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Determination of left–right asymmetry in mouse embryos is achieved by a leftward fluid flow (nodal flow) in the node cavity that is generated by clockwise rotational movement of 200–300 cilia in the node. The precise action of nodal flow and how much flow input is required for the robust read-out of left–right determination remains unknown. Here we show that a local leftward flow generated by as few as two rotating cilia is sufficient to break left–right symmetry. Quantitative analysis of fluid flow and ciliary rotation in the node of mouse embryos shows that left–right asymmetry is already established within a few hours after the onset of rotation by a subset of nodal cilia. Examination of various ciliary mutant mice shows that two rotating cilia are sufficient to initiate left–right asymmetric gene expression. Our results suggest the existence of a highly sensitive system in the node that is able to sense an extremely weak unidirectional flow, and may favour a model in which the flow is sensed as a mechanical force. The left–right asymmetry of an organism is patterned during development and is determined by fluid flow created by the movement of cilia. In this study, the asymmetry is shown to be determined early after the movement of cilia is established and that only two rotating cilia are required for breaking symmetry.

BI 1839100 is a selective antagonist of transient receptor potential ankyrin 1 (TRPA1). Topically applied TRPA1‐agonistic allyl isothiocyanate (AITC), inducing non‐invasively measurable increased dermal blood flow (DBF), is known as a skin challenge model to assess TRPA1‐target engagement and pharmacodynamic (PD) activity of TRPA1 inhibitors. This study aims to support the pharmacological rationale of BI 1839100 based on preclinical evidence and to test its safety, pharmacokinetic (PK) profile, and PD effects using an AITC skin challenge in a phase I first‐in‐human clinical study. In vitro and in vivo experiments were conducted in human TRPA1‐overexpressing human embryonal kidney (HEK)293 cells and mice, respectively. Exposure to BI 1839100 and AITC demonstrated a BI 1839100 exposure‐related reduction of AITC‐induced Ca2+ increase in HEK293 cells and skin edema in mice. Healthy male participants, aged 18–45 years, were randomized within 10 cohorts in the single‐ascending dose part (n = 80) and two cohorts in the PD part (n = 32). All received single doses of BI 1839100/placebo followed by safety and PK measurements. In the PD part, participants underwent an AITC skin challenge twice; at baseline and at time to peak drug concentration after BI 1839100/placebo administration. No significant imbalance in occurrence of adverse events was detected between single doses of BI 1839100 up to 300 mg and placebo, and PK profiles were dose‐proportional in the 40–300 mg range. BI 1839100 demonstrated a dose‐dependent inhibitory effect on DBF after the AITC skin challenge, indicating TRPA1‐targeted pharmacological activity and potentiating BI 1839100 for further clinical development for a broad range of TRPA1 antagonistic applications.