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DIAL designs synthetic promoters for generation of heritable setpoints of gene expression across a range of cell types.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Here, the authors developed a novel high-throughput, DNA barcoded overexpression platform, BOBA-seq, to uncover new gene functions among gut anaerobes involved in carbon utilization and stress tolerance.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the study.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

STING is an intracellular sensor of pathogen- or host-derived DNA. In this study, the authors identify an ESCRT complex that regulates STING degradation, thus acting as a homeostatic regulator of STING signalling and type-I interferon responses.

Hiʻiaka is the largest moon of the distant dwarf planet Haumea. Here, the authors report the first multi-chord stellar occultations of Hiʻiaka, revealing its size, shape, and density, suggesting an origin from Haumea’s icy mantle.

Cryptosporidium is an important threat to public health, yet it lacks a robust genetic toolkit. Here, Watson et al. introduce a targeted CRISPR-based screening method to identify parasite genes that are essential for its survival within the intestine.

Non-canonical amino acids can be incorporated into proteins through translation of orthogonal mRNAs. Now, automating the design of orthogonal mRNAs—which are more selectively and efficiently translated—in combination with compact orthogonal aminoacyl-tRNA synthetase/tRNA expression systems, enables the incorporation of four distinct non-canonical monomers via a 68-codon genetic code.

Targeting FSP1 in lymph nodes has considerable potential for blocking melanoma progression.

A mutant-selective AKT inhibitor shows potential as a targeted therapy for breast cancer, enabling enhanced target engagement and avoiding the dose-limiting toxicity associated with pan-AKT inhibitors.

An ‘intracrine’ signaling mechanism is proposed whereby a G-protein-coupled receptor (free fatty acid receptor 4) senses locally released fatty acids on intracellular membranes associated with lipid droplets to efficiently regulate lipolysis in adipocytes.

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

Quantitative connectivity matrices (or connectomes) for both adult sexes of the nematode Caenorhabditis elegans are presented that encompass all connections from sensory input to end-organ output across the entire animal.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Context-dependent, responsive synthetic promoters are crucial for a wide range of applications, yet currently available options are limited. Here, authors develop a library of thousands of candidate promoters based on binding motifs of hundreds transcription factors for use in mammalian cells.

Somatic small variants in cancer genomes are identified in both short-read and long-read data.

Newly evolved Xanthomonas citri pv. malvacearum isolates triggers recent bacterial blight outbreaks in cotton. Here, the authors show that a recently evolved TALE, Tal7b, activates host susceptibility genes GhSWEET14a and GhSWEET14b rather than GhSWEET10 to confer pathogenicity in these new isolates.

The expansion of clones with distinct SERPINA1 somatic mutants in the livers of alpha-1 antitrypsin deficiency (A1AT) patients is consistent with convergent evolution. These variants interfere with the auto-polymerization and intra-ER accumulation of the Z-A1AT protein, thus highlighting potentially targetable domains.

The authors report that a change to lysosome morphology, from vesicular to tubular form, supports lifespan extension upon dietary restriction and promotes heightened autophagy and healthy aging when stimulated artificially in well-fed animals.

Characterization of bacterial auxin degradation loci and their regulators reveals two distinct types across plant microbiome species, where only one, exemplified in Variovorax species, can interfere with root growth inhibition in a complex synthetic microbial community.

T cell receptors are identified in large-scale screening of T cell repertoires cloned from primary human T cells.

MGAT1 is a glycosyltransferase critical for the synthesis and maturation of complex N-glycans. Here, the authors show that MGAT1 modulation of CD73 glycosylation and function regulates tumor immune response in triple-negative breast cancer.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Light and temperature provide critical information guiding developmental transitions in plants. This study shows that blue light signals via PHOT2 and low temperature signals via CAMTA2 are linked, transducing a combined signal regulating flowering.

CRISPR activation/interference screens identify transcriptional regulators of human CD8⁺ T cells, including BATF3. BATF3 overexpression counteracts T cell exhaustion and enhances cancer immunotherapy in in vivo models.

Non-CRYPTOCHROME-dependent radical pairs can elicit responses to magnetic fields in neurons in Drosophila melanogaster.

Adherens junctions (AJs) mediate cell-cell adhesion between epithelial cells but tools to study their dynamic regulation are lacking. Here the authors develop an optochemical tool to stimulate the assembly of AJs through addition of a photocleavable tool and their dissociation upon exposure to light.

Synthetic gene circuits regulated by small molecules have been used to fine-tune glycosyltransferase expression in CHO cells, providing a method to produce therapeutic monoclonal antibodies with precise glycosylation states.

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).

Orthogonal acute inducible degradation cell lines are used to delineate the mechanisms of how extrusive cohesin, cohesive cohesin and condensin interact to remodel chromosome architecture from interphase to mitosis.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Screening libraries of genetically engineered microbes for secreted products is limited by the available assay throughput. Here the authors combine aptamer-based fluorescent detection with droplet microfluidics to achieve high throughput screening of yeast strains engineered for enhanced tyrosine or streptavidin production.

“Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. Here the authors show that PopZ condensate dynamics support cell division and using PopZ modular architecture, the tunable PopTag platform was developed to enable designer condensates.”

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain, and OPA1 oligomerization through multiple assembly interfaces promotes the helical assembly of a flexible OPA1 lattice on the membrane, driving mitochondrial fusion in cells.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Experiments in mice show that the perineural net has a key role in metabolic disease by controlling insulin access to neurons in the arcuate nucleus of the hypothalamus.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The synOptopatch approach enables all-optical access to synaptic communication via mutually exclusive expression of an optogenetic actuator and a voltage sensor in pre- and postsynaptic neurons, respectively.

Reconstitution of the SARS-CoV-2 RNA 5′ cap reveals the unconventional mechanism by which SARS-CoV-2 caps its RNA genome, providing a new target in the development of antiviral agents to treat COVID-19.

The REX element is associated with long-range enhancer–promoter interactions.

A synthetic receptor platform that enables mammalian cells to respond to soluble factors allows specific signalling networks to be precisely controlled, with a variety of therapeutic applications.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Reporter gene expression history in cells is recorded with engineered fluorescent protein fibers.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Premature termination codon suppression therapy could be used to treat a range of genetic disorders. Here the authors present a high-throughput cell-based assay to identify anticodon engineered tRNAs with high suppression activity.