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Here, using deep mutagenesis and cryo-EM, the authors unveil an autoinhibited conformation of a clamp loader from T4 bacteriophage, which is characterized by disassembled catalytic sites and blocked DNA binding.

Structural and single-molecule analyses show the CTPase, KorB, is a sliding DNA clamp that interacts with a clamp-locking protein KorA to inhibit gene expression over distances of more than 1 kb in the multi-drug resistance RK2 plasmid.

A strategy for isolating Escherichia coli ribosome–nascent chain complexes and analyzing their conformational dynamics and interactors at peptide level using hydrogen–deuterium exchange mass spectrometry is presented.

Antibodies that lock KRAS mutants in inactive conformations facilitate drug discovery.

CNS toxicity was unexpectedly observed for anti-miR-17 RGLS4326 in nonclinical studies. Here, authors identify AMPA receptor inhibition as the likely culprit. Replacement of 3’-terminus guanine to adenine leads to discovery of farabursen (RGLS8429) that is devoid of CNS toxicity.

Photovoltaic devices attached to immune cells travel through the blood to inflamed brain regions.

Dinoflagellates and cyanobacteria produce saxitoxin (STX) congeners that block voltage-gated sodium channels. Here authors show how amphibians may sequester STX congeners using a ‘lock and key’ mode, expanding the understanding of toxic sponge action.

The parallel intracellular recording of neurons via an array of 4,096 microhole electrodes on a semiconductor chip enables the large-scale mapping of synaptic connections, as shown with rat neuronal cultures.

Acute pancreatitis is a serious inflammatory disease, which is more severe in diabetic mice. Here the authors use mice lacking pancreatic acinar cell insulin receptors to show that this may be because insulin preserves glycolytic energy supply in acinar cell during pancreatitis, which prevents cytotoxic calcium overload and cell death.

Fragile X syndrome and autism spectrum disorders are associated with circuit hyperexcitability, however, its cellular and synaptic bases are not well understood. Here, the authors report abnormal synaptogenesis with an increased prevalence of polysynaptic spines with normal morphology in a mouse model of fragile X.

Transcription-coupled repair (TCR) removes DNA lesions from actively transcribed strands. Here, the authors unveil the structural basis for coordinated TFIIH recruitment to the TCR machinery and the role of ubiquitin modifications in directing the response toward DNA repair or proteasomal degradation.

Coagulase-negative staphylococci secrete natural products that prevent pathogen colonization. Here, the authors identify hominicin, a daptide bacteriocin produced by Staphylococcus hominis that has antimicrobial activity against a skin pathogen.

An electronic interface with 4,096 electrodes can intracellularly record postsynaptic potentials and action potentials from thousands of connected mammalian neurons in vitro.

Selective activation of the hepatoportal nerve plexus via peripheral focused ultrasound stimulation improves glucose homoeostasis and enhances glucose tolerance and utilization in rodent models of diabetes and in swine.

The SLC45A4 gene encodes a neuronal polyamine transporter and is linked to pain response in humans and mice.

Temporal and spatial integration of synaptic inputs onto dendrites can display linear, sublinear and supralinear motifs in vitro. A study now examines this issue in vivo in mouse binocular visual cortex. It shows that dendritic integration of binocular information is sublinear, leading to a divisive form of gain control that linearizes the output of binocular neurons and enhances orientation selectivity.

The p3 peptide, Aβ(17-40/42), rapidly forms amyloid fibrils by secondary nucleation which cross-seeds with full-length Aβ peptide. Furthermore, p3 annular and oligomer structures are cytotoxic, disrupt membrane integrity and form ion-channel pores.

The biological mechanisms of rehabilitation after stroke are not fully understood. Here authors identify parvalbumin interneurons as a key mediator of rehabilitation-induced stroke recovery and a drug targeting these neurons as a potential therapy.

Channelrhodopsins’ mechanism of light-gated ion conductance could be engineered for use in optogenetic tools. Here, structures of the slow-cycling mutant of HcKCR1, including an open state structure, provide insight into channel gating and selectivity.

The wireless and photoelectrochemical stimulation of primary rat dorsal root ganglion neurons is demonstrated by shining laser light onto coaxially doped silicon nanowires deposited on the neuronal membrane.

VARNAM is a red-shifted genetically encoded voltage sensor based on the Ace opsin. It is applied in Drosophila, mouse brain slices and behaving mice. It can be readily combined with blue-light-sensitive tools for dual-color applications.

Somatosensory hypersensitivity in Fmr-1 knockout mice is thought to arise from an increase in cortical circuit excitability. Here, the authors report that the loss of precision of sensory encoding in the Layer 4 of barrel cortex is the primary developmental circuit alteration that drives the other compensatory circuit dysfunction.

Photocaged molecules have advantages in terms of temporal and spatial control compared to conventional pharmacological compounds. The authors present a synthetic saxitoxin derivative affixed to a photocleavable group for precise modulation of Na channels.

A genome-wide analysis of replication profiles in different budding yeast mutants reveals that the alternative clamp loader component Ctf18 has a key role in the DNA replication checkpoint, acting together with Mrc1 to promote Rad53 phosphorylation.

Cryo-electron microscopy determination of anthrax toxin protective antigen pore structure at a resolution of 2.9 Å, revealing the catalytic Φ-clamp and the membrane-spanning translocation channel.

Cocaine-context associations rely on nucleus accumbens neuronal ensembles with engram-like properties unique to distinct stages of memory encoding. Here the authors show that ensemble reactivation parallels recall and selectively engages transcriptional plasticity programs.

Although cortical GABAergic interneuron (CIN) dysfunction is implicated in several neuropsychiatric disorders, we still know very little about how they attain their unique properties or how their dysfunction impacts neuropsychiatric disorders. In this study, authors show that conditional loss of Tsc1, causes SST+ CINs, which are distinct from PV+ CINs, to express PV and adopt fast-spiking properties, via MTOR activity

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

DNA packaging into nucleosomes presents a barrier to many motor proteins, including the transcriptional machinery. By unzipping DNA in single nucleosomes, a detailed map at near base pair resolution of histone-DNA interactions is now provided, suggesting that interaction with the two DNA strands is decoupled and that unraveling past the dyad axis of the nucleosome, as might occur when a motor protein passes through, is sufficient to displace histones.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

Using Xenopus epidermis as a model, John Wallingford and colleagues show that the planar cell polarity protein Dishevelled, acting in concert with Inturned and Rho, controls the apical positioning of basal bodies. Subsequently, Dvl and Rho are also required for directional ciliary beating, suggesting that a common signaling apparatus governs both apical docking and planar polarization of basal bodies.

Song and colleagues show that FDA-approved cough suppressant dextromethorphan could be used as an agonist of sigma non-opioid intracellular receptor 1 (SIGMAR1) to normalize the action potential in human cellular models and a mouse model of Timothy syndrome, a congenital disease with no available treatment. The researchers also show that dextromethorphan normalizes the action potential in human cellular models of two additional inherited cardiac arrhythmias: long QT syndrome types 1 and 2, which are caused by mutations in different genes.

In this study, the authors show that two K⁺ channels, SK3 and GIRK, are important for the pheromone-induced activation of olfactory neurons in the vomeronasal organ (VNO). In addition, they show that K⁺ ion concentrations are maintained at high levels in the VNO lumen, permitting inward K⁺ flux through these channels.

Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of Na_V1.7.