Calcium carbonate (CaCO(3)) is one of the most abundant substances on earth and has a large array of industrial applications. Considerable research has been conducted in an effort to synthesize calcium carbonate microparticles with controllable and specific morphologies and sizes. CaCO(3) produced by a precipitation reaction of calcium nitrate and sodium carbonate solution was found to have high polymorphism and batch to batch variability. In this study, we investigated the polymorphism of the precipitated material and analyzed the chemical composition, particle morphology, and crystalline state revealing that the presence of silicon atoms in the precipitant is a key factor effecting particle shape and crystal state. An elemental analysis of single particles within a polymorphic sample, using energy-dispersive X-ray spectroscopy (EDS) conjugated microscopy, showed that only spherical particles, but not irregular shaped one, contained traces of silicon atoms. In agreement, silicon-containing additives lead to homogenous, amorphous nanosphere particles, verified by X-ray powder diffraction (XRD). Our findings provide important insights into the mechanism of calcium carbonate synthesis, as well as introducing a method to control the precipitants at the micro-scale for many diverse applications.
Calcium carbonate (CaCO3) is one of the most abundant substances on earth and has a large array of industrial applications. Considerable research has been conducted in an effort to synthesize calcium carbonate microparticles with controllable and specific morphologies and sizes. CaCO3 produced by a precipitation reaction of calcium nitrate and sodium carbonate solution was found to have high polymorphism and batch to batch variability. In this study, we investigated the polymorphism of the precipitated material and analyzed the chemical composition, particle morphology, and crystalline state revealing that the presence of silicon atoms in the precipitant is a key factor effecting particle shape and crystal state. An elemental analysis of single particles within a polymorphic sample, using energy‐dispersive X‐ray spectroscopy (EDS) conjugated microscopy, showed that only spherical particles, but not irregular shaped one, contained traces of silicon atoms. In agreement, silicon‐containing additives lead to homogenous, amorphous nanosphere particles, verified by X‐ray powder diffraction (XRD). Our findings provide important insights into the mechanism of calcium carbonate synthesis, as well as introducing a method to control the precipitants at the micro‐scale for many diverse applications.
It has been suggested that local administration of topotecan (TT) could increase its efficacy in the treatment of glioblastoma. In this context, a PLGA implant model in the form of spheres with a porous core and stiff surface, loaded with TT and CaCl2 was developed. An array of formulations differing from each other by the type of PLGA used, the integrity of the surface, the concentrations of TT and CaCl2 added during the preparation, and the volume of water in the PLGA mix, was prepared, screened and explored by computerized multifactorial analysis. This analysis enabled the simultaneous identification of the most influential experimental factors on the experimental responses, which were pre-determined as the efficiency of TT loading and the TT % cumulative release at 14 days. The multifactorial analysis also revealed how the interactions among the experimental factors affect the performance of the various formulations. Thus, TT concentration and its factorial interaction with the concentration of CaCl2 added during the spheres' preparation were identified as most prominent on the loading efficiency, while the surface integrity (intact or punctured) and CaCl2 amount in the spheres were identified as most prominent on the TT % cumulative release from the spheres. TT was found to be cytotoxic towards glioblastoma U87 MG cells, an activity which was enhanced, synergistically, in the presence of CaCl2 (the relative viability was reduced from 36 to 28% with combination indices of 1.0, 0.37, 0.13 and 0.06 for EC50, EC75, EC90 and EC95, respectively). Interestingly, dividing the TT dose into 3 equal portions, replenished daily to the incubation medium, increased TT cytotoxicity. The relative viability was then reduced from 35 to 7% and in the presence of CaCl2 – from 28 to 1.9%, suggesting that a local, slow input of TT could be effective in the treatment of glioblastoma by an adjacent TT implant. The increased effect of CaCl2 on cytotoxicity was also observed when it was co-loaded into the TT spheres. In that case, the cells' viability was reduced from 72 to 27%. It is suggested that the PLGA spheres could be used for tunable local delivery of TT in post-resection adjuvant therapy of glioblastoma.
It has been suggested that local administration of topotecan (TT) could increase its efficacy in the treatment of glioblastoma. In this context, a PLGA implant model in the form of spheres with a porous core and stiff surface, loaded with TT and CaCl(2) was developed. An array of formulations differing from each other by the type of PLGA used, the integrity of the surface, the concentrations of TT and CaCl(2) added during the preparation, and the volume of water in the PLGA mix, was prepared, screened and explored by computerized multifactorial analysis. This analysis enabled the simultaneous identification of the most influential experimental factors on the experimental responses, which were pre-determined as the efficiency of TT loading and the TT % cumulative release at 14 days. The multifactorial analysis also revealed how the interactions among the experimental factors affect the performance of the various formulations. Thus, TT concentration and its factorial interaction with the concentration of CaCl(2) added during the spheres' preparation were identified as most prominent on the loading efficiency, while the surface integrity (intact or punctured) and CaCl(2) amount in the spheres were identified as most prominent on the TT % cumulative release from the spheres. TT was found to be cytotoxic towards glioblastoma U87 MG cells, an activity which was enhanced, synergistically, in the presence of CaCl(2) (the relative viability was reduced from 36 to 28% with combination indices of 1.0, 0.37, 0.13 and 0.06 for EC(50), EC(75), EC(90) and EC(95), respectively). Interestingly, dividing the TT dose into 3 equal portions, replenished daily to the incubation medium, increased TT cytotoxicity. The relative viability was then reduced from 35 to 7% and in the presence of CaCl(2) - from 28 to 1.9%, suggesting that a local, slow input of TT could be effective in the treatment of glioblastoma by an adjacent TT implant. The increased effect of CaCl(2) on cytotoxicity was also observed when it was co-loaded into the TT spheres. In that case, the cells' viability was reduced from 72 to 27%. It is suggested that the PLGA spheres could be used for tunable local delivery of TT in post-resection adjuvant therapy of glioblastoma.
It has been suggested that local administration of topotecan (TT) could increase its efficacy in the treatment of glioblastoma. In this context, a PLGA implant model in the form of spheres with a porous core and stiff surface, loaded with TT and CaCl(2) was developed. An array of formulations differing from each other by the type of PLGA used, the integrity of the surface, the concentrations of TT and CaCl(2) added during the preparation, and the volume of water in the PLGA mix, was prepared, screened and explored by computerized multifactorial analysis. This analysis enabled the simultaneous identification of the most influential experimental factors on the experimental responses, which were pre-determined as the efficiency of TT loading and the TT % cumulative release at 14 days. The multifactorial analysis also revealed how the interactions among the experimental factors affect the performance of the various formulations. Thus, TT concentration and its factorial interaction with the concentration of CaCl(2) added during the spheres' preparation were identified as most prominent on the loading efficiency, while the surface integrity (intact or punctured) and CaCl(2) amount in the spheres were identified as most prominent on the TT % cumulative release from the spheres. TT was found to be cytotoxic towards glioblastoma U87 MG cells, an activity which was enhanced, synergistically, in the presence of CaCl(2) (the relative viability was reduced from 36 to 28% with combination indices of 1.0, 0.37, 0.13 and 0.06 for EC(50), EC(75), EC(90) and EC(95), respectively). Interestingly, dividing the TT dose into 3 equal portions, replenished daily to the incubation medium, increased TT cytotoxicity. The relative viability was then reduced from 35 to 7% and in the presence of CaCl(2) - from 28 to 1.9%, suggesting that a local, slow input of TT could be effective in the treatment of glioblastoma by an adjacent TT implant. The increased effect of CaCl(2) on cytotoxicity was also observed when it was co-loaded into the TT spheres. In that case, the cells' viability was reduced from 72 to 27%. It is suggested that the PLGA spheres could be used for tunable local delivery of TT in post-resection adjuvant therapy of glioblastoma.
Understanding the tradeoffs faced by organisms is a major goal of evolutionary biology. One of the main approaches for identifying these tradeoffs is Pareto task inference (ParTI). Two recent papers claim that results obtained in ParTI studies are spurious due to phylogenetic dependence (Mikami T, Iwasaki W. 2021. The flipping t-ratio test: phylogenetically informed assessment of the Pareto theory for phenotypic evolution. Methods Ecol Evol. 12(4):696–706) or hypothetical p-hacking and population-structure concerns (Sun M, Zhang J. 2021. Rampant false detection of adaptive phenotypic optimization by ParTI-based Pareto front inference. Mol Biol Evol. 38(4):1653–1664). Here, we show that these claims are baseless. We present a new method to control for phylogenetic dependence, called SibSwap, and show that published ParTI inference is robust to phylogenetic dependence. We show how researchers avoided p-hacking by testing for the robustness of preprocessing choices. We also provide new methods to control for population structure and detail the experimental tests of ParTI in systems ranging from ammonites to cancer gene expression. The methods presented here may help to improve future ParTI studies.
Understanding the tradeoffs faced by organisms is a major goal of evolutionary biology. One of the main approaches for identifying these tradeoffs is Pareto task inference (ParTI). Two recent papers claim that results obtained in ParTI studies are spurious due to phylogenetic dependence (Mikami T, Iwasaki W. 2021. The flipping t-ratio test: phylogenetically informed assessment of the Pareto theory for phenotypic evolution. Methods Ecol Evol. 12(4):696–706) or hypothetical p-hacking and population-structure concerns (Sun M, Zhang J. 2021. Rampant false detection of adaptive phenotypic optimization by ParTI-based Pareto front inference. Mol Biol Evol. 38(4):1653–1664). Here, we show that these claims are baseless. We present a new method to control for phylogenetic dependence, called SibSwap, and show that published ParTI inference is robust to phylogenetic dependence. We show how researchers avoided p-hacking by testing for the robustness of preprocessing choices. We also provide new methods to control for population structure and detail the experimental tests of ParTI in systems ranging from ammonites to cancer gene expression. The methods presented here may help to improve future ParTI studies.
In the past decade, the identification of susceptibility genes for psychiatric disorders has become routine, but understanding the biology underlying these discoveries has proven extremely difficult. The large number of potential risk genes and the genetic overlap between disorders are major obstacles for studying the etiology of these conditions. Systems biology approaches relying on gene ontologies, gene coexpression, and protein-protein interactions are used to identify convergence of the genes in relation to biological processes, cell types, brain areas, and developmental stages. Across psychiatric disorders, there is a clear enrichment for genes expressed in the brain and especially in the cortex, but a higher resolution is vastly dependent on sample size and statistical power. There is indication that susceptibility genes tend to be expressed in the brain during periods preceding the typical onset of the disorders. Thus, the role of genes in prenatal brain development is more pronounced for childhood-onset disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder, but is much less so for bipolar disorder and depression. One of the most consistent findings across multiple disorders and classes of genetic variants is the role of genes intolerant to mutations in psychiatric disorders, yet this association is more pronounced for disorders with a clear neurodevelopmental component. Notwithstanding, a detailed understanding of the neurobiology of psychiatric disorders is still lacking. It is possible that it will only be revealed by studying the risk genes at the level of the development and function of neuronal networks and circuits.
We show a Gromov-Hausdorff approximation to the product of the standard spheres for Riemannian manifolds with positive Ricci curvature under some pinching condition on the eigenvalues of the Laplacian acting on functions and forms.
Following a rise in the life expectancy of cystic fibrosis (CF) patients, many adults with CF form couple relationships. Yet, dyadic coping has not been previously examined in people with CF. This study examined how adults with CF and their partners cope as a couple with the illness, and what meanings each partner and the couple as a unit attribute to the experience. Seventeen adult CF patients and their partners participated in separate semi-structured in-depth interviews. Two main patterns of dyadic coping with CF were identified as follows: cooperation and tension. For couples in cooperation, the marital relationship served as a resource for adaptive coping. These couples were characterized by similarities in their perception of the place of CF in their lives and of their roles in the marital relationship. Couples in tension described the couple relationship as strained by difficulty of accepting the disease, proliferation of negative emotions, and a sense of burden and loneliness in the process of coping. Findings point to the importance of mutual empathy, clear and accepted division of roles between the partners, and open communication for facilitating coping as a couple.
The value is a solution concept for n-person strategic games, developed by Nash,Shapley, and Harsanyi. The value of a game is an a priori evaluation of the economicworth of the position of each player, reflecting the players’ strategic possibilities,including their ability to make threats against one another. Applications of the value in economics have been rare, at least in part because the existing definition (for games with more than two players) consists of an ad hoc scheme that does not easily lend itself to computation. This paper makes three contributions: We provide an axiomatic foundation for the value; exhibit a simple formula for its computation; and extend the value—its definition, axiomatic characterization, and computational formula—to Bayesian games. We then apply the value in simple models of corruption, oligopolistic competition, and information sharing.
Morphogenesis and differentiation are important stages in organ development and shape determination. However, how they are balanced and tuned during development is not fully understood. In the compound leaved tomato, an extended morphogenesis phase allows for the initiation of leaflets, resulting in the compound form. Maintaining a prolonged morphogenetic phase in early stages of compound-leaf development in tomato is dependent on delayed activity of several factors that promote differentiation, including the CIN-TCP transcription factor (TF) LA, the MYB TF CLAU and the plant hormone Gibberellin (GA), as well as on the morphogenesis-promoting activity of the plant hormone cytokinin (CK). Here, we investigated the genetic regulation of the morphogenesis-differentiation balance by studying the relationship between LA, CLAU, TKN2, CK and GA. Our genetic and molecular examination suggest that LA is expressed earlier and more broadly than CLAU and determines the developmental context of CLAU activity. Genetic interaction analysis indicates that LA and CLAU likely promote differentiation in parallel genetic pathways. These pathways converge downstream on tuning the balance between CK and GA. Comprehensive transcriptomic analyses support the genetic data and provide insights into the broader molecular basis of differentiation and morphogenesis processes in plants.
The variability in leaf form in nature is immense. Leaf patterning occurs by differential growth, taking place during a limited window of morphogenetic activity at the leaf marginal meristem. While many regulators have been implicated in the designation of the morphogenetic window and in leaf patterning, how these effectors interact to generate a particular form is still not well understood. We investigated the interaction among different effectors of tomato (Solanum lycopersicum) compound-leaf development, using genetic and molecular analyses. Mutations in the tomato auxin response factor SlARF5/SlMP, which normally promotes leaflet formation, suppressed the increased leaf complexity of mutants with extended morphogenetic window. Impaired activity of the NAC/CUC transcription factor GOBLET (GOB), which specifies leaflet boundaries, also reduced leaf complexity in these backgrounds. Analysis of genetic interactions showed that the patterning factors SlMP, GOB and the MYB transcription factor LYRATE (LYR) coordinately regulate leaf patterning by modulating in parallel different aspects of leaflet formation and shaping. This work places an array of developmental regulators in a morphogenetic context. It reveals how organ-level differentiation rate and local growth are coordinated to sculpture an organ. These concepts are applicable to the coordination of pattering and differentiation in other species and developmental processes.
The role the mammary epithelial circadian clock plays in gland development and lactation is unknown. We hypothesized that mammary epithelial clocks function to regulate mammogenesis and lactogenesis, and propose the core clock transcription factor BMAL1:CLOCK regulates genes that control mammary epithelial development and milk synthesis. Our objective was to identify transcriptional targets of BMAL1 in undifferentiated (UNDIFF) and lactogen differentiated (DIFF) mammary epithelial cells (HC11) using ChIP-seq. Ensembl gene IDs with the nearest transcriptional start site to ChIP-seq peaks were explored as potential targets, and represented 846 protein coding genes common to UNDIFF and DIFF cells and 2773 unique to DIFF samples. Genes with overlapping peaks between samples (1343) enriched cell-cell adhesion, membrane transporters and lipid metabolism categories. To functionally verify targets, an HC11 line with Bmal1 gene knocked out (BMAL1-KO) using CRISPR-CAS was created. BMAL1-KO cultures had lower cell densities over an eight-day growth curve, which was associated with increased (p<0.05) levels of reactive oxygen species and lower expression of superoxide dismutase 3 (Sod3). RT-qPCR analysis also found lower expression of the putative targets, prolactin receptor (Prlr), Ppara, and beta-casein (Csn2). Findings support our hypothesis and highlight potential importance of clock in mammary development and substrate transport.
The coronavirus disease 2019 (COVID-19) pandemic stimulated both the scientific community and healthcare companies to undertake an unprecedented effort with the aim of understanding the molecular mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and developing effective therapeutic solutions. The peculiar immune response triggered by this virus, which seems to last only few months, led to a search for alternatives such as passive immunization in addition to conventional vaccinations. Convalescent sera, monoclonal antibodies selected from the most potent neutralizing binders induced by the virus infection, recombinant human single-domain antibodies, and binders of variable scaffold and different origin have been tested alone or in combination exploiting monovalent, multivalent and multispecific formats. In this review, we analyse the state of the research in this field and present a summary of the ongoing projects finalized to identify suitable molecules for therapies based on passive immunization.
The coronavirus disease 2019 (COVID-19) pandemic stimulated both the scientific community and healthcare companies to undertake an unprecedented effort with the aim of understanding the molecular mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and developing effective therapeutic solutions. The peculiar immune response triggered by this virus, which seems to last only few months, led to a search for alternatives such as passive immunization in addition to conventional vaccinations. Convalescent sera, monoclonal antibodies selected from the most potent neutralizing binders induced by the virus infection, recombinant human single-domain antibodies, and binders of variable scaffold and different origin have been tested alone or in combination exploiting monovalent, multivalent and multispecific formats. In this review, we analyse the state of the research in this field and present a summary of the ongoing projects finalized to identify suitable molecules for therapies based on passive immunization.
