Homes became the “everything space” during COVID-19: impact of changes to the home environment on children’s physical activity and sitting

BackgroundDuring the 2020 UK COVID-19 lockdown restrictions, children spent almost all of their time at home, which had a significant influence on their physical activity (PA) and sedentary behaviour. This study aimed to: 1) determine changes to the social and physical environment at home and children’s home-based sitting, PA, standing and sitting breaks as a result of the COVID-19 restrictions; and 2) examine associations between changes at home and children’s movement behaviours.MethodsOne hundred and two children had their PA and sitting, standing and sitting breaks at home objectively measured pre-COVID-19 and during the first COVID-19 lockdown (June-July 2020). Children’s parents (n = 101) completed an audit of their home physical environment and a survey on the home social environment at both time points. Changes in the home physical and social environment and behavioural outcomes were assessed using Wilcoxon signed ranked tests, paired t-tests, or chi-square. Repeated linear regression analyses examined associations between changes in homes and changes in the home-based behavioural outcomes.ResultsDuring COVID-19, households increased the amount of seated furniture and electronic media equipment at home. The number of books and PA equipment decreased and fewer parents enforced a screen-time rule. Children’s preference for physical activities and socialising at home decreased. Time at home and sitting at home increased during COVID-19, whilst PA, standing and sitting breaks decreased. Both MVPA and TPA were positively associated with child preference for PA, and negatively associated with attending school. Sitting was negatively associated with child preference for PA and child preference for socialising at home. Media equipment was negatively associated with sitting breaks, whilst PA equipment was positively associated with standing.ConclusionThe COVID-19 restrictions forced children to spend almost all their time at home. Children’s PA, standing, and sitting breaks at home declined during the restrictions, while sitting increased. Mostly negative changes occurred in homes, some of which impacted children’s behaviours at home. To avoid the changes persisting post-lockdown, interventions are needed to reset and promote children’s PA and discourage prolonged sitting time

A mutational signature in gastric cancer suggests therapeutic strategies.

Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Our results suggest that 7-12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors

Deciphering signatures of mutational processes operative in human cancer.

The genome of a cancer cell carries somatic mutations that are the cumulative consequences of the DNA damage and repair processes operative during the cellular lineage between the fertilized egg and the cancer cell. Remarkably, these mutational processes are poorly characterized. Global sequencing initiatives are yielding catalogs of somatic mutations from thousands of cancers, thus providing the unique opportunity to decipher the signatures of mutational processes operative in human cancer. However, until now there have been no theoretical models describing the signatures of mutational processes operative in cancer genomes and no systematic computational approaches are available to decipher these mutational signatures. Here, by modeling mutational processes as a blind source separation problem, we introduce a computational framework that effectively addresses these questions. Our approach provides a basis for characterizing mutational signatures from cancer-derived somatic mutational catalogs, paving the way to insights into the pathogenetic mechanism underlying all cancers

Short inverted repeats contribute to localized mutability in human somatic cells.

Selected repetitive sequences termed short inverted repeats (SIRs) have the propensity to form secondary DNA structures called hairpins. SIRs comprise palindromic arm sequences separated by short spacer sequences that form the hairpin stem and loop respectively. Here, we show that SIRs confer an increase in localized mutability in breast cancer, which is domain-dependent with the greatest mutability observed within spacer sequences (∼1.35-fold above background). Mutability is influenced by factors that increase the likelihood of formation of hairpins such as loop lengths (of 4-5 bp) and stem lengths (of 7-15 bp). Increased mutability is an intrinsic property of SIRs as evidenced by how almost all mutational processes demonstrate a higher rate of mutagenesis of spacer sequences. We further identified 88 spacer sequences showing enrichment from 1.8- to 90-fold of local mutability distributed across 283 sites in the genome that intriguingly, can be used to inform the biological status of a tumor

Integrating energy expertise into building design

Most commercial buildings designed to today will use more energy to operate, and cost more to design and construct than necessary. Significant energy savings cold be achieved with little or not increase in first cost if energy-efficient design technologies were used. Research into integration of building systems indicates that by considering energy performance early in the design process, energy savings between 30% and 50% of current energy consumption rates are technically and economically feasible. However, most building design teams do not adequately consider the energy impacts of design decisions to achieve these savings. The US Department of Energy has initiated a project, led by Pacific Northwest Laboratory, to develop advanced computer-based technologies that will help designers take advantage of these large potential energy savings. The objective of this work is to develop automated, intelligent, energy design assistance that can be integrated into computer aided design systems of the future. This paper examines the need for this technology by identifying the impediments to energy-efficient design, identifies essential and desirable features of such systems, presents the concept under development in this effort, illustrates how energy expertise might be incorporated into design, and discusses the importance of an integrated approach. 8 refs., 1 fig

DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis.

Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. DOI:http://dx.doi.org/10.7554/eLife.00534.001

Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle

AbstractPKD-mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Gö-6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Gö-6976 triggered calcium signaling and activated stress-inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Gö-6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD

Recurrent histone mutations in T-cell acute lymphoblastic leukaemia.

Mutations affecting key modifiable histone type 3 (H3; Supplementary Table 1) residues are frequent oncogenic events in certain solid tumours (Feinberg, et al 2016), and have also recently been implicated in a subset of acute myeloid leukaemia (AML)(Lehnertz, et al 2017). Here, we systematically reviewed the somatic mutations in >20,000 cancer specimens to identify tumours harbouring H3 mutations. In a subset of T-cell acute lymphoblastic leukaemia (T-ALL) we identified non-methionine mutations of the key modifiable H3 residues, lysine (K) 27 and 36

The genome as a record of environmental exposure.

Whole genome sequencing of human tumours has revealed distinct patterns of mutation that hint at the causative origins of cancer. Experimental investigations of the mutations and mutation spectra induced by environmental mutagens have traditionally focused on single genes. With the advent of faster cheaper sequencing platforms, it is now possible to assess mutation spectra in experimental models across the whole genome. As a proof of principle, we have examined the whole genome mutation profiles of mouse embryo fibroblasts immortalised following exposure to benzo[a]pyrene (BaP), ultraviolet light (UV) and aristolochic acid (AA). The results reveal that each mutagen induces a characteristic mutation signature: predominantly G→T mutations for BaP, C→T and CC→TT for UV and A→T for AA. The data are not only consistent with existing knowledge but also provide additional information at higher levels of genomic organisation. The approach holds promise for identifying agents responsible for mutations in human tumours and for shedding light on the aetiology of human cancer