Variation in the mitochondrial DNA (mtDNA) sequence is common in certain tumours. Two classes of cancer mtDNA variants can be identified de novo mutations that act as 'inducers' of carcinogenesis and functional variants that act as 'adaptors', permitting cancer cells to thrive in different environments. These mtDNA variants have three origins inherited variants, which run in families, somatic mutations arising within each cell or individual, and variants that are also associated with ancient mtDNA lineages (haplogroups) and are thought to permit adaptation to changing tissue or geographic environments. In addition to mtDNA sequence variation, mtDNA copy number and perhaps transfer of mtDNA sequences into the nucleus can contribute to certain cancers. Strong functional relevance of mtDNA variation has been demonstrated in oncocytoma and prostate cancer, while mtDNA variation has been reported in multiple other cancer types. Alterations in nuclear DNA-encoded mitochondrial genes have confirmed the importance of mitochondrial metabolism in cancer, affecting mitochondrial reactive oxygen species production, redox state and mitochondrial intermediates that act as substrates for chromatin-modifying enzymes. Hence, subtle changes in the mitochondrial genotype can have profound effects on the nucleus, as well as carcinogenesis and cancer progression.Evaluating the biomechanics of soft tissues at depths well below their surface, and at high precision and in real time, would open up diagnostic opportunities. Here, we report the development and application of miniaturized electromagnetic devices, each integrating a vibratory actuator and a soft strain-sensing sheet, for dynamically measuring the Young's modulus of skin and of other soft tissues at depths of approximately 1-8 mm, depending on the particular design of the sensor. We experimentally and computationally established the operational principles of the devices and evaluated their performance with a range of synthetic and biological materials and with human skin in healthy volunteers. Arrays of devices can be used to spatially map elastic moduli and to profile the modulus depth-wise. As an example of practical medical utility, we show that the devices can be used to accurately locate lesions associated with psoriasis. Compact electronic devices for the rapid and precise mechanical characterization of living tissues could be used to monitor and diagnose a range of health disorders.In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such '2-cell-like-cells' (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential.  https://www.selleckchem.com/products/avacopan-ccx168-.html  Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.The intensification of food production plays a central role in the evolution of complex human societies. However, it is unclear whether the standard model of intensification is theoretically or empirically justified. This leaves social scientists unable to make reasonable inferences about the relationship between intensification and the evolution of social complexity in past societies. To remedy this problem, I derive a model of intensification from human macroecology, settlement scaling theory, human behavioural ecology, cultural evolutionary theory and niche construction theory. The standard and cultural niche construction models are formalized and their predictions are tested using a comprehensive ethnographic dataset that describes food production in 40 human societies, ranging in complexity from foraging bands to agricultural states. Analysis of the ethnographic record suggests that we reject the standard model and tentatively accept the cultural niche construction model. I attempt to demonstrate the broader utility of the cultural niche construction model as a framework that may help explain the transition from small-scale to large-scale complex societies.In times of crisis, risk pooling can enhance the resilience of individuals, households and communities. Risk-pooling systems are most effective when their participants adhere to several principles (1) participants should agree that the pool is for needs that arise unpredictably, not for routine, predictable needs; (2) giving to those in need should not create an obligation for them to repay; (3) participants should not be expected to help others until they have taken care of their own needs; (4) participants should have a consensus about what constitutes need; (5) resources should be either naturally visible or made visible to reduce cheating; (6) individuals should be able to decide which partners to accept; and (7) the scale of the network should be large enough to cover the scale of risks. We discuss the cultural and evolutionary foundations of risk-pooling systems, their vulnerabilities and their relationship to commercial insurance.