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| Open AccessEffects of oxidative stress on hepatic encephalopathy pathogenesis in mice
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE). Here, authors show that the chemogenetic inhibition of GAD2 population in the SNr region, or the targeted overexpression of mitochondrial UCP2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug Mito-Q could effectively ameliorate HE.
- Yunhu Bai
- , Kenan Li
- & Yanling Yang
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Article
| Open AccessCytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr
The neuronal RNA-binding protein Ptbp2 is known to regulate neuronal differentiation by modulating alternative splicing. Here, the authors reveal an additional role of cytosolic Ptbp2, which regulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein hnRNP R.
- Saeede Salehi
- , Abdolhossein Zare
- & Michael Sendtner
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Article
| Open AccessBlood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson’s disease
Understanding molecular processes behind variable clinical features of Parkinson’s disease is valuable. Distinct molecular patterns in the brains, reflected in the blood, reveal mechanisms linked to clinical diversity in cognitive and motor decline.
- Krithi Irmady
- , Caryn R. Hale
- & Robert B. Darnell
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Article
| Open AccessDefining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution
The choroid plexus (ChP) modulates cerebrospinal fluid (CSF) composition and the blood-CSF barrier. Here the authors show that the ChP is a critical circadian component with time-of-day variations in translation, barrier, and metabolism to alter CSF composition.
- Ryann M. Fame
- , Peter N. Kalugin
- & Maria K. Lehtinen
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Article
| Open AccessDrosophila motor neuron boutons remodel through membrane blebbing coupled with muscle contraction
Neuronal remodeling is critical for neuronal function. Here, the authors report that motor neurons use membrane blebbing coupled to muscle contraction as a mechanism for synaptic bouton formation, suggesting that mechanical force plays a key role in neuronal remodeling.
- Andreia R. Fernandes
- , João P. Martins
- & Rita O. Teodoro
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| Open AccessCochlear transcript diversity and its role in auditory functions implied by an otoferlin short isoform
The repertoire of mRNA isoforms in the cochlea remains unknown. Here, authors generated a full-length transcriptome atlas by ScISOr-seq, identified and studied Otof short isoform, extended our understanding of auditory function in isoform resolution.
- Huihui Liu
- , Hongchao Liu
- & Hao Wu
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Article
| Open AccessMultisite regulation integrates multimodal context in sensory circuits to control persistent behavioral states in C. elegans
Animals must integrate multiple inputs to switch between behavioral states. Here, authors discover two C. elegans behavioral states and reveal a common regulatory logic through which they are controlled according to multimodal environmental changes.
- Saurabh Thapliyal
- , Isabel Beets
- & Dominique A. Glauser
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Article
| Open AccessGlycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation
Drosophila are able to survive for several weeks in the absence of glial glycolysis. Here, the authors show that glial cells can utilize fatty acids to supply neurons under restrictive conditions and glial cells act as a metabolic sensor and induce mobilization of peripheral energy stores.
- Ellen McMullen
- , Helen Hertenstein
- & Stefanie Schirmeier
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Article
| Open AccessTwo single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1
TRPV1 is a noxious heat sensor. Here, authors showed that tailed amphibians express TRPV1 with a reduced heat-activation threshold by substitution of two amino acids in the N-terminal region to contribute to cool-habitat selection.
- Shogo Hori
- , Michihiro Tateyama
- & Osamu Saitoh
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Article
| Open AccessSingle-cell analysis reveals inflammatory interactions driving macular degeneration
Single-nucleus RNA-seq was used to profile 11 retinas with varying stages of age-related macular degeneration and 6 control retinas. The authors identified shared glial states across neurodegeneration, indicating that the retina provides a human system for investigating therapeutic approaches in neurodegeneration.
- Manik Kuchroo
- , Marcello DiStasio
- & Brian P. Hafler
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Article
| Open AccessSymport and antiport mechanisms of human glutamate transporters
Ion gradients power the neurotransmitter transport by brain glutamate transporters. Here, the authors report cryo-EM structures of the EAAT3 transporter isoform with and without the ions and the neurotransmitter, revealing the coupling mechanisms.
- Biao Qiu
- & Olga Boudker
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Article
| Open AccessStructural basis for the self-recognition of sDSCAM in Chelicerata
Combining structural, biochemical, and cellular evidence, the authors elucidate the self-recognition mechanism of a neuronal receptor sDSCAM and provide insights into the evolutionary landscape of the cell recognition molecule diversity.
- Jie Cheng
- , Yamei Yu
- & Qiang Chen
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Article
| Open AccessNeural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice
Effective stress regulation is essential for the survival of vertebrates. Here, the authors show that the lateral habenula trace aminergic signalling activates the mesolimbic pathway through suppressing the rostromedial tegmental nucleus to manage stress.
- Soo Hyun Yang
- , Esther Yang
- & Hyun Kim
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Article
| Open AccessmiR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala
The role of miRNAs in regulating brain stress response remains relatively unexplored. Here the authors show that miR-483-5p-mediated repression of Pgap2 in amygdala of male mice offsets the functional and behavioural consequences of stress.
- Mariusz Mucha
- , Anna E. Skrzypiec
- & Robert Pawlak
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Article
| Open AccessControl of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
Cannabis impacts our brain by engaging the CB1 receptor. Here, the authors identify a protein called GAP43 that interacts with CB1 and blocks its synaptic functions. This finding provides a conceptual view to understand how CB1 acts in the brain.
- Irene B. Maroto
- , Carlos Costas-Insua
- & Manuel Guzmán
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Article
| Open AccessHippocampal sharp wave ripples underlie stress susceptibility in male mice
Stressful memories are a possible factor to induce psychiatric symptoms. Here, the authors demonstrate that stress susceptibility is related to memory consolidation mechanisms in the ventral hippocampus.
- Nahoko Kuga
- , Ryota Nakayama
- & Takuya Sasaki
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Article
| Open AccessParkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase
Mutations in the human ATP13A2, a lysosomal ATPase, is associated with pathogenesis of Parkinson’s disease. Here, the authors show that ATP13A2 functions as H + /K + transporting protein, preventing lysosomal alkalinization and α-synuclein accumulation.
- Takuto Fujii
- , Shushi Nagamori
- & Hideki Sakai
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Article
| Open AccessA combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop
The presynaptic release probability is a major determinant of synaptic transmission in brain. Here, the authors show that a trans-synaptic signaling complex comprising presynaptic Neurexin-3 and postsynaptic dystroglycan controls the release probability of diverse inhibitory synapses.
- Justin H. Trotter
- , Cosmos Yuqi Wang
- & Thomas C. Südhof
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Article
| Open AccessModulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.
- Danyang Zhang
- , Remigijus Lape
- & Ingo H. Greger
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Article
| Open AccessUNC-43/CaMKII-triggered anterograde signals recruit GABAARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs
The pre-and postsynaptic communication is critical for faithful synaptic transmission and induction of synaptic plasticity. Here, the authors found that CaMKII functions at GABAergic neurons to recruit GABAARs by triggering anterograde signals.
- Yue Hao
- , Haowen Liu
- & Xia-Jing Tong
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Article
| Open AccessTwo-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle
During Gq protein activation, the separated Gαq-GTP forms a stable complex with the ligand-activated hM3R and PLCβ. Here the authors demonstrate that a single M3 receptor FRET probe can display the real-time conformational dynamics of innate receptor by the downstream Gq protein cycle.
- Yong-Seok Kim
- , Jun-Hee Yeon
- & Byung-Chang Suh
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Article
| Open AccessParabrachial tachykinin1-expressing neurons involved in state-dependent breathing control
Breathing is controlled automatically but is also conditionally integrated with behavior and emotion in awake animals. Here, authors identify brainstem neurons that are important for controlling awake-state-dependent breathing patterns in mice.
- Joseph W. Arthurs
- , Anna J. Bowen
- & Nathan A. Baertsch
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Article
| Open AccessAstrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice
The role of glycolysis in depression is unclear. Here the authors report a glycolytic deficit under social stress and demonstrate that astrocytic LDHA affects neuronal excitability and depressive-like behaviours via lactate homeostasis in mice.
- Shan Yao
- , Min-Dong Xu
- & Xiang-Dong Sun
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Article
| Open AccessAn updated suite of viral vectors for in vivo calcium imaging using intracerebral and retro-orbital injections in male mice
Genetically encoded Ca2+ indicators (GECIs) are used to measure neural activity. Here, authors screen GECI constructs for suitability with systemic injections and soma-targeting, and modify a soma-targeting peptide for improved expression rate.
- Sverre Grødem
- , Ingeborg Nymoen
- & Marianne Fyhn
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| Open AccessMolecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3
The CaV2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human CaV2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.
- Yiwei Gao
- , Shuai Xu
- & Yan Zhao
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Article
| Open AccessSynaptic vesicle proteins and ATG9A self-organize in distinct vesicle phases within synapsin condensates
ATG9 is the only transmembrane protein of the core autophagy machinery known to be present at presynapses. Here, the authors show that both synaptophysin and ATG9A vesicles assemble into condensates with synapsin but remain segregated from each other.
- Daehun Park
- , Yumei Wu
- & Pietro De Camilli
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Article
| Open AccessConcerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions
LRRTM1 is a post synaptic adhesion protein, that promotes AMPA receptor mediated synaptic transmission. Here the authors show that LRRTM1 and the adhesion molecule SynCAM 1 act together to organize synapses in the prefrontal cortex with relevance for cognitive function in mice.
- Karen Perez de Arce
- , Adema Ribic
- & Thomas Biederer
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Article
| Open AccessRabphilin-3A undergoes phase separation to regulate GluN2A mobility and surface clustering
GluN2A and GluN2B, two predominant Glu2N subunits of NMDARs in hippocampus and cortex, display distinct organization and mobility in the neuronal surface. Here, authors show Rph3A, a GluN2A-specific binding protein, undergoes liquid-liquid phase separation, which regulate mobility, synaptic and extrasynaptic surface clustering, synaptic localization and synaptic response of GluN2A.
- Lei Yang
- , Mengping Wei
- & Chen Zhang
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Article
| Open AccessPost-transcriptional control of a stemness signature by RNA-binding protein MEX3A regulates murine adult neurogenesis
Here the authors identify RNA-binding protein MEX3A as a post-transcriptional regulator of quiescence and differentiation signatures at critical transitions along the murine subependymal neurogenic lineage
- Ana Domingo-Muelas
- , Pere Duart-Abadia
- & Isabel Fariñas
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Article
| Open AccessTranscriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease
In human and mouse models of Huntington’s disease, Matsushima, Pineda et al. show, using snRNAsequencing, the two axes defining identities of striatal projection neurons are multiplexed and differentially compromised, calling for distinct therapies.
- Ayano Matsushima
- , Sergio Sebastian Pineda
- & Ann M. Graybiel
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Article
| Open AccessmGluR5 is transiently confined in perisynaptic nanodomains to shape synaptic function
The subsynaptic organization of group I mGluRs modulates their activation and downstream signaling, essential for synaptic transmission and plasticity. Here, the authors describe how the C-terminal domain of mGluR5 controls its dynamic organization in perisynaptic nanodomains, and prevents mGluR5 form entering the synapse, allowing mGluR5 to finely tune synaptic signalling.
- Nicky Scheefhals
- , Manon Westra
- & Harold D. MacGillavry
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Article
| Open AccessMolecular subtypes of ALS are associated with differences in patient prognosis
Variability in ALS disease onset and progression are poorly understood. Our work identifies three distinct molecular states in post-mortem tissue that capture some of the observed differences in patient age of onset and survival.
- Jarrett Eshima
- , Samantha A. O’Connor
- & Barbara S. Smith
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Article
| Open AccessCell type diversity in a developing octopus brain
The brain cell types of Octopus vulgaris that control their sophisticated behavioral repertoire are still unknown. Here, authors use single-cell transcriptomics to profile neuronal and glial cell types and compare cell type relationships within the octopus brain and across species.
- Ruth Styfhals
- , Grygoriy Zolotarov
- & Eve Seuntjens
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Article
| Open AccessSOTIP is a versatile method for microenvironment modeling with spatial omics data
Methods that analyse heterogeneity and compare tissue microenvironments using spatial omics data are challenging to develop. Here, the authors present SOTIP, a method that can perform spatial heterogeneity, spatial domain, and differential microenvironment analyses across multiple spatial omics modalities.
- Zhiyuan Yuan
- , Yisi Li
- & Michael Q. Zhang
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Article
| Open AccessAscertaining cells’ synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries
Synaptic connections are critical for brain function but are hard to measure systematically. Here, authors present a method which uses rabies virus barcoding and single-cell RNAseq to parallelize monosynaptic network reconstruction from molecularly-profiled single cells.
- Arpiar Saunders
- , Kee Wui Huang
- & Steven A. McCarroll
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Article
| Open AccessIdentification of visual cortex cell types and species differences using single-cell RNA sequencing
The laminar organization of macaque V1 cortex is similar to that seen in humans. Here the authors describe a single-cell RNA sequencing dataset of macaque V1 cortex cells.
- Jia-Ru Wei
- , Zhao-Zhe Hao
- & Sheng Liu
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Article
| Open AccessSexually dimorphic architecture and function of a mechanosensory circuit in C. elegans
Mechanosensation is crucial for survival in many organisms. Here, authors reveal that the two sexes of C. elegans show dramatic differences in circuit architecture, neuronal activity and molecular components to drive mechanosensory behavior.
- Hagar Setty
- , Yehuda Salzberg
- & Meital Oren-Suissa
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Article
| Open AccessThe 3D structure of lipidic fibrils of α-synuclein
Interactions between α-synuclein fibrils and lipids have been associated with the development of Parkinson’s disease. This cryo-EM study reveals structural details of these interactions and suggests a mechanism for fibril-induced lipid extraction.
- Benedikt Frieg
- , Leif Antonschmidt
- & Gunnar F. Schröder
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Article
| Open AccessAn alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons
Krach et al. dissect the molecular mechanism of the alternative splicing modulator Branaplam in Huntington’s disease. They show that the drug lowers mutant HTT protein levels and ameliorates alternative splicing pathology in an iPSC disease model.
- Florian Krach
- , Judith Stemick
- & Juergen Winkler
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Article
| Open AccessCerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia.
- Jessica Gracias
- , Funda Orhan
- & Carl M. Sellgren
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Article
| Open AccessA hypothalamic dopamine locus for psychostimulant-induced hyperlocomotion in mice
The psychostimulant-sensitive neural mechanism linking the circadian clock to locomotion is unknown. Here, hypothalamic A14 neurons are shown to time diurnal activity by entraining the lateral septum, and their activity is shown to be sensitive to amphetamine.
- Solomiia Korchynska
- , Patrick Rebernik
- & Roman A. Romanov
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Article
| Open AccessSingle cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons
Matson et al. performed single nucleus sequencing of the “spared” spinal cord tissue distal to an injury in mice. They found that spinocerebellar neurons expressed a pro-regenerative gene signature and showed axon outgrowth after injury.
- Kaya J. E. Matson
- , Daniel E. Russ
- & Ariel J. Levine
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Article
| Open AccessThe clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils
Understanding how small molecules bind to pathological aggregates is of importance for therapeutic and diagnostic development in diseases such as Parkinson’s Disease. Here, the authors reveal a binding site of anle138b to lipid-induced α-synuclein fibrils.
- Leif Antonschmidt
- , Dirk Matthes
- & Loren B. Andreas
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Article
| Open AccessRetromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau
Tau and the Retromer complex are both linked to Parkinson’s and Alzheimer’s disease. Using Drosophila neurodegeneration models, this study finds that low retromer activity induces a specific increase of a highly toxic truncated form of human Tau.
- Jamshid Asadzadeh
- , Evelyne Ruchti
- & Brian D. McCabe
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Article
| Open AccessA direct excitatory projection from entorhinal layer 6b neurons to the hippocampus contributes to spatial coding and memory
The mammalian hippocampal formation plays a key role in several higher brain functions. Here, the authors show that excitatory neurons in layer 6b of the mouse EC project to all sub-regions comprising the hippocampal formation and receive input from the CA1, thalamus and claustrum.
- Yoav Ben-Simon
- , Karola Kaefer
- & Peter Jonas
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Article
| Open AccessAβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy
Loss of excitatory synapses occur prior to the formation of amyloid plaques in Alzheimer’s disease. Here the authors show in an animal model that the loss of synapses induced by amyloid-beta oligomers requires over-activation of a stress-response pathway inducing structural remodelling of mitochondria in dendrites of cortical and hippocampal neurons.
- Annie Lee
- , Chandana Kondapalli
- & Franck Polleux
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Article
| Open AccessOrexin neurons inhibit sleep to promote arousal
Sleep and wakefulness is stabilized by a population of orexin-expressing neurons. In this study, the authors demonstrate how these neurons drive arousal by silencing sleep-promoting neurons in the ventrolateral preoptic nucleus.
- Roberto De Luca
- , Stefano Nardone
- & Elda Arrigoni
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Article
| Open AccessInhibition of NMDA receptors through a membrane-to-channel path
Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.
- Madeleine R. Wilcox
- , Aparna Nigam
- & Jon W. Johnson
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Article
| Open AccessHumidity response in Drosophila olfactory sensory neurons requires the mechanosensitive channel TMEM63
Humidity detection is a feature of many species. Here the authors show that in Drosophila, Or42b neurons, located in sensilla with humidity-dependent shape act as humidity sensors via the mechanically gated channel TMEM63.
- Songling Li
- , Bingxue Li
- & Zhiqiang Yan