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Chondroitinase injections into monkey spinal cords 4 weeks after hemisection injury increased corticospinal axon growth and corticospinal synapse formation and improved functional outcomes.

Here, the authors demonstrate that CAND1 increases the dissociation rate of CRL2s, thus exerting an inhibitory effect, which in turn endows CRL2s with a selectivity for different targets based on their affinity for CRL2, thereby pacing protein degradation.

TG2 functions as an eraser and exchanger of H3 monoaminylations, including histaminylation of Gln5 of histone H3.

Learning to balance work, family, optimism and setbacks is a process for all early-career investigators. Stephanie Correa and Leng Han share their stories in this instalment of Career pathways.

The PNPLA3 gene is associated with fatty liver disease. Here, the authors define a role for PNPLA3 as a polyunsaturated triglyceride lipase that maintains the balance between hepatic triglyceride storage and secretion.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Zeng et al. show that TDP-43, known for repressing cryptic exon usage in frontotemporal dementia/amyotrophic lateral sclerosis, also controls alternative polyadenylation, impacting expression of disease-linked genes (SFPQ, NEFL and TMEM106B).

In wildlife tagging, stress from capture and handling can alter post- release behavior and potentially study interpretations. This study of 42 mammal species shows that these effects diminish within 4–7 days, and quicker for animals in high human activity areas indicating adaptation to disturbance.

Ahead of her 80th birthday, Judith Howard discussed her life in science, including the importance of women in crystallography from its inception, and her favourite breakthroughs in this field.

Paul and colleagues report the development and characterization of an antibody–drug conjugate targeting TRBC2 for the treatment of T cell malignancies.

Palmulli, Couty and colleagues show that the tetraspanin CD63 promotes accumulation of cholesterol in intraluminal vesicles (ILVs) at the expense of retrieval from endosomes; cholesterol stored in ILVs and exosomes is recovered in an NPC1-dependent manner.

Protein-mediated transport is implicated in trafficking fatty acids at contact sites of lipid droplets and mitochondria. Here, the authors use proteomics to catalogue the proteins at this contact site and report a mechanism of fatty acid transfer that regulates fatty acid oxidation and lipid homeostasis.

In the kidney, maintaining permeability of the filtration barrier is critical. Here, Sachs W. et al show that homeostasis of podocytes and glomerular endothelial cells relies on differing proteasome constitutions which orchestrate endocytic activity in addition to protein degradation.

The authors report a computational framework for determining the meiotic/mitotic origin of nondisjunction (NDJ) in trisomies without parental data. Applying this to Down syndrome, they uncover links between NDJ error stage and leukemia genomics.

The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitating the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

MYCN-amplified neuroblastoma remains an aggressive childhood cancer with its core regulatory circuits less understood. Here, the authors identify that the transcriptional corepressor Runx1t1 is indispensable for MYCN-driven neuroblastoma tumorigenesis.

Targeting noncoding nucleic acids with small molecules represents an important and significant challenge in chemical biology and drug discovery. Here the authors characterize DC-34, a small molecule that exhibits selective binding to specific G4 structures, and provide a structural basis for its selectivity

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

Itkin et al. identify a role for Fli-1 in hematopoietic stem cell activation during regenerative hematopoiesis. They show that Fli-1 coordinates hematopoietic stem cells to stimulate niche-derived Notch1 feedback signals for demand-needed hematopoietic cell output.

PTEN is a key cell signaling lipid phosphatase that is regulated by C-terminal phosphorylation. Biophysical methods were used to illuminate the structural basis for PTEN regulation, which involves a dynamic N-terminal helix that influences catalysis.

The cellular mechanisms underlying autophagy are conserved; however it is unclear how they evolved in higher organisms. Here the authors identify two oxidation-sensitive cysteine residues in the autophagy receptor SQSTM1/p62 in vertebrates which allow activation of pro-survival autophagy in stress conditions.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

During mammary gland involution, the organ undergoes extensive remodeling. Here, the authors explore the role of mammary gland adipose tissue (mgWAT) in this process and demonstrate that adipocyte hypertrophy and lipid trafficking underlie mgWAT expansion and epithelial regression.

STIM proteins sense Ca²⁺ depletion in the ER and activate store-operated Ca²⁺-entry (SOCE) in response, a process associated with dendritic cell functions. Here the authors show STIM1 is the major isoform controlling SOCE in mouse dendritic cells and provide a mechanism for its requirement in antigen cross-presentation.

Katherine Nathanson and colleagues report a genome-wide association study identifying two loci associated with susceptibility to testicular germ cell tumor.

The nuclear pore complex (NPC) is known to regulate p53 signaling and this has mainly been linked to peripheral NPC subunits. Here the authors show that Nup155 from the NPC inner ring regulates the p53 pathway by controlling p21 translation while also being a target of p53-mediated repression.

Astrocytes perform intriguing roles in neural circuits. Here, the authors show that in striatum, astrocytes adopt a satellite-like proximity to cholinergic interneurons, modulating excitability and downstream dopamine release on subsecond timescales.

The hypoxia response pathway can counter pathological damage caused by low oxygen availability. Here the authors employ a multiomics approach to show how the pathway reprograms metabolism towards gluconeogenesis to combat oxidative stress.

Cholinergic interneurons act at nicotinic receptors to depress dopamine release, interrupting its relationship to dopamine neuron firing and supporting an inverse scaling of dopamine release according to cholinergic activity.

Genome engineering in bacteria remains a complex multistep process. Here, the authors developed make-or-break Prime Editing, a precise method for genetic modification in Streptococcus pneumoniae that enables high-throughput and scalable genome editing.

Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection.

Ahead of his 60th birthday, Omar Yaghi discussed his life in science so far and where he believes is the exciting space for future developments.

The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.

In participants from a randomized controlled trial, doxy-PEP use over 6 months minimally affected the gut microbiome’s taxonomic composition but increased the abundance and active expression of tetracycline antibiotic resistance genes.

A bifunctional AURORA-A degrader induces the fast and specific degradation of this kinase in cancer cell lines, which enables targeting of non-catalytic, oncogenic functions of AURORA-A resulting in S-phase arrest and rampant apoptosis.

Environmental analyses predict extensive, yet to be realized natural product diversity. Herein, the authors report an approach that directly captures natural products from the environment, circumventing previous challenges and yielding compounds with unusual structures and activities.

Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. Here, a small molecule inhibitor of the Wnt pathway is identified and its direct target and mechanism of action are characterized, providing new insights into the physiological regulation of the Wnt pathway and new possibilities for targeted Wnt pathway therapeutics.

Plant cells maintain strict proton gradients over different membranes. Here, Dejonghe et al. show that several protonophores, including the known tyrosine kinase inhibitor TyrphostinA23, inhibit clathrin-mediated endocytosis by disturbing these gradients and causing cytoplasmic acidification.

The receptor tyrosine kinase c-Met continues to signal following its internalization, recruiting the small GTPase Rac to stimulate cell migration. Ménard et al.show that this Rac signalling results in distinct outcomes depending on the nature of the endosome in which the receptor resides.

Virus attenuation is used to obtain vaccine strains. Here, the rapid evolution of RNA viruses is exploited by engineering their genomes to encode sites that are a mutation away from a stop codon, a clever method to generate attenuated viruses.

Glaucoma is the most common cause of irreversible blindness worldwide. Here, the authors carry out a large meta-analysis of genetic data from individuals of European and Asian ancestry and identify 10 new loci associated with vertical cup-disc ratio, a key factor in the clinical assessment of patients with glaucoma.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Here the authors use single cell profiling of T cells across the human lifespan to show that a suboptimal TCR shift in T cells as we enter older age results in a molecular signature that resembles that of T cells from newborns and children.

Electrocatalysis offers a route to improving the treatment of wastewater, yet the need for supporting electrolytes complicates the purification of products. Here a cell is designed based on a porous solid electrolyte layer with a cation shuttling strategy that allows direct conversion of nitrate-containing wastewater into NH₃(g) and purified water.

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.