Search

Heat stress has broad effects on an organism and is an inevitable part of life. Embryos face a particular challenge when faced with heat stress - the intricate molecular processes that pattern the embryo can all be affected by heat, and the embryo lacks some of the strategies that adults can use to manage or avoid heat stress. We use Drosophila melanogaster as a model, as insects are capable of developing normally under a wide range of temperatures and are exposed to daily temperature swings as they develop. Research has focused on the heat shock pathway and the transcription of heat shock proteins as the main response to heat and heat damage. This review explores embryonic heat responses beyond the heat shock pathway. We examine the effects of heat from a biochemical standpoint, as well as highlighting other mechanisms of heat stress regulation, such as miRNA activity or other signaling pathways. We discuss how different elements of the heat stress response must be coordinated across the embryo to enable development under a wide range of temperatures. Studying heat stress in Drosophila melanogaster can be a powerful lens into how developmental systems ensure robustness to environmental factors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Merkel cell polyomavirus (MCV) and high-risk human papillomavirus (HPV) are human tumor viruses that cause Merkel cell carcinoma (MCC) and oropharyngeal squamous cell carcinoma (OSCC), respectively. HPV E7 and MCV large T (LT) oncoproteins target the retinoblastoma tumor suppressor protein (pRb) through the conserved LxCxE motif. We identified enhancer of zeste homolog 2 (EZH2) as a common host oncoprotein activated by both viral oncoproteins through the pRb binding motif. EZH2 is a catalytic subunit of the polycomb 2 (PRC2) complex that trimethylates histone H3 at lysine 27 (H3K27me3). In MCC tissues EZH2 was highly expressed, irrespective of MCV status. Loss-of-function studies revealed that viral HPV E6/E7 and T antigen expression are required for Ezh2 mRNA expression and that EZH2 is essential for HPV(+)OSCC and MCV(+)MCC cell growth. Furthermore, EZH2 protein degraders reduced cell viability efficiently and rapidly in HPV(+)OSCC and MCV(+)MCC cells, whereas EZH2 histone methyltransferase inhibitors did not affect cell proliferation or viability within the same treatment period. These results suggest that a methyltransferase-independent function of EZH2 contributes to tumorigenesis downstream of two viral oncoproteins, and that direct targeting of EZH2 protein expression could be a promising strategy for the inhibition of tumor growth in HPV(+)OSCC and MCV(+)MCC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

A collection of β-carbolines based on the natural product harmine, a compound known to target the heat shock 90 protein of Plasmodium falciparum, was synthesized and tested for antimalarial activity and potential toxicity. Several of these novel compounds display promising bioactivity, providing a new potential therapeutic with a mode of action that differs versus any currently available clinical treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Viral cancers show oncogene addiction to viral oncoproteins, which are required for survival and proliferation of the dedifferentiated cancer cell. Human Merkel cell carcinomas (MCCs) that harbor a clonally integrated Merkel cell polyomavirus (MCV) genome have low mutation burden and require viral T antigen expression for tumor growth. Here, we showed that MCV + MCC cells cocultured with keratinocytes undergo neuron-like differentiation with neurite outgrowth, secretory vesicle accumulation, and the generation of sodium-dependent action potentials, hallmarks of a neuronal cell lineage. Cocultured keratinocytes are essential for induction of the neuronal phenotype. Keratinocyte-conditioned medium was insufficient to induce this phenotype. Single-cell RNA sequencing revealed that T antigen knockdown inhibited cell cycle gene expression and reduced expression of key Merkel cell lineage/MCC marker genes, including HES6 , SOX2 , ATOH1 , and KRT20 Of these, T antigen knockdown directly inhibited Sox2 and Atoh1 expression. MCV large T up-regulated Sox2 through its retinoblastoma protein-inhibition domain, which in turn activated Atoh1 expression. The knockdown of Sox2 in MCV + MCCs mimicked T antigen knockdown by inducing MCC cell growth arrest and neuron-like differentiation. These results show Sox2-dependent conversion of an undifferentiated, aggressive cancer cell to a differentiated neuron-like phenotype and suggest that the ontology of MCC arises from a neuronal cell precursor., (Copyright © 2019 the Author(s). Published by PNAS.)

Objectives: To identify areas of Britain whose residents have relatively low age specific mortality, despite experiencing long-term economic adversity., Methods: Longitudinal, ecological study of all residents of Britain from 1971 to 2001., Results: 54 of Britain's 641 parliamentary constituencies were identified as having been persistently economically disadvantaged in the period 1971-2001. Within this group, there was marked variation in age group specific mortality and in the age ranges with relatively high or low mortality. A systematic scoring process identified 18 constituencies as providing strong and consistent evidence of low mortality across a range of age groups, relative to the 54 constituencies as a whole. These 18 were labelled "resilient". Among age groups >24 years, mortality rates in the resilient areas were significantly lower than in the other economically disadvantaged areas. For example, at ages 45-59 years, the average all cause mortality rate in the resilient constituencies was 607 per 100 000 population (95% CI 574 to 641) and 728 (670 to 787) in the non-resilient constituencies (p = 0.013)., Conclusions: Areas with similar adverse economic histories do not all have similarly high mortality rates. It is unlikely that a single factor explains these results. Selective migration cannot be discounted as an explanation, but particular sociocultural features of areas (including the political, economic, ethnic and religious characteristics of their population) may also be protective.