Pro-inflammatory mediators sensitise transient receptor potential melastatin 3 cation channel (TRPM3) function in mouse sensory neurons.

Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels.

Activation of the proton-sensing GPCR, GPR65 on fibroblast-like synoviocytes contributes to inflammatory joint pain.

Inflammation is associated with localized acidosis, however, attributing physiological and pathological roles to proton-sensitive receptors is challenging due to their diversity and widespread expression. Here, agonists of the proton-sensing GPCR, GPR65, were systematically characterized. The synthetic agonist BTB09089 (BTB) recapitulated many proton-induced signaling events and demonstrated selectivity for GPR65.

An updated reference genome sequence and annotation reveals gene losses and gains underlying naked mole-rat biology.

The naked mole-rat (NMR; ) is a eusocial subterranean rodent with a highly unusual set of physiological traits that has attracted great interest amongst the scientific community. However, the genetic basis of most of these traits has not been elucidated. To facilitate our understanding of the molecular mechanisms underlying NMR physiology and behaviour, we generated a long-read chromosomal-level genome assembly of the NMR.

Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights.

The intestinal barrier plays a crucial role in homeostasis by both facilitating the absorption of nutrients and fluids and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance.

Digging deeper into pain: an ethological behavior assay correlating well-being in mice with human pain experience.

The pressing need for safer, more efficacious analgesics is felt worldwide. Preclinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays that measure their responses to noxious stimuli.

A note on estimating absolute cytosolic Ca concentration in sensory neurons using a single wavelength Ca indicator.

Ca imaging is frequently used in the investigation of sensory neuronal function and nociception. In vitro imaging of acutely dissociated sensory neurons using membrane-permeant fluorescent Ca indicators remains the most common approach to study Ca signalling in sensory neurons. Fluo4 is a popular choice of single-wavelength indicator due to its brightness, high affinity for Ca and ease of use.

GIInger predicts homologous recombination deficiency and patient response to PARPi treatment from shallow genomic profiles.

Homologous recombination deficiency (HRD) is a predictive biomarker for poly(ADP-ribose) polymerase 1 inhibitor (PARPi) sensitivity. Routine HRD testing relies on identifying BRCA mutations, but additional HRD-positive patients can be identified by measuring genomic instability (GI), a consequence of HRD. However, the cost and complexity of available solutions hamper GI testing.

Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalization.

The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization.

Sensitization of colonic nociceptors by IL-13 is dependent on JAK and p38 MAPK activity.

The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis.

Persistent nociceptor hyperactivity as a painful evolutionary adaptation.

Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive.

Improved NGS-based detection of microsatellite instability using tumor-only data.

Microsatellite instability (MSI) is a molecular signature of mismatch repair deficiency (dMMR), a predictive marker of immune checkpoint inhibitor therapy response. Despite its recognized pan-cancer value, most methods only support detection of this signature in colorectal cancer. In addition to the tissue-specific differences that impact the sensitivity of MSI detection in other tissues, the performance of most methods is also affected by patient ethnicity, tumor content, and other sample-specific properties.

models for investigating itch.

Itch (pruritus) is a sensation that drives a desire to scratch, a behavior observed in many animals. Although generally short-lasting and not causing harm, there are several pathological conditions where chronic itch is a hallmark symptom and in which prolonged scratching can induce damage. Finding medications to counteract the sensation of chronic itch has proven difficult due to the molecular complexity that involves a multitude of triggers, receptors and signaling pathways between skin, immune and nerve cells.

Parallel evolution of semicircular canal form and sensitivity in subterranean mammals.

The vertebrate vestibular system is crucial for balance and navigation, and the evolution of its form and function in relation to species' lifestyle and mode of locomotion has been the focus of considerable recent study. Most research, however, has concentrated on aboveground mammals, with much less published on subterranean fauna. Here, we explored variation in anatomy and sensitivity of the semicircular canals among 91 mammal species, including both subterranean and non-subterranean representatives.

Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis.

Objective: Mesenchymal stem/stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) have been reported to alleviate pain in patients with knee osteoarthritis (OA). We undertook this study to determine whether MSCs and/or MSC-EVs reduce OA pain through influencing sensory neuron excitability in OA joints.

Methods: We induced knee OA in adult male C57BL/6J mice through destabilization of the medial meniscus (DMM) surgery.

Sensitization of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity.

Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut-related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro-inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons.

Skin Aging in Long-Lived Naked Mole-Rats Is Accompanied by Increased Expression of Longevity-Associated and Tumor Suppressor Genes.

Naked mole-rats (NMRs) (Heterocephalus glaber) are long-lived mammals that possess a natural resistance to cancer and other age-related pathologies, maintaining a healthy life span >30 years. In this study, using immunohistochemical and RNA-sequencing analyses, we compare skin morphology, cellular composition, and global transcriptome signatures between young and aged (aged 3‒4 vs. 19‒23 years, respectively) NMRs.

Multiscale mechanical consequences of ocean acidification for cold-water corals.

Ocean acidification is a threat to deep-sea corals and could lead to dramatic and rapid loss of the reef framework habitat they build. Weakening of structurally critical parts of the coral reef framework can lead to physical habitat collapse on an ecosystem scale, reducing the potential for biodiversity support. The mechanism underpinning crumbling and collapse of corals can be described via a combination of laboratory-scale experiments and mathematical and computational models.

Somatic mutation rates scale with lifespan across mammals.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species.

Prdm12 modulates pain-related behavior by remodeling gene expression in mature nociceptors.

Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors.

Functional Characterization of Ovine Dorsal Root Ganglion Neurons Reveal Peripheral Sensitization after Osteochondral Defect.

Knee joint trauma can cause an osteochondral defect (OD), a risk factor for osteoarthritis (OA) and cause of debilitating pain in patients. Rodent OD models are less translatable because of their smaller joint size and open growth plate. This study proposes sheep as a translationally relevant model to understand the neuronal basis of OD pain.

The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology.

The naked mole-rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g.

Some Exciting Future Directions for Work on Naked Mole-Rats.

The naked mole-rat is a species of growing research interest. Recent focus on this species from both a biomedical and zoological perspective has led to important discoveries regarding eusociality and ecophysiological and sensory traits associated with life below ground as well as natural protection from variable oxygen availability, acid-induced pain, and the vagaries of aging. These features serve to remind us that many foundational discoveries have arisen using extremophilic organisms and elucidating the mechanisms they employ to survive the harsh environmental conditions they encounter.

Naked Mole-Rats: Resistant to Developing Cancer or Good at Avoiding It?

It is widely accepted that cancer is driven by genetic mutations that confer uncontrolled cell proliferation and tumor formation. For tumors to take hold and grow, cancer cells evolve mechanisms to favorably shape their microenvironment and avoid being cleared by the immune system. Cancer is not unique to human, but rather affects nearly all multicellular organisms albeit to different degrees.

African Naked Mole-Rats Demonstrate Extreme Tolerance to Hypoxia and Hypercapnia.

Naked mole-rats are extremely tolerant to low concentrations of oxygen (hypoxia) and high concentrations of carbon dioxide (hypercapnia), which is consistent with the environment that they inhabit. Naked mole-rats combine subterranean living with living in very densely populated colonies where oxygen becomes depleted and carbon dioxide accumulates. In the laboratory, naked mole-rats fully recover from 5 h exposure to 5% O and 5 h exposure to 80% CO, whereas both conditions are rapidly lethal to similarly sized laboratory mice.