANPEP) at the protein level. Positive correlation was seen between ATM activity and CD13 protein expression using both “wildtype” (WT) and knockout (KO) ataxia telangiectasia (AT) cells through western blotting; with the same effect shown when treating neuroblastoma cancer cell line SH-SY5Y, as well as AT-WT cells, with ATM inhibitor (ATMi; KU55933). However, qPCR along with publically available RNAseq data from Hu et al. (J. Clin. Invest., 2021, 131, e139333), demonstrated no change in mRNA levels of CD13, suggesting that ATM regulates CD13 levels via controlling protein degradation. This is further supported by the observation that incubation with proteasome inhibitors led to restoration of CD13 protein levels in cells treated with ATMi. Migration assays showed ATM and CD13 inhibition impairs migration, with no additional effect observed when combined. This suggests an epistatic effect, and that both proteins may be acting in the same signaling pathway that influences cell migration. This work indicates a novel functional interaction between ATM and CD13, suggesting ATM may negatively regulate the degradation of CD13, and subsequently cell migration

Dimer coverings on the Sierpinski gasket with possible vacancies on the outmost vertices

We present the number of dimers $N_d(n)$ on the Sierpinski gasket $SG_d(n)$ at stage $n$ with dimension $d$ equal to two, three, four or five, where one of the outmost vertices is not covered when the number of vertices $v(n)$ is an odd number. The entropy of absorption of diatomic molecules per site, defined as $S_{SG_d}=\lim_{n \to \infty} \ln N_d(n)/v(n)$, is calculated to be $\ln(2)/3$ exactly for $SG_2(n)$. The numbers of dimers on the generalized Sierpinski gasket $SG_{d,b}(n)$ with $d=2$ and $b=3,4,5$ are also obtained exactly. Their entropies are equal to $\ln(6)/7$, $\ln(28)/12$, $\ln(200)/18$, respectively. The upper and lower bounds for the entropy are derived in terms of the results at a certain stage for $SG_d(n)$ with $d=3,4,5$. As the difference between these bounds converges quickly to zero as the calculated stage increases, the numerical value of $S_{SG_d}$ with $d=3,4,5$ can be evaluated with more than a hundred significant figures accurate.Comment: 35 pages, 20 figures and 1 tabl

Distribution of resonances for open quantum maps

We analyze simple models of classical chaotic open systems and of their quantizations (open quantum maps on the torus). Our models are similar to models recently studied in atomic and mesoscopic physics. They provide a numerical confirmation of the fractal Weyl law for the density of quantum resonances of such systems. The exponent in that law is related to the dimension of the classical repeller (or trapped set) of the system. In a simplified model, a rigorous argument gives the full resonance spectrum, which satisfies the fractal Weyl law. For this model, we can also compute a quantity characterizing the fluctuations of conductance through the system, namely the shot noise power: the value we obtain is close to the prediction of random matrix theory.Comment: 60 pages, no figures (numerical results are shown in other references

Increasing Seed Viability of Maize Haploid Inducing Lines by Genetic and Non-Genetic Approaches

Some haploid inducing lines used in the production of maize doubled haploids (DHs), express germination problems and reduced vigor. In this study, haploid inducing lines RWS, RWK-76 and their reciprocal hybrids RWS/RWK-76 and RWK-76/RWS were examined for viability by Tetrazolium (TZ) and germination ability by standard germination tests. Evaluation based on TZ tests showed that 59% of the seed of RWK-76/RWS were not viable, compared with only 12% dead seed in RWS/RWK-76. Similarly, the percentage and speed of germination in RWK- 76/RWS (25%, 1.53) was lower than for RWS/RWK-76 (74%, 4.30). In an effort to develop a quick method for assessing seed viability in these lines, the TZ test was repeated in a different way. Seed from each genotype was placed in beakers containing distilled water.Seed would either float or sink. Subsequent TZ testing confirmed that seed that floated was dead, and seed that sank was alive, although some of them had defective embryos. The dead seed in both genotypes failed to develop an embryo, leaving an empty cavity that would fill with air and cause seed to float on water. This feature can be exploited for a simple and practical method to separate living from dead seed. In addition, we surveyed theig1 (indeterminate gametophyte) gene as a candidate for germination problems in inducer lines.Sequencing data from theig1 region showed that RWS and RWK-76 differed in one nucleotide and amino acidin the firstexon of ig1.Segregation of ig1 alleles from RWS and RWK-76 wassignificantly (P=0.01) distortedin the respectiveF2 population relative to the expected Mendelian segregation ratio (1:2:1). Thus, either ig1 or a linked gene in the ig1 region affect seed viability