Aims. The solar activity in the past millennia can only be reconstructed from cosmogenic radionuclide proxy records in terrestrial archives. However, because of the diversity of the proxy archives, it is difficult to build a homogeneous reconstruction. All previous studies were based on individual, sometimes statistically averaged, proxy datasets. Here we aim to provide a new consistent multiproxy reconstruction of the solar activity over the last 9000 years, using all available long-span datasets of 10 Be and 14 C in terrestrial archives. Methods. A new method, based on a Bayesian approach, was applied for the first time to solar activity reconstruction. A Monte Carlo search (using the χ 2 statistic) for the most probable value of the modulation potential was performed to match data from different datasets for a given time. This provides a straightforward estimate of the related uncertainties. We used six 10 Be series of different lengths (from 500-10000 years) from Greenland and Antarctica, and the global 14 C production series. The 10 Be series were resampled to match wiggles related to the grand minima in the 14 C reference dataset. The stability of the long data series was tested.Results. The Greenland Ice-core Project (GRIP) and the Antarctic EDML (EPICA Dronning Maud Land) 10 Be series diverge from each other during the second half of the Holocene, while the 14 C series lies in between them. A likely reason for the discrepancy is the insufficiently precise beryllium transport and deposition model for Greenland, which leads to an undercorrection of the GRIP series for the geomagnetic shielding effect. A slow 6-7-millennia variability with lows at ca. 5500 BC and 1500 AD in the longterm evolution of solar activity is found. Two components of solar activity can be statistically distinguished: the main component, corresponding to the 'normal' moderate level, and a component corresponding to grand minima. A possible existence of a component representing grand maxima is indicated, but it cannot be separated from the main component in a statistically significant manner. Conclusions.A new consistent reconstruction of solar activity over the last nine millennia is presented with the most probable values of decadal sunspot numbers and their realistic uncertainties. Independent components of solar activity corresponding to the main moderate activity and the grand-minimum state are identified; they may be related to different operation modes of the dynamo.

Context. Changes in solar irradiance and in its spectral distribution are among the main natural drivers of the climate on Earth. However, irradiance measurements are only available for less than four decades, while assessment of solar influence on Earth requires much longer records. Aims. The aim of this work is to provide the most up-to-date physics-based reconstruction of the solar total and spectral irradiance (TSI/SSI) over the last nine millennia. Methods. The concentrations of the cosmogenic isotopes 14 C and 10 Be in natural archives have been converted to decadally averaged sunspot numbers through a chain of physics-based models. TSI and SSI are reconstructed with an updated SATIRE model. Reconstructions are carried out for each isotope record separately, as well as for their composite. Results. We present the first ever SSI reconstruction over the last 9000 years from the individual 14 C and 10 Be records as well as from their newest composite. The reconstruction employs physics-based models to describe the involved processes at each step of the procedure.Conclusions. Irradiance reconstructions based on two different cosmogenic isotope records, those of 14 C and 10 Be, agree well with each other in their long-term trends despite their different geochemical paths in the atmosphere of Earth. Over the last 9000 years, the reconstructed secular variability in TSI is of the order of 0.11%, or 1.5 W/m 2 . After the Maunder minimum, the reconstruction from the cosmogenic isotopes is consistent with that from the direct sunspot number observation. Furthermore, over the nineteenth century, the agreement of irradiance reconstructions using isotope records with the reconstruction from the sunspot number by Chatzistergos et al. (2017) is better than that with the reconstruction from the WDC-SILSO series (Clette et al. 2014), with a lower χ 2 -value.

Reconstructions of the global mean annual temperature evolution during the Holocene yield conflicting results. One temperature reconstruction shows global cooling during the late Holocene. The other reconstruction reveals global warming. Here we show that both a global warming mode and a cooling mode emerge when performing a spatio-temporal analysis of annual temperature variability during the Holocene using data from a transient climate model simulation. The warming mode is most pronounced in the tropics. The simulated cooling mode is determined by changes in the seasonal cycle of Arctic sea-ice that are forced by orbital variations and volcanic eruptions. The warming mode dominates in the mid-Holocene, whereas the cooling mode takes over in the late Holocene. The weighted sum of the two modes yields the simulated global temperature trend evolution. Our findings have strong implications for the interpretation of proxy data and the selection of proxy locations to compute global mean temperatures.

Reliable historical records of total solar irradiance (TSI) are needed for climate change attribution and research to assess the extent to which long-term variations in the Sun's radiant energy incident on the Earth may exacerbate (or mitigate) the more dominant warming in recent centuries due to increasing concentrations of greenhouse gases. We investigate potential impacts of the new Sunspot Index and Long-term Solar Observations (SILSO) sunspot-number time series on model reconstructions of TSI. In contemporary TSI records, variations on time scales longer than about a day are dominated by the opposing effects of sunspot darkening and facular brightening. These two surface magnetic features, retrieved either from direct observations or from solar activity proxies, are combined in TSI models to reproduce the current TSI observational record. Indices that manifest solarsurface magnetic activity, in particular the sunspot-number record, then enable the reconstruction of historical TSI. Revisions to the sunspot-number record therefore affect the magnitude and temporal structure of TSI variability on centennial time scales according to the model reconstruction methodologies. We estimate the effects of the new SILSO record on two widely used TSI reconstructions, namely the NRLTSI2 and the SATIRE models. We find that the SILSO record has little effect on either model after 1885 but leads to greater amplitude solar-cycle fluctuations in TSI reconstructions prior, suggesting many 18th and 19th century cycles could be similar in amplitude to those of the current Modern Maximum. TSI records based on the revised sunspot data do not suggest a significant change in Maunder Minimum TSI values, and comparing that era to the present we find only very small potential differences in estimated solar contributions to climate with this new sunspot record.

The natural compound 1,8-cineol, also known as eucalyptol, is a major constituent of eucalyptus oil. This epoxy-monoterpene is used as flavor and fragrance in consumer goods as well as medical therapies. Due to its anti-inflammatory properties, 1,8-cineol is also applied to treat upper and lower airway diseases. Despite its widespread use, only little is known about the genotoxicity of 1,8-cineol in mammalian cells. This study investigates the genotoxicity and cytotoxicity of 1,8-cineol in human and hamster cells. First, we observed a significant and concentration-dependent increase in oxidative DNA damage in human colon cancer cells, as detected by the Formamidopyrimidine-DNA glycosylase (Fpg)-modified alkaline comet assay. Pre-treatment of cells with the antioxidant N-acetylcysteine prevented the formation of Fpg-sensitive sites after 1,8-cineol treatment, supporting the notion that 1,8-cineol induces oxidative DNA damage. In the dose range of DNA damage induction, 1,8-cineol did neither reduce the viability of colon cancer cells nor affected their cell cycle distribution, suggesting that cells tolerate 1,8-cineol-induced oxidative DNA damage by engaging DNA repair. To test this hypothesis, hamster cell lines with defects in BRCA2 and Rad51, which are essentials players of homologous recombination (HR)-mediated repair, were treated with 1,8-cineol. The monoterpene induced oxidative DNA damage and subsequent DNA double-strand breaks in the hamster cell lines tested. Intriguingly, we detected a significant concentration-dependent decrease in viability of the HR-defective cells, whereas the corresponding wild-type cell lines with functional HR were not affected. Based on these findings, we conclude that 1,8-cineol is weakly genotoxic, inducing primarily oxidative DNA damage, which is most likely tolerated in DNA repair proficient cells without resulting in cell cycle arrest and cell death. However, cells with deficiency in HR were compromised after 1,8-cineol treatment, suggesting a protective role of HR in response to high doses of 1,8-cineol.

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Summary Background The protein kynureninase (KYNU) has recently been reported to participate in the pathological processes of various diseases. Aim To explore the expression and the biological function of KYNU in cutaneous squamous cell carcinoma (cSCC). Methods Expression of KYNU in cSCC cell lines and tissues was firstly evaluated based on the Gene Expression Omnibus and the Oncomine databases. Quantitative reverse transcription–PCR was performed to determine the mRNA expression of KYNU in cSCC cell lines. Small interfering RNA (siRNA) was used for silencing KYNU. The effect of KYNU on the growth and motility of cSCC cells was determined by cell counting kit‐8, wound‐healing and Transwell assays, and western blotting was used to determine the protein expression of KYNU, AKT, phosphoinositide 3‐kinase (PI3K), phosphorylated (p)‐AKT and p‐PI3K. Results KYNU was significantly upregulated in cSCC tissues and cell lines. Knockdown of KYNU using siRNA noticeably suppressed the proliferation, migration and invasion ability of SCL‐1 cells (P < 0.01). Western blotting revealed that phosphorylation of AKT and PI3K was markedly inhibited after silencing KYNU. The ratios of p‐AKT/AKT and p‐PI3K/PI3K were significantly decreased in the si‐KYNU group compared with the control group. Conclusion Depletion of KYNU could inhibit the growth of cSCC cells, possibly through modulating PI3K/AKT pathway. These data indicate that KYNU takes a key part in the malignant progression of cSCC, and could be considered as a promising therapeutic target for cSCC treatment.

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