Llamas (Llama glama) enhance proglacial ecosystem development in Cordillera Blanca, Peru.

Worldwide, mountain glaciers are shrinking rapidly. Consequently, large areas are becoming available for the development of novel alpine ecosystems. These harsh environments, however, delay primary succession. In this study with a local community, we conducted an inclusion experiment to investigate whether Llama glama influences soils and vegetation primary succession following glacial retreat. At the foot of the Uruashraju glacier in the Cordillera Blanca, Peru (~ 4680 m.a.s.l.), we established four llama inclusion plots and four control plots that we studied from 2019 to 2022, 24-40 years after deglacierization. After three years, the llama plots had significantly increased soil organic carbon and soil nitrogen. In the llama plots, we found a large, significant increase in vascular plant cover (+ 57%) between the second and third years of experimentation, and we identified four new species that were not present in 2019. Our results suggest that Llama glama, through their latrine behavior and role as a seed disperser, enhances the primary succession and novel ecosystem formation in recently deglacierized landscapes. Our study provides scientific support that rewilding of native Andean camelids may favor adaptation to glacier retreat and inform conservation and management strategies in proglacial landscapes.

Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo.

PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters. METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction. RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion. CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.

Origins and spread of formal ceremonial complexes in the Olmec and Maya regions revealed by airborne lidar.

City plans symbolizing cosmologies have long been recognized as a defining element of Mesoamerican civilizations. The origins of formal spatial configurations are thus the key to understanding early civilizations in the region. Assessment of this issue, however, has been hindered by the lack of systematic studies of site plans over broad areas. Here, we report the identification of 478 formal rectangular and square complexes, probably dating from 1,050 to 400 BC, through a lidar (laser imaging, detection and ranging) survey across the Olmec region and the western Maya lowlands. Our analysis of lidar data also revealed that the earlier Olmec centre of San Lorenzo had a central rectangular space, which possibly provided the spatial template for later sites. This format was probably formalized and spread after the decline of San Lorenzo through intensive interaction across various regions. These observations highlight the legacy of San Lorenzo and the critical role of inter-regional interaction.

Historical socioecological transformations in the global tropics as an Anthropocene analogue.

Large, low-density settlements of the tropical world disintegrated during the first and second millennia of the CE. This phenomenon, which occurred in South Asia, Southeast Asia, and Mesoamerica, is strongly associated with climate variability and extensive landscape transformation. These profound social transformations in the tropical world have been popularized as "collapse," yet archaeological evidence suggests a more complex and nuanced story characterized by persistence, adaptation, and resilience at the local and regional scales. The resulting tension between ideas of climate-driven collapse and evidence for diverse social responses challenges our understanding of long-term resilience and vulnerability to environmental change in the global tropics. Here, we compare the archetypal urban collapse of the Maya, in modern Belize, Guatemala, Honduras, and Mexico, during the 8th to 11th centuries CE, and the Khmer in modern Cambodia, Laos, Thailand, and Vietnam during the 14th to 15th centuries CE. We argue that the social response to environmental stress is spatially and temporally heterogenous, reflecting the generation of large-scale landesque capital surrounding the urban cores. Divergences between vulnerable urban elite and apparently resilient dispersed agricultural settlements sit uncomfortably with simplistic notions of social collapse and raise important questions for humanity as we move deeper into the Anthropocene.

Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.

Mechanism of succinate efflux upon reperfusion of the ischaemic heart.

AIMS: Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. METHODS AND RESULTS: To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. CONCLUSION: Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.

Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury.

Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by 'tuned' malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.

Selective Delivery of Dicarboxylates to Mitochondria by Conjugation to a Lipophilic Cation via a Cleavable Linker.

Many mitochondrial metabolites and bioactive molecules contain two carboxylic acid moieties that make them unable to cross biological membranes. Hence, there is considerable interest in facilitating the uptake of these molecules into cells and mitochondria to modify or report on their function. Conjugation to the triphenylphosphonium (TPP) lipophilic cation is widely used to deliver molecules selectively to mitochondria in response to the membrane potential. However, permanent attachment to the cation can disrupt the biological function of small dicarboxylates. Here, we have developed a strategy using TPP to release dicarboxylates selectively within mitochondria. For this, the dicarboxylate is attached to a TPP compound via a single ester bond, which is then cleaved by intramitochondrial esterase activity, releasing the dicarboxylate within the organelle. Leaving the second carboxylic acid free also means mitochondrial uptake is dependent on the pH gradient across the inner membrane. To assess this strategy, we synthesized a range of TPP monoesters of the model dicarboxylate, malonate. We then tested their mitochondrial accumulation and ability to deliver malonate to isolated mitochondria and to cells, in vitro and in vivo. A TPP-malonate monoester compound, TPP11-malonate, in which the dicarboxylate group was attached to the TPP compound via a hydrophobic undecyl link, was most effective at releasing malonate within mitochondria in cells and in vivo. Therefore, we have developed a TPP-monoester platform that enables the selective release of bioactive dicarboxylates within mitochondria.

Monumental architecture at Aguada Fénix and the rise of Maya civilization.

Archaeologists have traditionally thought that the development of Maya civilization was gradual, assuming that small villages began to emerge during the Middle Preclassic period (1000-350 BC; dates are calibrated throughout) along with the use of ceramics and the adoption of sedentism1. Recent finds of early ceremonial complexes are beginning to challenge this model. Here we describe an airborne lidar survey and excavations of the previously unknown site of Aguada Fénix (Tabasco, Mexico) with an artificial plateau, which measures 1,400 m in length and 10 to 15 m in height and has 9 causeways radiating out from it. We dated this construction to between 1000 and 800 BC using a Bayesian analysis of radiocarbon dates. To our knowledge, this is the oldest monumental construction ever found in the Maya area and the largest in the entire pre-Hispanic history of the region. Although the site exhibits some similarities to the earlier Olmec centre of San Lorenzo, the community of Aguada Fénix probably did not have marked social inequality comparable to that of San Lorenzo. Aguada Fénix and other ceremonial complexes of the same period suggest the importance of communal work in the initial development of Maya civilization.

Ancient Maya wetland fields revealed under tropical forest canopy from laser scanning and multiproxy evidence.

We report on a large area of ancient Maya wetland field systems in Belize, Central America, based on airborne lidar survey coupled with multiple proxies and radiocarbon dates that reveal ancient field uses and chronology. The lidar survey indicated four main areas of wetland complexes, including the Birds of Paradise wetland field complex that is five times larger than earlier remote and ground survey had indicated, and revealed a previously unknown wetland field complex that is even larger. The field systems date mainly to the Maya Late and Terminal Classic (∼1,400-1,000 y ago), but with evidence from as early as the Late Preclassic (∼1,800 y ago) and as late as the Early Postclassic (∼900 y ago). Previous study showed that these were polycultural systems that grew typical ancient Maya crops including maize, arrowroot, squash, avocado, and other fruits and harvested fauna. The wetland fields were active at a time of population expansion, landscape alteration, and droughts and could have been adaptations to all of these major shifts in Maya civilization. These wetland-farming systems add to the evidence for early and extensive human impacts on the global tropics. Broader evidence suggests a wide distribution of wetland agroecosystems across the Maya Lowlands and Americas, and we hypothesize the increase of atmospheric carbon dioxide and methane from burning, preparing, and maintaining these field systems contributed to the Early Anthropocene.

Archaeological assessment reveals Earth's early transformation through land use.

Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth's transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.

Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation.

During heart transplantation, storage in cold preservation solution is thought to protect the organ by slowing metabolism; by providing osmotic support; and by minimising ischaemia-reperfusion (IR) injury upon transplantation into the recipient1,2. Despite its widespread use our understanding of the metabolic changes prevented by cold storage and how warm ischaemia leads to damage is surprisingly poor. Here, we compare the metabolic changes during warm ischaemia (WI) and cold ischaemia (CI) in hearts from mouse, pig, and human. We identify common metabolic alterations during WI and those affected by CI, thereby elucidating mechanisms underlying the benefits of CI, and how WI causes damage. Succinate accumulation is a major feature within ischaemic hearts across species, and CI slows succinate generation, thereby reducing tissue damage upon reperfusion caused by the production of mitochondrial reactive oxygen species (ROS)3,4. Importantly, the inevitable periods of WI during organ procurement lead to the accumulation of damaging levels of succinate during transplantation, despite cooling organs as rapidly as possible. This damage is ameliorated by metabolic inhibitors that prevent succinate accumulation and oxidation. Our findings suggest how WI and CI contribute to transplant outcome and indicate new therapies for improving the quality of transplanted organs.

Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury.

Acute kidney injury (AKI) remains a major problem in critically unwell children and young adults. Ischaemia reperfusion (IR) injury is a major contributor to the development of AKI in a significant proportion of these cases and mitochondria are increasingly recognised as being central to this process through generation of a burst of reactive oxygen species early in reperfusion. Mitochondria have additionally been shown to have key roles in downstream processes including activation of the immune response, immunomodulation, and apoptosis and necrosis. The recognition of the central role of mitochondria in IR injury and an increased understanding of the pathophysiology that undermines these processes has resulted in identification of novel therapeutic targets and potential biomarkers. This review summarises a variety of therapeutic approaches that are currently under exploration and may have potential in ameliorating AKI in children in the future.

Kax and kol: collapse and resilience in lowland Maya civilization.

Episodes of population loss and cultural change, including the famous Classic Collapse, punctuated the long course of Maya civilization. In many cases, these downturns in the fortunes of individual sites and entire regions included significant environmental components such as droughts or anthropogenic environmental degradation. Some afflicted areas remained depopulated for long periods, whereas others recovered more quickly. We examine the dynamics of growth and decline in several areas in the Maya Lowlands in terms of both environmental and cultural resilience and with a focus on downturns that occurred in the Terminal Preclassic (second century Common Era) and Terminal Classic (9th and 10th centuries CE) periods. This examination of available data indicates that the elevated interior areas of the Yucatán Peninsula were more susceptible to system collapse and less suitable for resilient recovery than adjacent lower-lying areas.

Wetland fields as mirrors of drought and the Maya abandonment.

Getting at the Maya Collapse has both temporal and geographic dimensions, because it occurred over centuries and great distances. This requires a wide range of research sites and proxy records, ranging from lake cores to geomorphic evidence, such as stratigraphy and speleothems. This article synthesizes these lines of evidence, together with previously undescribed findings on Maya wetland formation and use in a key region near the heart of the central Maya Lowlands. Growing lines of evidence point to dryer periods in Maya history, which correlate to major periods of transition. The main line of evidence in this paper comes from wetland use and formation studies, which show evidence for both large-scale environmental change and human adaptation or response. Based on multiproxy studies, Maya wetland fields had a long and varied history, but most evidence indicates the start of disuse during or shortly after the Maya Terminal Classic. Hence, the pervasiveness of collapse extended into a range of wetlands, including perennial wetlands, which should have been less responsive to drought as a driver of disuse. A synthesis of the lines of evidence for canal infilling shows no attempts to reclaim them after the Classic Period.