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The SLC45A4 gene encodes a neuronal polyamine transporter and is linked to pain response in humans and mice.

Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.

Studies in humans and mice show that myocardial infarction recruits monocytes to the brain’s thalamus, promoting sleep, which in turn restricts cardiac inflammation and sympathetic signalling and assists healing.

The blood-brain barrier (BBB) restricts systemically delivered therapeutic antibodies into the brain. Here the authors engineer antibody Fc region to promote the binding to BBB expressed neonatal Fc receptor (FcRn) at neutral pH, therefore improving brain penetration and brain targeting efficacy both in mice and non-human primates.

Proteomic, transcriptomic, and genomic analysis has shown osteosarcoma (OS) to be a complex and heterogenous disease but revealed little about its carcinogenesis or potential therapeutic targets. Here, the authors profile the RNA interactome, transcriptome and proteome of cells derived from OS patients, identifying a targetable vulnerability to translation inhibition.

Site-specific and efficient RNA editing is achieved with a CasRx editor.

Early life is a critical window for immune development, marked by shifts in cell composition and function. Age and sex influence this process and are associated with epigenetic differences in immune-related DNA methylation, based on analysis of whole blood samples collected at ages 1 vs. 5 from a Canadian longitudinal paediatric cohort

SARS-CoV-2 variants with mutations in spike have emerged during the pandemic. Magaret et al. show that in Latin America, efficacy of the Ad26.COV2.S vaccine against moderate to severe–critical COVID-19 varied by sequence features, antibody escape scores, and neutralization impacting features of the SARS-CoV-2 variant.

Characterization of RNA-binding proteins (RBPs) in tissues has been hampered by technical constraints. Here, the authors describe ex vivo eRIC, a method for global profiling of RBPs active in mammalian organs, and report comprehensive RBP atlases from mouse brain, kidney and liver.

Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here they show that SYNCRIP safeguards HSC self-renewal during regenerative stress by maintaining both proteostasis and CDC42-regulated cell polarity.

A synthetic proteome-scale strategy enables the identification of a diverse range of human proteins that can induce the degradation or stabilization of a target protein in a proximity-dependent way.

Rare genetic variants in UNC93B1 predispose to childhood-onset lupus via TLR7/-8–IRAK1/-4, validated with a corresponding mouse model.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Cheng et al. demonstrate that an extra copy of the X-linked epigenetic regulator UTX in females increases natural killer (NK) cell effector function. As NK cells are critical for antiviral immunity, this may explain decreased severity of viral infections in females compared to males.

The formation of branched microtubule networks in mitotic spindles depends on the augmin complex. Zupa, Würtz et al. elucidate the molecular architecture and conformational plasticity of the augmin complex using integrative structural biology, providing structural insights into microtubule branching.

Single-cell transcriptomics and protein expression analyses of salivary glands and gingiva, along with the detection of infectious virus and virus-specific antibodies in saliva from SARS-CoV-2-infected individuals, support a potential role for the oral cavity in COVID-19 pathogenesis.

Whipworms are large parasites causing chronic disease in humans and other mammals. Here, the authors show how larvae create tunnels inside the gut lining and reveal the early host response to infection via Isg15 in mice and murine caecaloids.

Frameshift mutations that create arginine-rich basic tails in transcription factors and other proteins can lead to altered phase separation in the nucleolus, which in turn leads to syndromes such as brachyphalangy, polydactyly and tibial aplasia.

The molecular mechanisms underlying resistance to therapy in Chronic lymphocytic leukemia (CLL) remain to be explored. Here, the authors perform multi-omics analysis in a mouse model of ibrutinib resistance and suggest proteasome inhibition for overcoming it.

Lavdovskaia, Hanitsch, Linden et al. provide a comprehensive roadmap of mitoribosome biogenesis and establish that mitochondria use a unique pathway for the assembly of their translation machinery.

New optical methods for investigating the activity of small molecules in cells may facilitate development of anticancer therapeutics. Here, the authors use a super-resolution optical platform and single molecule tracking to gain insight into WRN regulation in cancer.

A nanoparticle integrating a fusion protein of apolipoprotein A1 and interleukin-4 and that targets myeloid-cell-rich haematopoietic organs resolves immunoparalysis in ex vivo and in vivo models of sepsis.

RNA interactome capture allows the detailed investigation of RNA-bound proteomes. Here the authors describe enhanced RNA-interactome capture using LNA-modified probes for increased sensitivity and specificity.

Here, Easter et al. generate a single-cell atlas of human periodontium including sulcular and junctional keratinocytes. Cell-cell communication analysis is used to predict keratinocyte-specific immune cell interactions.

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).

SIN3B is a histone deacetylase part of the holo-SIN3 complex. Here by cryo-electron microscopy we unveil the assembly, activation, specificity, and substrate recognition of the human SIN3B histone deacetylase complex.

Delivering immunomodulatory compounds to myeloid cells can activate innate immunity for cancer immunotherapy. Here the authors design a polymersome-based nanocarrier for delivering β-glucan to red pulp myeloid cells in the spleen and show that their strategy achieves tumour growth reduction in a melanoma model.

Anna Uryga and Mandy Grootaert et al. combine cell culture and animal models to examine how senescence of human vascular smooth muscle cells (VSMCs) and persistent telomere damage drive inflammation. Their results suggest that telomere injury can be the primary cause of premature senescence in VSMCs, and that DNA damage can be a major cause of persistent inflammation in vascular disease.

A new technique called immunoGAM, which combines genome architecture mapping (GAM) with immunoselection, enabled the discovery of specialized chromatin conformations linked to gene expression in specific cell populations from mouse brain tissues.

The brain is a genomic mosaic shaped by somatic mutations and cellular responses that correct or purge these mutations. Here, by manipulating genome stability during embryonic brain development, authors revealed robust mechanisms that eliminate cells with genome damage from the brain, and the consequences of leaving somatic mutants unpurged

Schreier et al. report a previously undescribed cytoplasmic condensate, termed the paternal epigenetic inheritance (PEI) granule, that contains the Argonaute protein WAGO-3 and 22G small RNAs and mediates paternal epigenetic inheritance in C. elegans.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.

The Rett syndrome protein MeCP2 regulates gene transcription by binding to methylated DNA. Here the authors find that MeCP2 also regulates key neuronal genes by binding to nonmethylated DNA, providing new insights into the disorder.

Heeren et al study the evolutionary genomics of leishmaniasis in Peru and Bolivia to show that parasite hybridization increases the prevalence, diversity and spread of viruses that have been previously associated with disease severity and treatment failure.

Although vaccination drops COVID-19 mortality in older adults, post-vaccine fatal COVID-19 in nursing home outbreaks was linked to Delta, Gamma and Mu variants, persistently detected in aerosols. Mortality was predicted by IFNB1 or age, ORF7a and ACE2 mRNAs.

Chromatin mediates transcription and DNA repair. Here, the authors show distinct roles of chromatin remodeler INO80 in expression of YY1-regulated genes and repair of DNA breaks by homologous recombination, a DNA repair pathway important for symmetrically-dividing neural progenitors.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

As the COVID-19 pandemic continues, variants of the virus are emerging. Here the authors present a diagnostic assay that can detect wildtype and known variants using engineered Cas12a.

Zhu et al. discover that in human brain there is widespread anatomic distribution of low-frequency somatic, mosaic L1 insertions, using deep whole-genome sequencing of neuronal and glial fractions and machine-learning analysis.

Trypanosomes evade the immune response through antigenic variation of a surface coat containing variant surface glycoproteins (VSG). They also express invariant surface glycoproteins (ISGs), which are less well understood. Here, Macleod et al. show that ISG65 of T. brucei is a receptor for complement component 3. They provide the crystal structure of T. brucei ISG65 in complex with complement C3d and show evidence that ISG65 is involved in reducing trypanosome susceptibility to C3-mediated clearance in vivo.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Activated B cells and T cells accumulate within joints of patients with rheumatoid arthritis. Here, the authors use single-cell transcriptome and repertoire profiling to identify clonally expanded synovial B cells and T cells and define their phenotypes and predicted cell-cell interactions.

Rapid and accurate detection of fusion genes is important in cancer diagnostics. Here, the authors demonstrate that targeted RNA sequencing provides fast, sensitive and quantitative gene fusion detection and overcomes the limitations of approaches currently in clinical use.

Many genetic variants have been associated with human traits, but the mechanism is often unknown. Here, the authors integrate local and distal genetic associations with multi-omics datasets to provide a roadmap to understand the underlying mechanisms of GWAS variants on complex traits.