The brutal attack on Ukraine by the Russian Federation has shocked the world. While the world works to end the violence and help refugees, as a scientific journal, our thoughts are also with those in the scientific community who are directly or indirectly impacted by the war. We have been inspired by and applaud the labs around the world that have opened their doors to displaced scientists and remain committed to supporting scientists, whoever and wherever they are. Because science requires collaboration and trust, we urge the scientific community to continue efforts like this and to remain united, especially in times as difficult as these. In this Voices piece, we feature short comments from scientists from Ukraine and scientists from Russia. This small sampling is far from exhaustive, but our sincere thanks go to those scientists who were willing to share their thoughts on this volatile and emotionally charged situation; the views expressed are those of the contributors alone. We join the world in hoping for a swift resolution to the conflict, for the good of humanity.

Dr. Deborah J. Cook's contributions in the field of critical care have not only impacted the intensive care unit (ICU) patients she treats and countless others worldwide but have also helped establish research programs and clinical trials as integral components of improving care and outcomes for the most seriously ill. Lara Szewczak spoke with Dr. Cook, recipient of the 2022 Canada Gairdner Wightman award, about critical care research, her reflections on the COVID-19 pandemic, and her views on mentorship. An edited version of this conversation is presented below.

A game-changing intervention in the COVID-19 pandemic has been the rapid implementation of highly effective vaccines against SARS-CoV-2. The 2022 Canada Gairdner International Award recognizes Pieter Cullis, Katalin Karikó, and Drew Weissman "for their pioneering work developing nucleoside-modified mRNA and lipid nanoparticle (LNP) drug delivery: the foundational technologies for the highly effective COVID-19 mRNA vaccines." Cell editor Cheri Sirois caught up with Pieter to discuss how a long interest in basic and applied questions in lipid biology led to this fortuitous collaboration. Excerpts of the conversation are presented below.

Maternal and childhood mortality are health indicators that show very wide gaps between rich and poor, and between countries. The 2022 John Dirks Global Health Award recognizes Zulfiqar Bhutta "for the development and evaluation of evidenced-based interventions in child and maternal health for marginalized populations, focusing on outcomes for the 'first thousand days' of life." Cell editor Nicole Neuman caught up with Zulfiqar to discuss how he became passionate about maternal and child health, how mentors have shaped his career, and the lessons of his work for high-income countries. Excerpts of the conversation are presented below and have been edited for clarity and conciseness.

Schistosomes cause morbidity and death throughout the developing world due to the massive numbers of eggs female worms deposit into the blood of their host. Studies dating back to the 1920s show that female schistosomes rely on constant physical contact with a male worm both to become and remain sexually mature; however, the molecular details governing this process remain elusive. Here, we uncover a nonribosomal peptide synthetase that is induced in male worms upon pairing with a female and find that it is essential for the ability of male worms to stimulate female development. We demonstrate that this enzyme generates β-alanyl-tryptamine that is released by paired male worms. Furthermore, synthetic β-alanyl-tryptamine can replace male worms to stimulate female sexual development and egg laying. These data reveal that peptide-based pheromone signaling controls female schistosome sexual maturation, suggesting avenues for therapeutic intervention and uncovering a role for nonribosomal peptides as metazoan signaling molecules.

Through studies in mice and in humans, Stuart Orkin showed that GATA-1 is a master transcriptional regulator of hematopoiesis. He has highlighted the role of BCL11A in the fetal-adult hemoglobin switch. The Gairdner Foundation Award recognizes Orkin's contribution to the development of gene therapy of sickle cell disease.

This year's Gairdner Foundation Award for Biomedical Research is awarded to John Dick for the discovery of leukemic stem cells and the hierarchical organization of acute myeloid leukemias. His work laid the foundation for the cancer stem cell model with numerous clinical implications for hematopoietic malignancies and solid tumors.

Argonaute proteins use single-stranded RNA or DNA guides to target complementary nucleic acids. This allows eukaryotic Argonaute proteins to mediate RNA interference and long prokaryotic Argonaute proteins to interfere with invading nucleic acids. The function and mechanisms of the phylogenetically distinct short prokaryotic Argonaute proteins remain poorly understood. We demonstrate that short prokaryotic Argonaute and the associated TIR-APAZ (SPARTA) proteins form heterodimeric complexes. Upon guide RNA-mediated target DNA binding, four SPARTA heterodimers form oligomers in which TIR domain-mediated NAD(P)ase activity is unleashed. When expressed in Escherichia coli, SPARTA is activated in the presence of highly transcribed multicopy plasmid DNA, which causes cell death through NAD(P)+ depletion. This results in the removal of plasmid-invaded cells from bacterial cultures. Furthermore, we show that SPARTA can be repurposed for the programmable detection of DNA sequences. In conclusion, our work identifies SPARTA as a prokaryotic immune system that reduces cell viability upon RNA-guided detection of invading DNA.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.

Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.

Small molecules encoded by biosynthetic pathways mediate cross-species interactions and harbor untapped potential, which has provided valuable compounds for medicine and biotechnology. Since studying biosynthetic gene clusters in their native context is often difficult, alternative efforts rely on heterologous expression, which is limited by host-specific metabolic capacity and regulation. Here, we describe a computational-experimental technology to redesign genes and their regulatory regions with hybrid elements for cross-species expression in Gram-negative and -positive bacteria and eukaryotes, decoupling biosynthetic capacity from host-range constraints to activate silenced pathways. These synthetic genetic elements enabled the discovery of a class of microbiome-derived nucleotide metabolites-tyrocitabines-from Lactobacillus iners. Tyrocitabines feature a remarkable orthoester-phosphate, inhibit translational activity, and invoke unexpected biosynthetic machinery, including a class of "Amadori synthases" and "abortive" tRNA synthetases. Our approach establishes a general strategy for the redesign, expression, mobilization, and characterization of genetic elements in diverse organisms and communities.

The Avars settled the Carpathian Basin in 567/68 CE, establishing an empire lasting over 200 years. Who they were and where they came from is highly debated. Contemporaries have disagreed about whether they were, as they claimed, the direct successors of the Mongolian Steppe Rouran empire that was destroyed by the Turks in ∼550 CE. Here, we analyze new genome-wide data from 66 pre-Avar and Avar-period Carpathian Basin individuals, including the 8 richest Avar-period burials and further elite sites from Avar's empire core region. Our results provide support for a rapid long-distance trans-Eurasian migration of Avar-period elites. These individuals carried Northeast Asian ancestry matching the profile of preceding Mongolian Steppe populations, particularly a genome available from the Rouran period. Some of the later elite individuals carried an additional non-local ancestry component broadly matching the steppe, which could point to a later migration or reflect greater genetic diversity within the initial migrant population.

In their recent Nature paper, Garcia-Martin et al. show that sequences within a microRNA influence how much of that microRNA is sent to another cell through extracellular vesicles. This supports a growing body of data demonstrating that cells use RNA to talk, but we know much less about how they listen.

In a recent issue of Nature, Melenhorst et al. perform an extensive analysis of CAR T cells that persist for ten years in CLL patients. They find a dominant cytotoxic CD4+ population, raising the possibility that CD4+ T cells play an important role in durable CAR T cell therapy.

The function and antigen-specificities of tumor-infiltrating B cells are mostly unknown. In a new study by Mazor et al., matrix metalloproteinase 14 (MMP14), a self-antigen that is overexpressed by ovarian cancers, is shown to drive B cell activation and autoantibody production in tertiary lymphoid structures (Mazor et al., 2022).

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems.