The production cross sections of heaviest isotopes of superheavy nuclei with charge numbers 112–118 are predicted in the xn–, pxn–, and αxn–evaporation channels of the 48Ca-induced complete fusion ...reactions for future experiments. The estimates of synthesis capabilities are based on a uniform and consistent set of input nuclear data. Nuclear masses, deformations, shell corrections, fission barriers and decay energies are calculated within the macroscopic-microscopic approach for even-even, odd-Z and odd-N nuclei. For odd systems the blocking procedure is used. To find saddle points, the Imaginary Water Flow technique is used and non-axiallity is taken into account. As shown, our calculations, based on a new set of mass and barriers, agree very well with the experimentally known cross-sections, especially in the 3n–evaporation channel. The dependencies of these predictions on the mass/fission barriers tables, the ratio af/a, and fusion models are discussed. A way is shown to produce directly unknown superheavy isotopes in the 1n– or 2n–evaporation channels. The synthesis of new superheavy isotopes unattainable in reactions with emission of neutrons is proposed in the promising channels with emission of protons (σpxn≃10−200 fb) and alphas (σαxn≃50−500 fb).
Subseasonal rainfall forecast skill is critical to support preparedness for hydrometeorological extremes. We assess how a process‐informed evaluation, which subsamples forecasting model members based ...on their ability to represent potential predictors of rainfall, can improve monthly rainfall forecasts within Central America in the following month, using Costa Rica and Guatemala as test cases. We generate a constrained ensemble mean by subsampling 130 members from five dynamic forecasting models in the C3S multimodel ensemble based on their representation of both (a) zonal wind direction and (b) Pacific and Atlantic sea surface temperatures (SSTs), at the time of initialization. Our results show in multiple months and locations increased mean squared error skill by 0.4 and improved detection rates of rainfall extremes. This method is transferrable to other regions driven by slowly‐changing processes. Process‐informed subsampling is successful because it identifies members that fail to represent the entire rainfall distribution when wind/SST error increases.
Plain Language Summary
Subseasonal rainfall forecasts provide alerts multiple weeks ahead. These forecasts present an opportunity to facilitate anticipatory actions yet are often unreliable to use when preparing for extreme weather. We develop a method to optimize rainfall forecasts by selecting individual members from a large ensemble of dynamic forecasting model outputs based on their ability to represent potential predictors of rainfall. We test our method on monthly rainfall forecasts within Central America in the following month, using Costa Rica and Guatemala as key test cases. We select members from five contributing models of the C3S multimodel ensemble using regional predictors, including wind direction and sea surface temperatures (SSTs). Our results show improvements in the detection of low and high rainfall extremes. This method is transferrable to other regions driven by slowly‐changing processes like SSTs and is beneficial for operational forecasters who can leverage regional expertise of relevant rainfall‐generating processes to subsample better performing ensemble members for their regions.
Key Points
Subsampling members using sea surface temperatures and zonal wind improves subseasonal ensemble rainfall forecasts in Central America
In multiple months and locations mean squared error skill increases by 0.4 and extreme rainfall skill improves by 0.5 (Heidke skill)
Process‐informed subsampling is useful because the models' representation of rainfall degrades as process error increases
The probabilities of xn-, pxn-, and αxn-evaporation channels in excited superheavy nuclei were evaluated using the Monte Carlo method. The calculations utilized microscopically determined nuclear ...level densities and were compared with results obtained from the phenomenological Jackson formula. Effective temperatures derived from the microscopic approach were incorporated into the Jackson formula for different evaporation channels at low and moderate excitation energies. Additionally, an analytical formula was introduced to estimate the average kinetic energy of emitted particles in multi-step processes.
Despite extensive efforts in the development of drugs for complex neurodegenerative diseases, treatment often remains challenging or ineffective, and hence new treatment strategies are necessary. One ...approach is the design of multi-target drugs, which can potentially address the complex nature of disorders such as Alzheimer's disease. We report a method for high throughput virtual screening aimed at identifying new dual target hit molecules. One of the identified hits,
,
-dimethyl-1-(4-(3-methyl-1,2,4triazolo4,3-apyrimidin-6-yl)phenyl)ethan-1-amine (Ý;mir-2), has dual-activity as an acetylcholinesterase (AChE) inhibitor and as an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist. Using computational chemistry methods, parallel and independent screening of a virtual compound library consisting of 3,848,234 drug-like and commercially available molecules from the ZINC15 database, resulted in an intersecting set of 57 compounds, that potentially possess activity at both of the two protein targets. Based on ligand efficiency as well as scaffold and molecular diversity, 16 of these compounds were purchased for in vitro validation by Ellman's method and two-electrode voltage-clamp electrophysiology. Ý;mir-2 was shown to exhibit the desired activity profile (AChE IC
= 2.58 ± 0.96 µM; α7 nAChR activation = 7.0 ± 0.9% at 200 µM) making it the first reported compound with this particular profile and providing further evidence of the feasibility of in silico methods for the identification of novel multi-target hit molecules.
Mesenchymal stem cells (MSCs) gain an increasing focus in the field of regenerative medicine due to their differentiation abilities into chondrocytes, adipocytes, and osteoblastic cells. However, it ...is apparent that the transformation processes are extremely complex and cause cellular heterogeneity. The study aimed to characterize differences between MSCs and cells after adipogenic (AD) or osteoblastic (OB) differentiation at the proteome level. Comparative proteomic profiling was performed using tandem mass spectrometry in data-independent acquisition mode. Proteins were quantified by deep neural networks in library-free mode and correlated to the Molecular Signature Database (MSigDB) hallmark gene set collections for functional annotation. We analyzed 4108 proteins across all samples, which revealed a distinct clustering between MSCs and cell differentiation states. Protein expression profiling identified activation of the
signaling pathway after AD. In addition, two distinct protein marker panels could be defined for osteoblastic and adipocytic cell lineages. Hereby, overexpression of AEBP1 and MCM4 for OB as well as of FABP4 for AD was detected as the most promising molecular markers. Combination of deep neural network and machine-learning algorithms with data-independent mass spectrometry distinguish MSCs and cell lineages after adipogenic or osteoblastic differentiation. We identified specific proteins as the molecular basis for bone formation, which could be used for regenerative medicine in the future.
Cultured human bone marrow stromal (mesenchymal) stem cells (hBM‐MSCs) are heterogenous cell populations exhibiting variable biological properties. Quantitative high‐content imaging technology allows ...identification of morphological markers at a single cell resolution that are determinant for cellular functions. We determined the morphological characteristics of cultured primary hBM‐MSCs and examined their predictive value for hBM‐MSC functionality. BM‐MSCs were isolated from 56 donors and characterized for their proliferative and differentiation potential. We correlated these data with cellular and nuclear morphological features determined by Operetta; a high‐content imaging system. Cell area, cell geometry, and nucleus geometry of cultured hBM‐MSCs exhibited significant correlation with expression of hBM‐MSC membrane markers: ALP, CD146, and CD271. Proliferation capacity correlated negatively with cell and nucleus area and positively with cytoskeleton texture features. In addition, in vitro differentiation to osteoblasts as well as in vivo heterotopic bone formation was associated with decreased ratio of nucleus width to length. Multivariable analysis applying a stability selection procedure identified nuclear geometry and texture as predictors for hBM‐MSCs differentiation potential to osteoblasts or adipocytes. Our data demonstrate that by employing a limited number of cell morphological characteristics, it is possible to predict the functional phenotype of cultured hBM‐MSCs and thus can be used as a screening test for “quality” of hBM‐MSCs prior their use in clinical protocols.
Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are ...observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. Selected participants were <50 years old to control for the confounder of older age.
Plasma levels of IL-6, IP10, sCD14, sCD163, and TGF-β and markers of T cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were measured in ART-treated, HIV+ participants grouped by CD4 T cell counts (
= 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC;
= 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics.
Proportions of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were elevated in HIV+ participants. When comparing proportions between INR and IR, INR had higher proportions of CD4 memory PD-1+, EM CD57+, TEM TIGIT+ and CD8 EM and TEM TIGIT+ cells. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-β levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1, and CD57 positively correlated with plasma levels of IL-6. Plasma levels of TGF-β negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets.
INR have lower levels of TGF-β and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked to higher proportions of T cell exhaustion and senescence seen in INR.
Osteoporosis is a systemic age-related disease characterized by reduced bone mass and microstructure deterioration, leading to increased risk of bone fragility fractures. Osteoporosis is a worldwide ...major health care problem and there is a need for preventive approaches.
Apigenin and Rutaecarpine are plant-derived antioxidants identified through functional screen of a natural product library (143 compounds) as enhancers of osteoblastic differentiation of human bone marrow stromal stem cells (hBMSCs). Global gene expression profiling and Western blot analysis revealed activation of several intra-cellular signaling pathways including focal adhesion kinase (FAK) and TGFβ. Pharmacological inhibition of FAK using PF-573228 (5 μM) and TGFβ using SB505124 (1μM), diminished Apigenin- and Rutaecarpine-induced osteoblast differentiation.
treatment with Apigenin and Rutaecarpine, of primary hBMSCs obtained from elderly female patients enhanced osteoblast differentiation compared with primary hBMSCs obtained from young female donors.
treatment with Apigenin and Rutaecarpine of organotypic embryonic chick-femur culture significantly increased bone volume and cortical thickness compared to control as estimated by μCT-scanning.
Our data revealed that Apigenin and Rutaecarpine enhance osteoblastic differentiation, bone formation, and reduce the age-related effects of hBMSCs. Therefore, Apigenin and Rutaecarpine cellular treatment represent a potential strategy for maintaining hBMSCs health during aging and osteoporosis.
Extracellular adenosine triphosphate (ATP) regulates pancreatic duct function via P2Y and P2X receptors. It is well known that ATP is released from upstream pancreatic acinar cells. The ATP ...homeostasis in pancreatic ducts, which secrete bicarbonate-rich fluid, has not yet been examined. First, our aim was to reveal whether pancreatic duct cells release ATP locally and whether they enzymatically modify extracellular nucleotides/sides. Second, we wished to explore which physiological and pathophysiological factors may be important in these processes. Using a human pancreatic duct cell line, Capan-1, and online luminescence measurement, we detected fast ATP release in response to pH changes, bile acid, mechanical stress and hypo-osmotic stress. ATP release following hypo-osmotic stress was sensitive to drugs affecting exocytosis, pannexin-1, connexins, maxi-anion channels and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, and corresponding transcripts were expressed in duct cells. Direct stimulation of intracellular Ca
2+
and cAMP signalling and ethanol application had negligible effects on ATP release. The released ATP was sequentially dephosphorylated through ecto-nucleoside triphosphate diphosphohydrolase (NTPDase2) and ecto-5′-nucleotidase/CD73 reactions, with respective generation of adenosine diphosphate (ADP) and adenosine and their maintenance in the extracellular medium at basal levels. In addition, Capan-1 cells express counteracting adenylate kinase (AK1) and nucleoside diphosphate kinase (NDPK) enzymes (NME1, 2), which contribute to metabolism and regeneration of extracellular ATP and other nucleotides (ADP, uridine diphosphate (UDP) and uridine triphosphate (UTP)). In conclusion, we illustrate a complex regulation of extracellular purine homeostasis in a pancreatic duct cell model involving: ATP release by several mechanisms and subsequent nucleotide breakdown and ATP regeneration via counteracting nucleotide-inactivating and nucleotide-phosphorylating ecto-enzymes. We suggest that extracellular ATP homeostasis in pancreatic ducts may be important in pancreas physiology and potentially in pancreas pathophysiology.
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