We assess the performance of these steps, when applied without user intervention, on several variations of a phantom imaging task. We used a rotating-tube phantom with five tubes ranging from Δχ=0.05 ppm to Δχ=0.336 ppm. MRI data was acquired at nine angles of rotation for four different pulse sequences. The images were processed by 10 phase estimation algorithms including Laplacian, region-growing, branch-cut, temporal unwrapping, and maximum-likelihood methods, resulting in approximately 90 different combinations of data acquisition and phase estimation methods. We analyzed errors between measured and expected phases using the probability mass function and Cumulative Distribution Function. Repeatable acquisition and estimation methods were identified based on the probability of relative phase errors. For single-echo GRE and segmented EPI sequences, a region-growing method was most reliable with Pr (relative error <0.1) = 0.95 and 0.90, respectively. For multiecho sequences, a maximum-likelihood method was most reliable with Pr (relative error <0.1) = 0.97. The most repeatable multiecho methods outperformed the most repeatable single-echo methods. We found a wide range of repeatability and reproducibility for off-the-shelf MRI acquisition and phase estimation approaches, and this variability may prevent the techniques from being widely integrated in clinical workflows. The error was dominated in many cases by spatially discontinuous phase unwrapping errors. Any postprocessing applied on erroneous phase estimates, such as QSM's background field removal and dipole inversion, would suffer from error propagation. Our paradigm identifies methods that yield consistent and accurate phase estimates that would ultimately yield consistent and accurate Δχ estimates.Quantitative Susceptibility Mapping (QSM) is an MRI tool with the potential to reveal pathological changes from magnetic susceptibility measurements. Before phase data can be used to recover susceptibility (Δ Quantitative Susceptibility Mapping (QSM)–3 is a min vivo and in phantoms, recent in vivo studies report lower reproducibility across MRI scanners with the same data processing method  to highlight the different convergence pattern (distribution/frequency of errors) in that domain. The CDF extends beyond εr=1.0 for any occurrence of relative errors greater than 100%.The CDF of ges to 1 . MAGPI aFεr(τ) as a function of data acquisition strategy. In Figures Fϵr(τ), ϵr is pooled across all pixels, background ROIs, slices, tubes, and variations of TR and resolution within that sequence type. We also explore variability of Fϵr(τ) with the frequency referencing method. For each sequence, we show CDFs in the ROI with the maximum Fϵr(τ=0.1)   of a method to frequency reference ROI selection.Next, we explore the behavior of Fϵr(10%) for a given sequence + method pair observed over all frequency reference ROIs, for every method, sequence, scan variation, tube, and slice.0; however, compared to previous work [A reliable pulse sequence protocol, with repeatable and reproducible phase estimation, is a necessary step to develop robust QSM methods for clinical use. Previous work examined the reproducibility of certain QSM methods using phantoms , 25, 55,ous work –59, moreμϵ less than 1 Hz , the only methods with μϵr <10% are SEGE + MEDI.RG (7.6%), MEGE + MAGPI-unopt (5.3%), and MAGPI (5.0%). We observed a similar trend with precision, whereby methods with the lowest relative standard deviation σϵr were MEGE + MEDI.LP (8.9%), MEGE + MAGPI-unopt (4.8%), and MAGPI (4.1%). The detailed behavior of the error is captured by the CDF (or PDF) of the data (Fϵr(10%), which captures the frequency by which relatively acceptable errors occur. An advantage of the Laplace-based methods is that they had smooth phase maps with qualitatively no apparent phase jumps. However, analysis showed that Laplace phase images result in quantitatively larger errors (a low Fϵr(10%)) than other methods, suggesting incorrect phase unwrapping results, similar to the work of Chen et al. [Fϵr(10%) were the unprocessed phase data, MEGE + Slope/Div, and MEGE + MEDI.RG, which had large phase unwrapping errors in a significant proportion of the data. Fϵr(10%) is an arbitrary point at which we highlight the behavior of Fϵr and does not represent the entirety of the distribution of error (or CDF). For example, Fϵr(10%) of SEGE + MEDI.RG was comparable to MEGE + MAGPI-unopt and MAGPI, despite the comparatively poorer (larger) μϵr and σϵr of SEGE + MEDI.RG. This is due to relative errors falling mostly within the chosen 10% threshold for these methods.Our results showed varying degrees of accuracy and precision over all tested methods. For example, while the majority of methods resulted in the data . A summan et al. . Other mFϵr(10%) observed across the 13 different frequency reference ROIs in the last column of We explored the dependence of errors on frequency reference ROI location . Since pThe results obtained with methods in Categories 1 and 2 were fundamentally similar. That is, additional 1D-temporal processing does not alter the performance of 3D spatial unwrapping methods . This redundancy is due to the inherent Nyquist limitation associated with the echo spacing. As a result, we focus on the distinctive results of Category 1: spatial phase unwrapping + weighted averaging of echoes .Some postprocessing methods used in MEGE Categories 1 and 2 performed more poorly with MEGE than with SEGE . We believe this is due to the relatively larger bandwidth used with MEGE acquisitions, resulting in noisier images at each echo. Higher BW acquisitions were needed with MEGE to accommodate temporal methods (MEGE Categories 3 and 4), which require short echo spacing. It is possible that MEGE + MEDI.RG would perform better with lower BW (wider echo spacing). Due to time/complexity constraints, we were unable to explore every possible MEGE variation that favors specific algorithms. This is a limitation of this study.MEGE Category 3 methods (Division/Slope) were straightforward to apply but resulted in a wide range of errors. This is due to large errors observed in frequency reference ROIs where the underlying frequency-offset value is larger than what is allowable by the smallest echo spacing. While such errors are avoidable with shorter echo spacing, this is not always possible (as was the case here) due to hardware constraints on readout bandwidth, resolution, FOV, and so forth. While Slope and Division are straightforward to apply, they result in a suboptimal combination of echoes, with noisy phase estimates.MEGE Category 4 methods have a similar performance to that of Category 3 methods. That is, spatial phase unwrapping did not seem to markedly improve the performance of temporal phase unwrapping. This is potentially due to the hard-to-unwrap noisy boundary lines observed with Category 3 methods, as shown in MEGE + Slope example in The MEGE data was processed using four broad classes of postprocessing algorithms. We note the following about these algorithms:Not all sequence + method pairs were invariant to scan and/or tube content. sEPI + Phun and sEPI + Unprocessed had greatest variability, followed by all of the Laplace-based methods , indicating that some methods produced inconsistent phase even in their best-case scenario. Laplace-based techniques generated smoothly varying, though numerically inaccurate phase maps, irrespective of sequence, and sEPI + Phun suffered from sequence-dependent errors.Considering the best-case ROI scenario, we did not observe consistent performance differences between pairing methods with either SEGE or sEPI. The sEPI sequence provides a significant acceleration over SEGE via its segmented GRE approach and performed better with some methods (GBC) and worse with others (Phun).FϵrB(10%) >  0.95) irrespective of the scan type used, while SEGE + Laplace was not always able to estimate the correct phase, irrespective of scan. SEGE + GBC, though, only struggled with Scan 2, which had a shorter TR than Scan 1.FϵrB(10%) close to 1.0 for all tubes and FϵrB(10%) = 0.91 in Tube 5. sEPI + Phun had inconsistent performance across tubes of similar content . Among the methods that maximized Fϵr(0.1), Tube 5 exhibited lower FϵrB(10%) compared to other tubes, which could be due to challenges defining Δχth and the complexity of CuSO4 compared to GdCl3.The same analysis can be applied to tube contents. MAGPI achieved Finally, we explored the dependence of the CDF on scan variability and tube contents , and we χ model (equation (B0 (five angles). That study used one method to estimate QSM [Overall, the consistently good performance across tube content, scan, and rotation angle in the absence of phase estimation errors validates the Δequation ) and demmate QSM –64 over mate QSM , Olsson mate QSM , comparein vivo. In vivo imaging may present different sources of phase errors not included here , and the phantom could present some challenges that are not encountered or are less prominent in the brain. This is a common problem with nearly all phantom studies, and it is counterbalanced by the advantage of having a known truth, which is not possible in vivo. Errors observed in phantoms are frequently observed in vivo, even when the geometry of the phantom is a gross simplification of human anatomy. For example, in T1 estimation, while phantoms can be used to refine a method, errors are amplified when methods are applied in vivo [A limitation of this work is that the geometric structure of the phantom was not identical to that encountered  in vivo . The man in vivo , 67.We introduced a wide range of variability to test repeatability and reproducibility of many data acquisition scenarios. While the performance of each method could be improved with additional “intervention” and potentially adapting the acquisition parameters to the intended postprocessing methods to be used later, our intent was to assess the ability of existing techniques in diverse imaging scenarios encountered in reality. The degree to which Steps 3 and 4 of QSM are sensitive to the errors introduced in Steps 1 and 2 requires further investigation. This phantom validation study allowed us to set a quantitative limit on the performance of various Steps 1 and 2 methods. Ongoing work focuses on evaluating the performance of a subset of these methods, paired with Steps 3 and 4 methods.In this work, we used a rotating-tube phantom to explore sources of error in QSM data acquisition and phase estimation. To assess the robustness and repeatability of methods, we did not manually intervene. The two most impactful parameters on reproducibility of measurements were (a) acquisition protocol  and (b) phase errors. The most repeatable and reproducible approaches were MAGPI and MAGPI-unopt, both methods based on the maximum-likelihood approach in phase estimation. For the remaining methods, performance varied greatly, even when systematically applied to the same underlying data from the same sequence or with the same method across different sequences. This assessment of which methods are repeatable and reproducible without manual intervention is an important step towards using QSM pipelines in clinical settings without experienced users.


Onion is one of the commonly cultivated and consumed vegetables rich in nutrients and phytochemicals. Various nutraceuticals are found in the outer fleshy layers and dry peel of onion which usually is treated as a common biowaste. Diabetes mellitus is a leading non communicable disease causing hyperglycemia and increased production of free radicals that potentially disrupts antioxidant enzymatic activity. Considering global consumption of wheat, the present study was designed to evaluate the anti-hyperglycemic and antioxidant effects of wheat bread supplemented with onion peel extract (OPE) or onion powder (OP) on diabetic rats.n = 7). Different regimens of supplemented wheat bread (OPE (1% and 3%) and OP (5% and 7%)) were given to diabetic rats for eight weeks, plain bread was used as the control. Blood glucose level, body weight and activities of SOD, CAT, GPx, GR, GSH and MDA in the liver and kidney tissues were evaluated. Statistical analysis was performed using SPSS Version (25) and Dunnett’s multiple comparison test.In this study, ethanolic extract of onion peel and onion bulb were prepared separately. Male Sprague Dawley rats were divided into 6 groups (Bread supplemented with 1% and 3% onion peel extract and 7% onion powder significantly reduced blood glucose levels and MDA in the treated rats compared with the control group diabetic rats. Body weight of diabetic rats was reduced for control group, while onion supplemented diet improved the body weight of treated rats. Onion supplementation also brought significant improvement in antioxidant enzyme activities among the treated diabetic rats.These findings suggested that onion supplementation is effective in lowering blood glucose and could potentially aid in protecting organs from oxidative stress. Diabetes is characterized by impaired carbohydrate, protein, and fat metabolism that results from poor insulin secretion, insulin resistance, or both. Diabetes mellitus is currently one of the most prevalent and life-threatening metabolic disorder globally. Based on several estimations, it is suggested that its incidence rate will rise even more rapidly in the coming future . RecurreTo understand the mechanism of diabetes and its relation to oxidative stress, several in vivo models were developed including alloxan-induced diabetes in mice. Alloxan, a pyrimidine derivative, is used to induce diabetes and produce cytotoxic free radicals that destroy animals’ pancreatic cells. These effects suggest that alloxan could influence the intrinsic antioxidant defense system in response to oxidative stress . The hazAllium cepa L.) is a widely cultivated and consumed vegetable that serves as an excellent source of macro and micronutrients [Triticum aestivum L.) is one of the most commonly consumed staple food [Several classes of drugs were developed to manage diabetes showing impressive results but many of the developed products resulted in side effects because the antidiabetic drugs are lifelong. Therefore, there is growing interest to incorporate medicinal plant-based products into the diet of the general population to reduce the medication use and thus their side effects and to obtain maximum preventive outcome . Onion  weighing 250–300 g, were purchased from the National Institute of Health (NIH) Islamabad-Pakistan and were acclimatized for 2 weeks in the animal house of the University of Lahore, Pakistan (March 2019–May 2019). Seven rats were kept in each cage and the environmental conditions such as humidity (55 ± 5%) and temperature 23 ± 2 °C) were sustained during the entire study with 12 h of light-dark period. Rats were given free access to the basal diet and water ad libitum. The rats were handled according to the international guidelines on the use and handling of experimental animals  [ ± 2 °C wExcellent quality, even-sized, undamaged onions  were procured from the local market. The outer dry and fleshy layers of onions were washed thoroughly using sterile water. Extraction was done with 60% ethanol at 50 °C for 3 h . The extThe obtained peeled onion bulbs were chopped using a sterile knife and placed in a drying oven at 50 °C for 3 days. The dried onion pieces were grounded into a fine powder using an electric grinder and the obtained powder was stored in an airtight container inside the refrigerator . The yie0) based on the basic AIN-93G diet without any supplementation; (2) bread with 1% onion peel extract (B1); (3) bread with 3% onion peel extract (B2); (4) bread with 5% onion powder (B3); and (5) bread with 7% onion powder (B4). The preparation of all mentioned types of bread was done by following the same procedure [Five different formulations of bread were prepared including 1) a control bread , 2% dry yeast  , 2% salt , and 1% dough improver  (eka-300) . For supectively , 27–29.w/v)) was also given to these rats to prevent fatal post-alloxan hypoglycemia. After 48 h of alloxan administration, the rats with fasting blood glucose levels>250 mg/dl were considered diabetic and were included in the study [Diabetes was induced in overnight fasted Sprague Dawley rats by injecting alloxan (120 mg/kg/BW) dissolved in normal saline, through the subcutaneous route. Glucose solution :NC): Normal rats fed with control bread.► Group 1 (DC): Diabetic rats fed with control bread.► Group 2 (OPE_1): Diabetic rats fed with bread supplemented with OPE (1%).► Group 3 (OPE_3): Diabetic rats fed with bread supplemented with OPE (3%).► Group 4 (OP_5): Diabetic rats fed with bread supplemented with onion powder (5%).► Group 5 (OP_7): Diabetic rats fed with bread supplemented with onion powder (7%).► Group 6  and body weight (g) were determined using a glucometer  and weigIn the liver and kidney tissue homogenates, the activity of superoxide dismutase (SOD) was determined by the Misra and Fridovich method using a Hitachi U-2000 spectrophotometer for 4 min at 480 nm. The potential enzymatic activity is stated based on its ability to inhibit the epinephrine oxidation up to 50%, that is equivalent to 1 U per milligram of protein , 35. Thep < 0.01) was performed to compare the antioxidants and enzymatic activity between the diabetic and control (DC) groups [Data were analyzed using SPSS (Version 25.0) . Dunnett) groups , 48.p < 0.01) (Table The results obtained in the current study indicated that the rat’s body weight (BW) was substantially reduced after induction of diabetes. The incorporation of bread supplemented with onion peel or onion powder significantly improved the body weight, although the effect was statistically significant by onion peel supplementation Table . The dif1) Table .Table 2Ep < 0.01) than the initial blood glucose levels (day 0). While comparing the treatment groups, it can be seen that in OPE_3 group blood glucose level dropped remarkably from 289 ± 5.8 on day 0 to 205 ± 3.3 on day 56 which is significantly high as compared to OPE_1 and OP_7 groups where the final day blood glucose level was 234 ± 6.2 and 230 ± 3.3 respectively. Whereas the glucose-lowering effect of 5% OP supplemented bread remained non-significant for most of the observation checkpoints except for the end-point measurement (day 56) (p < 0.01). The overall glucose-lowering effect of 3% OPE supplemented bread was more pronounced as compared to any other supplemented bread.Blood glucose levels were measured fortnightly and weekly variation in all the groups is presented in Table p < 0.01) rise in the level of malondialdehyde (MDA) and decline in catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx) activities, and glutathione (GSH) content were reported in the diabetic control group in comparison with the normal rats  in the liver’s superoxide dismutase and catalase activity, respectively.Significant p < 0.0 rise in ts Figs.  and 3. Ip < 0.01) increase in the activities of GPx, GR, CAT, SOD, and GSH levels but the effect was more pronounced in the group supplemented with 3% OPE bread. It was observed that MDA levels were reduced by (21%) in the liver of the 3% OPE treated group in comparison with the diabetic control. Along with the significant improvement in GPx, GR, and GSH levels, the similar group presented a prominent threefold increase in SOD and CAT levels in the liver as compared with the diabetic control group showing the restoration of the altered antioxidant defense system near to the normal level.Diabetic rat groups that were treated with OPE (1% and 3%) and OP (7%) showed a significant  , was also reduced in the hepatic and renal tissues of diabetic rats indicating impaired scavenging activity of lipid hydroperoxides and Htigation . When diAlso, it was observed in our present study that the enzymatic activity of GR was significantly reduced in diabetic rats due to a reduction in its production . In grouLipid peroxidation is another crucial factor that is strongly associated with the integrity of cellular membranes and it helps in evaluating the composition and structure of the tissue lipids. In diabetes, the raised level of free radicals in certain tissues may lead to a rise in the rate of lipid peroxidation . Hence mThe current study suggested that both onion peel and bulb may have beneficial effects against diabetes by lowering glucose levels and suppressing oxidative stress when given in a certain amount and this holds the hope of a new generation of functional foods. Onion peel is commonly treated as agro-biowaste but it contains useful phytochemicals that need the attention of the scientific community as well as the food industry. However, the present study has some limitations. The phenolic content and antioxidant capacity vary among different onion varieties  and the


Doping and intrinsic features endow Cs3Cu2I5: Mn with robust thermal stability and irradiation hardness that 71% or >95% of the initial radioluminescence intensity can be maintained in an ultra-broad temperature range of 77 K-433 K or after a total irradiation dose of 2590 Gy, respectively. These superiorities allow the fabrication of efficient and stable nuclear batteries, which show an output improvement of 237% respect to the photovoltaic device without scintillator. Luminescence mechanisms including self-trapped exciton, energy transfer, and impact excitation are proposed for the anomalous dramatic radioluminescence improvement. This work will open a window for the fields of nuclear battery and radiography.Fluorescent type nuclear battery consisting of scintillator and photovoltaic device enables semipermanent power source for devices working under harsh circumstances without instant energy supply. In spite of the progress of device structure design, the development of scintillators is far behind. Here, a Cs Fluorescent-type nuclear batteries are a promising semi-permanent power source, but performance is hindered by scintillator development. Here the authors report a scintillator with high light yield and stability, which leads to improved performance. Recently, the radioluminescent NBs have been researched extensively due to the possibilities of higher energy conversion efficiency and protection of terminal semiconductors3. Such kind of battery consists of three parts, namely, radiation source, scintillation layer, and photovoltaic device (PVD). The scintillation layer converts radiation energy into light emission and then, the PVD converts these photons into electricity. There is no doubt that the high efficiency of scintillator, radioluminescence (RL) spectrum consistent with the response of PVDs, perfect coupling between luminescent materials and PVDs are the dominating factors to achieve high conversion efficiency. Besides, a good stability of the scintillator against radiation and environmental attack is the basis of NB’s stability.In some particular applications, such as equipment for outer planet exploration and undersea detection, energy supply is usually challenging due to the absence of light and difficulties in charging or replacing power sources. These facilities may operate continuously for more than 10 years at places without human beings and this calls for energy systems that can generate energy themselves and work for a long time. Nuclear batteries (NBs)6, application of various scintillators (organic or inorganic ones)7, effect and optimization of physical parameters10, and coupling between scintillators and PVDs have been carried out to improve the NB efficiency11. Despite the power output and efficiency of NBs have been improved significantly, the scintillators employed in these researches were mainly conventional transition or rare earth metal doped phosphors13, which typically possess short emission wavelength or low light yield (LY). For standard PVDs, the conversion efficiency at short wavelength (mainly shorter than 450 nm) region is usually low. Though some scintillators can emit long-wavelength light, their LYs are commonly frustrating. Therefore, to further improve the performance of NBs, new scintillators with both long wavelength and high LY are urgently needed to break the bottleneck.In the past decade, investigations on the design of the device structure16. Their high photoluminescence quantum yield (PL QY) and good radiation absorption ability may endow them with high LY. Upon the first report of RL phenomenon of perovskite nanocrystals (NCs)17, demonstration of X-ray imaging based on perovskite NCs has been investigated extensively20. Though the emission wavelength of perovskite NCs can be modulated feasibly, their LY is indeed low compared with many commercial scintillators21. Besides, their poor stability and toxicity issues make it challenging in practical applications. Referring to the problem of lead, Tang et al. developed a new copper-based scintillator with ultrahigh LY23. Whereas, the emission peak locates in the UV region, which is not consistent with the response of PVDs. Kovalenko et al. reported the fabrication of zero-dimensional tin (Sn2+) halides and achieved relatively high LY and long-wavelength emission (660 nm) simultaneously24. But, Sn2+ is easily oxidized in air and the organic part may also be destroyed at high temperature. Very recently, a new kind of zero-dimensional copper halide (Cs3Cu2I5) NC was reported to exhibit high QY and good stability with self-trapped exciton (STE) based blue emission30, making it potential candidate of highly efficient and stable scintillator for NBs31.The success of lead halide perovskites in light-emitting applications redraw our attention back to metal halide scintillators2+ into Cs3Cu2I5 crystals can induce significantly improved RL efficiency compared to intrinsic Cs3Cu2I5 crystals and a maximum LY of ~67,000 ph MeV−1 at an emission wavelength of 564 nm was achieved. This is, to the best of our knowledge, almost the highest value at such a long emission wavelength based on low cost material32. Furthermore, the Mn doped Cs3Cu2I5 (Cs3Cu2I5:Mn) exhibits good stability against temperature variation that 71% of initial RL intensity can be maintained in an ultra-broad temperature range of 77–433 K while the RL intensity of pure Cs3Cu2I5 shows a severe deterioration of 92.5%. Additionally, when Cs3Cu2I5:Mn was irradiated continuously for one month, more than 95% of its initial RL intensity has remained after a total dose of ~2590 Gy. To figure the reasons for the abovementioned phenomena, the luminescence mechanism is discussed detailedly with thorough analyses of structural and luminescent properties. These superiorities imply the promising application of the fashionable copper halide in NBs. Efficient and stable NB based on Cs3Cu2I5:Mn and PVD was fabricated finally, which shows an output improvement of 237% respect to that without scintillator and a power output of 0.46 μW cm−2. It is expected that such a new and robust scintillator will open a window for the fields of NBs and radiography.Here we show that doping Mn2+ doping. Cs3Cu2I5 consists of zero-dimensional electronic structures, and Cu+ ions occupy two sites, a tetrahedral (Cu 1) and a trigonal (Cu 2) site  and Mn2+ (0.66 Å) makes the substitution process to happen easily. Therefore, replacement of Cu ions with Mn ions is possible from both crystal and energy factors.Theoretical calculations were firstly conducted to evaluate the influences of Mn doping. We can see that replacing either the tetrahedral or the trigonal Cu ions results in similar electronic structures and system energy with a difference of ~90 meV even at a heavy doping concentration  can be observed from both the Mn3% and Mn15% samples , and the spectral linewidth (2.51 mT) keep the same in these two samples, indicating the stationary coordination state of Mn2+ in the lattice despite the signal intensity variation resulted from increased concentration. The A in these samples is a bit larger than that in other metal halides, which might be derived from the low coordination number and large anion radius37. XPS results indicate the maintenance of Cu+ state that a 2p doublet with the binding energy of 932.1 eV (2p3/2) and 951.8 eV (2p1/2) is observed →4T2(4D)), and 485 nm (6A1(6 S)→4T1(4 G)), respectively. The UV part and that monitored at intrinsic emission wavelength are semblable, indicating the yellow emission from 4T1(4 G) to 6A1(6 S) can be achieved by energy transfer (ET) from Cs3Cu2I5 or direct excitation of Mn2+. Additionally, the similar shape of PLE spectra with different monitor wavelength indicates the single excited state. The inset in Fig. 39. Detailed QY results are shown in Supplementary Table Optical and anomalous scintillation properties. Intrinsic Csion Fig. . When me2+ concentrations . Two very strange phenomena were observed. First, though pure Cs3Cu2I5 showed obvious RL, the blue part almost disappeared when only a small amount of Mn2+ was doped. There only existed an obvious Mn2+ related yellow emission peaked at 564 nm along with a weak blue emission. The small redshift compared to the PL peak is in accord with other halides40. It is worth noting Mn2+ PL is still weak in low doping concentration as shown in Supplementary Fig. 3Cu2I5. The RL intensity increases along with the doping concentration and reaches a maximum at a concentration of 15%. Then, a sudden RL intensity reduction emerges when the doping concentration increases furtherly →4T2(4D)) excitation efficiency, which accords well with the direct excited PL results  → 4T1(4 G) transition (485 nm) show similar behaviors to that of exciting at 385 nm but less significant  and CBM (III) levels, as described in Fig. 2+ concentration, direct ET from CBM gradually dominates, which possess longer PL decay time.We make an assumption of the PL and RL mechanism as described in Fig. d electrons is not excited directly, lattice distortion is relatively weak compared to that resulted from UV light excitation of Cu 3d electrons. Then, the formation of STE under the excitation of X-ray is very weak, leading to faint blue RL intensity. As a result, majority of the electrons on CBM will transfer to Mn2+ levels (III) directly and contribute to strong yellow RL. This might be the main reason for the greatly reduced blue part under the excitation of X-ray compared to the PL curves.In contrast to light excitation of band-edge electrons, X-ray excited electrons from core band to much higher energy levels Fig.  right. T2+ may play a more important role in the RL behavior. First, doped ions can be directly excited through impact excitation (II) provided its concentration is large enough, and when this process occurs, it is strongly dominant. Since the Mn2+ doping concentration here is much higher than that of conventional rare earth elements, this mechanism may also make contributions. As we can see, though ET induced yellow emission in 450 °C-6 h sample is the strongest . Interestingly, despite the low RL intensity, Cs3Cu2I5 showed a persistent scintillation intensity even at 333 K with a total irradiation dose of ~29 Gy . Such robust thermal stability for lead-free halides has never been reported as far as we know. Future investigations should include the protection of these scintillators from the attack of moisture. Fortunately, the sealing technology nowadays is good enough to prevent the invasion of moisture.More than 95% of the initial RL intensity remained for Mn15% after an accumulated irradiation dose of ~2590 Gy at room temperature Fig. . Since C42. We then fabricate prototype NBs and the device structure is shown in Fig. −1) and drop-casting. Since the scintillator thickness will either influence the attenuation of X-ray or hinder light output efficiency by scattering, we therefor modulate the film thickness by changing the quantity of Mn15%.Characterization of nuclear battery. At this point, we have achieved a highly efficient scintillator with good stability against irradiation and high temperature. Besides, the emission wavelength locates in the region of PVD with high external quantum efficiency, ensuring a good device performance Fig. 42. We thI–V) results of different NBs with or without Mn15% scintillator layers under the irradiation of X-ray . The GaAs PVD sealed with a thin coverslip (0.13 mm) could directly convert X-ray into current with a maximum output power of 0.027 μW. When the Cs3Cu2I5:Mn film covered on the device, both the open circuit voltage and short circuit current increased under the same X-ray dose rate. Especially, the short circuit current increased greatly (an increase of 300%), indicating the vast generation of electrons with the assistance of the scintillator layer. Theoretically, the direct type device should exhibit higher efficiency compared to indirect devices due to additional RL step. However, thin film PVDs usually cannot absorb X-ray completely and increasing film thickness is inadvisable due to the limitation of carrier diffusion length and lifetime. Also, it is reported that taking full advantage of the direct and indirect conversion approaches can achieve better device performance40. Therefore, we should make a balance between scintillator film thickness and X-ray absorption. With the increase of scintillator film thickness, the output power showed a first rising and then decline trend. Obviously, both direct and indirect conversion procedures exist in our device and the optimized output power can reach 0.091 μW, a significant increase of 237% compared to the NB without scintillator. This improvement is much greater than that using CsPbBr3 NCs as the scintillator layer42. When other scintillators were applied as the transducer layer, lower output were achieved due to the low LY as shown in Supplementary Fig. 3Cu2I5:Mn and the protection of polymer, the NB exhibited a robust power output that after working under ambient conditions with a total irradiation dose of ~1290 Gy , specific packaging technology should be developed for future applications. Additionally, the detailed RL mechanism needs more investigations.This work presents a new Cs2·4H2O (99%) were purchased from Aladdin. All the chemicals were used without further purification.Cesium iodide , Cuprous iodide , and MnCl3Cu2I5:xMn2+ (0.3 ≤ x ≤ 0.25) were synthesized by a solid-state reaction method. The experimental steps were as follows: CsI, CuI, MnCl2.4H2O were put into the mortar or ball grinding tank in a certain proportion to get uniform mixtures. Subsequently, the resulting mixtures were encapsulated in a vacuum quartz tube and placed in a muffle furnace for calcination at 340–450 °C. The reaction time was 6–48 h. After the reaction finished and cooled naturally to room temperature, the calcined product was taken out and grinded to obtain light yellow Cs3Cu2I5:Mn2+ powders. Finally, the powder was washed with n-butanol twice to exclude the trace unreacted MnCl2. After centrifugation, the powder was dried under vacuum at 80 degrees for 12 h to obtain the final scintillator material. This purification process is very important otherwise the powders are not stable. Detailed information can be found in the following discussions.A series of Cs−1) was prepared as the matrix. Then, different weights (100–600 mg) of Cs3Cu2I5:Mn 15% were mixed with 1 mL PS solution. The mixtures were stirred rigorously for 4 h and casted on a thin glass substrate for the fabrication of scintillation layers. The thick films were dried under vacuum at room temperature, which were then covered on a GaAs solar cell (1 cm × 1 cm) sealed with a thin glass.First of all, a polystyrene (PS) toluene solution . X-ray photoelectron spectroscopy (XPS) measurements were performed using an achromatic Al Kα source (1486.6 eV) and a double pass cylindrical mirror analyzer (PHI QUANTERA II). The thermal gravimetric analyses were conducted on STA7000, HITACHI. Emission and excitation spectra were collected on Varian Cary Eclipse instrument. The PL lifetimes were measured by FLSP920 (EDINBURGH INSTRUMENTS LTD) equipped with both ns and μs light sources. The absolute quantum yield of the samples was determined using a Quantaurus-QY absolute photoluminescence quantum yield spectrometer . The X-ray source is produced from a commercial Amptek mini-x tube with Ag target and a maximum output power of 4W. All the radioluminescence and temperature-dependent spectra were recorded with a fiber spectrometer . The nuclear battery performances were measured with Keithley 2400 under the irradiation of X-ray.Powder X-ray diffraction was characterized by an X-ray diffractometer (Bruker D8 Advance XRD system), and the morphology and elements of Cs−4 eV in energy and 10−3 eV/Å in force. The Brillouin zone integration is sampled using a set of 3 × 3 × 3 Monkhorst-Pack k-points.The structural optimizations and electronic structure calculations are performed based on density functional theory as implemented in VASP code. Exchange correlation energies are considered by the generalized gradient approximation (GGA) using the Perdew-Burke-Ernzerh (PBE) functional. The wave functions are constructed using a projected augmented wave approach with plane wave cutoff energy of 500 eV. The convergence threshold was set as 10supplementary informationPeer Review File


In our estimates, we include deposits that have been neglected in global carbonate budgets: Holocene Halimeda bioherms located on the shelf, and postglacial pre-Holocene (now) drowned coral reefs located on the shelf edge. Our results show that in the Great Barrier Reef alone, these drowned reef deposits represent ca. 135 Gt CaCO3, comparatively representing 16–20% of the younger Holocene reef deposits. Globally, under plausible assumptions, we estimate the presence of ca. 8100 Gt CaCO3 of Holocene reef deposits, ca. 1500 Gt CaCO3 of drowned reef deposits and ca. 590 Gt CaCO3 of Halimeda shelf bioherms. Significantly, we found that in our scenarios the periods of pronounced reefal mass accumulation broadly encompass the occurrence of the Younger Dryas and periods of CO2 surge  observed in Antarctic ice cores. Our estimations are consistent with reef accretion episodes inferred from previous global carbon cycle models and with the chronology from reef cores from the shelf edge of the Great Barrier Reef.More accurate global volumetric estimations of shallow-water reef deposits are needed to better inform climate and carbon cycle models. Using recently acquired datasets and International Ocean Discovery Program (IODP) Expedition 325 cores, we calculated shallow-water CaCO The authors assigned a medium degree of confidence to the current estimates of atm-CO2 contributions from coral reef accretion and carbonate compensation depth changes. This uncertainty derives not just from the use of proxy data and their limited availability, but from the complex relationships between the carbon and other biogeochemical cycles. Such uncertainty is reflected in the range of the contributions to postglacial atm-CO2 attributed to shallow-water reefs in global carbon models (− 9 to 30 ppm5).The role of calcium carbonate deposits in the carbon cycle, and the influence on climate change during the late-Quaternary is poorly constrained. The fifth assessment report of the Intergovernmental Panel on Climate Changecoral reef hypothesis 7. This hypothesis proposes that the increase of the atm-CO2 is at least partly due to the enhanced shallow-water CaCO3 accretion by corals. This hypothesis relies on the availability of new areas of marine flooded shelf during the last transgression and on the consequent increase in coral reef development. This would have changed the alkalinity balance, at least locally, and ultimately increasing the transfer of CO2 to the atmosphere8. Because of the reduced marine shelf area during glacial times and the subsequent increase in reef area from glacial to Holocene times, it is assumed that the coral reefs acted as secondary amplifiers—not precursors—of a climatic change that had already initiated10 with early atm-CO2 rise generally preceding global surface temperature increase11.The role that coral reefs may have played in this process has been termed the coral reef hypothesis is supported by the extensive coral reefs of Holocene age worldwide16. Moreover, a possible lower contribution from terrestrial sources in this same period17 argues in favour of alternative carbon sources, such as that represented by reef accretion. Simplified box models7 have suggested that the activity of the coral reefs can explain a significant rise of the atm-CO2 during postglacial times. However, the dissolution ratios, accretion rates and calcite saturation depth informing these models are poorly constrained and they possibly overestimate the total carbon derived from corals.The 219. Notably, Ridgwell et al.5 inferred two possible minor episodes of global reef growth from 17.0 to 13.8 ka BP and from 12.3 to 11.2 ka BP. With no conclusive evidence available at that time for such global reef growth episodes20, they attributed the increase in CO2 to changes in the biogeochemical properties of the Southern Ocean surface.More complex models have considered the effect of coral reefs in postglacial atm-CO22). Globally, drowned reefs may constitute an important fraction of postglacial carbonate24 and an alternative earlier source of postglacial carbon. Halimeda bioherms are another contributing component, with recent investigations from the GBR suggesting they are volumetrically relevant in postglacial carbonate budgets27.Interestingly, recent evidence in Tahiti and the Great Barrier Reef (GBR) has revealed glacial and early-postglacial (30 to 10 ka BP) coral reef episodes in line with those inferred intervals (IODP Expeditions 310 & 32528 and applying parameters (e.g. reef area) with large associated uncertainties. New datasets are, however, providing valuable constraints to these parameters within the GBR region. For example, new GIS datasets of reef boundaries29 have the potential to improve the estimations of reef area. Additionally, the recent surveys and investigations on the drowned shelf edge reefs of the GBR represent the most complete dataset investigating drowned reefs: IODP Exp. 325 well-dated fossil reef cores31, seismic lines33, multibeam bathymetry34, and surface sediment and rock dredge samples36. New detailed bathymetry and interpretations are also providing new constraints on the spatial distribution and volume of Halimeda bioherms in the northern GBR27.Estimations of global and regional reef carbonate area and volume have been attempted using a range of assumptionsHalimeda deposits on regional  and global postglacial shallow-water CaCO3 budgets. Our scientific objectives are to: (1) estimate the volume, mass and timing of postglacial shallow calcium carbonate deposition across the entire GBR using the most recent GIS datasets, data from two IODP Exp. 325 control zones from the shelf-edge reef system and the regional volume of the Halimeda bioherms; (2) extend the resulting volumetric and mass estimates globally based on assumptions ground-truthed in the GBR; and (3) compare our results with past regional and global volumetric and mass estimates.In this paper we investigate the impact of drowned coral reefs and 38 controlled by major glacial-interglacial sea-level fluctuations. The last glacial-interglacial fluctuation initiated during the LGM30 when sea level was approaching minimum levels (120–130 m below present)39.The GBR shelf along the northeastern coast of Australia Fig.  accommod40. These reefs currently lie between 40 and 130 m below present sea level and extend for more than 2000 km from the northern to the southern central GBR and possibly farther42  layer of carbonate sands and mud, dominated by Halimeda fragments, foraminifera, mollusks and bryozoans47.As the glaciation ended and sea level rose during the postglacial, extensive fringing- and barrier-reef structures developed along the shelf edge of the GBR until ca. 10 ka BP48. Both Pleistocene and Holocene reef deposits in the GBR display local and regional variations that are the expression of broader physiographic trends and of the physical processes linked to the postglacial marine flooding49.The shallower structures of the modern GBR were colonized after ca. 9 ka BP following the demise of the shelf-edge reefs. Since then, extensive reef development has occurred along the whole GBR from the vicinity of Fraser Island in the south, to Cape York in the north50, and excluding continental islands and shelf-edge reefs. These features were sliced into latitudinal 50 km wide slices to assess latitudinal variations. We assumed that the reef area polygons represented the main reef and bioclastic deposits directly related to Holocene reef growth. However, unaccounted fore- and back-reef aprons may constitute a significant portion of the reefal carbonate volume51.We estimated the areal trends of the Holocene reefs in the GBR. Reef area was estimated from GIS layers containing polygons representing the outline of the Holocene reefs Figs.  and 2. T3 deposits by multiplying the area derived from the interpreted GIS layer by the thickness derived from historical reef cores that have drilled through the Holocene . The volumetric and mass calculations were also performed at a sub-regional level in 50 km wide latitudinal slices that allowed reconstruction of latitudinal trends  between 14° and 21° S  than our best estimate of 751 Gt CaCO3. However, Rees13 include reefs in the Australian region that are not part of the GBR system sensu stricto. The Kinsey and Hopley55 estimated reef area value is more in agreement with our figure: ca. 20,000 km2. A more recent estimate places the GBR’s shallow-water reef area at 16,110 km250, but they do not include sediment wedges associated with these reefs, which are found at greater depths and constitute up to the double of the reef framework volume51. If we calculate the mass areal accumulation (MAA) using Rees13 estimates (Table −2) than even the highest MAA in Hydrographers Passage , vertical accretion rate, the maximum cumulative thickness and petrophysical parameters. A regional bathymetric dataset57 provided the basis for the reconstruction for the postglacial marine flooded area in the GBR .The volume and mass of the shelf edge deposits at a regional scale were ground-truthed in two control zones along the shelf edge of the GBR: Hydrographers Passage and Noggin Passage Fig. . Here, eflooded area and the accumulation represented by the MAA, scaled back by the proportion of bathymetric surface covered by reefs (reef area ratio) without considering any temporal evolution. The latter, the postglacial-thickness method, attempts to reconstruct the temporal evolution of the reef accretion by considering the change in flooded area since the LGM. It is layer-based, with each layer corresponding to a 5 m sea-level step in which data-derived thickness constraints  the mass areal accumulation method and (2) the postglacial thickness method. The former is a bulk calculation of volume based on nts Fig.  are applnts Fig. b. It rel.31 Fig.  enabled The estimates obtained applying the mass areal accumulation method are lower than those estimated by applying the postglacial thickness method but are within the same order of magnitude. Not surprisingly, the application of both methods results in similar latitudinal trends Fig. e becausereef area ratio = ca. 20%). This proportion is almost twice the reef area ratio estimated at a regional scale for the shallower, Holocene reefs when considering the whole of the GBR shelf.In the control zones, Noggin Passage and Hydrographers Passage Fig. , ca. 20%−2, whilst inter-reef areas display MAA values that are an order of magnitude lower (7767–8406 kg m−2). The southern control zone (Hydrographers Passage) has a higher average MAA  than the northern site (Noggin Passage) in all the geomorphic areas assessed . This is consistent with a thinner reef veneer (< 10 m) in the terrace and outer geomorphic areas and less distinguishable barrier structures found at Noggin Passage40.In both control zones Table  we found40. On the contrary, in the southern-central GBR (e.g. Hydrographers Passage control zone) wider and a more gentle gradient provides more substrate availability34.Volumetrically, the carbonate deposits of the shelf edge wane in the northern GBR when compared to the central and southern GBR Fig. d, e. In 2  and 48% (maximum case) of the area occupied by banks with no Holocene cover in that same study. Kleypas58 inferred that the global area available for reef growth during the LGM lowstand was approximately 20% of that available today. In the GBR, that figure is at least within the same order of magnitude of our estimations: a maximum shelf edge flooded area of ca. 29,523 km2 .It is useful to establish some comparisons to appreciate the magnitude of the shelf edge deposits. At the shelf edge, our estimates suggest that the area covered by reef formations is between 3000 and 11,000 kmHalimeda bioherms are a significant component of the region’s postglacial carbonate budget. A comparison of the most up-to-date morphometric data27 shows that the postglacial Halimeda deposits are equivalent in mass to 5.5–10.5% of the Holocene reef mass on the GBR shelf . Despite these new constraints, questions remain about the extent of pre-Holocene Halimeda deposits, particularly at the shelf edge.3 deposits for the GBR to the entire globe using the reef area estimate of Spalding et al.56. Using this area, we applied the parameters ground-truthed in the GBR dataset. The global reef area (RAGLOBAL) was multiplied by average thickness and petrophysical parameters  to obtain global postglacial CaCO3 deposits. We accounted for the drowned postglacial reefs by applying two factors to the global Holocene estimates: a factor based in the ratio of shelf edge-to-Holocene reef area  and a factor based in the mass ratio  (Table We extrapolated the estimates and trends of CaCOM) Table .Table 3Greef area ratio at the shelf edge (ca. 20%) is twice the reef area ratio estimated for the whole GBR shelf  and shelf area in low latitudes  as reported in Kleypas58, suggesting a global reef area ratio of 5 to 6%. This percentage would be even lower if we apply the global reef areas of 300 × 103 km261, 255 × 103 km216 or 284 × 103 km256. The lower value of the global reef area ratio (5–6%) compared to the GBR values of this study (ca. 10%) could be partly explained by uncertainties in the topographic/bathymetric datasets used by Kleypas58 , and by difficulties in predicting reef habitat using the ReefHab model58, or by the inclusion of shelf areas that are not potential reef habitats. It is also possible that the GBR had more favourable regional conditions for reef development compared to other global locations.We found that the 2 by Spalding et al.56 is lower than estimates from other authors  ranging from 4073 Gt CaCO364 to a maximum of 54,550 Gt CaCO365 , we obtain a global value of 1460–1785 Gt CaCO3 accumulated in the drowned reefs from 19 to 10 ka BP. These results are modest compared to the combined Holocene reef deposits (ca. 8100 Gt CaCO3). However, given the direct evidence on large-scale pre-Holocene shelf edge reef systems in the GBR  and past evidence of other large-scale drowned reefs in global locations24, the question of the impact of drowned reefs on the LGM-to-postglacial global CaCO3 budgets remains relevant.If we extend the shelf edge-to-Holocene reef ratios estimated in the GBR to global scales  to a maximum of 3.2 Gt CaCO3 y−1 (using area in Copper65). However, if we split the averages between Holocene and pre-Holocene, we find the differences are of one order of magnitude . These were periods of high substrate availability and favourable environmental conditions for reef growth, as influenced by shelf physiography and sea-level rise49.The timing of the CaCO3 mass accumulation at regional level, but it can provide a broad temporal trend. The periods of higher CaCO3 accumulation in the shelf edge  . These findings are consistent with a more recent analysis of all available postglacial vertical reef accretion data (including IODP Exp. 325), which shows rapid accretion rates (9.6 to more than 20 mm yr−1) during these periods of higher CaCO3 accumulation .The postglacial thickness method cannot establish a precise chronology for CaCO3) and their global extrapolations (1500 Gt CaCO3) suggest that pre-Holocene reef accretion is likely to be more relevant to the global CaCO3 budgets  than currently recognized. The impact of these deposits in the atm-CO2 should be assessed by global process-based carbon models that reflect the full complexity of the atmosphere–ocean–land biogeochemical cycles . The latitudinal distribution of the shelf edge reefs is also strongly correlated to shelf availability.The shelf-edge reefs of the GBR constitute an important portion of the postglacial shallow reef deposits: these (now) drowned reefs occupy an area of between 3000 and 12,000 km3 from Holocene reefs (best estimate), which is consistent with previously published estimates. Following from recently published results in the GBR, a minimum of ca. 590 Gt CaCO3 from Halimeda deposits should be added to the global Holocene CaCO3 mass, representing a 4–8% increase in the budget.By globally extrapolating the GBR constraints, we estimate a total accumulation of 8100 Gt CaCO3 represent 16–20% more mass in the global postglacial budget than if considering the Holocene reef deposits alone. Their inclusion in global carbon models could provide new constraints on postglacial global atmospheric and climate models.Global extrapolations supported by recent surveys suggest that a significant proportion of postglacial, pre-Holocene shallow-water carbonate deposits can be attributed to now drowned postglacial reefs. These deposits of ca. 1500 Gt CaCO3 deposition in the GBR is broadly coeval with two distinct episodes of postglacial atm-CO2 increase (ca. 14.9–14.4 ka and ca. 13.0–11.5 ka BP67). Any causal relationship must be confirmed by more complex, process-based models of the global carbon and other biogeochemical cycles and global surveys of drowned reefs and reef areas.Our results support a more prominent role in the postglacial carbon cycle for pre-Holocene shallow-water coral reefs. Significantly, the timing of higher CaCOWe estimated the carbonate volume in the GBR for: (1) early postglacial reef deposits (21–10 ka); and (2) Holocene reef deposits. We also attempted a global extrapolation of these carbonate deposits based on these new and well-constrained regional GBR estimates.57, GIS layers with reef locations and extensions50; previous GBR Holocene drill cores (see Appendix 68 for data sources). We distinguished the areas at the shelf edge (defined here between the modern outer GBR reef front and the 130 m isobath) from the other areas of the shelf and extracted the corresponding bathymetric subset.Data were available across the whole GBR: bathymetry at ~ 100 m resolution47; (2) extensive and precise chronologic database (> 580 published U-Th and 14C ages), lithological and petrophysical properties directly measured from the IODP Exp. 325 drill holes and cores31; (3) high-resolution (5 m) bathymetric coverage in these sites34; and (4) extensive knowledge on the development history and age structure of the shelf-edge reef system21.More locally, data were available for two densely surveyed control zones at the shelf edge  = 2930 kg m−3Aragonite density (ρR) = 35%30.Reef formation porosity  as obtained from the seismic interpretations47. The three different velocity scenarios (1700–3300 m s−1) to convert from seismic time to true depth47 were considered to obtain a minimum, best estimate, and maximum values for each set of maps.Mass areal accumulation (MAA) [kg m−2] at the shelf-edge control zones: these values were calculated for each control zone by transforming each formation volume estimate to carbonate mass (CaCO3 mass = formation volume × ρA × (1—ΦR)) and subsequently dividing the mass by the total shelf edge area of the control zones (MAA = mass · [shelf edge area]−1). The calculations were also applied for each of the main geomorphic zones47: inner barrier, outer barrier, terrace and shelf break combined, and inner and outer platforms combined. Three values were applied to account for plausible minimum, best and maximum scenarios: the average MAA value of all reef locations, and the minimum and the maximum MAA value in any reef location (Table AA) kg m− at the sVertical accretion rate [m ky−1] at the shelf-edge control zones: the glacial-postglacial boundary recognized in the cores and the radiometric ages measured in the Exp. 325 core samples21 allowed the estimation of the vertical accretion gradients (m ky−1) for the entire postglacial Pleistocene time period (21–10 ka) , this became a necessary constraint to avoid unrealistic cumulative reef thickness as sea-level rise progressed .Postglacial shelf margin .49 Fig. . The relTo estimate the postglacial Pleistocene carbonate deposits, we first produced the following input for both of the estimation methods we applied:3 accumulation was calculated using the following parameters:Reef area [m2] from the Queensland coast to the outer GBR: the reef area was estimated from GIS layers containing polygons representing the outline of the Holocene reefs  and their interpretation, which could result in an overestimation of the reef area in the northern GBR, the under or overestimation of the extent of the bioclastic cover, or the misrepresentation of some locations as Holocene reefs when they might be older Pleistocene outcrops50.ef area m from thens Figs. , 3e. We Reef thickness from Holocene GBR drill cores [m]: a dataset of Holocene reef thicknesses was used to estimate minimum, average and maximum thickness values for the Holocene reef thickness68  was multiplied by the reef area ratio (RAR) and mass areal accumulation (MAA) values to obtain CaCO3 accumulation values in the GBR shelf margin  was converted to an equivalent rate relative to past sea-level steps. This allowed us to associate an incremental reef thickness to each of the 5 m sea-level steps considered. Conversion from geological age to equivalent sea level was performed using a simplified relative sea-level curve based on Lambeck et al.39 for ages more recent than 10 ka BP, and based on Webster et al.21, Yokoyama et al.31 for ages before 10 ka BP  by each sea-level step (5 m). Subsequently, the product of this thickness and the flooded area at each flooding stage (FASL) gave us the formation volume for each one of the thirty-three latitudinal zones and for each sea-level step. The volume was scaled down by the reef area ratio (RAR) values  and density (ρA):To obtain an estimate of reef volume at each sea-level step, we first estimated reef thickness by multiplying the converted postglacial ess Fig. . The CaCPleistocene CaCO3 mass for each sea level (SL) between 130 and 0 m:Incremental reef volume = VASL × 5 m × FASL × RARIncremental CaCO3 mass = Incremental reef volume × ρA × (1—ΦR)Cumulative CaCO3 mass = Σ CaCO3 mass of Holocene carbonate in the GBR, the reef thickness (RT) values were multiplied by the reef area (RA) to obtain cumulative Holocene carbonate volumes for the GBR as a whole and for each one of the thirty-three latitudinal zones  and density (ρA) (Table Holocene reef volume = RA × RTHolocene reef CaCO3 mass = Holocene reef volume × ρA × (1 − ΦR)To obtain values of total nes Fig. . Mass vaA) Table , as summ3 budgets. We extrapolated the estimates and trends of CaCO3 deposits for the GBR to the entire globe. We used published estimates of global reef area and parameters ground-truthed by the GBR dataset. The global reef area (RAGLOBAL) was multiplied by average thickness (RT) and petrophysical parameters  to obtain global postglacial CaCO3 deposits.We consider the contribution of drowned postglacial reefs in global CaCOA),Assumption 1: on average, the proportion of postglacial drowned reefs areas corresponding to a given Holocene reef area is similar across all reef provinces. We expressed this assumption as a ratio of shelf margin area to total Holocene reef area, the area adjustment factor .Assumption 2: on average, the postglacial drowned reefs mass corresponding to a given Holocene reef mass is similar across all reef provinces. We expressed this assumption as a ratio of shelf margin CaCOWe accounted for the drowned Pleistocene reefs by applying two assumptions in our calculations to obtain two equivalent results.RAglobal) have a large range of uncertainty as demonstrated by the range of values proposed by different authors  have a large associated uncertainty: despite the evidence for drowned reefs in other geographical locations, the exact global extension and morphology of drowned reefs is not well constrained. Other carbonate provinces might differ in morphology, in accretion trends and in the proportion of Pleistocene reefs present along their margins compared to the more recent Holocene deposits of those provinces.Global postglacial CaCO3 accumulation = RAglobal × RTGBR × ρA × (1—ΦR)Assumption 1:Area-adjusted global postglacial CaCO3 mass = RAglobal × RTGBR × ρA × (1—ΦR) × (1 + AFA)Assumption 2:Mass-adjusted global postglacial CaCO3 mass = RAglobal × RTGBR × ρA × (1—ΦR) × (1 + AFM).The values for global reef area  varying according to temperature, salinity and pressure70.The chemical equilibrium of the shallow ocean is complex, with the concentration of the main inorganic carbon species (CO71, reefal CaCO3 accretion provides CO2 to the environment by increasing the concentration of CO2 in the ocean water. The equivalent CO2 and C mass based on the stoichiometry of the chemical reaction: Ca2+  + 2HCO3− = => CaCO3 + CO2 + H2O66 gives an incomplete picture because the exact proportion would depend on physical conditions that would have varied during the postglacial period. Experimentally, it has been demonstrated that for each mole of CaCO3 precipitated in seawater only a fraction of a mole of CO2 is fed to the surrounding waters due to the buffering effect of marine water72. It is then unclear how much of this carbon is released into the atmosphere, especially at centennial timescales72. The pathways for the released CO2 molecules are varied—they can be absorbed into inorganic or organic marine carbon cycles, or they can also be transferred into the atmosphere by the balancing of the partial pressure of CO2. We have not attempted to quantify the corresponding postglacial CO2 contribution to the surrounding waters and to the atmosphere. This would require more complex carbon models which are beyond the scope of this study.According to the coral reef hypothesisSupplementary Information.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5.Supplementary Information 6.Supplementary Information 7.Supplementary Information 8.


The results showed that the earliest phase of pottery use was predominantly used to process riverine resources. Many of the vessels have molecular and isotopic characteristics consistent with migratory fish, such as sturgeon, confirmed by the identification of sturgeon bony structures embedded in the charred surface deposits. There was no evidence of dairy products in any of the vessels, despite the fact these have been routinely identified in coeval sites to the south. Further analysis of some of the mammalian bones using ZooMS failed to demonstrate that domesticated animals were present in the Early Neolithic. Nevertheless, we argue that intensive exploitation of seasonally migratory fish, accompanied by large-scale pottery production, created storable surpluses that led to similar socio-economic outcomes as documented in early agricultural societies.The emergence of pottery in Europe is associated with two distinct traditions: hunter-gatherers in the east of the continent during the early 6th millennium BC and early agricultural communities in the south-west in the late 7th millennium BC. Here we investigate the function of pottery from the site of Rakushechny Yar, located at the Southern fringe of Eastern Europe, in this putative contact zone between these two economic ‘worlds’. To investigate, organic residue analysis was conducted on 120 samples from the Early Neolithic phase (ca. mid-6The online version contains supplementary material available at 10.1007/s12520-021-01412-2. The transition to the Neolithic marks a period of profound socio-economic change, often related to increased sedentism, intensification of subsistence practices with the rise of new, more specialist strategies. Yet the economic transition that underpins this process has been interpreted differently. In the Western European archaeological tradition, ‘Neolithisation’ specifically refers to the economic transition from foraging to agriculture and the rearing of domesticated livestock, and is often associated with the introduction of a package of innovations, including pottery Dixon . To prehIn Europe, pottery was used by both hunter-gatherers in the north-east of the continent, during the early 6th millennium BC Piezonka  and by tSome of the earliest pottery vessels in Europe are found in the North Pontic-Caspian steppe during the early 6th millennium BC; a region lying between these worlds Fig. . Here, kIn order to examine the different aspects of pottery production in this region, here we present lipid residue analysis of vessels from one of the key sites, Rakushechny Yar, a hunter-gatherer site situated close to the putative forager/farmer contact zone in the Pontic steppe Fig.  that datIn support of the latter hypothesis, analysis of material culture found at Rakushechny Yar and more broadly in the North Pontic region suggests that the region was embedded in a wide cultural network that possibly encompassed farming communities to the south , and riverine resources including both freshwater  and anadromous  fish and shellfish (e.g. Unio spp. and Viviparus diluvianus) (Belanovskaya Trapa natans L.). Charcoal remains from the site are interpreted as waste from wood processing or smoking , modern shellfish  from the Lower Don River, modern fish (freshwater or migratory species) and wild ruminants  from Russia were analysed (Table Permissions were obtained to sample 120 samples (74 sherds and 46 foodcrusts) for organic residue analysis, representing 95 vessels typologically ascribed to the Early Neolithic phase. For 22 vessels permission was granted to only sample foodcrusts to minimise destruction to the vessel. The samples were obtained from early Neolithic layers N10–16, 19–21 and 23 from the older excavation made in 1966 (Belanovskaya ed Table  for comped Table .n = 20), to enable the detection of any triacylglycerols or wax esters. Lipid extracts were analysed using gas chromatography-mass spectrometry (GC–MS) with different columns and modes. For the methanolic acid extracts yielding a sufficient amount of lipids, the carbon isotope values of palmitic acid (C16:0) and stearic acid (C18:0) were obtained using gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Elemental analysis-isotope ratio mass spectrometry analysis (EA-IRMS) was also performed on charred foodcrusts samples (∼ 1 mg) for the determination of their stable nitrogen (δ15N) and carbon (δ13C) isotope values, as detailed in previous publications  using a modified one-step acidified methanol methodology , pig (n = 7), beaver , horse , zander (n = 4) and Wels catfish (n = 1) from Rakushechny Yar were selected  following routine protocols. Bone identifications have been tested by ZooMS, as described above, and collagen from the dated bones analysed by EA-IRMS, providing additional isotopic reference data. A summary of relevant methods and results, and a re-evaluation of legacy 6:0 to C30:0, monounsaturated fatty acids (C14-C24), branched fatty acids (C12-C19) and dicarboxylic acids (C5-C15)   Fig. . CholestSalix sp. willow and/or Populus sp. poplar)  displayed a different molecular profile Fig. , with di16:0 and C18:0) were measured for 112 samples in order to provide further information regarding contents. The Δ13C (δ13C18:0–δ13C16:0) value avoids environmental influences on the absolute δ13C values alkanoic acids (APAAs) containing 20 or more carbon atoms alongside at least one isoprenoid acid  consistent with values from authentic fish (> 0.06). Likewise, although phytanic acid occurs both in the tissues of aquatic and ruminant animals, the ratio of the phytanic diastereomers  provides an additional tool to distinguish these sources  than samples with aquatic biomarkers  in keeping with measurements made on collagen from beaver, horses and pigs from the site , the residues in the pottery are most likely attributed to anadromous fish, such as sturgeon, than marine species. Anadromous fish spend most of their lives in the sea and ocean and migrate into riverine habitats to spawn  and Wels catfish (Silurus glanis), constituting the major part of the fish remains in Rakushechny Yar  . The isotopic values between charred foodcrusts and their associated ceramics are moderately correlated , with no systematic offset  and δ13C18offset =  − 0.56 ± 1.56 (1σ), s2 = 2.44). Most likely, the ceramic matrix sample represents an accumulated lipid signal derived from multiple uses of the vessel where the foodcrusts represents more episodic cooking events, as suggested by long-term cooking experiments  for foodcrusts and mean δ13C16 =  − 27.47 ± 1.66‰ (1σ) for ceramic; mean δ13C18 =  − 27.46 ± 1.64‰ (1σ) for foodcrusts and mean δ13C18 =  − 28.02 ± 1.57‰ (1σ) for ceramic; T-test: t = 0.78, p = 0.44 for δ13C16 and t = 1.20, p = 0.24 for δ13C18) supporting our inference of specialist ‘aquatic’ use of the pottery over its entire use-life.The homogeneity of the residues at Rakushechny Yar is intriguing, given the typologically diverse pottery assemblage analysed, which ranges from very small vessels (< 0.5 L) to large containers (15–20 L) with a wide range of thicknesses Table . There w15N) and carbon (δ13C) isotope values of foodcrusts adhering to the ceramic vessels were measured. Figure 15N values of foodcrusts plotted against the C/N ratios. Six samples have relatively higher C:N ratios (i.e. > 20) along with δ15N values above + 10‰, which is consistent with fish oil  with over 85% of them having aquatic biomarkers , but they were also consumed potentially in large quantities. Given that an efficient way to extract mollusc meat from their shell is by boiling (Miracle Unio and Viviparus diluvianus) harvested in the Don River nearby Rakushechny Yar and corrected for the Suess effect  amount of ruminant fats due to differences in the fatty acid concentrations between these products. Furthermore, some of these samples exhibit more enriched δ13C values than archaeological and modern wild-ruminants from Rakushechny Yar and Western Russia, respectively, also indicating that they were mixed with anadromous fish  showed thin and compacted microstructure formed by vitrified shiny layers of charred matter. Interestingly, the appearance of the microstructure contrasts with previous analysis of charred material interpreted to be derived from boiling plant foods  widely present in the archaeological fish bone assemblage at the site  fish scales. Based on the observation of typical morphological traits   Table  characte0) Table , althoug0) Table . The abs0) Table  and d.Although the obtained results cannot rule out the presence of domesticated ruminant carcass fats in the pottery, these were likely to have been a minor contribution and are most likely derived from wild ruminants, in particular cervids, that dominate the mammalian bone assemblage  with little evidence for habitation structures.Consequently, there is no secure identification of any domesticated animals in the early phases of ceramic use at Rakushechny Yar. Based on our current knowledge, Rakushechny Yar should therefore be considered as an entirely forager site during the Early Neolithic. It should be noted however that only a relatively small area along the shoreline at Rakushechny Yar has so far been excavated Below is the link to the electronic supplementary material.


APOE ε4 genotyping. Relative regional brain volumes were calculated and linear regression models were fitted to examine DHA associations with brain volume. APOE genotype modulated serum DHA associations with entorhinal cortex volume and hippocampal volume. Linear models showed that greater serum DHA was associated with increased entorhinal cortex volume, but not hippocampal volume, in non APOΕ ε4 carriers. APOE also interacted with serum lysophosphatidylcholine DHA to predict hippocampal volume. After testing interactions between DHA and APOE on brain volume, we investigated whether DHA and APOE interact to predict spatial navigation performance on a novel virtual reality diagnostic test for Alzheimer’s disease in an independent population of APOE genotyped adults (n = 46). APOE genotype modulated DHA associations with spatial navigation performance, showing that DHA was inversely associated with path integration in APOE ε4 carriers only. This exploratory analysis suggests that interventions aiming to increase DHA blood levels to protect against cognitive decline should consider APOE ε4 carrier status. Future work should focus on replicating our initial findings and establishing whether a specific dose of supplementary DHA, at a particular time in the preclinical disease course can have a positive impact on Alzheimer’s disease progression in APOE ε4 carriers.Docosahexaenoic acid is the main long-chain omega-3 polyunsaturated fatty acids in the brain and accounts for 30−40% of fatty acids in the grey matter of the human cortex. Although the influence of docosahexaenoic acid on memory function is widely researched, its association with brain volumes is under investigated and its association with spatial navigation is virtually unknown. This is despite the fact that spatial navigation deficits are a new cognitive fingerprint for symptomatic and asymptomatic Alzheimer’s disease. We investigated the cross-sectional relationship between docosahexaenoic acid levels and the major structural and cognitive markers of preclinical Alzheimer’s disease, namely hippocampal volume, entorhinal volume and spatial navigation ability. Fifty-three cognitively normal adults underwent volumetric magnetic resonance imaging, measurements of serum docosahexaenoic acid  and  APOE genotype, with non-significant or inverse associations found in APOE ε4 carriers who are genetically-at-risk of Alzheimer’s disease.Docosahexaenoic acid’s neuroprotective effect may be concentrated in the entorhinal cortex and hippocampus. Here, we show that docosahexaenoic acid’s association with entorhinal volume and spatial navigation ability is modulated by the   Alzheimer’s disease is the most common form of dementia with increasing world-wide prevalence. In the absence of any licensed drugs to treat or reverse cognitive decline associated with Alzheimer’s disease, dietary behaviours that prevent or slow brain atrophy in the entorhinal cortex and the hippocampus hold tremendous potential.,,,Docosahexaenoic acid (DHA) is the main ω-3 PUFA in the brain and accounts for 30−40% of fatty acids in the grey matter of the human cortex. It is especially enriched at the synapse.Despite brain DHA levels being 10-fold higher in specific brain regions relative to most body tissues, and strong evidence for neurocognitive benefits proposed by animal models, the neuronal benefits in humans are less consistent. In the Framingham Heart Study, higher serum phosphatidylcholine DHA levels were associated with a 47% reduction in risk of dementia over 9 years of follow-up,APOE) genotype may be a major factor behind the mixed results from human studies.APOE ε4 isoform is the most important prevalent genetic determinant of Alzheimer’s disease riskAPOE isoforms (ε2/ε3).APOE ε4 carriers may impair the transport of circulating DHA to the brain, which has been shown in older APOE ε4 mice.APOE genotype would modulate circulating blood DHA associations with select brain volumes and spatial navigation. We further hypothesized that higher DHA levels would be positively related to preserved brain entorhinal and hippocampal volume, as well as spatial navigation performance in non ε4 carriers only. We expected that these associations would be non-significant or negative in ε4 carriers.The unexamined role of the apolipoprotein  obtained ethical approval from the Swinburne University Human Research Ethics Committee (Study identifier SHR Project 2015-208) for the Swinburne University of Technology site and the National Research Ethics Service Committee for the University of East Anglia site (Study identifier 14/EE/0189). Ethical approval for the second navigation study (Cohort 2) was obtained from the Faculty of Medicine and Health Sciences Ethics Committee at UEA, UK (Reference FMH/2016/2017-11). All participants from both studies provided informed signed consent before participating.n = 53). Participants from Cohort 2 were 61.3 (SD 5.6) years (n = 46). Exclusion criteria for both samples included diagnosis of mild cognitive impairment, clinical dementia, significant neurological/psychiatric disorder, MRI evidence of brain damage, previous vascular disorders including infarction or stroke and history of alcohol or drug dependency within the last 2 years. In addition, homozygous APOE ε4 carriers (2% of the population) and APOE ε2 carriers (13% of the UK population) were excluded, due to their low population prevalence. Included were (i) APOE ε3ε4 allele carriers, who are at a 3-fold increased risk of developing Alzheimer’s disease and represent 23% of the population  and (ii) age−gender matched ε3ε3 carriers, who represent the population wild-type genotype (60% of the population).Participants from Cohort 1 had a mean age of 64.7 (SD 7.6) years  of each participants blood sample, and placed in a ethylenediaminetetraacetic acid tube . In Cohort 2, DNA was extracted from a Darcon tip buccal swab , using a commercial DNA extraction kit . DNA from both samples underwent PCR amplification and plate read analysis using Applied Biosystems 7500 Fast Real-Time PCR System  to determine participants’ t-butyl ether were added, and the samples were mixed via vortex at room temperature for 1 h. After the addition of 50 µl of high purity water, a final sample mixing was performed before centrifugation at 210 000 g for 10 min. The upper, lipid-containing, methyl t-butyl ether phase was then extracted and analysed by liquid chromatography−mass spectrometry. The analytical method is detailed elsewhere.m/z) and retention time (510.35 m/z and 3.0 min).,Free/non-esterified fatty acid serum DHA and lysophosphatidylcholine (LPC) serum DHA were measured from a fasted blood samples, with 20 µl of serum used for the analysis. Ten microlitres of high purity water and 40 µl of MS-grade methanol were added, followed by a 2 minute vortex mix to precipitate proteins. Two hundred microlitres of methyl Erythrocyte DHA was measured from a non-fasted blood samples collected using a single drop of whole blood obtained via a finger prick collection kit . Blood samples were immobilized on a specially made card and sent to the University of Stirling  for analysis. See Carboni et al.1-weighted images were obtained using either a three-dimensional fast spoiled gradient echo brain volume imaging sequence in the sagittal orientation, repetition time (TR)/echo time (TE)/inversion time (TI) = 7040/2.612/900 ms, 0.9 mm isotropic resolution, field of view (FOV) = 230 × 230 mm, number of excitations (NEX) = 0.5, or a using a 3D magnetization prepared rapid gradient echo . The automized processing stream includes motion correction, removal of non-brain tissue, automated Talairach transformation, intensity correction, volumetric segmentation, cortical surface reconstruction and parcellation. Quality checks included skull stripping and pial surface errors, intensity normalization, white matter segmentation errors and were conducted on Freeview after processing and before statistical analysis. Entorhinal volume was derived from the Desikan-Killiany atlas.ex vivo data and in vivo data.Cortical surface reconstruction and segmentation was performed with FreeSurfer image analysis suite (version 6.0.0) . Models were adjusted for age, sex, education, test centre and total estimated intracranial volume. Additional dietary variables such as total intake of green vegetables and fruit did not contribute to overall model fit based on the Bayesian information criterion criteria and were not retained in the final models. In the spatial navigation dataset, adjustments for test centre and intracranial volume were dropped as volumetric MRI was not the outcome variable and data collection took place at one site only. Standardized residuals were extracted and plotted against fitted values to examine underlining assumption of normal distribution and heteroscedasticity. In the case of significant APOE ×DHA interactions, posthoc linear models were specified with APOΕ ε4 carriers (ε3ε4) and non-carriers (ε3ε3) separately. All statistical tests are two-tailed: P < 0.05. Partial eta squared (np2) was used as a measure of effect sizes and was derived from lmSupport package in R (https://cran.r-project.org/web/packages/lmSupport). np2 is the ratio of variance associated with an effect plus that effect and its associated error variance (np2 = SSeffect/SSeffect + SSerror).The data were analysed using RStudio (version 1.0.153). Linear regression models were specified with entorhinal and hippocampal volume as outcome variables, and DHA and The authors have carefully documented all data and materials used to conduct the research in this article and agree to share anonymized data by request from any qualified investigator.The participant characteristics for cohorts 1 and 2 are summarized in t = 2.15, P = 0.03, np2 = 0.09) and left , with a trend evident for the right side . Independent linear models for APOE ε3ε3 and APOE ε3ε4 carrier groups revealed a positive association between serum free DHA levels and entorhinal volume in ε3ε3 carriers only . The DHA × APOE interaction was not significant for hippocampal volume, although there was a trend towards significance  predicted right (n = 30). LPC DHA predicted right hippocampal volume , with a significant LPC DHA × APOE interaction  and a positive and negative association trend evident in APOE ε3ε3 carriers and APOE ε3ε4 carrier’s respectively, which was not significant. Against predictions, there was no main effect of LPC DHA and entorhinal volume, suggesting the serum free DHA is associated with entorhinal cortex, but the LPC fraction is more strongly associated with the hippocampus in this sample.LPC data were available from one of the two research sites in Cohort 1  or hippocampus volume , adjusting for age, sex, education, test site and total intracranial volume. See We also investigated if the n = 46). Both processes tap into grid-cell mechanisms in the entorhinal cortex, which translate information to place cells in the hippocampus.t = −2.017, P = 0.058). The effect of DHA on egocentric path integration was not significant  although as expected, APOE genotype modulated DHA associations with egocentric path integration . DHA was inversely associated with path integration  in ε3ε4, but not in ε3ε3 , and navigational processes vulnerable to early Alzheimer’s disease. Specifically, we tested DHA associations with boundary-based place memory and egocentric path integration  on brain volume were found  on brain health.,APOE ε4 group, increased circulating DHA was associated with decreased navigation performance, supporting evidence that APOE ε4 disrupts blood−brain barrier function predicting cognitive decline.,,The spatial navigation study from Cohort 2 supported this theory. Among adults ε4 allele carriers, circulating DHA predicted worse navigation proficiency. To the best of our knowledge, this is the first report of a significant association between circulating DHA and Alzheimer’s disease vulnerable spatial navigation performance. Path integration, a sub-process involved in navigation ability, involves the capacity to use self-motion cues (or movements cues) to update and learn spatial location information in relation to a start locationAPOΕ ε4 carriers. The authors report that APOE ε4 carriers present with blood–brain barrier breakdown in the hippocampus and medial temporal lobes leading to cognitive decline. Lower brain uptake of DHA in older APOE ε4 mice has also been shown to limit the accumulation of DHA in cerebral tissues, providing a potential mechanistic explanation for the inverse association between DHA and spatial navigation in APOE ε4 shown here.APOE ε4 carriers with less available for brain tissue absorption via the blood−brain barrier. Other potential explanations for the increase in free serum DHA among APOE ε4 may be that this reflects greater activation of phospholipase A2, which liberates esterified DHA from phospholipid,A landmark paper by Montague and colleagues provides important insights into a deficit blood−brain barrier transport system in APOE ε4 on the association between circulating DHA, entorhinal cortex, hippocampal volume and spatial navigation, which is uncommon as most studies focus on memory or other cognitive functions. Strengths of our study include a rigorous DHA analysis, including the serum LPC−DHA lipid fraction, a comprehensive phenotyping of participants, adjusting for confounders, as well as the inclusion of a virtual reality spatial navigation diagnostic test of Alzheimer’s disease. The findings produced in this study have the following limitations however, (i) although a unified model with an interaction term is the optimum method to test effect modification, an important limitation is that more statistical power is required than for association testing, and thus false-negative results may be seen in smaller samples. There were fewer ε4 carriers in Cohort 1, compared with Cohort 2, which may account for why in in APOE ε4 carriers we found a significant inverse association between DHA and navigation performance, but a null association between DHA and entorhinal−hippocampal brain volume. (ii) Likewise, the moderate sample sizes do not preclude the possibility that our findings could be observed by chance. These results will nevertheless play an important role in hypothesis-generating for future cross-sectional studies and RCTs. (iii) While spatial navigation crucially relies on the integrity and function of the entorhinal cortex and the hippocampus, we cannot directly relate the participants across Cohort 1 and 2. Future studies should thus examine if entorhinal and hippocampal brain volume directly mediates the relationships between DHA and spatial navigation. (iv) Given the observational nature of the study, and that DHA (fish intake) is a component of an overall healthy diet,We examined the effect of APOE genotype modifies DHA associations with brain volume and spatial navigation ability, typically affected in the first stages of Alzheimer’s disease. Future studies should examine the mechanisms behind the APOE genotype modulating effect of DHA, brain volume and cognitive function associations, particularly blood−brain barrier integrity. Future positron emission tomography studies needed to measure rates of DHA incorporation from serum into the brain,APOE ε4 carriers, leading to spatial navigation impairment. As over 50% of APOE ε4 carriers do not develop clinical Alzheimer’s disease, longitudinal studies are clearly required to determine whether APOE ε4, coupled with disrupted DHA absorption to the brain, has diagnostic utility, and can predict conversion to clinical Alzheimer’s disease with a high degree of accuracy.APOE ε4 carriers to mitigate the negative effect of the allele on brain health. For example, it is possible that cyclophilin A inhibitors might suppress the pathway that is believed to cause blood−brain barrier breakdown in the cerebral blood vessels of APOE ε4 carriers, and thereby may slow spatial navigation impairment and other cognitive functions that rely on blood supply to the brain.,APOE ε4 carriers, as previously suggested.In conclusion, we provide novel preliminarily evidence that the Brain Communications online.fcab085_Supplementary_DataClick here for additional data file.