In this paper, we introduce a mortar-based approach to discretizing flow in fractured porous media, which we term the mixed-dimensional flux coupling scheme. Our formulation is agnostic to the ...discretizations used to discretize the fluid flow equations in the porous medium and in the fractures, and as such it represents a unified approach to integrated fractured geometries into any existing discretization framework. In particular, several existing discretization approaches for fractured porous media can be seen as special instances of the approach proposed herein. We provide an abstract stability theory for our approach, which provides explicit guidance into the grids used to discretize the fractures and the porous medium, as dependent on discretization methods chosen for the respective domains. The theoretical results are sustained by numerical examples, wherein we utilize our framework to simulate flow in 2D and 3D fractured media using control volume methods (both two- and multi-point flux), Lagrangian finite element methods, mixed finite element methods, and virtual element methods. As expected, regardless of the ambient methods chosen, our approach leads to stable and convergent discretizations for the fractured problems considered, within the limits of the discretization schemes.
ABSTRACT
The abundance of galaxy clusters is a sensitive probe to the amplitude of matter density fluctuations, the total amount of matter in the Universe as well as its expansion history. Inferring ...correct values and accurate uncertainties of cosmological parameters requires accurate knowledge of cluster abundance statistics, encoded in the likelihood function. In this paper, we test the accuracy of cluster abundance likelihoods used in the literature, namely the Poisson and Gaussian likelihoods as well as the more complete description of the Gauss–Poisson Compound likelihood. This is repeated for a variety of binning choices and analysis setups. In order to evaluate the accuracy of a given likelihood, this work compares individual posterior covariances to the covariance of estimators over the 1000 simulated dark matter halo catalogues obtained from PINOCCHIO algorithm. We find that for Rubin/LSST and Euclid-like surveys the Gaussian likelihood gives robust constraints over a large range of binning choices. The Poisson likelihood, that does not account for sample covariance, always underestimates the errors on the parameters, even when the sample volume is reduced or only high-mass clusters are considered. We find no benefit in using the more complex Gauss–Poisson Compound likelihood as it gives essentially the same results as the Gaussian likelihood, but at a greater computational cost. Finally, in this ideal setup, we note only a small gain on the parameter error bars when using a large number of bins in the mass–redshift plane.
The present study aims to identify antigens in protein extracts of promastigote and amastigote-like Leishmania (Leishmania) chagasi syn. L. (L.) infantum recognized by antibodies present in the sera ...of dogs with asymptomatic and symptomatic visceral leishmaniasis (VL).
Proteins recognized by sera samples were separated by two-dimensional electrophoresis (2DE) and identified by mass spectrometry. A total of 550 spots were observed in the 2DE gels, and approximately 104 proteins were identified. Several stage-specific proteins could be identified by either or both classes of sera, including, as expected, previously known proteins identified as diagnosis, virulence factors, drug targets, or vaccine candidates. Three, seven, and five hypothetical proteins could be identified in promastigote antigenic extracts; while two, eleven, and three hypothetical proteins could be identified in amastigote-like antigenic extracts by asymptomatic and symptomatic sera, as well as a combination of both, respectively.
The present study represents a significant contribution not only in identifying stage-specific L. infantum molecules, but also in revealing the expression of a large number of hypothetical proteins. Moreover, when combined, the identified proteins constitute a significant source of information for the improvement of diagnostic tools and/or vaccine development to VL.
Treatment against visceral leishmaniasis (VL) presents problems by the toxicity of drugs, high cost and/or emergence of resistant strains. The diagnosis is hampered by variable sensitivity and/or ...specificity of tests. In this context, prophylactic vaccination could represent a control measure against disease. In this study, the protective efficacy of Leishmania LiHyC protein was evaluated in a murine model against Leishmania infantum infection. LiHyC was used as recombinant protein (rLiHyC) associated with saponin (rLiHyC/S) or Poloxamer 407‐based polymeric micelles (rLiHyC/M) to immunize mice. Animals received also saline, saponin or empty micelles as controls. The immunogenicity was evaluated before and after the challenge, and results showed that vaccination with rLiHyC/S or rLiHyC/M induced the production of high levels of interferon‐gamma (IFN‐γ), interleukin (IL)‐12 and granulocyte‐macrophage colony‐stimulating factor in cell culture supernatants, as well as higher IFN‐γ expression evaluated by RT‐qPCR and involvement from CD4+ and CD8+ T‐cell subtypes producing IFN‐γ, tumor necrosis factor‐α and IL‐2. A positive lymphoproliferative response was also found in cell cultures from vaccinated animals, besides high levels of rLiHyC‐ and parasite‐specific nitrite and IgG2a antibodies. Immunological assays correlated with significant reductions in the parasite load in the spleens, livers, bone marrows and draining lymph nodes from vaccinated mice, when compared to values found in the controls. The micellar composition showed slightly better immunological and parasitological data, as compared to rLiHyC/S. Results suggest that rLiHyC associated with adjuvants could be considered for future studies as a vaccine candidate against VL.
The serodiagnosis of human tegumentary leishmaniasis (TL) presents some problems, such as the low level of antileishmanial antibodies found in most of the patients, as well as the cross-reactivity in ...subjects infected by other trypanosomatids. In the present study, an immunoproteomic approach was performed aimed at identification of antigens in total extracts of stationary-phase promastigote and amastigote-like forms of Leishmania (Viannia) braziliensis using sera from TL patients. With the purpose of reducing the cross-reactivity of the identified proteins, spots recognized by sera from TL patients, as well as those recognized by antibodies present in sera from noninfected patients living in areas where TL is endemic and sera from Chagas disease patients, were discarded. Two Leishmania hypothetical proteins and 18 proteins with known functions were identified as antigenic. The study was extended with some of them to validate the results of the immunoscreening. The coding regions of five of the characterized antigens (enolase, tryparedoxin peroxidase, eukaryotic initiation factor 5a, β-tubulin, and one of the hypothetical proteins) were cloned in a prokaryotic expression vector, and the corresponding recombinant proteins were purified and evaluated for the serodiagnosis of TL. The antigens presented sensitivity and specificity values ranging from 95.4 to 100% and 82.5 to 100%, respectively. As a comparative antigen, a preparation of Leishmania extract showed sensitivity and specificity values of 65.1 and 57.5%, respectively. The present study has enabled the identification of proteins able to be employed for the serodiagnosis of TL.
•Combination of rLiHyp1, MPLA and AmpB was an effective immunotherapy in L. infantum-infected BALB/c. mice.•A Th1-type immune response was developed after treatment using rLiHyp1/MPLA/AmpB.•This ...combination reduced the parasite load in all organs compared to controls.
Treatment of visceral leishmaniasis (VL) is compromised by drug toxicity, high cost and/or the emergence of resistant strains. Though canine vaccines are available, there are no licensed prophylactic human vaccines. One strategy to improve clinical outcome for infected patients is immunotherapy, which associates a chemotherapy that acts directly to reduce parasitism and the administration of an immunogen-adjuvant that activates the host protective Th1-type immune response. In this study, we evaluated an immunotherapy protocol in a murine model by combining recombinant (r)LiHyp1 (a hypothetical amastigote-specific Leishmania protein protective against Leishmania infantum infection), with monophosphoryl-lipid A (MPLA) as adjuvant and amphotericin B (AmpB) as reference antileishmanial drug. We used this protocol to treat L. infantum infected-BALB/c mice, and parasitological, immunological and toxicological evaluations were performed at 1 and 30 days after treatment. Results showed that mice treated with rLiHyp1/MPLA/AmpB presented the lowest parasite burden in all organs evaluated, when both a limiting dilution technique and qPCR were used. In addition, these animals produced higher levels of IFN-γ and IL-12 cytokines and IgG2a isotype antibody, which were associated with lower production of IL-4 and IL-10 and IgG1 isotype. Furthermore, low levels of renal and hepatic damage markers were found in animals treated with rLiHyp1/MPLA/AmpB possibly reflecting the lower parasite load, as compared to the other groups. We conclude that the rLiHyp1/MPLA/AmpB combination could be considered in future studies as an immunotherapy protocol to treat against VL.
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•Two synthetic derivatives from vanillin were used against L. infantum infection.•They were incorporated into Poloxamer 407-containing polymeric micelles.•The compositions were ...effective to treat infected BALB/c mice.•Treated animals showed low parasitism, Th1-type immunity and any toxicity.•Higher therapeutic efficacy was found as compared to amphotericin B and Ambisome®.
Treatment against visceral leishmaniasis (VL) presents problems, mainly related to drug toxicity, high cost and/or by emergence of resistant strains. In the present study, two vanillin synthetic derivatives, 3 s 4-(2-hydroxy-3-(4-octyl-1H-1,2,3-triazol-1-yl)propoxy)-3-methoxybenzaldehyde and 3 t 4-(3-(4-decyl-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)-3-methoxybenzaldehyde, were evaluated as therapeutic candidates in a murine model against Leishmania infantum infection. Molecules were used pure (3 s and 3 t) or incorporated into Poloxamer 407-based micelles (3 s/M and 3 t/M) in the infected animals, which also received amphotericin B (AmpB) or Ambisome® as control. Results showed that 3 s/M and 3 t/M compositions induced a Th1-type immune response in treated animals, with higher levels of IFN-γ, IL-2, TNF-α, IL-12, nitrite, and IgG2a antibodies. Animals presented also low toxicity and significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, as compared as control groups mice, with the evaluations performed one and 30 days after the application of the therapeutics. In conclusion, preliminary data suggest that 3 s/M and 3 t/M could be considered for future studies as therapeutic agents against VL.
This article analyzes the dispositio and ordinatio of the most important and popular edition of the works of the Mexican poet and nun, Sor Juana Inés
de la Cruz: those planned by Daniel Cossío ...Villegas and Pedro Henríquez Ureña at
the beginning of the Biblioteca Americana collection by the publishing house Fondo
de Cultura Económica and carried out by Alfonso Méndez Plancarte and Alberto
G. Salceda. After its critical and historical consideration, the different dispositio of
its first early editions are analyzed based on its paratextual function, which gives
meaning to the entire book and the entire work. Based on both analyses, the decision of the modern edition to reorganize the materials without considering the
meanings that the dispositio granted is questioned
En este artículo se analizan las dispositio y ordinatio de la edición más importante y divulgada de las obras de la poeta y monja mexicana, sor Juana Inés de la Cruz: aquellas planeadas por Daniel Cossío Villegas y Pedro Henríquez Ureña en los inicios de la Biblioteca Americana de la editorial Fondo de Cultura Económica y llevadas a cabo por Alfonso Méndez Plancarte y Alberto G. Salceda. Luego de su consideración crítica e histórica se analizan las distintas dispositio de sus primeras ediciones antiguas a partir de su función paratextual, que otorga sentido a todo el libro y a toda la obra. A partir de ambos análisis se cuestiona la decisión de la edición moderna de reorganizar los materiales sin contemplar los sentidos que la dispositio otorgaba.
Amphotericin B (AmpB) is active against leishmaniasis, but its use is hampered due to its high toxicity observed in patients. In this study, a nanoparticles-delivery system for AmpB (NQC-AmpB), ...containing chitosan and chondroitin sulfate molecules, was evaluated in BALB/c mice against Leishmania amazonensis. An in vivo biodistribution study, including biochemical and toxicological evaluations, was performed to evaluate the toxicity of AmpB. Nanoparticles were radiolabeled with technetium-99m and injected in mice. The products presented a similar biodistribution in the liver, spleen, and kidneys of the animals. Free AmpB induced alterations in the body weight of the mice, which, in the biochemical analysis, indicated hepatic and renal injury, as well as morphological damage to the kidneys of the animals. In general, no significant organic alteration was observed in the animals treated with NQC-AmpB. Mice were infected with L. amazonensis and treated with the nanoparticles or free AmpB; then, parasitological and immunological analyses were performed. The NQC-AmpB group, as compared to the control groups, presented significant reductions in the lesion size and in the parasite burden in all evaluated organs. These animals presented significantly higher levels of IFN-γ and IL-12, and low levels of IL-4 and IL-10, when compared to the control groups. The NQC-AmpB system was effective in reducing the infection in the animals, and proved to be effective in diminishing the toxicity evoked by AmpB, which was observed when it was administered alone. In conclusion, NQC-AmpB could be considered a viable possibility for future studies in the treatment of leishmaniasis.
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