Search

Roßmann and colleagues report a simple strategy to generate a panel of fluorescent HaloTag Ligands that enable visualisation of cell surface proteins at low concentrations and with brief incubation times. They use these probes to label neuromodulatory receptors in neurons, allowing for the distinction of surface versus internal receptors of the presynaptic terminal.

This study finds that prime editing of Adrb1^A187V in the mouse brain boosts excitability of β1- adrenergic neurons, wake behaviors, and memory, while lowering sleep pressure. In an Alzheimer’s model, Adrb1^A187V also restored physiological REM sleep amounts.

Via high-throughput imaging and tracking over 140 million single mycobacteria, the authors show that drug- and strain-specific killing predict treatment outcomes, with potential to improve drug development and personalized therapy.

Analysis of 100 consecutive personalized bacteriophage therapy cases supports the use of personalized and sometimes pre-adapted, bacteriophage preparations, often in combination with antibiotics.

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

Patients with different small round cell sarcoma (SRCS) often receive the same treatment regimen but for some SRCS subtypes, response to chemotherapy is poor and targeted treatment options are limited. Here, the authors establish a biobank of paediatric patient-derived SRCS tumoroids and perform drug screening, identifying MCL inhibition as a potential therapeutic strategy in CIC::DUX4 sarcomas.

Monoclonal antibodies and ligands targeting CD40 exhibit diverse agonistic and antitumor activities that are influenced by their design. Here, the authors identify mechanistic differences between clinically relevant anti-CD40 subclasses and CD40L, focusing on the dynamics and strengths of multi-bond formation at the single-molecule level.

TEAD transcription factors are critical effectors and druggable sites of the Hippo pathway in cancer, however, the development of small molecule inhibitors and degraders remains underexplored. Here, the authors identify and characterize bifunctional IAP-based degraders targeting TEAD1 via a lipid pocket and recruit different members of the inhibitor of apoptosis proteins (IAPs) family, offering a comprehensive toolkit for structural, biophysical and cellular profiling.

Spin-enhanced lateral flow tests use nanodiamonds for the sensitive, robust detection of disease biomarkers. Here, authors report a clinical evaluation of a test for SARS-CoV-2 antigen, finding 95.1% sensitivity (Ct ≤ 30) and 100% specificity, with detection 2.0 days earlier than conventional tests.

Root microorganisms can trigger the release of immune-stimulating N-hydroxypipecolic acid from Arabidopsis roots by manipulating a standby circuit of its continuous synthesis and immobilization. N-hydroxypipecolic acid thereby influences shoot growth and pathogen defence.

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but establish good ligandability of ATG8 isoforms through fragment screening and docking.

Tools for high spatiotemporal control of cell-cell adhesions are lacking. Here, authors propose an optogenetic tool, opto-E-cadherin, that allows reversible control of E-cadherin-mediated cell-cell adhesions with blue light.

Antibodies targeting the spike protein of coronaviruses are potential candidates for therapeutic development. Here, Bertoglio et al. use phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve universal antibody gene libraries HAL9/10 that block interaction with ACE2 receptor to inhibit infection.

AAV-mediated base editing corrects an autosomal recessive mutation in the Pah^enu2 gene and ameliorates molecular deficits in a mouse model of metabolic liver disease.

MacDonald et al. show that EGF triggers de-sialylation of plasma membrane glycoproteins like integrins in a mechanism that depends on the Na⁺/H⁺ antiporter NHE1 and the neuraminidases Neu1 and Neu3. Integrins are trafficked to the Golgi and re-sialylated.

Despite advances in GPCR structures and peptide design, creating high-affinity ligands remains a challenge. Here the authors develop a computational method, successfully identifying peptide-based molecules for KOR: their platform shows promise for streamlined GPCR ligand discovery.

A combination of gentle stimulated emission depletion microscopy imaging and deep-learning-based improvements in signal-to-noise ratio enables high-resolution reconstruction of neuronal architecture in living tissue.

Ponsioen et al. use a FRET‐based ERK biosensor EKAREN5 in patient‐derived organoids to show that EGFR activity amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways.

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 disease.

Guide RNA selection plays an essential role in CRISPR screens, the Vienna Bioactivity CRISPR (VBC) scoring system provides an improved selection for sgRNAs that generate loss-of-function alleles.

There is no universal reference material to develop extracellular vesicle (EV) separation methods and carry out calibration and normalization. Here the authors use HIV-derived gag proteins to assemble recombinant fluorescent EV as a trackable reference material resembling the physical and biochemical properties of sample EV.

Bis(monoacylglycero)phosphate (BMP) is an important component of late endosomal and lysosomal membranes. In this study, the authors show that both intra- and extralysosomal pathways can contribute to BMP synthesis.

Tissue-resident memory T cells (T_RM cells) are important for the localized protection of specific body compartments. Nakayama and colleagues identify heterogeneity in lung T_RM cells, with one subset driving fibrosis and inflammation and another reining in pathology in response to fungal challenge.

In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping.

Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.

Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer

Here the authors show that CD4⁺ effector T cells prevent or reverse CD8⁺ T cell dysfunction by licensing Kupffer cells to trigger IL-27 production, defining a liver-specific immune circuit and a potential target for chronic HBV therapeutics.

The number of ligand binding sites in the dopamine transporter is enigmatic due to conflicting data from structures and molecular pharmacology. Here, force spectra reveal the position and dynamics of a previously invisible transient site.

T helper 2 (Th2) cell responses are essential for immunity against parasites, but how Th2 response is modulated in the gut is still unclear. Here the authors show that distinct dendritic cell subsets distinguishable by CD11b, CD103 and IRF4 function in the small intestine or colon to promote Th2 responses.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

Neisseria meningitidis capsular polysaccharide (CPS) is a major virulence factor and vaccine formulations against Neisseria meningitidis serogroup A (NmA) contain O-acetylated CPS. Here, the authors provide mechanistic insights into CPS O-acetylation in NmA by determining the crystal structure of the O-acetyltransferase CsaC and NMR measurements further reveal that the CsaC-mediated reaction is regioselective for O3 and that the O4 modification results from spontaneous O-acetyl migration.

Eusociality evolved independently in Hymenoptera and in termites. Here, the authors sequence genomes of the German cockroach and a drywood termite and provide insights into the evolutionary signatures of termite eusociality.

Chromatin condensation does not impede nucleosome sliding by ISWI remodelers. Notably, ATP energy is used not only for remodeling but also for enzyme mobility and to prevent solidification of chromatin. A ‘monkey-bar’ model rationalizes the findings.

Results of an exploratory interim analysis from a phase I trial show that an RNA vaccine targeted towards four melanoma-associated antigens produces durable objective responses in patients with melanoma that are accompanied by strong CD4⁺ and CD8⁺ T-cell immunity.

Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.

Roles of specific synaptic proteins in postsynaptic organization revealed by acute, Auxin-Inducible Degron 2 Technology-mediated degradation of synaptic fusion proteins, combined with real time measurements of consequences at individual synapses.

Aspiration of cellular content accompanied by confocal microscope-usage within the SS2000 allows investigation of organelle-enriched fractions and sheds light on selective effects of Aβ peptides.

Genetic and epigenetic abnormalities have been found to result from reprogramming of differentiated cells into human induced pluripotent stem cells (hiPSCs). Here, Klawitter et al.identify endogenous L1, Alu and SVA mobilization during reprogramming, highlighting the risk of insertional mutagens in hiPSCs.

Ruiz-Orera et al. used comparative transcriptomics and translatomics to analyze the cardiac evolution in primates and discovered species-specific and lineage-specific genomic innovations that might contribute to cardiac development and disease.

AL amyloidosis is caused by the accumulation of overproduced light chain (LC) fragments as fibrils in patient organs and it is the most prevalent systemic amyloidosis. Here, the authors combine biochemical and biophysical experiments to characterise the lag phase of a patient-derived truncated LC and they identify structural transitions that precede fibril formation.

Different gut bacteria have been shown to promote colorectal cancer (CRC) progression. The authors identify formate as an oncometabolite derived from Fusobacterium nucleatum, which promotes CRC formation by increasing cancer stemness.

Manioglu et al use high-resolution atomic force microscopy to resolve how polymyxins interact with the bacterial membrane. Polymyxins arrange the bacterial lipids into regular hexagonal structures that stiffen the membrane and lead to rupture.

LMNA mutations cause severe heart dysfunction. Here the authors show that Lamin A/C plays a key role in 3D chromatin architecture in naïve pluripotent stem cells, which ensures proper cardiovascular cell fate and function, and shed light on the mechanisms involved in LMNA cardiomyopathies.

Red and green genetically encoded indicators for norepinephrine have been developed and employed to monitor norepinephrine during locomotion and reward behavior in mice. The strategy used for generating these indicators also produced indicators for other neuromodulators.

Infection with SARS-COV-2 can result in self-limited upper airway infection or progress to a more systemic inflammatory condition including pneumonic COVID-19. Here the authors utilise a multi-omics approach to interrogate the immune response of patients with self-limiting upper respiratory SARS-CoV-2 infection and reveal a temporal immune trajectory they associate with viral containment and restriction from pneumonic progressive disease.

miR-132 was shown to drive pathological cardiac remodeling, a hallmark of heart failure. Here, the authors show that an antisense inhibitor of miR-132 has favourable pharmacokinetics, safety-tolerability and preclinical efficacy in mouse and porcine models of heart failure.

The protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccine expressing the SARS-CoV-2 spike protein in non-human primates is demonstrated.

Obstructive lung diseases are a frequent cause of morbidity worldwide. Here, the authors identify the endocannabinoid anandamide (AEA) as an airway relaxant under physiological and pathophysiological conditions that can be locally applied to the lung as an aerosol in mice.

The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.