Measurement of long‐term iron absorption and loss during iron supplementation using a stable isotope of iron (57Fe)

We report the first measurements of long‐term iron absorption and loss during iron supplementation in African children using a stable isotope of iron (⁵⁷Fe). After uniform labelling of body iron with ⁵⁷Fe, iron absorption is proportional to the rate of decrease in the ⁵⁷Fe tracer concentration, while iron loss is proportional to the rate of decrease in the ⁵⁷Fe tracer amount. Anaemic Gambian toddlers were given 2 mg ⁵⁷Fe orally to equilibrate with total body iron over 8–11 months. After assignment to the positive control arm of the HIGH study, 22 toddlers consumed a micronutrient powder containing 12 mg iron for 12 weeks followed by 12 weeks without iron supplementation. Their daily iron absorption increased 3·8‐fold during the iron supplementation period compared to the control period [median (interquartile range, IQR): 1·00 (0·82; 1·28) mg/day vs. 0·26 (0·22; 0·35) mg/day; P = 0·001]. Unexpectedly, during the supplementation period, daily iron loss also increased by 3·4‐fold [0·75 (0·55; 0·87) mg/day vs. 0·22 (0·19; 0·29) mg/day; P = 0·005]. Consequently, most (~72%) of the absorbed iron was lost during supplementation. Long‐term studies of iron absorption and loss are a promising and accurate method for assessing and quantifying long‐term iron balance and may provide a reference method for evaluating iron intervention programs in vulnerable population groups. This study was registered as ISRCTN 0720906.     

Dominant eukaryotic export production during ocean anoxic events reflects the importance of recycled NH4+

The Mesozoic is marked by several widespread occurrences of intense organic matter burial. Sediments from the largest of these events, the Cenomanian–Turonian Oceanic Anoxic Event (OAE 2) are characterized by lower nitrogen isotope ratios than are seen in modern marine settings. It has remained a challenge to describe a nitrogen cycle that could achieve such isotopic depletion. Here we use nitrogen-isotope ratios of porphyrins to show that eukaryotes contributed the quantitative majority of export production throughout OAE 2, whereas cyanobacteria contributed on average approximately 20%. Such data require that any explanation for the OAE nitrogen cycle and its isotopic values be consistent with a eukaryote-dominated ecosystem. Our results agree with models that suggest the OAEs were high-productivity events, supported by vigorous upwelling. Upwelling of anoxic deep waters would have supplied reduced N species (i.e., ) to primary producers. We propose that new production during OAE 2 primarily was driven by direct -assimilation supplemented by diazotrophy, whereas chemocline denitrification and anammox quantitatively consumed and . A marine nitrogen reservoir dominated by , in combination with known kinetic isotope effects, could lead to eukaryotic biomass depleted in ¹⁵N.     

A Miocene to Pleistocene climate and elevation record of the Sierra Nevada (California)

Orographic precipitation of Pacific-sourced moisture creates a rain shadow across the central part of the Sierra Nevada (California) that contrasts with the southern part of the range, where seasonal monsoonal precipitation sourced to the south obscures this rain shadow effect. Orographic rainout systematically lowers the hydrogen isotope composition of precipitation (deltaD(ppt)) and therefore deltaD(ppt) reflects a measure of the magnitude of the rain shadow. Hydrogen isotope compositions of volcanic glass (deltaD(glass)) hydrated at the earth's surface provide a unique opportunity to track the elevation and precipitation history of the Sierra Nevada and adjacent Basin and Range Province. Analysis of 67 well dated volcanic glass samples from widespread volcanic ash-fall deposits located from the Pacific coast to the Basin and Range Province demonstrates that between 0.6 and 12.1 Ma the hydrogen isotope compositions of meteoric water displayed a large (>40 per thousand) decrease from the windward to the leeward side of the central Sierra Nevada, consistent with the existence of a rain shadow of modern magnitude over that time. Evidence for a Miocene-to-recent rain shadow of constant magnitude and systematic changes in the longitudinal climate and precipitation patterns strongly suggest that the modern first-order topographic elements of the Sierra Nevada characterized the landscape over at least the last 12 million years.     

Vapor hydrogen and oxygen isotopes reflect water of combustion in the urban atmosphere

Anthropogenic modification of the water cycle involves a diversity of processes, many of which have been studied intensively using models and observations. Effective tools for measuring the contribution and fate of combustion-derived water vapor in the atmosphere are lacking, however, and this flux has received relatively little attention. We provide theoretical estimates and a first set of measurements demonstrating that water of combustion is characterized by a distinctive combination of H and O isotope ratios. We show that during periods of relatively low humidity and/or atmospheric stagnation, this isotopic signature can be used to quantify the concentration of water of combustion in the atmospheric boundary layer over Salt Lake City. Combustion-derived vapor concentrations vary between periods of atmospheric stratification and mixing, both on multiday and diurnal timescales, and respond over periods of hours to variations in surface emissions. Our estimates suggest that up to 13% of the boundary layer vapor during the period of study was derived from combustion sources, and both the temporal pattern and magnitude of this contribution were closely reproduced by an independent atmospheric model forced with a fossil fuel emissions data product. Our findings suggest potential for water vapor isotope ratio measurements to be used in conjunction with other tracers to refine the apportionment of urban emissions, and imply that water vapor emissions associated with combustion may be a significant component of the water budget of the urban boundary layer, with potential implications for urban climate, ecohydrology, and photochemistry.Anthropogenic perturbation of the atmospheric water cycle is expressed over a wide range of spatial and temporal scales. Recent global changes resulting from warming-associated increases in saturation vapor pressure have been observed in satellite and reanalysis data (1, 2). Regional impacts related to large-scale land use change are detectible in precipitation data and models (3–5). Humidity anomalies (both positive and negative) have been observed in many urban centers and associated with changes in land cover, direct anthropogenic sources, and interaction of evapotranspiration and condensation processes with the urban heat island effect (6–10).Fossil fuel combustion releases water vapor to the atmosphere. Assuming an average molar ratio of H₂O to CO₂ emission of 1.5 (see Water of Combustion) and current anthropogenic carbon emission rates of 9.5 Pg C/y (11), global combustion vapor emissions total ∼21 Pg/y. At the global scale, these numbers are four orders of magnitude smaller than the gross global exchange of water vapor between the Earth surface and the atmosphere, which totals more than 480,000 Pg/y (12). However, anthropogenic emissions are highly concentrated in space and time and, locally, may be a significant source of vapor and impact atmospheric water cycling, ambient humidity, and photochemistry. Water of combustion has been hypothesized to be an important contributor of urban boundary layer vapor in some studies of urban−rural humidity gradients (13, 14), but in other cases has been dismissed as a minor source (6). Thus far it has not been possible to directly observe or quantify the concentration of combustion-derived vapor in the atmosphere.Here we report data and modeling that indicates that water of combustion can be identified in the atmospheric boundary layer using stable isotope ratio measurements of ambient water vapor. Our data document winter season boundary layer vapor in Salt Lake City, Utah (SLC; 40.7662°N, 111.8477°W, elevation 1440 m). Salt Lake City is situated in a north−south oriented basin, surrounded on three sides by substantial mountain ranges, and is subject to prolonged cold air inversion events during the winter season. Previous work has documented the accumulation of combustion-derived CO₂ in the boundary layer during these events (15–17). We show that water vapor deuterium excess (d = δ²H – 8 × δ¹⁸O) closely tracks changes in CO₂ through inversion events and across a daily cycle dominated by patterns of human activity. Deuterium excess reflects deviations in the coupled H and O isotopic compositions of water from a covariant trend established by equilibrium phase-change reactions in the atmosphere, and has previously been used to diagnose vapor source region conditions, nonequilibrium processes, and vertical mixing (18–21). We demonstrate that combustion-derived water vapor is characterized by a distinctive d value due to its unique mode of production, illustrate that this strong signal is detectible and can be used to quantify the concentration of combustion-derived vapor in the SLC wintertime atmosphere, and demonstrate congruence between these estimates and those derived from a mass-balance model forced by meteorological and emissions data.     

Centromere retention and loss during the descent of maize from a tetraploid ancestor

Although centromere function is highly conserved in eukaryotes, centromere sequences are highly variable. Only a few centromeres have been sequenced in higher eukaryotes because of their repetitive nature, thus hindering study of their structure and evolution. Conserved single-copy sequences in pericentromeres (CSCPs) of sorghum and maize were found to be diagnostic characteristics of adjacent centromeres. By analyzing comparative map data and CSCP sequences of sorghum, maize, and rice, the major evolutionary events related to centromere dynamics were discovered for the maize lineage after its divergence from a common ancestor with sorghum. (i) Remnants of ancient CSCP regions were found for the 10 lost ancestral centromeres, indicating that two ancient homeologous chromosome pairs did not contribute any centromeres to the current maize genome, whereas two other pairs contributed both of their centromeres. (ii) Five cases of long-distance, intrachromosome movement of CSCPs were detected in the retained centromeres, with inversion the major process involved. (iii) The 12 major chromosomal rearrangements that led to maize chromosome number reduction from 20 to 10 were uncovered. (iv) In addition to whole chromosome insertion near (but not always into) other centromeres, translocation and fusion were found to be important mechanisms underlying grass chromosome number reduction. (v) Comparison of chromosome structures confirms the polyploid event that led to the tetraploid ancestor of modern maize.     

Environments and trypanosomiasis risks for early herders in the later Holocene of the Lake Victoria basin,Kenya

Specialized pastoralism developed ∼3 kya among Pastoral Neolithic Elmenteitan herders in eastern Africa. During this time, a mosaic of hunters and herders using diverse economic strategies flourished in southern Kenya. It has been argued that the risk for trypanosomiasis (sleeping sickness), carried by tsetse flies in bushy environments, had a significant influence on pastoral diversification and migration out of eastern Africa toward southern Africa ∼2 kya. Elmenteitan levels at Gogo Falls (ca. 1.9–1.6 kya) preserve a unique faunal record, including wild mammalian herbivores, domestic cattle and caprines, fish, and birds. It has been suggested that a bushy/woodland habitat that harbored tsetse fly constrained production of domestic herds and resulted in subsistence diversification. Stable isotope analysis of herbivore tooth enamel (n = 86) from this site reveals, instead, extensive C₄ grazing by both domesticates and the majority of wild herbivores. Integrated with other ecological proxies (pollen and leaf wax biomarkers), these data imply an abundance of C₄ grasses in the Lake Victoria basin at this time, and thus little risk for tsetse-related barriers to specialized pastoralism. These data provide empirical evidence for the existence of a grassy corridor through which small groups of herders could have passed to reach southern Africa.Herding was the earliest form of food production in Africa, originating in the arid eastern Sahara ∼8 kya. Adoption of food production and increasing mobility in northeastern Africa allowed prehistoric people to manage resource availability amid a drastically changing climate (1) and transformed local populations of people and animals. Saharan herders and hunters spread southward to the Sahel, reaching eastern Africa by 4.5 kya, and eventually reaching southern Africa with sheep and cattle around 2 kya (1–8). The southern African data have been much debated, but recent genetic studies support at least limited movement of early herders from eastern to southern Africa (5, 7). Iron Age Bantu agriculturalist migrations and forager exchange processes also contributed to livestock spread. In contrast to Iron Age farmers, however, the sparse archaeological evidence suggests slow and small-scale southern pastoral migrations (9). Researchers have attributed the limited penetration of southern Africa by stone-using pastoralists to the prevalence of woodland habitats, the distribution of tsetse fly, and the influence of trypanosomiasis on livestock production from Lake Victoria and the Serengeti southward (10, 11). However, site-based paleoenvironmental data have proven difficult to obtain, and although often assumed, the proposition that ancient closed or bushy environments represented a barrier to herding has been seldom examined. Here we present stable isotope analysis of herbivore tooth enamel (n = 86) from Elmenteitan Pastoral Neolithic levels at Gogo Falls (ca. 1.9–1.6 kya) near Lake Victoria, one of the northernmost “woodland tsetse belts” modeled for Africa ca. 2,000 y ago (12, 13). Rather than providing evidence for the Lake Victoria basin as a wooded tsetse fly harboring habitat, these new fine-resolution paleoenvironmental data document extensive C₄ grazing by both domesticates and the majority of wild herbivores. A synthesis of lacustrine and terrestrial signals further supports the existence of grassy areas in the Lake Victoria basin at 2,000 B.P., indicating a change in ecology to bushy environments more recently than previously thought, and an ecosystem that would not have supported the tsetse fly around Lake Victoria.Early herders in northern Kenya relied on sheep, goats, fish, and diverse wild vertebrates (1, 14). Research in western Kenya, and specifically the Lake Victoria basin (Fig. 1), has revealed southwestward movement of Elmenteitan herders into an area populated by complex ceramic-using, fishing hunter-gatherers and a more varied process of adoption of food production. Domestic sheep and goats appear in low numbers starting around 3.7 kya at Wadh Lang’o, and perhaps also at Gogo Falls and Usenge 3 (15), but not at other sites such as Siror (16), suggesting patchy adoption of herding. Specialized dependence on livestock in Africa is first documented in Elmenteitan sites, which date at the earliest to 3.1 kya at Njoro River Cave, east of Lake Victoria (17, 18). Elmenteitan sites occur to the north in Laikipia, on the Mau Escarpment, on the southern end of the Loita Hills and the northern Mara Plains, and at Gogo Falls (the westernmost extent) (18). Despite opportunities for hunting, fauna from Elmenteitan sites on the Mara plains are >90% domestic (19, 20). The exception to this is the site of Gogo Falls, which has a diverse and abundant faunal assemblage, including fish and wild herbivores (21). The unique faunal assemblages from Elmenteitan levels at Gogo Falls and from Prolonged Drift (22), which has a mixed Savanna Pastoral Neolithic stone tool assemblage, have sparked considerable debate over the significance of subsistence variability for understanding environmental risks and the dynamics of frontier pastoral-hunter-gather subsistence during the spread of food production. Foragers in the process of adopting herding, loss of stock by pastoralists, and environmental and disease constraints have all been considered possible factors leading to heavy reliance on wild resources (21–24). South of the Mara plains and Lake Victoria, ancient herders left fewer material traces, leading to arguments regarding the existence of a long-term pastoral-forager frontier, south of which herders did not thrive (25–27).Open in a separate windowFig. 1.Location of Gogo Falls in relation to other Holocene archaeological sites (●) and towns (○) in the Lake Victoria basin.The presence of tsetse flies in eastern Africa has been used as an explanation for observed patterns of subsistence diversity among early pastoralists in the Lake Victoria basin (21, 28) and for limited southward movement (15, 20, 29, 30). A range of zoonoses posed threats for early herders, but trypanosomiasis risks have an especially widespread effect on human communities, even today (10, 12, 13, 30). Mesic, bushy/wooded environments that may have harbored large numbers of tsetse fly (Glossina spp.) would have been poorly suited to extensive cattle stock-keeping. The tsetse fly carries trypanosome parasites that transfer to hosts during blood meals and eventually cause often-fatal sleeping sickness in ungulates (predominately domesticates) and humans. In modern and precolonial times, herders have controlled tsetse fly numbers by heavy grazing, burning and destruction of woody areas, and managed livestock to avoid areas with abundant tsetse (10, 31, 32). It is not unreasonable to assume, then, that bushy, tsetse-rich environments would have impeded heavy reliance on livestock by early herders and may have even created a boundary beyond which it was difficult for large numbers of herders to settle (20, 33). Despite an abundance of archaeological sites, however, terrestrial paleoecological data for the Holocene in Kenya are scarce and have been based primarily on lacustrine archives, rather than sites themselves. Pollen and leaf wax biomarkers from lacustrine records from Lake Victoria yield somewhat conflicting paleoenvironmental interpretations: pollen data indicate decreasing moist tree and shrub presence (indicated by Moraceae pollen) in the Lake Victoria basin until ∼2 kya, when grass pollen (Poaceae) increased (Fig. 2) (34), contrasting with stable carbon isotopes from lacustrine leaf wax biomarkers, which indicate persistence of C₄ grasses throughout the last 6 kya, with only a sharp decrease in C₄ around 3 kya (Fig. 2) (35). These contrasting results could be explained by differences in spatial integration, with lipids recording a more localized signal within the catchment and pollen recording a more regional vegetation signal (36), and likely also point to varied, fluctuating input from C₄ grasses during this period. Even so, pollen evidence suggests only minor (∼10%) moist forest in the region compared with ∼20–30% input from grasses. These records offer the important wider ecological context of regional (pollen) and basinal (leaf waxes) ecology, yet they are too coarse to understand specialized pastoralist expansions, and especially for local evidence (site-based reconstruction) of habitats harboring tsetse.Open in a separate windowFig. 2.(A) Holocene pottery traditions present at archaeological sites in the Victoria basin. (B) Leaf wax δ¹³C and modeled %C₄ from lacustrine sedimentary cores in Lake Victoria (35). (C) Moraceae (tropical mesic trees and shrubs) pollen counts from lacustrine sedimentary cores in Lake Victoria (data from ref. 34). (D) Poaceae (grass) pollen counts from lacustrine sedimentary cores in Lake Victoria (data from ref. 34). B, C, and D modified with permission from Elsevier; www.sciencedirect.com/science/journal/02773791.To determine whether or not shifting tsetse-rich environments were present at particular locales during specific periods, direct stable isotope-based paleoecological analysis at archaeological sites can provide a complement to faunal analysis (21, 37–39). Isotopic measurements of enamel carbon (δ¹³C) and oxygen (δ¹⁸O) can be used to understand diet, habitat, and climate (40, 41). Although bone and tooth collagen have been previously used to assess paleoenvironment at Holocene archaeological sites in Kenya (42), tooth enamel is preferred, as it resists digenetic alteration and can be easily compared with fauna from older periods of geologic time (43). In some instances, faunal tooth enamel isotopes may provide our best estimates of environmental change over time, because these signals are less temporally and spatially attenuated than other proxies, such as leaf wax biomarkers (44), which may be influenced by reservoir effects during catchment transport before deposition (45, 46). The environmental context of the Elmenteitan layers of Gogo Falls has been previously interpreted as a grassland/bushland mosaic, based on analysis of wild species diversity and the presence of modern browsing taxa such as roan or sable antelope (Tragelaphini) and bushpig (Potamochoerus), as well as grazers such as oribi (21). The relatively low proportions of domestic stock were interpreted as reflecting environmental constraints on pastoral productivity in the region. The presence of the tsetse fly in a presumed seasonally mesic, bushy/woody environment, it was argued, prevented herders from relying exclusively on domesticates, which resulted in seasonal fishing and hunting of large wild ungulates (21). These interpretations have not yet been ground-truthed with a local, terrestrial paleoecological indicator.     

The rise of oxygen and siderite oxidation during the Lomagundi Event

The Paleoproterozoic Lomagundi Event is an interval of 130–250 million years, ca. 2.3–2.1 billion years ago, in which extraordinarily ¹³C enriched (>10‰) limestones and dolostones occur globally. The high levels of organic carbon burial implied by the positive δ¹³C values suggest the production of vast quantities of O₂ as well as an alkalinity imbalance demanding extremely low levels of weathering. The oxidation of sulfides has been proposed as a mechanism capable of ameliorating these imbalances: It is a potent sink for O₂ as well as a source of acidity. However, sulfide oxidation consumes more O₂ than it can supply CO₂, leading to insurmountable imbalances in both carbon and oxygen. In contrast, the oxidation of siderite (FeCO₃ proper, as well as other Fe²⁺-bearing carbonate minerals), produces 4 times more CO₂ than it consumes O₂ and is a common—although often overlooked—constituent of Archean and Early Proterozoic sedimentary successions. Here we propose that following the initial rise of O₂ in the atmosphere, oxidation of siderite provided the necessary carbon for the continued oxidation of sulfides, burial of organic carbon, and, most importantly, accumulation of free O₂. The duration and magnitude of the Lomagundi Event were determined by the size of the preexisting Archean siderite reservoir, which was consumed through oxidative weathering. Our proposal helps resolve a long-standing conundrum and advances our understanding of the geologic history of atmospheric O₂.Reconstructing the geologic history of atmospheric oxygen is among the foremost scientific challenges of our time (1). The level of atmospheric oxygen (pO₂) without doubt played a key role in the evolution of the Earth System (2), exerting a major influence on the biosphere, especially the evolution of metazoans (3). With no direct way of measuring oxygen concentrations in deep geologic time, the stable isotopes of carbon recorded in marine limestones provide key constraints (4). Carbon enters the ocean−atmosphere system through volcanoes and weathering of carbon-bearing sedimentary rocks and can exit in one of two ways: (i) uptake during photosynthesis and burial of organic carbon leading to O₂ production and (ii) reaction during weathering and formation of CaCO₃ in the ocean. The carbon isotopic record tells us how carbon was partitioned between these two sinks: A δ¹³C value of 0‰ indicates that ∼80% of incoming carbon was buried as carbonate carbon and 20% as organic carbon. Positive excursions in δ¹³C are unusual and indicate that a larger fraction of carbon was fixed and buried as organic carbon and, with it, a larger amount of O₂ was produced.Following the indications for the first rise of O₂ in the atmosphere (5, 6) is the largest and most protracted period of ¹³C enrichment in the geologic record, known as the Lomagundi Event (Fig. 1). Limestones and dolostones with extreme carbon isotopic values of +  8‰ to greater than +  15‰ occur globally (6–8), and a duration of between 128 million years (m.y.) and 249 m.y. is suggested by current age constraints (9). The highly elevated δ¹³C values indicate the burial of tremendous amounts of organic carbon, and the production of correspondingly vast amounts of O₂. In fact, the duration and magnitude of the isotopic excursion in δ¹³C bespeak of O₂ fluxes so large that they challenge our understanding of geochemical cycles. Calculations indicate an integrated production of far larger amounts of O₂ than currently exist—or likely ever existed—in Earth’s atmosphere, implying the concurrent existence of effective O₂ sinks (10).Open in a separate windowFig. 1.Archean and Proterozoic carbon and sulfur isotopic data. The Lomagundi Event refers to the interval of highly positive δ¹³C values (black band) between 2.3 Ga and 2.0 Ga (9). The preceding collapse in the range of Δ³³S values (in red and gray) indicates the increase in atmospheric O₂ levels from vanishing Archean levels for the first time (5). Adapted with permission from Macmillan Publishers Ltd: Nature ref. 35.A second, hitherto unrecognized problem exists as well. The elevated δ¹³C values indicate a repartitioning of the incoming carbon in favor of organic carbon burial. However, if the total amount of carbon entering the ocean−atmosphere system remains unchanged, then any increase in the organic carbon burial flux can only be at the expense of the other output flux, that of carbonate carbon. However, the burial of carbonate carbon represents the burial not only of carbon but also of alkalinity, and thus a decrease in its magnitude demands a commensurate decrease in the input of alkalinity from weathering. Critically, δ¹³C values of +10‰ indicate the burial of so large a fraction of organic carbon that a 90% reduction in carbonate burial, and hence weathering, would have been necessary to balance it (see SI Appendix for calculation). Assuming that weathering is proportional to pCO₂ to the 0.3 power (11, 12), a 90% reduction in weathering would have entailed a decline from a pCO₂ baseline of 10,000 ppm to single part per million levels. Consequently, in the face of such high levels of organic carbon burial, without an additional source of CO₂ or sink for alkalinity, a near-complete shutdown of weathering would have been required to balance the inputs and outputs of carbon.The more plausible alternative is that during Lomagundi times processes that consume O₂ and release CO₂ compensated the inferred imbalances such that pCO₂ levels were bolstered and pO₂ levels moderated. The oxidation of sedimentary sulfides is an attractive option for alleviating the attendant imbalances, as it is a potent sink for oxygen (13) and, in conjunction with acidification of carbonates, a source of CO₂ (14). The oxidation of sulfides following the first rise of oxygen is supported by evidence including the disappearance of detrital pyrites (15, 16), the appearance of sedimentary evaporites (17), and Cr enrichment in iron-rich sedimentary rocks indicating a highly acidic weathering regime (18).Nonetheless, sulfide oxidation alone could not have fully compensated the imbalances resulting from the elevated burial of organic carbon during the Lomagundi Event. Close examination of Eqs. 1–3 reveals that pyrite oxidation coupled to acidification of carbonates leads to unavoidable imbalances in carbon and oxygen due to the stoichiometry of the overall reaction, which consumes more oxygen than it releases carbon. The oxidation of 4 mol of pyrite requires 15 mol of O₂ (Eq. 1), while the associated acidification of carbonates can release at most only 8 mol of CO₂ (Eq. 2). Thus, on the whole, pyrite oxidation consumes 15 mol of O₂ but produces only 8 mol of CO₂ (Eq. 3).4FeS₂ + 15O₂ + 8H₂O → 8H₂SO₄ + 2Fe₂O₃[1]8CaCO₃ + 8H₂SO₄ → 8CaSO₄ + 8H₂O + 8CO₂[2]4FeS₂ + 15O₂ + 8CaCO₃ → 2Fe₂O₃ + 8CaSO₄ + 8CO₂.[3]However, the continued oxidation of pyrite requires the burial of 15 mol of CO₂ as organic carbon (Eq. 4)—7 mol more than can be supplied by pyrite oxidation coupled to the acidification of carbonates.15CO₂ + 15H₂O → 15CH₂O + 15O₂.[4]Conversely, if the amount of CO₂ required by organic carbon burial is assumed to balance the amount that can be supplied by pyrite oxidation coupled to acidification of carbonates (8 mol), not enough oxygen is produced during organic carbon burial (8 mol) to balance the demand of pyrite oxidation (15 mol), such that any pyrite oxidation would grind to a halt. Consequently, the oxidation of sulfides cannot be a sustained source of carbon over geological timescales, even during intervals of highly elevated oxygen production, and much less so during periods when this is not the case (14).Here we suggest that siderite oxidation (including siderite proper, FeCO₃, as well as other Fe²⁺ bearing carbonate minerals) provided the necessary CO₂ during Lomagundi times. Siderite is a major constituent of Archean and Early Proterozoic sediments: It is extremely abundant in banded iron formations, often even more so than iron oxides (19). Siderite is also found in anomalously high concentrations in Proterozoic limestones and dolomites (20), where it arises from the replacement of Ca²⁺ and Mg²⁺ by Fe²⁺ in the carbonate mineral lattice. Crucially, the oxidation of siderite produces 4 times more CO₂ than it requires O₂. The oxidation of siderite (Eq. 5) followed by photosynthetic CO₂ fixation (Eq. 6) is a net source of oxygen (Eq. 7),4FeCO₃ + O₂ → 2Fe₂O₃ + 4CO₂[5]4CO₂ + 4H₂O = 4CH₂O + 4O₂[6]4FeCO₃ + 4H₂O = 2Fe₂O₃ + 4CH₂O + 3O₂.[7]Hence, in principle, the burial of the CO₂ evolved from siderite oxidation as organic carbon can produce oxygen 3 times in excess of the O₂ required by siderite oxidation, with the surplus going to the oxidation of sulfide, oxidation of reduced crustal iron, and the accumulation of free O₂ (21).     

Predicting the extent and location of coronary artery disease during the early postinfarction period by quantitative thallium-201 scintigraphy

The ability of quantitative thallium-201 scintigraphy to predict the extent and location of coronary artery disease before hospital discharge after acute myocardial infarction was evaluated in 52 patients. All patients underwent coronary angiography and serial thallium-201 imaging either at rest (10 patients) or after submaximal exercise stress (42 patients; target heart rate 120 beats/min). Two or three vessel disease was designated if abnormal thallium-201 uptake or washout patterns, or both, were seen in two or three vascular segments, respectively. Of 156 vessels analyzed in the 52 patients, 91 stenoses of 70 percent or greater were found by angiography. Seventy-four (81 percent) of these were predicted by scintigraphy. The specificity of scintigraphy for identifying vessel stenoses was 92 percent. Sensitivity for detecting and localizing stenoses supplying an infarct zone was 96 percent compared with 62 percent for stenoses supplying myocardium remote from the acute infarct. Perfusion abnormalities were more frequently seen in the distribution of vessels with severe (90 percent or greater) stenoses than in those with moderate (70 to 90 percent) stenoses (87 versus 53 percent, p <0.01). Scintigraphy detected a greater proportion of left anterior descending and right coronary arterial stenoses than circumflex stenoses (91 and 87 versus 63 percent, respectively, p <0.006).In the 42 patients who underwent submaximal exercise testing, multivariate analysis of 23 clinical and laboratory variables identified multiple thallium-201 defects as the best predictor of multivessel disease. The predictive accuracy of exercise-induced S-T segment depression was only 45 percent compared with 88 percent (p <0.05) for thallium-201 scintigraphy. Thus, 2 weeks after myocardial infarction, exercise thallium-201 scintigraphy is useful for predicting the extent and location of coronary artery disease, particularly stenoses in the left anterior descending and right coronary arteries. Moreover, thallium-201 imaging at rest is reliable in assessing the extent of coronary disease in hospitalized patients who cannot undergo exercise testing because of unstable angina, uncompensated heart failure, poorly controlled arrhythmias or physical limitations.     

Circulating cytokines in relation to the extent and composition of coronary atherosclerosis: Results from the ATHEROREMO-IVUS study

Objective

We investigated whether concentrations of TNF-α, TNF-β, TNF-receptor 2, interferon-γ, IL-6, IL-8, IL-10 and IL-18 are associated with extent and composition of coronary atherosclerosis determined by grayscale and virtual histology (VH)- intravascular ultrasound (IVUS).

Methods

Between 2008 and 2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients (stable angina pectoris (SAP), n = 261; acute coronary syndrome (ACS), n = 309) undergoing coronary angiography from the ATHEROREMO-IVUS study. Plaque burden, presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, and presence of VH-TCFA lesions with plaque burden ≥70% were assessed. Blood samples for cytokine measurement were drawn from the arterial sheath prior to the angiography procedure. We applied linear and logistic regression.

Results

TNF-α levels were positively associated with plaque burden (beta (β) [95%CI]: 4.45 [0.99–7.91], for highest vs lowest TNF-α tertile) and presence of VH-TCFA lesions (odds ratio (OR) [95%CI] 2.30 (1.17–4.52), highest vs lowest TNF-α tertile) in SAP patients. Overall, an inverse association was found between IL-10 concentration and plaque burden (β [95%CI]: −1.52 [−2.49 to −0.55], per Ln (pg/mL) IL-10) as well as IL-10 and VH-TCFA lesions with plaque burden ≥70% (OR: 0.31 [0.12–0.80],highest vs lowest IL-10 tertile). These effects did not reach statistical significance in the separate SAP and ACS groups.

Conclusion

Higher circulating TNF-α was associated with higher plaque burden and VH-TCFA lesions in SAP patients. Lower circulating IL-10 was associated with higher plaque burden and large VH-TCFA lesions. These in-vivo findings suggest a role for these cytokines in extent and vulnerability of atherosclerosis.     

Genetic loss of the muscarinic M3 receptor markedly alters bile formation and cholestatic liver injury in mice

Aim

Hepatic innervation represents a potentially underestimated regulator of liver function and regeneration. The muscarinic 3 receptor (M₃‐R) is the primary cholangiocyte receptor for the afferent parasympathetic innervation of bile ducts. We aimed to determine the specific role of the M₃‐R in bile formation and models for cholestatic liver disease in mice.

Methods

We compared bile flow and composition in M₃‐R knock‐out mice (M₃‐R^?/?) and wild type littermates (WT). Furthermore, we compared liver inury of M₃‐R^?/? and WT mice after 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) feeding, a well‐characterized preclinical model of cholestatic liver disease. To analyze the possible role of the M₃‐R as a therapeutic target, we treated 4‐week‐old Mdr2^?/? mice, a preclinical model for sclerosing cholangitis, with the M₃‐R agonist bethanechol for 4 weeks.

Results

M₃‐R^?/? mice showed significantly reduced bile flow compared to WT mice, most likely due to decreased biliary HCO₃^? secretion. However, even aged M₃‐R^?/? mice did not spontaneously develop liver injury or cholestasis. Challenging M₃‐R^?/? and WT littermates with DDC feeding showed substantially aggravated liver injury in M₃‐R^?/? mice. After 4 weeks bethanechol treatment, Mdr2^?/? mice showed less liver injury compared to controls.

Conclusion

Our experimental findings suggest that M₃‐R‐signalling significantly influences bile formation. Loss of the M₃‐R increases susceptibility to cholestatic injury in DDC‐fed mice. Since treatment of Mdr2^?/? mice with a M₃‐R agonist decreases liver injury, M3‐R signaling may represent a therapeutic target in specific cholangiopathies.

     

The influence of myocardial edema formation on the energy consumption of the heart during aerobiosis and hypoxia

Summary Isolated rat and guinea pig hearts show, during perfusion with aequeous salt solutions, myocardial edema formation of different degree. The extent of tissue fluid accumulation is dependent on the species, the osmolality, and the oxygen partial pressure of the perfusion medium. With increasing edema formation there is, in both species, an increasing energy requirement for the same hemodynamic state. Addition of 50 mM mannitol to the perfusion medium can diminish edema of the hypoxic perfused rat heart and improves the myocardial function during hypoxia. The beneficial effect of hyperosmolality in the isolated hypoxic rat heart is discussed in terms of an improvement of myocardial energy balance and coronary microcirculation.Supported by the Deutsche Forschungsgemeinschaft, SFB 89-Kardiologie Göttingen.     

Features of the Arabidopsis recombination landscape resulting from the combined loss of sequence variation and DNA methylation

The rate of meiotic crossing over (CO) varies considerably along chromosomes, leading to marked distortions between physical and genetic distances. The causes underlying this variation are being unraveled, and DNA sequence and chromatin states have emerged as key factors. However, the extent to which the suppression of COs within the repeat-rich pericentromeric regions of plant and mammalian chromosomes results from their high level of DNA polymorphisms and from their heterochromatic state, notably their dense DNA methylation, remains unknown. Here, we test the combined effect of removing sequence polymorphisms and repeat-associated DNA methylation on the meiotic recombination landscape of an Arabidopsis mapping population. To do so, we use genome-wide DNA methylation data from a large panel of isogenic epigenetic recombinant inbred lines (epiRILs) to derive a recombination map based on 126 meiotically stable, differentially methylated regions covering 81.9% of the genome. We demonstrate that the suppression of COs within pericentromeric regions of chromosomes persists in this experimental setting. Moreover, suppression is reinforced within 3-Mb regions flanking pericentromeric boundaries, and this effect appears to be compensated by increased recombination activity in chromosome arms. A direct comparison with 17 classical Arabidopsis crosses shows that these recombination changes place the epiRILs at the boundary of the range of natural variation but are not severe enough to transgress that boundary significantly. This level of robustness is remarkable, considering that this population represents an extreme with key recombination barriers having been forced to a minimum.     

MT1E在肝癌形成过程中的表达及其在肝癌细胞中的作用

目的: 探讨MT1E基因在肝癌形成过程中不同阶段的表达及其在肝癌细胞中的生物学功能.方法: DEN诱发大鼠肝癌形成模型,分别观察造模4、8、16、20 wk后肝脏组织病理形态学的改变以及MT1E基因表达的差异;针对MT1E基因mRNA序列设计2个siRNA靶点,分别经质粒重组后电转入SMMC-7721肝癌细胞株中,实时荧光定量PCR检测MT1E基因的表达,MTT法检测细胞生长增殖.结果: 大鼠肝癌造模4、8 wk时肝组织主要表现为炎性病变,而到16 wk后呈现典型的增生病变,20 wk后已全部发展为肝细胞癌. MT1E基因在造模16 wk后表达明显增加,与对照组比较差异显著(芯片读数: 11524 vs 5462). 成功筛选到MT1E基因RNA干扰的一个有效靶序列,电转染72 h后该基因的表达量较空白对照组与阴性对照组明显降低(0.38 vs 1.00,0.93,P<0.01). 与阴性对照组比较,有效干扰靶点电转染144 h后细胞的生长增殖得到了明显抑制(0.1700±0.0313 vs 0.5748±0.0480,P<0.01).结论: 成功应用D E N诱发大鼠肝癌形成,MT1E基因在肝癌形成的后期表达明显升高,其高表达与肿瘤细胞的恶性增殖有关.     

扶正化瘀方对肝纤维化大鼠不同病理阶段肝组织蛋白质组变化的影响

目的探讨四氯化碳（CCl4）大鼠肝纤维化形成及消减不同时期肝组织蛋白质组的动态变化及扶正化瘀方的干预作用。方法40％CCl4-橄榄油溶液皮下注射法制备CCl4大鼠肝纤维化模型，治疗组给予扶正化瘀方灌胃，在第4、8、12和第16周末分批处死大鼠，观察各组大鼠肝组织病理学、羟脯氨酸（Hyp）含量变化，并提取肝组织蛋白质进行二维电泳，运用PDQUEST 2-DE软件对蛋白质图谱进行分析，以MALDI—TOF—MS鉴定差异表达的蛋白质。结果（1）二维电泳结果：模型大鼠特有蛋白质和表达量差异的蛋白质从第4周始出现，第12周达顶峰，（2）质谱鉴定的蛋白质多数在第4周出现，四个时间段均出现的有10个，其中有8个是正常组所没有的，（3）扶正化瘀方对表达差异的蛋白质调节表现在：第4、8周对上调的蛋白质降低作用显著，在第8、12、16周对下调的蛋白质的升高作用较显著，模型大鼠特有的蛋白质经扶正化瘀方干预后，通过降解、下调表达量等形式，趋向正常表达。结论（1）蛋白质表达改变是肝纤维化整体病变的物质基础。表达异常的蛋白质涉及机体的物质代谢、神经内分泌、细胞增殖凋亡等系统，（2）扶正化瘀方在抗细胞增生、促进正常蛋白质合成等方面有综合优势，通过对多个蛋白质、多途径的综合调节达到抗肝纤维化的效果。     

Clinical significance of down-beating nystagmus and postural control loss when returning to a sitting position during the canalith repositioning maneuver

Patients with benign paroxysmal positional vertigo (BPPV) occasionally experience severe dizziness, could not maintain the sitting posture, and then fall onto or off the examination table when they return to the sitting position, which is the last step of the barbecue maneuver and Epley maneuver (EM); down-beating nystagmus is also observed. This study aims to investigate the clinical characteristics and significance of these findings. We retrospectively reviewed video data showing nystagmus and medical records of adult patients diagnosed with canalolithiasis of the horizontal canal and the posterior canal (PC) BPPV who underwent barbecue maneuver and EM, respectively, in outpatient clinics from April 2014 to March 2019. This study included 112 patients (28 horizontal canal BPPV and 94 PC BPPV cases). Among the 122 BPPV cases, only 14 (14.9%) were analyzed, due to their occurrence during EM. Down-beating nystagmus appeared at 3.6 seconds on average after returning to the sitting position, and the patients fell onto or off the examination table at 4.4 seconds on average after the onset of the nystagmus. The average duration of the down-beating nystagmus was 20.3 seconds. In all 14 cases, no nystagmus was induced by the Dix–Hallpike test performed again after EM, confirming that the treatment was successful. During the EM, down-beating nystagmus and falling onto or off the examination table occurred in approximately 15% of cases. As the risk of falls increases, the patient should be secured immediately after EM. Moreover, it can be inferred that the findings occur when otoconia in the PC enter the utricle, suggesting a successful treatment.     

A systematic review of ecological momentary assessment studies of appetite and affect in the experience of temptations and lapses during weight loss dieting

Dietary temptations and lapses challenge control over eating and act as barriers toward successful weight loss. These are difficult to assess in laboratory settings or with retrospective measures as they occur momentarily and driven by the current environment. A better understanding of how these experiences unfold within real-world dieting attempts could help inform strategies to increase the capacity to cope with the changes in appetitive and affective factors that surround these experiences. We performed a narrative synthesis on the empirical evidence of appetitive and affective outcomes measured using ecological momentary assessment (EMA) during dieting in individuals with obesity and their association with dietary temptations and lapses. A search of three databases (Scopus, Medline, and PsycInfo) identified 10 studies. Within-person changes in appetite and affect accompany temptations and lapses and are observable in the moments precipitating a lapse. Lapsing in response to these may be mediated through the strength of a temptation. Negative abstinence-violation effects occur following a lapse, which negatively impact self-attitudes. Engagement in coping strategies during temptations is effective for preventing lapses. These findings indicate that monitoring changes in sensations during dieting could help identify the crucial moments when coping strategies are most effective for aiding with dietary adherence.     

Electrical connection between the right atrium and the superior vena cava,and the extent of myocardial sleeve in a patient with atrial fibrillation originating from the superior vena cava

We describe a case in which the superior vena cava (SVC) was electrically isolated by an application of radiofrequency energy to a point with electrical connection between the right atrium and the SVC in a patient with atrial fibrillation (AF) originating from the SVC. The connection was located in the posteroseptal region between the right atrium and the myocardial sleeve extending into the SVC. Local AF occurred after radiofrequency ablation and rapid activities were recorded all around the SVC, whereas the atrium was still in sinus rhythm. It is suggested that focal AF in the SVC contributes not only to the initiation but also to the maintenance of AF, and the myocardial sleeve extends into the SVC through a connection point to cover the entire internal lumen.     

短暂性单眼视野缺损眼部动脉血流动力学改变及颅内段颈内动脉狭窄特点

目的探讨短暂性单眼视野缺损眼部动脉血流动力学改变规律及颈内动脉狭窄的特点。方法采用回顾性病例对照研究。收集因短暂性单眼视野缺损(TMVL)就诊患者(共30例)的临床资料(TMVL组)。同时采集非视网膜缺血性病变的正常志愿者临床资料作为正常对照组。两组均行眼动脉、视网膜中央动脉、睫状后动脉超声检查,测量参数包括收缩峰流速、舒张峰流速、阻力指数及搏动指数,同时行头颈部CT血管成像检查,测量颈内动脉颅内段狭窄程度。结果 TMVL组眼动脉收缩峰流速较正常对照组明显下降(28.40±3.69 cm/s比32.58±2.75 cm/s P=0.000),舒张峰流速较正常对照组明显下降(6.10±1.70 cm/s比7.35±1.49 cm/s,P=0.001);TMVL组视网膜中央动脉收缩峰流速较正常对照组明显下降(8.38±1.68 cm/s比9.92±2.30 cm/s,P=0.005),舒张峰流速较正常对照组明显下降(2.35±0.80 cm/s比2.88±0.62 cm/s,P=0.007);TMVL组睫状后动脉收缩峰流速较正常对照组收缩峰流速明显下降(10.01±2.25 cm/s比11.43±1.69 cm/s,P=0.008),舒张峰流速较正常对照组明显下降(3.30±1.16 cm/s比4.14±1.06 cm/s,P=0.006)。TMVL组阻力指数、搏动指数在眼动脉、视网膜中央动脉及睫状后动脉较正常对照组均无统计学差异。TMVL组颈内动脉中、重度狭窄患者比例(约占63.33%)较正常对照组(10.00%)明显增高,差异有统计学意义(P=0.000)。结论 TMVL患者较正常对照组眼部血流明显下降,而颈内动脉发生中、重度狭窄概率较正常对照组明显升高。     

Alcohols induce beta-hematin formation via the dissociation of aggregated heme and reduction in interfacial tension of the solution

The formation of the malarial pigment, a unique hemozoin crystal with unit cells comprised of heme dimers, has been proposed as an ideal target for antimalarial screening. The mechanism of beta-hematin formation (a synthetic crystal structurally identical to hemozoin) has been suggested that a hydrophobic interaction is needed to solubilize heme, but this hypothesis needs further evidence. Direct study of the process of hemozoin formation in the malarial food vacuole has not been performed, due to complicated groups of lipids and proteins. To overcome this difficulty and to explore the environmental conditions for beta-hematin formation, we systematically studied beta-hematin formation induced by a series of small normal alcohols (methanol, ethanol, n-propanol, and n-butanol), which are structurally similar. For the first time, the ability of beta-hematin inducer could be evaluated by its concentration that is required to enhance heme crystallization by 50% (EC(50) values). These values provide a rapid and convenient tool for comparing the ability of initiators in beta-hematin formation. Our results showed that the ability of alcohols to induce beta-hematin formation in the order: n-butanol>n-propanol>ethanol>methanol. The induction of beta-hematin formation by alcohols is related with their degree of hydrophobicity and ability to solubilize heme, suggesting that the dissociation of aggregated heme by alcohols is a major factor in beta-hematin formation. In addition, alcohols can reduce the surface tension of a solution, thus lowering the energy barrier for creating critical nuclei.