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This flagship study from the European Solve-Rare Diseases Consortium presents a diagnostic framework including bioinformatic analysis of clinical, pedigree and genomic data coupled with expert panel review, leading to 500 new diagnoses in a cohort of 6,000 families with suspected rare diseases.

In this study, the authors performed single-cell RNA-sequencing across various isogenic mutant FUS and TDP43 neurons. Mitochondrial dysfunction emerged as pathway unique to motor neurons demonstrating shared toxic gain of-function mechanisms, uncoupled from protein mislocalization.

Using a zebrafish-based screen, Civiletto and colleagues identify the herb-derived metabolites thymol and carvacrol as activators of autophagy and mitophagy, demonstrating their therapeutic potential in C. elegans and mouse models.

An improved method for detecting proteins phosphorylated by the ERK kinase reveals multiple new in vitro ERK substrates, including three nucleoporin proteins. Nup50 is phosphorylated in FG repeats by ERK2 in vivo and in vitro, suggesting a new mechanism by which MAP kinase signaling controls nuclear translocation of proteins.

Non-reciprocal interactions (NRI) are ubiquitous in active systems, but, in the presence of NRI, it is difficult to predict which microscopic systems correspond to a given macroscopic description. Dinelli et al. relate microscopic and macroscopic dynamics of active mixtures and show that non-reciprocity strongly depends on the scale of description.

The antidiabetic action of metformin raises heptocyte intracellular AMP levels, causing allosteric inhibition of fructose-1,6-bisphosphatase and thus reductions in gluconeogenesis.

The authors find that deletion from Schwann cells of an E3 ubiquitin ligase component called Fbxw7 leads to a phenotype reminiscent of myelination in the central nervous system where a single oligodendrocyte ensheaths multiple axons.

The authors uncover one of the largest mitoribosomes, dedicated to translating only three proteins in lethal human eukaryotic pathogens of the Apicomplexa phylum. All members of mitochondrial DNA-containing Myzozoa, including Toxoplasma gondii, have commandeered three lineage-specific families of RNA-binding proteins to meticulously piece together over 40 mitochondrial rRNA fragments to build an operational mitoribosome.

Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

Zika virus (ZIKV) can infect the central nervous system, but it is not clear how it reaches the brain. Here, Ayala-Nunez et al. show in ex vivo and in vivo models that ZIKV can hitch a ride in monocytes in a Trojan Horse manner to cross the endothelium and disseminate the virus.

Eukaryotes acquired their prokaryotic genes in two episodes of evolutionary influx corresponding to the origin of mitochondria and plastids, respectively, followed by extensive differential gene loss, uncovering a massive imprint of endosymbiosis in the nuclear genomes of complex cells.

In mitosis, Aurora B switches substrate specificity in response to phosphorylation of S227 in the activation loop by a cell cycle-processed active fragment of PKCε. Here, the authors show that this switch protects from chromosome non-disjunction by delaying anaphase entry and promoting TopoIIα-dependent resolution.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Here the authors investigate how the E3 ubiquitin ligase Cryptic Loci Regulator Complex mediates the transition from RNAi-dependent co-transcriptional gene silencing to transcriptional gene silencing suggesting the involvement of phase separation in the transition during heterochromatin formation.

Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.

Nicotinamide adenine dinucleotide (NAD⁺) sustains cellular energy metabolism, functions as a substrate of Sirt and PARP enzymes, and its supplementation is explored therapeutically in aging and other contexts. Here the authors provide insight into the role of endogenous NAD⁺ metabolism by studying nicotinamide riboside kinase 1 (NRK1) deficient mice.

The perennial grass Miscanthus is a promising biomass crop. Here, via genomics and transcriptomics, the authors reveal its allotetraploid origin, characterize gene expression associated with rhizome development and nutrient recycling, and describe the hybrid origin of the triploid M. x giganteus.

Cells trigger an unfolded protein response (UPR) in the endoplasmic reticulum, but its regulation by mitochondria is unclear. Here, the authors report a 54-residue microprotein PIGBOS that participates in inter-organelle contact between the endoplasmic reticulum and the mitochondria and may regulate UPR.

The IFNγ response pathway is associated with response to immunotherapy in cancer. Here the authors show that high levels of the IFNγ-receptor (IFNγ-R1) affect the outcome of immunotherapy in a context-dependent fashion and identify the E3 ubiquitin ligase STUB1 as a negative regulator of IFNγ-R1/JAK1 expression in cancer cells.

The (G4C2)-RNA hexanucleotide repeat expansion upstream of the start codon of the C9orf72 gene plays a critical role in familial ALS. The authors show that Sig1R, a ligand-regulated molecular chaperone, counteracts the aberrant nucleocytoplasmic distribution of Ran caused by the (G4C2)-RNA repeats.

The ability to manage ill health and care needs might be affected by who a person lives with. Here, authors show that living alone or with co-residents with multimorbidity poses additional risk for unplanned hospitalisation and care home transition beyond an individual’s characteristics.

The biogenesis of AMPA-type glutamate receptor (AMPAR) complexes is only partially understood. Here the authors identify transient assemblies of GluA1-4 proteins and proteins FRRS1l/CPT1c that drive formation of mature AMPAR complexes in the ER. Mutations in FRRS1l are associated with intellectual disability and epilepsy in three families.

Female Swallowtail butterflies will only lay their eggs on a small number of plants, which they choose by detecting specific chemicals on the leaf surface. Here, a gustatory receptor,PxutGr1, is identified in Papilio xuthus, which is used by the butterfly to detect synephrine when selecting a host plant.

Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al.show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.

A faint gamma-ray burst (GRB 170817A) has been recently detected in coincidence with the gravitational wave (GW) event GW 170817. Here, the authors report that another faint short GRB at a cosmological distance (GRB150101B) and its late time emission are analogous to the neutron star merger event GRB 170817A.

Trigonelline is identified as a human metabolite that can be used for NAD⁺ synthesis and is shown to improve muscle function in aged worms and mice.

Programmed cell death of infected host cells builds up the first line of defence against viruses. Here, Mocarski and colleagues describe the tight regulation of caspase 8-dependent apoptosis and programmed necrosis and discuss how viral inhibitors of cell death may have contributed to the evolution of programmed necrosis to promote host survival.

CCCTC-binding factor (CTCF) is a DNA-binding protein that has various, often seemingly contradictory, roles in gene regulation. This Review describes these disparate functions and how the context-dependent looping of DNA regions by CTCF is emerging as a potential unifying mechanism that underpins these diverse roles.

The involvement of the RNA-binding protein TDP43 in neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration, has become well established. However, the mechanisms by which the protein is linked to the disease process remain unclear. Trojanowski and colleagues describe our current understanding of TDP43 pathology and discuss how gains of toxic function or losses of normal TDP43 function may contribute to neurodegeneration.

Platelets from patients with visceral obesity, which highly express miR-19a, can strongly promote colon cancer growth in a xenograft colon cancer model, with miR-19a administration by AAV injection increasing tumor growth.

Cunningham-Burley, McCartney, Campbell, Flaig, Orange et al. assess the ethics and potential benefit of secondary data use from newborn blood spot archives for research in a Citizen’s jury that agreed this was in the public interest. They also investigate and demonstrate the feasibility of using the archives for research purposes.

Perico et al. use co-expression analysis and a FRET-FLIM approach to show that the Arabidopsis MyoB myosin receptor, MRF7, triggers the relocation of Myosin XI-K to the Golgi. As such, this study provides evidence for plant myosin recruitment and control of organelle movement.