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Characterizing the temporal uncertainty in palaeoclimate records is crucial for analysing past climate change, correlating climate events between records, assessing climate periodicities, identifying potential triggers and evaluating climate model simulations. The first global compilation of speleothem isotope records by the SISAL (Speleothem Isotope Synthesis and Analysis) working group showed that age model uncertainties are not systematically reported in the published literature, and these are only available for a limited number of records (ca. 15 %, n = 107/691). To improve the usefulness of the SISAL database, we have (i) improved the database's spatio-temporal coverage and (ii) created new chronologies using seven different approaches for age- depth modelling. We have applied these alternative chronologies to the records from the first version of the SISAL database (SISALv1) and to new records compiled since the release of SISALv1. This paper documents the necessary changes in the structure of the SISAL database to accommodate the inclusion of the new age models and their uncertainties as well as the expansion of the database to include new records and the qualitycontrol measures applied. This paper also documents the age-depth model approaches used to calculate the new chronologies. The updated version of the SISAL database (SISALv2) contains isotopic data from 691 speleothem records from 294 cave sites and new age-depth models, including age-depth temporal uncertainties for 512 speleothems.

Terrestrial photosynthesis is the basis for vegetation growth and drives the land carbon cycle. Accurately simulating gross primary production (GPP, ecosystem-level apparent photosynthesis) is key for satellite monitoring and Earth system model predictions under climate change. While robust models exist for describing leaf-level photosynthesis, predictions diverge due to uncertain photosynthetic traits and parameters which vary on multiple spatial and temporal scales. Here, we describe and evaluate a GPP (photosynthesis per unit ground area) model, the P-model, that combines the Farquhar-von Caemmerer-Berry model for C3 photosynthesis with an optimality principle for the carbon assimilation-Transpiration trade-off, and predicts a multi-day average light use efficiency (LUE) for any climate and C3 vegetation type. The model builds on the theory developed in Prentice et al. (2014) and Wang et al. (2017a) and is extended to include low temperature effects on the intrinsic quantum yield and an empirical soil moisture stress factor. The model is forced with site-level data of the fraction of absorbed photosynthetically active radiation (fAPAR) and meteorological data and is evaluated against GPP estimates from a globally distributed network of ecosystem flux measurements. Although the P-model requires relatively few inputs, the R2 is reduced to 0.70 when not accounting for the reduction in quantum yield at low temperatures and effects of low soil moisture on LUE. The R2 for the P-model-predicted LUE is 0.32 (means by site) and 0.48 (means by vegetation type). Applying this model for global-scale simulations yields a total global GPP of 106-122 Pg C yr-1 (mean of 2001-2011), depending on the fAPAR forcing data. The P-model provides a simple but powerful method for predicting-rather than prescribing-light use efficiency and simulating terrestrial photosynthesis across a wide range of conditions. The model is available as an R package (rpmodel).

Global constraints on momentum and energy govern the variability of the rainfall belt in the intertropical convergence zone and the structure of the zonal mean tropical circulation. The continental-scale monsoon systems are also facets of a momentum- and energy-constrained global circulation, but their modern and palaeo variability deviates substantially from that of the intertropical convergence zone. The mechanisms underlying deviations from expectations based on the longitudinal mean budgets are neither fully understood nor simulated accurately. We argue that a framework grounded in global constraints on energy and momentum yet encompassing the complexities of monsoon dynamics is needed to identify the causes of the mismatch between theory, models and observations, and ultimately to improve regional climate projections. In a first step towards this goal, disparate regional processes must be distilled into gross measures of energy flow in and out of continents and between the surface and the tropopause, so that monsoon dynamics may be coherently diagnosed across modern and palaeo observations and across idealized and comprehensive simulations. Accounting for zonal asymmetries in the circulation, land/ocean differences in surface fluxes, and the character of convective systems, such a monsoon framework would integrate our understanding at all relevant scales: from the fine details of how moisture and energy are lifted in the updrafts of thunderclouds, up to the global circulations.

Understanding the consequences of extreme climatic events is a growing challenge in ecology. Climatic extremes may differentially affect varying elements of biodiversity, and may not always produce ecological effects exceeding those of "normal" climatic variation in space and time. We asked how the extreme drought years of 2013- 2014 affected the cover, species richness, functional trait means, functional diversity, and phylogenetic diversity of herbaceous plant communities across the California Floristic Province. We compared the directions and magnitudes of these drought effects with expectations from four "pre-drought" studies of variation in water availability: (1) a watering experiment, (2) a long- Term (15-yr) monitoring of interannual variability, (3) a resampling of historic (57-yr- old) plots within a warming and drying region, and (4) natural variation in communities over a broad geographic gradient in precipitation. We found that the drought was associated with consistent reductions in species richness and cover, especially for annual forbs and exotic annual grasses, but not with changes in functional or phylogenetic diversity. Except for total cover and cover of exotic annual grasses, most drought effects did not exceed quantitative expectations based on the four pre-drought studies. Qualitatively, plant community responses to the drought were most concordant with responses to pre-drought interannual rainfall variability in the 15-yr monitoring study, and least concordant with responses to the geographic gradient in precipitation. Our results suggest that, at least in the short term, extreme drought may cause only a subset of community metrics to respond in ways that exceed normal background variability.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) protects against childhood tuberculosis; and unlike most vaccines, BCG broadly impacts immunity to other pathogens and even some cancers. Early in the COVID-19 pandemic, epidemiological studies identified a protective association between BCG vaccination and outcomes of SARS-CoV-2, but the associations in later studies were inconsistent. We sought possible reasons and noticed the study populations often lived in the same country. Since individuals from the same regions can share common ancestors, we hypothesized that genetic background could influence associations between BCG and SARS-CoV-2. To explore this hypothesis in a controlled environment, we performed a pilot study using Diversity Outbred mice. First, we identified amino acid sequences shared by BCG and SARS-CoV-2 spike protein. Next, we tested for IgG reactive to spike protein from BCG-vaccinated mice. Sera from some, but not all, BCG-vaccinated Diversity Outbred mice contained higher levels of IgG cross-reactive to SARS-CoV-2 spike protein than sera from BCG-vaccinated C57BL/6J inbred mice and unvaccinated mice. Although larger experimental studies are needed to obtain mechanistic insight, these findings suggest that genetic background may be an important variable contributing to different associations observed in human randomized clinical trials evaluating BCG vaccination on SARS-CoV-2 and COVID-19.

Abstract Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug treatment in cells and tissues but are presently lacking. Here, we present SigPath, a targeted mass spectrometry (MS) assay that measures 284 phosphosites in 200 phosphoproteins of biological interest. SigPath probes a broad swath of signaling biology with high throughput and quantitative precision. We applied the assay to investigate changes in phospho‐signaling in drug‐treated cancer cell lines, breast cancer preclinical models, and human medulloblastoma tumors. In addition to validating previous findings, SigPath detected and quantified a large number of differentially regulated phosphosites newly associated with disease models and human tumors at baseline or with drug perturbation. Our results highlight the potential of SigPath to monitor phosphoproteomic signaling events and to nominate mechanistic hypotheses regarding oncogenesis, response, and resistance to therapy.

SUMMARY. A 20-month-old boy presented with biopsy-proven recurrent alveolar rhabdomyosarcoma without metastasis. He was previously treated with multiagent chemotherapy and external beam irradiation showing a complete response. Upon relapse, he was treated with chemotherapy, orbital exenteration, and brachytherapy. Customized, intraoperative brachytherapy has potential to limit the sequelae associated with radiation adjuvant therapy.

Abstract Background Macrophages are innate immune cells with diverse functional and molecular phenotypes. This diversity is largely unexplored at the level of single-cell proteomes because of the limitations of quantitative single-cell protein analysis. Results To overcome this limitation, we develop SCoPE2, which substantially increases quantitative accuracy and throughput while lowering cost and hands-on time by introducing automated and miniaturized sample preparation. These advances enable us to analyze the emergence of cellular heterogeneity as homogeneous monocytes differentiate into macrophage-like cells in the absence of polarizing cytokines. SCoPE2 quantifies over 3042 proteins in 1490 single monocytes and macrophages in 10 days of instrument time, and the quantified proteins allow us to discern single cells by cell type. Furthermore, the data uncover a continuous gradient of proteome states for the macrophages, suggesting that macrophage heterogeneity may emerge in the absence of polarizing cytokines. Parallel measurements of transcripts by 10× Genomics suggest that our measurements sample 20-fold more protein copies than RNA copies per gene, and thus, SCoPE2 supports quantification with improved count statistics. This allowed exploring regulatory interactions, such as interactions between the tumor suppressor p53, its transcript, and the transcripts of genes regulated by p53. Conclusions Even in a homogeneous environment, macrophage proteomes are heterogeneous. This heterogeneity correlates to the inflammatory axis of classically and alternatively activated macrophages. Our methodology lays the foundation for automated and quantitative single-cell analysis of proteins by mass spectrometry and demonstrates the potential for inferring transcriptional and post-transcriptional regulation from variability across single cells.

OBJECTIVES:. To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN:. Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING:. The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS:. We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS:. We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS:. Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

Plants acclimate to temperature by adjusting their photosynthetic capacity over weeks to months. However, most evidence for photosynthetic acclimation derives from leaf-scale experiments. Here we address the scarcity of evidence for canopy-scale photosynthetic acclimation by examining the correlation between maximum photosynthetic rates (A max,2,000 ) and growth temperature ( T air ¯ ) across a range of concurrent temperatures and canopy foliage quantity, using data from >200 eddy covariance sites. We detect widespread thermal acclimation of canopy-scale photosynthesis, demonstrated by enhanced A max,2,000 under higher T air ¯ , across flux sites with adequate water availability. A 14-day period is identified as the most relevant timescale for acclimation across all sites, with a range of 12-25 days for different plant functional types. The mean apparent thermal acclimation rate across all ecosystems is 0.41 (-0.38-1.04 for 5th-95th percentile range) µmol m -2  s -1  °C -1 , with croplands showing the largest acclimation rates and grasslands the lowest. Incorporating an optimality-based prediction of leaf photosynthetic capacities into a biochemical photosynthesis model is shown to improve the representation of thermal acclimation. Our results underscore the critical need for enhanced understanding and modelling of canopy-scale photosynthetic capacity to accurately predict plant responses to warmer growing seasons., (© 2024. The Author(s).)

Interactions between carbon (C) and nitrogen (N) cycles in terrestrial ecosystems are simulated in advanced vegetation models, yet methodologies vary widely, leading to divergent simulations of past land C balance trends. This underscores the need to reassess our understanding of ecosystem processes, given recent theoretical advancements and empirical data. We review current knowledge, emphasising evidence from experiments and trait data compilations for vegetation responses to CO 2 and N input, alongside theoretical and ecological principles for modelling. N fertilisation increases leaf N content but inconsistently enhances leaf-level photosynthetic capacity. Whole-plant responses include increased leaf area and biomass, with reduced root allocation and increased aboveground biomass. Elevated atmospheric CO 2 also boosts leaf area and biomass but intensifies belowground allocation, depleting soil N and likely reducing N losses. Global leaf traits data confirm these findings, indicating that soil N availability influences leaf N content more than photosynthetic capacity. A demonstration model based on the functional balance hypothesis accurately predicts responses to N and CO 2 fertilisation on tissue allocation, growth and biomass, offering a path to reduce uncertainty in global C cycle projections., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Many terrestrial plant communities, especially forests, have been shown to lag in response to rapid climate change. Grassland communities may respond more quickly to novel climates, as they consist mostly of short-lived species, which are directly exposed to macroclimate change. Here we report the rapid response of grassland communities to climate change in the California Floristic Province. We estimated 349 vascular plant species' climatic niches from 829,337 occurrence records, compiled 15 long-term community composition datasets from 12 observational studies and 3 global change experiments, and analysed community compositional shifts in the climate niche space. We show that communities experienced significant shifts towards species associated with warmer and drier locations at rates of 0.0216 ± 0.00592 °C yr - 1 (mean ± s.e.) and -3.04 ± 0.742 mm yr - 1 , and these changes occurred at a pace similar to that of climate warming and drying. These directional shifts were consistent across observations and experiments. Our findings contrast with the lagged responses observed in communities dominated by long-lived plants and suggest greater biodiversity changes than expected in the near future., (© 2024. The Author(s).)

Objectives: Hepatic ischemia and hypoxia are accompanied by reduced bile flow, biliary sludge and cholestasis. Hepatobiliary transport systems, nuclear receptors and aquaporins were studied after hypoxia and reoxygenation in human hepatic cells., Methods: Expression of Aquaporin 8 (AQP8), Aquaporin 9 (AQP9), Pregnane X receptor (PXR), Farnesoid X receptor (FXR), Organic anion transporting polypeptide 1 (OATP1), and the Multidrug resistance-associated protein 4 (MRP4) were investigated in induced pluripotent stem cells (iPSCs) derived hepatic cells and the immortalized hepatic line HepG2. HepG2 was subjected to combined oxygen and glucose deprivation for 4 h followed by reoxygenation., Results: Expression of AQP8 and AQP9 increased during differentiation in iPSC-derived hepatic cells. Hypoxia did not alter mRNA levels of AQP8, but reoxygenation caused a marked increase in AQP8 mRNA expression. While expression of OATP1 had a transient increase during reoxygenation, MRP4 showed a delayed downregulation. Knock-down of FXR did not alter the expression of AQP8, AQP9, MRP4, or OATP1. Post-hypoxic protein levels of AQP8 were reduced after 68 h of reoxygenation compared to normoxic controls., Conclusions: Post-transcriptional mechanisms rather than reduced transcription cause reduction in AQP8 protein concentration after hypoxia-reoxygenation in hepatic cells. Expression patterns differed between hepatobiliary transport systems during hypoxia and reoxygenation., Impact: Expression of AQP8 and AQP9 increased during differentiation in induced pluripotent stem cells. Expression of hepatobiliary transporters varies during hypoxia and reoxygenation. Post-hypoxic protein levels of AQP8 were reduced after 68 h of reoxygenation. Post-transcriptional mechanisms rather than reduced transcription cause reduction in AQP8 protein concentration after hypoxia-reoxygenation in hepatic cells. Hypoxia and reoxygenation may affect aquaporins in hepatic cells and potentially affect bile composition., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: Parenteral nutrition (PN) is used for patients of varying ages with intestinal failure to supplement calories. Premature newborns with low birth weight are at a high risk for developing PN associated liver disease (PNALD) including steatosis, cholestasis, and gallbladder sludge/stones. To optimize nutrition regimens, models are required to predict PNALD., Methods: We have exploited induced pluripotent stem cell derived liver organoids to provide a testing platform for PNALD. Liver organoids mimic the developing liver and contain the different hepatic cell types. The organoids have an early postnatal maturity making them a suitable model for premature newborns. To mimic PN treatment we used medium supplemented with either clinoleic (80% olive oil/20% soybean oil) or intralipid (100% soybean oil) for 7 days., Results: Homogenous HNF4a staining was found in all organoids and PN treatments caused accumulation of lipids in hepatocytes. Organoids exhibited a dose dependent decrease in CYP3A4 activity and expression of hepatocyte functional genes. The lipid emulsions did not affect overall organoid viability and glucose levels had no contributory effect to the observed results., Conclusions: Liver organoids could be utilized as a potential screening platform for the development of new, less hepatotoxic PN solutions. Both lipid treatments caused hepatic lipid accumulation, a significant decrease in CYP3A4 activity and a decrease in the RNA levels of both CYP3A4 and CYP1A2 in a dose dependent manner. The presence of high glucose had no additive effect, while Clinoleic at high dose, caused significant upregulation of interleukin 6 and TLR4 expression., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Leaf dark respiration (R d ) acclimates to environmental changes. However, the magnitude, controls and time scales of acclimation remain unclear and are inconsistently treated in ecosystem models. We hypothesized that R d and Rubisco carboxylation capacity (V cmax ) at 25°C (R d,25 , V cmax,25 ) are coordinated so that R d,25 variations support V cmax,25 at a level allowing full light use, with V cmax,25 reflecting daytime conditions (for photosynthesis), and R d,25 /V cmax,25 reflecting night-time conditions (for starch degradation and sucrose export). We tested this hypothesis temporally using a 5-yr warming experiment, and spatially using an extensive field-measurement data set. We compared the results to three published alternatives: R d,25 declines linearly with daily average prior temperature; R d at average prior night temperatures tends towards a constant value; and R d,25 /V cmax,25 is constant. Our hypothesis accounted for more variation in observed R d,25 over time (R 2  = 0.74) and space (R 2  = 0.68) than the alternatives. Night-time temperature dominated the seasonal time-course of R d , with an apparent response time scale of c. 2 wk. V cmax dominated the spatial patterns. Our acclimation hypothesis results in a smaller increase in global R d in response to rising CO 2 and warming than is projected by the two of three alternative hypotheses, and by current models., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Recent variability in West African monsoon rainfall (WAMR) has been shown to be influenced by multiple ocean-atmosphere modes, including the El Niño Southern Oscillation, Atlantic Multidecadal Oscillation and the Interdecadal Pacific Oscillation. How these modes will change in response to long term forcing is less well understood. Here we use four transient simulations driven by changes in orbital forcing and greenhouse gas concentrations over the past 6000 years to examine the relationship between West African monsoon rainfall multiscale variability and changes in the modes associated with this variability. All four models show a near linear decline in monsoon rainfall over the past 6000 years in response to the gradual weakening of the interhemispheric gradient in sea surface temperatures. The only indices that show a long-term trend are those associated with the strengthening of the El Niño Southern Oscillation from the mid-Holocene onwards. At the interannual-to-decadal timescale, WAMR variability is largely influenced by Pacific-Atlantic - Mediterranean Sea teleconnections in all simulations; the exact configurations are model sensitive. The WAMR interannual-to-decadal variability depicts marked multi-centennial oscillations, with La Niña/negative Pacific Decadal Oscillation and a weakening and/or poleward shift of subtropical high-pressure systems over the Atlantic favoring wet WAMR anomalies. The WAMR interannual-to-decadal variability also depicts an overall decreasing trend throughout the Holocene that is consistent among the simulations. This decreasing trend relates to changes in the North Atlantic and Gulf of Guinea Sea Surface Temperature variability., Supplementary Information: The online version contains supplementary material available at 10.1007/s00382-023-07023-y., Competing Interests: Conflicts of interestThe authors declare they have no financial interests., (© The Author(s) 2023.)

Background & Aims: Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now., Methods: A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies., Results: One specific variant (c.-98G>T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G>T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2)., Conclusions: c.-98G>T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome., Impact and Implications: The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The lack of physiological parity between 2D cell culture and in vivo culture has led to the development of more organotypic models, such as organoids. Organoid models have been developed for a number of tissues, including the liver. Current organoid protocols are characterized by a reliance on extracellular matrices (ECMs), patterning in 2D culture, costly growth factors and a lack of cellular diversity, structure, and organization. Current hepatic organoid models are generally simplistic and composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant compared to native tissue. We have developed an approach that does not require 2D patterning, is ECM independent, and employs small molecules to mimic embryonic liver development that produces large quantities of liver-like organoids. Using single-cell RNA sequencing and immunofluorescence, we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, and a population of resident macrophages: Kupffer cells. The organoids exhibit key liver functions, including drug metabolism, serum protein production, urea synthesis and coagulation factor production, with preserved post-translational modifications such as N-glycosylation and functionality. The organoids can be transplanted and maintained long term in mice producing human albumin. The organoids exhibit a complex cellular repertoire reflective of the organ and have de novo vascularization and liver-like function. These characteristics are a prerequisite for many applications from cellular therapy, tissue engineering, drug toxicity assessment, and disease modeling to basic developmental biology., (© 2023. The Author(s).)

Ecological theory posits that temporal stability patterns in plant populations are associated with differences in species' ecological strategies. However, empirical evidence is lacking about which traits, or trade-offs, underlie species stability, especially across different biomes. We compiled a worldwide collection of long-term permanent vegetation records (greater than 7000 plots from 78 datasets) from a large range of habitats which we combined with existing trait databases. We tested whether the observed inter-annual variability in species abundance (coefficient of variation) was related to multiple individual traits. We found that populations with greater leaf dry matter content and seed mass were more stable over time. Despite the variability explained by these traits being low, their effect was consistent across different datasets. Other traits played a significant, albeit weaker, role in species stability, and the inclusion of multi-variate axes or phylogeny did not substantially modify nor improve predictions. These results provide empirical evidence and highlight the relevance of specific ecological trade-offs, i.e. in different resource-use and dispersal strategies, for plant populations stability across multiple biomes. Further research is, however, necessary to integrate and evaluate the role of other specific traits, often not available in databases, and intraspecific trait variability in modulating species stability.

The bleeding phenotype of hereditary coagulation disorders is caused by the low or undetectable activity of the proteins involved in hemostasis, due to a broad spectrum of genetic alterations. Most of the affected coagulation factors are produced in the liver. Therefore, two-dimensional (2D) cultures of primary human hepatocytes and recombinant overexpression of the factors in non-human cell lines have been primarily used to mimic disease pathogenesis and as a model for innovative therapeutic strategies. However, neither human nor animal cells fully represent the hepatocellular biology and do not harbor the exact genetic background of the patient. As a result, the inability of the current in vitro models in recapitulating the in vivo situation has limited the studies of these inherited coagulation disorders. Induced Pluripotent Stem Cell (iPSC) technology offers a possible solution to overcome these limitations by reprogramming patient somatic cells into an embryonic-like pluripotent state, thus giving the possibility of generating an unlimited number of liver cells needed for modeling or therapeutic purposes. By combining this potential and the recent advances in the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology, it allows for the generation of autologous and gene corrected liver cells in the form of three-dimensional (3D) liver organoids. The organoids recapitulate cellular composition and organization of the liver, providing a more physiological model to study the biology of coagulation proteins and modeling hereditary coagulation disorders. This advanced methodology can pave the way for the development of cell-based therapeutic approaches to treat inherited coagulation disorders. In this review we will explore the use of liver organoids as a state-of-the-art methodology for modeling coagulation factors disorders and the possibilities of using organoid technology to treat the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Roman, Stavik, Lauritzen, Sandset, Harrison, Sullivan and Chollet.)

Recent increases in vegetation greenness over much of the world reflect increasing CO 2 globally and warming in cold areas. However, the strength of the response to both CO 2 and warming in those areas appears to be declining for unclear reasons, contributing to large uncertainties in predicting how vegetation will respond to future global changes. Here, we investigated the changes of satellite-observed peak season absorbed photosynthetically active radiation (F max ) on the Tibetan Plateau between 1982 and 2016. Although climate trends are similar across the Plateau, we identified robust divergent responses (a greening of 0.31 ± 0.14% year -1 in drier regions and a browning of 0.12 ± 0.08% year -1 in wetter regions). Using an eco-evolutionary optimality (EEO) concept of plant acclimation/adaptation, we propose a parsimonious modelling framework that quantitatively explains these changes in terms of water and energy limitations. Our model captured the variations in F max with a correlation coefficient (r) of .76 and a root mean squared error of .12 and predicted the divergent trends of greening (0.32 ± 0.19% year -1 ) and browning (0.07 ± 0.06% year -1 ). We also predicted the observed reduced sensitivities of F max to precipitation and temperature. The model allows us to explain these changes: Enhanced growing season cumulative radiation has opposite effects on water use and energy uptake. Increased precipitation has an overwhelmingly positive effect in drier regions, whereas warming reduces F max in wetter regions by increasing the cost of building and maintaining leaf area. Rising CO 2 stimulates vegetation growth by enhancing water-use efficiency, but its effect on photosynthesis saturates. The large decrease in the sensitivity of vegetation to climate reflects a shift from water to energy limitation. Our study demonstrates the potential of EEO approaches to reveal the mechanisms underlying recent trends in vegetation greenness and provides further insight into the response of alpine ecosystems to ongoing climate change., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Plant functional traits represent adaptive strategies to the environment, linked to biophysical and biogeochemical processes and ecosystem functioning. Compilations of trait data facilitate research in multiple fields from plant ecology through to land-surface modelling. Here we present version 2 of the China Plant Trait Database, which contains information on morphometric, physical, chemical, photosynthetic and hydraulic traits from 1529 unique species in 140 sites spanning a diversity of vegetation types. Version 2 has five improvements compared to the previous version: (1) new data from a 4-km elevation transect on the edge of Tibetan Plateau, including alpine vegetation types not sampled previously; (2) inclusion of traits related to hydraulic processes, including specific sapwood conductance, the area ratio of sapwood to leaf, wood density and turgor loss point; (3) inclusion of information on soil properties to complement the existing data on climate and vegetation (4) assessments and flagging the reliability of individual trait measurements; and (5) inclusion of standardized templates for systematical field sampling and measurements., (© 2022. The Author(s).)

Here we provide the 'Global Spectrum of Plant Form and Function Dataset', containing species mean values for six vascular plant traits. Together, these traits -plant height, stem specific density, leaf area, leaf mass per area, leaf nitrogen content per dry mass, and diaspore (seed or spore) mass - define the primary axes of variation in plant form and function. The dataset is based on ca. 1 million trait records received via the TRY database (representing ca. 2,500 original publications) and additional unpublished data. It provides 92,159 species mean values for the six traits, covering 46,047 species. The data are complemented by higher-level taxonomic classification and six categorical traits (woodiness, growth form, succulence, adaptation to terrestrial or aquatic habitats, nutrition type and leaf type). Data quality management is based on a probabilistic approach combined with comprehensive validation against expert knowledge and external information. Intense data acquisition and thorough quality control produced the largest and, to our knowledge, most accurate compilation of empirically observed vascular plant species mean traits to date., (© 2022. The Author(s).)

Aim: Biomisation has been the most widely used technique to reconstruct past regional vegetation patterns because it does not require an extensive modern pollen dataset. However, it has well-known limitations including its dependence on expert judgement for the assignment of pollen taxa to plant functional types (PFTs) and PFTs to biomes. Here we present a new method that combines the strengths of biomisation with those of the alternative dissimilarity-based techniques., Location: The Eastern Mediterranean-Black Sea Caspian Corridor (EMBSeCBIO)., Taxon: Plants., Methods: Modern pollen samples, assigned to biomes based on potential natural vegetation data, are used to characterize the within-biome means and standard deviations of the abundances of each taxon. These values are used to calculate a dissimilarity index between any pollen sample and every biome, and thus assign the sample to the most likely biome. We calculate a threshold value for each modern biome; fossil samples with scores below the threshold for all modern biomes are thus identified as non-analogue vegetation. We applied the new method to the EMBSeCBIO region to compare its performance with existing reconstructions., Results: The method captured changes in the importance of individual taxa along environmental gradients. The balanced accuracy obtained for the EMBSeCBIO region using the new method was better than obtained using biomisation (77% vs. 65%). When the method was applied to high-resolution fossil records, 70% of the entities showed more temporally stable biome assignments than obtained using biomisation. The technique also identified likely non-analogue assemblages in a synthetic modern dataset and in fossil records., Main Conclusions: The new method yields more accurate and stable reconstructions of vegetation than biomisation. It requires an extensive modern pollen dataset, but is conceptually simple, and avoids subjective choices about taxon allocations to PFTs and PFTs to biomes., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Journal of Biogeography published by John Wiley & Sons Ltd.)

Abrupt events are a feature of many palaeoclimate records during the Holocene. The best example is the 8.2 ka event, which was triggered by a release of meltwater into the Labrador Sea and resulted in a weakening of poleward heat transport in the North Atlantic. We use an objective method to identify rapid climate events in globally distributed speleothem oxygen isotope records during the Holocene. We show that the 8.2 ka event can be identified in >70% of the speleothem records and is the most coherent signal of abrupt climate change during the last 12,000 years. The isotopic changes during the event are regionally homogenous: positive oxygen isotope anomalies are observed across Asia and negative anomalies are seen across Europe, the Mediterranean, South America and southern Africa. The magnitude of the isotopic excursions in Europe and Asia are statistically indistinguishable. There is no significant difference in the duration and timing of the 8.2 ka event between regions, or between the speleothem records and Greenland ice core records. Our study supports a rapid and global climate response to the 8.2 ka freshwater pulse into the North Atlantic, likely transmitted globally via atmospheric teleconnections., (© 2022. The Author(s).)

Leaf morphological traits vary systematically along climatic gradients. However, recent studies in plant functional ecology have mainly analysed quantitative traits, while numerical models of species distributions and vegetation function have focused on traits associated with resource acquisition; both ignore the wider functional significance of leaf morphology.A dataset comprising 22 leaf morphological traits for 662 woody species from 92 sites, representing all biomes present in China, was subjected to multivariate analysis in order to identify leading dimensions of trait covariation (correspondence analysis), quantify climatic and phylogenetic contributions (canonical correspondence analysis with variation partitioning) and characterise co-occurring trait syndromes ( k -means clustering) and their climatic preferences.Three axes accounted for >20% of trait variation in both evergreen and deciduous species. Moisture index, precipitation seasonality and growing-season temperature explained 8%-10% of trait variation; family 15%-32%. Microphyll or larger, mid- to dark green leaves with drip tips in wetter climates contrasted with nanophyll or smaller glaucous leaves without drip tips in drier climates. Thick, entire leaves in less seasonal climates contrasted with thin, marginal dissected, aromatic and involute/revolute leaves in more seasonal climates. Thick, involute, hairy leaves in colder climates contrasted with thin leaves with marked surface structures (surface patterning) in warmer climates. Distinctive trait clusters were linked to the driest and most seasonal climates, for example the clustering of picophyll, fleshy and succulent leaves in the driest climates and leptophyll, linear, dissected, revolute or involute and aromatic leaves in regions with highly seasonal rainfall. Several trait clusters co-occurred in wetter climates, including clusters characterised by microphyll, moderately thick, patent and entire leaves or notophyll, waxy, dark green leaves. Synthesis . The plastic response of size, shape, colour and other leaf morphological traits to climate is muted, thus their apparent shift along climate gradients reflects plant adaptations to environment at a community level as determined by species replacement. Information on leaf morphological traits, widely available in floras, could be used to strengthen predictive models of species distribution and vegetation function., Competing Interests: The authors declare that there is no conflict of interest., (© 2022 The Authors. Journal of Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Windstorms are one of the most important disturbance factors in European forest ecosystems. An understanding of the major drivers causing observed changes in forests is essential to improve prediction models and as a basis for forest management. In the present study, we use machine learning techniques in combination with data sets on tree properties, bioclimatic and geomorphic conditions, to analyse the level of forest damage by windstorms in the Sudety Mountains over the period 2004-2010. We tested four scenarios under five classification model frameworks: logistic regression, random forest, support vector machines, neural networks, and gradient boosted modelling. Gradient boosted modelling and random forest have the best predictive power. Tree volume and age are the most important predictors of windstorm damage; climate and geomorphic variables are less important. Forest damage maps based on forest data from 2020 show lower probabilities of damage compared to the end of 20th and the beginning of 21st century., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Extreme drought and increasing temperatures can decrease the resilience of plant communities to fires. Not only may extremely dry conditions during or after fires lead to higher plant mortality and poorer recruitment, but severe pre-fire droughts may reduce the seed production and belowground vigor that are essential to post-fire plant recovery, and may indirectly facilitate invasion. We studied survival, recruitment, and growth of shrubs and herbs in chaparral (shrubland) communities in Northern California after a 2015 fire that immediately followed California's extreme 3-yr drought. We followed the same protocols used to study similar, adjacent communities after a 1999 fire that did not follow a drought, and we compared the two recovery trajectories. Overall, the 2015 fire was not more severe than the 1999 fire, yet it caused higher mortality and lower growth of resprouting shrubs on fertile (sandstone) soils. In contrast, the 2015 fire did not affect the mortality or growth of resprouting shrubs on infertile (serpentine) soils, the density of shrub seedlings, or the richness or cover of native herbs differently than the 1999 fire. However, the 2015 fire facilitated a massive increase in exotic herbaceous cover, especially on fertile soils, possibly portending the early stages of a type conversion to exotic-dominated grassland. Our findings indicate that the consequences of climate change on fire-dependent communities will include effects of pre-fire as well as post-fire climate, and that resprouting shrubs are particularly likely to be sensitive to pre-fire drought., (© 2021 by the Ecological Society of America.)

Amazonia experienced unusually devastating fires in August 2019, leading to huge regional and global environmental and economic losses. The increase in fires has been largely attributed to anthropogenic deforestation, but anomalous climate conditions could also have contributed. This study investigates the climate influence on Amazonia fires in August 2019 and underlying mechanisms, based on statistical correlation and multiple linear regression analyses of 2001-2019 satellite-based fire products and multiple observational or reanalyzed climate datasets. Positive fire anomalies in August 2019 were mainly located in southern Amazonia. These anomalies were mainly driven by low precipitation and relative humidity, which increased fuel dryness and contributed to 38.9 ± 9.5% of the 2019 anomaly in pyrogenic carbon emissions over the southern Amazonia. The dry conditions were associated with southerly wind anomalies over southern Amazonia that suppressed the climatological southward transport of water vapor originating from the Atlantic. The southerly wind anomalies were caused by the combination of a Gill-type cyclonic response to the warmer North Atlantic sea surface temperature (SST), and enhancement of the Walker and Hadley circulations over South America due to the colder SST in the eastern Pacific, and a mid-latitude wave train triggered by the warmer condition in the western Indian Ocean. Our study highlights, for the first time, the important role of Indian Ocean SST for fires in Amazonia. It also reveals how cold SST anomalies in the tropical eastern Pacific link the warm phase of the El Niño-Southern Oscillation (ENSO) in the preceding December-January to the dry-season fires in Amazonia. Our findings can develop theoretical basis of global tropical SST-based fire prediction, and have potential to improve prediction skill of extreme fires in Amazonia and thus to take steps to mitigate their impacts which is urgency given that dry conditions led to the extreme fires are becoming common in Amazonia., Competing Interests: Declaration of competing interest We declare that we don't have any competing financial interests or personal relationships with other people or organizations that could influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Close coupling between water loss and carbon dioxide uptake requires coordination of plant hydraulics and photosynthesis. However, there is still limited information on the quantitative relationships between hydraulic and photosynthetic traits. We propose a basis for these relationships based on optimality theory, and test its predictions by analysis of measurements on 107 species from 11 sites, distributed along a nearly 3000-m elevation gradient. Hydraulic and leaf economic traits were less plastic, and more closely associated with phylogeny, than photosynthetic traits. The two sets of traits were linked by the sapwood to leaf area ratio (Huber value, v H ). The observed coordination between v H and sapwood hydraulic conductivity (K S ) and photosynthetic capacity (V cmax ) conformed to the proposed quantitative theory. Substantial hydraulic diversity was related to the trade-off between K S and v H . Leaf drought tolerance (inferred from turgor loss point, -Ψ tlp ) increased with wood density, but the trade-off between hydraulic efficiency (K S ) and -Ψ tlp was weak. Plant trait effects on v H were dominated by variation in K S , while effects of environment were dominated by variation in temperature. This research unifies hydraulics, photosynthesis and the leaf economics spectrum in a common theoretical framework, and suggests a route towards the integration of photosynthesis and hydraulics in land-surface models., (© 2021 The Authors. New Phytologist © 2021 New Phytologist Foundation.)

Global vegetation and land-surface models embody interdisciplinary scientific understanding of the behaviour of plants and ecosystems, and are indispensable to project the impacts of environmental change on vegetation and the interactions between vegetation and climate. However, systematic errors and persistently large differences among carbon and water cycle projections by different models highlight the limitations of current process formulations. In this review, focusing on core plant functions in the terrestrial carbon and water cycles, we show how unifying hypotheses derived from eco-evolutionary optimality (EEO) principles can provide novel, parameter-sparse representations of plant and vegetation processes. We present case studies that demonstrate how EEO generates parsimonious representations of core, leaf-level processes that are individually testable and supported by evidence. EEO approaches to photosynthesis and primary production, dark respiration and stomatal behaviour are ripe for implementation in global models. EEO approaches to other important traits, including the leaf economics spectrum and applications of EEO at the community level are active research areas. Independently tested modules emerging from EEO studies could profitably be integrated into modelling frameworks that account for the multiple time scales on which plants and plant communities adjust to environmental change., (© 2021 The Authors New Phytologist © 2021 New Phytologist Foundation.)