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Convective Self‐Aggregation (CSA) is a common feature of idealized numerical simulations of the tropical atmosphere in Radiative‐Convective Equilibrium (RCE). However, at coarse grid resolution where deep convection is not fully resolved, the occurrence of this phenomenon is extremely sensitive to subgrid‐scale processes. This study examines the role of mixing and entrainment, provided by the turbulence model and the implicit numerical diffusion. The study compares the results of two models, WRF and SAM, by varying turbulence models, initial conditions, and horizontal spatial resolution. At a coarse grid resolution of 3 km, the removal of turbulent mixing prevents CSA in models with low numerical diffusivity but is preserved in models with high numerical diffusivity. When the horizontal grid resolution is refined to 1 km, CSA can only be achieved by increasing explicit turbulent mixing, even with a small amount of shallow clouds. Therefore, the sensitivity of CSA to horizontal grid resolution is not primarily caused by the decrease in shallow clouds. The analysis of the total water path spectrum suggests that the amplitude of initial humidity perturbations introduced by convection in the free troposphere is the key factor. This amplitude is regulated by turbulent mixing and diffusion at small scales. Prior to the onset of CSA, increased mixing makes updrafts more sensitive to the dryness of the free troposphere, which strengthens the moisture‐convection feedback. This leads to an increased distance between convective cores and a stronger humidity perturbation in the free troposphere, which can destabilize the RCE state. Plain Language Summary: Convection transports moisture from the surface to the troposphere and forms clouds. Clouds developing in dry environments can be diluted by turbulent mixing, while mixing in moist environments favors their deepening. Turbulent mixing thus favors convection over moist regions, making them moister, while the opposite is true for dry regions. This phenomenon is known as the moisture‐convection feedback. In atmospheric models with a horizontal grid resolution of about 1 km, the feedback is represented by the turbulence model and the numerical discretization errors. This study found that when simulating deep tropical convection, the use of coarse grid resolution strengthens the moisture‐convection feedback, initially creating larger clusters of clouds separated by larger areas free of convection. In these areas where convection is suppressed, the upper troposphere will dry out. The amplitude of this area and its associated dry perturbation of the upper troposphere are key factors in determining whether convection will continue to be suppressed or if it will be able to penetrate the free troposphere. The final clustering of clouds into a single moist patch, known as convective self‐aggregation, depends on these conditions. Therefore, it is necessary to accurately represent sub‐grid scale mixing processes to capture the convective self‐aggregation phenomenon in high‐resolution atmospheric models. Key Points: The initial amplitude of humidity perturbations introduced by convection in the free troposphere is the key factor for the onset of convective self‐aggregation.Prior to the onset of self‐aggregation, this amplitude is regulated by turbulent mixing and numerical diffusion, rather than the amount of shallow clouds.Coarse resolutions impose larger mixing which increases the distance between convective cores and the associated humidity perturbation in the free troposphere. [ABSTRACT FROM AUTHOR]

The radiative‐convective equilibrium (RCE) of two models exhibiting convective aggregation has been compared. The goal of the work, following the suggestion from the RCE Model Intercomparison Project (RCEMIP), is to identify key parameters controlling self‐aggregation in RCE for both models, to discuss the processes controlled by these parameters and to underline the models similarities and differences. The two cloud resolving models studied, the SAM (System for Atmospheric Modeling) and the ARPS (Advanced Regional Prediction System), present similar statistics concerning precipitation, but different warming, and drying of the atmosphere, within the spread of the RCEMIP values. On the other hand, the two models show different strengths of the moisture feedback, due to the different saturation of the sub‐cloud layer. A saturated sub‐cloud layer in ARPS (which was not artificially imposed in the numerical setup) allows the localization of convection in moist regions, by weakening the negative influence of cold pools. Such a mechanism leads to a lower degree of aggregation (based on three organization metrics) and a weaker effect of the organized state on the average domain statistics in ARPS. Stronger cold pools in SAM, instead, help the creation of shallow clouds in dry regions, increasing the longwave feedback responsible for their expansion; while delocalizing convection in moist regions and therefore opposing high‐cloud radiative‐feedback. Further experiments are needed to generalize such findings to other RCEMIP models, also investigating the role of microphysics and turbulence schemes in regulating such mechanisms. Plain Language Summary: Radiative‐convective equilibrium is an example for studying convective motion of the tropical atmosphere, where the clustering of clouds can spontaneously occur and it can substantially affect the energy budget of the climate system. To study this phenomenon, we selected two atmospheric models, with different numerics and physics, able to reproduce individual clouds. We investigated the equilibrium statistics. The two models show similar precipitation, but different warming, and drying of the atmosphere. We found that, if a model reaches saturation in the layer below clouds, rain can not evaporate and weaker cold pools are not able to disperse convection. In this case, moist regions gets moister and dry regions get drier, resulting in a less organized state. On the other hand, cold pools, strong enough to form low clouds in the dry regions, allow them to expand on the expenses of moist regions. The saturation was found to happen spontaneously in one of the two models, and the subsequent convection organization could reflect different ways of clustering in the real tropical atmosphere. Key Points: A saturated sub‐cloud layer is found to spontaneously occur in the radiative‐convective equilibrium simulation of the Advanced Regional Prediction System modelThe closer the sub‐cloud layer to saturation, the lower the degree of aggregation and the weaker its effect on the average domain statisticsThe appearance of an up‐gradient moist static energy circulation which expand dry regions needs, a strong cold pool effect to generate low clouds [ABSTRACT FROM AUTHOR]

Background Iron is essential for hemoglobin synthesis during terminal erythropoiesis. To supply adequate iron the carrier transferrin is required together with transferrin receptor endosomal cycle and normal mitochondrial iron utilization. Iron and iron protein deficiencies result in different types of anemia. Iron-deficiency anemia is the commonest anemia worldwide due to increased requirements, malnutrition, chronic blood losses and malabsorption. Mutations of transferrin, transferrin receptor cycle proteins, enzymes of the first step of heme synthesis and iron sulfur cluster biogenesis lead to rare anemias, usually accompanied by iron overload. Hepcidin plays an indirect role in erythropoiesis by controlling plasma iron. Inappropriately high hepcidin levels characterize the rare genetic iron-refractory iron-deficiency anemia (IRIDA) and the common anemia of chronic disease. Iron modulates both effective and ineffective erythropoiesis: iron restriction reduces heme and alpha-globin synthesis that may be of benefit in thalassemia. Material and Methods This review relies on the analysis of the most recent literature and personal data. Results Erythropoiesis controls iron homeostasis, by releasing erythroferrone that inhibits hepcidin transcription to increase iron acquisition in iron deficiency, hypoxia and EPO treatment. Erythroferrone, produced by EPO-stimulated erythropoiesis, inhibits hepcidin only when the activity of BMP/SMAD pathway is low, suggesting that EPO somehow modulates the latter signaling. Erythroblasts sense circulating iron through the second transferrin receptor (TFR2) that, in animal models, modulates the sensitivity of the erythroid cells to EPO. Discussion The advanced knowledge of the regulation of systemic iron homeostasis and erythropoiesis-mediated hepcidin regulation is leading to the development of targeted therapies for anemias and iron disorders. [ABSTRACT FROM AUTHOR]

We present high precision Molecular Dynamics simulations for the dynamical structure function, S(k, ω), of the classical Coulomb One Component Plasma (OCP), for a wide range of the coupling parameter Γ (from 0.05 to 10 000). We follow the positive-to-negative transition of the slope of the ω(k) dispersion curve at small wave numbers caused by the onset of correlations with increasing coupling. The high signal-to-noise ratio of the data over several orders of magnitude allows examination of a wide dynamical range of S(k, ω), including extreme values of ω and k, and the identification of waves at higher harmonics of the plasma frequency. Sum rules are found to be accurately satisfied. [ABSTRACT FROM AUTHOR]

ABSTRACT In the last years, fluorescence light sheet microscopy has attracted an increasing interest among the microscopy community. One of the most promising applications of this technique is the reconstruction of macroscopic biological specimens with microscopic resolution, without physical sectioning. To this aim, light sheet microscopy is combined with clearing protocols based on refractive index matching, which render the tissue transparent. However, these protocols lead to a huge drop in the fluorescence signal, limiting their practical applicability. The reduction of signal to background ratio is commonly ascribed to chemical degradation of the fluorophores by the organic solvents used for clearing. This view however completely neglects another important factor of contrast loss, i.e., optical aberrations. In fact, commercially available objectives suitable for light sheet microscopy are not designed for the refractive index of the clearing solutions, and this mismatch introduces severe spherical aberration. Here we simulated the aberrated point spread function (PSF) of a light sheet microscope with confocal slit detection. We investigated the variation of the PSF as a function of objective numerical aperture (NA) and of imaging depth inside the clearing solution. We also explored the possibility of correcting such spherical aberration by introducing extra optical devices in the detection path. By correcting up to the second order spherical aberration, a quasi-diffraction-limited regime can be recovered, and image quality is restored. Microsc. Res. Tech. 77:483-491, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The genus Philornis (Diptera: Muscidae) comprises Neotropical parasitic flies that parasitize bird nestlings while in their larval stage. The ecology of most species of these parasitic flies is largely unknown. Here, we contribute with data that shed some light on the environmental factors that are associated with variations in parasitism intensity of Philornis torquans, and examine whether increased intensity is followed by greater probability of mortality or reduced nestling growth. Intensive examination of nestlings of the bird community present in a 30 ha area was carried out weekly along two breeding seasons in Santa Fe, Argentina. Some nestlings of the most frequently parasitized bird species were followed twice a week, from hatching to fledging, to assess the impact of the parasites. High average maximum temperature and increased rainfall were significantly positively correlated with mean Philornis intensity. In turn, heavily parasitized nestlings were more likely to die: 10 larvae doubled the chances of mortality, and growth was affected in those that survived. The greater precipitation and warmer weather predicted for some areas of South America pose a potential impact on nestlings via this parasitism, and consequently on the population dynamics of native birds. [ABSTRACT FROM AUTHOR]

Analysis of the variable region gene sequences of a human hybridoma rheumatoid factor (RF), derived from a patient with rheumatoid arthritis (RA), revealed the expression of genes from the VλI and VH3 families. Specifically, the C304 RF had rearranged the DPL8/Hum1v1042 and VH26 germline VL and VH genes, respectively. This gene usage has been observed in the rearrangement of human anti-viral antibodies specific for the herpes group of viruses. This overlap between the autoimmune and anti-viral antibody gene repertoires suggests a possible structural relationship between the immune response directed against ubiquitous pathogens and the induction of RF production. [ABSTRACT FROM AUTHOR]

Modern pacing systems are becoming more and more sophisticated. Conversion of the information supplied by a sensor into suitable parameters for a rate controlling algorithm and the management of complex timing are common tasks for an integrated circuit (IC) in cardiac pacing. An effective solution consists of using a microprocessor to implement algorithms and pacing modes in a flexible way. The key point of using the same hardware resources for different tasks on a time sharing basis allows the design of a less complex IC when compared to a random logic structure with the same performances. The major design problems in a full microprocessor solution are its relatively low operating speed due to the low frequency clock necessary for low current drain, and the sequential structure of the machine itself. This can lead to unacceptable timing inaccuracy in all situations requiring the management of complex decision trees. In order to take full benefit from the advantages of a microprocessor structure without these drawbacks, a mixed microprocessor-random logic approach has been investigated. This architecture uses a microprocessor core to perform all high level nonreal-time operations (setup of the pacing cycle, data reduction and processing, data integrity checks) while a set of random logic peripherals is used for all critical timing aspects. [ABSTRACT FROM AUTHOR]

β-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for β-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor β pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb th3/+ thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbb th3/+ mice with or without hematopoietic Tfr2 (Tfr2 BMKO /Hbb th3/+ ) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbb th3/+ and Tfr2 BMKO /Hbb th3/+ animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP-SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP-SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo-oligomerization and ALK2-ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12-ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP-SMAD signaling and characterized by low hepcidin and high BMP6 expression., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

β-thalassemia is a genetic disorder caused by mutations in the β-globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion-dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications. Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron-regulatory hormone hepcidin in the liver and a modulator of erythropoietin signaling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron-overload in non-TDT mice, both as a monotherapy and, even more strikingly, in combination with iron-restricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here, we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbb th1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α-globin, which partially corrects the unbalance with β-globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long-term blood transfusions required for survival of Hbb th1/th2 animals, preventing mortality due to chronic anemia and reducing transfusion-associated complications, such as progressive iron-loading. Altogether, TFR2 targeting might represent a promising therapeutic option also for TDT., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Despite its essential role in many biological processes, iron is toxic when in excess due to its propensity to generate reactive oxygen species. To prevent diseases associated with iron deficiency or iron loading, iron homeostasis must be tightly controlled. Intracellular iron content is regulated by the Iron Regulatory Element-Iron Regulatory Protein (IRE-IRP) system, whereas systemic iron availability is adjusted to body iron needs chiefly by the hepcidin-ferroportin (FPN) axis. Here, we aimed to review advances in the field that shed light on cell-type-specific regulatory mechanisms that control or modify systemic and local iron balance, and how shifts in cellular iron levels may affect specialized cell functions., (© 2020 Wiley Periodicals LLC.)

Hemojuvelin (HJV), the coreceptor of the BMP-SMAD pathway that up-regulates hepcidin transcription, is a repulsive guidance molecule (RGMc) which undergoes a complex intracellular processing. Following autoproteolysis, it is exported to the cell surface both as a full-length and a heterodimeric protein. In vitro membrane HJV (m-HJV) is cleaved by the transmembrane serine protease TMPRSS6 to attenuate signalling and to inhibit hepcidin expression. In this study, we investigated the number and position of HJV cleavage sites by mutagenizing arginine residues (R), potential TMPRSS6 targets, to alanine (A). We analysed translation and membrane expression of HJV R mutants and the pattern of fragments they release in the culture media in the presence of TMPRSS6. Abnormal fragments were observed for mutants at arginine 121, 176, 218, 288 and 326. Considering that all variants, except HJV(R121A) , lack autoproteolytic activity and some (HJV(R176A) and HJV(R288A) ) are expressed at reduced levels on cell surface, we identified the fragments originating from either full-length or heterodimeric proteins and defined the residues 121 and 326 as the TMPRSS6 cleavage sites in both isoforms. Using the N-terminal FLAG-tagged HJV, we showed that residue 121 is critical also in the rearrangement of the N-terminal heterodimeric HJV. Exploiting the recently reported RGMb crystallographic structure, we generated a model of HJV that was used as input structure for all-atoms molecular dynamics simulation in explicit solvent. As assessed by in silico studies, we concluded that some arginines in the von Willebrand domain appear TMPRSS6 insensitive, likely because of partial protein structure destabilization., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

The role of iron in the pathogenesis of Alzheimer's disease (AD) is still unclear, despite the evidence that it accumulates in the same brain regions characterized by the amyloid beta peptide (Abeta) accumulation. Here we propose that iron directly influences the Abeta production through the modulation of furin, a proconvertase involved in the regulation of the alpha-secretase-dependent processing of the amyloid protein precursor (APP).

Unlabelled: Rationale In technology assessment in health-related fields the construction of a model for interpreting the economic implications of the introduction of a technology is only a part of the problem. The most important part is often the formulation of a model that can be used for selecting patients to submit to the new cost-saving procedure or medical strategy. The model is usually complicated by the fact that data are often non-homogeneous with respect to some uncontrolled variables and are correlated. The most typical example is the so-called hospital effect in multi-centre studies., Aims and Objectives: We show the implications derived by different choices in modelling strategies when evaluating the usefulness of preoperative chest radiography, an exam performed before surgery, usually with the aim to detect unsuspected abnormalities that could influence the anaesthetic management and/or surgical plan., Method: We analyze the data from a multi-centre study including more than 7000 patients. We use about 6000 patients to fit regression models using both a population averaged and a subject-specific approach. We explore the limitations of these models when used for predictive purposes using a validation set of more than 1000 patients., Results: We show the importance of taking into account the heterogeneity among observations and the correlation structure of the data and propose an approach for integrating a population-averaged and subject specific approach into a single modeling strategy. We find that the hospital represents an important variable causing heterogeneity that influences the probability of a useful POCR., Conclusions: We find that starting with a marginal model, evaluating the shrinkage effect and eventually move to a more detailed model for the heterogeneity is preferable. This kind of flexible approach seems to be more informative at various phases of the model-building strategy.