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Liposomal probes actuated by engineered peptide-based pores control MRI contrast by regulating water access to liposome-encapsulated gadolinium chelators and enable molecular target detection in vivo.

Alternative lengthening of telomeres (ALT) is a telomerase-independent pathway that enables cancer cells to maintain their telomeres. Here, using Oxford Nanopore sequencing, the authors uncover molecular milestones during ALT establishment in yeast and demonstrate that telomere extension proceeds through highly error prone copying of telomeric circles.

The authors show that Rap1 protein coverage protects telomeres by physically blocking the Mre11–Rad50–Xrs2^NBS1 complex. Longer, denser Rap1 arrays better prevent DNA damage responses, providing a mechanism for how cells detect short telomeres and maintain genome stability

CASP5 expression is restricted to the human intestinal epithelium, and the CASP5C isoform has a key role in promoting Wnt signalling, which is required for epithelial homeostasis, through binding to dishevelled and cleavage of APC to regulate β-catenin turnover.

Polyamides (PAs) or nylons are types of plastics with wide applications, but due to their accumulation in the environment, strategies for their deconstruction are of interest. Here, the authors screen 40 potential nylon-hydrolyzing enzymes (nylonases) using a mass spectrometry-based approach and identify a thermostabilized N-terminal nucleophile hydrolase as the most promising for further development, as well as crucial targets for progressing PA6 enzymatic depolymerization.

The genetically encoded voltage indicators JEDI3sub and JEDI3hyp enhance monitoring of subthreshold neuronal activity in the awake mouse brain using a variety of two-photon microscopy techniques.

A dispersive sensing technique, termed the radiofrequency electron cascade, can perform singlet-triplet readout of two exchange-coupled electron spins in a natural silicon planar metal–oxide–semiconductor quantum-dot array.

Interleukin (IL)-1β has been shown to promote tumour growth in non-small cell lung cancer (NSCLC). Here the authors show using chemo-immunotherapy resistant mouse tumour models that IL-1β improves CD8 T cell recruitment in a CXCL10-dependent manner and IL-1β therapy could be a useful adjunct to chemotherapy and anti-PD-1.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

A fresh approach to protein design that incorporates excited intermediate states enables precise control over the lifetime of protein interactions, with potential applications in cell-signalling modulation and in biosensors and synthetic circuits.

Current media for neuronal cell and organoid cultures are suboptimal for functional imaging and optogenetics experiments, owing to phototoxicity and unphysiological performance. Here the authors formulate an optimised neuronal medium to support live cell imaging and electrophysiological activity.

Multiplexed single cell sequencing allows the identification of functional TCRα-TCRβ pairs

Researchers show that a disease-causing Tau mutation disrupts the autophagy-lysosome pathway in human neurons, leading to Tau accumulation, and that enhancing autophagy can partially restore protein clearance.

Small molecule drugs promise to remain a valuable tool in controlling the ongoing COVID-19 pandemic. Here the authors describe optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for potential treatment of COVID-19.

Tau misfolds in Alzheimer’s disease, but how the link between tau filament structure and pathogenicity is unclear. This study shows that both filament core structure and phosphorylation in the fuzzy coat are required for full seeding capacity.

Using a non-human primate model, the authors identified the tissue sites of initial viral rebound after discontinuation of antiretroviral therapy, demonstrating that such rebound preferentially occurs in the gastrointestinal tract-associated lymphoid tissues.

Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca²⁺ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants.

Holocene aquifers are the source of much arsenic poisoning in south and southeast Asia, whereas Pleistocene aquifers are mostly safe; here the delayed arsenic contamination of a Pleistocene aquifer is described and modelled.

A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, but platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, the authors design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone, which exhibit the activity of both parent anticancer compounds and can overcome drug efflux effectively due to covalent binding to intracellular biomolecules.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

Massively parallel reporter assays across five cell types identify thousands of causal, noncoding regulatory variants among 220,000 loci, revealing diverse regulatory mechanisms shaping complex traits and disease.

EDI048 is a gastrointestinal-targeted Cryptosporidium PI(4)K inhibitor that undergoes a predictable metabolism and limits systemic exposure without compromising its anti-parasitic activity.

TDP-43 dysfunction in ALS/FTD causes faulty splicing of the KCNQ2 ion channel, leading to toxic protein buildup, neuron hyperactivity and a potential new biomarker and treatment target using RNA-based therapies.

Overexpression of certain transcription factors can reprogram somatic cells into induced pluripotent stem (iPS) cells; however, only a minority of donor somatic cells can be reprogrammed to pluripotency. Here, this reprogramming is shown to be a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression; changing certain parameters results in accelerated iPS cell formation.

Environmental micro-compartment genomics provides efficient and high-throughput single-particle DNA sequencing that captures overlooked members of microbial communities.

Monoclonalization, the isolation and expansion of a single cell derived from a cultured population, is an essential step in large-scale human cell culture and experiments. A new deep learning-based workflow called Monoqlo automatically detects colony presence and identifies clonality from cellular imaging, enabling single-cell selection protocols to be scalable while minimizing technical variability.

Little is known about the ecology and evolution of the nosocomial pathogen Acinetobacter baumannii outside the hospital. Here, Wilharm et al. show that the lifestyle of A. baumannii includes soil-dwelling and airborne dissemination, which helps to explain its adaptability and predisposition to establish within hospitals.

Analysis of the conidial surface proteome of the fungal pathogen Aspergillus fumigatus and three closely related species reveals factors important for evasion and modulation of host immunity

Improved biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE) are needed. Here, the authors show that Complement Factor H Related 5 protein, a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker in 5 independent cohorts.

Harrington et al report their discovery of Nemacol, which is a small molecule inhibitor of the vesicular acetylcholine transporter (VAChT). VAChT loads synaptic vesicles with acetylcholine and is a key point of vulnerability in animals. Harrington et al show that Nemacol has nematode selectivity and potential utility against nematode parasites.

LEVA is a label-free immobilization method for studying surface-bound extracellular vesicles.

Data suggest that autophagy, a process normally associated with cell survival, also promotes cell death, depending on the stimulus or cell type. Thorburn and colleagues find that differences in basal autophagy levels in cells determine survival or death in response to death receptor activation, through modulation of Fap-1 degradation.

By coupling robotic cell culture systems with artificial intelligence–powered image analysis, Schiff et al. identify previously unseen characteristics of Parkinson’s disease in patient skin cells that distinguish them from healthy controls.

The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.

This Resource presents the genetic subset of the 136,000 chemical and genetic perturbations tested by the Joint Undertaking for Morphological Profiling (JUMP) Cell Painting Consortium and associated analysis of phenotypic profiles.

Fluorescent markers in microscopy-based drug screens carry information on how compounds affect biological processes, but practical considerations may hinder their use. Wong et al. develop a deep learning method for generating images in drug discovery, with broad applicability across diverse fluorescence microscopy datasets.

A potent and selective inhibitor of KRAS^G12D, the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Therapeutic checkpoint for acute myeloid leukemia requires further investigations. The authors here identify ST2⁺ Treg cells facilitate AML growth by inducing CD8⁺ T cell depletion and exhaustion, while targeting ST2 by antibodies depletes ST2⁺ Treg cells and improves AML prognosis.

A combination of genome-wide CRISPR screens in target cancer cells identifies pathways that regulate γδ T cell killing and BTN3A cell surface expression.

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

Methane emissions from oil and gas systems are underestimated in official inventories. Here the authors synthesize thousands of field measurements and develop an inventory-based model for a better understanding of why this underestimation exists and how it can be fixed.

Nebulized mRNA delivery has broad therapeutic potential but has proven challenging. Here, the authors report on a modified lipid nanoparticle with improved conditions to allow nebulization and demonstrate its application for delivering mRNA to the lungs.

Amino acids possess a new and broad colloidal property: they stabilize patchy nanoscale colloids, such as proteins, by adsorbing onto their surfaces through weak interactions.

Straussman and colleagues undertake clonal analyses and show that drug tolerance to EGFR therapy in lung cancer cell populations is an inherited continuous trait that is determined by IRS1 phosphorylation.

Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.

Broad and potent neutralizing antibodies to SARS-CoV-2 variants can be efficiently identified via accurate deep-mutational-scanning-based prediction of viral evolution and delivered to mice using mRNA–lipid nanoparticles.

Current vaccines induce broadly cross-reactive cellular immunity against SARS-CoV-2 variants, including Omicron, and provide protection against severe disease despite a substantially reduced neutralizing antibody response.

Here the authors develop a single molecule array (Simoa) immunoassay for detection of SARS-CoV-2 nucleocapsid protein in venous and dried capillary blood as well as saliva. The assay shows good performance in symptomatic, asymptomatic, and pre-symptomatic PCR+ individuals.

Preventing endosomal damage sensing or using lipids that create reparable endosomal holes reduces inflammation caused by RNA-lipid nanoparticles while enabling high RNA expression.