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Abstract Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England’s 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an “FFPEImpact” score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many.

Abstract Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.

Abstract Over recent years, the surge in mobile communication has deepened global connectivity. With escalating demands for faster data rates, the push for higher carrier frequencies intensifies. The 7–20 GHz range, located between the 5G sub-6 GHz and the mm-wave spectra, provides an excellent trade-off between network capacity and coverage, and constitutes a yet-to-be-explored range for 5G and 6G applications. This work proposes a technological platform able to deliver CMOS-compatible, on-chip multi-frequency, low-loss, wide-band, and compact filters for cellular radios operating in this range by leveraging the micro-to-nano scaling of acoustic electromechanical resonators. The results showcase the first-ever demonstrated low insertion loss bank of 7 nanoacoustic passband filters in the X-band. Most of the filters showcase fractional bandwidths above 3% and sub-dB loss per stage in an extremely compact form factor, enabling the manufacturing of filters and duplexers for the next generation of mobile handsets operating in the X-band and beyond.

Here, Prakasam and colleagues show that polyQ-expanded androgen receptor toxicity can be attenuated using artificial miRNAs targeting Lsd1 and Prmt6, two AR-co-activators overexpressed in an androgen-dependent manner specifically in skeletal muscle, thus ameliorating spinal-bulbar muscular atrophy phenotypes in flies and mice.

Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.

Abstract Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish.

This paper demonstrates Lithium Niobate based Piezoelectric Micromachined Ultrasonic Transducers. The devices allow activation of multiple vibration modes, achieve a high communication link, and monitor an implanted medical device up to 13.5 cm inside the body.

Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition.

Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.

Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity.

Schistosomes undergo several develepmental stages during infection of humans. Here, the authors perform single-cell RNA sequencing on the earliest intra-mammalian stage of Schistosoma mansoni and generate a comprehensive cell-type atlas for this human parasite.

Ultrathin plasmonic metasurfaces have proven their ability to control and manipulate light at unprecedented levels, leading to exciting optical functionalities and applications. Although to date metasurfaces have mainly been investigated from an electromagnetic perspective, their ultrathin nature may also provide novel and useful mechanical properties. Here we propose a thin piezoelectric plasmonic metasurface forming the resonant body of a nanomechanical resonator with simultaneously tailored optical and electromechanical properties. We experimentally demonstrate that it is possible to achieve high thermomechanical coupling between electromagnetic and mechanical resonances in a single ultrathin piezoelectric nanoplate. The combination of nanoplasmonic and piezoelectric resonances allows the proposed device to selectively detect long-wavelength infrared radiation with unprecedented electromechanical performance and thermal capabilities. These attributes lead to the demonstration of a fast, high-resolution, uncooled infrared detector with ∼80% absorption for an optimized spectral bandwidth centered around 8.8 μm.

How a catalyst behaves microscopically under reaction conditions, and what kinds of active sites transiently exist on its surface, is still very much a mystery to the scientific community. Here the authors report on in situ observation of a redox active copper catalyst by a combination of in situ imaging and spectroscopy tools.

Spatial information is passed from the hippocampus via the subiculum to the ventral striatum. Here, the authors show that inhibiting this projection after spatial learning disrupts learning induced plasticity and spatial memory consolidation.

Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish.

The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.

The biogenesis of eukaryotic ribosomes is a multi-step process involving the action of more than 200 different ribosome assembly factors. Here the authors show that Rps20 acts as a conduit to coordinate maturation steps across the head domain of the nascent small ribosomal subunit.

Abstract Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.

Large protein complexes and ribonucleoprotein particles (RNPs) such as pre-ribosomes are transported from the nucleus to the cytoplasm through the nuclear pore complex (NPC). Here the authors use ultrafast freezing and electron tomography to catch snapshots of native RNPs crossing the NPC and estimate their transit time using a probabilistic model.

Long-lived excitons in a two-dimensional metal-organic crystal can be produced by visible light and detected by infrared radiation. Here, the authors show that the excitonic state of a biomimetic macrocycle can be ‘read’ by measuring the vibrations of an adsorbed ligand.

The mechanisms that control ciliogenesis have been extensively explored however the signaling mechanisms that control cilium stability remain unclear. Here the authors show that GPCR signaling regulates cilia resorption via the ubiquitin-proteasome system.

The miniaturization of antennas beyond a wavelength is limited by designs which rely on electromagnetic resonances. Here, Nan et al. have developed acoustically actuated antennas that couple the acoustic resonance of the antenna with the electromagnetic wave, reducing the antenna footprint by up to 100.

Here, the authors combinein vivopatch-clamp recordings and optogenetics to show that balanced dendritic excitation and inhibition provides a sensitive ‘push-pull’ mechanism that generates the bidirectional modulation of Purkinje cell SSp output necessary for normal locomotor behaviour.

Notch signalling is involved in prostate cancer progression and therapeutic resistance. Here, the authors show that loss of PTEN in prostate cancer models results in increased Notch1 cleavage and activation through CUX1-mediated transactivation of ADAM17.

Plasmonic metasurfaces can provide exciting optical functionalities. Here, Hui et al. demonstrate an infrared sensor by combining plasmonic and piezoelectric electromechanical resonances, demonstrating efficient transduction of vibration with a strong and polarization-independent absorption over an ultrathin thickness.

In response to intracellular signals, bacterial translational riboswitches embedded in mRNAs can regulate gene expression through inhibition of translation initiation. Here, the authors describe SiM-KARTS, a novel approach for detecting changes in the structure of single RNA molecules in response to a ligand.