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Optimized base editors targeting the exon-7 mutation in SMN2 restore expression of the survival motor neuron (SMN) protein to normal levels, as shown in mice with spinal muscular atrophy and in fibroblasts from patients with this genetic disease.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

First-in-human combined intrathalamic and intrathecal gene therapy in two patients with Tay-Sachs disease provides early evidence on the safety and feasibility of the approach.

A phase 1/2 trial of dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis, administered by bilateral intrathalamic, cisterna magna and intrathecal delivery found a dose-dependent biochemical correction of the disease.

Endogenous retroviruses, or genomic relics of ancient viral infection, have been associated with certain neurodegenerative diseases. Here, Liu et al. report a pathway by which reactivated viral gene products contribute to intercellular protein aggregate spreading.

Here the authors investigate of the structural basis of substrate recognition and the catalytic mechanism of the mannosyltransferase PimE, which is crucial for the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs) in Mycobacterium tuberculosis.

Targetable delivery vectors for genetic cargo are needed. Here the authors report a modular platform with separate fusion and targeting components—Delivery to Intended REcipient Cells Through Envelope Design (DIRECTED)—and show cell type-specific delivery.

Interleukin-13 receptor alpha 2 is highly expressed in glioblastoma multiforme but its role in this malignancy is unclear. Here the authors show that this receptor interacts with mutant EGFR, stimulating its kinase activity, thus inducing proliferation.

The dogma is that limb muscle cells originate from somite, while connective tissue fibroblasts derive from lateral plate mesoderm. Here the authors identify a fibroblast population that undergoes myoblast conversion in response to BMP and contributes nuclei to myotubes at the myotendinous junction.

Extracellular vesicles (EVs) act as a conduit for intercellular communication through the exchange of cellular materials without direct cell-to-cell contacts. Here the authors develop a multiplexed reporter system that allows monitoring of EV exchange, cargo delivery and protein translation between different cell populations.

This international Consensus Statement provides guidelines on the management of pituitary incidentalomas.

Cryo-EM characterization of Agrobacterium phage 7-7-1 reveals the structural composition and flexibility of the phage, showing how capsid fibers initiate binding to the host flagellum before engaging surface receptors to establish infection.

Sonani et al. report the cryo-EM structures of the Milano phage tail, unraveling the mechanism of its flexible-to-rigid transformation, the inter-chain disulfide network hindering tail contraction and the structural organization of receptor binding proteins.

Mutations in profilin 1 (PFN1), which modulates actin dynamics, are associated with ALS. Here the authors show that expression of ALS-PFN1 is sufficient to induce deficits in human microglia-like cells, including impaired phagocytosis and lipid metabolism, and that gain-of-function interactions between ALS-PFN1 and PI3P may underlie these deficits.

Tumour-associated myeloid cells have been linked to patient outcome and treatment response in multiple cancer types. Here, the authors use deconvolution of single cell RNA-sequencing data to identify myeloid populations which are prognostic across cancer types.

The CDP-alcohol phosphatidyltransferase family is involved in phospholipid biosynthesis. Here, Nogly et al.report the crystal structure of a bifunctional enzyme from this family, show that magnesium is required for enzymatic activity, and propose a structure-based catalytic mechanism.

Adenine base editors are evolved to be more efficient and more compatible with Cas9 variants.

A divalent siRNA architecture enables sustained silencing of gene expression in deep regions of the brain.

WABS patient derived cells display loss of sister chromatid cohesion. Here the authors by analyzing WABS patient derived cells, reveal a role of the DDX11 helicase in resolving G-Quadruplex structures to support sister chromatid cohesion.

Amphiphilic self-assembly is ubiquitous both in nature and synthetic systems, yet the underlying mechanisms governing the transition from molecules to assemblies have not yet been fully resolved. Now, the role of liquid–liquid phase separation prior to the assembly process has been explored through the detailed analysis of a model block-copolymer system.

Emerging variants of SARS-CoV-2 raise concerns about vaccine efficiency. Here, the authors present a post-hoc analysis for the ChAdOx1 nCoV-19 (AZD1222) vaccine trial in Brazil and provide efficacy against symptomatic COVID-19 caused by the Zeta (P.2) and other variants.

In a preclinical study, the delivery of an AAV-based gene therapy encoding GDNF in the brain prevented the return to alcohol use behaviors in a non-human primate model.

Epidemics of whooping cough caused by Bordetella pertussis have been seen and are linked to waning immunity globally. Here the authors explore responses to inactivated poliovirus (IPV) in the Tdap-IPV vaccine and show it stimulates early antiviral responses in monocytes and dendritic cells that are associated with long-lived pertussis antibody responses.

The past year has seen several new developments in the field of male reproductive health, including a major revision of how urologists should assess semen quality following the release of new WHO guidelines, novel approaches to sperm selection for intracytoplasmic sperm injection, and changes in how clinicians might evaluate and treat patients with hematospermia.

Hedgehog (Hh) proteins are involved in multiple developmental processes. Hedgehog-interacting proteins (Hhips) bind and inhibit vertebrate Hh proteins. A structure of HHIP in complex with human SHH now shows a distinct binding site from previous ligand structures, with the pseudocatalytic site having a key role in binding.

Materials that can generate physical unclonable functions (PUF) are needed for anti-counterfeiting applications. Here, self-assembly of liquid crystals with ionic liquids in a gelatin matrix is used to generate biodegradable optical PUF tags.

DeActs are genetically encoded tools that perturb the actin cytoskeleton. In contrast to drugs such as latrunculin, they can be targeted to specific cell types, which is demonstrated in the developing mouse brain and in Caenorhabditis elegans.

The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.