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Dystonias are a group of neurodegenerative disorders that result in altered physiology associated with motor movements. Both the basal ganglia and the cerebellum, brain regions involved in motor learning, sensory perception integration, and reward, have been implicated in the pathology of dystonia, but the cellular and subcellular mechanisms remain diverse and for some forms of dystonia, elusive. The goal of the current review is to summarize recent evidence of cerebellar involvement in different subtypes of dystonia with a focus on Purkinje cell (PC) and cerebellar nuclei (CN) dysfunction, to find commonalities in the pathology that could lay the groundwork for the future development of therapeutics for patients with dystonia. Here we will briefly discuss the physical and functional connections between the basal ganglia and the cerebellum and how these connections could contribute to dystonic symptoms. We proceed to use human and animal model data to discuss the contributions of cerebellar cell types to specific dystonias and movement disorders where dystonia is a secondary symptom. Ultimately, we suggest PC and CN irregularity could be a locus for dystonia through impaired calcium dynamics. [ABSTRACT FROM AUTHOR]

Bile acids play important roles in the human body, and changes in their pool can be used as markers for various liver pathologies. In addition to their functional effects in modulating inflammatory responses and cellular survivability, the unconjugated or conjugated, secondary, or primary nature of bile acids accounts for their various ligand effects. The common hydrophilic bile acids have been used successfully as local treatment to resolve drug-induced cell damage or to ameliorate hearing loss. From various literature references, bile acids show concentration and tissue-dependent effects. Some hydrophobic bile acids act as ligands modulating vitamin D receptors, muscarinic receptors, and calcium-activated potassium channels, important proteins in the inner ear system. Currently, there are limited resources investigating the therapeutic effects of bile acid on hearing loss and little to no information on detecting bile acids in the remote ear system, let alone baseline bile acid levels and their prevalence in healthy and disease conditions. This review presents both hydrophilic and hydrophobic human bile acids and their tissue-specific effects in modulating cellular integrity, thus considering the possible effects and extended therapeutic applicability of bile acids to the inner ear tissue., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Acetone–butanol–ethanol (ABE) fermentation by solventogenic clostridia can be harnessed to produce CO2 emission neutral bio-based 1-butanol, a valuable compound with a broad range of applications, e.g., in industrial production, as a solvent and as a fuel additive or replacement. However, the relatively low butanol titers and high feedstock costs prevent bio-butanol production on an industrial scale. Agricultural side-stream materials, like milling byproducts, are starch-rich, low-cost and produced all year round. They could be suitable substrates for bio-butanol production by ABE fermentation. Results: The milling byproducts wheat red dog (WRD), rye second flour (RSF), wheat bran (WB), rye bran (RB) and ergot sclerotia-containing rye waste stream (ER) were found to contain between ~ 30 and ~ 85% glucan, most of which was starch based. WRD, RSF and ER had the highest glucan content, while the brans contained significant xylan concentrations. Four strains selected from the collection of solventogenic clostridia available in our group produced > 6 g/L butanol on the majority of these substrates, with Clostridium beijerinckii NCIMB 8052 showing the best ABE production performance when regarding all tested substrates. Toxic ergot sclerotia-containing waste material was found to be a suited substrate for ABE fermentation. Strain NCIMB 8052 exhibited butanol titers of up to 9 g/L on substrate mixtures of WRD plus ER and the highest butanol yield per used sugars. Finally, a semi-continuous ABE fermentation of C. beijerinckii NCIMB 8052 on WRD plus ER could be maintained for 96 h. The volumetric ABE productivity during the continuous phase of fermentation was ~ 0.41 g L−1 h−1 and a total of 37.7 g ABE was produced out of 168.2 g substrate. Conclusions: Based on their carbohydrate composition, WRD, RSF and ER were the milling byproducts best suited as substrates for bio-butanol production by clostridial ABE fermentation. Importantly, also ergot sclerotia-containing waste materials can be used as substrates, which can help to reduce process costs. The semi-continuous fermentation showed that clostridial ABE fermentation on milling byproducts may represent a suitable avenue for commercial butanol production after further process and/or strain optimization. [ABSTRACT FROM AUTHOR]

K+ secretion in the distal nephron has a critical role in K+ homeostasis and is the primary route by which K+ is lost from the body. Renal K+ secretion is enhanced by increases in dietary K+ intake and by increases in tubular flow rate in the distal nephron. This review addresses new and important insights regarding the mechanisms underlying flow‐induced K+ secretion (FIKS). While basal K+ secretion in the distal nephron is mediated by renal outer medullary K+ (ROMK) channels in principal cells (PCs), FIKS is mediated by large conductance, Ca2+/stretch activated K+ (BK) channels in intercalated cells (ICs), a distinct cell type. BK channel activation requires an increase in intracellular Ca2+ concentration ([Ca2+]i), and both PCs and ICs exhibit increases in [Ca2+]i in response to increases in tubular fluid flow rate, associated with an increase in tubular diameter. PIEZO1, a mechanosensitive, nonselective cation channel, is expressed in the basolateral membranes of PCs and ICs, where it functions as a mechanosensor. The loss of flow‐induced [Ca2+]i transients in ICs and BK channel‐mediated FIKS in microperfused collecting ducts isolated from mice with IC‐specific deletion of Piezo1 in the CCD underscores the importance of PIEZO1 in the renal regulation of K+ transport. [ABSTRACT FROM AUTHOR]

Background: Elaeocarpus spp. stem blight, caused by Pseudocryphonectria elaeocarpicola, is a destructive disease, which will significantly reduce the productivity and longevity of Elaeocarpus spp. plants, especially in the Guangdong Province of China. However, few information is available for P. elaeocarpicola. To unravel the potential adaptation mechanism of stem adaptation, the whole genome of P. elaeocarpicola was sequenced by using the DNBSEQ and PacBio platforms. Results: P. elaeocarpicola harbors 44.49 Mb genome with 10,894 predicted coding genes. Genome analysis revealed that the P. elaeocarpicola genome encodes a plethora of pathogenicity-related genes. Analysis of carbohydrate-active enzymes (CAZymes) revealed a rich variety of enzymes participated in plant cell wall degradation, which could effectively degrade cellulose, hemicellulose and xyloglucans in the plant cell wall and promote the invasion of the host plant. There are 213 CAZyme families found in P. elaeocarpicola, among which glycoside hydrolase (GH) family has the largest number, far exceeding other tested fungi by 53%. Besides, P. elaeocarpicola has twice as many genes encoding chitin and cellulose degradation as Cryphonectria parasitica, which belong to the same family. The predicted typical secreted proteins of P. elaeocarpicola are numerous and functional, including many known virulence effector factors, indicating that P. elaeocarpicola has great potential to secrete virulence effectors to promote pathogenicity on host plants. AntiSMASH revealed that the genome encoded 61 secondary metabolic gene clusters including 86 secondary metabolic core genes which was much higher than C. parasitica (49). Among them, two gene cluster of P. elaeocarpicola, cluster12 and cluster52 showed 100% similarity with the mycotoxins synthesis clusters from Aspergillus steynii and Alternaria alternata, respectively. In addition, we annotated cytochrome P450 related enzymes, transporters, and transcription factors in P. elaeocarpicola, which are important virulence determinants of pathogenic fungi. Conclusions: Taken together, our study represents the first genome assembly for P. elaeocarpicola and reveals the key virulence factors in the pathogenic process of P. elaeocarpicola, which will promote our understanding of its pathogenic mechanism. The acquired knowledge lays a foundation for further exploration of molecular interactions with the host and provide target for management strategies in future research. [ABSTRACT FROM AUTHOR]

Variants in potassium channel‐related genes are one of the most important mechanisms underlying abnormal neuronal excitation and disturbances in the cellular resting membrane potential. These variants can cause different forms of epilepsy, which can seriously affect the physical and mental health of patients, especially those with refractory epilepsy or status epilepticus, which are common among pediatric patients and are potentially life‐threatening. Variants in potassium ion channel‐related genes have been reported in few studies; however, to our knowledge, no systematic review has been published. This study aimed to summarize the epilepsy phenotypes, functional studies, and pharmacological advances associated with different potassium channel gene variants to assist clinical practitioners and drug development teams to develop evidence‐based medicine and guide research strategies. PubMed and Google Scholar were searched for relevant literature on potassium channel‐related epilepsy reported in the past 5–10 years. Various common potassium ion channel gene variants can lead to heterogeneous epilepsy phenotypes, and functional effects can result from gene deletions and compound effects. Administration of select anti‐seizure medications is the primary treatment for this type of epilepsy. Most patients are refractory to anti‐seizure medications, and some novel anti‐seizure medications have been found to improve seizures. Use of targeted drugs to correct aberrant channel function based on the type of potassium channel gene variant can be used as an evidence‐based pathway to achieve precise and individualized treatment for children with epilepsy. Plain Language Summary: In this article, the pathogenesis and clinical characteristics of epilepsy caused by different types of potassium channel gene variants are reviewed in the light of the latest research literature at home and abroad, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of children with this type of disease. [ABSTRACT FROM AUTHOR]

Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and retinal neurons have been reported to express multiple mechanical-sensitive channels (MSCs) in recent decades. However, the role of MSCs in visual functions and pressure-related retinal conditions has been unclear. This review will focus on the variety and functional significance of the MSCs permeable to K+, Na+, and Ca2+, primarily including the big potassium channel (BK); the two-pore domain potassium channels TRAAK and TREK; Piezo; the epithelial sodium channel (ENaC); and the transient receptor potential channels vanilloid TRPV1, TRPV2, and TRPV4 in retinal photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells. Most MSCs do not directly mediate visual signals in vertebrate retinas. On the other hand, some studies have shown that MSCs can open in physiological conditions and regulate the activities of retinal neurons. While these data reasonably predict the crossing of visual and mechanical signals, how retinal light pathways deal with endogenous and exogenous mechanical stimulation is uncertain. [ABSTRACT FROM AUTHOR]

Large Conductance Voltage- and Calcium-activated K+ (BK) channels are transmembrane pore-forming proteins that regulate cell excitability and are also expressed in non-excitable cells. They play a role in regulating vascular tone, neuronal excitability, neurotransmitter release, and muscle contraction. Dysfunction of the BK channel can lead to arterial hypertension, hearing disorders, epilepsy, and ataxia. Here, we provide an overview of BK channel functioning and the implications of its abnormal functioning in various diseases. Understanding the function of BK channels is crucial for comprehending the mechanisms involved in regulating vital physiological processes, both in normal and pathological conditions, controlled by BK. This understanding may lead to the development of therapeutic interventions to address BK channelopathies. [ABSTRACT FROM AUTHOR]

In 1999, the first biosynthetic gene cluster (BGC), synthesizing the virulence factor DHN melanin, was characterized in Aspergillus fumigatus. Since then, 19 additional BGCs have been linked to specific secondary metabolites (SMs) in this species. Here, we provide a comprehensive timeline of A. fumigatus BGC discovery and find that initial advances centered around the commonly expressed SMs where chemical structure informed rationale identification of the producing BGC (e.g., gliotoxin, fumigaclavine, fumitremorgin, pseurotin A, helvolic acid, fumiquinazoline). Further advances followed the transcriptional profiling of a ΔlaeA mutant, which aided in the identification of endocrocin, fumagillin, hexadehydroastechrome, trypacidin, and fumisoquin BGCs. These SMs and their precursors are the commonly produced metabolites in most A. fumigatus studies. Characterization of other BGC/SM pairs required additional efforts, such as induction treatments, including co-culture with bacteria (fumicycline/neosartoricin, fumigermin) or growth under copper starvation (fumivaline, fumicicolin). Finally, four BGC/SM pairs were discovered via overexpression technologies, including the use of heterologous hosts (fumicycline/neosartoricin, fumihopaside, sphingofungin, and sartorypyrone). Initial analysis of the two most studied A. fumigatus isolates, Af293 and A1160, suggested that both harbored ca. 34–36 BGCs. However, an examination of 264 available genomes of A. fumigatus shows up to 20 additional BGCs, with some strains showing considerable variations in BGC number and composition. These new BGCs present a new frontier in the future of secondary metabolism characterization in this important species. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pore-forming α subunits of the voltage- and Ca 2+ -activated K + channel with large conductance (BKα) promote malignant phenotypes of breast tumour cells. Auxiliary subunits such as the leucine-rich repeat containing 26 (LRRC26) protein, also termed BKγ1, may be required to permit activation of BK currents at a depolarized resting membrane potential that frequently occur in non-excitable tumour cells., Experimental Approach: Anti-tumour effects of BKα loss were investigated in breast tumour-bearing MMTV-PyMT transgenic BKα knockout (KO) mice, primary MMTV-PyMT cell cultures, and in a syngeneic transplantation model of breast cancer derived from these cells. The therapeutic relevance of BK channels in the context of endocrine treatment was assessed in human breast cancer cell lines expressing either low (MCF-7) or high (MDA-MB-453) levels of BKα and BKγ1, as well as in BKα-negative MDA-MB-157., Key Results: BKα promoted breast cancer onset and overall survival in preclinical models. Conversely, lack of BKα and/or knockdown of BKγ1 attenuated proliferation of murine and human breast cancer cells in vitro. At low concentrations, tamoxifen and its major active metabolites stimulated proliferation of BKα/γ1-positive breast cancer cells, independent of the genomic signalling controlled by the oestrogen receptor. Finally, tamoxifen increased the relative survival time of BKα KO but not of wild-type tumour cell recipient mice., Conclusion and Implications: Breast cancer initiation, progression, and tamoxifen sensitivity depend on functional BK channels thereby providing a rationale for the future exploration of the oncogenic actions of BK channels in clinical outcomes with anti-oestrogen therapy., Linked Articles: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc., (© 2020 The British Pharmacological Society.)

Background: Schema therapy is effective for most outpatients with personality disorders (PDs). However, a subgroup does not sufficiently benefit from outpatient programmes. Despite its common clinical use, a thorough evaluation of day treatment group schema therapy (GST) is lacking. Aims: This study aimed to investigate the effectiveness of day treatment GST for patients with PDs. Methods and Procedures: Negative core beliefs were the primary outcome in a multiple baseline single‐case design, measured weekly before and during 30 weeks of day treatment GST. Secondary outcomes included severity of primary PD, early maladaptive schemas (EMS), schema modes and general psychopathology measured before and after day treatment GST. Intervention effects were evaluated through visual inspection and randomization test analysis, with a reliable change index calculated for the secondary outcome measures. Outcomes and Results: A total of 79% of treatment completers showed a significant positive effect of day treatment GST with large effect sizes (Cohen's d: 0.96–10.04). Secondary outcomes supported these findings: 56% had a significant decrease in the severity of primary PD and 53% in general psychopathology. In addition, 63% of EMS and 72% of schema modes (87.5% for functional schema modes) showed significant positive reliable changes. Conclusions and Implications: This is the first empirical study that demonstrated the effectiveness of day treatment GST in patients with severe PDs. Day treatment GST can serve as a stepped care treatment option for nonresponsive patients in outpatient programmes. Further randomized controlled (cost‐)effectiveness research is necessary to substantiate these findings and investigate the specific patient populations for which day treatment is essential. [ABSTRACT FROM AUTHOR]

Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the KCa1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions. [ABSTRACT FROM AUTHOR]

Novel KCNMA1 variants, encoding the BK K+ channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation. [ABSTRACT FROM AUTHOR]

Hydrophobins (HFBs) are a group of small, secreted amphipathic proteins of fungi with multiple physiological functions and potential commercial applications. In this study, HFB genes of the edible mushroom, Grifola frondosa, were systematically identified and characterized, and their transcriptional profiles during fungal development were determined. In total, 19 typical class I HFB genes were discovered and bioinformatically analyzed. Gene expression profile examination showed that Gf.hyd9954 was particularly highly upregulated during primordia formation, suggesting its major role as the predominant HFB in the lifecycle of G. frondosa. The wettability alteration profile and the surface modification ability of recombinant rGf.hyd9954 were greater than for the Grifola HFB HGFII-his. rGf.hyd9954 was also demonstrated to form the typical class I HFB characteristic-rodlet bundles. In addition, rGf.hyd9954 was shown to possess nanoparticle characteristics and emulsification activities. This research sheds light on the regulation of fungal development and its association with the expression of HFB genes. [ABSTRACT FROM AUTHOR]

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. Yet, functional recovery after surgical repair is often disappointing. The basis for poor recovery is progressive deterioration with time and distance of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. Nonetheless, chronically denervated atrophic muscle retains the capacity for reinnervation. Declining electrical activity of motoneurons accompanies the progressive fall in axotomized neuronal and denervated SC expression of regeneration-associated-genes and declining regenerative success. Reduced motoneuronal activity is due to the withdrawal of synaptic contacts from the soma. Exogenous neurotrophic factors that promote nerve regeneration can replace the endogenous factors whose expression declines with time. But the profuse axonal outgrowth they provoke and the difficulties in their delivery hinder their efficacy. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) proximal to the injury site promotes the expression of endogenous growth factors and, in turn, dramatically accelerates axon outgrowth and target reinnervation. The latter ES effect has been demonstrated in both rats and humans. A conditioning ES of intact nerve days prior to nerve injury increases axonal outgrowth and regeneration rate. Thereby, this form of ES is amenable for nerve transfer surgeries and end-to-side neurorrhaphies. However, additional surgery for applying the required electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes. [ABSTRACT FROM AUTHOR]

Mutations of large conductance Ca2+- and voltage-activated K+ channels (BK) are associated with cognitive impairment. Here we report that CA1 pyramidal neuron-specific conditional BK knock-out (cKO) mice display normal locomotor and anxiety behavior. They do, however, exhibit impaired memory acquisition and retrieval in the Morris Water Maze (MWM) when compared to littermate controls (CTRL). In line with cognitive impairment in vivo, electrical and chemical long-term potentiation (LTP) in cKO brain slices were impaired in vitro. We further used a genetically encoded fluorescent K+ biosensor and a Ca2+-sensitive probe to observe cultured hippocampal neurons during chemical LTP (cLTP) induction. cLTP massively reduced intracellular K+ concentration ([K+]i) while elevating L-Type Ca2+ channel- and NMDA receptor-dependent Ca2+ oscillation frequencies. Both, [K+]i decrease and Ca2+ oscillation frequency increase were absent after pharmacological BK inhibition or in cells lacking BK. Our data suggest that L-Type- and NMDAR-dependent BK-mediated K+ outflow significantly contributes to hippocampal LTP, as well as learning and memory. [ABSTRACT FROM AUTHOR]

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into separate classes based on the hormone each cell type secretes. Recent studies have revealed more diverse hormone profiles and communication modalities for EECs including direct synaptic communication with peripheral neurons. EECs known as neuropod cells rapidly relay signals from gut to brain via a direct communication with vagal and primary sensory neurons. Further, this review discusses the complex information processing machinery within EECs, including receptors that transduce intraluminal signals and the ion channel complement that govern initiation and propagation of these signals. Deeper understanding of EEC physiology is necessary to safely treat devastating and pervasive conditions like irritable bowel syndrome and obesity. [ABSTRACT FROM AUTHOR]

The class II hydrophobin group (HFBII) is an extracellular group of proteins that contain the HFBII domain and eight conserved cysteine residues. These proteins are exclusively secreted by fungi and have multiple functions with a probable role as effectors. In the present study, a total of 45 amino acid sequences of hydrophobin class II proteins from different phytopathogenic fungi were retrieved from the NCBI database. We used the integration of well-designed bioinformatic tools to characterize and predict their physicochemical parameters, novel motifs, 3D structures, multiple sequence alignment (MSA), evolution, and functions as effector proteins through molecular docking. The results revealed new features for these protein members. The ProtParam tool detected the hydrophobicity properties of all proteins except for one hydrophilic protein (KAI3335996.1). Out of 45 proteins, six of them were detected as GPI-anchored proteins by the PredGPI server. Different 3D structure templates with high pTM scores were designed by Multifold v1, AlphaFold2, and trRosetta. Most of the studied proteins were anticipated as apoplastic effectors and matched with the ghyd5 gene of Fusarium graminearum as virulence factors. A protein–protein interaction (PPI) analysis unraveled the molecular function of this group as GTP-binding proteins, while a molecular docking analysis detected a chitin-binding effector role. From the MSA analysis, it was observed that the HFBII sequences shared conserved 2 Pro (P) and 2 Gly (G) amino acids besides the known eight conserved cysteine residues. The evolutionary analysis and phylogenetic tree provided evidence of episodic diversifying selection at the branch level using the aBSREL tool. A detailed in silico analysis of this family and the present findings will provide a better understanding of the HFBII characters and evolutionary relationships, which could be very useful in future studies. [ABSTRACT FROM AUTHOR]

Hydrophobins are amphipathic proteins with small molecular weights produced in filamentous fungi. These proteins are highly stable due to the disulfide bonds formed between the protected cysteine residues. They have great potential for usage in many different fields such as surface modifications, tissue engineering, and drug transport systems because hydrophobins are surfactants and soluble in harsh mediums. In this study, it was aimed to determine the hydrophobin proteins responsible for the hydrophobicity of the super-hydrophobic fungi isolates in the culture medium and to carry out the molecular characterization of the hydrophobin producer species. As a result of measuring surface hydrophobicity by determining the water contact angle, five different fungi with the highest hydrophobicity were classified as Cladosporium by classical and molecular (ITS and D1-D2 regions) methods. Also, protein extraction according to the recommended method for obtaining hydrophobins from spores of these Cladosporium species indicated that the isolates have similar protein profiles. Ultimately, the isolate named A5 with the highest water contact angle was identified as Cladosporium macrocarpum, and the 7 kDa band was appointed as a hydrophobin since it was the most abundant protein in protein extraction for this species. [ABSTRACT FROM AUTHOR]

The increasing demand for customized products is a core driver of novel automation concepts in Industry 4.0. For the case of machining complex free-form workpieces, e.g., in die making and mold making, individualized manufacturing is already the industrial practice. The varying process conditions and demanding machining processes lead to a high relevance of machining domain experts and a low degree of manufacturing flow automation. In order to increase the degree of automation, online process monitoring and the prediction of the quality-related remaining cutting tool life is indispensable. However, the varying process conditions complicate this as the correlation between the sensor signals and tool condition is not directly apparent. Furthermore, machine learning (ML) knowledge is limited on the shop floor, preventing a manual adaption of the models to changing conditions. Therefore, this paper introduces a new method for remaining tool life prediction in individualized production using automated machine learning (AutoML). The method enables the incorporation of machining expert knowledge via the model inputs and outputs. It automatically creates end-to-end ML pipelines based on optimized ensembles of regression and forecasting models. An explainability algorithm visualizes the relevance of the model inputs for the decision making. The method is analyzed and compared to a manual state-of-the-art approach for series production in a comprehensive evaluation using a new milling dataset. The dataset represents gradual tool wear under changing workpieces and process parameters. Our AutoML method outperforms the state-of-the-art approach and the evaluation indicates that a transfer of methods designed for series production to variable process conditions is not easily possible. Overall, the new method optimizes individualized production economically and in terms of resources. Machining experts with limited ML knowledge can leverage their domain knowledge to develop, validate and adapt tool life models. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle voltage-gated potassium (Kv) channels have been proposed to contribute to myogenic autoregulation. Surprisingly, in initial experiments, we observed that the Kv2 channel inhibitor stromatoxin induced vasomotion without affecting myogenic tone. Thus, we tested the hypothesis that Kv2 channels contribute to myogenic autoregulation by fine-tuning the myogenic response. Expression of Kv2 channel mRNA was determined using real-time PCR and 'multiplex' single-cell RT-PCR. Potassium currents were measured using the patch-clamp technique. Contractile responses of intact arteries were studied using isobaric myography. Expression of Kv2.1 but not Kv2.2 channels was detected in intact rat superior cerebellar arteries and in single smooth muscle cells. Stromatoxin, a high-affinity inhibitor of Kv2 channels, reduced smooth muscle Kv currents by 61% at saturating concentrations (EC50 36 nmol/L). Further, stromatoxin (10–100 nmol/L) induced pronounced vasomotion in 48% of the vessels studied. In vessels not exhibiting vasomotion, stromatoxin did not affect myogenic reactivity. Notably, in vessels exhibiting stromatoxin-induced vasomotion, pressure increases evoked two effects: First, they facilitated the occurrence of random vasodilations and/or vasoconstrictions, disturbing the myogenic response (24% of the vessels). Second, they modified the vasomotion by decreasing its amplitude and increasing its frequency, thereby destabilizing myogenic tone (76% of the vessels). Our study demonstrates that (i) Kv2.1 channels are the predominantly expressed Kv channels in smooth muscle cells of rat superior cerebellar arteries, and (ii) Kv2.1 channels provide a novel type of negative feedback mechanism in myogenic autoregulation by preventing vasomotion and thereby safeguarding the myogenic response. [ABSTRACT FROM AUTHOR]

Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calcium-activated potassium (BKCa) channels were proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their auditory alterations was not specifically addressed. Furthermore, studies on the acoustic phenotypes of FXS animal models mostly focused on central rather than peripheral auditory pathways. Here, we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of adult mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle phenotype with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs) compared to their wild-type (WT) littermates. BKCa expression was markedly reduced in the IHCs of KOs compared to WT mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to adult hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs. [ABSTRACT FROM AUTHOR]

The ergosterol pathway is a promising target for the development of new antifungals since its enzymes are essential for fungal cell growth. Appropriate screening assays are therefore needed that allow the identification of potential inhibitors. We developed a whole-cell screening method, which can be used to identify compounds interacting with the enzymes of isoprenoid biosynthesis, an important part of the ergosterol biosynthesis pathway. The method was validated according to the EMEA guideline on bioanalytical method validation. Aspergillus fumigatus hyphae and Saccharomyces cerevisiae cells were lysed mechanically in an aqueous buffer optimized for the enzymatic deconjugation of isoprenoid pyrophosphates. The residual alcohols were extracted, silylated and analyzed by GC-MS. The obtained isoprenoid pattern provides an indication of the inhibited enzyme, due to the accumulation of specific substrates. By analyzing terbinafine-treated A. fumigatus and mutant strains containing tunable gene copies of erg9 or erg1, respectively, the method was verified. Downregulation of erg9 resulted in a high accumulation of intracellular farnesol as well as elevated levels of geranylgeraniol and isoprenol. The decreased expression of erg1 as well as terbinafine treatment led to an increased squalene content. Additional analysis of growth medium revealed high farnesyl pyrophosphate levels extruded during erg9 downregulation. [ABSTRACT FROM AUTHOR]

Objective: People who hear voices (auditory verbal hallucinations) often have post-traumatic stress disorder (PTSD) symptoms. Cognitive behavioural therapies (CBT) have yielded inconsistent findings when treating voices and PTSD symptoms in voice hearers. Preliminary evidence suggests imagery rescripting (ImRs) is associated with large reductions in voice hearing and PTSD symptoms. This study replicated past studies using a larger sample to examine the effectiveness of ImRs in reducing such symptoms., Method: Participants (N = 49; 65.3% female; M age  = 35.86) were clients at an Australian transdiagnostic clinic for voice hearers. A one-arm open trial design was used with three pre-treatment baselines and a mid-treatment, post-treatment and 3-month follow up assessments of PTSD symptoms (Posttraumatic Diagnostic Scale for DSM-5), voices (Hamilton Program for Schizophrenia Voices Questionnaire) and emotional symptoms (Depression Anxiety and Stress Scales-21). Five single-item measures were administered weekly to explore the trajectories of change in trauma intrusions, voice-related distress, voice frequency and positive and negative voice valance., Results: ImRs was associated with very large reductions in PTSD symptoms and voices (both emotional and physical characteristics of voices) and emotional symptoms at post-treatment and follow-up (η 2 p  = 0.24-0.44). There were medium-large to large reductions in weekly symptoms of intrusions, voice-related distress, voice frequency and negative voices (η 2 p  = 0.12-0.16) and a non-significant increase in positive voices (η 2 p  = 0.05)., Conclusions: This study provides further evidence that ImRs is an effective treatment for voices and PTSD symptoms in voice hearers with a range of diagnoses. Randomised controlled trials are needed to compare the efficacy of ImRs to CBT protocols., (© 2024 The Author(s). Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Ergot alkaloids are a large family of fungal specialized metabolites that are important as toxins in agriculture and as the foundation of powerful pharmaceuticals. Fungi from several lineages and diverse ecological niches produce ergot alkaloids from at least one of several branches of the ergot alkaloid pathway. The biochemical and genetic bases for the different branches have been established and are summarized briefly herein. Several pathway branches overlap among fungal lineages and ecological niches, indicating activities of ergot alkaloids benefit fungi in different environments and conditions. Understanding the functions of the multiple genes in each branch of the pathway allows researchers to parse the abundant genomic sequence data available in public databases in order to assess the ergot alkaloid biosynthesis capacity of previously unexplored fungi. Moreover, the characterization of the genes involved in the various branches provides opportunities and resources for the biotechnological manipulation of ergot alkaloids for experimentation and pharmaceutical development. [ABSTRACT FROM AUTHOR]

Hydrophobins are small-secreted proteins comprising both hydrophobic and hydrophilic parts, that can self-assemble into an amphiphilic film at the air-liquid interface. More than 20 hydrophobin genes have been estimated in the white-rot fungus Pleurotus ostreatus. In our previous studies, three hydrophobin genes were shown to be predominantly expressed under ligninolytic conditions, and only vmh3 was downregulated in both the delignification-deficient mutant Δ gat1 and Δ hir1 strains. Here, we focused on the function of the hydrophobin Vmh3 to clarify its physiological role in lignin degradation. When the hyphae were observed by transmission electron microscopy, deletion of vmh3 resulted in the disappearance of black aggregates at the interface between the cell wall and outer environment. Deletion of vmh3 resulted in reduced hydrophobicity when 0.2% sodium dodecyl sulfate was dropped onto the mycelial surface. These results suggest that Vmh3 functions on the cell surface and plays a major role in mycelial hydrophobization. Furthermore, the Δ vmh3 strain showed a marked delay in lignin degradation on beech wood sawdust medium, while the production of lignin-modifying enzymes was not reduced. This study demonstrated, for the first time, the possible effect of hydrophobin on lignin degradation by a white-rot fungus. [ABSTRACT FROM AUTHOR]

Migraine is a primary headache disorder ranked as the leading cause of years lived with disability among individuals younger than 50 years. The aetiology of migraine is complex and might involve several molecules of different signalling pathways. Emerging evidence implicates potassium channels, predominantly ATP-sensitive potassium (KATP) channels and large (big) calcium-sensitive potassium (BKCa) channels in migraine attack initiation. Basic neuroscience revealed that stimulation of potassium channels activated and sensitized trigeminovascular neurons. Clinical trials showed that administration of potassium channel openers caused headache and migraine attack associated with dilation of cephalic arteries. The present review highlights the molecular structure and physiological function of KATP and BKCa channels, presents recent insights into the role of potassium channels in migraine pathophysiology, and discusses possible complementary effects and interdependence of potassium channels in migraine attack initiation. [ABSTRACT FROM AUTHOR]

Detecting the field maturity moment for maize (Zea mays L.) crop represents a relevant point to estimate its optimal harvest time. Knowing the optimal harvest time (defined by grain moisture content) at the end of the crop season is a major concern for maize farmers, as it could lead to substantial economic losses if not harvested on time. For this crop, optimal harvest time usually occurs 3–4 weeks after field maturity, depending on weather conditions. Therefore, this study focused on the interferometric coherence time-series analysis at the end of the maize crop season, to indirectly estimate the field maturity. For such purpose, a coherence object-based change detection method using Sentinel-1 SAR images was developed aiming to estimate the potential field maturity time. These estimations were assessed using an independent data set of field maturity dates obtained through field inspection and crop growth modelling. The technique was tested over 52 fields in the northwest region of Kansas, United States, with a detection rate of 80%, and a field maturity estimation error of 10 days (assessed with the root mean square error). The proposed method constitutes a promising approach to estimating the maize field maturity in near-real time, determining the field harvest readiness, and developing a decision support tool to assist farmers in prioritizing the allocation of fields at harvest time. [ABSTRACT FROM AUTHOR]

BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we discuss current evidence highlighting the physiological importance of this ubiquitous channel in regulating brain function and its role in the pathophysiology of different neurological disorders. [ABSTRACT FROM AUTHOR]

B References b Wolfsgruber, W., Feil, S., Brummer, S., Kuppinger, O., Hofmann, F., Feil, R. 2003, 'A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells.', I Proc Natl Acad Sci USA, 100 i (23), 13519-13524 Segura-Puimedon, M., Mergia, E., Al-Hasani, J., Aherrahrou, R., Stoelting, S., Kremer, F., Freyer, J., Koesling, D., Erdmann, J., Schunkert, H., de Wit, C., Aherrahrou, Z. 2016, 'Proatherosclerotic effect of the alpha1-subunit of soluble guanylyl cyclase by promoting smooth muscle phenotypic switching.', I Am J Pathol, 186 i (8), 2220-2231 Lukowski, R., Weinmeister, P., Bernhard, D., Feil, S., Gotthardt, M., Herz, J., Massberg, S., Zernecke, A., Weber, C., Hofmann, F., Feil, R. 2008, 'Role of smooth muscle cGMP/cGKI signaling in murine vascular restenosis.', I Arterioscler Thromb Vasc Biol, 28 i (7), 1244-1250 Thunemann, M., Wen, L., Hillenbrand, M., Vachaviolos, A., Feil, S., Ott, T., Han, X., Fukumura, D., Jain, R. K., Russwurm, M., de Wit, C., Feil, R. 2013, "Transgenic mice for cGMP imaging.", I Circ Res, 113 i (4), 365-371 P23 Heme Redox switch impacts the binding of sGC stimulators to H-NOX domain Garyfallia I. Makrynitsa1, Aikaterini I. Argyriou1, Aikaterini A. Zompra1, Konstantinos Salag... 1University of Patras, Department of Pharmacy, Rio/Patras, Greece; 2National and Kapodistrian... Correspondence: Garyfallia I. Makrynitsa (garyfalliamkrn@gmail.com) I J Transl Med i 2022, B 21(1) b :P23 I Published in: Front Cell Dev Biol, 2022;10:925457. i https://doi.org/10.3389/fcell.2022.925457. [Extracted from the article]

Introduction: Visual hallucinations (VH) are more common than previously thought and are linked to higher levels of distress and disability in people with a psychotic illness. Despite this, scant attention has been given to VHs in the clinical literature, and the few therapy case series of cognitive behavioural therapy (CBT) published to date have not demonstrated reliable change. In other areas of clinical research, problematic mental imagery has been found to be more strongly related to negative affect in psychological disorders than negative linguistic thinking, and imagery focused techniques have commonly been found to improve the outcomes in CBT trials. Given VHs have many similarities with visual mental imagery and many of the distressing beliefs associated with VHs targeted in CBT are maintained by accompanying mental imagery (i.e., imaging a hallucinated figure attacking them), it seems plausible that an imagery-focused approach to treating VHs may be most effective., Methods: The current study is a multiple baseline case series (N = 11) of a 10-session imagery-focused therapy for VH in a transdiagnostic sample., Results: The study had good attendance and feedback, no adverse events and only one [seemly unrelated] drop-out, suggesting good feasibility, safety and acceptability. The majority of clients reported reduction on both full-scale measures (administered at 3 baselines, midtherapy, posttherapy and 3-month follow-up) and weekly measures of VH severity and distress, ranging from medium to large effect sizes., Conclusions: The case series suggests that an imagery-focused approach to treating VHs may be beneficial, with a recommendation for more rigorous clinical trials to follow., (© 2024 The Authors. Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Ligamentous Lisfranc injuries cause debilitating pain and loss of function. Even small diastasis of this normally rigid joint after injury requires surgical treatment, but outcomes remain poor. Existing literature has compared the different surgical procedures using cadaveric models, but no approach has been recommended over others. This study uses a computational biomechanical approach consistent with a cadaveric study to evaluate the different procedures' ability to stabilize the Lisfranc joint without inducing secondary consequences. A validated rigid body model for the cadaver foot with a Lisfranc injury was extended to compare the stability of four different surgical repairs—three open reduction and internal fixation procedures with different hardware (cannulated screws, endobuttons, and screws with a dorsal plate) and primary arthrodesis with screws. Forces calculated from the rigid body model for 50% partial weight bearing provided boundary conditions for a finite element model of the surgical repairs. Comparing the different surgical procedures, the open reduction and internal fixation with screws and primary arthrodesis with screws showed the most stable postoperative Lisfranc joint. However, the use of cannulated screws for fixation showed regions of high stress that may be susceptible to breakage and also resulted in higher contact forces in joints adjacent to the surgery site. Endobuttons and dorsal plates did not restore sufficient stability. Since all procedures showed different points of concern that could impact outcomes, additional surgical approaches could be needed in the future. This study offers a standard protocol for benchmarking the new procedures against those currently used. [ABSTRACT FROM AUTHOR]

Locus coeruleus (LC) neurons, with their extensive innervations throughout the brain, control a broad range of physiological processes. Several ion channels have been characterized in LC neurons that control intrinsic membrane properties and excitability. However, ERG (ether-à-go-go–related gene) K+ channels that are particularly important in setting neuronal firing rhythms and automaticity have not as yet been discovered in the LC. Moreover, the neurophysiological and pathophysiological roles of ERG channels in the brain remain unclear despite their expression in several structures. By performing immunohistochemical investigations, we found that ERG-1A, ERG-1B, ERG-2 and ERG-3 are highly expressed in the LC neurons of mice. To examine the functional role of ERG channels, current-clamp recordings were performed on mouse LC neurons in brain slices under visual control. ERG channel blockade by WAY-123,398, a class III anti-arrhythmic agent, increased the spontaneous firing activity and discharge irregularity of LC neurons. Here, we have shown the presence of distinct ERG channel subunits in the LC which play an imperative role in modulating neuronal discharge patterns. Thus, we propose that ERG channels are important players behind the changes in, and/or maintenance of, LC firing patterns that are implicated in the generation of different behaviors and in several disorders. [ABSTRACT FROM AUTHOR]

Spiking neural networks were introduced to understand spatiotemporal information processing in neurons and have found their application in pattern encoding, data discrimination, and classification. Bioinspired network architectures are considered for event-driven tasks, and scientists have looked at different theories based on the architecture and functioning. Motor tasks, for example, have networks inspired by cerebellar architecture where the granular layer recodes sparse representations of the mossy fiber (MF) inputs and has more roles in motor learning. Using abstractions from cerebellar connections and learning rules of deep learning network (DLN), patterns were discriminated within datasets, and the same algorithm was used for trajectory optimization. In the current work, a cerebellum-inspired spiking neural network with dynamics of cerebellar neurons and learning mechanisms attributed to the granular layer, Purkinje cell (PC) layer, and cerebellar nuclei interconnected by excitatory and inhibitory synapses was implemented. The model's pattern discrimination capability was tested for two tasks on standard machine learning (ML) datasets and on following a trajectory of a low-cost sensor-free robotic articulator. Tuned for supervised learning, the pattern classification capability of the cerebellum-inspired network algorithm has produced more generalized models than data-specific precision models on smaller training datasets. The model showed an accuracy of 72%, which was comparable to standard ML algorithms, such as MLP (78%), Dl4jMlpClassifier (64%), RBFNetwork (71.4%), and libSVM-linear (85.7%). The cerebellar model increased the network's capability and decreased storage, augmenting faster computations. Additionally, the network model could also implicitly reconstruct the trajectory of a 6-degree of freedom (DOF) robotic arm with a low error rate by reconstructing the kinematic parameters. The variability between the actual and predicted trajectory points was noted to be ± 3 cm (while moving to a position in a cuboid space of 25 x 30 x 40 cm). Although a few known learning rules were implemented among known types of plasticity in the cerebellum, the network model showed a generalized processing capability for a range of signals, modulating the data through the interconnected neural populations. In addition to potential use on sensor-free or feed-forward based controllers for robotic arms and as a generalized pattern classification algorithm, this model adds implications to motor learning theory. [ABSTRACT FROM AUTHOR]

Ogilvie's syndrome, also known as acute colonic pseudo-obstruction (ACPO), is a rare, nonobstructive dilation of the colon of unclear etiology. We present the case of a patient who presented with Ogilvie's syndrome and significant hypokalemia due to colonic loss despite repletion. This case report demonstrates the difficulty in diagnosis, treatment, and outcome. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic brain disease that makes serious cognitive and motor retardation. Ion channels affect the occurrence of epilepsy in various ways, but the mechanisms have not yet been fully elucidated. Transient receptor potential melastain2 (TRPM2) ion channel is a non-selective cationic channel that can permeate Ca2+ and critical for epilepsy. Here, TRPM2 gene knockout mice were used to generate a chronic kindling epilepsy model by PTZ administration in mice. We found that TRPM2 knockout mice were more susceptible to epilepsy than WT mice. Furthermore, the neuronal excitability in the hippocampal CA1 region of TRPM2 knockout mice was significantly increased. Compared with WT group, there were no significant differences in the input resistance and after hyperpolarization of CA1 neurons in TRPM2 knockout mice. Firing adaptation rate of hippocampal CA1 pyramidal neurons of TRPM2 knockout mice was lower than that of WT mice. We also found that activation of Kv7 channel by retigabine reduced the firing frequency of action potential in the hippocampal pyramidal neurons of TRPM2 knockout mice. However, inhibiting Kv7 channel increased the firing frequency of action potential in hippocampal pyramidal neurons of WT mice. The data suggest that activation of Kv7 channel can effectively reduce epileptic seizures in TRPM2 knockout mice. We conclude that genetic knockout of TRPM2 in hippocampal CA1 pyramidal neurons may increase neuronal excitability by inhibiting Kv7 channel, affecting the susceptibility to epilepsy. These findings may provide a potential therapeutic target for epilepsy. [ABSTRACT FROM AUTHOR]

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of KC currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept. [ABSTRACT FROM AUTHOR]

Previous works showed that opioid peptides are produced by olivocochlear efferent neurons, while cochlear hair cells express opioid receptors. It has been proposed that opioids protect the auditory system from damage by intense stimulation, although their use for therapeutic or illicit purposes links to hearing impairment. Therefore, it is relevant to study the effect of opioids in the auditory system to define their functional expression and mechanism of action. This study investigated the modulation of the Ca2+ currents by opioid peptides in the rat outer hair cells (OHC) using the whole‐cell patch‐clamp technique. The influence of agonists of the three opioid receptor subtypes (μ, δ, and κ) was studied. The κ opioid receptor agonist U‐50488 inhibits the Ca2+ currents in a partially reversible form. Coincidently, norbinaltorphimine (a κ receptor antagonist) blocked the U‐50488 inhibitory effect on the Ca2+ current. The δ and the μ opioid receptor agonists did not significantly affect the Ca2+ currents. These results indicate that the κ opioid receptor activation inhibits the Ca2+ current in OHC, modulating the intracellular Ca2+ concentration when OHCs depolarize. The modulation of the auditory function by opioids constitutes a relevant mechanism with a potential role in the physiopathology of auditory disturbances. [ABSTRACT FROM AUTHOR]

Mutations in ion channel genes underlie a number of human neurological diseases. Historically, human mutations in ion channel genes, the so-called channelopathies, have been identified to cause episodic disorders. In the last decade, however, mutations in ion channel genes have been demonstrated to result in progressive neurodegenerative and neurodevelopmental disorders in humans, particularly with ion channels that are enriched in the cerebellum. This was unexpected given prior rodent ion channel knock-out models that almost never display neurodegeneration. Human ataxia-causing channelopathies that result in even haploinsufficiency can result in cerebellar atrophy and cerebellar Purkinje neuron loss. Rodent neurons with ion channel loss-of-function appear to, therefore, be significantly more resistant to neurodegeneration compared to human neurons. Fundamental differences in susceptibility of human and rodent cerebellar neurons in ataxia-causing channelopathies must therefore be present. In this review, we explore the properties of human neurons that may contribute to their vulnerability to cerebellar degeneration secondary to ion channel loss-of-function mutations. We present a model taking into account the known allometric scaling of neuronal ion channel density in humans and other mammals that may explain the preferential vulnerability of human cerebellar neurons to degeneration in ataxia-causing channelopathies. We also speculate on the vulnerability of cerebellar neurons to degeneration in mouse models of spinocerebellar ataxia (SCA) where ion channel transcript dysregulation has recently been implicated in disease pathogenesis. [ABSTRACT FROM AUTHOR]

Claviceps purpurea produces many pharmacologically important ergot alkaloids (EAS), which are widely used to treat migraine and hypertension and to aid childbirth. Although an EAS biosynthetic cluster of C. purpurea has been discovered more than 20 years ago, the complete biosynthetic pathway of EAS has not been fully characterized until now. The main obstacle to elucidating this pathway and strain modification is the lack of efficient genome-editing tools for C. purpurea. The conventional gene manipulation method for C. purpurea relies on homologous recombination (HR), although the efficiency of HR in C. purpurea is very low (~1-5%). Consequently, the disruption of target genes is laborious and time-consuming. Although CRISPR/Cas9 genome-editing methods based on in vivo Cas9 expression and gRNA transcription have been reported recently, their genedisruption efficiency is still very low. Here, we developed an efficient genome-editing system in C. purpurea based on in vitro assembled CRISPR/Cas9 gRNA ribonucleoprotein complexes. As proof of principle, three target genes were efficiently knocked out using this CRISPR/Cas9 ribonucleoprotein complex-mediated HR system, with editing efficiencies ranging from 50% to 100%. Inactivation of the three genes, which are closely related to uridine biosynthesis (ura5), hypha morphology (rac), and EAS production (easA), resulted in a uridine auxotrophic mutant, a mutant with a drastically different phenotype in axenic culture, and a mutant that did not produce EAS, respectively. Our ribonucleoprotein-based genome-editing system has a great advantage over conventional and in vivo CRISPR/Cas9 methods for genome editing in C. purpurea, which will greatly facilitate elucidation of the EAS biosynthetic pathway and other future basic and applied research on C. purpurea. [ABSTRACT FROM AUTHOR]

The 3′,5′‐cGMP pathway triggers cytoprotective responses and improves cardiomyocyte survival during myocardial ischaemia and reperfusion (I/R) injury. These beneficial effects were attributed to NO‐sensitive GC induced cGMP production leading to activation of cGMP‐dependent protein kinase I (cGKI). cGKI in turn phosphorylates many substrates, which eventually facilitate opening of mitochondrial ATP‐sensitive potassium channels (mitoKATP) and Ca2+‐activated potassium channels of the BK type (mitoBK). Accordingly, agents activating mitoKATP or mitoBK provide protection against I/R‐induced damages. Here, we provide an up‐to‐date summary of the infarct‐limiting actions exhibited by the GC/cGMP axis and discuss how mitoKATP and mitoBK, which are present at the inner mitochondrial membrane, confer mito‐ and cytoprotective effects on cardiomyocytes exposed to I/R injury. In view of this, we believe that the functional connection between the cGMP cascade and mitoK+ channels should be exploited further as adjunct to reperfusion therapy in myocardial infarction. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc [ABSTRACT FROM AUTHOR]

cGMP is generated by the cGMP‐forming guanylyl cyclases (GCs), the intracellular nitric oxide (NO)‐sensitive (soluble) guanylyl cyclase (sGC) and transmembrane GC (e.g. GC‐A and GC‐B). In summarizing the particular role of cGMP signalling for hearing, we show that GC generally do not interfere significantly with basic hearing function but rather sustain a healthy state for proper temporal coding, fast discrimination and adjustments during injury. sGC is critical for the integrity of the first synapse in the ascending auditory pathway, the inner hair cell synapse. GC‐A promotes hair cell stability under stressful conditions such as acoustic trauma or ageing. GC‐B plays a role in the development of efferent feed‐back and gain control. Regarding the crucial role hearing has for language development, speech discrimination and cognitive brain functions, differential pharmaceutical targeting of GCs offers therapeutic promise for the restoration of hearing. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc [ABSTRACT FROM AUTHOR]