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The blood-brain barrier (BBB) restricts systemically delivered therapeutic antibodies into the brain. Here the authors engineer antibody Fc region to promote the binding to BBB expressed neonatal Fc receptor (FcRn) at neutral pH, therefore improving brain penetration and brain targeting efficacy both in mice and non-human primates.

The mechanism underlying YAP/TAZ transactivation remains to be explored. Here the authors report that the hydrophobic transcriptional activation domains of YAP/TAZ exert dual functions on transcriptional initiation and elongation through interactions with TAF4 and MED15, which could be targeted for anti-cancer therapy.

Late-stage acute liver failure (ALF) has limited therapies. The authors show that the bioactive compound SCM-198 extends the ALF treatment window from 3 to 24 hours in mice by selectively targeting the identified AdipoR2-CaM-CaMKII-NOS3-NO axis.

Here the authors show structures of the vesicular acetylcholine transporter in its apo state and in complex with the substrate acetylcholine and the inhibitor vesamicol, providing insights into substrate recognition, proton coupling and conformational transition mechanisms.

Understanding the reprogramming of gene expression and metabolism is critical for the success of somatic embryogenesis-based plant tissue regeneration. Here, the authors report single-cell RNA-sequencing, spatial transcriptomics and spatial metabolomics analyses during cotton somatic embryo development.

There are limited therapeutics available for treatment of mpox. In this study, the authors identify two non-competing human neutralizing monoclonal antibodies with protective effects against orthopoxvirus infection in a mouse model and structurally resolve the targeted epitope within the MPXV B6 protein.

AcrIF25 inhibits the type I-F CRISPR–Cas system by disassembling its ribonucleoprotein effector complex without an external energy source.

The SMN protein recognizes symmetric dimethylarginine by its Tudor ___domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor ___domain and disrupts the interaction between SMN and RNA Polymerase II.

The CRISPR/Cas system is an RNA-guided bacterial protection system against foreign nucleic acids of bacterial and archaeal origin; here a high-resolution crystal structure of the CRIPSR RNA–Cas complex shows that the CRIPSR RNA plays an essential role not only in target recognition but also in complex assembly.

Anti-CRISPR proteins can help to evade bacterial immunity. Here, the authors elucidate the mechanism of AcrIIA15, which inhibits CRISPR-Cas9 system and also functions as a transcriptional repressor of itself as a fusion protein.

Gut microbiota-derived succinate promotes CitC succinyltransferase-dependent succinylation of PurR to alleviate T3SS repression and promote virulence in enterohaemorrhagic Escherichia coli and Citrobacter rodentium.

Transposon-associated inverted repeats play a role in drought resistance and yield-related traits in maize.

The innate immune system relies on a series of specific receptors that recognize RNAs that might come from viruses. The structure of the C terminal ___domain of one such receptor, RIG-I, in complex with 5'ppp-dsRNA, now indicates the basis of recognition of the observable 5'pp-RNA, through interactions that are shown to be needed for tight binding and a cellular response to this trigger.

Domain insertion into the loop region of AcrIIC1 leads to a variant with enhanced inhibitory activity toward Neisseria meningitides Cas9, while structure-guided design turns AcrIIC1 into a potent inhibitor of Staphylococcus aureus Cas9.

Anti-CRISPR proteins offer the means of regulating CRISPR-Cas9 activity. Here the authors present the structure and biochemical characterisation of AcrIIC2_Nme alone and in complex with Cas9.

F₁F_o-ATP synthase is a key enzyme for energy production in fungi. Here, the authors show that the δ subunit of the enzyme is required for Candida albicans lethal infection and represents a potential therapeutic target.

SOS1 is a unique electroneutral Na⁺ /H⁺ antiporter at the plasma membrane of higher plants and plays a central role in resisting salt stress. Here, the authors report the structures of SOS1 in occluded state, identify the key autoinhibitory elements, and elucidate their molecular mechanism.

Sodium/proton exchanger 1 (NHE1) and its obligate binding partner Calcineurin B-homologous protein 1 (CHP1) regulate intracellular pH and volume homeostasis. Structures of the human NHE1-CHP1 complex offer insight into the regulation of NHE1 pH-sensitivity by CHP1 and into the interactions with NHE1 inhibitors.

SETDB1 is a histone methyltransferase that generates H3K9me3 marks in euchromatic regions. Here the authors show that the triple Tudor ___domain (3TD) of SETDB1 binds histone H3 tails containing K14 acetylation combined with K9 methylation, and that the K9me–K14ac modification defines a novel chromatin state enriched at SETDB1 binding sites.

Exposure to early variants of SARS-CoV-2 results in immune imprinting in mouse models and in humans, reducing neutralizing antibody titres against Omicron variants, which could be mitigated with multiple updated boosters.

Discovery of a chemical probe targeting the PWWP ___domain of NSD2 reveals insight into mechanisms that govern NSD2 localization. The compound and its negative control represent valuable tools for further defining NSD2 biology.

Oncoprotein SS18-SSX is a hallmark of synovial sarcoma. Here the authors report phase separation of SS18-SSX and the binding of SS18-SSX to chromatin remodeling complex are important for the transformation activity of the oncoprotein SS18-SSX.

Cryo-EM structures of the human pentameric glycosylphosphatidylinositol transamidase (GPIT) complex reveal its subunit assembly and its catalytic and GPI-binding sites.

CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.

Cas12i, class 2 type V CRISPR-Cas system protein, uses a single RuvC ___domain for cleavage of both strands of target DNA. Structures of Cas12i2–crRNA–DNA complexes not only provide insight into the mechanism of DNA recognition and cleavage by Cas12i2, but also the DNA cleavage mechanism by RuvC-containing Cas proteins.

The influenza A H3N2 subtype protein NS1 possesses a short sequence resembling the N-terminal tail of histone H3 that is used to hijack host proteins. Here, Qin et al.establish the structural basis for the imperfect NS1 mimicry, which allows the virus to target only a subset of chromatin interactors.

MLL3 and MLL4 are members of the SET1/MLL family of histone H3K4 methyltransferases, which are responsible for monomethylating histone H3K4 on enhancers. Here the authors show that an extended PHD ___domain (ePHD₆) in MLL3 and MLL4 specifically recognizes an H4H18-containing fragment of histone H4, and that modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4.

Chromodomains in chromatin-associated proteins act as ‘readers’ of methylated lysines within histones. Structural and computational design led to the identification of UNC3866, a potent, cell-active peptide-based inhibitor of the methyllysine reading functions of CBX and CDY chromodomains.

Na_V1.3 is involved in neuronal development, hormone secretion and pain perception. Here, the authors elucidate the molecular mechanism for modulation of Na_V1.3 by a site-2 neurotoxin bulleyaconitine A and a subtype selective antagonist ICA121431.

Met¹-linked linear ubiquitination (M¹-Ubi) is catalyzed by linear ubiquitin chain assembly complex (LUBAC). Here the authors show that Ago2 protein is M¹-Ubi modified by LUBAC complex under hypoxia condition leading to less association of miRNA target mRNAs to Ago2 protein and de-repression of miRNA targets.

Neurons compute by integrating synaptic inputs across their dendritic arbor. Here, the authors show that distinct cell-types of mouse retinal ganglion cells that receive similar excitatory inputs have different biophysical mechanisms of input integration to generate their unique response tuning.

DNA hydrogels have received considerable attention in analytical science but limitations still exist in the applications of intelligent hydrogels. Here, the authors describe a DNA hydrogel sensor for quantitative detection of cocaine based on the permeability change in a DNA hydrogel film.

The hypoxic microenvironment in solid tumors limits the efficacy of photodynamic therapy (PDT) since oxygen is necessary to produce high cytotoxic singlet oxygen species. Here, the authors develop an improved self-assembled single-atom nanozyme which allows oxygen generation to enhance PDT efficacy.

The Ca_V2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human Ca_V2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.

Ye and colleagues show that an oncolytic virus that delivers tumor-irrelevant bystander T cell epitopes to tumor cells can exploit the abundant population of bystander T cells in the tumor for anti-tumor immunity and potentiate cancer immunotherapy.

The sperm flagellum is composed of tubulin-based microtubules and is critical for sperm motility and thus male fertility. Here, the authors show that STYXL1 regulates CCT complex-facilitated tubulin folding and is essential for sperm flagella formation.

Excitatory amino acid transporter 2 (EAAT2) mediates glutamate uptake in the synapse. Here, authors report cryo-EM structures of the human EAAT2 in complexes with glutamate or selective inhibitor WAY-213613, revealing important insights into substrate recognition and selective inhibition.

Crops with broad-spectrum resistance to multiple diseases are highly desirable in agricultural production. This study reports a natural gene variant that produces a proteasome maturation factor and improves rice resistance to four notorious pathogens.

As part of the miRNA-generating machinery, TARBP2 stabilizes the RNA-induced silencing complex (RISC) loading complex (RLC). Here, Chen et al.show that sumoylation of TARBP2 regulates RNAi efficiency by increasing precursor miRNAs loaded on RLC.

The authors report the structures of glutamate-gated kainate receptors in complex with NETO2 in both the resting and the desensitized states and reveal how kainate receptors in the brain are regulated by NETO2.

Mice are able to discriminate colors, at least in the upper visual field. Here, the authors provide a comprehensive characterization of retinal circuits underlying this behavior.

Nucleolar stress can disrupt ribosome biogenesis and in turn energy metabolism and lipid storage, but how this is regulated is unclear. Here, the authors show in C. elegans that the transcription factor PHA-4/FOXA acts as a sensor for nucleolar stress and can regulate expression of lipogenic genes