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Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Pro-inflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. 505 men (85.0±4.2yrs) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP) and a subsample (n=305) with interleukin (IL-6, IL-1β, IL-17A) and tumor necrosis factor-α (TNF-α)) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23-92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p0.05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se.

Mapping in situ eddy covariance measurements of terrestrial land–atmosphere fluxes to the globe is a key method for diagnosing the Earth system from a data-driven perspective. We describe the first global products (called X-BASE) from a newly implemented upscaling framework, FLUXCOM-X, representing an advancement from the previous generation of FLUXCOM products in terms of flexibility and technical capabilities. The X-BASE products are comprised of estimates of CO2 net ecosystem exchange (NEE), gross primary productivity (GPP), evapotranspiration (ET), and for the first time a novel, fully data-driven global transpiration product (ETT), at high spatial (0.05°) and temporal (hourly) resolution. X-BASE estimates the global NEE at −5.75 ± 0.33 Pg C yr−1 for the period 2001–2020, showing a much higher consistency with independent atmospheric carbon cycle constraints compared to the previous versions of FLUXCOM. The improvement of global NEE was likely only possible thanks to the international effort to increase the precision and consistency of eddy covariance collection and processing pipelines, as well as to the extension of the measurements to more site years resulting in a wider coverage of bioclimatic conditions. However, X-BASE global net ecosystem exchange shows a very low interannual variability, which is common to state-of-the-art data-driven flux products and remains a scientific challenge. With 125 ± 2.1 Pg C yr−1 for the same period, X-BASE GPP is slightly higher than previous FLUXCOM estimates, mostly in temperate and boreal areas. X-BASE evapotranspiration amounts to 74.7×103 ± 0.9×103 km3 globally for the years 2001–2020 but exceeds precipitation in many dry areas, likely indicating overestimation in these regions. On average 57 % of evapotranspiration is estimated to be transpiration, in good agreement with isotope-based approaches, but higher than estimates from many land surface models. Despite considerable improvements to the previous upscaling products, many further opportunities for development exist. Pathways of exploration include methodological choices in the selection and processing of eddy covariance and satellite observations, their ingestion into the framework, and the configuration of machine learning methods. For this, the new FLUXCOM-X framework was specifically designed to have the necessary flexibility to experiment, diagnose, and converge to more accurate global flux estimates.

Samarium diiodide (SmI2) is a single electron reductant and versatile synthetic tool that can be used to create carbon- carbon bonds or other synthetic transformations. SmI2 is typically used with an Argon atmosphere glovebox and anhydrous solvents from a solvent purification system; however, not all labs have access to these equipment. A more accessible air-free option is Schlenk line glassware. Here in reports an optimized method for the synthesis and use of SmI2 on a Schlenk line. During optimization of the system, it was found that the largest impact on the success of SmI2 was the THF solvent. Anhydrous solvent was achieved though distillation, but after storage of the solvent over two weeks enough moisture/air was accumulated to significantly impact the concentration of the SmI2 formed in solution. The use of molecular sieves further indicates that the impact of water accumulation in the solvent compared to oxygen has the most significant factor on the success of synthesizing SmI2. These observations of THF storage overtime are important to account for when carrying out SmI2 reactions and other air-sensitive reactions on the Schlenk line.

Abstract Dulaglutide is a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, which stimulates insulin release via activation of GLP‐1 receptors on pancreatic beta cells. We report the case of a 45‐year‐old woman with type 2 diabetes mellitus who started dulaglutide subcutaneously and developed, a few minutes after the fourth administration, a persistent itchy reaction at the injection site, followed, after two more administrations, by a diffuse itchy delayed urticaria‐like rash, healed in 7 days after drug interruption. Skin test performed after 3 months from the event demonstrated the culprit role of the drug. Given the limited evidence in literature, there is currently no standardised protocol for testing patients sensitised to one or more glucagon‐like peptide‐1 receptor agonists. Performing skin tests, especially intradermal tests, is pivotal to confirm the aetiological role of the drug in the suspected hypersensitivity reaction, and possibly to identify an alternative to be proposed before precluding the entire drug class. To the best of our knowledge, this is the first case of systemic hypersensitivity reaction to dulaglutide presenting as a delayed urticaria‐like rash and confirmed by positive skin test.

When developing a distributed application, several issues need to be handled, and software components should include some mechanisms to make their execution resilient when network faults, delays, or tampering occur. For example, synchronous calls represent a too-tight connection between a client requesting a service and the service itself, whereby potential network delays or temporary server overloads would keep the client side hanging, exposing it to a domino effect. The proposed approach assists developers in dealing with such issues by providing an automatic tool that enhances a distributed application using simple blocking calls and makes it robust in the face of adverse events. The proposed devised solution consists in automatically identifying the parts of the application that connect to remote services using simple synchronous calls and substituting them with a generated customized snippet of code that handles potential network delays or faults. To accurately perform the proposed transformation, the devised tool finds application code statements that are data-dependent on the results of the original synchronous calls. Then, for the dependent statements, a solution involving guarding code, proper synchronization, and timeouts is injected. We experimented with the analysis and transformation of several applications and report a meaningful example, together with the analysis of the results achieved.

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p

This study is addressed at the cultural heritage of the UNESCO historical centre of Urbino (Italy) through the focus on a very peculiar building and ornamental carbonate porous (spongy) stone also found in the opus quadratum Roman dry walls. For these rocks, the mathematician and historian Bernardino Baldi (16th century AD) and the mineralogist Francesco Rodolico (middle of the 20th century AD) introduced, respectively, the popular terms of Tufo spugnoso or Pietra Spugna. Physical observations and stable isotope data (δ13C and δ18O) of these rocks allowed, for the first time, their classification as calcareous tufas, thus contributing to the valorization of the stone heritage of the city. This carbonate lithotype was formed by the chemical precipitation of CaCO3, driven by the CO2 degassing of supersaturated calcium-bicarbonate-rich waters, coupled with the passive encrustations of organic material in continental environments. Radiocarbon analyses dated these stones mostly between 9100 and 4700 yr. BP when a maximum growth of these carbonate continental deposits occurred in Mediterranean regions and northern Europe, i.e., during the Holocene Atlantic climatic optimum. Work is still in progress on a perched springline of calcareous tufas found along the Metauro Valley (a few km from Urbino), being good candidates for provenance, at least for those blocks exploited by the Romans and successively reused in the architectural framework of Urbino.

Blockchain technology offers unique features, such as transparency, the immutability of data, and the capacity to establish trust without a central authority. Such characteristics can be leveraged to support the collaboration among several different software systems operating within the healthcare ecosystem, while ensuring data integrity and make electronic health records (EHRs) more easily accessible. To provide a solution based on blockchain technology, this paper has evaluated the main issues that arise when large amounts of data are expected, i.e., mainly cost and performance. A balanced approach that maximizes the benefits and mitigates the constraints of the blockchain has been designed. The proposed decentralized application (dApp) architecture employs a hybrid storage strategy that involves storing medical records locally, on users’ devices, while utilizing blockchain to manage an index of these data. The dApp clients facilitate interactions among participants, leveraging a smart contract to enable patients to set authorization policies, thereby ensuring that only designated healthcare providers and authorized entities have access to specific medical records. The blockchain data-immutability property is used to validate data stored externally. This solution significantly reduces the costs related to the utilization of the blockchain, while retaining its advantages, and improves performance, since the majority of data are available off-chain.

The eddy covariance (EC) technique is used to measure the net ecosystem exchange (NEE) of CO2 between ecosystems and the atmosphere, offering a unique opportunity to study ecosystem responses to climate change. NEE is the difference between the total CO2 release due to all respiration processes (RECO), and the gross carbon uptake by photosynthesis (GPP). These two gross CO2 fluxes are derived from EC measurements by applying partitioning methods that rely on physiologically based functional relationships with a limited number of environmental drivers. However, the partitioning methods applied in the global FLUXNET network of EC observations do not account for the multiple co-acting factors that modulate GPP and RECO flux dynamics. To overcome this limitation, we developed a hybrid data-driven approach based on combined neural networks (NNC-part ). NNC-part incorporates process knowledge by introducing a photosynthetic response based on the light-use efficiency (LUE) concept, and uses a comprehensive dataset of soil and micrometeorological variables as fluxes drivers. We applied the method to 36 sites from the FLUXNET2015 dataset and found a high consistency in the results with those derived from other standard partitioning methods for both GPP (R2  > .94) and RECO (R2  > .8). High consistency was also found for (a) the diurnal and seasonal patterns of fluxes and (b) the ecosystem functional responses. NNC-part performed more realistic than the traditional methods for predicting additional patterns of gross CO2 fluxes, such as: (a) the GPP response to VPD, (b) direct effects of air temperature on GPP dynamics, (c) hysteresis in the diel cycle of gross CO2 fluxes, (d) the sensitivity of LUE to the diffuse to direct radiation ratio, and (e) the post rain respiration pulse after a long dry period. In conclusion, NNC-part is a valid data-driven approach to provide GPP and RECO estimates and complementary to the existing partitioning methods.