Fruits are a key feature defining angiosperms, yet how local growth is coordinated during development to generate diverse fruits remains unclear. Here, we demonstrate that the Capsella rubella C2H2-zinc finger transcription factor JAGGED (CrJAG) controls fruit shape determination by promoting both cell division and anisotropic growth. At the molecular level, CrJAG physically interacts with members of the Capsella rubella MULTICOPY SUPPRESSOR OF IRA1 (CrMSI)  histone chaperone family, increasing the chromatin accessibility and thereby sustaining the expression of genes involved in fruit morphogenesis. The resulting closed chromatin state in Crjag fruits is characterized by a reduction of the active histone marker (H3K18ac) and an increase of the repressive marker (H3K27me3). Further expression and pharmacological treatment analyses indicate that the developmental defects in Crjag fruits are largely attributable to down-regulation of the key cell-cycle regulator CrAUR2. Collectively, our findings therefore suggest that fine-tuning the cell cycle via epigenetic modification represents an additional, essential layer of regulation critical to organ development and diversification.

BACKGROUND:Neisseria meningitidis serogroups A, B, C, W, and Y (MenA, Men B, MenC, MenW, and MenY) cause nearly all invasive meningococcal disease globally, and clinical outcomes are often severe. We aimed to evaluate the safety and immunological non-inferiority of a MenABCWY vaccine, comprising MenB-fHbp and MenACWY-TT, compared with US-licensed vaccines MenB-fHbp and MenACWY-CRM, in healthy adolescents and young adults. METHODS:In this phase 3, observer-blinded, active-controlled trial at 75 sites in the USA, the Czech Republic, Denmark, Hungary, and Poland, healthy individuals aged 10-25 years were randomly allocated (2:1), stratified by previous MenACWY vaccination status, to receive two doses of MenABCWY vaccine (at months 0 and 6) or two doses of MenB-fHbp vaccine (months 0 and 6) plus one dose of MenACWY-CRM vaccine (month 0). This study had two primary immunogenicity objectives: evaluating MenA, MenC, MenW, and MenY immune responses following two doses of MenABCWY versus one dose of MenACWY-CRM in ACWY-naive and ACWY-primed participants, and evaluating MenB immune responses following two doses of MenABCWY versus two doses of MenB-fHbp. Immune responses were evaluated by human serum bactericidal assay using human complement against MenA, MenC, MenW, and MenY strains and four diverse, vaccine-heterologous MenB strains. Non-inferiority was shown if the lower bounds of the 95% CIs for the differences in rates of seroresponse or composite response (all MenB strains combined) exceeded -10%. Safety objectives comprised evaluating frequencies of solicited local reactions and systemic events reported within 7 days after each vaccination and adverse events up to 1 month after the second vaccination. This study is registered with ClinicalTrials.gov, NCT04440163, and with EudraCT, 2019-004313-13, and is completed. FINDINGS:Between June 17, 2020, and Aug 3, 2021, 2431 participants were recruited and randomly allocated. At baseline, the safety population (n=2412) had a median age of 16·0 years (IQR not calculated) and a mean age of 16·1 years (SD 4·55), with 1176 (49%) male and 1236 (51%) female participants. 1881 (78%) participants were White, and 621 (26%) were Hispanic or Latino in ethnicity. Among ACWY-naive participants, differences in MenA, MenC, MenW, and MenY seroresponse rates between vaccination groups receiving two MenABCWY doses versus one MenACWY-CRM dose ranged from 2·5% (95% CI -0·2 to 6·0) for MenA to 41·0% (95% CI 34·4 to 47·5) for MenC. Among ACWY-primed participants, differences in MenA, MenC, MenW, and MenY seroresponse rates between vaccination groups ranged from -3·2% (95% CI -6·5 to 0·5) for MenA to 0·7% (95% CI -2·2 to 4·3) for MenW. The differences in MenB seroresponse rates across test strains between vaccination groups receiving two MenABCWY doses versus two MenB-fHbp doses ranged from 1·4% (95% CI -1·0 to 4·3) for MenB test strains expressing fHbp variant A56 to 10·9% (95% CI 5·2 to 16·6) for MenB test strains expressing fHbp variant B24; the difference in composite response for all MenB test strains was 9·6% (95% CI 4·2 to 15·2). Reactogenicity events, mostly mild to moderate in severity, were reported at similar frequencies across groups; none led to study withdrawal. Similar proportions of each group reported one or more adverse events (368 [21%] of 1763 participants in the MenABCWY group vs 132 [20%] of 649 participants in the MenB-fHbp plus MenACWY-CRM group). INTERPRETATION:The immunological non-inferiority and safety profile of a two-dose MenABCWY series (months 0 and 6) compared with three separate injections of MenB-fHbp (months 0 and 6) and MenACWY-CRM (month 0) for protection against MenA, MenB, MenC, MenW, and MenY indicate that MenABCWY could simplify the vaccination strategy against invasive meningococcal disease through fewer injections, potentially increasing vaccination rates among adolescents and young adults. FUNDING:Pfizer.

Long COVID represents a significant global health challenge with an unclear etiology. Alongside accumulating evidence of mitochondrial dysfunction in patients with acute SARS-CoV-2 infection, a symptomatic overlap exists between long COVID and mitochondrial disorders. However, the genetic underpinnings of mitochondrial dysfunction in long COVID have not been previously explored. We employed whole genome sequencing to analyze 13 patients with severe long COVID to identify genetic defects related to mitochondrial function. We performed extracellular bioenergetics flux analysis on peripheral blood mononuclear cells and proteomics to evaluate cellular bioenergetics and compared the results to those of healthy controls. Our investigation identified 10 variants classified as pathogenic or likely pathogenic and 83 variants of unknown significance affecting a wide range of mitochondria-associated biological functions. Bioenergetics flux analysis in peripheral blood mononuclear cells revealed an altered ATP production rate in four long COVID patients compared to healthy controls. This study presents initial evidence of a potential underlying genetic predisposition to mitochondrial dysfunction in long COVID while demonstrating altered cellular energy capacity in a subset of these patients. These findings open avenues for further research into the role of mitochondrial dysfunction and pathology in patients suffering from long COVID and may pave the way for targeted therapeutic strategies aimed at mitigating mitochondrial dysfunction.

Gynoecium patterning is dependent on the dynamic distribution of auxin, the signalling of which is transduced through several distinct pathways. ETTIN (ETT)-mediated signalling occurs independently of the canonical auxin pathway, and ETT shares partial redundancy with Auxin Response Factor 4 (ARF4) in the gynoecium. ETT and ARF4 were previously hypothesized to translate auxin gradients into patterns of tissue polarity alongside other ARFs. As ARF repressors, ETT/ARF were assumed to antagonistically regulate targets shared with ARF activators of the canonical pathway. Here, comparative transcriptomics identified the distinct and overlapping targets of ETT/ARF4 in the Arabidopsis gynoecium. However, ETT/ARF4 targets with known roles in gynoecium development did not conform to models of A-B ARF antagonism, leaving the relationship with the canonical pathway unclear. Mutants in tir1 afb2 ett were therefore generated in Arabidopsis and Capsella to assess the relationship between the two pathways, and their conservation in species with distinct fruit shapes. The data presented indicate conserved synergism between the two pathways in gynoecium development and suggest a role for ARF4 in the integration of these pathways in Brassicaceae with distinct fruit shapes.

The emergence of molecular biology, along with the use of Arabidopsis thaliana as a model organism, has significantly enhanced our understanding of plant development. Research on Arabidopsis has led to the identification of key regulatory genes involved in various developmental processes. In the past decade, advances in genome sequencing and the decoding of numerous plant genomes have enabled the application of these findings from Arabidopsis to crop species. In this review, leading plant scientists summarize historical insights gained from Arabidopsis studies and highlight their implications for crop development, with the aim of inspiring further research in these promising new areas.

The phytohormone auxin affects processes throughout plant growth and development. While auxin signalling has been mainly attributed to a repressor degradation-based pathway, numerous alternative mechanisms for how auxin mediates its effect have been revealed in recent years. One such mechanism involves a direct auxin-induced switch in the transcriptional regulatory activity of the Auxin Response Factor (ARF) ETTIN (ETT). ETT lacks a conserved C-terminus domain involved in canonical pathway interactions but contains a middle region domain mediating auxin binding. As the ETT clade only exists in the angiosperms, it remains unknown when the pathway evolved. Here we provide evidence for a two-step origin of the ETT clade and its neofunctionalisation through the gain of auxin perception in gynoecium patterning. Phylogenetic analyses reveal the structural divergence of ETT and its paralogue ARF4 after their duplication from an ancestral euphyllophyte ARF3/4 clade. Auxin sensitivity was identified as an ETT-specific innovation that likely originated in the last common angiosperm ancestor. Furthermore, in planta complementation experiments demonstrated the full genetic redundancy of ETT and ARF4 in leaf and ovary development, but a specialised role for the ETT-mediated auxin signalling pathway in style development. Our work thus provides evidence that ETT was recruited from an ancestral role in leaf development and subsequently underwent neofunctionalisation through the acquisition of direct auxin sensing for a novel role in gynoecium patterning. ### Competing Interest Statement The authors have declared no competing interest.

Gynoecium polarity establishment is regulated by auxin, a phytohormone whose signal is transduced through several pathways. The relationship between the ETT and canonical TIR1/AFB pathways, and their relevance for carpel development beyond Arabidopsis thaliana , have not been investigated. The data presented here show that the expression patterns of canonical and ETT-mediated signalling components, and phenotypes of higher order mutants are shared between Arabidopsis and Capsella rubella . tir1 afb2 ett mutants partially phenocopy ett arf4 double mutants, suggesting a role for AUXIN RESPONSE FACTOR 4 (ARF4) in the integration of canonical and ETT-mediated signalling. Comparative transcriptomics revealed that the auxin-independent mis-regulation of YABBY genes correlate with patterning defects observed in Arabidopsis ett arf4 mutants. Together, the data presented suggest conserved synergism between canonical and ETT-mediated pathways in gynoecium polarity establishment in the Brassicaceae . Finally, the data suggest that ETT/ARF4 function to prevent the auxin-induced expression of a range of targets in Arabidopsis , consistent with activator-repressor ARF antagonism, and implying that the maintenance of auxin insensitivity by repressive ARFs is important for a range of biological processes. Summary Statement Here the relationship between canonical and ETT-mediated auxin signalling machineries is investigated in Arabidopsis and Capsella revealing conserved synergism between these two pathways in Brassicaceae with distinct fruit shapes. ### Competing Interest Statement The authors have declared no competing interest.

Staphylococcus aureus is a major cause of prosthetic vascular graft or endograft infections (VGEIs) and the optimal choice of antibiotics is unclear. We investigated various antibiotic choices as either monotherapy or combination therapy with rifampicin against MRSA in vitro and in vivo.Fosfomycin, daptomycin and vancomycin alone or in combination with rifampicin was used against MRSA USA300 FPR3757. Each antibiotic was tested for synergism or antagonism with rifampicin in vitro, and all antibiotic regimens were tested against actively growing bacteria in media and non-growing bacteria in buffer, both as planktonic cells and in biofilms. A rat model of VGEI was used to quantify the therapeutic efficacy of antibiotics in vivo by measuring bacterial load on grafts and in spleen, liver and kidneys.In vitro, rifampicin combinations did not reveal any synergism or antagonism in relation to growth inhibition. However, quantification of bactericidal activity revealed a strong antagonistic effect, both on biofilms and planktonic cells. This effect was only observed when treating active bacteria, as all antibiotics had little or no effect on inactive cells. Only daptomycin showed some biocidal activity against inactive cells. In vivo evaluation of therapy against VGEI contrasted the in vitro results. Rifampicin significantly increased the efficacy of both daptomycin and vancomycin. The combination of daptomycin and rifampicin was by far the most effective, curing 8 of 13 infected animals.Our study demonstrates that daptomycin in combination with rifampicin shows promising potential against VGEI caused by MRSA. Furthermore, we show how in vitro evaluation of antibiotic combinations in laboratory media does not predict their therapeutic effect against VGEI in vivo, presumably due to a difference in the metabolic state of the bacteria.

In animals and plants, organ shape is primarily determined during primordium development by carefully coordinated growth and cell division1–3. Rare examples of post-primordial change in morphology (reshaping) exist that offer tractable systems for the study of mechanisms required for organ shape determination and diversification. One such example is morphogenesis in Capsella fruits whose heart-shaped appearance emerges by reshaping of the ovate spheroid gynoecium upon fertilization4. Here we use whole-organ live-cell imaging and single-cell RNA sequencing (scRNA-seq) analysis to show that Capsella fruit shape determination is based on dynamic changes in cell growth and cell division coupled with local maintenance of meristematic identity. At the molecular level, we reveal an auxin-induced mechanism that is required for morphological alteration and ultimately determined by a single cis-regulatory element. This element resides in the promoter of the Capsella rubella SHOOTMERISTEMLESS5 (CrSTM) gene. The CrSTM meristem identity factor positively regulates its own expression through binding to this element, thereby providing a feed-forward loop at the position and time of protrusion emergence to form the heart. Independent evolution of the STM-binding element in STM promoters across Brassicaceae species correlates with those undergoing a gynoecium-to-fruit shape change. Accordingly, genetic and phenotypic studies show that the STM-binding element is required to facilitate the shape transition and suggest a conserved molecular mechanism for organ morphogenesis. This study identifies a molecular mechanism promoting fruit shape variation. Local meristem identity is maintained through autoregulatory activation of the STM gene to allow post-fertilization changes in fruit morphology.

In animals and plants, organ shape is primarily determined during primordium development by carefully coordinated growth and cell division 1-3 . Rare examples of post-primordial change in morphology (reshaping) exist that offer tractable systems to study mechanisms required for organ-shape determination and diversification. One such example is the heart-shape formation of Capsella fruits that occurs by reshaping the ovate spheroid gynoecium upon fertilization 4 . Here we use whole-organ live-imaging to show that dynamic changes in growth and cell division coupled with local maintenance of meristematic identity drives Capsella fruit-shape formation. At the molecular level, we reveal an auxin-induced mechanism ultimately descending on a single cis regulatory element to mediate morphological alteration. This element resides in the promoter of the Capsella rubella SHOOTMERISTEMLESS 5 ( CrSTM ) gene. The CrSTM meristem identity factor positively regulates its own expression through binding to this element thereby providing a feed-forward loop at the position and time when protrusions emerge to form the heart. Independent evolution of the STM-binding element in STM promoters across Brassicaceae species correlates with those undergoing a gynoecium-to-fruit metamorphosis. Accordingly, genetic and phenotypic studies showed that the STM-binding element is required to facilitate the shape transition and reveals a conserved molecular mechanism for organ morphogenesis.