Stochastic Yield Catastrophes and Robustness in Self-Assembly

A guiding principle in self-assembly is that, for high production yield, nucleation of structures must be significantly slower than their growth. However, details of the mechanism that impedes nucleation are broadly considered irrelevant. Here, we analyze self-assembly into finite-sized target structures employing mathematical modeling. We investigate two key scenarios to delay nucleation: (i) by introducing a slow activation step for the assembling constituents and, (ii) by decreasing the dimerization rate. These scenarios have widely different characteristics. While the dimerization scenario exhibits robust behavior, the activation scenario is highly sensitive to demographic fluctuations. These demographic fluctuations ultimately disfavor growth compared to nucleation and can suppress yield completely. The occurrence of this stochastic yield catastrophe does not depend on model details but is generic as soon as number fluctuations between constituents are taken into account. On a broader perspective, our results reveal that stochasticity is an important limiting factor for self-assembly and that the specific implementation of the nucleation process plays a significant role in determining the yield

Sustainable Transportation: Transforming Utah Through Community Action

Transportation in the United States accounts for 4% of global greenhouse gas emissions. Over half of these emissions come from on-road vehicles. Nationwide, Utah has the third highest rate of car ownership, and the resulting air pollution from on-road vehicles has significant implications for the climate and public health. This fact sheet provides information on how Utah’s government and other entities are working to expand modes of transport that minimize harm to communities and the environment

Exploiting ecology in drug pulse sequences in favour of population reduction

A deterministic population dynamics model involving birth and death for a two-species system, comprising a wild-type and more resistant species competing via logistic growth, is subjected to two distinct stress environments designed to mimic those that would typically be induced by temporal variation in the concentration of a drug (antibiotic or chemotherapeutic) as it permeates through the population and is progressively degraded. Different treatment regimes, involving single or periodical doses, are evaluated in terms of the minimal population size (a measure of the extinction probability), and the population composition (a measure of the selection pressure for resistance or tolerance during the treatment). We show that there exist timescales over which the low-stress regime is as effective as the high-stress regime, due to the competition between the two species. For multiple periodic treatments, competition can ensure that the minimal population size is attained during the first pulse when the high-stress regime is short, which implies that a single short pulse can be more effective than a more protracted regime. Our results suggest that when the duration of the high-stress environment is restricted, a treatment with one or multiple shorter pulses can produce better outcomes than a single long treatment. If ecological competition is to be exploited for treatments, it is crucial to determine these timescales, and estimate for the minimal population threshold that suffices for extinction. These parameters can be quantified by experiment

Interleukin‐6 initiates muscle‐ and adipose tissue wasting in a novel C57BL/6 model of cancer‐associated cachexia

BACKGROUND: Cancer‐associated cachexia (CAC) is a wasting syndrome drastically reducing efficacy of chemotherapy and life expectancy of patients. CAC affects up to 80% of cancer patients, yet the mechanisms underlying the disease are not well understood and no approved disease‐specific medication exists. As a multiorgan disorder, CAC can only be studied on an organismal level. To cover the diverse aetiologies of CAC, researchers rely on the availability of a multifaceted pool of cancer models with varying degrees of cachexia symptoms. So far, no tumour model syngeneic to C57BL/6 mice exists that allows direct comparison between cachexigenic‐ and non‐cachexigenic tumours. METHODS: MCA207 and CHX207 fibrosarcoma cells were intramuscularly implanted into male or female, 10–11‐week‐old C57BL/6J mice. Tumour tissues were subjected to magnetic resonance imaging, immunohistochemical‐, and transcriptomic analysis. Mice were analysed for tumour growth, body weight and ‐composition, food‐ and water intake, locomotor activity, O(2) consumption, CO(2) production, circulating blood cells, metabolites, and tumourkines. Mice were sacrificed with same tumour weights in all groups. Adipose tissues were examined using high‐resolution respirometry, lipolysis measurements in vitro and ex vivo, and radioactive tracer studies in vivo. Gene expression was determined in adipose‐ and muscle tissues by quantitative PCR and Western blotting analyses. Muscles and cultured myotubes were analysed histologically and by immunofluorescence microscopy for myofibre cross sectional area and myofibre diameter, respectively. Interleukin‐6 (Il‐6) was deleted from cancer cells using CRISPR/Cas9 mediated gene editing. RESULTS: CHX207, but not MCA207‐tumour‐bearing mice exhibited major clinical features of CAC, including systemic inflammation, increased plasma IL‐6 concentrations (190 pg/mL, P ≤ 0.0001), increased energy expenditure (+28%, P ≤ 0.01), adipose tissue loss (−47%, P ≤ 0.0001), skeletal muscle wasting (−18%, P ≤ 0.001), and body weight reduction (−13%, P ≤ 0.01) 13 days after cancer cell inoculation. Adipose tissue loss resulted from reduced lipid uptake and ‐synthesis combined with increased lipolysis but was not associated with elevated beta‐adrenergic signalling or adipose tissue browning. Muscle atrophy was evident by reduced myofibre cross sectional area (−21.8%, P ≤ 0.001), increased catabolic‐ and reduced anabolic signalling. Deletion of IL‐6 from CHX207 cancer cells completely protected CHX207(IL6KO)‐tumour‐bearing mice from CAC. CONCLUSIONS: In this study, we present CHX207 fibrosarcoma cells as a novel tool to investigate the mediators and metabolic consequences of CAC in C57BL/6 mice in comparison to non‐cachectic MCA207‐tumour‐bearing mice. IL‐6 represents an essential trigger for CAC development in CHX207‐tumour‐bearing mice

Developing a lifestyle intervention program for overweight or obese preconception, pregnant and postpartum women using qualitative methods.

The time period before, during and after pregnancy represents a unique opportunity for interventions to cultivate sustained healthy lifestyle behaviors to improve the metabolic health of mothers and their offspring. However, the success of a lifestyle intervention is dependent on uptake and continued compliance. To identify enablers and barriers towards engagement with a lifestyle intervention, thematic analysis of 15 in-depth interviews with overweight or obese women in the preconception, pregnancy or postpartum periods was undertaken, using the integrated-Promoting Action on Research Implementation in Health Services framework as a guide to systematically chart factors influencing adoption of a novel lifestyle intervention. Barrier factors include time constraints, poor baseline knowledge, family culture, food accessibility, and lack of relevant data sources. Enabling factors were motivation to be healthy for themselves and their offspring, family and social support, a holistic delivery platform providing desired information delivered at appropriate times, regular feedback, goal setting, and nudges. From the findings of this study, we propose components of an idealized lifestyle intervention including (i) taking a holistic life-course approach to education, (ii) using mobile health platforms to reduce barriers, provide personalized feedback and promote goal-setting, and (iii) health nudges to cultivate sustained lifestyle habits

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and databas

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types