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In light of the disappointing termination of clinical trials with potent complex I inhibitors, such as IACS-010759, justification for oxidative phosphorylation inhibitors and mitochondrial targeting strategies has been called into question. Consideration of these agents’ potency, tissue selectivity and toxicity demonstrate what lessons can be learned from this failure and where new opportunities lie.

SiR-Hoechst (SiR-DNA) is a far-red fluorescent DNA probe being used widely for time-lapse imaging of living cells that is reported to be minimally toxic at concentrations as high as 10–25 µM. However, measuring nuclear import of Cyclin B1, inhibition of mitotic entry, and the induction of γH2AX foci in cultured human cells reveals that SiR-Hoechst induces DNA damage responses and G2 arrest at concentrations well below 1 µM. SiR-Hoechst is useful for live cell imaging, but it should be used with caution and at the lowest practicable concentration.

Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. UK National Institute for Health Research, Health Technology Assessment Programme.

Optical atomic clocks 1 , 2 use electronic energy levels to precisely keep track of time. A clock based on nuclear energy levels promises a next-generation platform for precision metrology and fundamental physics studies. Thorium-229 nuclei exhibit a uniquely low-energy nuclear transition within reach of state-of-the-art vacuum ultraviolet (VUV) laser light sources and have, therefore, been proposed for construction of a nuclear clock 3 , 4 . However, quantum-state-resolved spectroscopy of the 229m Th isomer to determine the underlying nuclear structure and establish a direct frequency connection with existing atomic clocks has yet to be performed. Here, we use a VUV frequency comb to directly excite the narrow 229 Th nuclear clock transition in a solid-state CaF 2 host material and determine the absolute transition frequency. We stabilize the fundamental frequency comb to the JILA 87 Sr clock 2 and coherently upconvert the fundamental to its seventh harmonic in the VUV range by using a femtosecond enhancement cavity. This VUV comb establishes a frequency link between nuclear and electronic energy levels and allows us to directly measure the frequency ratio of the 229 Th nuclear clock transition and the 87 Sr atomic clock. We also precisely measure the nuclear quadrupole splittings and extract intrinsic properties of the isomer. These results mark the start of nuclear-based solid-state optical clocks and demonstrate the first comparison, to our knowledge, of nuclear and atomic clocks for fundamental physics studies. This work represents a confluence of precision metrology, ultrafast strong-field physics, nuclear physics and fundamental physics. A vacuum ultraviolet frequency comb is used to directly excite the narrow 229 Th nuclear clock transition in a solid-state CaF 2 host material, marking the start of nuclear-based solid-state optical clocks.

The new Longwood fountain will incorporate effects that would make Louis XIV, the patron of Versailles, hold tight to his powdered wig: a total of 1,719 coordinated jets and streams, some emanating from robotic nozzles that swivel to make the jets dance; water pumps that dial the pressure up or down; LED lights that will bring colours never before seen in fountains; bursts of water propelled by compressed air; fire incorporated into the columns of water; an advanced sound system; and software programming that will blend the spectacle together with split-second synchronisation. The backbone of the garden is an entirely new network of underground concrete tunnels - 1,400 linear feet that will house and provide maintenance access to the miles of plumbing, electrical and propane gas lines, and the pumps and valves that animate the water displays. [...]colour is much more complicated than that.\"

Measuring protein turnover in cells has been greatly assisted by fluorescent timers (FT). However, FT quantification requires relatively high fluorescence intensity samples, prohibiting their use for proteins with low or non-uniform expression like transcription factor Nrf2, the master regulator of redox homeostasis. To visualise changes in stability/turnover of Nrf2, we constructed a genetically encoded tag combining sfGFP and mCherry and used intensity-independent Fluorescence Lifetime Imaging (FLIM) to measure Förster Resonance Energy Transfer (FRET) within the tag (named FLIM-timer). We show that the ability of mCherry to act as a FRET-acceptor develops as the protein matures, allowing the use of FLIM-FRET as a readout of the FLIM-timer. FLIM-timer-tagged Nrf2 allowed to observe differences in its turnover between cellular compartments with equal precision in regions of high and low brightness. The reduction in fluorescence lifetime of FLIM-timer-Nrf2 confirmed its stabilisation by sulforaphane. Depletion of a degron for either Keap1-Cul3 or SCF β-TrCP -mediated degradation decreased the fluorescence lifetime of Nrf2-FLIM-timer. FLIM-timer labelled cyclin B was also successfully used to track its destabilisation during mitotic exit. Thus, FLIM-timer methodology increases the FT applicability for visualisation and quantification of protein turnover, expanding it to cells with low and variable levels of any protein of interest.