The Global Boundary Stratotype Section and Point (GSSP) defining the base of the Chibanian Stage and Middle Pleistocene Subseries at the Chiba section, Japan, was ratified on January 17, 2020. Although this completed a process initiated by the International Union for Quaternary Research in 1973, the term Middle Pleistocene had been in use since the 1860s. The Chiba GSSP occurs immediately below the top of Marine Isotope Substage (MIS) 19c and has an astronomical age of 774.1 ka. The Matuyama–Brunhes paleomagnetic reversal has a directional midpoint just 1.1 m above the GSSP and serves as the primary guide to the boundary. This reversal lies within the Early–Middle Pleistocene transition and has long been favoured to mark the base of the Middle Pleistocene. MIS 19 occurs within an interval of low-amplitude orbital eccentricity and was triggered by an obliquity cycle. It spans two insolation peaks resulting from precession minima and has a duration of ~ 28 to 33 kyr. MIS 19c begins ~ 791–787.5 ka, includes full interglacial conditions which lasted for ~ 8–12.5 kyr, and ends with glacial inception at ~ 774–777 ka. This inception has left an array of climatostratigraphic signals close to the Early–Middle Pleistocene boundary. MIS 19b–a contains a series of three or four interstadials often with rectangular-shaped waveforms and marked by abrupt (< 200 year) transitions. Intervening stadials including the inception of glaciation are linked to the calving of ice sheets into the northern North Atlantic and consequent disruption of the Atlantic meridional overturning circulation (AMOC), which by means of the thermal bipolar seesaw caused phase-lagged warming events in the Antarctic. The coherence of stadial–interstadial oscillations during MIS 19b–a across the Asian–Pacific and North Atlantic–Mediterranean realms suggests AMOC-originated shifts in the Intertropical Convergence Zone and pacing by equatorial insolation forcing. Low-latitude monsoon dynamics appear to have amplified responses regionally although high-latitude teleconnections may also have played a role. On January 17, 2020, the Executive Committee of the International Union of Geological Sciences ratified the Global Boundary Stratotype Section and Point (GSSP) defining the base of the Chibanian Stage and Middle Pleistocene Subseries at the Chiba section, Japan  within the International Chronostratigraphic Chart  11  as a substitute for his Newer Pliocene  held in Leningrad in 1932, and subseries terms were used in a formal sense by Zeuner , 1945 whThe Japanese geophysicist Motonori Matsuyama  was the first to document clearly from basalts in the Genbudō , Japan Matuyama , the revThe XIVth INQUA Congress in Berlin in 1995 focused on three potential candidate GSSPs: Chiba in Japan, Montalbano Jonico in Basilicata, Italy, and the Wanganui Basin in New Zealand Pillans , the latDeciding upon the primary guide to the boundary should be made prior to the consideration of candidate sections because the expression of this guide in the GSSP must be exemplary  is expressed by directional changes  and changes in the geomagnetic field intensity based on both the paleomagnetic record and a coherent record of its proxy, the authigenic 10Be/9Be record at this site serves as a proxy for the geomagnetic field intensity site and reveals a peak (field intensity minimum) at the approximate position of the M–B reversal as determined by the marine isotope record  tephra bed  and the decline to heavier values towards the end of MIS 19c, terminating with a glacial inception  and MIS 19-i1 to MIS 19-i4 . MIS 19-s1 is the first of these millennial-scale climatic episodes and broadly coincides with the glacial inception marked by MIS 19b. They are recognized primarily in planktonic records including planktonic foraminiferal δFigure 18O peaks recorded from Core MD900963 in the tropical Indian Ocean  record from ODP Site 983 on the Gardar Drift, North Atlantic  usually featuring three or four millennial-scale isotopically light peaks and occurring within a second precession cycle. There might be merit in dividing MIS 19 into just two substages separated by the current MIS 19c/b boundary as this most reasonably represents the inception of glaciation  may be discerned, and the planktonic / terrestrial record in which as many as four stadials (MIS 19-s1 to MIS 19-s4) and four interstadials (MIS 19-i1 to MIS 19-i4) may be identified. It resolves the incompatibility between the benthic isotopic record which may contain a strong regional to global signal especially at deep-ocean sites and upon which MIS substages are often based, and the planktonic and terrestrial signals that emphasize more localized climatic variations and permit the most reliable characterization of stadials and interstadials. This approach can be used alongside informal climatic schemes that in some cases already facilitate the recognition of stadials and interstadials in the latter part of MIS 19  was continued by Marino et al.  which is tuned to the insolation curve for 65° N  onwards  and then Younger Dryas-like cooling (Med-YDTIX) prior to final rapid warming early in MIS 19c. This same succession is observed at Sulmona  at 774–777 ka and represents a more stable episode mostly coinciding with full interglacial conditions Table .In spite of weak eccentricity at this time, planktonic and benthic foraminiferal isotope data for central North Atlantic Site U1313 Fig. b reflectIODP Site U1385 off southwestern Portugal  marked by the expansion of temperate forests. These forests were dominated by broad-leaved trees and indicate a warm and relatively humid climate. This climatic optimum extends from the sapropel-like layer to the top of MIS 19c at ~ 774 ka, with a duration of 11.5 ± 3.4 kyr  foraminiferal δ18O values show considerable fluctuations  that define two stable states between higher and lower benthic foraminiferal δ18O values  for the Middle Pleistocene Subseries/Subepoch and Chibanian Stage/Age Fig. . A borehThe Chiba section exposes the middle of the Kokumoto Formation which itself is within the middle part of the Kazusa Group. The Kazusa Group is approximately 3000 m in thickness and represents the Lower and Middle Pleistocene infill of a forearc basin, the Kanto Tectonic Basin Fig. b, resultZoophycos in the CbCS . It comprises thick silty beds along with alternating sand and thinner silt beds    Fig. g, h. Han–4) Fig.  invoked The CbCS documents changes in the Kuroshio Extension system through MIS 19, including rapid north–south shifts associated with stadial/interstadial alternations during MIS 19b–a  increase in the relative abundance of the dinoflagellate Protoceratium reticulatum  Globorotalia inflata, and the surface-dwelling Globigerina bulloides. While all records show millennial-scale alternations during MIS 19b–a, the amplitude of the G. bulloides record reasonably suggests that the source of these alternations was from surface-water processes (Haneda et al. o2 appears to lead slightly that of interstadial i2 (Fig. 18O values have been considered primarily to reflect temperature, with ΔT (δ18Obenthic minus δ18Obulloides; Fig. 18O values for Globorotalia inflata and Globigerina bulloides (Suganuma et al. Florisphaera profunda (Kameo et al. Haneda et al.  used ver i2 Fig. g. Detail2 concentrations along with extended Northern Hemisphere ice sheets, as must have been developing after the glacial inception near the end of MIS 19c (see above, also Vavrus et al. Latitudinal changes in the ITCZ best explain the millennial-scale oscillations at the CbCS and their teleconnection to the North Atlantic and Mediterranean records (Haneda et al. 18O records (Fig. T; Fig. Time series analyses of planktonic foraminiferal δrds Fig. g includiDespite the significant advances reviewed above (Suganuma et al. Over the western Pacific at present, a significant divergence exists between winter and summer positions of the ITCZ owing to summer heating across Asia. For example, the ITCZ occurs over northern India in summer but shifts to just north of Australia in winter Fig.  along wiThe dinoflagellate cyst record may represent in part a late spring–early autumn signal and shows significant fluctuations through MIS 19c and across stadial s1 into interstadial i1 within MIS 19a (zones Df7 and Df8 in Balota et al. A high-resolution pollen record at the CbCS similarly extends only to the MIS 19b–a boundary (Suganuma et al. Further evidence for climatic oscillations in the latter part of MIS 19 during summer is found in the higher-latitude biogenic silica records of Lake Baikal which was strongly influenced by precessional variation (Prokopenko et al. The GSSP defining the base of the Chibanian Stage and Middle Pleistocene Subseries at the Chiba section, Japan, was ratified on January 17, 2020, by the Executive Committee of the IUGS (Suganuma et al. o1 to -o4 (Fig. The M–B reversal facilitates global recognition in marine, terrestrial, and ice-core records, and places the GSSP appropriately in the middle of the Early–Middle Pleistocene Transition, an interval of profound and lasting climatic change (Head and Gibbard -o4 Fig. .2 levels seem to have been similar until about 8000 years ago when they began to rise in the Middle Holocene (Fig. MIS 19 is characterized by a reduced-amplitude 400 ky eccentricity cycle similar to our present interglacial Fig.  but obliene Fig. . A Youngene Fig. . The onsene Fig. .During MIS 19c, both Pacific and North Atlantic–Mediterranean planktonic records show variability in the half- or quarter-precession bandwidth, indicating the influence of equatorial insolation variation at low and mid-latitudes at a time when AMOC disruption was minimal. The interruption of westerlies carrying moisture to the western Mediterranean may have led to the northward transport of moisture, feeding ice sheets which were progressively expanding through much of MIS 19c as boreal summer insolation decreased (Sánchez-Goñi et al. MIS 19b–a corresponds to a second precessional minimum, in antiphase with obliquity, that results in a suppressed insolation peak Fig.  transposAlthough MIS 19c represents a close orbital analogue to the present interglacial, the dominant ~ 5 kyr cyclicity in global records of MIS 19 contrasts with the dominant 2.5 kyr cyclicity of MIS 1, calling into question the assumed close similarity of these two interglacial stages (Sánchez-Goñi et al.


Using climate model simulations, we show that it is exceptionally unlikely (<1% probability) that this trend can be explained by internal variability. Instead, TEEI is achieved only upon accounting for the increase in anthropogenic radiative forcing and the associated climate response. TEEI is driven by a large decrease in reflected solar radiation and a small increase in emitted infrared radiation. This is because recent changes in forcing and feedbacks are additive in the solar spectrum, while being nearly offset by each other in the infrared. We conclude that the satellite record provides clear evidence of a human-influenced climate system.The observed trend in Earth’s energy imbalance (TEEI), a measure of the acceleration of heat uptake by the planet, is a fundamental indicator of perturbations to climate. Satellite observations (2001–2020) reveal a significant positive globally-averaged TEEI of 0.38 ± 0.24 Wm Satellite observations reveal a significant positive trend in Earth’s energy imbalance, but the contributing drivers have yet to be understood. Here, the authors show that it is exceptionally unlikely that this trend can be explained by internal variability; instead, anthropogenic forcing and feedbacks cause the trend. Thus, EEI is a fundamental measure of the degree to which the Earth’s global climate system is out of balance. A trend in EEI measures the acceleration of heat uptake by the planet and hence is an indicator of perturbations to the coupled atmosphere-ocean-land-ice system8. The mean EEI during 2005–2015 was estimated to be 0.71 ± 0.10 Wm−2. Oceans store 90% of this excess heat9. Because of this close relationship between EEI and ocean heating, EEI trends have an important bearing on the warming of the global climate system, sea-level rise, and marine health3. In addition, understanding historical trends in EEI and its components improves the modeling of the projections of future climate change11, which in turn forms the basis for policymaking and mitigation efforts12.Earth’s energy imbalance (EEI) is the difference between the incoming solar radiation (Sϵ), effective radiative forcing (ΔERF), and the radiative response (λΔTs) change EEI16. Thus, an anomaly in EEI can be expressed as the sum of these three terms.In the contemporary climate system, internal variability  and anthropogenic , as well as rapid adjustments in response to the forcing13.Climate feedbacks and surface temperature are represented by 0, RSW, and OLR, allowing the study of TEEI17. While the mean EEI in CERES data is adjusted to be consistent with in-situ ocean observations, the interannual variations and trends observed by CERES are reliable, as evidenced by the excellent agreement between the three satellites CERES derives its data from refs. 18. While we know that TEEI is influenced by internal variability in the climate system, external forcings, and climate feedbacks, the extent of the contribution from each has not been previously determined30. In particular, due to the inherent noise in the Earth system, a single observed 20-year time series of EEI is only one of many possible time series that internal variability could produce32, and therefore, it is imperative to quantify the contribution of internal variability (ϵ) to TEEI.Satellite observations by Clouds and the Earth’s Radiant Energy System Energy Balance and Filled (CERES EBAF) have provided an uninterrupted two-decade-long time series (January 2001–December 2020) of EEI along with S33 to better understand the contributions of the three components of Eq. (We focus here on the investigation of the trend in EEI (TEEI). In particular, the contributions to TEEI by the drivers of the OLR and RSW trends, are an unexplored and unquantified area in the explanation of the observed satellite record. We use Coupled Model Intercomparison Project Phase 6 (CMIP6) experiments and design a hierarchy of climate model experiments with the Geophysical Fluid Dynamics Laboratory Coupled/Atmospheric Model 4.0 (GFDL CM4/AM4)s of Eq.  to the C−2decade−1  (see “Methods” section). Although there is excellent agreement between the individual satellites CERES derives its data from, there is, however, the potential for systematic errors associated with the observed trend due to instrument drift. We attach an estimate of 0.20 Wm−2decade−1  to CERES trends, based on best realistic appraisals of observational uncertainty 38.The trends in EEI (TEEI), RSW, and OLR are computed by taking the linear fits of the ΔEEI, ΔRSW, and ΔOLR time series, respectively. The observed ΔEEI time series yields a significant positive trend of 0.38 ± 0.24 Wm−2 over this period. This TEEI is consistent with ocean observations that showed an increase in ocean heat uptake over the last two decades40. The trends for all latitudes have a positive TEEI, which indicates an increase in radiative energy across the system . GFDL AM4 simulations of EEI, RSW, and OLR are validated against CERES observations and are in excellent agreement  using climate model simulations. For all five sets of estimates, we calculate ϵ as the ±2σ range of 20-year trends across the realizations. Two sets of estimates ϵ come from CMIP6 fully coupled model simulations (which have freely evolving SSTs and sea ice): one with forcing agents at 1850 levels (CMIP6 Control) and historical forcing in another . These provide estimates of ϵ in coupled models in the preindustrial era (CM PI) and present-day (CM PD). Three sets of estimates of ϵ come from atmosphere-only model experiments that we conducted with the GFDL model . Here, we investigate how sensitive ϵ is to repeated sea surface temperature (SST) and sea ice boundary conditions (AM4 Control), prescribed observed boundary conditions (AM4 PSST), and prescribed observed boundary conditions and prescribed forcing agents (AM4 PSST+ERF).Our hierarchy of modeling experiments allows us to investigate the possible contributions of trends in ΔERFϵ as the ±2σ range of all 1293 trends. We also compute ϵ for each of the 47 models and the multi-model mean results in the same estimate of ϵ , we compute ϵ in an atmosphere model in the absence of changing forcing agents, as well as changing SST and sea ice boundary conditions (AM PI). In AM4 PSST , each realization has fixed radiative forcing, but prescribed SSTs and sea ice (AMIP PD estimate of ϵ). Because forcing agents are held fixed at 2014 levels, the trend in force is 0, i.e., ΔERF = 0 in Eq. λΔTS trend. It is important to note that this experiment contains imprints of a forced system  since SSTs and sea ice are prescribed but do not include the direct radiative impact of the forcing agent changes  (see “Methods” section).In AM4 Control , the same SSTs and sea ice are prescribed every year with forcing agents at 1850 levels (see “Methods” section). This provides an estimate of λΔTS and the ±2σ range of the twenty trends provides the fifth estimate of ϵ (another AMIP PD estimate). It follows that the difference between AM4 PSST and AM4 PSST+ERF ensemble-mean trends provide an estimate of the trend due to the effective radiative forcing changes (ΔERF), i.e., the impact of changing forcing agents on the radiation budget (see “Methods” section).In the final experiment , in addition to prescribed SSTs and sea ice (observed), we also prescribe the CMIP6 forcing time series  to obtain the sum of the radiative forcing and response changes (see “Methods” section). Similar to AM4 PSST, the ensemble mean provides the best estimate of ΔERF + ϵ association with each of our 5 estimates is nearly identical at ~±0.19 Wm−2decade−1 over a 20-year period despite having very different boundary conditions and forcing conditions . The similar ϵ value in trends is not seen in the amplitude of interannual anomalies, where variability in ΔEEI increases with the inclusion of SST variability ) . This ϵ is the model ensemble-generated uncertainty due to internal variability  lies outside of our estimates of internal variability (ϵ ~ ± 0.19 Wm−2decade−1) no matter which of our five experiment ensembles we estimate it from  in Fig. 42.We find that the CERES-observed TEEI lies outside the range of trends driven by internal variability alone using two different uncertainty metrics. In the first metric, we compare CERES , a single realization, to the ±2ity Fig. . The CERϵ is robust across 47 different CMIP6 Control models (Supplementary Table ϵ = ±0.20 Wm−2decade−1), is representative of the CMIP6 Control ensemble and is further analyzed in Fig. ϵ (ESM2M Control and CM3 Control).The value of −2decade−2) is (1) greater than 0 and (2) greater than the AM4 Control and CMIP6 Control ensemble means with their 95% CI uncertainty estimates   is  greater de−2) is  greater σ range of trends  would overestimate the uncertainty since CERES’s standard error component of the 95% CI uncertainty is also a measure of the range of trends that could have been obtained by variability in the climate system. In fact, an alternative 95% CI for CERES could be to replace the standard error component with the modeled internal variability as a broader estimate of internal variability uncertainty   to the ±2nty Fig. . Hereaft(ϵ) Fig.  and CERE(ϵ) Fig. . These rϵ comprises a range of trends in EEI due to internal variability, the value of ϵ, ±0.19 Wm−2decade−1, informs us of the estimated contribution internal variability can make to TEEI. Following Eq. λΔTs trend, but with a large range of 0.11–0.65 Wm−2decade−1  model trend estimates , anthropogenic aerosols (0.12 ± 0.10 Wm−2decade−1), and natural (−0.03 ± 0.10 Wm−2decade−1) ) while well-mixed greenhouse gas concentrations are held fixed at 2014 levels, resulting in more infrared radiation emitted by Earth. This damping of the climate system in the absence of forcing is consistent with the dominance of the Planck and lapse rate feedbacks that alter OLR, which is Earth’s primary way to lose energy to space.The CERES-observed trend in OLR is found to be 0.28 ± 0.22 Wm−2decade−1  and greenhouse gas forcing (−0.12 Wm−2decade−1) in reducing reflection of shortwave radiation  and from the clouds which have smaller optical depths and liquid water paths (indirect effect)48. Indeed, we find that satellite observations from MODIS49 show a decrease in liquid water path over the northern extra-tropics, consistent with AM4 PSST+ERF liquid water path trends for that region  comes from the tropics . Two different metrics of Pacific SST gradients66 show equal East Pacific and West Pacific warming trends, i.e., a neutral pattern, yet there is a negative modeled tropical RSW trend. Furthermore, CERES observations show a much stronger tropical RSW trend , the model could match the observed global reduction in RSW. The model-observation discrepancies and uncertainty are further examined in the Discussion section.The other half of the AM4 PSST RSW trend comes from the northern extra-tropics. This is dominated by the clear-sky component ty Figs. 31,68. OnλΔTs). Because of the role internal variability can play at short timescales, this rate of gain need not have significantly outpaced the rate of loss, i.e., display a detectable positive EEI trend. For example, Supplementary Fig. The observed positive EEI trend shows that the heat uptake by the Earth system has accelerated over the past two decades. This occurred because Earth has gained energy at a faster rate than it has lost . When observations and the model do not agree even after accounting for internal variability, model biases could be the cause of the discrepancy. For example, our modeled RSW and OLR trends are mostly consistent with the observed trends, however, the model also shows some inconsistencies with the observations. First, the model reflects more sunlight than observations in the tropics during this period. This could arise from a lack of aerosol decrease in the tropics, weak greenhouse gas rapid cloud adjustment, or weak response to the underlying SST pattern. Second, in the extra-tropics and poles, the model displays more reflection of sunlight than observations, arising from discrepancies between observations and the model’s land-use changes, excessive aerosol drawdown over China, CMIP6 prescribed sea-ice boundary conditions, and modeled Southern Ocean cloud cover. Third, the model traps more infrared radiation than observations due to the weaker modeled tropical longwave cloud radiative effect trend . Existing tropical pattern effect theories only help explain monthly-annual variations in RSW but cannot explain the decadal trend  per model and slice the piControl time series into consecutive, non-overlapping 20-year periods. The ±2σ spread of all these trends  is our estimate of ϵ for CMIP6 Control. Furthermore, for each model, we calculate ϵ. The multi-model mean ϵ is identical to the ϵ obtained by computing the ±2σ range for all 1293 trends  is 0.28 Wm−2. See Supplementary Table ϵ values. In addition, we used multimillennial simulations71 from two older generations of GFDL models (ESM2M and CM3) to study the trends in EEI over hundreds of consecutive 20-year periods.Apart from GFDL CM4 Control, none of the models had significant drift, so we use the full-time series available. In the case of CM4 Control, 1 of the 47 models, the simulation had 650 years of data, but we exclude the first 20 years due to drift  and SSP2-4.5 forcing (2015–2020) in coupled models during the CERES era period January 2001–December 2020. See Supplementary Table 014 and Sσ spread of these 100 trends is our estimate of ϵ for AM4 Control. Forcing was fixed at 1850 levels.The AM4 Control experiment was conducted by providing GFDL AM4 with the SST pattern of a GFDL CM4 piControl simulation (CM4 Control). This SST pattern was then repeated year after year for 200 years as the boundary condition for GFDL AM4. We then randomly picked years from the 200-year EEI time series and made a 2000-year time series (bootstrap). Next, 100 20-year periods . These AMIP simulations used the monthly SSTs and sea ice concentrations prepared for the CMIP6 historical AMIP simulations76, which were extended to December 2020 using the NOAA Optimum Interpolation (OI) SST V2 data77. Further details regarding the prescription and forcing datasets are listed in the GFDL AM4 model description (Appendix A)11. We created an initial condition large ensemble78 with 20 realizations of Earth over this time period with forcing agents fixed at 2014 levels. The ±2σ spread of these 20 trends provides our estimate of ϵ for AM4 PSST (units: Wm−2 decade−1). The year 2014 is used since it marks the end of CMIP6 emission prescriptions. Since we are studying the trends in an interannual time series, the particular year at which we fix forcing agents does not matter. It is important to note that although forcing was fixed, the boundary conditions were already forced since they were prescribed. The warming trend has an impact on the top-of-atmosphere radiation budget, e.g., OLR increase.In AM4 Fixed Forcing, we prescribed observed SSTs and sea ice over 2001–2020 in GFDL AM4  of the trends in the AM4 Control experiment instead of using the small 3-member ensemble of the RFMIP experiments in order to get a more representative uncertainty. Differences in forcing estimated from (AM4 PSST+ERF−AM4 PSST) and RFMIP are negligible because they both use the same CMIP6 forcing-agent time series and only differ in boundary conditions (fixed SSTs for RFMIP and varying SSTs for AM4 PSST+ERF) . There were four temporal evolutions with different forcing agents: greenhouse gas only, aerosol only, natural forcings, and all forcings. These experiments were prescribed with AM4 Control boundary conditions (SST and sea ice) and forcing agents were allowed to vary. Uncertainties given in Table F) Table .We used observations of top-of-atmosphere radiation from the Clouds and the Earth’s Radiant Energy System Energy Balance and Filled (CERES EBAF Ed4.1). MODIS data from January 2001–July 2002 was obtained using the Terra platform alone and data from July 2002-December 2020 was obtained using an average of Terra and Aqua platforms. MODIS data poleward of 55° was ignored due to insufficient coverage (<19% of Earth’s surface area). MODIS LWP data is pixel-weighted.37.We omit 2000 in the analysis because CERES does not provide 2000’s January and February data. To compare complete years (Jan-Dec), we begin with 2001. The significant positive trend in EEI in CERES EBAF 4.1 was not seen in an earlier data product version: CERES EBAF Ed2.8. This is because there was a smaller reduction in RSW in Ed2.8. This was mostly due to diurnal corrections used in Ed2.8 and not because of calibration differences17. However, since our study focuses on decadal trends, observational uncertainty due to the stability of the CERES instruments is more important than absolute accuracy.CERES observational uncertainty in the absolute magnitude of fluxes arises from instrument calibration uncertainty, EBAF diurnal correction, and radiance-to-flux conversion−2 decade−1 observational uncertainty in EEI, RSW, and OLR at every grid point. The total probability that internal variability could have caused the global-mean observed TEEI, even in the presence of large observational uncertainty, is less than 1% because the right-end tail of the internal variability probability distribution is being multiplied by the left-end tail of an assumed normal distribution of the observational uncertainty. Moreover, this result is insensitive to the probability density function  that is assumed for the observational uncertainty. The two probabilities can be multiplied to obtain the total probability because they are independent events. Further uncertainty details in CERES and MODIS are outlined in their data product manuscripts49.Although CERES is highly stable, systematic errors in observational uncertainties in decadal trends could still arise and so we assume a 0.20 WmσObs. = 0.2 Wm−2 decade−1 and σVar. is the standard error associated with the linear fit82. The standard-error derived uncertainty35 in CERES, an uncertainty that represents internal variability uncertainty, is similar in magnitude to the model-generated internal variability uncertainty (ϵ).95% confidence intervals are listed for observations, as well as for model ensembles. For observations , this 95% CI ϵ as another way of estimating the 95% CI on CERES σObs. and σVar.) are added in quadrature because they are independent uncertainties. For model ensembles, which contain multiple realizations, we make use of the spread in trends (linear fits) in the ensemble. The model ensemble mean confidence interval is calculated as: σ is one standard deviation of trends in the ensemble and n is the number of realizations in the ensemble. Therefore, the model ensembles in Supplementary Fig. Therefore, we also apply the model-derived mentclass2pt{minim65. When the West Pacific is anomalously warmer than the East Pacific, the moist adiabat changes for the rest of the tropics too (weak temperature gradient83). This in turn would lead to a more negative lapse rate feedback and a more stable atmosphere in subsidence regions, yielding more low clouds and a more negative cloud feedback. Conversely, when the East Pacific is anomalously warmer than the West Pacific, there is a more positive lapse rate feedback and a more positive cloud feedback. This would lead to a more positive total climate feedback and hence a larger EEI.Past work has suggested that East–West SST gradients in the tropical Pacific can modulate radiation and feedbacks, i.e., the pattern effectWe hypothesize that this pattern effect would be observable over a 20-year period with the unforced simulations (CM4 Control), the forced simulations (AM4 PSST), and the satellite observations (CERES). Year-to-year forcing changes were removed in the latter dataset using the estimate of forcing from our experiments (Supplementary Fig. 66. These results are confirmed by the fully coupled model results (Supplementary Fig. We find that on an interannual basis, indeed, global ΔRSW decreases as the East Pacific warms more than the West Pacific (Supplementary Fig. Supplementary InformationPeer Review File


Strain engineeringprovides an effective way of tailoring the electronicand optoelectronic properties of semiconductor nanomaterials and nanodevices,giving rise to novel functionalities. Here, we present direct experimentalevidence of strain-induced modifications of hole mobility in individualgallium arsenide (GaAs) nanowires, using in situ transmission electronmicroscopy (TEM). The conductivity of the nanowires varied with applieduniaxial tensile stress, showing an initial decrease of ∼5–20%up to a stress of 1–2 GPa, subsequently increasing up to theelastic limit of the nanowires. This is attributed to a hole mobilityvariation due to changes in the valence band structure caused by stressand strain. The corresponding lattice strain in the nanowires wasquantified by in situ four dimensional scanning TEM and showed a complexspatial distribution at all stress levels. Meanwhile, a significantred shift of the band gap induced by the stress and strain was unveiledby monochromated electron energy loss spectroscopy. GaAs nanostructures, especially nanowires, have been fabricatedand demonstrated an attractive potential for performance enhancement.7 The other strategy is to optimize material functionalities by engineeringmaterial structure through, for instance, mechanical strain. The couplingbetween mechanical stress/strain and electronic and optoelectronicproperties of semiconductors has attracted extensive research interestsince the discovery of piezoresistance effect in Si.11 Strain engineering has also been shown to have a distinct effecton the properties of bulk GaAs.14 The understanding of strain effecton charge transport in GaAs nanowires is thus of great importancefor developing nanoscale semiconductor devices with improved and novelfunctionalities.Gallium arsenide (GaAs) exhibitsoutstanding charge transport and optical characteristics, like highcharge carrier mobility and the ability to efficiently detect andemit light.15 Chargetransport properties of individual InAsP and InAs nanowires have showna sensitive response to mechanical stress.17 Light emission in zinc blende (ZB) GaAs nanowires has been tunedby uniaxial compressive and tensile strain over a large spectrum range.18 A large variation in the band gap of GaAs nanowiresdue to lattice-mismatch strain has been observed in GaAs/InxGax1–As core/shellnanowires.19 A direct-to-indirect bandgap transition introduced by uniaxial stress and strain has been reportedin wurtzite GaAs nanowires.20 The effectof bending deformation on charge transport in GaAs nanowires has alsobeen investigated.21 Hole transport characteristicsin GaAs are critical for its application in field effect transistorsand solar cells,22 but the strain effect on holetransport in GaAs nanowires is not fully understood due to the complexityin their valence band structure.10 Controversialresults have been theoretically predicted.26 In this work, we studied the effect of uniaxial tensile stress ontransport properties in individual p-doped GaAs nanowires. With anin situ transmission electron microscopy (TEM) setup, we applied tensilestress on the nanowires along the length direction up to ∼5GPa. The resulting lattice strain in the nanowires was quantifiedusing scanning TEM-nanobeam electron diffraction (STEM-NBED) strainmapping at the nanometer resolution. The simultaneously measured changesin the I–V characteristicswere attributed to the strain-induced changes in hole mobility thatoriginated from electronic band structure modification, which wasverified by tight-binding simulations. In addition, a red shift ofband gap energy due to tensile strain was observed by in situ electronenergy loss spectroscopy (EELS). The present investigation verifiesthe scenario of a competition between effective mass change and chargescattering rate modification due to strain in the GaAs nanowires.Distinct strain effects on electronic structureand electricalas well as optical properties of GaAs and related semiconductor nanomaterialshave been found previously. Pressure-induced band structure modificationhas been observed in InP nanowires.27 The in situ tensile testand electrical transport properties measurements on the nanowiresin TEM were enabled by a Hysitron PI95 nanoindenter TEM holder withan electrical push-to-pull (EPTP) microelectromechanical system (MEMS)device (Supporting Information S1).28The GaAs nanowires used in this study were grown on Si(111) substrateusing a molecular beam epitaxy (MBE) system by a self-catalyzed vapor–liquid–solid(VLS) method.Supporting Information. The mechanical stress applied on the nanowireis extracted from the force–displacement characteristics ofthe nanoindenter in the in situ TEM holder. The indentation force–indenterdisplacement relationship was measured for the EPTP MEMS device withoutthe nanowire and for the case where the nanowire was mounted on theMEMS device  are described below. Additionaldata from other nanowires are provided in S device 1a. The iS device 1b. At th31 The nanowire has a ZB crystal structure, shown by atomic resolutionSTEM imaging and electron diffraction (Supporting Information S2). The [2–1–1] zone axis of thenanowire is aligned with the incident electron beam direction forSTEM-NBED data collection (Supporting Information S3). Local strain within the nanowire is measured along thenanowire length direction ([111] direction or x direction)and the perpendicular direction ([02–2] direction or y direction). The resultant nanoscale 2D strain maps forεxx . When the applied tensile stress reaches ∼2.05GPa, the whole nanowire is strained along the [111] direction. Asthe stress increases further, the εxx map maintains a similar spatial strain distribution pattern untilfracture. In the εyy map, the compressivestrain starts to emerge on the right side of the strain map when thestress is increased to ∼1 GPa. At around 1 GPa, the mean strain⟨εyy⟩ and standarddeviation σyy are around −0.2%and 0.29%, respectively. Then, the region with compressive strainincreases in size and expands to the left side of the nanowire asthe stress increases. Despite the local inhomogeneous strain distributionin the nanowire along both x and y directions, the absolute values of average strains ⟨εxx⟩ and ⟨εyy⟩ increase linearly with applied stress untilfracture, showing elastic deformation of the nanowire structure undertensile stress (xx⟩−σ)data in yy⟩ and ⟨εxx⟩,which is calculated to be ∼0.22 (±0.03). Young’smodules of several GaAs nanowires have been measured and vary from∼90 GPa to ∼120 GPa. In comparison, the bulk Young’smodulus of GaAs along [111] direction is ∼142 GPa.32 The Poisson’s ratio of bulk GaAs is around∼0.19.32Lattice strain and its distribution in the GaAs nanowireare quantifiedby in situ STEM-NBED strain mapping. STEM-NBED measurements providequantitative strain distribution information with high precision,high spatial resolution and large field of view. forεxx 2a and εyεxx . Parameters, including the nanowire resistance (conductance) andthe Schottky barrier heights, were extracted by fitting the modelto the experimental I–V curves(Supporting Information S6 and S7). Throughsuch quantitative analysis, the nanowire conductance can be reliablyobtained by decoupling the effect of electric contacts on the I–V characteristics. When the appliedtensile stress increases from 0 to ∼1 GPa, the conductanceof the nanowire decreases about 5%, from ∼0.71 to ∼0.671/MΩ. As the stress increases to ∼2.05 GPa, the conductanceincreases to a value similar as that at 0 GPa. When the applied stresselevates further, the conductance of the nanowire gradually increases.The conductance shows an almost linear increase with stress after2 GPa. At ∼3 GPa, the nanowire conductance becomes ∼0.801/MΩ. Finally, the nanowire conductance reaches around 0.871/MΩ at ∼4.21 GPa. The variation in conductance of thenanowire is reproducible based on the repeated measurements performedon the same nanowire. The conductance change due to dimension variationof the nanowire is negligible, so the predominant source of conductancechange is the alternation in conductivity of the nanowire. The initialreduction of nanowire conductivity followed by an enlargement in conductivitydue to tensile stress is observed in all the p-GaAs nanowires we studied.Mechanical stress andstrain induce modifications in the chargetransport properties of the nanowire. In the electrical measurementsetup, the GaAs nanowire is connected to metal electrodes on the EPTPdevice, forming a metal–semiconductor–metal (M–S–M)structure. tructure 3a show s36 Without strain, at the Γ point, the bottom of the conductionband is formed by a single and almost parabolic band. The top of thevalence band consists of a heavy hole (HH) band, a light hole (LH)band, and a split-off band. HH and LH bands are degenerate at theΓ point in the absence of strain. Under tensile strain, theconduction band shifts downward in energy. The changes in valenceband are more complicated.21 The degeneracybetween the HH and LH bands is lifted due to strain, causing bandsplitting. The HH band moves upward along energy axis, while the LHband shifts downward. These modifications in band structure of GaAsby tensile strain have also been predicted previously using the k·pmethod,18 and observed experimentally.37 The splitting and shift of the band edges willresult in a reduction in the band gap of GaAs, which is experimentallyobserved here by the in situ monochromated EELS measurements . Under tensile stress and strain,the band gap onset in the EEL spectra shows a red shift. At zero strain,the band gap onset is around 1.4 eV, which is in line with the bandgap values reported previously for ZB GaAs at room temperature.1 As the average tensile strain within the nanowiregrows, this band gap onset gradually shifts to lower energy. Witharound 3% tensile strain, the band gap energy decreases about 0.1eV. The rate of band gap energy change as a function of applied stressis ∼30 meV/GPa. Such a change in band gap is consistent withthat predicated by the band structure modeling  with strain,18 the splitting betweenthe HH and LH bands exceeds the optical phonon energy when the inducedtensile strain is above about 0.8% according to our simulation , but smaller reductions of around 5% are observed in other nanowires, whereafter it gradually increasesas the stress and strain increases. Such an unusual change in nanowireconductivity is due to the alternation in the hole mobility of thenanowires, which originates from strain-induced modification of thevalence band structure. This study helps to improve our understandingof the intriguing correlation between lattice deformation, band structurevariation, and charge transport in semiconductor nanomaterials. Italso demonstrates that mechanical strain can be used to delicatelytailor electronic and optoelectronic properties of nanoscale materials.


Numerous small, well-controlled laboratory studies have reported beneficial health effects of inorganic NO3− consumption on blood pressure, endothelial function, cerebrovascular blood flow, cognitive function, and exercise performance. Translating the findings from small laboratory studies into ‘real-world’ applications requires careful consideration.Dietary inorganic nitrate  conducting large-scale, longer duration trials with hard clinical endpoints (e.g. cardiovascular disease incidence); 2) exploring the feasibility and acceptability of different strategies to facilitate a prolonged increase in dietary NO3− intake; 3) exploitation of existing cohort studies to explore associations between NO3− intake and health outcomes, a research approach allowing larger samples sizes and longer duration follow up than is feasible in randomised controlled trials; 4) identifying factors which might account for individual differences in the response to inorganic NO3−  and could assist with targeted/personalised nutritional interventions; 5) exploring the influence of oral health and medication on the therapeutic potential of NO3− supplementation; and 6) examining potential risk of adverse events with long term high- NO3− diets.This article provides a brief overview of the existing empirical evidence basis for the purported health-promoting effects of dietary NO3− are well established in small, well-controlled laboratory studies. Much less is known about the feasibility and efficacy of long-term dietary NO3− enrichment for promoting health, and the factors which might explain the variable responsiveness to dietary NO3− supplementation between individuals. Future research focussing on the translation of laboratory data will provide valuable insight into the potential applications of dietary NO3− supplementation to improve population health.The salutary effects of dietary NO These effects have largely been attributed to its ability to serve as a substrate for the ubiquitous gasotransmitter, nitric oxide  of the ingested NO3− is excreted in the urine [2−) by facultative anaerobic bacteria residing primarily on the dorsal surface of the tongue [2− is then swallowed and a portion is converted into NO and other nitrogen oxides in the acidic environment of the stomach [2− reaches the systemic circulation, where it can be transported to various tissues and reduced to NO by a range of enzymatic and non-enzymatic catalysis [3− has the capacity to elicit far-reaching effects in the human body.Dietary inorganic nitrate  he urine . Howeverhe urine , and sec. Most ~ 0% of thee tongue . Salivar stomach , 9. A fu3− consumption is a decrease in blood pressure (BP), an effect which was first demonstrated by Larsen and colleagues from the Karolinska Institute in 2006 [3− salts (0.1 mmol/kg/d sodium NO3−) reduced diastolic and mean arterial BP by − 3.7 and − 3.2 mmHg, respectively, in young healthy adults. A number of independent research groups [3− consumption have also emerged. Notably, NO3− has been shown to improve a range of cardiovascular risk factors [3− on cognitive function – effects which may be underpinned by alterations in cerebrovascular blood flow [3− has been identified as a potential prebiotic for the oral microbiome [3− consumption has been demonstrated to improve performance during continuous [3− have not been fully resolved, but may include: 1) improvements in mitochondrial efficiency ; 2) enh by some –56; and  by some , 58, but by some –63).3− supplementation strategies  [3−.Current research has provided valuable insight into optimisation of NOuration) , 64, 65 uration) , 57, 66.3− consumption has been linked with a range of positive health outcomes, the majority of trials exploring the salutary effects of inorganic NO3− have involved short-term supplementation regimens, typically a few days in duration. Only a handful of trials have explored the medium- to longer-term effects of NO3− consumption (4 weeks to 6 months), usually focusing on BP or endothelial function as an outcome. Whilst not a universal finding [3− supplementation protocols have been reported in some trials [3−-rich beetroot juice (~ 6.5 mmol/d NO3−) decreased 24-h systolic and diastolic BP by − 10.8 and − 5.4 mmHg, respectively, in a Sub-Saharan African setting. Similar effects were also observed when NO3− rich beetroot juice was co-ingested alongside folate. In another study, Mills and colleagues [3−-rich beetroot juice (~ 11 mmol/d NO3−) decreased central systolic pressure by − 2.6 mmHg. Likewise, Kapil et al. [3−-rich beetroot juice supplementation (6.4 mmol/d NO3−) with no change after placebo. Although focusing on different outcomes to the above trials, a study by Thompson et al. [3− rich beetroot juice (13 mmol/d) over a 4-week period, providing further evidence of a benefit of this supplement when given over prolonged periods.Although NO finding , 68, bene trials –71. For e trials  found thlleagues  showed tn et al.  also sho3− interventions on BP. The lack of effect in these studies could be related to the relatively low NO3− doses administered . Conversely, the source of NO3− (vegetables or NO3− pills rather than NO3−-rich beetroot juice) could be relevant in explaining the lack of effect in these studies, given different foods providing equivalent doses of NO3− appear to have divergent effects on plasma NO2− concentration and BP [3− has been administered as beetroot juice, which is also rich in a constellation of different bioactive compounds, particularly (poly) phenols and the betalains [3−, betalains have been shown to possess antioxidant [3− from other compounds in beetroot juice, researchers often compare the effects of a NO3− rich beetroot juice to a taste-, smell- and appearance-matched NO3− depleted juice. One limitation of this strategy is that it cannot account for any synergistic interactions between NO3− and the other bioactive compounds that may augment the physiological effects of beetroot juice; in other words, we cannot be certain if the positive effects in these studies are simply due to NO3− or its interactions with the other bioactive compounds present. Thus, studies chiefly aimed at untangling the mechanistic effects of NO3− may prefer to administer NO3− in the form of NO3− salts instead of food-based supplements that contain other compounds. Overall, additional comparisons of NO3− rich beetroot juice and sodium NO2− or NO3− supplements are required. When interpreting the findings of the studies discussed in this review, it is important the reader is aware that studies with NO3− salts and NO3− -rich beetroot juice do not contain the same compounds and therefore different effects are possible. Notwithstanding, as discussed in Section 4 of this review, cross-talk between NO3− and other dietary components or participant-level differences in the response to NO3− could also account for the lack of effect of NO3− in the studies of Blekkenhorst [By contrast, studies by Blekkenhorst  and Sundn and BP , which cn and BP . Indeed,etalains . Indepenioxidant , anti-inioxidant , and vasioxidant  propertikenhorst  and Sundkenhorst .3− could elicit longer-term health benefits. In order to fully appreciate the potential applications of NO3− on population health, large-scale (e.g. n= > 1000), longer duration (e.g. 2–5 years) trials which focus not only on risk factors , but also incidence of key non-communicable diseases  are warranted. Specific considerations for the design of such studies are provided in Table 3−intake by a sufficient quantity and for a sufficient period to obtain long lasting health benefits. This information is critical for the design of feasible longer-term trials and translation to the general population, and will be explored in more detail in the next section.Based around the current evidence it is likely that, under the right circumstances (which remain to be fully elucidated), consumption of inorganic NO3− intake. Mixed findings have been reported. For example, Ormesher and colleagues [3−) and, after 8 days of ingestion, 97% of participants indicated they would consume the supplement again, if they were experiencing benefits. However, only 62% of participants reported finding it easy to consume the beetroot juice and just over half of the participants rated the drink as palatable (54%). These findings suggest that longer-term consumption of beetroot juice may be difficult in this cohort, which could impede longer-term adherence. More recently, Kandhari et al. [To date, a limited number of studies have reported data on the feasibility and acceptability of beetroot juice as a vehicle for increasing habitual NOlleagues  gave 40 i et al.  evaluatei et al.  and Kandi et al.  both admi et al. , which wi et al. , which wi et al.  study wei et al. .3−, at least in certain cohorts. However, future studies need to evaluate the feasibility and acceptability of beetroot juice consumption over longer periods  and in other populations.In another study, Babateen et al.  examined3− sufficient to influence myriad health outcomes. This form of beetroot juice has also been shown to be more effective at reducing BP  than non-concentrated beetroot juice when the same dose is administered [3− consumption. This could include other NO3−-rich foods , gels, powders, crystals, capsules and non-beetroot drinks. To this end, both Blekkenhorst et al. [3−-rich vegetables, which were well tolerated with minimal side effects. Importantly, Sundqvist et al. [3−-rich vegetables and NO3−-containing pills (> 97% vs. > 98%). Nevertheless, neither Blekkenhorst et al. [3− doses provided (~ 2.4 and 4.8 mmol/d respectively) or other methodological factors which were discussed in Section 1 of this review. A comprehensive investigation of patient preferences and the real and perceived barriers of adopting a high-NO3− diet or consuming NO3−-rich supplements warrants further investigation. In addition, studies need to determine the amount of NO3−-rich vegetables required to elicit beneficial physiological effects, whether this is achievable for different populations, and whether effects are superior to non-vegetable NO3− sources. Finally, it is worth exploring whether there are regional and population preferences, as this knowledge could be used to develop more targeted NO3− products.Concentrated, commercially available beetroot juice shots have the advantage of being readily available (they are now sold in many major supermarket chains) and contain a standardised dose of NOnistered . In addit et al.  . The initial results suggesting a harmful role of dietary NO3− intake (from food) were mostly derived from animal models and weakly designed epidemiological studies which have had a prominent, almost demonizing, influence on defining the role of dietary NO3− for human health [3− intake in humans which was set at 3.7 mg/ kg body weight [3− as a risk factor started to change with the discovery of the role of NO3− as key substrate for the NO3−-NO2−-NO pathway and the evidence of a beneficial effect of NO3− on health parameters such as BP.The role of dietary NOn health . These iy weight . The per3−, there was a rapid surge in research testing the effects of dietary NO3− on health outcomes [3− content to support an accurate dietary assessment [3− intake (e.g. 24-h urinary NO3− concentrations) [3− content of vegetables will vary by farming method (whether NO3− fertiliser is used or not), growing conditions, time of year the crop is harvested, and storage conditions [3− intake values [3− food content from published sources in an attempt to obtain valid estimates of NO3− intake and evaluate associations with health outcomes [3− intake for the reasons mentioned above. In addition, NO3− concentrations measured in biological fluids have been used in some analysis as indirect markers of NO3− intake [3− intake show stronger links with health outcomes compared with subjective, self-reported NO3− intake values, is the subject of ongoing research. A summary of the key non-cancer related epidemiological studies testing the association of inorganic NO3− with health outcomes is provided in Table After the study by Larsen et al.  in 2006,outcomes . Howeveroutcomes –92. One sessment . An addirations) . This isnditions , such the values . Severaloutcomes , 97. Alt− intake . Whether3− intake and health outcomes were conducted in 2016 in Iran (two studies) [3− intake with risk of chronic kidney disease in the Tehran Lipid and Glucose Study and found a higher prevalence of chronic kidney disease (CKD) at baseline  in the high- NO3− intake group whereas no significant association with CKD risk was observed after a 3-year follow up [3− intake, overall and from animal sources, was not associated with prospective risk of diabetes. The US study was conducted in a very large sample  and assessed dietary NO3− intake in the Nurses’ Health Study and the Health Professionals Follow-up Study [3− intake [3− and prospective risk of coronary heart disease [3− intake or urinary NO3− concentrations (as a proxy for NO3− intake) with cardiovascular outcomes including lower BP [3− concentrations in the Framingham Offspring Study [3− concentrations in participants with impaired kidney function included in the analysis and highlights the potential risk of reverse causality in these investigations. The improvements in physical performance and cognition observed in some of the NO3− supplementation trials were also explored in two cross sectional studies [3− intake [3− concentrations measured in spot urine samples were not associated with improved cognition in 1015 older Americans participants enrolled in the National Health and Nutrition Examination Survey [3− held in 2016 [3− consumption for the prevention as well as treatment of chronic diseases. The consensus statement also encouraged the development of detailed and country-specific NO3− food composition tables for a more accurate assessment of the exposure to dietary NO3− [3− intake for cardiovascular events and mortality whereas the predictive role for cancer risk is still undefined as latest meta-analyses on the topic indicate a lack of association between dietary NO3− consumption and cancer risk [3− intake with other chronic conditions with established links with NO3−/NO2− and NO pathways such as diabetes, hypertension, physical disability or dementia. Further epidemiological studies in this area are therefore warranted. Such research will complement the findings from RCTs, by providing information on the effectiveness of a NO3− for disease reduction in real-world circumstances with greater sample sizes and longer follow up than is logistically feasible in most RCTs [The first studies to evaluate the association between dietary NOstudies) , 101 andstudies) . The forollow up  found th disease . More relower BP , risk oflower BP , common lower BP , congestlower BP  and CVD lower BP . Conversng Study  were ass studies , 112. Imn Survey . The NIH in 2016  advocateary NO3− . The curcer risk , 117. Thost RCTs , 91.3−, irrespective of the vehicle used to provide this inorganic anion [3− supplementation between individuals [3− between individuals. These include individual characteristics such as age [Section 5 of this review). In addition, between-participant differences in potentially plastic lifestyle factors such as smoking status [3−. We briefly review the impact of these variables on the effects of NO3− below.At the individual participant level, several groups have suggested the existence of possible ‘responders’ and ‘non-responders’ to NOic anion , 119. Itividuals , 121. Siividuals , 123. Neh as age , 125, heh as age  and exerh as age , 49, sexh as age , genetich as age , and difg status , use of g status , and habg status  might al3− supplementation [3− supplementation from any source enhanced exercise performance in recreational level athletes (V̇O2peak 40–60 ml/kg/min), such effects were less pronounced or non-existent in well-trained and elite endurance athletes  [3− dose are held content, individuals with a higher aerobic fitness status are less responsive to the ergogenic effects of NO3−. Indeed, those authors reported beneficial effects of sodium NO3− on 3 km running performance in individuals with low (V̇O2peak: 28.2–44.1 ml/kg/min), and moderate (V̇O2peak: 45.5–57.1 ml/kg/min), but not high (V̇O2peak: 63.9–81.1 ml/kg/min) aerobic fitness levels. Several possible explanations have been put forth to try and explain why high fitness levels might render NO3− supplementation less effective, and these are discussed in detail elsewhere [3− as a substrate for NO generation [3− might elicit preferential effects on type II compared with type I muscle fibres [3− supplementation given a lower proportion of type II, and a higher proportion of type I, muscle fibres compared with recreationally active individuals [3− in well-trained athletes [3− supplementation, irrespective of vehicle, in well-trained athletes in comparison to healthy, physically active, individuals. This is likely because well-trained athletes are only a small fraction of the population, and are logistically harder to test and recruit to studies due to their desire to avoid potential training interruptions. Thus, more research is still required to ascertain the influence of aerobic fitness levels on the responsiveness to NO3− supplementation.Individuals with lower aerobic fitness levels may respond more favourably to NOentation , 131. Th/kg/min) –135. Porlsewhere . One proneration . Furthere fibres , 57, 58.ividuals , 138. Inathletes , 139–1413− [3− (at least in regard to the effects of NO3− on BP) between the sexes, which warrants further investigation. Women have been demonstrated to have greater oral NO3− reducing capacity than men due to an oral microflora composition that is more conducive for NO3− reduction to NO2− [3−  in men with higher baseline BP and lower plasma NO2− concentrations but not in women. Likewise, in a meta-analysis by Jackson et al. [3− were greater in studies with more male participants. Those authors speculated that this could be related to a greater vascular production of NO in pre-menopausal women due to oestrogen-related release and activity of NO [3− in women compared with men.Women are underrepresented in research into the health effects of dietary NO3− . Neverth to NO2− . Neverth to NO2−  and Cole to NO2−  both demn et al. , BP reduty of NO , diminis3− supplementation are partly explained by polymorphisms in the eNOS gene. This was first explored by Hobbs et al., [3− supplementation on BP in patients with and without a specific polymorphism in the eNOS gene (G894T), which has been suggested to inhibit NO production from eNOS [n = 14), Hobbs et al., [3− supplementation (beetroot bread) only reduced BP in patients who were both T allele carriers and had the G894T polymorphism in the eNOS gene. A more recent study examined the influence of the G894T polymorphism and NO3− therapy on mortality in chronic heart failure patients [3− therapy (source not specified) increased the risk of mortality in patients with the G894T polymorphism, and to a greater extent in G allele carriers, suggesting that NO3− therapy might increase mortality in advanced heart failure. However, as this study was observational, cause-effect relationships cannot be established. Moreover, the findings are at contrast to the beneficial effects of NO3− shown in most [3− improves cardiac function and/or exercise capacity in heart failure patients. Clearly, more studies with larger cohorts are required to determine the extent to which genetic variation influences the responsiveness to NO3− supplementation, but the findings from these two studies raise the possibility that that genetic factors could contribute towards the inter-individual variability reported by many studies.Although studies remain scarce, there is some evidence that the heterogeneous responses to NO et al., , who exarom eNOS . Althougrom eNOS , the G89rom eNOS –149, of rom eNOS , 151. In et al.,  found thpatients . Somewhapatients , Azzam epatients  found th in most –155, but in most , 157, sh3− into the salivary glands [2−. Consequently, it is possible that smokers will experience compromised NO3− metabolism and thus a diminished physiological response to NO3− supplementation versus non-smokers. Indeed, Bailey et al. [3−, plasma NO3− and NO2− concentration, and an attenuated BP response, following a NO3− bolus (beetroot juice) in smokers compared to non-smoking controls.Smoking has been shown to increase plasma and salivary concentrations of thiocyanate , a compoy glands , potentiy et al.  demonstr3− is ineffective at eliciting meaningful physiological changes in individuals habitually consuming a high NO3− diet. Nevertheless, as population intake of NO3− is typically low — Babateen et al. [3− levels to match those provided through supplementation [3− intake is unlikely to explain a lack of response to NO3− supplementation in most ‘non-responders’. Alternatively, there is compelling evidence to suggest that consumption of other dietary compounds alongside NO3− may have the capacity to influence response to this compound, such that an individual’s background diet could determine (at least transiently) their status as a NO3− ‘responder’ or ‘non-responder’. For example, consumption of glucosinolate-rich vegetables, such as those from the Brassica family like broccoli, cauliflower, and cabbage, proximal to consumption of NO3−-rich vegetables was shown to blunt the BP lowering response of the latter [3−. Specifically, during processes that result in plant cell membrane damage such as mastication, glucosinolates are exposed to the enzyme myrosinase, which catalyses the hydrolysis of glucosinolates into thiocyanate [3−-rich smoothie was attenuated by the presence of thiocyanate rich vegetables. In that study, thiocyanate did not seem to interfere with NO3− transport into the mouth , suggesting that thiocyanate may influence other aspects of NO3− metabolism. Specifically, co-ingestion of thiocyanate synthesising vegetables and NO3−-rich vegetables lowered salivary NO2− concentration compared to ingestion of NO3−-rich vegetables alone. This suggests that some Brassica vegetables might transiently alter the oral microbiome, consistent with the antimicrobial effects of thiocyanate derivatives in the oral cavity [It is possible that supplemental NOn et al.  reportedentation , high hae latter . Interesocyanate . Althougocyanate  showed tl cavity .3− alongside conjugated linoleic acid, an unsaturated fatty acid particularly abundant in dairy and meat products, attenuated the rise in plasma NO3− and NO2− concentrations and supressed the BP-lowering and platelet-inhibiting effects that were apparent when supplements were administered in isolation. Mechanistically, co-consumption of conjugated linoleic acid altered the metabolic fate of ingested NO3− leading to the formation of conjugated linoleic acid nitration products, which do not appear to have the same vasodilatory and platelet inhibiting properties as NO2− and NO. Likewise, Bailey et al. [3− uptake [3− concentration when co ingested with NO3− rich beetroot juice. However, the increase in salivary and plasma NO2− concentration, alongside the lowering of BP, were similar compared with NO3− alone. Finally, a possible interaction between dietary NO3− and sulphate was identified by Kuhnle et al. [3− intake was associated with lower BP. Conversely, when sulphate intake was high, this association was reversed, such that greater NO3− intake was actually associated with higher BP. The mechanistic basis through which sulphate could modulate the BP lowering effects of dietary NO3− is presently unknown.A study by Hughan et al.  found thy et al.  found thy et al.  and know− uptake , lowerede et al.  who indi3− is unlikely to be uniform between individuals, and could also potentially differ within individuals based around malleable lifestyle factors such as habitual diet. Better understanding the factors that influence responsiveness to NO3− is crucial to maximise the efficacy of NO3−-based interventions and will facilitate the development of targeted interventions for individuals most likely to benefit from consumption of this compound. Given many of the factors which appear to moderate the effectiveness of NO3− impact the oral conversion of this compound into NO2−, future research could also explore the potential physiological effects of direct NO2− administration , which ple, see .3− is reduced to NO2− during the anaerobic respiration of facultative and obligate bacteria which are particularly abundant on the dorsal surface of the tongue [3− reducers, the majority of which are from the genera Veillonella, Prevotella, Neisseria, and Haemophilus [. A greater relative abundance of these bacteria on the tongue has been shown to augment the rate and magnitude of salivary NO2− production following the ingestion of NO3− rich beetroot juice [. Conversely, disruption of the oral microbiome by antibacterial mouthwash causes a transient loss of viable NO3−-reducing bacteria [2− in the saliva [3−-NO2−-NO pathway [Once in the oral cavity, NOe tongue . The orae tongue . To datemophilus . A greatot juice . Conversbacteria  and sevee saliva . Strong  pathway –176. The pathway .3−-rich beetroot juice has been shown to increase salivary pH and cause meaningful alterations to the oral microbiome in favour of oral health [3−-reducing bacteria [2− increased following the ingestion of NO3−-rich beetroot juice. This was despite participants standardising their diet, physical activity, use of mouthwash, teeth brushing, and tongue cleaning between visits. The unpredictability in how different individuals respond to NO3− supplementation and how the same individual responds across repeated visits poses a particular challenge for researchers who wish to explore the therapeutic effects of this dietary intervention.The mouth is continually exposed to the external environment and is regularly subjected to brushing, flossing, and nutrient intake, all of which may influence the physiological conditions inside the oral cavity and alter the composition of the bacterial milieu . Ageing l health , 185. Gibacteria . Of note2− and NO3− reductase gene expression of the oral bacteria. Furthermore, data from epidemiological studies and short-term intervention trials seem to support the notion that increasing habitual dietary intake of NO3− can improve markers of oral health and reduce the incidence of caries [3− supplementation may also be an effective treatment method for those already suffering from oral diseases such as chronic periodontitis.While recent advancements in genomic sequencing techniques have greatly enhanced our understanding of human bacterial interactions in the context of NO homeostasis, several important questions remain unanswered. To date, the majority of the research exploring links between the oral microbiome and health outcomes has only reported the relative abundance of phyla, genera, or species. Although this quantifies the proportional makeup of the community structure it does not reveal the metabolic activities of individual bacterial species  which maf caries , 189. It3− is increasingly recognised as a beneficial ion that protects against chronic disease, yet, as noted in Section 3 of this review, historically, it was considered a food contaminant with adverse health effects, particularly increased risk of certain cancers and methaemoglobinaemia [3− of 3.7 mg/kg of body mass remain in place today, the discovery of multiple positive health effects of NO3− have prompted a re-examination of these claims.NObinaemia , 88. Whi3− intake yet, in 2008, a panel of experts from the European Food Safety Authority, concluded that the epidemiological evidence did not support an association between NO3− and cancer risk [3− from food or water was carcinogenic in humans [3− might cause infant methemoglobinemia, which was first mooted in the 1940s [3− and methemoglobinemia in infants [3− intake such as nausea and sickness, to the authors knowledge, no serious adverse events have ever been reported in clinical trials administering NO3− [In 2004 the WHO reaffirmed their restrictions on NOcer risk . Similarn humans . Evidenche 1940s , has als infants . It is aing NO3− .3− above the ADI could harm health. Currently, at least with short to medium term intakes, research suggests that doses exceeding the ADI are needed to optimise vascular health or exercise performance [3− intake, the long-term safety of consuming NO3− in amounts that exceed the ADI is not well understood. At present, epidemiological studies provide the strongest evidence that prolonged, high intakes of NO3− are safe. Indeed, these indicate that rather than being harmful, dietary NO3− intake is inversely associated with cardiovascular disease risk [3−, at least through plants, is more likely to be associated with health benefits than adverse effects.Notwithstanding, the available evidence does not rule out the possibility that prolonged consumption of NOformance , 48. Becase risk , 194 andase risk . Furtherase risk , 196, prase risk  and chroase risk , and impase risk , 200 andase risk , 202. Th3− intake on health. In a study in rats, 10 weeks of a low sodium NO3− dose (0.1 mmol/kg/d), which the authors suggest is equivalent to amounts achievable in the human diet, reduced BP, whereas a much higher dose (1 mmol/kg/d), elevated BP [3− dose down-regulated eNOS activity, not only suggesting a crosstalk between the canonical and NO3−- NO2−-NO pathway, but also that any vascular benefits afforded by NO3− supplementation could wane over time. Nonetheless, these findings were not supported by a more recent animal study from the same group. Hezel and colleagues [3−. After 17 months, mice consuming the high NO3− diet did not have elevated BP or any other adverse health effects, despite the fact the dose exceeded the WHO recommended ADI for an adult under ~ 95 kg. On the contrary, the high NO3− diet decreased plasma insulin and modulated inflammation, findings consistent with the metabolic benefits observed in acute human studies [3− intake are not harmful to health.Some animal studies have explored the longer-term effects of high dietary NOvated BP . Intereslleagues  fed mice studies . These e3− intake could be mitigated by the intake of antioxidants such as vitamin C or (poly) phenols, which are present in most fruits and vegetables. Studies have shown that vitamin C and E are effective inhibitors of nitrosamine formation [3− sources such as spinach and beetroot [3− intake through a greater vegetable intake may significantly lessen the risk of any NO3− induced nitrosamine formation. This could partly explain why diets high in vegetables are associated with a reduced and not heightened risk of cancer.It is important to note that any carcinogenic risk attributed to NOormation . In addibeetroot , can alsbeetroot . Thus, i3−-rich vegetables [3−-rich vegetables [Health concerns have also been raised over the high oxalate content of NOgetables , 208. Oxgetables . Intake getables –211, thugetables . Howevergetables . Furthergetables . The autgetables . While m3− promotes cancer or methemoglobinemia, or that dietary oxalates cause kidney stones are weak and unsubstantiated. Rather, there is compelling evidence that dietary NO3− has salutary health effects and warrants consideration as a long-term therapeutic treatment strategy to manage vascular and metabolic health. Notwithstanding, longer-term studies in humans are lacking and thus it cannot be ruled out that a prolonged increase in NO3− intake, above the WHO recommended ADI, may have adverse effects for some individuals. Thus, it is incumbent that researchers examine the long-term safety of increasing dietary NO3− consumption in a range of contexts and populations. This research will be vital for convincing the public and regulators that NO3− consumption is safe and that current recommendations to limit dietary NO3− intake should be re-considered.To summarise, claims that dietary NO3−. Six key areas worthy of future research were identified to enhance understanding of the potential role of NO3− in improving population health. As such, it is hoped that this article will help direct researchers to further explore the role of NO3− as a potential health-promoting dietary component.This article has briefly outlined the current state of knowledge around the potential health effects of dietary inorganic NO


Our data indicate a syndepositional/early diagenetic origin of the Datangpo superheavy pyrite, with 34S-enriched H2S supplied from sulfidic (H2S rich) seawater. Instructed by a novel sulfur-cycling model, we propose that the emission of 34S-depleted volatile organosulfur compounds (VOSC) that were generated via sulfide methylation may have contributed to the formation of 34S-enriched sulfidic seawater and superheavy pyrite. The global emission of VOSC may be attributed to enhanced organic matter production after the Sturtian glaciation in the context of widespread sulfidic conditions. These findings demonstrate that VOSC cycling is an important component of the sulfur cycle in Proterozoic oceans.The global deposition of superheavy pyrite  defies explanation using the canonical marine sulfur cycle system. Here we report petrographic and sulfur isotopic data (δ This paper presents a new marine sulfur-cycling model that quantitatively describes the worldwide deposition of superheavy pyrite after the Neoproterozoic Snowball Earth glaciation. Sulfate diffusion coefficient(Ds), sulfate concentration and sedimentation rate (s) are 3.61 × 10−6 cm2 s−1  due to chemical reactions or biological activities . H2S is generated by MSR. It is then converted to VOSC that is emitted into the atmosphere. Pyrite is mainly formed near SWI with Fe supply from sediment and H2S diffusion from sulfidic seawater  model to simulate the δlue Fig. A. With ttrations . MSR in ter Fig. A.The transmission term in the model can be expressed by the one-dimensional advection-diffusion equation:D2SH mentioned above in 2S.where 2S is generated by MSR, and the chemical reaction for MSR is as follows:HkMSR):Assuming an unlimited supply of organic matter and invariant pH, the rate of MSR (dmsr/dt) is only controlled by the concentration of sulfate and the reaction rate constant  is a function of Hd is the diffusion coefficient of sulfate in seawater  at 0.0005 yr−1 [kVOSC) at 0.001 yr−1 [34SH2S gradient in sulfidic water column  or a nearly stagnant ocean is required for the sustention of the high δ34SH2S values and strong vertical δ34SH2S gradient.Assuming the δ005 yr−1  and VOSC001 yr−1 , the modent Fig. . In addi34SH2S depth gradient in sulfidic conditions. In our model, superheavy pyrite in the Datangpo Formation was mainly precipitated at or near the SWI, where both seawater sulfate and sulfide have high δ34S values. Our model is seemingly inconsistent with low δ34Ssw values based on carbonate-associated sulfate data  δ34SH2S in the water column should be lower than δ34SH2S at the SWI or within sediment porewater, and (ii) δ34Spy of shallow water sections should be lower than that of deep-water sections. The latter is validated by the spatial gradient in δ34Spy recorded in the Datangpo Formation: pyrite from the outer shelf sections has lower δ34Spy values than the slope sections [There is no direct geological or geochemical tracer for VOSC emission in paleoceans, so the VOSC model proposed here needs to be tested further. This model can be indirectly tested by evaluating the δsections .2S as well as high DOC concentrations in a euxinic wedge [34SH2S depth gradient. Superheavy pyrite precipitates at the seafloor or within sediment porewater that is characterized with high δ34SH2S.The global occurrence of superheavy pyrite also implies widespread and massive VOSC emission during the Cryogenian non-glacial interval. VOSC emission is favored by intense MSR that generates abundant Hic wedge . We propic wedge ,59–61 thLarge organic matter flux might be favored in the non-glacial interval due to the following reasons. First, deglacial intense continental weathering led to a surge of nutrient supply to the ocean, stimulating surface ocean primary productivity ,62,63. S34Spy in the non-glacial interval  does not cause any significant perturbation in δ34Ssw. VOSC in the modern ocean is mainly produced by the DMSP degradation pathway, while H2S methylation is quantitatively unimportant, given that sulfidic seawater covers less than 0.1% of modern seafloor [2S methylation is also dampened by extremely low seawater DOC concentrations, and seawater DOC is mainly composed of refractory molecules that are chemically inert [2S methylation does occur in some limited sulfidic areas, such as the Black Sea [−1) [2 concentrations, and vigorous vertical oceanic mixing also homogenizes the ocean and reduces the depth gradient.In the modern ocean, high VOSC emission  . In addi2S methylation might have played a more important role in the Proterozoic sulfur cycle, when euxinic wedges were common and seawater sulfate concentrations were low [2S is readily available for the formation of H2S-derived VOSC. In addition, a large DOC pool in the Proterozoic ocean ensures the supply of organic carbon molecules [2S may be a more important process in the Proterozoic marine sulfur cycle than in the Phanerozoic.In contrast, Hwere low ,58,70–72olecules . Therefo34SH2S depth gradients in sulfidic water column [34SH2S depth gradient as well [It is notable that sulfide methylation alone does not guarantee global superheavy formation. In fact, superheavy pyrite occurred only sporadically in other geological intervals characterized by widespread sulfidic conditions, for example, during the Boring Billion , after the Marinoan glaciation, in the Permian-Triassic transition, and during Ocean Anoxic Events in Cretaceous ,73. We sr column . On the  as well ,78. Ther as well , (ii) th as well ,65, and 2S methylation is a previously underappreciated pathway in the Proterozoic marine sulfur cycle. The interpretation of Proterozoic sulfur isotope data needs to fully consider the organosulfur cycle, which may have contributed to—if it was not solely responsible for—the sustained and global occurrence of superheavy pyrite in the Cryogenian non-glacial interval.To summarize, although additional data are needed to further test the model proposed here, our study does show that H2S. Dried Ag2S powder was mixed with 1–2 mg V2O5, and was analyzed for S isotopic compositions on a Delta V Advantage gas source mass spectrometer coupled with an Elemental Analyzer. Sulfur isotopic compositions are expressed in standard δ-notation as per mil (‰) deviations from the VCDT standard (Vienna Canon Diablo Troilite). The analytical error is <0.2‰ based on replicate analyses of samples and laboratory standards. Samples were calibrated on two international standards: IAEA-S-1: −0.3‰; IAEA-S-2: +22.7‰.Stable sulfur isotope analysis was performed in the Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences. One to three grams of powder was prepared for pyrite extraction using the chromium reduction method. Pyrite-rich powder was finally converted to Agfram is framboidal pyrite area in the microphotograph, and AT is the total pyrite area in the microphotograph. The mean framboidal pyrite proportion in each section was calculated by: n is the microphotograph sequence number.The proportion of framboidal pyrite relative to total pyrite mass is estimated using back scattered electron images and reflected microphotographs. For each microphotograph, the proportion of framboidal pyrite can be calculated by: The data that support the findings of this study are available from the corresponding author upon reasonable request.nwab034_Supplemental_FileClick here for additional data file.


Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental organic contaminants generated by incomplete combustion of organic materials that are widely distributed in soils. This study represents the first attempt to examine the health toxicity of 16 detected PAHs in contaminated soil, via different exposure pathways to populations in northwestern Algeria.The toxicity equivalency quotients (TEQ) of PAHs were evaluated. The carcinogenic risk assessment of incremental lifetime cancer risk (ILCR) from ingestion, inhalation, and dermal exposure pathways to each PAH in soil are described.−6–10−4) for adults and children. The total cancer risk of PAH-contaminated soils for children, adolescents and adults was 2.48×10−5, 2.04×10−5 and 3.12×10−5mg.kg−1d−1, respectively. The highest potential cancer risks were identified for adults and children, with adolescents having the lowest risks. Across exposure pathways, the dermal contact and ingestion pathways had the greatest contributions to the carcinogenic risk of human exposure to PAHs.Incremental lifetime cancer risk values were in the upper limit of the tolerable range (10Further research and guidelines are needed for risk assessments of PAHs in agricultural, residential/urban, and industrial areas, and further risk assessments should include risks posed by exposure through air.The authors declare no competing financial interests. Polycyclic aromatic hydrocarbons (PAHs) are a class of organic molecules that contain more than two fused aromatic benzene rings.1The majority of PAHs present in the environment are due to incomplete combustion and pyrolysis of organic matter.18Polyaromatic hydrocarbons are widespread in the studied area of northwestern Algeria as a result of industrial, commercial and transportation activities, and cereal cultivation.20This research represents the first evaluation of the cancer risk for three population groups: children (2 to 12 years old), adolescents (13 to 20 years old), and adults (over 20 years old) who were exposed to 16 PAHs through contaminated surface soils via three different exposure pathways: ingestion, inhalation, and dermal contact in northwestern Algeria.BaPeqBaP toxic equivalent concentrationCDIChronic daily intakeECToxic equivalent quotientUSEPAUnited States Environmental Protection Agency, which covers an area of 33 030 km2 and have a density of 1 582 818 inhabitants. With a median age of about 28.5 years, this population accounts for 3.65% of all Algerian residents.20The population of Algeria's northwestern region is concentrated in five cities  .Previous studies and published results in this area of northwestern Algeria have reported monitoring data on 16 individual PAHs in surface soils, as seen in .2Benzo[a]pyrene is one of the most potent carcinogenic PAHs.ingestion is the chronic daily intake related to soil particle ingestion (mg/kg/day). The CDI of PAHs in other mediums was not considered as this study only addresses the PAHs carried by soil dust particles. CSsoil is the concentration of PAHs in soil (mg/kg), IRsoil is the ingestion rate of soils (mg/day), EF is the exposure frequency (d. year−1), ED denotes exposure duration (years), BW is the bodyweight of the exposed individual (kg),−6 kg/mg), CDIinhalation is the chronic daily intake via inhalation of soil particles (mg kg−1 d−1), HR is the air inhalation rate (m3/d), PEFsoil is the soil particle emission factor, CDIdermal contact is the chronic daily intake for dermal contact of soil (mg/kg/d), SA is the skin surface area available for contact soil (cm2/day), AF is the relative skin adherence factor for soil (mg/cm−2), and ABS is the dermal absorption fraction. The values of all variables are reported in In this research, chronic daily intakes (CDIs) associated with PAH exposure in the soil through the three pathways  were evaluated by the formulae reported by the USEPA (1991)According to the USEPA's Exposure Factor Handbook,ILCR = CDI × Cancer oral slope factor (CSF)ingestion, CSFdermal, and CSFinhalation of BaP were considered to be 7.3, 25, and 3.85 (mg/kg/day)−1, respectively, based on the cancer-causing ability of BaP.30Where CSF is the carcinogenic slope factor (mg/kg/day). CSFR represents the total risk of cancer resulting from the sum of the ILRC associated with each exposure contact as follows in Where Cs is the PAH concentration of soil samples (mg/kg), other variables are shown in −6 denotes the level of risk considered acceptable or inconsequential, an ILCR of ≥10−4 is considered a serious risk requiring high priority attention, and an ILCR from < 10−6 to <10−4 reflects a potential risk to human health.−6 is considered unacceptable according to the USEPA.35According to the USEPA and regulatory programs, an ILCR of ≤10Only benzo(a)pyrene, from of the 16 PAHs considered in the present study, has toxicity data that can be used to calculate the carcinogenicity factor. The carcinogenic risk due to exposure to each PAH was estimated by the toxicity equivalent of BaP (BaPeq).. Intake daily contacts (CDIs) and carcinogenic risks (ILCRs) for each PAH for three age groups  and exposure pathways  in the study area were evaluated based on The human health risk is assessed based on possible exposures to PAH-contaminated soil surfaces, either directly or indirectly, and according to various parameters for children, adolescents, and adults such as exposure frequency, exposure duration, body weight, and average life span In the present assessment of human health exposure to PAH-contaminated soils, the ILCR was chosen to assess and diagnose the potential cancer risk (R) for different age groups via three pathway exposures, based on the CSF and CDI. The results of ILCRs and R values  for three population groups: children (2–12 years of age), adolescents (13–20 years of age), and adults (>20 years of age), via different exposure pathways  are presented in −5 to 1.99 × 10−5, while the risk levels of cancer via ingestion ranged from 3.35 × 10−6 to 1.12 × 10−5 and inhalation exposures ranged from 2.08 × 10−10 to 6.96 × 10−10. In addition, the cancer risk level for adults was 3.12 × 10−5, 2.48 × 10−5 for children, and 2.04 × 10−5 for adolescents (Table 6).The average values of total ILCRs calculated for the study area indicate that risk levels via dermal contact for children, adolescents, and adults ranged from 1.37 × 10−1..The present study revealed that BaPeq values for 16 PAHs in the study area averaged 280.28 g/kg, which is less than 300 g/kg and much lower than the Canadian Soil Quality Guideline recommendation of TEQ < 600 g/kg.Table 1). These results show that BaP (38.6%) and dibenzoanthracene (38.3%) were the highest contributors to the risk of carcinogenicity according to the TEQ, similar to the results reported in the Indian states of Assam and Chhattisgarh,Carcin) contributes more than 96.5% of the total Σ16 BaPeq level in the present study, explaining why the seven carcinogenic PAHs are the most toxic of the 16 PAH total components.The contribution of BaPeq for each PAH to total TEQ estimates were in the following order: benzo[a]pyrene (BaP) (38.6%) > dibenzoanthracene (38.3%) > benzo[a]anthracene > benzo[b]fluoranthene > benzo[k]fluoranthene > benzo perylene > indenopyrene > chrysene > anthracene > fluoranthene > pyrene > phenanthrene> acenaphthylene > naphthalene > fluorene > acenaphthene 50The results of TEQ in northwestern Algerian surface soils −6 denote a negligible risk, ILCRs of 10−6 to 10−4 indicate potential risk, and ILCRs greater than 10−4 indicate potential high risk.52To date, no environmental guidelines have yet been established in Algeria for PAH-contaminated soils. According to most regulatory programs and guidelines around the world, an ILCR less than or equal to 10LMW−ΣPAHs (5.39 × 10−12 – 1.53 × 10−7 mg/kg/d) for all age groups are less than those of high molecular weight (HMW) HMW−ΣPAHs (4.87 × 10−11 – 1.83 × 10−6 mg/kg/d) . The 4-ring PAHs and the 6-ring PAHs are the main contributors to BaPeq and increasing CDIs among the 16 PAHs.The chronic daily intakes (CDIs) of the sum of low molecular weight (LMW) –5 polluted with fluoranthene, pyrene, benzo[b]fluoranthene, and benzo[a]anthracene contributes substantially to the potential cancer risk (ILCR ≥ 10−6) of children and adults by ingestion and dermal contact exposures, and these compounds also contribute to potential cancer risk (ILCR ≥ 10−6) of adolescents via dermal contact. In the present study, the high molecular weight polycyclic aromatic hydrocarbons (HMW PAHs) with four rings contributed the most to the ILCRs for all age groups (5). The 5- and 6-ring HMW PAHs such as benzo[a]pyrene (BaP), benzo[b]fluoranthene, benzo[k]fluoranthene, indenopyrene, and benzoperylene have a moderate contribution to the cancer risk for adults and children. The remaining 2- and 3-ring PAHs with ILCRs lower than 10−6 are classified as lower cancer risk for humans, according to USEPA standards, where the acceptable risk of cancer from individual PAHs is (10−6 – 10−4).53The results of the ILCR carcinogenic risk of individual PAH surface soil −13~10−10 ), and the dermal contact and ingestion routes with a magnitude of (10−8~10−6) and (10−9~10−6), respectively. The results indicate that the dermal contact and ingestion pathways greatly contribute to the carcinogenic risk of human exposure to each PAH. Thus, higher dermal exposure contact can be explained by the emission of PAHs during traffic road, industrial and agricultural activities, which can be transferred to the surface of tools and clothing to the skin.54In addition, the risks from individual PAH exposure pathways were summarized to determine the key exposure pathway for each PAH compound contaminant surface soil in the study area. The results presented in In summary, the carcinogenicity of each PAH depends on its chemical structure and physical-chemical properties. The HMW PAHs are more potent carcinogens, and many studies have reported that exposure to HMW PAHs is linked to increased incidences of leukemia, bone, brain, bladder and scrotal cancers, and adverse pregnancy outcomes.55−5, 2.04 × 10−5, and 3.12 × 10−5 mg/kg/d, respectively (Table 6). These values are in the unacceptable range (10−6 ~10−4) an indicate a potential cancer risk to human health. In addition, the results showed that the ILCRs through the ingestion and dermal contact pathways ranged from 10−7 and 10−5 in soil samples, while the cancer risk through inhalation was 10−12 to 10−9, about 104 to 105 times lower than that through ingestion and dermal exposures. As shown in et al. (2018) in Nanjing, China.10In the present study, the cancer risk (R) of a total of 16 PAHs for children, adolescents, and adults had means of 2.48 × 10ectively . These v−5), showing that both dermal contact and ingestion had a significant contribution to the cancer risk in children and adults. Nevertheless, the risk of ingestion for adolescents (< 10−6) was lower than for children and adults, because children are more likely to be exposed to environmental pollutants and considered the most sensitive group age with frequent hand-to-mouth or object-to-mouth activities which facilitates ingestion of contaminated soils.−05) was higher than for children and adolescents. This result is similar to the human cancer risk resulting from PAH exposure to surface soil in China cities , due to the larger dermal exposure with a long exposure period for adults.For children and adults, the cancer risk levels via dermal contact were in the same order of magnitude , the ILCRs for adolescents were lower due to lower soil ingestion rates and shorter exposure time. As shown in −6, 10−6 to 10−4, and >10−4 correspond to negligible risk, potential risk, and high risk of cancer, respectively.Table 6) were comparable with the ILCRs reported for various African locations like Warri city, Nigeria ,−5; adults 2.1 × 10−4),−2; adults, 5.11 × 10−3),−1; adults 1.02),−3; adults, 1.49 × 10−3),−1; adults, 2.56 × 10−2),−5 ; children 6.22 × 10−5)−5; children 1.85 × 10−5).−4; children 1.56 × 10−4),−4 – 1.13 × 10−2; children, 2.26 × 10−5 – 1.23 × 10−3),−8; children, 2.9 × 10−7).40Based on national and international regulatory agencies' delineated ILCR values, ≤ 10. Similar results have been reported in surface soils from the Tianjin coastal new region in China by Rongguang Shi et al. (2020),soil and EF in children and adults were higher than in adolescents.The R level for adults in the present study was higher than for children, while adolescents had the lowest risk −6, indicating that the study area has the potential for human carcinogenic risk. Compared to other studies, the obtained results show that the total R values were in agreement with those reported in contaminated soils from Hong Kong metropolitan soils and urban soil from Nigeria.67In addition, the R for children and adults in the study area was greater than the acceptable value of 1 × 10In general, preliminary health assessment results from the study area indicate that PAH-contaminated soils present a cancer risk to the resident population via cumulative ingestion and through dermal contact routes. The R for the three age groups in the present study indicate a potential health risk for adults and children, indicating that special attention should be paid to the health risks of children.et al. found a high incidence of liver cancer in the province, the highest in Algeria, suggesting a high prevalence of risk factors.Benarba −5, 2.04 × 10−5 and 3.12 × 10−5 mg/kg/d. The risk of cancer for adolescents was within the acceptable range, with no potential risk of cancer, but there was a higher risk of moderate to severe cancer in children and adults in the study area. Among different exposure pathways, the observed cancer risks through dermal contact had the highest contribution to total cancer risks in the study area. Further research should focus on risk assessment of PAHs in specific areas as agricultural, residential/urban, and industrial, and should include exposure through air.The present study represents the first health risk assessment from PAH-contaminated soils in northwestern Algeria. Total cancer risks of 16 PAHs for children, adolescents and adults were 2.48 × 10Click here for additional data file.