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Monogenetic volcanism in the Maniototo Basin in the Dunedin Volcanic Group was unusual because the eroded lavas, plugs and dikes comprise spatially and temporally restricted silica-saturated and silica-undersaturated magmas. 40Ar/39Ar dating coupled with existing data and field relationships indicate that volcanism was focused at ∼11 Ma. Major and trace element data show the volcanic rocks to have mafic compositions and little evidence for fractionation and/or crustal contamination, but to have been variably altered. The volcanic rocks comprise an alkaline group and an alkaline to subalkaline transitional group, with one intermediate unit. With the exception of one flow, the transitional group has more radiogenic 87Sr/86Sr and less radiogenic 143Nd/144Nd, 206Pb/204Pb and 208Pb/204Pb than the alkaline group, as well as smaller Ti and K primitive mantle-normalised anomalies. Overall, the different magma compositions cannot be related to varying degrees of melting of equivalent mantle sources. Trace element ratios indicate that residual Ti and K-bearing mantle phases (amphibole, phlogopite) probably played a major role in the source of alkaline group but a smaller role in the transitional group. Therefore, the varying compositions of the Maniototo volcanic rocks relates to melting of a heterogeneous lithospheric mantle, or/and varying degrees of interaction with mantle hydrous metasomes as the magmas ascended. [ABSTRACT FROM AUTHOR]

Over recent years, advances in medical care have significantly improved the survival of children with severe chronic conditions. These children, referred to as children with medical complexity (CMC), present unique and demanding healthcare challenges. Although definitions of CMC remain inconsistent, these patients are typically characterized by chronic, often severe conditions requiring daily specialized treatments and the use of various medical devices. CMC represent a substantial burden for healthcare systems due to their high medical costs, and place considerable strain on caregivers, who must provide continuous assistance. Airway colonization by pathogens such as Pseudomonas aeruginosa , methicillin-resistant Staphylococcus aureus (MRSA), and Haemophilus influenzae is common in CMC and contributes to recurrent respiratory infections, increased hospitalizations, and progressive lung damage. The management of airway colonization in this population is a topic of ongoing debate, often involving a combination of airway clearance techniques (ACT) and antibiotic therapies. Antibiotics may be administered systemically, nebulized, or in combination, depending on the clinical context and severity of the condition. This review highlights the complexities of managing airway colonization in CMC, emphasizing the need for tailored therapeutic approaches to mitigate respiratory complications and improve outcomes.

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to integrate information obtained from diverse experimental approaches. To address this challenge, we present a community-based, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to potentially address a range of scientific questions. In this article, we describe the methods used to set up simulations to reproduce in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce experimental findings. Finally, we make data, code, and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This community-based model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Romani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The back-propagation of an action potential (AP) from the axon/soma to the dendrites plays a central role in dendritic integration. This process involves an intricate orchestration of various ion channels, but a comprehensive understanding of the contribution of each channel type remains elusive. In this study, we leverage ultrafast membrane potential recordings (V m ) and Ca 2+ imaging techniques to shed light on the involvement of N-type voltage-gated Ca 2+ channels (VGCCs) in layer-5 neocortical pyramidal neurons' apical dendrites. We found a selective interaction between N-type VGCCs and large-conductance Ca 2+ -activated K + channels (BK CAKCs). Remarkably, we observe that BK CAKCs are activated within a mere 500 μs after the AP peak, preceding the peak of the Ca 2+ current triggered by the AP. Consequently, when N-type VGCCs are inhibited, the early broadening of the AP shape amplifies the activity of other VGCCs, leading to an augmented total Ca 2+ influx. A NEURON model, constructed to replicate and support these experimental results, reveals the critical coupling between N-type and BK channels. This study not only redefines the conventional role of N-type VGCCs as primarily involved in presynaptic neurotransmitter release but also establishes their distinct and essential function as activators of BK CAKCs in neuronal dendrites. Furthermore, our results provide original functional validation of a physical interaction between Ca 2+ and K + channels, elucidated through ultrafast kinetic reconstruction. This insight enhances our understanding of the intricate mechanisms governing neuronal signaling and may have far-reaching implications in the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Blömer, Giacalone, Abbas, Filipis, Tegolo, Migliore and Canepari.)

Dorsal and ventral medial entorhinal cortex (mEC) regions have distinct neural network firing patterns to differentially support functions such as spatial memory. Accordingly, mEC layer II dorsal stellate neurons are less excitable than ventral neurons. This is partly because the densities of inhibitory conductances are higher in dorsal than ventral neurons. Here, we report that T-type Ca 2+ currents increase 3-fold along the dorsal-ventral axis in mEC layer II stellate neurons, with twice as much Ca V 3.2 mRNA in ventral mEC compared with dorsal mEC. Long depolarizing stimuli trigger T-type Ca 2+ currents, which interact with persistent Na + currents to elevate the membrane voltage and spike firing in ventral, not dorsal, neurons. T-type Ca 2+ currents themselves prolong excitatory postsynaptic potentials (EPSPs) to enhance their summation and spike coupling in ventral neurons only. These findings indicate that T-type Ca 2+ currents critically influence the dorsal-ventral mEC stellate neuron excitability gradient and, thereby, mEC dorsal-ventral circuit activity., Competing Interests: Declaration of interests The authors declare no completing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gradual decline in cognitive and non-cognitive functions are considered clinical hallmarks of Alzheimer's Disease (AD). Post-mortem autoptic analysis shows the presence of amyloid β deposits, neuroinflammation and severe brain atrophy. However, brain circuit alterations and cellular derailments, assessed in very early stages of AD, still remain elusive. The understanding of these early alterations is crucial to tackle defective mechanisms. In a previous study we proved that the Tg2576 mouse model of AD displays functional deficits in the dorsal hippocampus and relevant behavioural AD-related alterations. We had shown that these deficits in Tg2576 mice correlate with the precocious degeneration of dopamine (DA) neurons in the Ventral Tegmental Area (VTA) and can be restored by L-DOPA treatment. Due to the distinct functionality and connectivity of dorsal versus ventral hippocampus, here we investigated neuronal excitability and synaptic functionality in the ventral CA1 hippocampal sub-region of Tg2576 mice. We found an age-dependent alteration of cell excitability and firing in pyramidal neurons starting at 3 months of age, that correlates with reduced levels in the ventral CA1 of tyrosine hydroxylase - the rate-limiting enzyme of DA synthesis. Additionally, at odds with the dorsal hippocampus, we found no alterations in basal glutamatergic transmission and long-term plasticity of ventral neurons in 8-month old Tg2576 mice compared to age-matched controls. Last, we used computational analysis to model the early derailments of firing properties observed and hypothesize that the neuronal alterations found could depend on dysfunctional sodium and potassium conductances, leading to anticipated depolarization-block of action potential firing. The present study depicts that impairment of cell excitability and homeostatic control of firing in ventral CA1 pyramidal neurons is a prodromal feature in Tg2576 AD mice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Within the confinements of critical infrastructures, the COVID-19 pandemic is posing a series of challenges to Health Management. In the spotlight of highly contagious and quick spreading diseases within such enclosed facilities, whether it be a detention facility or otherwise, the health and safety of those living within its internment is paramount. This paper aims to highlight the specific challenges and the possible solutions to counteract this problem, starting from the lessons learnt from the Italian prison system case study. Following the general description of the available resources within the Italian prisons, the study aimed at specifically describing the first counteracting measures deployed by the Italian prison authorities during the first phase of the COVID-19 outbreak (February-July 2020). The aim was to propose an integrated plan capable of responding to a biological threat within the prisons. In particular, the study describes the actions and technical features that, in accordance with national and international legal frameworks and the relevant organisational bodies that run the Italian Prison Service, had been adopted in managing, right from the start, the COVID-19 pandemic until Summer 2020. Available information and data showed the ability of the prison administration to comply almost completely with WHO's technical and human rights recommendations and also, in successfully handling prison emergencies both in terms of the sick and the deceased in line with the epidemiological framework of the general population. In addition, the paper proposes a draft of guidelines that should involve the National Health Service and the Prison Service that are aimed at supporting the local prison facilities with drawing up their own biological incident contingency plans. An approved, legal, standardised plan could increase the awareness of prison managers. It could even increase their self-confidence, in particular, with regard to cases of dispute and their ability to respond to them. In fact, it is valuable and forward-thinking to be able to demonstrate that every endeavour has been taken and that 'certified' best practices have been put in place in accordance with the national standards.

Deep-time (=pre-Quaternary) maar lakes and certain other, hydrologically deep volcanogenic lakes, are often excellent Konservat-Lagerstätten representing unique windows into past biota and ecosystems. Many deposits from such lakes contain animal and plant remains in extraordinary preservation, often with soft tissues or fine morphological and anatomical details preserved. Such Lagerstätten have the potential to provide in-depth information on a variety of organisms, which is important for understanding their biology and ecology, their evolution and palaeobiogeography, but also for elucidating entire ecosystems with their numerous biotic and abiotic interactions. The formation of such Lagerstätten is intimately linked to volcanic processes, amongst which phreatomagmatic explosions that formed maar-diatreme volcanoes are probably the most important, but also other volcanic processes can lead to the formation of deep volcanogenic lakes (e.g. in certain calderas). Maar lakes and other volcanogenic Konservat-Lagerstätten occur in a large number of volcanically active regions worldwide, although older deposits are often difficult to access as they are more likely to be eroded or covered by younger deposits. The accessibility of many of the better-known localities is often connected to the mining of natural resources, ranging from diamonds, to volcanic rocks such as basalts to the lacustrine sediments that may have filled volcanic craters, including diatomites and 'oil-shales'. Most or even all of the maar and other volcanogenic lakes presented here in greater detail, can be considered as important geoheritage sites. Although currently some of these deposits have at least some kind of legal protection as monuments of natural heritage, others remain in danger of being exploited commercially for natural resources and hence, ultimately destroyed. Moreover, many scientific questions related to these ancient lakes and their biota covered here in more detail, as well as those related to lakes only briefly mentioned in passing, have not been posed, let alone answered. This makes maar lakes and other volcanogenic lakes important resources for present-day and future research. The present contribution should be seen as a global call to scientists to find further localities that represent similar volcanogenic lacustrine settings, as they may be the source of vital and surprising new information about the plants, animals, and environments of the past. Examples of pre-Quaternary maar and other volcanogenic lakes that are presented here in greater detail include the following localities: Paleocene: Menat (France); Eocene: Messel, Eckfeld (Germany), Mahenge (Tanzania); Oligocene: Enspel, Rott, Hammerunterwiesenthal, Baruth, Kleinsaubernitz (Germany); Miocene: Foulden Maar, Hindon Maar Complex (New Zealand), Randeck Maar, Hirnkopf-Maar, Höwenegg, Öhningen (Germany); Pliocene: Ruppach-Goldhausen (Germany), Camp dels Ninots (Spain). [ABSTRACT FROM AUTHOR]

The occurrence of volcanic basanite cobbles in Pleistocene terraces at Galloway and in the upper Clutha valley in Central Otago, in an area devoid of known volcanic edifices, has implications for Cenozoic intraplate volcanism and Pleistocene drainage in the region. We present petrographic, mineralogical, whole rock geochemical and Sr-Nd-Pb isotopic data, as well as an 39Ar-40Ar date of 24.4 ± 0.06 Ma, together with mineral analyses of enclosed peridotite xenoliths. We conclude from this dataset that these alkaline basanite cobbles are most likely derived from the Alpine Dike Swarm in northwest Otago, probably in the Lake Wanaka-Hawea-Luggate area, which extends the volcanic field east of its known extent. The pilotaxitic textures and presence of intersertal glass, along with the volume of basanitic material, suggests that the source rocks were likely effusive, which would make this the first such known component of the Alpine Dike Swarm and requires emergent land at that time. The occurrence of the Galloway basanite cobbles implies that Pleistocene Clutha River flowed through or over what is now the Dunstan Range. The young (late Pleistocene) age of all the basanite-bearing gravels means that the basanite cobbles have likely been reworked several times before final deposition. [ABSTRACT FROM AUTHOR]

Active conductances tune the kinetics of axonal action potentials (APs) to support specialized functions of neuron types. However, the temporal characteristics of voltage signals strongly depend on the size of neuronal structures, as capacitive and resistive effects slow down voltage discharges in the membranes of small elements. Axonal action potentials are particularly sensitive to these inherent biophysical effects because of the large diameter variabilities within individual axons, potentially implying bouton size-dependent synaptic effects. However, using direct patch-clamp recordings and voltage imaging in small hippocampal axons in acute slices from rat brains, we demonstrate that AP shapes remain uniform within the same axons, even across an order of magnitude difference in caliber. Our results show that smaller axonal structures have more Kv1 potassium channels that locally re-accelerate AP repolarization and contribute to size-independent APs, while they do not preclude the plasticity of AP shapes. Thus, size-independent axonal APs ensure consistent digital signals for each synapse within axons of same types. Why is the repolarization phase of the neuronal actional potential so uniform despite the variability in axon diameters? This study shows that increased Kv1 potassium currents in smaller axonal structures compensate for their biophysical constraints resulting in size-independent synaptic trigger signals along the entire axon. [ABSTRACT FROM AUTHOR]

Bottom-up, data-driven, large-scale models provide a mechanistic understanding of neuronal functions. A new study in PLOS Biology builds a biologically realistic model of the rodent CA1 region that aims to become an accessible tool for the whole hippocampal community. Bottom-up, data-driven, large-scale models can provide a mechanistic understanding of neuronal functions. This Primer explores a new study in PLOS Biology that builds a biologically realistic model of the rodent CA1 region that aims to become an accessible tool for the whole hippocampus community. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis. [ABSTRACT FROM AUTHOR]

Spatial overlap between wildlife and related domestic animals can lead to disease transmission, with substantial evidence for viral and bacterial spillover. Domestic and wild animals can also share potentially harmful helminth parasites, many of which have environmental transmission stages that do not require direct contact between hosts. We used camera traps, fecal sampling, and mathematical modeling to evaluate the potential for hookworm parasites to spillover from domestic dogs to wild cats in the Osa Peninsula, Costa Rica. Traditional microscopy was found to be more sensitive than DNA‐based diagnostics for parasites, though the methods were complementary. We found high hookworm (Ancylostoma spp.) prevalence in domestic dogs (74.2%, 95% CI: 67.0%–80.7%, N = 155), and considerable spatial overlap with ocelots (Leopardus pardalis) and pumas (Puma concolor), particularly on trails and dirt roads. Pumas had hookworm prevalence of 36.4% (18.6%–57.2%, N = 22), and ocelots had 27.3% (7.6%–56.5%, N = 11); however, molecular identification of these parasites was inconclusive. We developed a macroparasite transmission model to infer the likelihood of spillover, compared with separate parasite cycles, or different parasite species in each host. According to the model, spillover of hookworm from dogs would lead to a prevalence of less than 10% in wild hosts. Low presumed compatibility between wild hosts and parasites adapted to domestic species limits the prevalence that could be reached in wild species, even under potentially higher overlap. The prevalence observed was more consistent with a model that assumes hookworms in wild cats in the Osa are a cat‐specific parasite. The combination of parasitology, molecular diagnostics, and mathematical modeling used here could complement wildlife disease monitoring programs worldwide to shed light on understudied helminth–host dynamics at the domestic–wild animal interface. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex–mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD. Editor's summary: Vision loss in the late stages of neovascular age-related macular degeneration (nvAMD) is mainly caused by the formation of new blood vessels in the choroid layer of the eye. Current therapeutic strategies to inhibit choroidal neovascularization (CNV) are only partially effective. Dong et al. used a CNV mouse model and tissue samples from patients with nvAMD to show that natural killer cells accumulated in the choroid layer of the diseased eye. Depletion of NK cells prevented NETosis, a process known to regulate vascular remodeling, and aggravated pathology in CNV mice. IL-2–mediated NK cell expansion curbed the development of CNV in mice, highlighting the protective effects of NK cells. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Optical brain clearing combined with immunolabeling is valuable for analyzing molecular tissue structures, including complex synaptic connectivity. However, the presence of aberrant lipid deposition due to aging and brain disorders poses a challenge for achieving antibody penetration throughout the entire brain volume. Herein, we present an efficient brain-wide immunolabeling method, the immuno-active clearing technique (iACT). The treatment of brain tissues with a zwitterionic detergent, specifically SB3-12, significantly enhanced tissue permeability by effectively mitigating lipid barriers. Notably, Quadrol treatment further refines the methodology by effectively eliminating residual detergents from cleared brain tissues, subsequently amplifying volumetric fluorescence signals. Employing iACT, we uncover disrupted axonal projections within the mesolimbic dopaminergic (DA) circuits in 5xFAD mice. Subsequent characterization of DA neural circuits in 5xFAD mice revealed proximal axonal swelling and misrouting of distal axonal compartments in proximity to amyloid-beta plaques. Importantly, these structural anomalies in DA axons correlate with a marked reduction in DA release within the nucleus accumbens. Collectively, our findings highlight the efficacy of optical volumetric imaging with iACT in resolving intricate structural alterations in deep brain neural circuits. Furthermore, we unveil the compromised integrity of DA pathways, contributing to the underlying neuropathology of Alzheimer's disease. The iACT technique thus holds significant promise as a valuable asset for advancing our understanding of complex neurodegenerative disorders and may pave the way for targeted therapeutic interventions. The axonal projection of DA neurons in the septum and the NAc showed dystrophic phenotypes such as growth cone-like enlargement of the axonal terminus and aggregated neurites. Brain-wide imaging of structural defects in the neural circuits was facilitated with brain clearing and antibody penetration assisted with SB3-12 and Quadrol pre-treatment. The whole volumetric imaging process could be completed in a week with the robust iACT method. Created with https://www.biorender.com/. [ABSTRACT FROM AUTHOR]

A decline in hippocampal function has long been associated with the progression of cognitive impairments in patients with Alzheimer's disease (AD). The disruption of hippocampal synaptic plasticity [primarily the reduction of long-term potentiation LTP] by excess production of soluble beta-amyloid (Aβ) has long been accepted as the mechanism by which AD pathology impairs memory, at least during the early stages of AD pathogenesis. However, the premise that hippocampal LTP underpins the formation of associative, long-term memories has been challenged. Here, we consider evidence that this canonical view of LTP needs to be refined. Similarly, the view that the hippocampus simply supports memory ignores the wealth of data showing that the hippocampus is functionally heterogeneous along its septo-temporal axis. The ventral (but not the dorsal) hippocampus plays a major role in modulating emotional reactions to conflict. Here, we suggest that hippocampal LTP is not involved in forming long-term associative memories, but instead contributes to the disambiguation of overlapping memories in situations of conflict and associative interference. This conceptualisation of hippocampal synaptic plasticity may help explain how early-stage AD pathology may impact both memory and anxiety., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Introduction: Deterioration of cognitive functions is commonly associated with aging, although there is wide variation in the onset and manifestation. Albeit heterogeneity in age-related cognitive decline has been studied at the cellular and molecular level, there is poor evidence for electrophysiological correlates. The aim of the current study was to address the electrophysiological basis of heterogeneity of cognitive functions in cognitively Inferior and Superior old (19-20 months) rats in the ventral tegmental area (VTA) and the hippocampus, having Young (12 weeks) rats as a control. The midbrain VTA operates as a hub amidst affective and cognitive facets, processing sensory inputs related to motivated behaviours and hippocampal memory. Increasing evidence shows direct dopaminergic and non-dopaminergic input from the VTA to the hippocampus. Methods: Aged Superior and Inferior male rats were selected from a cohort of 88 animals based on their performance in a spatial learning and memory task. Using in vivo single-cell recording in the VTA, we examined the electrical activity of different neuronal populations (putative dopaminergic, glutamatergic and GABAergic neurons). In the same animals, basal synaptic transmission and synaptic plasticity were examined in hippocampal slices. Results: Electrophysiological recordings from the VTA and hippocampus showed alterations associated with aging per se, together with differences specifically linked to the cognitive status of aged animals. In particular, the bursting activity of dopamine neurons was lower, while the firing frequency of glutamatergic neurons was higher in VTA of Inferior old rats. The response to high-frequency stimulation in hippocampal slices also discriminated between Superior and Inferior aged animals. Discussion: This study provides new insight into electrophysiological information underlying compromised cerebral ageing. Further understanding of brain senescence, possibly related to neurocognitive decline, will help develop new strategies towards the preservation of a high quality of life. [ABSTRACT FROM AUTHOR]

The back-propagation of an action potential (AP) from the axon/soma to the dendrites plays a central role in dendritic integration. This process involves an intricate orchestration of various ion channels, but a comprehensive understanding of the contribution of each channel type remains elusive. In this study, we leverage ultrafast membrane potential recordings (Vm) and Ca2+ imaging techniques to shed light on the involvement of N-type voltage-gated Ca2+ channels (VGCCs) in layer-5 neocortical pyramidal neurons’ apical dendrites. We found a selective interaction between N-type VGCCs and large-conductance Ca2+-activated K+ channels (BK CAKCs). Remarkably, we observe that BK CAKCs are activated within a mere 500 µs after the AP peak, preceding the peak of the Ca2+ current triggered by the AP. Consequently, when N-type VGCCs are inhibited, the early broadening of the AP shape amplifies the activity of other VGCCs, leading to an augmented total Ca2+ influx. A NEURON model, constructed to replicate and support these experimental results, reveals the critical coupling between N-type and BK channels. This study not only redefines the conventional role of N-type VGCCs as primarily involved in presynaptic neurotransmitter release but also establishes their distinct and essential function as activators of BK CAKCs in neuronal dendrites. Furthermore, our results provide original functional validation of a physical interaction between Ca2+ and K+ channels, elucidated through ultrafast kinetic reconstruction. This insight enhances our understanding of the intricate mechanisms governing neuronal signaling and may have far-reaching implications in the field. [ABSTRACT FROM AUTHOR]

We studied four Quaternary volcanic phonolitic explosive edifices on Petite-Terre Island (Mayotte, Comoros Archipelago, Western Indian Ocean) to quantify magma fragmentation processes and eruptive dynamics. Petite-Terre explosive volcanism is the westernmost subaerial expression of a 60-km-long volcanic chain, whose eastern tip was the site of the 2018–2020 submarine eruption of the new Fani Maoré volcano. The persistence of deep seismic activity and magmatic degassing along the volcanic chain poses the question of a possible reactivation on land. Through geomorphology, stratigraphy, grain size, and componentry data, we show that Petite-Terre "maars" are actually tuff rings and tuff cones likely formed by several closely spaced eruptions. The eruptive sequences of each edifice are composed of thin (cm–dm), coarse, lithic-poor pumice fallout layers containing abundant ballistic clasts, and fine ash-rich deposits mostly emplaced by dilute pyroclastic density currents (PDCs). Deposits are composed of vesiculated, juvenile fragments (pumice clasts, dense clasts, and obsidian), and non-juvenile clasts (from older mafic scoria cones, coral reef, the volcanic shield of Mayotte, as well as occasional mantle xenoliths). We conclude that phonolitic magma ascended directly and rapidly from depth (around 17 km) and experienced a first, purely magmatic fragmentation, at depth (≈ 1 km in depth). The fragmented pyroclasts then underwent a second shallower hydromagmatic fragmentation when they interacted with water, producing fine ash and building the tuff rings and tuff cones. [ABSTRACT FROM AUTHOR]

Besides its role in the circadian rhythm, the pineal gland hormone melatonin (MLT) also possesses antiepileptogenic, antineoplastic, and cardioprotective properties, among others. The dosages necessary to elicit beneficial effects in these diseases often far surpass physiological concentrations. Although even high doses of MLT are considered to be largely harmless to humans, the possible side effects of pharmacological concentrations are so far not well investigated. In the present study, we report that pharmacological doses of MLT (3 mM) strongly altered the electrophysiological characteristics of cultured primary mouse cerebellar granule cells (CGCs). Using whole‐cell patch clamp and ratiometric Ca2+ imaging, we observed that pharmacological concentrations of MLT inhibited several types of voltage‐gated Na+, K+, and Ca2+ channels in CGCs independently of known MLT‐receptors, altering the character and pattern of elicited action potentials (APs) significantly, quickly and reversibly. Specifically, MLT reduced AP frequency, afterhyperpolarization, and rheobase, whereas AP amplitude and threshold potential remained unchanged. The altered biophysical profile of the cells could constitute a possible mechanism underlying the proposed beneficial effects of MLT in brain‐related disorders, such as epilepsy. On the other hand, it suggests potential adverse effects of pharmacological MLT concentrations on neurons, which should be considered when using MLT as a pharmacological compound. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener. Reduced BKCa channel functionality has been reported in FXS patients, suggesting that molecules activating these channels could serve as promising treatments for this syndrome. Here, we sought to characterize the therapeutic potential of chlorzoxazone using the Fmr1-KO mouse model of FXS which recapitulates the main phenotypes of FXS, including BKCa channel alterations. Chlorzoxazone, administered either acutely or chronically, rescued hyperactivity and acoustic hyper-responsiveness as well as impaired social interactions exhibited by Fmr1-KO mice. Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Although the characterization of the sticking and aggregation probability is essential to the description of volcanic ash dispersal and sedimentation, there is still no general model describing the sticking probability of volcanic ash. Experiments of dry particle–plate collisions in an enclosed box were carried out to characterize quantitatively the sticking efficiency of volcanic particles and silica beads in a limit case scenario where the mass of one of the particles is much greater than the others. Silica beads and volcanic particles from a Sakurajima Vulcanian eruption were filmed impacting a glass plate with a High-Speed Camera. The sticking probability is calculated from an equation depending on the particle diameter, impact velocity, and two experimental parameters (a, q). Particle size was found to dominantly control the sticking probability, with small particles more likely sticking on the glass plate than large particles. These experiments represent a significant step forward in the quantification of the sticking efficiency of fine volcanic ash (< 63 μm). [ABSTRACT FROM AUTHOR]

Structures that facilitate fluid migration are common in sedimentary basins. We document several possible hydrothermal and/or volcanic vents located above a >157 km2, late Cretaceous volcanic field in the Great South Basin, offshore New Zealand. Three of the four vents are vertically stacked, suggesting episodic re‐use of the same fluid pathway between ca. 75 and 56 Ma. A palaeo‐pockmark dated to ca. 49 Ma and free gas occurring within strata ca. 21 Myr old are located directly above these stacked vents. The spatial association of the vents, pockmark and free gas further suggests re‐use of the fluid migration pathway(s) extended for over 54 Myr. Our results imply that reutilization of fluid flow pathways can affect the distribution of fluids within basins over prolonged periods, potentially impacting hydrocarbon/geothermal exploration and geohazard assessment. [ABSTRACT FROM AUTHOR]