Explore the vast range of titles available.

Identifying effective therapeutic targets for Parkinson’s disease (PD) is challenging, with no current disease-modifying therapies available. To address this, The Michael J. Fox Foundation for Parkinson’s Research launched the Targets to Therapies (T2T) initiative, uniting experts to prioritize and validate promising targets. T2T aims to develop validation strategies, create comprehensive target data profiles, and build tools to support drug development, ultimately accelerating the discovery of new therapies for PD patients.

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2 , demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy. Several genomic features have been found for acute myeloid leukaemia (AML) but targeted clinical genetic testing fails to predict prognosis. Here, the authors generate an AML prognostic score from RNA-seq data of patients, which successfully stratifies AML patients and which may provide guidance for therapeutic strategies.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2 , which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B , a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. Histones modified in common lymphomas Despite being a focus of research activity for many years, the mutations driving the two most common non-Hodgkin lymphomas — follicular lymphoma and diffuse large B-cell lymphoma — have remained cryptic. Whole genome sequencing, combined with transcriptome analysis and further resequencing of candidate genes in additional tumours, now show that histone methyltransferases and acetylases are frequently affected by mutations in these tumours. This study suggests a previously unappreciated importance of chromatin biology in lymphomagenesis.

Primary triple-negative breast cancers are shown to vary widely and continuously in the degree of clonal evolution and mutational content at the time of diagnosis, with implications for future studies of the disease. Genomics of triple-receptor-negative breast cancers Samuel Aparicio et al . provide an in-depth genomic view of primary triple-negative breast cancers (TNBC), which represent approximately 16% of all breast cancers. TNBC cells are deficient in the expression of receptors for oestrogen, progesterone and epidermal growth factor. Through a combination of transcriptomic data and copy-number variation, this study shows that TNBCs vary widely and continuously in the content of clonal genotypes at the time of diagnosis. This means that future studies will need to consider individual tumour clonal genotypes. Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers 1 . Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time—to our knowledge—in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC 2 , 3 showing more variation than non-basal TNBC. Although p53 (also known as TP53 ), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.

Intrinsic magnetoelectric coupling describes the interaction between magnetic and electric polarization through an inherent microscopic mechanism in a single-phase material. This phenomenon has the potential to control the magnetic state of a material with an electric field, an enticing prospect for device engineering. Here, we demonstrate ‘giant’ magnetoelectric cross-field control in a tetravalent titanate film. In bulk form, EuTiO 3 , is antiferromagnetic. However, both anti and ferromagnetic interactions coexist between different nearest europium neighbours. In thin epitaxial films, strain was used to alter the relative strength of the magnetic exchange constants. We not only show that moderate biaxial compression precipitates local magnetic competition, but also demonstrate that the application of an electric field at this strain condition switches the magnetic ground state. Using first-principles density functional theory, we resolve the underlying microscopic mechanism resulting in G-type magnetic order and illustrate how it is responsible for the ‘giant’ magnetoelectric effect. The ability to control the magnetic order in a material with an electric field will enable low-power non-volatile memories and new types of computer logic. Ryan et al . demonstrate that europium titanate under moderate strain exhibits strong magnetoelectric coupling that could be valuable to this endeavour.

A new family of tunable microwave dielectrics with unparalleled performance at frequencies up to 125 GHz at room temperature has been created, using dimensionality to add and control a local ferroelectric instability in a system with exceptionally low dielectric loss. Microwave-proof insulators Tunable dielectric materials are valuable components for complex microwave circuitry, yet such materials tend to suffer losses when operated at microwave frequencies owing to intrinsic defects in their structures. Che-Hui Lee and colleagues have selected a family of dielectrics known to exhibit exceptionally low loss, and now show how these materials can be engineered to boost their tunability and attain levels of performance that rival all known tunable microwave dielectrics. The miniaturization and integration of frequency-agile microwave circuits—relevant to electronically tunable filters, antennas, resonators and phase shifters—with microelectronics offers tantalizing device possibilities, yet requires thin films whose dielectric constant at gigahertz frequencies can be tuned by applying a quasi-static electric field 1 . Appropriate systems such as Ba x Sr 1− x TiO 3 have a paraelectric–ferroelectric transition just below ambient temperature, providing high tunability 1 , 2 , 3 . Unfortunately, such films suffer significant losses arising from defects. Recognizing that progress is stymied by dielectric loss, we start with a system with exceptionally low loss—Sr n +1 Ti n O 3 n +1 phases 4 , 5 —in which (SrO) 2 crystallographic shear 6 , 7 planes provide an alternative to the formation of point defects for accommodating non-stoichiometry 8 , 9 . Here we report the experimental realization of a highly tunable ground state arising from the emergence of a local ferroelectric instability 10 in biaxially strained Sr n +1 Ti n O 3 n +1 phases with n  ≥ 3 at frequencies up to 125 GHz. In contrast to traditional methods of modifying ferroelectrics—doping 1 , 2 , 3 , 11 , 12 or strain 13 , 14 , 15 , 16 —in this unique system an increase in the separation between the (SrO) 2 planes, which can be achieved by changing n , bolsters the local ferroelectric instability. This new control parameter, n , can be exploited to achieve a figure of merit at room temperature that rivals all known tunable microwave dielectrics 3 .

Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET domain of EZH2 and reduce the ability of PRC2 to trimethylate H3K27 in vitro . Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells 1 . Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-κB pathway 2 , 3 that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified 4 . Here we report recurrent somatic mutations affecting the polycomb-group oncogene 5 EZH2 , which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A ( UTX ), which encodes the histone H3K27me3 demethylase UTX, in several cancer types 6 , EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro .

The Steller sea lion is the largest member of the Otariidae family and is found in the coastal waters of the northern Pacific Rim. Here, we present the Steller sea lion genome, determined through DNA sequencing approaches that utilized microfluidic partitioning library construction, as well as nanopore technologies. These methods constructed a highly contiguous assembly with a scaffold N50 length of over 14 megabases, a contig N50 length of over 242 kilobases and a total length of 2.404 gigabases. As a measure of completeness, 95.1% of 4104 highly conserved mammalian genes were found to be complete within the assembly. Further annotation identified 19,668 protein coding genes. The assembled genome sequence and underlying sequence data can be found at the National Center for Biotechnology Information (NCBI) under the BioProject accession number PRJNA475770.