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In this study, we tested two plotless sampling methods, the ordered distance method and point-centred quarter method, to estimate the tree density and basal area in some managed Alpine forests in northeastern Italy. We selected nine independent forest stands, classified according to the spatial distribution patterns of trees (cluster, random, regular). A plotless sampling survey was simulated within the selected stands and the tree density and basal area were estimated by applying both the ordered distance method and point-centred quarter method. We compared the estimates, in terms of accuracy and precision, between the two methods and against estimates obtained from a simulated survey based on a plot-based sampling method. The point-centred quarter method outperformed the ordered distance method in terms of both accuracy and precision, showing higher robustness towards the bias related to non-random spatial patterns. However, both the plotless methods we tested can provide unbiased accuracy of estimates which, in addition, do not differ from estimates of plot-based sampling. The satisfactory results are encouraging for further tests over other Italian Alpine as well as Apennine forests. If confirmed, the plotless sampling method, especially the point-centred quarter method, could represent an effective alternative whenever plot-based sampling is deemed redundant, or expensive.

Fire danger rating systems are essential tools for fire management activities, allowing optimal allocation of resources both before and during the fire danger periods. Veneto Region's Forest Service is testing the Canadian Forest Fire Weather Index (FWI) System to assess fire intensity, accounting for the effect of wind and the moisture content of inflammable material. The following steps were taken to apply the FWI system: (a) selection of the smallest number (ideally 10 - 15) of weather stations to obtain input data. Principal Components Analysis was carried out on 62 time-series of 30 years (1960-1990), including mean monthly temperature (minimum and maximum) and rainfall. The results highlighted two principal directions of climatic variability that were interpolated by the co-kriging method, allowing to delineate 11 relatively homogeneous areas in the Veneto Region. One station representative of each area was chosen to provide daily data for computing the daily fire danger index by the Regional Rating Service; (b) automation of the FWI system. A SAS v.9.1® application runs the calculations and generates a regional map of daily fire danger for the Forest Service personnel. Graphics and tabular data are also available via intranet.

Regeneration structures and spatial patterns of European larch (Larix decidua Miller), Swiss stone pine (Pinus cembra L.) and Norway spruce (Picea abies (L.) Karst.), were analyzed in three high elevation LTER area in the Dolomites (North-Eastern Alps). Larch and spruce regeneration is mainly affected by dense forest cover and grasses competition whereas stone pine is mostly sensitive to late snow melting, fungal diseases and wild ungulate damages. The current stand and regeneration structure suggests that larch has been highly fostered in the past due to silvo-pastoral management practices. All species show a clear tendency to spatial intraspecific aggregation especially at short-distances. The spatial patterns of larch regeneration are more complex than the other two species, more heavily affected by a main factor such as the nutcracker (Nucifraga caryocatactes L.) seed dispersal for stone pine or presence of canopy gaps for spruce. However, spatial patterns of all species depend on the number of the available microsites, that often match at small distance driving the formation of small mixed and unevenaged patches. Combining the age structure and spatial pattern information we were able to better understand the small-scale patterns and processes and the role of the past disturbances on the regeneration dynamics in space and time.

Abstract: The response of forest growth to climate variability varies along environmental gradients. A growth increase and decrease with warming is usually observed in cold‐humid and warm‐dry regions, respectively. However, it remains poorly known where the sign of these temperature effects switches. Here we introduce a newly developed European tree ring network that has been specifically collected to reconstruct forest aboveground biomass increment (ABI). We quantify, how the long‐term (1910–2009) interannual variability of ABI depends on local mean May–August temperature and test, if a dynamic global vegetation model ensemble reflects the resulting patterns. We find that sites at 8 °C mean May–August temperature increase ABI on average by 5.7 ± 1.3%, whereas sites at 20 °C decrease ABI by 3.0 ± 1.8% m−2 year−1 Δ°C−1. A threshold temperature between beneficial and detrimental effects of warming and the associated increase in water demand on tree growth emerged at 15.9 ± 1.4 °C mean May–August temperature. Because interannual variability increases proportionally with mean growth rate—that is, the coefficient of variation stays constant—we were able to validate these findings with a much larger tree ring data set that had been established following classic dendrochronological sampling schemes. While the observed climate sensitivity pattern is well reflected in the dynamic global vegetation model ensemble, there is a large spread of threshold temperatures between the individual models. Also, individual models disagree strongly on the magnitude of climate impact at the coldest and warmest locations, suggesting where model improvement is most needed to more accurately predict forest growth and effectively guide silvicultural practices. [ABSTRACT FROM AUTHOR]

Relationships between reproductive strategies and population spatial structure have often been suggested for lichens, but there is a lack of supporting aerobiological data. For the first time, this study couples aerobiological investigations on meiospore dispersal by Caloplaca crenulatella (Nyl.) H. Olivier and Rhizocarpon geographicum (L.) DC. with analysis of local spatial patterns of thalli of both species. During a two-year monitoring period carried out on the walls of a medieval castle in NW Italy, a total of 169 polar diblastic spores, 20% of which were morphologically attributable to C. crenulatella, was detected in the mycoareosol, while muriform spores of R. geographicum were never found. Laboratory experiments confirmed that different dispersal patterns characterize the two species, the meiospores of R. geographicum being poorly discharged and only recovered at a short distance from thalli, whereas those of C. crenulatella were more abundantly discharged, suspended and better dispersed by a moderate air flow. This difference was reflected on the castle walls by the random spatial pattern of C. crenulatella, while R. geographicum showed a clustered distribution. Different discharge rates and take-off limitations, possibly related to size differences between the spores, are not sufficient to explain the different colonization patterns and dynamics of the two species. Additional intrinsic and extrinsic factors are likely to drive their dispersal and establishment success. Nevertheless, information on the relationships between different dispersal patterns of the species and the local spatial structure of their populations might help to predict the recovery potential of lichen species exposed to habitat loss or disturbance, or encrusting monument surfaces. [ABSTRACT FROM AUTHOR]

Highlights: [•] We analysed fir, spruce and beech growth response to climate in a mesic forest. [•] Over 250years, species response to inter-annual climate variability has changed. [•] Decadal summer temperature variations mainly affected spruce growth trends. [•] Climate differently affected species radial growth in a mixed forest. [ABSTRACT FROM AUTHOR]

Climate warming is altering snowpack permanence in alpine tundra, modifying shrub growth and distribution. Plant acclimation to snowpack changes depends on the capability to guarantee growth and carbon storage, suggesting that the content of non-structural carbohydrates (NSC) in plant organs can be a key trait to depict the plant response under different snow regimes. To test this hypothesis, we designed a 3-years long manipulative experiment aimed at evaluating the effect of snow melt timing (i.e., early, control, and late) on NSC content in needles, bark and wood of Juniperus communis L. growing at high elevation in the Alps. Starch evidenced a general decrease from late spring to summer in control and early melting, while starch was low but stable in plants subjected to a late snow melt. Leaves, bark and wood have different level of soluble NSC changing during growing season: in bark, sugars content decreased significantly in late summer, while there was no seasonal effect in needles and wood. Soluble NSC and starch were differently related with the plant growth, when considering different tissues and snow treatment. In leaf and bark we observed a starch depletion in control and early melting plants, consistently to a higher growth (i.e., twig elongation), while in late snow melt, we did not find any significant relationship between growth and NSC concentration. Our findings confirmed that snowpack duration affects the onset of the growing season promoting a change in carbon allocation in plant organs and, between bark and wood in twigs. Finally, our results suggest that plants, at this elevation, could take advantage from an early snow melt caused by climate warming, most likely due to photosynthetic activity by maintaining the level of reserves and enhancing the carbon investment for growth., Competing Interests: Declaration of competing interest 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 © 2024. Published by Elsevier B.V.)

Background/aims: Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression., Methods: We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo., Results: Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice., Conclusions: KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

Objective: We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs., Method: We first induced lupus-like disease in T cell specific Rictor , a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti- Rictor antisense oligonucleotide ( Rictor -ASO) in a mouse model of lupus: MRL/ lpr mice. Finally, we examined the beneficial effects of RICTOR -ASO on SLE patients' PBMCs using an in vitro T-B cell coculture assay., Results: T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4 + T cells accompanied by restored CD4 + T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor -ASO treatment improves renal function and pathology in MRL/ lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR- ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05)., Conclusion: Targeting mTORC2 could be a promising therapeutic for SLE., Competing Interests: Conflict of interest MC and PJ are paid employees of Ionis Pharmaceuticals. Competing interests: Michele Carrer and Paymaan Jafar-nejad are paid employees of Ionis Pharmaceuticals.

We report a case of Klebsiella pneumoniae bacteraemia in an 80-year-old man in France with no history of travel to Asia, complicated by endogenous endophthalmitis, multiple cerebral microbleeds and hepatic microabscesses, associated with a Bentall endocarditis. Hypervirulence pathotype was suggested based on clinical picture, bacterial isolate genomic sequence and hypermucoidy. Interestingly, the isolate had the non-K1/K2-capsular serotype locus KL113-like, carried a KpVP-1-like virulence plasmid, and belonged to the emerging sublineage SL660 (comprising the sequence type ST660)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We develop ∂-HylleraasMD (∂-HyMD), a fully end-to-end differentiable molecular dynamics software based on the Hamiltonian hybrid particle-field formalism, and use it to establish a protocol for automated optimization of force field parameters. ∂-HyMD is templated on the recently released HylleraaasMD software, while using the JAX autodiff framework as the main engine for the differentiable dynamics. ∂-HyMD exploits an embarrassingly parallel optimization algorithm by spawning independent simulations, whose trajectories are simultaneously processed by reverse mode automatic differentiation to calculate the gradient of the loss function, which is in turn used for iterative optimization of the force-field parameters. We show that parallel organization facilitates the convergence of the minimization procedure, avoiding the known memory and numerical stability issues of differentiable molecular dynamics approaches. We showcase the effectiveness of our implementation by producing a library of force field parameters for standard phospholipids, with either zwitterionic or anionic heads and with saturated or unsaturated tails. Compared to the all-atom reference, the force field obtained by ∂-HyMD yields better density profiles than the parameters derived from previously utilized gradient-free optimization procedures. Moreover, ∂-HyMD models can predict with good accuracy properties not included in the learning objective, such as lateral pressure profiles, and are transferable to other systems, including triglycerides.

Climate change impacts on forest trees will be particularly severe for relict species endemic to the subalpine forest, such as Pinus cembra in the Alps and Carpathians. Most current knowledge about the response of this species to climate comes from tree-ring width analysis. However, this approach cannot perform in-depth and highly time-resolved analysis on the climate influence on specific growth processes and xylem functions. We analyzed xylem anatomical traits from six sites covering most of the longitudinal range of this species. Associations between climate and cell number, lumen area and cell wall thickness were computed for the 1920-2010 period using climate records aligned to degree-day temperature sum thresholds. The anatomical chronologies were clearly distinct between the Alps and Carpathians. However, climate responses were similar for all sites, suggesting common species-specific response mechanisms. Temperature showed a positive correlation with both cell number and cell wall thickness. Cell lumen size exhibited an early positive association, followed by strong negative association with temperature and a positive one with precipitation. This highlights that the cell enlargement process was negatively related to high temperature at high elevation, where meristematic processes are rather supposed to be constrained by low temperatures. Therefore, long-term climate warming can have negative consequences on the xylem potential to transport water at all investigated sites. Moreover, in the last 30 years, we observed a slight anticipation of some responses and a decrease in climate sensitivity of some xylem parameters. Our findings provide evidence of temporally unstable but spatially consistent climate response of Pinus cembra from the Alps to the Carpathians. The low diversity in xylem phenotypic responses to climate suggests that future warming could extensively and evenly affect the species throughout its entire distribution., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. A mouse model (Notch3 em1Ecan ) harboring a 6691-TAATGA mutation in the Notch3 locus that results in a functional outcome analogous to LMS exhibits cancellous and cortical bone osteopenia. We tested Notch3 antisense oligonucleotides (ASOs) specific to the Notch3 6691-TAATGA mutation for their effects on Notch3 downregulation and on the osteopenia of Notch3 em1Ecan mice. Twenty-four mouse Notch3 mutant ASOs were designed and tested for toxic effects in vivo, and 12 safe ASOs were tested for their impact on the downregulation of Notch3 6691- TA ATGA and Notch3 mRNA in osteoblast cultures from Notch3 em1Ecan mice. Three ASOs downregulated Notch3 mutant transcripts specifically and were tested in vivo for their effects on the bone microarchitecture of Notch3 em1Ecan mice. All three ASOs were well tolerated. One of these ASOs had more consistent effects in vivo and was studied in detail. The Notch3 mutant ASO downregulated Notch3 mutant transcripts in osteoblasts and bone marrow stromal cells and had no effect on other Notch receptors. The subcutaneous administration of Notch3 mutant ASO at 50 mg/Kg decreased Notch3 6691-TAATGA mRNA in bone without apparent toxicity; microcomputed tomography demonstrated that the ASO ameliorated the cortical osteopenia of Notch3 em1Ecan mice but not the cancellous bone osteopenia. In conclusion, a Notch3 ASO that downregulates Notch3 mutant expression specifically ameliorates the cortical osteopenia in Notch3 em1Ecan mice. ASOs may become useful strategies in the management of monogenic disorders affecting the skeleton., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest with the contents of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Forests are threatened by increasingly severe and more frequent drought events worldwide. Mono-specific forests, developed as a consequence of widespread management practices established early last century, seem particularly susceptible to global warming and drought compared with mixed-species forests. Although, in several contexts, mixed-species forests display higher species diversity, higher productivity, and higher resilience, previous studies highlighted contrasting findings, with not only many positive but also neutral or negative effects on tree performance that could be related to tree species diversity. Processes underlying this relationship need to be investigated. Wood anatomical traits are informative proxies of tree functioning, and they can potentially provide novel long-term insights in this regard. However, wood anatomical traits are critically understudied in such a context. Here, we assess the role of tree admixture on Pinus sylvestris L. xylem traits such as mean hydraulic diameter, cell wall thickness, and anatomical wood density, and we test the variability of these traits in response to climatic parameters such as temperature, precipitation, and drought event frequency and intensity., Methods: Three monocultural plots of P. sylvestris and three mixed-stand plots of P. sylvestris and Quercus sp. were identified in Poland and Spain, representing Continental and Mediterranean climate types, respectively. In each plot, we analyzed xylem traits from three P. sylvestris trees, for a total of nine trees in monocultures and nine in mixed stands per study location., Results: The results highlighted that anatomical wood density was one of the most sensitive traits to detect tree responses to climatic conditions and drought under different climate and forest types. Inter-specific facilitation mechanisms were detected in the admixture between P. sylvestris and Quercus sp., especially during the early growing season and during stressful events such as spring droughts, although they had negligible effects in the late growing season., Discussion: Our findings suggest that the admixture between P. sylvestris and Quercus sp. increases the resilience of P. sylvestris to extreme droughts. In a global warming scenario, this admixture could represent a useful adaptive management option., 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 Giberti, von Arx, Giovannelli, du Toit, Unterholzner, Bielak, Carrer, Uhl, Bravo, Tonon and Wellstein.)

Current global change is inducing heterogeneous warming trends worldwide, with faster rates at higher latitudes in the Northern Hemisphere. Consequently, tundra vegetation is experiencing an increase in growth rate and uneven but expanding distribution. Yet, the drivers of this heterogeneity in woody species responses are still unclear. Here, applying a retrospective approach and focusing on long-term responses, we aim to get insight into growth trends and climate sensitivity of long-lived woody species belonging to different functional types with contrasting growth forms and leaf habits (shrub vs. tree and deciduous vs. evergreen). A total of 530 samples from 7 species (common juniper, dwarf birch, woolly willow, Norway spruce, lodgepole pine, rowan, and downy birch) were collected in 10 sites across Iceland. We modelled growth trends and contrasted yearly ring-width measurements, filtering in high- and low-frequency components, with precipitation, land- and sea-surface temperature records (1967-2018). Shrubs and trees showed divergent growth trends, with shrubs closely tracking the recent warming, whereas trees, especially broadleaved, showed strong fluctuations but no long-term growth trends. Secondary growth, particularly the high-frequency component, was positively correlated with summer temperatures for most of the species. On the contrary, growth responses to sea surface temperature, especially in the low frequency, were highly diverging between growth forms, with a strong positive association for shrubs and a negative for trees. Within comparable vegetation assemblage, long-lived woody species could show contrasting responses to similar climatic conditions. Given the predominant role of oceanic masses in shaping climate patterns in the Arctic and Low Arctic, further investigations are needed to deepen the knowledge on the complex interplay between coastal tundra ecosystems and land-sea surface temperature dynamics., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

The size-related xylem adjustments required to maintain a constant leaf-specific sapwood conductance (KLEAF) with increasing height (H) are still under discussion. Alternative hypotheses are that: (i) the conduit hydraulic diameter (Dh) at any position in the stem and/or (ii) the number of sapwood rings at stem base (NSWr) increase with H. In addition, (iii) reduced stem elongation (ΔH) increases the tip-to-base conductance through inner xylem rings, thus possibly the NSWr contributing to KLEAF. A detailed stem analysis showed that Dh increased with the distance from the ring apex (DCA) in all rings of a Picea abies and a Fagus sylvatica tree. Net of DCA effect, Dh did not increase with H. Using sapwood traits from a global dataset, NSWr increased with H, decreased with ΔH, and the mean sapwood ring width (SWrw) increased with ΔH. A numerical model based on anatomical patterns predicted the effects of H and ΔH on the conductance of inner xylem rings. Our results suggest that the sapwood/heartwood transition depends on both H and ΔH, and is set when the carbon allocation to maintenance respiration of living cells in inner sapwood rings produces a lower gain in total conductance than investing the same carbon in new vascular conduits., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We report a physicochemical investigation of the lipid transport properties of model lipid membranes in the presence of the antimicrobial peptide indolicidin through comparisons of experimental SANS/SAXS scattering techniques to fully atomistic molecular dynamics simulations. In agreement with the experiment, we show that upon peripheral binding of the peptides, even at low concentrations, lipid flip-flop dynamics is greatly accelerated. Computer modeling elucidates the interplay between structural changes and lipid dynamics induced by peptides and proposes a mechanism for the mode of action of antimicrobial peptides, assessing the major role of entropy for the catalysis of the flipping events. The mechanism introduced here is universal for all peptides with preferential peripheral binding to the membrane as it does not depend on the specific amino acid sequence.

Earth system models and various climate proxy sources indicate global warming is unprecedented during at least the Common Era 1 . However, tree-ring proxies often estimate temperatures during the Medieval Climate Anomaly (950-1250 CE) that are similar to, or exceed, those recorded for the past century 2,3 , in contrast to simulation experiments at regional scales 4 . This not only calls into question the reliability of models and proxies but also contributes to uncertainty in future climate projections 5 . Here we show that the current climate of the Fennoscandian Peninsula is substantially warmer than that of the medieval period. This highlights the dominant role of anthropogenic forcing in climate warming even at the regional scale, thereby reconciling inconsistencies between reconstructions and model simulations. We used an annually resolved 1,170-year-long tree-ring record that relies exclusively on tracheid anatomical measurements from Pinus sylvestris trees, providing high-fidelity measurements of instrumental temperature variability during the warm season. We therefore call for the construction of more such millennia-long records to further improve our understanding and reduce uncertainties around historical and future climate change at inter-regional and eventually global scales., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Aurora B, together with IN-box, the C-terminal part of INCENP, forms an enzymatic complex that ensures faithful cell division. The [Aurora B/IN-box] complex is activated by autophosphorylation in the Aurora B activation loop and in IN-box, but it is not clear how these phosphorylations activate the enzyme. We used a combination of experimental and computational studies to investigate the effects of phosphorylation on the molecular dynamics and structure of [Aurora B/IN-box]. In addition, we generated partially phosphorylated intermediates to analyze the contribution of each phosphorylation independently. We found that the dynamics of Aurora and IN-box are interconnected, and IN-box plays both positive and negative regulatory roles depending on the phosphorylation status of the enzyme complex. Phosphorylation in the activation loop of Aurora B occurs intramolecularly and prepares the enzyme complex for activation, but two phosphorylated sites are synergistically responsible for full enzyme activity., Competing Interests: DS, OH, HG, JD, SH, MC, BB, MC, NS No competing interests declared, (© 2023, Segura-Peña et al.)

We present HylleraasMD (HyMD), a comprehensive implementation of the recently proposed Hamiltonian formulation of hybrid particle-field molecular dynamics. The methodology is based on a tunable, grid-independent length-scale of coarse graining, obtained by filtering particle densities in reciprocal space. This enables systematic convergence of energies and forces by grid refinement, also eliminating nonphysical force aliasing. Separating the time integration of fast modes associated with internal molecular motion from slow modes associated with their density fields, we enable the first time-reversible, energy-conserving hybrid particle-field simulations. HyMD comprises the optional use of explicit electrostatics, which, in this formalism, corresponds to the long-range potential in particle-mesh Ewald. We demonstrate the ability of HyMD to perform simulations in the microcanonical and canonical ensembles with a series of test cases, comprising lipid bilayers and vesicles, surfactant micelles, and polypeptide chains, comparing our results to established literature. An on-the-fly increase of the characteristic coarse-grain length significantly speeds up dynamics, accelerating self-diffusion and leading to expedited aggregation. Exploiting this acceleration, we find that the time scales involved in the self-assembly of polymeric structures can lie in the tens to hundreds of picoseconds instead of the multimicrosecond regime observed with comparable coarse-grained models.

Background: Determining the etiology of aortitis is often challenging, in particular to distinguish infectious aortitis (IA) and noninfectious aortitis (NIA). This study aims to describe and compare the clinical, biological, and radiological characteristics of IA and NIA and their outcomes., Methods: A multicenter retrospective study was performed in 10 French centers, including patients with aortitis between 1 January 2014 and 31 December 2019., Results: One hundred eighty-three patients were included. Of these, 66 had IA (36.1%); the causative organism was Enterobacterales and streptococci in 18.2% each, Staphylococcus aureus in 13.6%, and Coxiella burnetii in 10.6%. NIA was diagnosed in 117 patients (63.9%), mainly due to vasculitides (49.6%), followed by idiopathic aortitis (39.3%). IA was more frequently associated with aortic aneurysms compared with NIA (78.8% vs 17.6%, P < .001), especially located in the abdominal aorta (69.7% vs 23.1%, P < .001). Crude and adjusted survival were significantly lower in IA compared to NIA (P < .001 and P = .006, respectively). In the IA cohort, high American Society of Anesthesiologists score (hazard ratio [HR], 2.47 [95% confidence interval {CI}, 1.08-5.66]; P = .033) and free aneurysm rupture (HR, 9.54 [95% CI, 1.04-87.11]; P = .046) were significantly associated with mortality after adjusting for age, sex, and Charlson comorbidity score. Effective empiric antimicrobial therapy, initiated before any microbial documentation, was associated with a decreased mortality (HR, 0.23, 95% CI, .08-.71]; P = .01)., Conclusions: IA was complicated by significantly higher mortality rates compared with NIA. An appropriate initial antibiotic therapy appeared as a protective factor in IA., Competing Interests: Potential conflicts of interest. P. R. reports payment or honoraria from Celgene, Novartis, and AdLiva and support for attending meetings and/or travel from Janssen-Cilag, Amgen, Roche, Takeda, Mylan, and Celgene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Unlike typical chorismate mutases, the enzyme from Mycobacterium tuberculosis (MtCM) has only low activity on its own. Remarkably, its catalytic efficiency k cat / K m can be boosted more than 100-fold by complex formation with a partner enzyme. Recently, an autonomously fully active MtCM variant was generated using directed evolution, and its structure was solved by X-ray crystallography. However, key residues were involved in crystal contacts, challenging the functional interpretation of the structural changes. Here, we address these challenges by microsecond molecular dynamics simulations, followed up by additional kinetic and structural analyses of selected sets of specifically engineered enzyme variants. A comparison of wild-type MtCM with naturally and artificially activated MtCMs revealed the overall dynamic profiles of these enzymes as well as key interactions between the C-terminus and the active site loop. In the artificially evolved variant of this model enzyme, this loop is preorganized and stabilized by Pro52 and Asp55, two highly conserved residues in typical, highly active chorismate mutases. Asp55 stretches across the active site and helps to appropriately position active site residues Arg18 and Arg46 for catalysis. The role of Asp55 can be taken over by another acidic residue, if introduced at position 88 close to the C-terminus of MtCM, as suggested by molecular dynamics simulations and confirmed by kinetic investigations of engineered variants.

Extreme climate events such as late spring frosts (LSFs) negatively affect productivity and tree growth in temperate beech forests. However, detailed information on how these forests recover after such events are still missing. We investigated how LSFs affected forest cover and radial growth in European beech (Fagus sylvatica L.) populations located at different elevations at four sites in the Italian Apennines, where LSFs have been recorded. We combined tree-ring and remote-sensing data to analyse the sensitivity and recovery capacity of beech populations to LSFs. Using daily temperature records, we reconstructed LSF events and assessed legacy effects on growth. We also evaluated the role played by elevation and stand structure as modulators of LSFs impacts. Finally, using satellite images we computed Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI) and LAI (Leaf Area Index) to evaluate the post-LSF canopy recovery. The growth reduction in LSF-affected trees ranged from 36 % to 84 %. We detected a negative impact of LSF on growth only during the LSF year, with growth recovery occurring within 1-2 years after the event. LSF-affected stands featured low vegetation indices until late June, i.e. on average 75 days after the frost events. We did not find a clear relationship between beech forest elevation and occurrence of LSFs defoliations. Our results indicate a high recovery capacity of common beech and no legacy effects of LSFs., 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 © 2022 Elsevier B.V. All rights reserved.)

The identification of regulatory challenges for nanotechnology-enabled health products, followed by discussions with the involved stakeholders, is the first step towards a strategic planning of how such challenges can be successfully addressed in the future. In order to better understand whether the identified regulatory needs are sector-specific for health products or might also hinder the progress in other domains, the REFINE consortium reached out to communities representing other sectors that also exploit the potential of nanotechnology, i.e. industrial chemicals, food and cosmetics. Through a series of trans-sectorial workshops, REFINE partners identified common as well as sector-specific challenges and discussed possible ways forward. Potential solutions lie in a more strengthen collaboration between regulatory and research communities resulting in a targeted production and exploitation of academic data for the regulatory decision-making. Furthermore, a coordinated use of knowledge sharing platforms and databases, trans-sectorial standardisation activities and harmonisation of regulatory activities between geographical regions are possible ways forward, in line with the upcoming European political initiatives such as the Chemical Strategy for Sustainability (CSS). Finally, we also discuss the perspectives for further development and sustainability of methods and tools developed in the REFINE project., (© 2022. The Author(s).)

High-elevation ecosystems are one of the most sensitive to climate change. The analysis of growth and xylem structure of trees from marginal populations, especially the ones growing at the treeline, could provide early-warning signs to better understand species-specific responses to future climate conditions. In this study, we combined classical dendrochronology with wood density and anatomical measurements to investigate the climate sensitivity of Pinus cembra L., a typical European high-elevation tree species distributed in isolated patches in the Carpathians. Samples were collected from the Retezat Mountains, South-Western Romania. We analyzed ring width (TRW), maximum density (MXD), xylem anatomical traits [cell number per ring (CNo), cell density (CD), conduit area (CA), and cell wall thickness (CWT)] time series, split into ring sectors and assessed the relationships with monthly and daily climate records over the last century (1901-2015). The analysis showed a strong dependency of TRW on CNo and MXD on CWT. Summer temperature positively correlated with MXD and CWT [monthly correlation ( r) were 0.65 and 0.48 respectively] from the early to late wood but not TRW ( r = 0.22). CA positively correlated with water availability ( r = 0.37) and negatively correlated with temperature ( r = -0.39). This study improves our general understanding of the climate-growth relationships of a European high-elevation tree species and the results could be considered for forecasting population dynamics on projected changes in climate., 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 © 2022 Știrbu, Roibu, Carrer, Mursa, Unterholzner and Prendin.)

Notch receptors are determinants of cell fate and function, and play an important role in the regulation of bone development and skeletal remodeling. Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. LMS presents with neurological developmental abnormalities and bone loss. We created a mouse model (Notch3em1Ecan) harboring a 6691TAATGA mutation in the Notch3 locus, and heterozygous Notch3em1Ecan mice exhibit cancellous and cortical bone osteopenia. In the present work, we explored whether Notch3 antisense oligonucleotides (ASO) downregulate Notch3 and have the potential to ameliorate the osteopenia of Notch3em1Ecan mice. Notch3 ASOs decreased the expression of Notch3 wild type and Notch36691-TAATGA mutant mRNA expressed by Notch3em1Ecan mice in osteoblast cultures without evidence of cellular toxicity. The effect was specific since ASOs did not downregulate Notch1, Notch2 or Notch4. The expression of Notch3 wild type and Notch36691-TAATGA mutant transcripts also was decreased in bone marrow stromal cells and osteocytes following exposure to Notch3 ASOs. In vivo, the subcutaneous administration of Notch3 ASOs at 25 to 50 mg/Kg decreased Notch3 mRNA in the liver, heart and bone. Microcomputed tomography demonstrated that the administration of Notch3 ASOs ameliorates the cortical osteopenia of Notch3em1Ecan mice, and ASOs decreased femoral cortical porosity and increased cortical thickness and bone volume. However, the administration of Notch3 ASOs did not ameliorate the cancellous bone osteopenia of Notchem1Ecan mice. In conclusion, Notch3 ASOs downregulate Notch3 expression in skeletal cells and their systemic administration ameliorates cortical osteopenia in Notch3em1Ecan mice; as such ASOs may become useful strategies in the management of skeletal diseases affected by Notch gain-of-function., Competing Interests: The authors have declared that no competing interests exist.

With the recent climate warming, tundra ecotones are facing a progressive acceleration of spring snowpack melting and extension of the growing season, with evident consequences to vegetation. Along with summer temperature, winter precipitation has been recently recognised as a crucial factor for tundra shrub growth and physiology. However, gaps of knowledge still exist on long-living plant responses to different snowpack duration, especially on how intra-specific and year-to-year variability together with multiple functional trait adjustments could influence the long-term responses. To fill this gap, we conducted a 3 years snow manipulation experiment above the Alpine treeline on the typical tundra species Juniperus communis , the conifer with the widest distributional range in the north emisphere. We tested shoot elongation, leaf area, stomatal density, leaf dry weight and leaf non-structural carbohydrate content of plants subjected to anticipated, natural and postponed snowpack duration. Anticipated snowpack melting enhanced new shoot elongation and increased stomatal density. However, plants under prolonged snow cover seemed to compensate for the shorter growing period, likely increasing carbon allocation to growth. In fact, these latter showed larger needles and low starch content at the beginning of the growing season. Variability between treatments slightly decreased over time, suggesting a progressive acclimation of juniper to new conditions. In the context of future warming scenarios, our results support the hypothesis of shrub biomass increase within the tundra biome. Yet, the picture is still far from being complete and further research should focus on transient and fading effects of changing conditions in the long term., 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 © 2022 Unterholzner, Prendin, Dibona, Menardi, Casolo, Gargiulo, Boscutti and Carrer.)

Objective: The purpose of the present study was to evaluate the survival and freedom from reinfection for patients with infected native aortic aneurysms (INAAs) treated with in situ revascularization (ISR), using either open surgical repair (OSR) or endovascular aneurysm repair (EVAR), and to identify the predictors of outcome., Methods: Patients with INAAs who had undergone ISR from January 2005 to December 2020 were included in the present retrospective single-center study. The diagnosis of INAAs required a combination of two or more of the following criteria: (1) clinical presentation, (2) laboratory results, (3) imaging findings, and (4) intraoperative findings. The primary endpoint was 30-day mortality. The secondary endpoints were in-hospital mortality, estimated survival, patency, and freedom from reinfection using the Kaplan-Meier method. The predictive factors for adverse outcomes were evaluated using the Mann-Whitney U test or the Fisher exact test and multivariate regression analysis., Results: A total of 65 patients (53 men [81.5%]; median age, 69.0 years; interquartile range, 61.5-75.0 years) were included, 31 (47.7%) were immunocompromised, 60 were symptomatic (92.3%), and 32 (49.2%) had presented with rupture, including 3 aortocaval fistulas (4.6%) and 12 aortoenteric fistulas (18.5%). The most common location was infrarenal (n = 39; 60.0%). Of the 65 patients, 55 (84.6%) had undergone primary OSR with ISR, 3 (4.6%) had required EVAR as a bridge to OSR, and 8 (12.3%) had undergone EVAR as definitive treatment. The approach was a midline laparotomy for 44 patients (67.7%), mostly followed by reconstruction and aortic-aortic bypass (n = 28; 40.6%) and the use of a silver and triclosan Dacron graft (n = 30; 43.5%). Causative organisms were identified in 55 patients (84.6%). The 30-day and in-hospital mortality rates were 6.2% (n = 4) and 10.8% (n = 7). The median follow-up was 33.5 months (interquartile range, 13.6-62.3 months). The estimated 1- and 5-year survival rates were 79.7% (95% confidence interval [CI], 67.6%-87.7%) and 67.4% (95% CI, 51.2%-79.3%). The corresponding freedom from reinfection rates were 92.5% (95% CI, 81.1%-97.1%) and 79.4% (95% CI, 59.1%-90.3%). On multivariate analysis, in-hospital mortality increased with uncontrolled sepsis (P < .0001), rapidly expanding aneurysms (P = .008), and fusiform aneurysms (P = .03). The incidence of reinfection increased with longer operating times (P = .009)., Conclusions: The selective use of ISR and OSR combined with targeted antimicrobial therapy functioned reasonably well in the treatment of INAAs, although larger, prospective, multicenter studies with appropriately powered comparative cohorts are necessary to confirm our findings and to determine the best vascular substitute and precise role of EVAR as a bridge to OSR or definitive treatment., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The combined effects of climate change and nutrient availability on Arctic vegetation growth are poorly understood. Archaeological sites in the Arctic could represent unique nutrient hotspots for studying the long-term effect of nutrient enrichment. In this study, we analysed a time-series of ring widths of Salix glauca L. collected at nine archaeological sites and in their natural surroundings along a climate gradient in the Nuuk fjord region, Southwest Greenland, stretching from the edge of the Greenlandic Ice Sheet in the east to the open sea in the west. We assessed the temperature-growth relationship for the last four decades distinguishing between soils with past anthropogenic nutrient enrichment (PANE) and without (controls). Along the East-West gradient, the inner fjord sites showed a stronger temperature signal compared to the outermost ones. Individuals growing in PANE soils had wider ring widths than individuals growing in the control soils and a stronger climate-growth relation, especially in the inner fjord sites. Thereby, the individuals growing on the archaeological sites seem to have benefited more from the climate warming in recent decades. Our results suggest that higher nutrient availability due to past human activities plays a role in Arctic vegetation growth and should be considered when assessing both the future impact of plants on archaeological sites and the general greening in landscapes with contrasting nutrient availability., (© 2022. The Author(s).)

In 2010-2018, Northern Patagonia featured the longest severe drought of the last millennium. This extreme dry spell triggered widespread growth decline and forest dieback. Nonetheless, the roles played by the two major mechanisms driving dieback, hydraulic failure and carbon starvation, are still not clear and understudied in this seasonally dry region. Here, for the 1800-2017 period, we apply a retrospective analysis of radial growth, wood anatomical traits (lumen area, cell-wall thickness) and δ 13 C and δ 18 O stable isotopes to assess dieback causes of the iconic conifer Araucaria araucana. We selected three stands where declining (defoliated) and nondeclining (not defoliated) trees coexisted along a precipitation gradient from the warm-dry Coastal Range to the cool-wet Andes. At all sites declining trees showed lower radial growth and lower theoretical hydraulic conductivity, suggesting a long-lasting process of hydraulic deterioration in their water transport system compared to nondeclining, coexisting trees. Wood anatomical traits evidenced that this divergence between declining and nondeclining trees started at least seven decades before canopy dieback. In the drier stands, declining trees showed higher water-use efficiency (WUE) throughout the whole period, which we attributed to early stomatal closure, suggesting a greater carbon starvation risk consistent with thinner cell walls. In the wettest stand, we found the opposite pattern. Here, a reduction in WUE coupled with thicker cell walls suggested increased carbon assimilation rates and exposure to drought-induced hydraulic failure. The δ 18 O values indicated different strategies of gas exchange between sites, which are likely a consequence of microsite conditions and water sources. Multiproxy, retrospective quantifications of xylem anatomical traits and tree-ring isotopes provide a robust tool to identify and forecast, which stands or trees will show dieback or, on the contrary, which will likely withstand and be more resilient to future hotter droughts., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)-induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 ( JAG1 ) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1 -directed antisense oligonucleotide (ASO) and a hepatocyte-specific N -acetylgalactosamine (GalNAc)-modified siRNA, both of which reduced NASH diet-induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Climate warming is expected to positively alter upward and poleward treelines which are controlled by low temperature and a short growing season. Despite the importance of treelines as a bioassay of climate change, a global field assessment and posterior forecasting of tree growth at annual scales is lacking. Using annually resolved tree-ring data located across Eurasia and the Americas, we quantified and modeled the relationship between temperature and radial growth at treeline during the 20th century. We then tested whether this temperature-growth association will remain stable during the 21st century using a forward model under two climate scenarios (RCP 4.5 and 8.5). During the 20th century, growth enhancements were common in most sites, and temperature and growth showed positive trends. Interestingly, the relationship between temperature and growth trends was contingent on tree age suggesting biogeographic patterns in treeline growth are contingent on local factors besides climate warming. Simulations forecast temperature-growth decoupling during the 21st century. The growing season at treeline is projected to lengthen and growth rates would increase and become less dependent on temperature rise. These forecasts illustrate how growth may decouple from climate warming in cold regions and near the margins of tree existence. Such projected temperature-growth decoupling could impact ecosystem processes in mountain and polar biomes, with feedbacks on climate warming., (© 2021 John Wiley & Sons Ltd.)

Insect defoliations are a major natural disturbance in high-latitude ecosystems and are expected to increase in frequency and severity due to current climatic change. Defoliations cause severe reductions in biomass and carbon investments that affect the functioning and productivity of tundra ecosystems. Here we combined dendro-anatomical analysis with chemical imaging to investigate the direct and lagged effects of insect outbreaks on carbon investment. We analysed the content of lignin vs. holocellulose, i.e. unspecified carbohydrates in xylem samples of Salix glauca L. collected at Iffiartarfik, Nuuk fjord, Greenland, featuring two outbreak events of the moth Eurois occulta L. Cross sections of the growth rings corresponding to both outbreaks ±3 years were analysed using confocal Raman imaging to identify possible chemical signatures related to insect defoliation on fibres, vessels, and ray parenchyma cells and to get insight into species-specific defence responses. Outbreak years with narrower rings and thinner fibre cell walls are accompanied by a change in the content of cell-wall polymers but not their underlying chemistry. Indeed, during the outbreaks the ratio between lignin and carbohydrates significantly increased in fibre but not vessel cell walls due to an increase in lignin content coupled with a reduced content of carbohydrates. Parenchyma cell walls and cell corners did not show any significant changes in the cell-wall biopolymer content. The selective adjustment of the cell-wall composition of fibres but not vessels under stressful conditions could be related to the plants priority to maintain an efficient hydraulic system rather than mechanical support. However, the higher lignin content of fibre cell walls formed during the outbreak events could increase mechanical stiffness to the thin walls by optimizing the available resources. Chemical analysis of xylem traits with Raman imaging is a promising approach to highlight hidden effects of defoliation otherwise overlooked with classical dendroecological methods., 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 © 2020 Elsevier B.V. All rights reserved.)

We report 5 cases of vascular Q fever complicated by polymicrobial superinfection in patients who had no risk factors for acute Q fever. Q fever was diagnosed by serologic and molecular assays for Coxiella burnetii. We confirmed additional infections using conventional graft cultures.

The performance and distribution of woody species strongly depend on their adjustment to environmental conditions based on genotypic and phenotypic properties. Since more intense and frequent drought events are expected due to climate change, xylem hydraulic traits will play a key role under future conditions, and thus, knowledge of hydraulic variability is of key importance. In this study, we aimed to investigate the variability in hydraulic safety and efficiency of the conifer shrub Juniperus communis based on analyses along an elevational transect and a common garden approach. We studied (i) juniper plants growing between 700 and 2000 m a.s.l. Innsbruck, Austria, and (ii) plants grown in the Innsbruck botanical garden (Austria) from seeds collected at different sites across Europe (France, Austria, Ireland, Germany and Sweden). Due to contrasting environmental conditions at different elevation and provenance sites and the wide geographical study area, pronounced variation in xylem hydraulics was expected. Vulnerability to drought-induced embolisms (hydraulic safety) was assessed via the Cavitron and ultrasonic acoustic emission techniques, and the specific hydraulic conductivity (hydraulic efficiency) via flow measurements. Contrary to our hypothesis, relevant variability in hydraulic safety and efficiency was neither observed across elevations, indicating a low phenotypic variation, nor between provenances, despite expected genotypic differences. Interestingly, the provenance from the most humid and warmest site (Ireland) and the northernmost provenance (Sweden) showed the highest and the lowest embolism resistance, respectively. The hydraulic conductivity was correlated with plant height, which indicates that observed variation in hydraulic traits was mainly related to morphological differences between plants. We encourage future studies to underlie anatomical traits and the role of hydraulics for the broad ecological amplitude of J. communis., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Using thermodynamic integration, we study the solvation free energy of 18 amino acid side chain equivalents in solvents with different polarities, ranging from the most polar water to the most non-polar cyclohexane. The amino acid side chain equivalents are obtained from the 20 natural amino acids by replacing the backbone part with a hydrogen atom, and discarding proline and glycine that have special properties. A detailed analysis of the relative solvation free energies suggests how it is possible to achieve a robust and unambiguous hydrophobic scale for the amino acids. By discriminating the relative contributions of the entropic and enthalpic terms, we find strong negative correlations in water and ethanol, associated with the well-known entropy-enthalpy compensation, and a much reduced correlation in cyclohexane. This shows that in general the role of the polar and non-polar moieties cannot be reversed in a non-polar solvent. Our findings are compared with past experimental as well as numerical results, and may shed additional light on the unique role of water as a biological solvent.

We investigate the self-assembly process of a surfactant with inverted polarity in water and cyclohexane using both all-atom and coarse-grained hybrid particle-field molecular dynamics simulations. Unlike conventional surfactants, the molecule under study, proposed in a recent experiment, is formed by a rigid and compact hydrophobic adamantane moiety, and a long and floppy triethylene glycol tail. In water, we report the formation of stable inverted micelles with the adamantane heads grouping together into a hydrophobic core and the tails forming hydrogen bonds with water. By contrast, microsecond simulations do not provide evidence of stable micelle formation in cyclohexane. Validating the computational results by comparison with experimental diffusion constant and small-angle X-ray scattering intensity, we show that at laboratory thermodynamic conditions the mixture resides in the supercritical region of the phase diagram, where aggregated and free surfactant states coexist in solution. Our simulations also provide indications as to how to escape this region to produce thermodynamically stable micellar aggregates.

Defoliator insects are a major disturbance agent in many forests worldwide. During outbreaks, they can strongly reduce photosynthetic carbon uptake and impact tree growth. In the Alps, larch budmoth ( Zeiraphera diniana ) outbreaks affect European larch ( Larix decidua ) radial growth over several years. However, immediate and legacy effects on xylem formation, structure, and functionality are still largely unknown. In this study, we aimed at assessing the impact of budmoth defoliations on larch xylem anatomical features and tree-ring structure. Analyses were performed in the Lötschental (Swiss Alps) within (1,900 m a.s.l.) and above (2,200 m a.s.l.) the optimum elevational range of larch budmoth. We investigated variability of xylem anatomical traits along century-long tree-ring series of larch (host) and Norway spruce (non-host) trees. We identified eight outbreaks affecting larch xylem anatomy during the 20 th century, particularly at 1,900 m a.s.l. Tracheid number always showed a higher percent reduction than properties of individual cells. Cell lumen size was slightly reduced in the first 2-3 years of outbreaks, especially in the early part of the ring. The more carbon-demanding cell wall was thinned along the entire ring, but more evidently in the last part. Theoretical tree-ring hydraulic conductivity was reduced for several years (up to 6), mostly due to cell number decrease. Reduced cell wall area and cell number resulted in a strong reduction of the tree-ring biomass, especially in the first year of outbreak. Our study shows that, under carbon source limitations caused by natural defoliation, cell division is more impacted than wall thickening and cell enlargement (the least affected process). Consequences on both xylem hydraulic properties and tree-ring biomass should be considered when assessing long-term defoliator effects on xylem functioning, forest dynamics, and terrestrial carbon cycle., (Copyright © 2020 Castagneri, Prendin, Peters, Carrer, von Arx and Fonti.)

Goblet cell metaplasia, excessive mucus production, and inadequate mucus clearance accompany and exacerbate multiple chronic respiratory disorders, such as asthma and chronic obstructive pulmonary disease. Notch signaling plays a central role in controlling the fate of multiple cell types in the lung, including goblet cells. In the present study, we explored the therapeutic potential of modulating the Notch pathway in the adult murine lung using chemically modified antisense oligonucleotides (ASOs). To this end, we designed and characterized ASOs targeting the Notch receptors Notch1, Notch2, and Notch3 and the Notch ligands Jag1 (Jagged 1) and Jag2 (Jagged 2). Pulmonary delivery of ASOs in healthy mice or mice exposed to house dust mite, a commonly used mouse model of asthma, resulted in a significant reduction of the respective mRNAs in the lung. Furthermore, ASO-mediated knockdown of Jag1 or Notch2 in the lungs of healthy adult mice led to the downregulation of the club cell marker Scgb1a1 and the concomitant upregulation of the ciliated cell marker FoxJ1 (forkhead box J1). Similarly, ASO-mediated knockdown of Jag1 or Notch2 in the house dust mite disease model led to reduced goblet cell metaplasia and decreased mucus production. Because goblet cell metaplasia and excessive mucus secretion are a common basis for many lung pathologies, we propose that ASO-mediated inhibition of JAG1 could provide a novel therapeutic path for the treatment of multiple chronic respiratory diseases.

Drought limits the long-distance transport of water in the xylem due to the reduced leaf-to-soil water potential difference and possible embolism-related losses of conductance and of sugars in the phloem due to the higher viscosity of the dehydrated sugary solution. This condition can have cascading effects in water and carbon (C) fluxes that may ultimately cause tree death. We hypothesize that the maintenance of xylem and phloem conductances is fundamental for survival also under reduced resource availability, when trees may produce effective and low C cost anatomical adjustments in the xylem and phloem close to the treetop where most of the hydraulic resistance is concentrated. We analyzed the treetop xylem and phloem anatomical characteristics in coexisting Scots pine trees, symptomatic and non-symptomatic of drought-induced dieback. We selected the topmost 55 cm of the main stem and selected several sampling positions at different distances from the stem apex to test for differences in the axial patterns between the two groups of trees. We measured the annual ring area, the tracheid hydraulic diameter (Dh) and cell wall thickness (CWT), the conductive phloem area and the average lumen diameter of the 20 largest phloem sieve cells (Dph). Declining trees grew less than the non-declining ones, and despite the similar axial scaling of anatomical traits, had larger Dh and lower CWT. Moreover, declining trees had wider Dph. Our results demonstrate that even under drought stress, maintenance of xylem and phloem efficiencies is of primary importance for survival, even if producing fewer larger tracheids may lead to a xylem more vulnerable to embolism formation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Notch receptors play critical roles in cell-fate decisions and in the regulation of skeletal development and bone remodeling. Gain-of-function NOTCH2 mutations can cause Hajdu-Cheney syndrome, an untreatable disease characterized by osteoporosis and fractures, craniofacial developmental abnormalities, and acro-osteolysis. We have previously created a mouse model harboring a point 6955C→T mutation in the Notch2 locus upstream of the PEST domain, and we termed this model Notch2 tm1.1Ecan Heterozygous Notch2 tm1.1Ecan mutant mice exhibit severe cancellous and cortical bone osteopenia due to increased bone resorption. In this work, we demonstrate that the subcutaneous administration of Notch2 antisense oligonucleotides (ASO) down-regulates Notch2 and the Notch target genes Hes-related family basic helix-loop-helix transcription factor with YRPW motif 1 ( Hey1 ), Hey2 , and HeyL in skeletal tissue from Notch2 tm1.1Ecan mice. Results of microcomputed tomography experiments indicated that the administration of Notch2 ASOs ameliorates the cancellous osteopenia of Notch2 tm1.1Ecan mice, and bone histomorphometry analysis revealed decreased osteoclast numbers in Notch2 ASO-treated Notch2 tm1.1Ecan mice. Notch2 ASOs decreased the induction of mRNA levels of TNF superfamily member 11 ( Tnfsf11 , encoding the osteoclastogenic protein RANKL) in cultured osteoblasts and osteocytes from Notch2 tm1.1Ecan mice. Bone marrow-derived macrophage cultures from the Notch2 tm1.1Ecan mice displayed enhanced osteoclastogenesis, which was suppressed by Notch2 ASOs. In conclusion, Notch2 tm1.1Ecan mice exhibit cancellous bone osteopenia that can be ameliorated by systemic administration of Notch2 ASOs., (© 2020 Canalis et al.)