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Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC. The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.

In October 1998, Lendsay was hired by the Indigenous Works board to build partnership strategies and create a more inclusive work environment for Indigenous peoples in the corporate world (personal phone interview, March 15, 2020). According to Lendsay, effective leaders must care about the people in their organization, operate with integrity, and constantly focus on vision and innovation. [...]it is difficult for them to invest in Indigenous strategies and develop an Indigenous workforce (personal phone interview, March 15, 2020). Some of the downsides of Indigenous communities becoming too economically reliant on raw resource-based sectors include unstable market conditions and lack of human capital and financial experience, as well as limited access to the required resources.

Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology. Tighanimine et al. perform integrative time-resolved transcriptome and metabolome analysis in senescent cells and find that glycerol-3-phosphate and phosphoethanolamine accumulate and rewire lipid metabolism to promote senescence.

Continued waves, new variants, and limited vaccine deployment mean that SARS-CoV-2 tests remain vital to constrain the coronavirus disease 2019 (COVID-19) pandemic. Affordable, point-of-care (PoC) tests allow rapid screening in non-medical settings. Reverse-transcription loop-mediated isothermal amplification (RT-LAMP) is an appealing approach. A crucial step is to optimize testing in low/medium resource settings. Here, we optimized RT-LAMP for SARS-CoV-2 and human β-actin, and tested clinical samples in multiple countries. “TTTT” linker primers did not improve performance, and while guanidine hydrochloride, betaine and/or Igepal-CA-630 enhanced detection of synthetic RNA, only the latter two improved direct assays on nasopharygeal samples. With extracted clinical RNA, a 20 min RT-LAMP assay was essentially as sensitive as RT-PCR. With raw Canadian nasopharygeal samples, sensitivity was 100% (95% CI: 67.6% - 100%) for those with RT-qPCR Ct values ≤ 25, and 80% (95% CI: 58.4% - 91.9%) for those with 25 < Ct ≤ 27.2. Highly infectious, high titer cases were also detected in Colombian and Ecuadorian labs. We further demonstrate the utility of replacing thermocyclers with a portable PoC device (FluoroPLUM). These combined PoC molecular and hardware tools may help to limit community transmission of SARS-CoV-2.

Continued waves, new variants, and limited vaccine deployment mean that SARS-CoV-2 tests remain vital to constrain the coronavirus disease 2019 (COVID-19) pandemic. Affordable, point-of-care (PoC) tests allow rapid screening in non-medical settings. Reverse-transcription loop-mediated isothermal amplification (RT-LAMP) is an appealing approach. A crucial step is to optimize testing in low/medium resource settings. Here, we optimized RT-LAMP for SARS-CoV-2 and human β-actin, and tested clinical samples in multiple countries. \"TTTT\" linker primers did not improve performance, and while guanidine hydrochloride, betaine and/or Igepal-CA-630 enhanced detection of synthetic RNA, only the latter two improved direct assays on nasopharygeal samples. With extracted clinical RNA, a 20 min RT-LAMP assay was essentially as sensitive as RT-PCR. With raw Canadian nasopharygeal samples, sensitivity was 100% (95% CI: 67.6% - 100%) for those with RT-qPCR Ct values ≤ 25, and 80% (95% CI: 58.4% - 91.9%) for those with 25 < Ct ≤ 27.2. Highly infectious, high titer cases were also detected in Colombian and Ecuadorian labs. We further demonstrate the utility of replacing thermocyclers with a portable PoC device (FluoroPLUM). These combined PoC molecular and hardware tools may help to limit community transmission of SARS-CoV-2.

Many selectable phenotypes in microbial systems, including antibiotic resistance, can be conferred by single point mutations. This is frequently exploited in research, where the selection and use of microbial mutants that are spontaneously resistant to antibiotics like rifampicin and streptomycin facilitate the recovery and/or quantification of a target microbe. Such mutations are commonly employed as genetic markers for in vitro and in vivo experiments, often with little consideration as to the ultimate system-level impact of these single nucleotide mutations on the physiology of the microbe. There is substantial literature on the pleiotropic effects of point mutations conferring antibiotic resistance; yet, it is unclear whether this work is considered by the research communities outside of the discipline. This review examines some of the known pleiotropic effects of point mutations that provide selectable resistance markers, and how these mutations may impact general physiology and growth in host and non-host environments. This review examines the pleiotropic effects of point mutations conferring antibiotic resistance, and the implications of using these resistance mutants in both in vitro and in vivo assays.

Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeutic targeting of senescence for health benefits. Here, we examined the possibility that the epigenetic state of enhancers determines senescent cell fate. We explored this by generating time-resolved transcriptomes and epigenome profiles during oncogenic RAS-induced senescence and validating central findings in different cell biology and disease models of senescence. Through integrative analysis and functional validation, we reveal links between enhancer chromatin, transcription factor recruitment and senescence competence. We demonstrate that activator protein 1 (AP-1) ‘pioneers’ the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells. Together, our findings enabled us to manipulate the senescence phenotype with potential therapeutic implications.Bischof and colleagues report that AP-1 bookmarks prospective senescence enhancers for future activation to achieve a timely execution of the senescence programme.

In this thesis, a thermodynamically consistent phase field formulation was developed to identify the physical origin of interfacial transitions that drive macroscopic phenomena, starting at the single-particle length scale and building up to the polycrystalline length scale. At the single-particle length scale, the framework identified two interfacial phases that are stable at the surface of Sn nanoparticles: 1) a disordered interfacial phase, i.e., the experimentally observed premelted surface layer; and 2) an ordered surficial phase displaying a remnant degree of order in fully melted particles. Regimes of melting behavior as a function of particle size and temperature are discussed. To bridge the gap between single-particle and densified polycrystals, an analytical model was developed to capture the physical driving forces for densification during electric field-assisted sintering. Here, the model acknowledges the structural contributions of particle-particle interfaces to the strength of mechanical, electrical, and surficial driving forces for densification, and shows good agreement with experimental flash sintering data. Finally, the theory was applied to polycrystalline LiCoO2 (LCO) and shows that the experimentally observed metal-insulator transition is driven by grain boundary lithium segregation, the interfacial misorientation, and the size of the abutting grains. A critical misorientation as a function of the macroscopic lithium content exists above which the grain boundaries undergo a metal-insulating transition, suggesting that the fabrication of textured LCO microstructures will delay the metal-insulator transition.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.