Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice.

Nail growth arrest under low body temperature during hibernation.

Growth and differentiation are reduced or stopped during hibernation, an energy conserving strategy in harsh seasons by lowered metabolism and body temperature. However, few studies evaluated this in a same individual using a non-invasive method. In this study, we applied a non-invasive tracking method of the nail growth throughout the hibernation period in the same hibernating animals, the Syrian hamster (Mesocricetus auratus).

Slow decrease in temperature produces readthrough transcripts in mammalian hibernation.

Accumulating evidence suggests that various cellular stresses interfere with the end processing of mRNA synthesis and lead to the production of abnormally long transcripts, known as readthrough transcripts (RTTs), which extend beyond the termination sites. Small mammalian hibernators repeatedly enter a state referred to as deep torpor (DT), where the metabolic rate, respiration rate, and core body temperature become extremely low, which produces various types of cellular stresses and therefore induces RTTs. However, the types of stresses and processes around the DT that cause RTTs are unclear.

Cold-induced suspension and resetting of Ca and transcriptional rhythms in the suprachiasmatic nucleus neurons.

Does the circadian clock keep running under such hypothermic states as daily torpor and hibernation? This fundamental question has been a research subject for decades but has remained unsettled. We addressed this subject by monitoring the circadian rhythm of clock gene transcription and intracellular Ca in the neurons of the suprachiasmatic nucleus (SCN), master circadian clock, under a cold environment. We discovered that the transcriptional and Ca rhythms are maintained at 22°C-28°C, but suspended at 15°C, accompanied by a large Ca increase.

Spontaneous recurrence of a summer-like diel rhythm in the body temperature of the Syrian hamster after hibernation.

Mammalian hibernation is a survival strategy characterized by metabolic suppression and drastically lowering body temperature (Tb), used during harsh seasons with food shortages and cold. The Syrian hamster commences hibernation in response to a short photoperiod and cold but spontaneously concludes hibernation after several months without environmental cues. Little is known about the changes in diel rhythms during hibernation.

Text mining online disinformation about antihypertensive agents ACEI/ARB and COVID-19 on Sina Weibo.

Background: The global COVID-19 pandemic outbreak has caused a significant social and economic burden, with over 4.7 million confirmed cases and thousands of casualties. Moreover, pandemic-related misinformation and disinformation on social media platforms have led to intense psychosocial issues.

Generation of transgenic mice expressing a FRET biosensor, SMART, that responds to necroptosis.

Necroptosis is a regulated form of cell death involved in various pathological conditions, including ischemic reperfusion injuries, virus infections, and drug-induced tissue injuries. However, it is not fully understood when and where necroptosis occurs in vivo. We previously generated a Forster resonance energy transfer (FRET) biosensor, termed SMART (the sensor for MLKL activation by RIPK3 based on FRET), which monitors conformational changes of MLKL along with progression of necroptosis in human and murine cell lines in vitro.

Step-by-step protocols for non-viral derivation of transgene-free induced pluripotent stem cells from somatic fibroblasts of multiple mammalian species.

Potentials of immortal proliferation and unlimited differentiation into all the three germ layers and germ cells in induced pluripotent stem cells (iPSCs) render them important bioresources for in vitro reconstitution and modeling of intravital tissues and organs in various animal models, thus contributing to the elucidation of pathomechanisms, drug discovery and stem cell-based regenerative medicine. We previously reported promising approaches for deriving transgene-free iPSCs from somatic fibroblasts of multiple mammalian species by episomal vector or RNA transfection, although the respective step-by-step protocols and the combinatorial usage of these methods, which achieved high induction efficiency, have not been described in the literature so far. Here, we provide a detailed step-by-step description of these methods with critical tips and slight modifications (improvements) to previously reported methods.

Hepatic resistance to cold ferroptosis in a mammalian hibernator Syrian hamster depends on effective storage of diet-derived α-tocopherol.

Mammalian hibernators endure severe and prolonged hypothermia that is lethal to non-hibernators, including humans and mice. The mechanisms responsible for the cold resistance remain poorly understood. Here, we found that hepatocytes from a mammalian hibernator, the Syrian hamster, exhibited remarkable resistance to prolonged cold culture, whereas murine hepatocytes underwent cold-induced cell death that fulfills the hallmarks of ferroptosis such as necrotic morphology, lipid peroxidation and prevention by an iron chelator.

Caspase-3 regulates ureteric branching in mice via cell migration.

Inhibition of caspase-3 (Casp3) reduces ureteric branching in organ culture but the mechanism remains unclear. Since Casp3 has non-apoptotic functions, we examined whether Casp3 regulates ureteric branching by promoting cell migration, using a ureteric bud (UB) cell line and Casp3-deficient (Casp3-/-) mice. Also, we examined whether Casp3 plays a role in the reduced ureteric branching of metanephroi from nutrient restricted mothers, in which Casp3 activity is suppressed.

Evidence for the involvement of caspases in establishing proper cerebrospinal fluid hydrodynamics.

A large number of cells undergo apoptosis via caspase activation during and after neural tube closure (NTC) in mammals. Apoptosis is executed by either intrinsic or extrinsic apoptotic pathways, and inhibition of each pathway causes developmental defects around NTC stages, which hampers the physiological roles of apoptosis and caspases after NTC. We generated transgenic mice in which a broad spectrum of caspases could be suppressed in a spatiotemporal manner by pan-caspase inhibitor protein p35 originating from baculovirus.

Apoptosis is involved in maintaining the character of the midbrain and the diencephalon roof plate after neural tube closure.

Apoptosis, a major form of programmed cell death, is massively observed in neural plate border and subsequently in the roof plate (RP). While deficiency of apoptosis often results in brain malformations including exencephaly and hydrocephalus, the impact of apoptosis on RP formation and maintenance remains unclear. Here we described that mouse embryos deficient in Apaf1, a gene crucial for the intrinsic apoptotic pathway, in C57BL/6 genetic background exhibited narrow and discontinuous expression of RP marker genes in the midline of the midbrain and the diencephalon.

A Fluorescent Probe for Rapid, High-Contrast Visualization of Folate-Receptor-Expressing Tumors In Vivo.

Folate receptors (FRs) are membrane proteins involved in folic acid uptake, and the alpha isoform (FR-α) is overexpressed in ovarian and endometrial cancer cells. For fluorescence imaging of FRs in vivo, the near-infrared (NIR) region (650-900 nm), in which tissue penetration is high and autofluorescence is low, is optimal, but existing NIR fluorescent probes targeting FR-α show high non-specific tissue adsorption, and require prolonged washout to visualize tumors. We have designed and synthesized a new NIR fluorescent probe, FolateSiR-1, utilizing a Si-rhodamine fluorophore having a carboxy group at the benzene moiety, coupled to a folate ligand moiety through a negatively charged tripeptide linker.

In vivo detection of programmed cell death during mouse heart development.

Despite the great progress on the cell biology of programmed cell death (PCD), its incidence and exact time course during embryonic and particular heart development are still unclear. This is also due to the lack of models enabling to directly identify and monitor PCD cells at different time points in vivo. Herein we report generation of transgenic murine embryonic stem cell and mouse models expressing secreted Annexin V-YFP under control of the CAG promoter.

Temporal regulation of Lin28a during mammalian neurulation contributes to neonatal body size control.

Background: The timing of developmental events is tightly regulated along a time axis for normal development. Although the RNA-binding protein Lin28a plays a crucial role in the regulation of developmental timing in Caenorhabditis elegans, how the timing of Lin28a expression affects the rate and/or duration of developmental events during mammalian development remains to be addressed.

Results: In this study, we discovered that the timing and the duration of Lin28a expression affect embryonic growth.

A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain.

Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signalling, cell death and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function.

Caspase-1 initiates apoptosis in the absence of gasdermin D.

Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells.

Loss of the small GTPase Arl8b results in abnormal development of the roof plate in mouse embryos.

Lysosomes are acidic organelles responsible for degrading both exogenous and endogenous materials. The small GTPase Arl8 localizes primarily to lysosomes and is involved in lysosomal function. In the present study, using Arl8b gene-trapped mutant (Arl8b ) mice, we show that Arl8b is required for the development of dorsal structures of the neural tube, including the thalamus and hippocampus.

Addendum: A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.

The cDNA sequence of human SMART described in this Article was misreported, as described in the accompanying Addendum. This error does not affect the results or any conclusion of the Article.

Molecular Basis of White Adipose Tissue Remodeling That Precedes and Coincides With Hibernation in the Syrian Hamster, a Food-Storing Hibernator.

Mammalian hibernators store fat extensively in white adipose tissues (WATs) during pre-hibernation period (Pre-HIB) to prepare for hibernation. However, the molecular mechanisms underlying the pre-hibernation remodeling of WAT have not been fully elucidated. Syrian hamsters, a food-storing hibernator, can hibernate when exposed to a winter-like short day photoperiod and cold ambient temperature (SD-Cold).

A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.

Necroptosis is a regulated form of necrosis that depends on receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like (MLKL). While danger-associated molecular pattern (DAMP)s are involved in various pathological conditions and released from dead cells, the underlying mechanisms are not fully understood. Here we develop a fluorescence resonance energy transfer (FRET) biosensor, termed SMART (a sensor for MLKL activation by RIPK3 based on FRET).

Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure.

Developing embryos rewire energy metabolism for developmental processes. However, little is known about how metabolic rewiring is coupled with development in a spatiotemporal manner. Here, we show that mammalian embryos display plasticity of glucose metabolism in response to the extracellular environment at the neural tube closure (NTC) stage, when the intrauterine environment changes upon placentation.