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Alkenes are essential functional groups in organic chemistry, featuring well-defined geometries and bond orders of 2. In this study, cubene and 1,7-quadricyclene are calculated to possess unusual hyperpyramidalized geometries and low alkene bond orders near 1.5. Their resultant high reactivities ultimately permit access to intricate scaffolds and new chemical space.

VRACs are ubiquitously expressed osmosensitive ion channels assembled from LRRC8A-E subunits. Here, the authors determine the structures of a LRRC8A:D VRAC using cryo-EM and identified that these channels are gated by lipids inside the channel pore.

The enzyme PCMT1 was found to install a C-terminal cyclic imide modification on proteins that marks them for degradation by CRBN, uncovering a conserved protein turnover pathway with implications in metabolism and neurological function.

Genomic deletions in poxviruses are not well understood, the authors found large deletions in >2% of Mpox virus genomes during routine surveillance, highlighting their role in poxvirus evolution and potential impact on diagnostics and therapeutics.

Hepatitis C virus utilizes flavin adenine dinucleotide as a non-canonical initiating nucleotide for the viral RNA polymerase, resulting in 5′ capping of viral RNA, which provides protection against the host innate immune response.

Recently published results from a Phase I trial showed the blood brain barrier could be transiently opened in glioblastoma patients using low-intensity ultrasound and microbubbles. Here, the authors develop a microfluidic chip to capture tumour-derived extracellular vesicles and particles in response to paclitaxel treatment.

DNA double strand breaks result in various types of damaged termini and are resolved by non-homologous end joining, but how cells coordinate the different steps that occur during repair is not clear. Here the authors show that a DNA ligase coordinates processing prior to the ligation step to limit errors.

Christina Termini’s tweet on her do-it-yourself system for managing lab inventory went viral. Here’s how to implement the tool.

The main protease, a key enzyme of SARS-CoV-2, can protect itself from oxidative damage. Here, Reinke, Schubert, and colleagues used XFEL radiation to image the enzyme, revealing the disulfide and NOS/SONOS bonds that form in response to oxygen.

The contribution of central and peripheral channels of nuclear pores to transport of transmembrane proteins is unclear. Here the authors show that most inner nuclear membrane proteins use only peripheral channels, but some extend nuclear localization signals into the central channel for directed nuclear transport.

C-terminal cyclic imides are physiological degrons that enable the ubiquitin E3 ligase adapter protein cereblon to target substrates for degradation.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

piggyBat is the only known DNA transposon active in mammals. Here the authors used cellular assays and 3D structure to show that sequences within the transposon ends restrict activity, and also how transposition activity can be substantially increased.

PepMLM designs peptide binders against diverse targets using masked language modeling.

Most agents that generate breaks in DNA leave 'dirty ends' that cannot be joined immediately; instead, intervening steps are required to restore the integrity of nucleotides at the break. Here it is shown that the non-homologous end joining pathway requires a 5′-dRP/AP lyase activity to remove abasic sites at double-strand breaks. Surprisingly, this activity is catalysed by the Ku70 protein, which, together with its partner Ku86, had been thought only to recognize broken DNA ends and to recruit other factors that process ends.

Newly formed endosomes mature into early endosomes by shedding one protein and acquiring another. Here, the authors describe a trigger-and-convert mechanism driven by endosomal collisions and fusions that govern timeliness in ensemble maturations.

By learning to embed DNA k-mers and cells into a joint space, CellSpace improves single-cell ATAC-seq analysis in multiple tasks such as latent structure discovery, transcription factor activity inference and batch effect mitigation.

Bacteria can secrete diffusible protein toxins that kill competing bacteria. Here, the authors use biochemical, biophysical and structural analyses to show how one of these toxins exploits TolC (a major antibiotic efflux channel) to transport itself across the outer membrane of target cells.

Specific tissues are developed by legumes during symbiosis to host soil bacteria that will fix nitrogen from air. One single t-SNARE gene in Medicago can switch from a housekeeping to a symbiosome-specific function by alternative transcription.

In human cells, P5B‐ATPases execute export of spermine from lysosomes to the cytosol, but the mechanisms of spermine recognition, uptake and transport remain elusive. Here the authors present cryo‐EM structures of a yeast homolog of human ATP13A2‐5, Ypk9, which depict three separate transport cycle intermediates, including spermine‐bound conformations

In this phase 1 trial of a personalized, neoantigen-specific autologous T cell therapy, BNT221, when given as monotherapy in patients with metastatic melanoma refractory to PD-1 and CTLA-4 inhibitor regimens, the therapy was safe and showed preliminary clinical activity and neoantigen-specific T cell responses.

Targeted protein degradation uses small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation, but only a few human E3 ligases are amenable to this strategy. Here, the authors identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12, containing an FKBP12 ligand appended with a flexible alkylamine tail that is metabolized to an active aldehyde species which recruits the SCF^FBXO22 ligase for FKBP12 degradation.

Understanding the human antibody response to influenza A virus strains is important for vaccine development. Here, Creanga et al. generate a panel of 55 replication-deficient reporter viruses representing diversity of human H1N1 and H3N2, and pandemic subtypes and characterize the neutralization profile of 24 antibodies and polyclonal sera.

Agonists of the orexin receptor 2 (OX₂R) show promise in the treatment of narcolepsy. Cryo-EM structures of active-state OX₂R bound to an endogenous peptide agonist and a small-molecule agonist suggest a molecular mechanism that rationalizes both receptor activation and inhibition.

Gram-positive bacterial envelopes comprise proteinaceous surface layers (S-layers) important for survival and virulence that are often anchored to the cell wall through secondary cell wall polymers. Here the authors use a structural and biophysical approach to define the molecular mechanism of this important interaction.

An investigation of plant receptor-like kinases identifies regions of these proteins that control whether immune or symbiotic signalling pathways are activated, with minimal changes to specific residues in one of these regions being sufficient to alter signalling specificity.

Monoclonal antibodies targeting the conserved neuraminidase catalytic site mimic sialic acid and use coordinated water molecules to inhibit diverse influenza A and B viruses, including H5N1, providing broad prophylactic protection in mice.

Tools for imaging and manipulating proteins in their native environments are critical to understand their function. Here, the authors develop antibody-based probes to visualize and manipulate AMPA-type glutamate receptors in neurons.

Ni, Wei, Vona and colleagues use human brain organoids to dissect patient AIRIM variants associated with neurodevelopmental features. A subset of variants impaired ribosome production and protein synthesis, and delayed radial glial cell specification.

A disulfide tethering screen identified a molecule that covalently interacts with pro-apoptotic BAX at C126, inhibiting its activation.

Bleeding complications limits the use of effective antithrombotics therapeutics. Here, the authors developed next-generation direct thrombin inhibitors with low bleeding risks as safe peri-percutaneous coronary intervention anticoagulants when used in combination with antiplatelets.

Haematopoietic stem cells (HSCs) are used in a variety of cellular therapies, but our ability to support these cells ex vivo remains technically challenging. A new study discovers that inhibiting ferroptosis promotes HSC expansion ex vivo and applies these findings to HSC transplant and gene editing approaches.

A new synthetic method provides a coveted motif, the bicyclo[2.1.1]hexane scaffold, using the uncommon coupling of two strained diradicaloid fragments: transiently generated cyclic allenes and bicyclo[1.1.0]butanes.

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.

Prediction of HLA class I epitopes is improved in accuracy and breath with peptidomes from 95 mono-allelic cell lines.

Alternative splicing expands the genetic coding capacity and proteomic diversity of the cell. Here the authors create a synthetic biology platform for regulating four programmable exons in modular transcription factors.

It is unclear how incoming influenza viruses counteract the cells’ first line of defence, the interferon (IFN) response. Here Liedmann et al.show that a distinct amino-acid motif in polymerases PB1 and PA, which are packaged in the viral particles, inhibit early IFN induction.

The molecular heterogeneity of glycosylated biotherapeutics often complicates analysis by intact mass spectrometry. Here, the authors propose a simplified procedure for characterization that employs proton transfer charge reduction. Integration with glycomic and glycopeptide datasets can further provide glycoform-level information.

Cryo-EM analyses together with liposome and cellular assays reveal that human ATG9A forms a trimer that mediates phospholipid flipping and promotes autophagosome membrane expansion.

A structural and functional study including a mutational analysis of C. elegans POFUT2 with GDP and a peptide substrate helps explain how this and other fucosyltransferases recognize protein substrates with diverse sequences.

Synaptic assembly depends on trans-synaptic Neurexin/Neuroligin signalling. Here, Muhammad et al. show that Spinophilin, a pre-synaptic scaffolding protein, interacts with Neurexin, in competition with Syd-1, to regulate the formation and function of synaptic active zones at Drosophilaneuromuscular junctions.

Single-stranded RNA viruses are responsible for the common cold, cancer, AIDS and other serious health threats. The genomes of these viruses form conserved secondary structures that have functional and regulatory roles, but most potential regulatory elements in viral RNA genomes remain uncharacterized. Here however, the structure of an entire HIV-1 genome at single nucleotide resolution is reported.

Therapeutic modulation of the complement system has gained interest over the past two decades. Here, the authors provide molecular-level insight into the mode-of-action, target selectivity and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.