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Spatiotemporal patterns of plant water uptake, loss, and storage exert a first-order control on photosynthesis and evapotranspiration. Many studies of plant responses to water stress have focused on differences between species because of their different stomatal closure, xylem conductance, and root traits. However, several other ecohydrological factors are also relevant, including soil hydraulics, topographically driven redistribution of water, plant adaptation to local climatic variations, and changes in vegetation density. Here, we seek to understand the relative importance of the dominant species for regional-scale variations in woody plant responses to water stress. We map plant water sensitivity (PWS) based on the response of remotely sensed live fuel moisture content to variations in hydrometeorology using an auto-regressive model. Live fuel moisture content dynamics are informative of PWS because they directly reflect vegetation water content and therefore patterns of plant water uptake and evapotranspiration. The PWS is studied using 21,455 wooded locations containing U.S. Forest Service Forest Inventory and Analysis plots across the western United States, where species cover is known and where a single species is locally dominant. Using a species-specific mean PWS value explains 23% of observed PWS variability. By contrast, a random forest driven by mean vegetation density, mean climate, soil properties, and topographic descriptors explains 43% of observed PWS variability. Thus, the dominant species explains only 53% (23% compared to 43%) of explainable variations in PWS. Mean climate and mean NDVI also exert significant influence on PWS. Our results suggest that studies of differences between species should explicitly consider the environments (climate, soil, topography) in which observations for each species are made, and whether those environments are representative of the entire species range.

Abstract Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting, comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines and showed disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detect a native mutant ADNP protein. In addition, an N-terminal immunoprecipitation-competent ADNP antibody enriched truncating mutants in overexpression lysates, whereas implementation of the same method failed to enrich a possible native mutant protein in immortalized patient-derived lymphoblastoid cell lines. This study aims to shape awareness for critical assessment of mutant ADNP protein analysis in Helsmoortel-Van der Aa syndrome.

Abstract Background Helsmoortel–Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation. Results The clinical presentation of the patient was representative of the Helsmoortel–Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein–protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain. Conclusion This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel–Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel–Van der Aa syndrome and holds promise as a new therapeutic target. Graphical abstract

Concentrated solar power (CSP) technologies deliver concentrated solar energy as a heat source to industrial processes, power generation cycles, and chemical cycles. CSP systems require accurate and reliable high flux measurements, and next generation CSP systems will require flux measurement up to 1000 W/cm2. Existing flux measurement devices do not comprehensively meet the flux rating, cycle life, cost, and lead-time needs of stakeholders, necessitating the development of an improved flux sensor. In this study, Sandia National Laboratories (SNL) partnered with Hukseflux Thermal Sensors to develop a low-cost, short lead-time, and robust flux sensor rated to 250 W/cm2. Three prototype circular foil gauge designs were assessed for performance at the National Solar Thermal Test Facility (NSTTF) at SNL. Each gauge design measured flux up to 250 W/cm2 with 500 W/cm2 flux exposure, but measurement error was found to increase after foil coatings reached 400 °C. The results of this study suggest that coating optical properties change at excessive temperatures and that foil coating temperature, rather than heat flux level, dictates the acceptable gauge measurement range.

Abstract Vegetation optical depth (VOD) satellite microwave retrievals provide significant insights into vegetation water content and responses to hydroclimatic changes. While VOD variations are commonly linked to dry biomass and live fuel moisture content (LFMC), the impact of canopy temperature (Tc) remains overlooked in large‐scale studies. Here, we investigated the impact of Tc on L‐band (1.4 GHz) and X‐band (10.7 GHz) VOD at diurnal and seasonal timescales. Synthetic benchmark VOD was created using realistic fields of Tc, LFMC, and biomass in an electromagnetic model. Perturbation experiments revealed that Tc strongly affects diurnal VOD variations at both L‐band and X‐band. Seasonally, while biomass emerges as the largest contributor to VOD variations in 70% (at X‐band) and 90% (at L‐band) of our study region, Tc and LFMC still play substantial roles. The findings stress the importance of refining retrieval algorithms to distinguish Tc, LFMC, and biomass effects for future VOD applications in ecohydrology.

Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged

Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis. For example, disturbances in LM profiles and especially those derived from the ω-6 PUFA arachidonic acid (AA) have been reported in people with MS (PwMS), where they may contribute to the chronicity of neuroinflammatory processes. Moreover, we have previously shown that certain AA-derived LMs also associated with neurodegenerative processes in PwMS, suggesting that AA-derived LMs are involved in more pathological events than solely neuroinflammation. Yet, to date, a comprehensive overview of the contribution of these LMs to MS-associated pathological processes remains elusive. Main body This review summarizes and critically evaluates the current body of literature on the eicosanoid biosynthetic pathway and its contribution to key pathological hallmarks of MS during different disease stages. Various parts of the eicosanoid pathway are highlighted, namely, the prostanoid, leukotriene, and hydroxyeicosatetraenoic acids (HETEs) biochemical routes that include specific enzymes of the cyclooxygenases (COXs) and lipoxygenases (LOX) families. In addition, cellular sources of LMs and their potential target cells based on receptor expression profiles will be discussed in the context of MS. Finally, we propose novel therapeutic approaches based on eicosanoid pathway and/or receptor modulation to ultimately target chronic neuroinflammation, demyelination and neurodegeneration in MS. Short conclusion The eicosanoid pathway is intrinsically linked to specific aspects of MS pathogenesis. Therefore, we propose that novel intervention strategies, with the aim of accurately modulating the eicosanoid pathway towards the biosynthesis of beneficial LMs, can potentially contribute to more patient- and MS subtype-specific treatment opportunities to combat MS. Graphical Abstract

Dense tantalum-based carbonitride materials featuring >95 % relative density, TaC, Ta2C1.5N0.5, Ta2CN, Ta2C0.5N1.5 and TaN, were prepared by Spark Plasma Sintering (SPS) at 1873 K with a dwell time of 10 min and a pressure of 50 MPa. Despite the presence of an oxide phase (i.e. 5 vol%) and some W inclusions (i.e. 1 vol%), the mechanical properties of such ultra-high temperature ceramics (UHTC) show promising values. Indeed, the Young's moduli measured by nano-indentation were approx. 600–700 GPa, which is higher than literature values reported for similar UHTC. The hardness values increased from 16.4 ± 0.8 GPa for TaC to 27.9 ± 1.3 GPa for TaN, with an approximately linear trend for the carbonitride samples while the ratio of plastic deformation work over the total indentation work followed the opposite trend.

Stakeholders of CSP and non-CSP high-intensity broadband flux measurements were surveyed and interviewed to obtain flux sensor design and calibration requirements. Existing sensor technologies and existing calibration facilities were then compared against this standard. Stakeholders require a flux sensor designed for >5,000 kW/m2 flux measurements, >1,000 life cycles, 60-minute exposure at maximum flux, and

Madurella mycetomatis is the main cause of mycetoma, a chronic granulomatous infection for which currently no adequate therapy is available. To improve therapy, more knowledge on a molecular level is required to understand how M. mycetomatis is able to cause this disease. However, the genetic toolbox for M. mycetomatis is limited. To date, no method is available to genetically modify M. mycetomatis. In this paper, a protoplast-mediated transformation protocol was successfully developed for this fungal species, using hygromycin as a selection marker. Furthermore, using this method, a cytoplasmic-GFP-expressing M. mycetomatis strain was created. The reported methodology will be invaluable to explore the pathogenicity of M. mycetomatis and to develop reporter strains which can be useful in drug discovery as well as in genetic studies.

Abstract Stomatal optimization theory is a commonly used framework for modeling how plants regulate transpiration in response to the environment. Most stomatal optimization models assume that plants instantaneously optimize a reward function such as carbon gain. However, plants are expected to optimize over longer timescales given the rapid environmental variability they encounter. There are currently no observational constraints on these timescales. Here, a new stomatal model is developed and is used to analyze the timescales over which stomatal closure is optimized. The proposed model assumes plants maximize carbon gain subject to the constraint that they cannot draw down soil moisture below a critical value. The reward is integrated over time, after being weighted by a discount factor that represents the timescale (τ) that a plant considers when optimizing stomatal conductance to save water. The model is simple enough to be analytically solvable, which allows the value of τ to be inferred from observations of stomatal behavior under known environmental conditions. The model is fitted to eddy covariance data in a range of ecosystems, finding the value of τ that best predicts the dynamics of evapotranspiration at each site. Across 82 sites, the climate metrics with the strongest correlation to τ are measures of the average number of dry days between rainfall events. Values of τ are similar in magnitude to the longest such dry period encountered in an average year. The results here shed light on which climate characteristics shape spatial variations in ecosystem‐level water use strategy.