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Lung cancer etiology has largely been studied in homogenous populations of European descent. Here, targeted sequencing in African American lung adenocarcinomas finds significantly higher prevalence of PTPRTand JAK2 mutations, validated independently by whole exome sequencing, highlighting potentially clinically actionable mutations in this population.

Targeted deletion of the chemokine Cxcl12 in different bone marrow stromal cell populations shows that distinct niches exist in the bone marrow for haematopoietic stem cells and lineage-committed progenitors.

Identification of an improved glucose-6-phosphate dehydrogenase (G6PD) inhibitor G6PDi-1 blocks G6PD activity more robustly than the widely cited antagonist DHEA. G6PDi-1 treatment blocks T cell cytokine production and neutrophil oxidative burst.

Extrachromosomal DNA makes cancerous tumours resistant to treatment, but this research demonstrates that increasing transcription–replication conflict allows for targeted elimination of cancer cells containing extrachromosomal DNA, and thus sustained tumour regression in mice.

Cytosolic coat proteins capture secretory cargo and sculpt membrane carriers for intracellular transport, such as COPII which mediates Endoplasmic Reticulum to Golgi trafficking of thousands of cargoes. Here authors visualise the complete, membrane-assembled COPII coat by cryo-electron tomography and subtomogram averaging, revealing the full network of interactions within and between coat layers.

Spatial and single-cell transcriptomic characterization of microglia in the mouse somatosensory cortex show that the state of these cells is determined by signals from diverse surrounding neurons.

There is a requirement for improved adjuvants to improve responses to vaccines, including adjuvants that induce Th17 cells. Here, the authors use a MINCLE and TLR9 agonist-based vaccine adjuvant and show induction of Th17 and mucosal immune responses to vaccine recall antigens in mice and non-human primate models of vaccination.

Enhancers for endodermal organs are primed at the chromatin level prior to lineage induction by FOXA pioneer transcription factors; how pervasive this is, is not well known. Here the authors show that only a small subset of organ-specific enhancers are bound and primed by FOXA prior to lineage induction, whereas the majority do not undergo chromatin priming and engage FOXA upon lineage induction.

The extent, origins and consequences of genetic variation within human cell lines are studied, providing a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.

Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.

HIV vaccine development can be aided by knowledge of correlates of protection. Here the authors identify engagement and reprogramming of tolerogenic CD14⁺ myeloid cells mediating a spatiotemporal balance of pro- and anti-inflammatory responses, as correlates of efficacy in female macaques vaccinated with the DNA/ALVAC/gp120/Alum platform.

Deconvolution methods infer levels of immune infiltration from bulk expression of tumour samples. Here, authors assess 6 published and 22 community-contributed methods via a DREAM Challenge using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells.

Destici, Zhu, et al. identify human-specific cis-regulatory elements (CREs) through a comparative epigenomic analysis of human and mouse cardiomyocytes at early stage of development and show that these CREs could contribute to species-specific cardiac features. Human-specific enhancers were particularly enriched in SNPs associated with human-specific traits (such as increased heart resting rate, atrial fibrillation and QRS duration), and the acquisition of human-specific enhancers could expand the functionality of the conserved transcriptional regulator ZIC3 by modifying its spatio-temporal expression.

Our understanding of cytosolic delivery is hindered by existing methods for quantification which suffer from being indirect and showing low sensitivity. Here the authors report a SLEEQ (Split Luciferase Endosomal Escape Quantification) assay to assess cytosolic delivery of cell-penetrating peptides.

Human respiratory bronchioles contain a unique population of secretory cells called respiratory airway secretory cells that are distinct from the cells in the larger proximal airways, and act as unidirectional progenitors for alveolar type 2 cells.

Resolution of G4s has been suggested to be required for efficient DNA replication. Here, the authors show that the nuclease DNA2 and the DNA repair complex MutSα (MSH2-MSH6) are required to remove G4 stabilized by environmental compounds to allow efficient telomere replication.

The role of Ifi27l2a, an interferon-induced gene, remains poorly understood in diseased brains. Here, authors show age and stroke-dependent upregulation of Ifi27l2a in microglia, and that reduction of Ifi27l2a leads to reduced brain injury and functional deficits after ischemic stroke.

A framework for studying and engineering gene regulatory DNA sequences, based on deep neural sequence-to-expression models trained on large-scale libraries of random DNA, provides insight into the evolution, evolvability and fitness landscapes of regulatory DNA.

Yelland et al. use yeast genetics and cryo-EM to show how 2′-O-methylation on a single rRNA base gates the assembly of the ribosome via regulating interaction with the essential GTPase Nog2.

Splicing factor PTBP1 is reported to promote oncogenic functions in glioblastoma (GBM). Here the authors show splicing factor SON upregulates PTBP1 expression while supresses its paralog PTBP2 through alternative splicing and the inhibition of SON reduces GBM stemness and growth.

Perilipin 5 is a lipid droplet protein that interacts with PGC1α in the nucleus to regulate mitochondrial metabolism. Here the authors use genetically engineered mouse models to determine the physiologic role of Perilipin 5, and show that it regulates mitochondrial adaptations to cold, as well as systemic energy metabolism.

Human pluripotent cells (hPSCs) in standard culture are similar to mouse epiblast cells, but heterogeneity within hPSC cultures complicates comparisons. Here the authors show that a subpopulation of hPSCs enriched for self-renewal capacity have distinct cell cycle, metabolic, DNA methylation, and ATAC-seq profiles.

The authors have developed a barcoded library that enables the high-throughput tracking of tumor cell dynamics and clonal evolution in response to therapy.

High pathogenicity avian influenza virus has a wide host range and has been detected across a large geographic area. Here, the authors present evidence of spread to the Antarctic and sub-Antarctic regions, with signs of clinical infection and positive virus detection in birds and elephant seals.

Self-supervised representation learning on data from imaging mass cytometry can be used to distinguish morphological differences in tumour microenvironments and to precisely characterize distinct microenvironment signatures.

Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.

Dpr (Defective proboscis extension response) and DIP (Dpr Interacting Proteins) are immunoglobulin-like cell-cell adhesion proteins that form highly specific pairwise interactions, which control synaptic connectivity during Drosophila development. Here, the authors combine a computational approach with binding affinity measurements and find that DIP/Dpr binding specificity is controlled by negative constraints that interfere with non-cognate binding.

Miniature Cas12f editing systems are well suited for in vivo editing applications. Here the authors characterize the intrinsic activity of SpCas12f1 in plant and animal cells.

CaST is a Ca²⁺-activated version of split-TurboID. The tool allows labeling active neurons quickly, simply by administration of exogenous biotin, thus enabling the study of behaviors that would be impaired by hardware required for the use of other, light-dependent tools.

Regulatory elements for specific human genes are rapidly identified with CRISPR epigenome editing.

O’Donnell and colleagues report that activation of the integrated stress response in non-small cell lung cancer cells by impairing heme production leads to enhanced PD-L1 translation in an eIF5B-dependent manner.

Louveau et al. demonstrate that meningeal lymphatics drain CSF-derived macromolecules and immune cells and play a key role in regulating neuroinflammation. Meningeal lymphatics may represent a new therapeutic target for multiple sclerosis.

A structural and functional analysis of the systems involved in oligosaccharide uptake in gut Bacteroidetes describes multicomponent complexes termed utilisomes that include pre-processing and transport subunits.

Stem cells exist in vitro in a spectrum of interconvertible pluripotent states. Here, authors show that pluripotency and self-renewal processes have a high level of regulatory complexity and suggest that genetic factors contribute to cell state transitions in human iPSC lines.

Strong acoustic fields applied to solutions of linear polymers typically result in mid-chain scission, yielding products half the molecular weight of the original. Now it has been shown that poly(o-phthalaldehyde), a polymer with a ceiling temperature below room temperature, undergoes chain scission and subsequent depolymerization to monomers. Introduction of an appropriate initiator to the monomer regenerates poly(o-phthaladehyde) macromolecules.

COVID-19 has impacted health systems unequally and widespread SARS-CoV-2 testing for community surveillance has been limited globally. This work in Malawi highlights how river and wastewater can be used to detect emerging SARS-CoV-2 waves, identify variants of concern, and provide an early warning system.

There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.

Pneumocystis jirovecii is a fungus that can cause life-threatening pneumonia in immunocompromised patients. Here, the authors sequence the genomes of P. jirovecii and two other Pneumocystisspecies, and show the unexpected absence of chitin (a near universal fungal cell wall component).

Conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1⁺ mouse macrophages ameliorates heart failure and substantially reduces fibroblast activation.

The molecular features of paediatric central nervous system (CNS) tumours are not fully understood, posing a challenge for targeted therapies. Here, the authors characterise paediatric CNS tumours using single-nucleus RNA-seq; they identify cell type populations associated with specific tumour types and with response to therapy.

Cellular lysine residues can be both methylated and acetylated on the same sidechain to form N^ε-acetyl-N^ε-methyllysine (Kacme), which is found on histone H4 across a range of species and across mammalian tissues and is associated with active chromatin.

Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.

Phenotypic screens in organoids and primary cells are scaled up using perturbation pooling.

Amyloid-like proteins are central to age-related diseases, such as Alzheimer’s and Parkinson’s. Here, the authors show that transcription errors can produce mutant proteins with enhanced amyloid- and prion-like properties in human cells.

Wong et al. report that expanding human embryonic stem cell-derived endodermal progenitors serve as a ventral foregut model, through which they identify a link between progenitor expansion and tissue-specific changes in the enhancer landscape.

The two major mechanisms for peptide fragmentation by mass spectrometry, collision-activated dissociation (CAD) or a newer method, electron transfer dissociation (ETD), display different efficacies for different peptide chemistries. A decision tree algorithm, which can be embedded into instruments with both CAD and ETD capabilities, selects the optimal fragmentation method to improve the chances of successful peptide identification.