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Mechanosensitive ion channels are crucial for normal cell function and facilitate physiological function, such as blood pressure regulation. So far little is known about the molecular mechanisms of how channels sense mechanical force. Canonical vertebrate epithelial Na⁺ channel (ENaC) formed by α-, β-, and γ-subunits is a shear force (SF) sensor and a member of the ENaC/degenerin protein family. ENaC activity in epithelial cells contributes to electrolyte/fluid-homeostasis and blood pressure regulation. Furthermore, ENaC in endothelial cells mediates vascular responsiveness to regulate blood pressure. Here, we provide evidence that ENaC’s ability to mediate SF responsiveness relies on the “force-from-filament” principle involving extracellular tethers and the extracellular matrix (ECM). Two glycosylated asparagines, respectively their N-glycans localized in the palm and knuckle domains of αENaC, were identified as potential tethers. Decreased SF-induced ENaC currents were observed following removal of the ECM/glycocalyx, replacement of these glycosylated asparagines, or removal of N-glycans. Endothelial-specific overexpression of αENaC in mice induced hypertension. In contrast, expression of αENaC lacking these glycosylated asparagines blunted this effect. In summary, glycosylated asparagines in the palm and knuckle domains of αENaC are important for SF sensing. In accordance with the force-from-filament principle, they may provide a connection to the ECM that facilitates vascular responsiveness contributing to blood pressure regulation.

We investigated the extent to which activity induced by chronic electrical stimulation could restore the mass and contractile function of rabbit tibialis anterior (TA) muscles that had undergone atrophy as a result of prolonged denervation. Denervation was carried out by selectively interrupting the motor nerve branches to the ankle dorsiflexors in one hind limb. Stimulators were implanted, with electrodes on the superficial and deep surfaces of the denervated TA muscle. Ten weeks later, the mass and mid-belly cross-sectional area (CSA) of TA muscles subjected to denervation alone had fallen to approximately 40% of normal. At this stage, stimulators in the other rabbits were activated for 1 h/day to deliver 20-ms rectangular bipolar constant-current pulses of 4 mA amplitude at 20 Hz with a duty cycle of 1s ON/2s OFF, a total of 24,000 impulses/day. The animals were examined after a further 2, 6 or 10 weeks. Stimulation restored the wet weight of the denervated muscles to values not significantly different to those of normal, innervated controls. It increased CSA from 39% to 66% of normal, and there was a commensurate increase in maximum isometric tetanic force from 27% to 50% of normal. Light and electron microscopic examination revealed a marked improvement in the size, packing, and internal organization of the stimulated-denervated muscle fibres, suggestive of an ongoing process of restoration. Excitability, contractile speed, power, and fatigue resistance had not, however, been restored to normal levels after 10 weeks of stimulation. Similar results were found for muscles that had been denervated for 39 weeks and then stimulated for 12 weeks. The study demonstrates worthwhile benefits of long-term electrical stimulation in the treatment of established denervation atrophy.

Vascular smooth muscle cells (VSMCs) help to maintain the normal physiological contractility of arterial vessels to control blood pressure; they can also contribute to vascular disease such as atherosclerosis. Ca2+/calmodulin-dependent kinase II (CaMKII), a multifunctional enzyme with four isoforms and multiple alternative splice variants, contributes to numerous functions within VSMCs. The role of these isoforms has been widely studied across numerous tissue types; however, their functions are still largely unknown within the vasculature. Even more understudied is the role of the different splice variants of each isoform in such signaling pathways. This review evaluates the role of the different CaMKII splice variants in vascular pathological and physiological mechanisms, aiming to show the need for more research to highlight both the deleterious and protective functions of the various splice variants.

Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17β-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0–3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease.

Mechanotransduction describes how cells perceive their mechanical environment and mechanosensitive ion channels are important for this process. ENaC (epithelial Na+ channel)/DEG (degenerin) proteins form mechanosensitive ion channels and it is hypothesized their interaction with the extracellular matrix (ECM) via `tethers is required for mechanotransduction. Channels formed by vertebrate , and ENaC proteins are activated by shear force (SF) and mediate electrolyte/fluid-homeostasis and blood pressure regulation. Here, we report an interdependent activity of ENaC and the ECM that mediates SF effects in murine arteries and heterologously expressed channels. Furthermore, replacement of conserved extracellular N-glycosylated asparagines of ENaC decreased the SF response indicating that the attached N-glycans provide a connection to the ECM. Insertion of N-glycosylation sites into a channel subunit, innately lacking these motifs, increased its SF response. These experiments confirm an interdependent channel/ECM activity of mechanosensitive ENaC channel and highlight the role of channel N-glycans as new constituents for the translation of mechanical force into cellular signals.

Last month, the Bank of England's new governor Mark Carney became the latest to make public his plans to more closely scrutinise national shadow-banking operations. The drivers for reform are broadly consistent across developed and developing markets. Traditional banks' continued retreat from lending in the face of mounting regulatory pressures has prompted a corresponding rise in increasingly innovative non-bank funding alternatives. Operating outside the realms of traditional finance, such funding sources do not have access to central bank support or conventional safeguards such as deposit insurance and debt guarantees. As markets worldwide grow more reliant on the ability of non-banks to channel funds where most needed, concerns are growing as to maturity and liquidity transformation, as well as unregulated credit provision in general - an unease exacerbated by now discredited pre-crisis innovations in structured credit products.

Australia is one of the regions strongly affected by the El Niño‐Southern Oscillation (ENSO). The recent 2020–2023 La Niña event was marked by record‐breaking rainfall and flooding across eastern Australia. The continuous wet conditions during the triple La Niña motivated us to explore the impacts of single‐year and multi‐year ENSO events on Australian rainfall using observational data sets. We find that, while there is no difference in the rainfall impacts during single or double El Niño events, Australian rainfall tends to increase in the third year of triple La Niña events compared to the first and second years. The enhanced rainfall impact during the third La Niña year occurs despite no strengthening of La Niña in the tropical Pacific, suggesting that other processes such as local rainfall‐soil moisture feedback may play a role in prolonging the effects of multi‐year La Niña events in Australia. Plain Language Summary Australia is strongly affected by the El Niño‐Southern Oscillation (ENSO), with rainfall more likely to increase during La Niña and below‐average rainfall more common during El Niño. The recent 2020–2023 multi‐year La Niña was marked by continuous wet conditions across eastern Australia, leading to record‐breaking rainfall and flooding. Multi‐year La Niña events, where La Niña occurs in two or three consecutive austral summers, happened in about 50% of all La Niña events, including five triple La Niña events since 1900. We explored the impacts of multi‐year ENSO events on Australian rainfall and found that, while there is no difference in the rainfall impacts during single or double El Niño events, rainfall tends to increase in the third year of triple La Niña events compared to the first and second years. This rainfall increase occurs despite no strengthening of La Niña in the tropical Pacific Ocean, suggesting that local processes such as feedback between high/saturated soil moisture and rainfall may play a role in prolonging the effects of multi‐year La Niña events in Australia. Key Points Eastern Australia tends to experience record‐breaking rainfall and flooding during La Niña events Rainfall impact of multi‐year El Niño‐Southern Oscillation (ENSO) persists during double and triple events, despite no strengthening of ENSO Australian rainfall increases in the third year of triple La Niña likely due to soil moisture‐rainfall feedback

Until recent events, the Antarctic was the only major geographical region in which high pathogenicity avian influenza virus (HPAIV) had never previously been detected. Here we report on the detection of clade 2.3.4.4b H5N1 HPAIV in the Antarctic and sub-Antarctic regions of South Georgia and the Falkland Islands, respectively. We initially detected H5N1 HPAIV in samples collected from brown skuas at Bird Island, South Georgia on 8th October 2023. Since this detection, mortalities were observed in several avian and mammalian species at multiple sites across South Georgia. Subsequent testing confirmed H5N1 HPAIV across several sampling locations in multiple avian species and two seal species. Simultaneously, we also confirmed H5N1 HPAIV in southern fulmar and black-browed albatross in the Falkland Islands. Genetic assessment of the virus indicates spread from South America, likely through movement of migratory birds. Critically, genetic assessment of sequences from mammalian species demonstrates no increased risk to human populations above that observed in other instances of mammalian infections globally. Here we describe the detection, species impact and genetic composition of the virus and propose both introductory routes and potential long-term impact on avian and mammalian species across the Antarctic region. We also speculate on the threat to specific populations following recent reports in the area. High pathogenicity avian influenza virus has a wide host range and has been detected across a large geographic area. Here, the authors present evidence of spread to the Antarctic and sub-Antarctic regions, with signs of clinical infection and positive virus detection in birds and elephant seals.

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain C. neoformans in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, C. neoformans will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, C. neoformans possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and C. neoformans will determine the disease progression. In this review, we describe the current understanding of how C. neoformans migrates to the brain across the blood–brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that C. neoformans uses to modulate host immune responses.

The parasitic mite Varroa destructor is a leading cause of mortality for Western honey bee ( Apis mellifera ) colonies around the globe. We sought to confirm the presence and likely introduction of only one V. destructor haplotype in New Zealand, and describe the viral community within both V. destructor mites and the bees that they parasitise. A 1232 bp fragment from mitochondrial gene regions suggests the likely introduction of only one V. destructor haplotype to New Zealand. Seventeen viruses were found in bees. The most prevalent and abundant was the Deformed wing virus A (DWV-A) strain, which explained 95.0% of the variation in the viral community of bees. Black queen cell virus , Sacbrood virus , and Varroa destructor virus 2 (VDV-2) played secondary roles. DWV-B and the Israeli acute paralysis virus appeared absent from New Zealand. Ten viruses were observed in V. destructor , with > 99.9% of viral reads from DWV-A and VDV-2. Substantially more variation in viral loads was observed in bees compared to mites. Where high levels of VDV-2 occurred in mites, reduced DWV-A occurred in both the mites and the bees co-occurring within the same hive. Where there were high loads of DWV-A in mites, there were typically high viral loads in bees.