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Significance The diet of fossil organisms can be inferred through isotopic analysis of skeletal tissues, largely assessed using isotopic and elemental systems such as carbon isotopes (δ ¹³C) and strontium/calcium (Sr/Ca) and barium/calcium (Ba/Ca) concentration ratios. In the case of complex dietary habits such as omnivory, these systems must be used jointly together with new proxies. Based on the expectation that fractionation of bio-essential metals occurs during metabolism, we explore the isotopic variability of magnesium (δ ²⁶Mg) in tooth enamel sampled from an assemblage of modern mammals. We demonstrate that δ ²⁶Mg increases from herbivores to higher-level consumers, discriminating most of the identified trophic steps. This, combined with δ ¹³C, Ba/Ca, and/or δ ⁴⁴Ca might prove useful in paleodietary studies. Geochemical inferences on ancient diet using bone and enamel apatite rely mainly on carbon isotope ratios (δ ¹³C) and to a lesser extent on strontium/calcium (Sr/Ca) and barium/calcium (Ba/Ca) elemental ratios. Recent developments in nontraditional stable isotopes provide an unprecedented opportunity to use additional paleodietary proxies to disentangle complex diets such as omnivory. Of particular relevance for paleodietary reconstruction are metals present in large quantity in bone and enamel apatite, providing that biologically mediated fractionation processes are constrained. Calcium isotope ratios (δ ⁴⁴Ca) meet these criteria but exhibit complex ecological patterning. Stable magnesium isotope ratios (δ ²⁶Mg) also meet these criteria but a comprehensive understanding of its variability awaits new isotopic data. Here, 11 extant mammal species of known ecology from a single locality in equatorial Africa were sampled for tooth enamel and, together with vegetation and feces, analyzed for δ ²⁶Mg, δ ¹³C, Sr/Ca, and Ba/Ca ratios. The results demonstrate that δ ²⁶Mg incorporated in tooth enamel becomes heavier from strict herbivores to omnivores/faunivores. Using data from experimentally raised sheep, we suggest that this ²⁶Mg enrichment up the trophic chain is due to a ²⁶Mg enrichment in muscle relative to bone. Notably, it is possible to distinguish omnivores from herbivores, using δ ²⁶Mg coupled to Ba/Ca ratios. The potential effects of metabolic and dietary changes on the enamel δ ²⁶Mg composition remain to be explored but, in the future, multiproxy approaches would permit a substantial refinement of dietary behaviors or enable accurate trophic reconstruction despite specimen-limited sampling, as is often the case for fossil assemblages.

Diet is a major driver of hominin evolution, but most of the geochemical evidence relies on carbon isotopes (δ 13 C). Here, we report enamel stable calcium isotope (δ 44/42 Ca) values against δ 13 C values for several hominins and co-existing primates in the Turkana Basin area, circa 4 to 2 Ma. Australopithecus anamensis clusters with mammal browsers, Kenyanthropus platyops is distinct from A . anamensis in foraging into more open environments and the coexisting Theropithecus brumpti encompasses both the grazer and omnivore/carnivore domains. Early Homo is remarkable for its wide distribution in δ 44/42 Ca values, possibly reflecting omnivorous and opportunistic preferences. Paranthropus boisei is uniquely distributed in the δ 13 C versus δ 44/42 Ca iso-space being distinct from all other hominins from the Turkana Basin area as well as from the co-existing Theropithecus oswaldi . Several hypotheses are explored to discuss the unique δ 44/42 Ca values of Paranthropus boisei including significant differences observed with δ 44/42 Ca values recently reported for P . robustus from South Africa, questioning the monophyly of this genus. Non-traditional stable isotopes, such as of calcium, have potential to expand our understanding of ancient diets. Here, Martin et al. use stable calcium isotopes recovered from fossil tooth enamel to compare the dietary ecology of hominins and other primates in the Turkana Basin 2-4 million years ago.

Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation. The metallome is crucial for normal cell functioning but remains largely overlooked in mammals. Here the authors analyze the metallome and copper and zinc isotope compositions in aging mice and show networks of interactions that are organ-specific, age-dependent, isotopically-typified and associated with a wealth of clinical and molecular traits.

Significance In cancer, the metabolism of copper and sulfur are dysregulated, leading to deleterious side effects. These issues are commonly addressed by studying the variations of concentrations of the elements, but here we have used, for the first time to our knowledge, copper and sulfur stable isotope compositions variations, using methods widespread in Earth sciences. We show that in hepatocellular carcinomas patients, blood copper and sulfur are enriched in light isotopes compared with control subjects. These isotopic signatures are not compatible with a dietary origin, but rather reflect the massive reallocation in the body of copper immobilized within cysteine-rich proteins such as metallothioneins. We also propose that sulfur isotope compositions could serve to track sulfur originating from tumor-derived sulfides. The widespread hypoxic conditions of the tumor microenvironment can impair the metabolism of bioessential elements such as copper and sulfur, notably by changing their redox state and, as a consequence, their ability to bind specific molecules. Because competing redox state is known to drive isotopic fractionation, we have used here the stable isotope compositions of copper ( ⁶⁵Cu/ ⁶³Cu) and sulfur ( ³⁴S/ ³²S) in the blood of patients with hepatocellular carcinoma (HCC) as a tool to explore the cancer-driven copper and sulfur imbalances. We report that copper is ⁶³Cu-enriched by ∼0.4‰ and sulfur is ³²S-enriched by ∼1.5‰ in the blood of patients compared with that of control subjects. As expected, HCC patients have more copper in red blood cells and serum compared with control subjects. However, the isotopic signature of this blood extra copper burden is not in favor of a dietary origin but rather suggests a reallocation in the body of copper bound to cysteine-rich proteins such as metallothioneins. The magnitude of the sulfur isotope effect is similar in red blood cells and serum of HCC patients, implying that sulfur fractionation is systemic. The ³²S-enrichment of sulfur in the blood of HCC patients is compatible with the notion that sulfur partly originates from tumor-derived sulfides. The measurement of natural variations of stable isotope compositions, using techniques developed in the field of Earth sciences, can provide new means to detect and quantify cancer metabolic changes and provide insights into underlying mechanisms.

Hypomagnesemia is frequently associated with type 2 diabetes and generally correlates with unfavorable disease progression, but the magnesium status in pre-diabetic conditions remains unclear. Here, the magnesium metabolism is scrutinized in a minipig model of obesity and insulin resistance by measuring variations of the metallome—the set of inorganic elements—and the magnesium stable isotope composition in six organs of lean and obese minipigs raised on normal and Western-type diet, respectively. We found that metallomic variations are most generally insensitive to lean or obese phenotypes. The magnesium stable isotope composition of plasma, liver, kidney, and heart in lean minipigs are significantly heavier than in obese minipigs. For both lean and obese minipigs, the magnesium isotope composition of plasma and liver were negatively correlated to clinical phenotypes and plasma lipoproteins concentration as well as positively correlated to hyperinsulinemic-euglycemic clamp output. Because the magnesium isotope composition was not associated to insulin secretion, our results suggest that it is rather sensitive to whole body insulin sensitivity, opening perspectives to better comprehend the onset of insulin-resistant diabetic conditions.

In biological systems, strontium (Sr) and barium (Ba) are two non-essential elements, in comparison to calcium (Ca) which is essential. The Sr/Ca and Ba/Ca ratios tend to decrease in biochemical pathways which include Ca as an essential element, and these processes are termed biopurification of Ca. The quantitative pathway of the biopurification of Ca in relation to Sr and Ba between two biological reservoirs$(R\\,_{\\rm{n}} $and$R_{{\\rm{n}}\\,\\,{\\rm{ - 1}}} {\\rm{)}}$is measured with an observed ratio (OR) expressed by the$({\\rm{Sr/Ca}})\\,_{Rn} \\,{\\rm{/}}({\\rm{Sr/Ca}})\\,_{Rn - 1} $and$({\\rm{Ba/Ca}})_{\\,Rn} \\,{\\rm{/}}({\\rm{Ba/Ca}})\\,_{Rn - 1} $ratios. For a mammalian organism, during the whole biopurification of Ca starting with the diet to the ultimate reservoir of Ca which is the bone, the mean values for${\\rm{OR}}_{{\\rm{Sr}}}$and${\\rm{OR}}_{{\\rm{Ba}}}$are 0.25 and 0.2, respectively. In this study, published Sr/Ca and Ba/Ca ratios are used for three sets of soils, plants, and bones of herbivorous and carnivorous mammals, each comprising a trophic chain, to illustrate the biopurification of Ca at the level of trophic chains. Calculated${\\rm{OR}}_{{\\rm{Sr}}}$and${\\rm{OR}}_{{\\rm{Ba}}}$of herbivore bones in relation to plants and of bones of carnivores in relation to bones of herbivores give${\\rm{OR}}_{{\\rm{Sr}}} = 0.30 \\pm 0.08$and${\\rm{OR}}_{{\\rm{Ba}}} = 0.16 \\pm 0.08,$thus suggesting that trophic chains reflect the Sr/Ca and Ba/Ca fluxes that are prevalent at the level of a mammalian organism. The slopes of the three regression equations of log(Sr/Ca) vs. log(Ba/Ca) are similar, indicating that the process of biopurification of Ca with respect to Sr and Ba is due to biological processes and is independent of the geological settings. Modifications of the logarithmic expression of the Sr/Ca and Ba/Ca relationship allow a new formula of the biopurification process to be deduced, leading to the general equation${\\rm{OR}}_{{\\rm{Ba}}} = {\\rm{OR}}_{{\\rm{Sr}}} ^{1.79 \\pm 0.33},$where the allometric coefficient is the mean of the slopes of the three regression equations. Some recent examples are used to illustrate this new analysis of predator-prey relations between mammals. This opens up new possibilities for the utilization of Ba/Ca and Sr/Ca in addition to stable isotope ratios$(\\delta ^{13} {\\rm{C}}$and$\\delta ^{15} {\\rm{N)}}$for the determination of the relative contribution of different food sources to an animal's diet.

The cellular prion protein PrP C /CD230 is a GPI-anchor protein highly expressed in cells from the nervous and immune systems and well conserved among vertebrates. In the last decade, several studies suggested that PrP C displays antiviral properties by restricting the replication of different viruses, and in particular retroviruses such as murine leukemia virus (MuLV) and the human immunodeficiency virus type 1 (HIV-1). In this context, we previously showed that PrP C displays important similarities with the HIV-1 nucleocapsid protein and found that PrP C expression in a human cell line strongly reduced HIV-1 expression and virus production. Using different PrP C mutants, we report here that the anti-HIV-1 properties are mostly associated with the amino-terminal 24-KRPKP-28 basic domain. In agreement with its reported RNA chaperone activity, we found that PrP C binds to the viral genomic RNA of HIV-1 and negatively affects its translation. Using a combination of biochemical and cell imaging strategies, we found that PrP C colocalizes with the virus assembly machinery at the plasma membrane and at the virological synapse in infected T cells. Depletion of PrP C in infected T cells and microglial cells favors HIV-1 replication, confirming its negative impact on the HIV-1 life cycle.

Hereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of hemochromatosis patients and is sensitive to the amount of total iron removed by the phlebotomy treatment. The use of stable isotopes to unravel the pathological mechanisms of iron overload diseases is promising but hampered by the lack of data in organs involved in the iron metabolism. Here, we use H fe −/− mice, a model of hereditary hemochromatosis, to study the impact of the knock-out on iron isotope compositions of erythrocytes, spleen and liver. Iron concentration increases in liver and red blood cells of H fe −/− mice compared to controls. The iron stable isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of iron heavy isotopes in H fe −/− mice. In contrast, no difference in the iron concentration nor isotope composition is observed in spleen of H fe −/− and control mice. Our results in mice suggest that the observed increase of whole blood isotope composition in hemochromatosis human patients does not originate from, but is aggravated by, bloodletting. The subsequent rapid increase of whole blood iron isotope composition of treated hemochromatosis patients is rather due to the release of hepatic heavy isotope-enriched iron than augmented iron dietary absorption. Further research is required to uncover the iron light isotope component that needs to balance the accumulation of hepatic iron heavy isotope, and to better understand the iron isotope fractionation associated to metabolism dysregulation during hereditary hemochromatosis.

Social anthropology and ethnographic studies have described kinship systems and networks of contact and exchange in extant populations 1 – 4 . However, for prehistoric societies, these systems can be studied only indirectly from biological and cultural remains. Stable isotope data, sex and age at death can provide insights into the demographic structure of a burial community and identify local versus non-local childhood signatures, archaeogenetic data can reconstruct the biological relationships between individuals, which enables the reconstruction of pedigrees, and combined evidence informs on kinship practices and residence patterns in prehistoric societies. Here we report ancient DNA, strontium isotope and contextual data from more than 100 individuals from the site Gurgy ‘les Noisats’ (France), dated to the western European Neolithic around 4850–4500  bc . We find that this burial community was genetically connected by two main pedigrees, spanning seven generations, that were patrilocal and patrilineal, with evidence for female exogamy and exchange with genetically close neighbouring groups. The microdemographic structure of individuals linked and unlinked to the pedigrees reveals additional information about the social structure, living conditions and site occupation. The absence of half-siblings and the high number of adult full siblings suggest that there were stable health conditions and a supportive social network, facilitating high fertility and low mortality 5 . Age-structure differences and strontium isotope results by generation indicate that the site was used for just a few decades, providing new insights into shifting sedentary farming practices during the European Neolithic. The burial community at Gurgy ‘les Noisats’ (France) was genetically connected by two main pedigrees, spanning seven generations, that were patrilocal and patrilineal, with evidence for female exogamy and exchange with genetically close neighbouring groups.

Zinc, an essential trace element that serves as a cofactor for numerous cellular and viral proteins, plays a central role in the dynamics of HIV-1 infection. Among the viral proteins, the nucleocapsid NCp7, which contains two zinc finger motifs, is abundantly present viral particles and plays a crucial role in coating HIV-1 genomic RNA, thus concentrating zinc within virions. In this study, we investigated whether HIV-1 virus production impacts cellular zinc homeostasis and whether isotopic fractionation occurs between the growth medium, the producing cells, and the viral particles. We found that HIV-1 captures a significant proportion of cellular zinc in the neo-produced particles. Furthermore, as cells grow, they accumulate lighter zinc isotopes from the medium, resulting in a concentration of heavier isotopes in the media, and the viruses exhibit a similar isotopic fractionation to the producing cells. Moreover, we generated HIV-1 particles in HEK293T cells enriched with each of the five zinc isotopes to assess the potential effects on the structure and infectivity of the viruses. As no strong difference was observed between the HIV-1 particles produced in the various conditions, we have demonstrated that enriched isotopes can be accurately used in future studies to trace the fate of zinc in cells infected by HIV-1 particles. Comprehending the mechanisms underlying zinc absorption by HIV-1 viral particles offers the potential to provide insights for developing future treatments aimed at addressing this specific facet of the virus’s life cycle.