Inhibitor-induced kinase degradation is a common event that positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

Inhibition of the histone methyltransferase NSD2 and the androgen receptor in preclinical models can reverse lineage plasticity to suppress tumour growth and promote cell death in multiple subtypes of castration-resistant prostate cancer.

The CRL4CRBN E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. Known cere...

A prime editor screen systematically identifies deleterious synonymous variants in human cells.

We present a computational approach to the design of high-efficiency enzymes with catalytic parameters comparable to natural enzymes, enabling programming of stable, high-efficiency, new-to-nature Kem...

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

R9AP is a key receptor for entry of Epstein–Barr virus into human epithelial and B cells, and interacts directly with the viral glycoprotein gH/gL complex to mediate virus–host membrane fusion.

moPepGen enables the detection of peptides across species, proteases and technologies.

Xiao, Dong, Xie, Feng et al. developed FRα-targeting chimeras (FRTACs) for targeted membrane protein degradation by conjugating multiple folate molecules to antibodies of targeted proteins. The folate...

Interrogation of electronic health records and the B and T cell repertoires of people with PSC shows a link between Epstein–Barr virus and primary sclerosing cholangitis, an incurable autoimmune liver...

He and colleagues develop LucaOne, a biological foundation model pre-trained on nucleic acid and protein sequences from 169,861 species. It shows an emerging understanding of molecular biology’s centr...

Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographi...

The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeri...

Fuentealba and colleagues build and validate a DNA methylation clock of intrinsic capacity (IC) to bridge resource-intensive clinical assessments of IC with molecular readouts of aging, highlighting s...

Here the authors show that PD-1 controls coinhibitory receptor expression by Treg cells. The absence of PD-1 expression could induce CD30 expression, thereby enhancing Treg function and tumor escape, ...

A single dose of the anti-sporozoite monoclonal antibody CIS43LS can achieve durable, sterile protection against Plasmodium falciparum infection.

Preliminary results from a phase 2a trial involving 71 patients suggest that a new agent, discovered and designed with artificial intelligence assistance, is safe and effective for the treatment of id...

A ketogenic diet and the ketone body β-hydroxybutyrate are shown to confer resistance to malaria in mice by inducing metabolic reprogramming in Plasmodium parasites, suggesting a dietary strategy for ...

The authors describe how reduced dietary availability and systemic loss of cysteine leads to adipose tissue browning and rapid weight loss in mice and humans.

The herpes simplex virus 1 uracil-DNA glycosylase counters host APOBEC1 to evade genome editing and to enable viral replication that promotes encephalitis in mice.

Acquired therapeutic resistance is a key contributor to cancer treatment failure, requiring new approaches to address its complex mechanisms. In this Roadmap, Soragni, Knudsen and colleagues discuss t...

Preclinical and observational studies suggest that exercise may improve cancer outcomes. However, definitive level 1 evidence is lacking. In this phase 3, randomized trial conducted at 55 centers, ...

Muscle samples from over 120 people were analyzed to identify molecular patterns linked to insulin resistance, a key feature of type 2 diabetes. The findings reveal new insights that could help tailor...

Comprehensive single-cell transcriptomic analysis of 35 human tissues reveals 12 cross-tissue coordinated cellular modules that exhibit intramodule communication and dynamic changes with ageing, and w...

In vivo gene delivery to haematopoietic stem and progenitor cells in newborn mice using engineered lentiviral vectors shows promise as an effective treatment for genetic diseases.

Gkioni et al. show that trametinib, which targets the Ras–Mek–Erk pathway, extends lifespan in male and female mice and that co-treatment with the known geroprotector rapamycin additively extends life...

Base editing of the pathogenic trinucleotide repeat expansions underlying Huntington’s disease and Friedreich’s ataxia introduces repeat interruptions that reduce somatic expansion in patient cells an...

This large integrated analysis of the KRASG12C inhibitor sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 trials shows that low expression of TTF-1 and h...

In the Tumor Profiler proof-of-concept observational study, a multiomics approach for profiling tumors from patients with melanoma was feasible, returning data within 4 weeks and informing treatment r...

InterpolAI leverages optimal flow-based artificial intelligence to produce synthetic images between pairs of images for diverse three-dimensional image types. InterpolAI is more robust and accurate th...

During poxvirus-induced shutoff, certain cellular and viral mRNAs continue to be translated through distinct modes of non-canonical initiation, in part due to altered ribosome activity, to produce hos...

Nature - Protein-primed homopolymer synthesis by an antiviral reverse transcriptase

Linkers are traditionally seen as important for PROTAC activity. Here, the authors demonstrate that linker-free PROTACs can outperform traditional designs, marking a paradigm shift in PROTAC developme...

Based on a proteogenomic analysis, Perreault and colleagues report that the majority of predicted tumor antigens originate from unmutated genomic sequences in melanoma and non-small cell lung cancer.

Zero-distance photo-crosslinking reveals direct protein-DNA interactions in living cells, enabling quantitative analysis of the DNA-interacting proteome on a timescale of minutes with single-amino-aci...

Mitochondria fulfill central functions in metabolism and energy supply. They express their own genome, which encodes key subunits of the oxidative phosphorylation system. However, central mechanisms u...

Deep learning has advanced the design of static protein structures, but the controlled conformational changes that are hallmarks of natural signaling proteins have remained inaccessible to de novo des...

The combination of AI and national health databases offers opportunities, but may also be exploited by unethical agents. This study shows that there has been an explosion of formulaic research article...

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

Serotonin transporter (SERT) inhibits CD8 T cell antitumor immunity by depleting intratumoral serotonin. SERT-blocking selective serotonin reuptake inhibitor (SSRI) antidepressants enhance CD8 T cell ...

Ben-Simon et al. present a comprehensive toolkit of transgenic lines and enhancer AAVs for targeted study of mammalian cortical cell types, facilitating understanding of brain function in health and d...

PCSK9 regulates low density lipoprotein-cholesterol import and determines organ preference of metastatic pancreatic ductal adenocarcinoma, with PCSK9-low cells metastasizing to the liver and PCSK9-hig...

An in vivo screen of small-molecule compounds to inhibit the mosquito-stage development of Plasmodium identified hits that can be incorporated into bed nets and led to effective parasite killing in th...

Vannini and colleagues report that an age-associated decline in nicotinamide adenine dinucleotide levels is associated with mitochondrial dysfunction and reduced antitumor efficacy of chimeric antigen...

A transient in vivo prime editing strategy is developed for the liver by delivering the prime editor as mRNA encapsulated in LNP.

Modifications enhancing degradation resistance and albumin affinity enabled the delivery of an siRNA conjugate silencing MMP13 to guinea pig and murine arthritic joints, improving therapeutic outcomes...