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5-hydroxythalidomide is a primary thalidomide metabolite generated by the cytochrome P450 isozymes. The reported data, including crystal structure of the 5-hydroxythalidomide-mediated complex of CRBN with SALL4, elucidate how additional hydroxy group of the metabolite enhances the interaction of CRBN with the neosubstrate SALL4.

Noncoding variants in a TTTG microsatellite on 15q26.1 are identified in Japanese patients with childhood and adult-onset thyroid abnormalities. Functional analyses suggest that these variants affect the role of the microsatellite as a potential regulator of thyroid cell growth.

The antiangiogenic effect of siRNAs does not depend on the target of the siRNA, or on intraocular administration. Rather, the siRNAs activate TLR3, a cell surface receptor for long viral dsRNAs, and innate immunity.

Satoshi Narumi, Tomonobu Hasegawa and colleagues describe a new adrenal hypoplasia syndrome termed MIRAGE that is caused by mutations in the endosome fusion facilitator SAMD9. They find that patients with these mutations have severe growth restriction phenotypes, and they observe adaptation by aneuploidy, where there is accompanying protective loss of mutation-carrying chromosome 7.

Schuermans et al. identify a causal relationship between the circulating proteins spondin-1 and atrial fibrillation and SPINT1 and coronary artery disease and show that adding proteomic data improves clinical risk factor-based cardiovascular risk prediction.

Using biobank data from over 250,000 participants, the authors present a detailed picture of regional and individual variation in the tripartite ancestral structure of modern Japanese populations and demonstrate its impact on elevated body mass index.

Adolescent idiopathic scoliosis (AIS) is a common pediatric disease leading to spinal deformities. Here, the authors report GWAS followed by genome-wide meta-analysis in up to 79,211 Japanese individuals, identifying 20 genetic loci for AIS, 14 of which were previously unreported, and perform in vitro validation for rs1978060.

Mitotic spindle assembles in each blastomere to segregate duplicated chromosomes during cleavage of the fertilized egg. Here, the authors establish functional assays in fish embryos and find that Ran-GTP assembles a microtubule network at the metaphase spindle center that is essential for chromosome segregation.

The glutamate transporter GLAST in astrocyte regulates synapse function by glutamate clearance. Here, the authors show that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synaptogenesis through the intercellular association with GLAST in the developing cerebellum.

Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.

On-surface synthesis is a key tool to access low dimensional carbon-based nanomaterials with atomic precision. Here, the authors synthesize a nitrogen-doped nanographene structure with an [18]annulene pore on Ag(111) through sequential debromination, aryl–aryl coupling, cyclodehydrogenation and C–N coupling reactions from a 3,12-dibromo-7,8-diaza[5]helicene precursor.

Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.

Peripheral CD4⁺ T cells can develop into Intestinal intraepithelial lymphocytes (IEL) in the lamina propria. Here the authors characterise how IEL generation from CD4⁺ T cells is regulated and show using scRNA sequencing that Ccr9 is involved in this process through limiting IEL precursor differentiation.

Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.

VAPB is a type IV transmembrane protein at the ER, and Iiis unknown how the VAPB MSP domain facing the cytosol is secreted. Here, the authors show that secretion of ER the protein VAPB requires topological inversion and Mmp1-mediated cleavage.

This paper reports the efficient generation of human alveolar cells from induced pluripotent stem cells and their expansion in 3D culture.

John Chambers, Jaspal Kooner, Pim van der Harst, Shyong Tai, Paul Elliott, Jiang He, Norihiro Kato and colleagues performed a genome-wide association study of blood pressure phenotypes in individuals of European, East Asian and South Asian ancestry. They find trait-associated SNPs at 12 loci, some of which are associated with methylation at nearby CpG sites.

Understanding blood and lymphatic vasculature networks is currently limited by existing imaging systems and quantification methods. Here the authors use the tissue clearing method CUBIC to generate 3D images, machine learning to capture the signals, and extract geometric features by topological data analysis.

Hata and colleagues identify lorlatinib analogs that overcome acquired therapy resistance to current ALK inhibitors and show their efficacy in preclinical models of non-small cell lung cancer bearing compound therapy-resistant ALK alterations.

Mitochondrial supercomplex assembly may efficiently supply energy, yet its role remains controversial. Here, the authors show that SYK inhibitors increase supercomplex assembly and mitochondrial respiration in cells and can enhance exercise performance in mice.

Functional brain architecture underlying autonomic adjustments to exercise has remained unknown. Here, the authors reveal a subcortical pathway that relays volitional motor signals to drive locomotor activities and sympathetic cardiovascular responses.

Collided ribosomes are marked by ubiquitination to induce quality control mechanisms. Here, authors show that mammalian disomes form a distinct structural interface, in which uS10 K63-linked polyubiquitination is critical for ribosome dissociation.

A polygenic risk score for coronary artery disease developed using data from individuals of five different ancestries has increased accuracy across diverse populations.

Investigating genetically correlated cancers can enhance our understanding of carcinogenesis. Here, the authors perform Pan-cancer and cross-population GWAS meta-analysis to identify novel cancer risk loci and highlight shared heritability between breast and prostate cancer.

PROTACs and molecular glues target E3 ubiquitin ligases to substrate proteins. Here, the authors develop a proximity biotinylation-based method to identify drug-induced E3 ligase-substrate interactions, enabling the assessment of the target spectrum of PROTACs and molecular glues in cells.

How enhancers transition from a hypoacetylated primed state to a hyperacetylated-active state in response to differentiation stimuli is incompletely understood. Here the authors show that SETD5 forms a complex with NCoR-HDAC3 co-repressor to prevent histone acetylation of master adipogenic gene enhancers, while SETD5 degradation triggers enhancer hyperacetylation and transition to active state.

Ketogenesis is critical for survival during the neonatal and perinatal periods. Arima et al. determine that hepatic ketogenesis prevents hyperacetylation of mitochondrial proteins and disruption of mitochondrial energetics.

ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.

Different molecular subtypes defined by specific gene rearrangements have been described for acute lymphoblastic leukaemia (ALL). Here, the authors show that ZNF384 fusion activates FLT3 expression conferring a therapeutic vulnerability for ZNF384- rearranged ALL subtype.

The UFM1 system, a ubiquitin-like conjugation system is crucial for endoplasmic reticulum (ER) homeostasis. Here, authors found that CYB5R3 is covalently conjugated with UFM1, which becomes a signal for ER-phagy, a selective autophagy of ER.