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The integration of independent pan-cancer CRISPR-Cas9 datasets allows better representation of genomic heterogeneity across different cancer types. Here, the authors propose a strategy for the integration of two large CRISPR-Cas9 screens and report increased coverage of molecular diversity and genetic dependencies.

Striatal spiny neurons (SPNs) transition from a hyperpolarized 'down state' to a sustained depolarized 'up state' to regulate action selection. The authors report that glutamate uncaging on proximal dendritic spines of SPNs evokes somatic up states that track the input time course. However, glutamate uncaging on distal spines evokes up states that last hundreds of milliseconds.

Analysis of large-scale CRISPR screening data, combined with experiments in patient-derived tumour organoid models, identifies PELO as a potential therapeutic target in chromosomal 9p21.3-deleted cancers and microsatellite-unstable cancers harbouring specific mutations.

Using patterned optogenetic stimulation and chronic in vivo imaging of dendritic spines, this study shows that the precise pattern of neural spiking—rather than total number of spikes—is the major determinant of dendritic spine stability in cortical pyramidal neurons.

Parkinson’s disease and L-DOPA-induced dyskinesia are both associated with imbalances in activity between populations of spiny projection neurons. Fieblinger et al.show that homeostatic adaptations in excitability are engaged by these disease states, but synaptic strengths are not scaled accordingly.

The role of ancestry in target discovery remains to be systematically explored. Here, the authors analyse data from 611 genome scale CRISPR/Cas9 viability experiments in human cell line models as part of The Cancer Dependency Map and identify ancestry-associated genetic dependencies.

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.

The authors used long-read sequencing to reveal novel isoforms and differential transcript use in a transgenic model of tau pathology. Similar patterns were found in the human cortex, supporting a role for alternative splicing in Alzheimer’s disease.

The pathology in Parkinson's disease is known to extend beyond mesencephalic dopaminergic neurons, but it is unclear why. Here the authors show that vulnerable neurons in the dorsal motor nucleus of the vagus have similar physiological features, including basal mitochondrial oxidant stress, providing an insight into the distributed disease pathology.

The Cancer Dependency Map (DepMap) is a data repository and research platform that can be utilized to systematically identify cancer vulnerabilities. Here Arafeh, Shibue et al. outline the current limitations and future strategies to enhance the DepMap project.

Combinatorial CRISPR screens can be utilized to identify genetic interactions and functional redundancies of multiple genes. Here, the authors benchmark ten digenic CRISPR technologies and identify novel Cas9 tracrRNA combinations that show superior performance.

Integrating independent large-scale pharmacogenomic screens can enable unprecedented characterization of genetic vulnerabilities in cancers. Here, the authors show that the two largest independent CRISPR-Cas9 gene-dependency screens are concordant, paving the way for joint analysis of the data sets.

Cancer cells possess unique molecular features that can confer an increased dependence on specific genes. Here, the authors use CRISPR-Cas9 screens to identify selectively essential genes and therapeutic targets in chordoma.

Golub and colleagues identify the phosphate exporter XPR1 as a therapeutic vulnerability in ovarian and uterine cancers, and show that phosphate efflux inhibition reduces tumor cell viability through accumulation of intracellular phosphate.

A pediatric cancer dependency map generated with genome-scale CRISPR–Cas9 loss-of-function screens in 82 pediatric cancer cell lines highlights genetic dependencies across a range of tumor types.

Integrated analyses of multiple large-scale screenings can be complicated by batch effects and technical artefacts. McFarland et al. introduce DEMETER2, a hierarchical model coupled with model-based normalization, which allows the assessment of differential dependencies across genes and cell lines.

T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Mitsiades and colleagues utilize functional genomics data in over 700 cancer cell lines, to identify genes with preferentially essential functions in multiple myeloma, which may represent targets for precision medicine strategies.

Noncanonical open reading frames are shown to be essential for cancer cell function.

A combination of genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling enables the discovery of therapeutically targetable tumor dependencies in rare tumors.