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Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

An anti-HIV-1 antibody that targets an N332_gp120 glycan-independent V3 epitope, a site of Env vulnerability, can decline viremia in HIV-1-infected humanized mice while overcoming classical V3 escape mutations.

Langstein-Skora, Schmid, Huth et al. propose that intrinsically disordered region functionality can be driven by the interplay between linear binding motifs and contextual chemical characteristics such as charge and hydrophobicity.

Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into molecular glue degraders.

Here the authors show that transient cell cycle arrest reprograms CD8⁺ T cells into a highly energized state, increasing proliferation and antitumor activity and boosting efficacy of immunotherapies in cancer models.

The authors describe the discovery of a series of potent non-competitive allosteric inhibitors of the ZIKV NS2B-NS3 protease, which exhibit antiviral activity in vitro and robust oral efficacy against ZIKV infections in a mouse model.

A bottleneck in high-throughput chemical synthesis is analyzing reaction products. This protocol describes a direct mass spectrometry approach where the loss of a characteristic neutral fragment from a starting material defines product analysis.

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

This study shows how the bacterial retron Eco2 defends against viruses. Phage nucleases trigger activation of Eco2, which cuts RNAs, shuts down protein production and stops phage replication.

Natural and sexual selection can be in opposition favouring different trait sizes, but disentangling these processes empirically is difficult. Here Okada et al. show that predation on males shifts the balance of selection in experimentally evolving beetle populations, disfavoring a sexually-selected male trait but increasing female fitness.

Bessler et al. developed a human organoid model for H3.3K27M-altered diffuse midline glioma that recapitulates key tumor features and demonstrated its utility for modeling CAR T cell and microglia functions.

The authors report on engineering metazoan fatty acid synthase variants with tunable selectivity to obtain short- and medium-chain fatty acids, alcohols and aldehydes. Pairing these optimized enzymes with a yeast strain designed for efficient β-oxidation yields high production levels of medium-chain fatty acids.

Allosteric transcription factors (aTFs) are promising tools for environmental and human health monitoring. Here the authors develop a multi-objective, machine learning-guided method to engineer an aTF-based portable diagnostic for environment sensing of lead in drinking water at the legal limit.

Klein and colleagues characterize 04_A06, a new V_H1-2-encoded broadly neutralizing antibody that has marked breadth and potency against extended multiclade HIV-1 pseudovirus panels and can maintain full viral suppression in HIV-1-infected humanized mice.

In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.

Presence of peritoneal metastasis is associated with a decreased survival in patients with colorectal cancer. Here, the authors show that peritoneal-resident macrophages promote the formation of an immunosuppressive environment that facilitate peritoneal metastasis in colorectal cancer.

An intestinal organoid model recapitulates human microfold (M) cell function and transcriptomic profiling and biochemical assays demonstrate that M cells uptake and present antigens to the immune system via the class II major histocompatibility complex.

This study presents a BRET biosensor that measures how anticancer drugs cooperatively engage PRMT5 complexes in cells, revealing how cellular metabolites such as SAM and MTA enhance drug action and enable precision therapies for MTAP-deleted tumors.

The antibiotic polymyxin B requires bacterial metabolic activity to cause sufficient damage to the outer membrane to access the inner membrane, which it permeabilizes via an energy-independent mechanism to kill the cell.

Molecular glues are monovalent compounds that can recruit a protein of interest to an E3 ligase so the protein of interest can be targeted for degradation. Here, Hughes et al. identify a molecule that selectively and potently degrades BRD9.

In a phase 1b/2 trial, an off-the-shelf vaccine using gorilla adenoviral and modified vaccinia Ankara vectors with over 200 mutated peptides known to be present in persons with mismatch-repair-deficient tumors is safe and elicits neoantigen-specific T cells in individuals with Lynch syndrome.

Spatial and temporal variations among individual human cell proteomes are comprehensively mapped across the cell cycle using proteomic imaging and transcriptomics.

Using brain organoids models, Prigione and colleagues uncovered the impact of Huntington’s disease on human brain developmental and identified early dysregulation of CHCHD2, which disrupted mitochondria and might serve as a therapeutic target.

Stanage et al. identify a role for transfer RNA nuclease SLFN11 in replication-stress-induced cell death in cisplatin-treated cells lacking PrimPol. SLFN11 is activated upon single-stranded DNA accumulation at stalled forks followed by replication protein A exhaustion and cell death.

CAR-T cells are engineered to express CBD-IL-12 upon STEAP1 recognition to enhance tumour-specific immune responses in mice.

This study provides new insights into the role of endoglin (ENG) as a co-receptor in endothelial cells and addresses a gap-in-knowledge on how ENG could be involved in both TGF-β and BMP9 signalling. Such knowledge greatly facilitates therapeutic targeting of ENG-related pathways.

A method termed ac⁴C-seq is introduced for the transcriptome-wide mapping of the RNA modification N⁴-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.

An effective CRISPR RNA occlusion strategy enhances mismatch detection when using Cas13.

Cellular target engagement technologies enable quantification of intracellular drug binding, but the simultaneous assessment of drug-associated phenotypes is challenging. Here, the authors develop CeTEAM (cellular target engagement by accumulation of mutant), a platform that can simultaneously evaluate drug-target interactions and phenotypic responses for holistic assessment of drug pharmacology using conditionally stabilized drug biosensors.

Bartonella bacilliformis, a bacterium endemic in South America, causes the deadly Oroya fever, marked by massive red blood damage. This study identifies that porin A and α/β-hydrolase are important bacterial proteins in driving this hemolytic process.

Gram-negative bacteria use a multiprotein complex, LptB₂FGC, to transport lipopolysaccharides (LPS) to the outer membrane. Here, Fiorentino et al. present cryo-EM structures of the complex from Pseudomonas aeruginosa, revealing species-specific features and providing insights into LPS transport mechanisms.

The chemical complexity of post-consumer ‘mixed’ plastic waste limits its use as a feedstock for biomanufacturing. Here the authors combine transition-metal-free plastic deconstruction with a microbial consortium platform to upcycle real-world mixed plastic waste into value-added chemicals.

Targeted protein degradation using PROTACs doesn’t discriminate functional from disease-causing versions of the same protein. Here, we describe small molecule TRIMTACs that recruit the unique E3 ligase TRIM21 and allow state-selective protein degradation, including challenging substrates like tau.

Replicating intercellular communication in synthetic cells is challenging. Here, the authors report on engineered connexin nanopores that can be controlled with light to exchange distinct chemical signals between synthetic cells, creating programmable communication networks that mimic cellular interactions.

Human metapneumovirus (hMPV) can cause severe acute respiratory illness in children but effective therapeutic monoclonal antibodies require further exploration. The authors here isolate a panel of monoclonal antibodies from children previously infected with hMPV, test their in vitro neutralizing potency, reveal their cryo-EM structures and manifest their in vivo prophylactic efficacy.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

Engineering polymerases to synthesize alternative genetic polymers remains a challenging problem in synthetic biology. The current study offers insights into the structural and biochemical changes responsible for improving the fidelity and catalytic activity of a laboratory evolved TNA polymerase.

The effect of new viral mutations on T cell responses remains unclear. Here, Balogh et al. show that most new mutations in SARS-CoV-2 are C > U, a bias that leads to an enhanced T cell response.

MethyLYZR, an epigenetic classifier of brain tumors, provides clinically relevant cancer classification results within 15 min of sequencing, with potential applications for neurosurgical intraoperative use.

The impact of ACKR3 constitutive activity is unknown. Here, the authors suppress basal ACKR3 activity using inverse agonistic nanobodies to stabilize an inactive conformation and revealing a role for ACKR3 in basal cell motility.

This study reports a modular-cloning-based platform for high-throughput chloroplast engineering in Chlamydomonas reinhardtii that allows large-scale characterization of genetic parts and prototyping of new traits, as demonstrated for the photorespiration pathway.

Regulatory T cells (Tregs) are known for suppressing inflammatory processes, but their full capacity for tissue regeneration is yet to be harnessed. Here, the authors demonstrate the efficiency of Tregs in facilitating tissue healing in mouse models of bone, muscle, and skin injury, with monocytes/macrophages and interleukin-10 playing a key mechanistic role in the process.

LaccID, an engineered laccase, enables hydrogen-peroxide-free proximity labeling and electron microscopy (EM) in mammalian cells. Notably, LaccID is selectively active at the cell surface, enabling the mapping of the dynamic T cell–tumor surfaceome and its use as a genetically encodable EM tag, expanding the toolkit for cell-based imaging and proteomics.

High-throughput screening and hit optimization have led to the development of a small molecule, CIM-834, that targets the SARS-CoV-2 membrane protein and blocks assembly of the virus.

Tumour-antigen-pulsed mature dendritic cells (DC) have not been as efficient for cancer therapy as hoped to be, due to their sub-optimal antigen-presentation and migration capacities. Here the authors utilise DC progenitors, constitutively expressing IL-12 and an engineered extracellular vesicle-internalizing receptor (EVIR), which give rise to mature conventional type 1 DCs with improved antigen presenting capacities, resulting in improved anti-tumour immunity in a mouse model of melanoma.

In this study, the authors develop a flavivirus vaccine strategy by introducing mutations into envelope glycoproteins resulting in structural changes that conceal the ADE-prone fusion loop epitope. They show that the Zika virus-specific construct protects mice against viral challenge and prevents ADE by Dengue virus.

Fusion genes involving KMT2A rearrangements are frequent oncogenic drivers of acute myeloid leukaemia (KMT2A-r AML) but the cell of origin remains unclear. Here, using preclinical models of EVI1 positive KMT2A-r AML the authors investigate the cell of origin and find that the presence of exogenous factors influences AML initiation and the resulting phenotype.

The Toxoplasma gondii effector TgROP1 mimics host factors to bind VAPA/B, thereby establishing parasite–host ER contact sites.