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While CDK4/6 inhibitors (CDK4/6i) are often initially successful in many breast cancer subtypes, often resistance develops and other subtypes like triple-negative breast cancer (TNBC) fail to respond. Here, the authors demonstrate that the CDK2 inhibitor BLU-222, alone or with CDK4/6i, restores cell-cycle control via p21/p27 induction overcoming resistance in preclinical models of breast cancer, including TNBC.

In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

Chen et al. report all-site alloying for 3D perovskites where B-site strontium doping retards the crystallisation and induces sequential A-site doping with annealing. The controllable crystallisation enables blue LEDs with peak efficiency of 23.3% at 487 nm and tuneable emission to 463 nm.

Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

The authors discover a tissue-scale fitness sensing mechanism in the lung, where mesenchymal Yap antagonizes epithelial Yap to dictate epithelial cell fate. This inter-tissue cell competition orchestrates lung architecture and lung disease.

Hepatitis C virus (HCV) variability and its phenotypic consequences aren’t well studied in relation to viral replication fitness and disease severity. Here, the authors identify a replication-enhancing domain in non-structural protein 5A, linking high replication fitness to severe disease outcomes, with implications for understanding HCV pathogenesis in immunocompromised patients.

Despite extensive structural studies elucidating how antigens are anchored to antigen-presenting molecules and presented to T cells, little is known about the display mechanism of the lipid-antigen-presenting molecule CD1c. Here, by combining structural immunology, lipidomics, and biophysical analysis, the authors reveal that the CD1c binding cleft accommodates two different lipids, one of them with a bulky headgroup positioned sideways for display to T cells, rather than upwards, different from the conventional upright antigen-presentation mode

Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.

Non-pharmaceutical interventions for COVID-19 also reduced circulation of endemic viruses which may have led to immune waning. Here, the authors use multiplex serology data from King County, Washington, US to characterise age-specific changes in antibody levels to a range of endemic viruses during the COVID-19 pandemic.

Translation initiation and elongation factors can be targets for cancer treatment. Here, the authors show that inhibiting translation elongation through eIF5A impairs mitochondrial function, slowing the proliferation of tumour cells.

The kinase ZAK is activated at collided ribosomes to mediate the ribotoxic stress response.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

High-throughput chemical ligand discovery is challenged by false positives. Here, authors introduce a scalable enantioselective affinity-selection mass spectrometry approach for proteome-wide ligand discovery with high sensitivity and selectivity

Host antibodies can alter the glycan binding of adhesin proteins from infectious bacteria, but the antibodies’ mechanisms of action remain unclear. Here, the authors define four mechanisms of modulation, including ligand mimicry and multiple modes of allosteric interference.

CD16a triggers antibody-dependent cellular cytotoxicity but CD16a shedding dampens its anti-tumor activity. Here the authors develop a monoclonal antibody (F9H4) that prevents CD16a shedding, which synergizes with a tumor cell opsonizing antibody (cetuximab) to elicit natural killer cell-driven immunity.

Deep learning-based generative tools are used to design protein building blocks with well-defined directional bonding interactions, allowing the generation of a variety of scalable protein assemblies from a small set of reusable subunits.

Thousands of recombinant antibodies enriched for specificity against defined targets are assembled in multivalent mixtures with enhanced therapeutic activity.

Adoptive T-cell immunotherapy offers promise to patients who are resistant to standard anti-viral strategies. Here the authors describe clinical observations in patients with viral complications treated with adoptive immunotherapy over the last 15 years.

Padi and Godek et al. solve cryo-electron microscopy structures of protein phosphatase 2A (PP2A):B55 bound to p107 and Eya3, which, together with nuclear magnetic resonance dephosphorylation experiments, show how PP2A:B55 recruits specific substrates and how it achieves efficient dephosphorylation of phosphosites with high cellular fidelity.

Understanding the mechanisms behind clinical immunity to malaria is crucial for developing effective interventions. Here, the authors demonstrate that clinical immunity to Plasmodium vivax develops rapidly after a single controlled human malaria infection, reducing inflammatory responses and protecting against symptoms, while not significantly affecting parasite load.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

This study maps chromatin accessibility in neurons and glia in schizophrenia, revealing fetal-like regulatory patterns in adult neurons enriched for genetic risk variants, linking early brain development to schizophrenia pathogenesis

Thermal soaring, inspired by gliding birds, is an appealing model behavior for understanding motion control and how it is learned by animals and engineered autonomous systems. The authors propose a deep reinforcement learning framework to study the learning process of thermal soaring under horizontal wind conditions.

Efficient adenine base editors (ABEs) often induce bystander and off-target effects. Here, Shang et al. developed a YA (Y = T or C) motif preferred ABE(ABE8e-YA) that minimizes these effects, enabling precise and effective pathogenic mutation correction, disease modeling, and in vivo gene therapy.

Africa’s savannahs and shrublands have been assumed to provide a large area for the expansion of cropland with relatively little damage to the environment. Research now shows that conversion would be likely to have high carbon and biodiversity costs.

Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.

Using visible-light-induced crosslinking, a local stiffening approach is developed for ex vivo mouse and human lung tissue as an early lung injury model, directing epithelial cell mechanosensing, differentiation and nascent protein deposition.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Combination immunotherapy approaches might be effective in inducing sustained control of HIV by slowing rebound and improving CD8⁺ T cell responses.

Bacteria of the phylum Bacteroidota move by gliding and export proteins using a type-9 secretion system. Here, Liu et al. show that these two processes use a shared mechanism in which outer membrane proteins are covalently attached by disulfide bonds to a moving track structure inside the cell.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Jansen et al. determined the cryo-electron microscopy structure of human GTPase-activating protein complex GATOR2 bound to CASTOR1 in the absence of arginine, providing insight into how CASTOR1 binds to GATOR2 to disinhibit GATOR1 when arginine levels are low, promoting mechanistic target of rapamycin complex 1 inactivation.

Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.

An atlas study of adipose tissue in people with obesity undergoing weight loss and their lean counterparts reveals that weight loss reduces cell senescence but cannot reverse all the metabolic problems caused by obesity.

IPF arises from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than AT1 cells. Here, Warren, R et al. report that stem cells with the highest Myc levels become supercompetitors that drive remodeling.

A DNA sequencing method with single-molecule fidelity detects mismatches and damage present in only one of the two DNA strands with patterns that are both similar and distinct compared to known mutation patterns.

Small-molecule senolytic compounds targeting BCL-xL were beneficial in a mouse model of diabetic edema and well tolerated when tested in a phase 1 trial involving eight patients with diabetic macular edema.

Here we show how PFL2 and PFL3 neurons in the Drosophila brain compare a representation of direction with internal spatial goals, both anchored in world-centric coordinates, and produce body-centric steering commands that act to correct deviations from the goal direction. 

A cryo-electron microscopy reconstruction shows the ring-shaped structure of the polymerase and capping domains of the L protein bound to a tetramer of phosphoprotein P of the human metapneumovirus.

Current first-line treatments of pediatric UC maintain a 6-month remission in only half of the patients. Here, applying multi-omics on intestinal biopsies from treatment-naïve children, the authors show that relapse-prediction using separate omics data is outperformed by a robust machine learning approach combining microbiomes and epigenomes.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

This flagship study from the European Solve-Rare Diseases Consortium presents a diagnostic framework including bioinformatic analysis of clinical, pedigree and genomic data coupled with expert panel review, leading to 500 new diagnoses in a cohort of 6,000 families with suspected rare diseases.

The Legionella pneumophila effector MavC inhibits the human ubiquitin-conjugating enzyme Ube2N. Here, the authors combine NMR, X-ray crystallography and biochemical assays and show that MavC catalyses the intramolecular transglutaminase reaction between the Ube2N and Ub subunits of the Ube2N∼Ub conjugate and present the substrate- and product-bound MavC crystal structures.

Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15⁺ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.

Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.