Polymorphic systems with arrays : decidability and undecidability

Polymorphic systems with arrays (PSAs) is a general class of nondeterministic reactive systems. A PSA is polymorphic in the sense that it depends on a signature, which consists of a number of type variables, and a number of symbols whose types can be built from the type variables. Some of the state variables of a PSA can be arrays, which are functions from one type to another. We present several new decidability and undecidability results for parameterised control-state reachability problems on subclasses of PSAs

Separating the effects of early and later life adiposity on colorectal cancer risk:a Mendelian randomization study

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02702-9

Assortative Mating between European Corn Borer Pheromone Races: Beyond Assortative Meeting

BACKGROUND: Sex pheromone communication systems may be a major force driving moth speciation by causing behavioral reproductive isolation via assortative meeting of conspecific individuals. The 'E' and 'Z' pheromone races of the European corn borer (ECB) are a textbook example in this respect. 'Z' females produce and 'Z' males preferentially respond to a 'Z' pheromone blend, while the 'E' race communicates via an 'E' blend. Both races do not freely hybridize in nature and their populations are genetically differentiated. A straightforward explanation would be that their reproductive isolation is a mere consequence of "assortative meeting" resulting from their different pheromones specifically attracting males towards same-race females at long range. However, previous laboratory experiments and those performed here show that even when moths are paired in a small box - i.e., when the meeting between sexual partners is forced - inter-race couples still have a lower mating success than intra-race ones. Hence, either the difference in attractivity of E vs. Z pheromones for males of either race still holds at short distance or the reproductive isolation between E and Z moths may not only be favoured by assortative meeting, but must also result from an additional mechanism ensuring significant assortative mating at close range. Here, we test whether this close-range mechanism is linked to the E/Z female sex pheromone communication system. METHODOLOGY/PRINCIPAL FINDINGS: Using crosses and backcrosses of E and Z strains, we found no difference in mating success between full-sisters emitting different sex pheromones. Conversely, the mating success of females with identical pheromone types but different coefficients of relatedness to the two parental strains was significantly different, and was higher when their genetic background was closer to that of their male partner's pheromone race. CONCLUSIONS/SIGNIFICANCE: We conclude that the close-range mechanism ensuring assortative mating between the E and Z ECB pheromone races is unrelated to the difference in female sex pheromone. Although the nature of this mechanism remains elusive, our results show that it is expressed in females, acts at close range, segregates independently of the autosome carrying Pher and of both sex chromosomes, and is widely distributed since it occurs both in France and in the US

Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes

Background Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67–0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78–0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. Interpretation Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk

On model checking data-independent systems with arrays with whole-array operations

We consider programs which are data independent with respect to two type variables X and Y, and can in addition use arrays indexed by X and storing values from Y. We are interested in whether a program satisfies its control-state unreachability specification for all non-empty finite instances of X and Y. The decidability of this problem without whole-array operations is a corollary to earlier results. We address the possible addition of two whole-array operations: an array reset instruction, which sets every element of an array to a particular value, and an array assignment or copy instruction. For programs with reset, we obtain decidability if there is only one array or if Y is fixed to be the boolean type, and we obtain undecidability otherwise. For programs with array assignment, we show that they are more expressive than programs with reset, which yields undecidability if there are at least three arrays. We also obtain undecidability for two arrays directly

A computational justification for guessing attack formalisms

Recently attempts have been made to extend the Dolev-Yao security model by allowing an intruder to learn weak secrets, such as poorly-chosen passwords, by off-line guessing. In such an attack, the intruder is able to verify a guessed value g if he can use it to produce a value called a verifier. In such a case we say that g is verifier-producing. The definition was formed by inspection of known guessing attacks.A more intuitive definition might be formed as follows: a value is verifiable if there exists some computational process that can somehow recognise a correct guess over any other value.We formalise this intuitive definition, and use it to justify the soundness and completeness of the existing definition. Specifically we show that a value is recognisable if and only if the value is either already Dolev-Yao deducible or it is verifier-producing. In order to do this it was necessary to clarify the definition of verifier production slightly, revealing an ambiguity in the original definition.</p