Summary Background Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)‐4 and IL‐13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate‐to‐severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate‐to‐severe AD inadequately controlled with topical medications. Objectives To further characterize the safety of dupilumab by evaluating clinical laboratory findings from three randomized, double‐blinded, placebo‐controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). Methods Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. Results Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab‐treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab‐treated and placebo‐treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. Conclusions There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports the use of dupilumab as a systemic treatment for moderate‐to‐severe AD that does not require laboratory monitoring. What's already known about this topic? Long‐term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side‐effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)‐4 and IL‐13] is approved for the treatment of patients with inadequately controlled, moderate‐to‐severe AD. In 16‐week and 52‐week studies, dupilumab demonstrated a positive risk/benefit profile in moderate‐to‐severe AD. What does this study add? This study is the first comprehensive analysis of dupilumab laboratory safety data of the 16‐week SOLO 1 & 2 (pooled N = 1376) and 52‐week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate‐to‐severe AD treated with dupilumab. Our data support the use of dupilumab as a systemic treatment for the long‐term management of moderate‐to‐severe AD without routine laboratory monitoring in clinical practice.

SummaryPectate lyase genes have been documented as excellent candidates for improvement of fruit firmness. However, implementation of pectate lyase in regulating fruit postharvest deterioration has not been fully explored. In this report, 22 individual pectate lyase genes in tomato were identified, and one pectate lyase gene SlPL (Solyc03g111690) showed dominant expression during fruit maturation. RNA interference of SlPL resulted in enhanced fruit firmness and changes in pericarp cells. More importantly, the SlPL‐RNAi fruit demonstrated greater antirotting and pathogen‐resisting ability. Compared to wild‐type, SlPL‐RNAi fruit had higher levels of cellulose and hemicellulose, whereas the level of water‐soluble pectin was lower. Consistent with this, the activities of peroxidase, superoxide dismutase and catalase were higher in SlPL‐RNAi fruit, and the malondialdehyde concentration was lower. RNA‐Seq results showed large amounts of differentially expressed genes involved in hormone signalling, cell wall modification, oxidative stress and pathogen resistance. Collectively, these data demonstrate that pectate lyase plays an important role in both fruit softening and pathogen resistance. This may advance knowledge of postharvest fruit preservation in tomato and other fleshy fruit.

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SummaryIn Arabidopsis, the miR171‐GRAS module has been clarified as key player in meristem maintenance. However, the knowledge about its role in fruit crops like tomato (Solanum lycopersicum) remains scarce. We previously identified tomato SlGRAS24 as a target gene of Sly‐miR171. To study the role of this probable transcription factor, we generated transgenic tomato plants underexpressing SlGRAS24, overexpressing SlGRAS24, overexpressing Sly‐miR171 and expressing β‐glucuronidase (GUS) under the SlGRAS24 promoter (proSlGRAS24‐GUS). Plants overexpressing SlGRAS24 (SlGRAS24‐OE) had pleiotropic phenotypes associated with multiple agronomical traits including plant height, flowering time, leaf architecture, lateral branch number, root length, fruit set and development. Many GA/auxin‐related genes were down‐regulated and altered responsiveness to exogenous IAA/NAA or GA 3 application was observed in SlGRAS24‐OE seedlings. Moreover, compromised fruit set and development in SlGRAS24‐OE was also observed. These newly identified phenotypes for SlGRAS24 homologs in tomato were later proved to be caused by impaired pollen sacs and fewer viable pollen grains. At anthesis, the comparative transcriptome results showed altered expression of genes involved in pollen development and hormone signalling. Taken together, our data demonstrate that SlGRAS24 participates in a series of developmental processes through modulating gibberellin and auxin signalling, which sheds new light on the involvement of hormone crosstalk in tomato development.

Fluorescent Ca2+ indicators have been essential for the analysis of Ca2+ signaling events within the cells of the CNS. However, a systematic evaluation of their potential adverse effects is lacking. Here we show that chemical Ca2+ indicators, but not a genetically encoded Ca2+ indicator, potently suppress the activity of Na+- and K+-dependent adenosine triphosphatase (Na,K-ATPase), independently from their Ca2+ chelating activity. Loading of commonly utilized Ca2+ indicators, including Fluo-4 acetoxymethyl (AM), Rhod-2 AM, Fura-2 AM and the Ca2+ chelator BAPTA AM, in cultures of neurons, astrocytes, cardiomyocytes and kidney proximal tubule epithelial cells suppressed Na,KATPase activity by 30–80%. Ca2+ indicators also suppressed agonist-induced activation of Na,K-ATPase, altered metabolic status and produced a dose-dependent loss of cell viability. In vivo, loading of Ca2+ indicators significantly altered brain extracellular concentrations of K+ and ATP. A critical review of the previous observations based on chemical Ca2+ indicators is therefore warranted.