The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif.

Comment in Sci Signal. 2022 May 17;15(734):eadc9985. Nat Rev Immunol. 2022 Jul;22(7):408-409. Nat Rev Cancer. 2022 Jul;22(7):377. Trends Cancer. 2022 Aug;8(8):623-625. Cancer Cell. 2022 Aug 8;40(8):812-814.

Comment in Nat Rev Drug Discov. 2022 Jul;21(7):493.

Update of bioRxiv. 2022 Feb 22;:

Comment in Dev Cell. 2022 Jul 25;57(14):1680-1682.

Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

Comment in Cell. 2022 May 26;185(11):1809-1810.

Comment in Trends Biochem Sci. 2022 Dec;47(12):996-998.

Comment in Cell. 2022 May 26;185(11):1807-1808.

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1 retrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 10-4 per locus per generation. Recurrent inversions exhibit a sex-chromosomal bias and co-localize with genomic disorder critical regions. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes specific haplotypes to disease-causing CNVs.

Comment in Cell. 2022 May 26;185(11):1840-1841.

Comment on Cell. 2022 May 26;185(11):1960-1973.e11.

Comment on Cell. 2021 Apr 15;184(8):2212-2228.e12. Cell. 2022 May 26;185(11):1837-1839.

Comment in Curr Biol. 2022 Jun 6;32(11):R535-R538.

Detecting large genomic inversions has long been challenging. In a new study, Porubsky et al. resolve these complex rearrangements in 41 individuals and discover wide regions that undergo recurrent inversions, some of which even toggle back and forth (Porubsky et al., 2022). Many of these regions are associated with genomic disorders.

Comment on Cell. 2022 May 26;185(11):1860-1874.e12.

Comment in Trends Immunol. 2022 Jul;43(7):500-502. Med (N Y). 2022 Jun 10;3(6):358-360.

Comment in Cell Res. 2022 Jul;32(7):603-604.

Atherosclerosis is an inflammatory disease of the large arteries that is the major cause of cardiovascular disease (CVD) and stroke. Here, we review the current understanding of the molecular, cellular, genetic, and environmental contributions to atherosclerosis, from both individual pathway and systems perspectives. We place an emphasis on recent developments, some of which have yielded unexpected biology, including previously unknown heterogeneity of inflammatory and smooth muscle cells in atherosclerotic lesions, roles for senescence and clonal hematopoiesis, and links to the gut microbiome.

Comment in Cell. 2022 May 12;185(10):1625-1627.

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNARBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2.

Erratum in Cell. 2022 Jun 23;185(13):2387-2389.

Comment in Nat Rev Immunol. 2022 Jun;22(6):336-337. Trends Immunol. 2022 Jun;43(6):420-422.

Comment in Signal Transduct Target Ther. 2022 Jul 6;7(1):213.

Comment in Nat Rev Drug Discov. 2022 Jun;21(6):414. Clin Transl Med. 2022 Aug;12(8):e1024.

Comment in Sci Signal. 2022 May 24;15(735):eadd1034. Signal Transduct Target Ther. 2022 Aug 12;7(1):283.

Comment on Cell. 2022 May 12;185(10):1777-1792.e21.

Comment on Cell. 2022 May 12;185(10):1676-1693.e23.

Comment on Science. 2022 Mar 18;375(6586):eabm1670.

Incomplete lineage sorting (ILS) makes ancestral genetic polymorphisms persist during rapid speciation events, inducing incongruences between gene trees and species trees. ILS has complicated phylogenetic inference in many lineages, including hominids. However, we lack empirical evidence that ILS leads to incongruent phenotypic variation. Here, we performed phylogenomic analyses to show that the South American monito del monte is the sister lineage of all Australian marsupials, although over 31% of its genome is closer to the Diprotodontia than to other Australian groups due to ILS during ancient radiation. Pervasive conflicting phylogenetic signals across the whole genome are consistent with some of the morphological variation among extant marsupials. We detected hundreds of genes that experienced stochastic fixation during ILS, encoding the same amino acids in non-sister species. Using functional experiments, we confirm how ILS may have directly contributed to hemiplasy in morphological traits that were established during rapid marsupial speciation ca. 60 mya.

Progress in studying sex as a biological variable (SABV) is slow, and the influence of gendered effects of the social environment on biology is largely unknown. Yet incorporating these concepts into basic science research will enhance our understanding of human health and disease. We provide steps to move this process forward.