Alexander Strzalkowski

. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

BACKGROUND: The protein and carbohydrate composition of formula fed infants' diets in the United States (US) has not been described. The aims of this study were to characterize these dietary exposures in infant formula purchased in the US and to estimate the proportion of formula purchased which is hypoallergenic or lactose-reduced formula. METHODS: Powdered infant formula purchase data from all major physical stores in the US prior to the COVID-19 pandemic, between 2017 and 2019, were obtained from Information Resources, Inc. Protein and carbohydrate composition and scoop sizes for each formula were obtained from manufacturers. Ready to feed liquid products, products for premature infants and products for over 1 year old were not included. RESULTS: Total volumes of term formula purchased were 216 million kg of formula powder (equivalent to 1.65 billion litres) over 3 years. Intact protein formula was 67.9% of formula purchased, 26.6% was partially hydrolysed and 5.5% was hypoallergenic (5.2% extensively hydrolysed protein; 0.3% amino acid based). Soy protein formula represented 5.1% of formula purchased. Carbohydrate content overall was 52.7% lactose, 42.3% glucose polymers and 5.0% sucrose. 23.7% of formula purchased included sucrose as a carbohydrate. Of all formula purchased, 59.0% was lactose reduced, containing a non-lactose carbohydrate. Of 'standard' formula, defined as intact protein, non-thickened, cow's milk formula, 32.3% was lactose reduced. The proportion of hypoallergenic formula purchased significantly exceeded the prevalence of cow's milk protein allergy and increased over the 3-year study period from 4.9% to 7.6% of all formula sold. CONCLUSIONS: US infants are exposed to unnecessarily high levels of non-lactose carbohydrates and hypoallergenic formula, and this may represent a significant nutritional health risk.

Requirements for iron and docosahexaenoic acid (DHA) content of infant formula varies by country. Powdered full-term infant formula purchase data from all major physical stores in the US between 2017-2019 were obtained from CIRCANA, Inc. Iron and DHA composition and scoop sizes for each formula were obtained from manufacturers. The equivalent liquid ounces of prepared formula were calculated. Average iron and DHA content were compared between formula types and to both US and European formula composition requirements. These data represent 55.8 billion ounces of formula. The average iron content of all formula purchased was: 1.80 mg/100 kcal. This iron concentration is within the FDA regulations. However, it exceeds the maximum allowable iron concentration of infant formula (Stage 1) set by the European Commission of 1.3 mg/100 kcal. A total of 96% of formula purchased had an iron concentration of >1.3 mg/100 kcal. DHA is not a required ingredient in US formulas. The average DHA content of all formula purchased was: 12.6 mg/100 kcal. This DHA concentration is far below the minimum required DHA concentrations of infant formula (Stage 1) and follow-on formula (Stage 2) set by the European Commission of 20 mg/100 kcal. These are novel insights into the iron and DHA intake of formula-fed infants in the US. As international infant formulas have entered the US market due to the formula shortage, parents and providers need to be aware of regulatory differences in formula nutrient composition.

Abstract During development, mulitpotent cells differentiate through a hierarchy of increasingly restricted progenitor cell types until they realize specialized cell types. A cell differentiation map describes this hierarchy, and inferring these maps is an active area of research spanning traditional single marker lineage studies to data-driven trajectory inference methods on single-cell RNA-seq data. Recent high-throughput lineage tracing technologies profile lineages and cell types at scale, but current methods to infer cell differentiation maps from these data rely on simple models with restrictive assumptions about the developmental process. We introduce a mathematical framework for cell differentiation maps based on the concept of potency, and develop an algorithm, Carta , that infers an optimal cell differentiation map from single-cell lineage tracing data. The key insight in Carta is to balance the trade-off between the complexity of the cell differentiation map and the number of unobserved cell type transitions on the lineage tree. We show that Carta more accurately infers cell differentiation maps on both simulated and real data compared to existing methods. In models of mammalian trunk development and mouse hematopoiesis, Carta identifies important features of development that are not revealed by other methods including convergent differentiation of specialized cell types, progenitor differentiation dynamics, and the refinement of routes of differentiation via new intermediate progenitors. Code availability Carta software is available at https://github.com/raphael-group/CARTA