Jonathan Ashmore

Despite significant advances in early detection and therapeutic opportunities, cancer remains a critical global health challenge. The greatest barrier to reducing cancer‐associated mortality is the persistent problem of therapeutic resistance and metastasis. Standard treatment approaches, including surgery combined with chemotherapy and radiation, are effective for many patients with localised disease. However, a substantial proportion of patients will experience recurrence and therapy resistance, leading to treatment failure and poor outcomes. This adverse prognosis for patients highlights the critical need to identify new therapeutic targets capable of improving long‐term survival. The ion transportome comprises ion channels, solute transporters and pumps that regulate controlled movement of sodium (Na ⁺ ), potassium (K ⁺ ), calcium (Ca ²⁺ ), chloride (Cl ⁻ ) and hydrogen (H ⁺ ) across cell membranes. Ion transport is central to many cellular processes, including cell growth, volume regulation, proliferation and migration. In many solid tumours, the finely tuned ionic balance becomes dysregulated, with aberrant expression or activity of membrane transport proteins being closely linked to many of the hallmarks of cancer. Ion channel modulation using pharmacological agents designed to treat channelopathies has demonstrated promise in suppressing cancer progression in preclinical models. Thus, targeting ion‐driven vulnerabilities within solid tumours may complement existing therapies to overcome resistance and improve patient outcomes. The dynamic nature of ion transport mechanisms means that addressing critical research questions regarding their suitability as pharmacological targets is challenging, highlighting the need to develop innovative approaches to study these processes in oncology. image

The role of cochlear outer hair cells (OHCs) in mammal hearing is compromised by the ‘RC time constant problem’. The issue arises because if the cells are to op

The origin of cellular complexity characterizing eukaryotic cells remains a central unresolved issue in the study of diversification of cellular life on Earth. The isolation by Imachi et al.¹ of a member of the Asgard archaea² - a contemporary relative of organisms thought to have given rise to eukaryotic cells about 2 billion years ago - now promises new insight. The complete genome sequence of the isolated Lokiarchaeum strain confirms that the eukaryotic signature proteins (ESPs) previously identified in the Lokiarchaeota³ and other Asgard archaea² are indeed encoded by these archaeal genomes and do not represent contamination from eukaryotes. These ESPs encode homologs of eukaryotic actins, small GTPases and the ESCRT complex proteins and are required for the functioning of complex eukaryotic cells. The new, slowly growing, anaerobic laboratory strain allows a first direct look at these organisms and provides key insights into the morphology and metabolism of an Asgard archaeal organism. The work has provided valuable information for other laboratories that aim to isolate and characterize related organisms from other environments.

In 1867 Herman Helmholtz, physiologist, keen musician and soon to become professor of physics in Berlin, added an appendix to the second edition of his text “On the Sensations of Tone"^#. He suggested that it was possible to model the cochlea of the inner ear like a miniature piano. Each string – for he saw fibres lying in parallel all along the coiled inner ear structure – could, like a musical instrument, be conceived to resonate at a particular frequency. Short fibres would vibrate only at high frequencies, and longer fibres would respond to low frequencies. The hypothesis was based on work from the school of anatomists at Wurzburg where fifteen years earlier a Sicilian aristocrat, Alfonso Corti, had completed his PhD studying the inner ear structure subsequently named after him.

Cryo electron microscopy (cryoEM) is a fast-growing technique for structure determination. Two recent papers report the first atomic resolution structure of a protein obtained by averaging images of frozen-hydrated biomolecules. They both describe maps of symmetric apoferritin assemblies, a common test specimen, in unprecedented detail. New instrument improvements, different in the two studies, have contributed better images, and image analysis can extract structural information sufficient to resolve individual atomic positions. While true atomic resolution maps will not be routine for most proteins, the studies suggest structures determined by cryoEM will continue to improve, increasing their impact on biology and medicine.

Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 30% of the IHCs are electrochemically coupled in ‘mini-syncytia’. This coupling permits transfer of fluorescently-labeled metabolites and macromolecular tracers. The membrane capacitance, Ca²⁺-current, and resting current increase with the number of dye-coupled IHCs. Dual voltage-clamp experiments substantiate low resistance electrical coupling. Pharmacology and tracer permeability rule out coupling by gap junctions and purinoceptors. 3D electron microscopy indicates instead that IHCs are coupled by membrane fusion sites. Consequently, depolarization of one IHC triggers presynaptic Ca²⁺-influx at active zones in the entire mini-syncytium. Based on our findings and modeling, we propose that IHC-mini-syncytia enhance sensitivity and reliability of cochlear sound encoding.