The characterization of protein binding sites is a major challenge in computational biology. Proteins interact with a wide variety of molecules and understanding of such complex interactions is ...essential to gain deeper knowledge of protein function. Shape complementarity is known to be important in determining protein-ligand interactions. Furthermore, these protein structural features have been shown to be useful in assisting medicinal chemists during lead discovery and optimization.
We developed KVFinder, a highly versatile and easy-to-use tool for cavity prospection and spatial characterization. KVFinder is a geometry-based method that has an innovative customization of the search space. This feature provides the possibility of cavity segmentation, which alongside with the large set of customizable parameters, allows detailed cavity analyses. Although the main focus of KVFinder is the steered prospection of cavities, we tested it against a benchmark dataset of 198 known drug targets in order to validate our software and compare it with some of the largely accepted methods. Using the one click mode, we performed better than most of the other methods, staying behind only of hybrid prospection methods. When using just one of KVFinder's customizable features, we were able to outperform all other compared methods. KVFinder is also user friendly, as it is available as a PyMOL plugin, or command-line version.
KVFinder presents novel usability features, granting full customizable and highly detailed cavity prospection on proteins, alongside with a friendly graphical interface. KVFinder is freely available on http://lnbio.cnpem.br/bioinformatics/main/software/.
Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In ...this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification.
Background Phospholamban ( PLN ) is a crucial Ca2+ cycling protein and a primary mediator of the β-adrenergic effects resulting in enhanced cardiac output. Mutations in the gene encoding PLN have ...been associated with idiopathic dilated cardiomyopathy; however, no systematic search for PLN mutations in heart failure has been conducted. Methods We screened a cohort of 1,014 Brazilian patients with heart failure for mutations in the PLN gene. Molecular modeling studies of the mutations found were developed. Different disease etiologies were present in our sample: idiopathic, ischemic, Chagas, valvular, hypertensive, and others. Results We identified 4 unrelated patients with PLN mutations (prevalence of 0.4%), 3 of them in the same amino acid residue (R9). Two patients presented a G-T missense mutation at the G26 nucleotide, which encodes an Arg-Leu substitution at codon 9 (R9L). One patient presented a G-A missense mutation at the same nucleotide, which encodes an Arg-His substitution at codon 9 (R9H). The fourth affected patient presented a T-G nonsense mutation at the nucleotide 116, substituting a termination codon for Leu-39 (L39stop). Molecular modeling studies suggested that R9L and R9H mutations might affect the region involved in protein kinase A docking and probably affect the mechanism modulating the release of phosphorylated PLN from the substrate binding site of protein kinase A. Conclusions Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology. The Arg9 and Leu39 residues are the leading location of mutations described at this locus to date. Despite the few mutated residues described to date, the clinical spectrum of presentation appears to vary considerably.
Thermal decomposition of coffee husks was investigated by thermogravimetric analyses. The proximate, ultimate and composition analyses were performed. Thermogravimetric tests were realized, the ...material was heated to 1173 K using five heating rates: 5, 10, 15, 20, 25 K min-1. The kinetic parameters were estimated using the methods of Kissinger-Akahira-Sunose and Friedman, the distributed activation energy model and the independent parallel reactions model. The isoconversional models of Kissinger-Akahira-Sunose and Friedman showed the dependence between determined values of activation energy and mass conversion, the activation energy values varied from 1437.39 to 199.22 kJ mol-1 for Kissinger-Akahira-Sunose and from 127.81 to 230.35 kJ mol-1 for Friedman model. The values of activation energy were determined for Miura-Maki method; varying from 137.39 to 199.22 kJ mol-1. The model of parallel and independent reactions showed the presence of six different reactions (with activation energy values varying from 42.0 to 214.2 kJ mol-1) occurring during coffee husks pyrolysis, indicating a complex reaction. Currently, works regarding the determination of kinetic parameters for coffee husks pyrolysis are not common. The present work is the first report using the model of parallel and independent reactions to estimate kinetic parameters for pyrolysis of coffee husks, a residue widely generated worldwide.
Summary
The release of extracellular vesicles (EV) by fungal organisms is considered an alternative transport mechanism to trans‐cell wall passage of macromolecules. Previous studies have revealed ...the presence of EV in culture supernatants from fungal pathogens, such as Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii, Malassezia sympodialis and Candida albicans. Here we investigated the size, composition, kinetics of internalization by bone marrow‐derived murine macrophages (MO) and dendritic cells (DC), and the immunomodulatory activity of C. albicans EV. We also evaluated the impact of EV on fungal virulence using the Galleria mellonella larvae model. By transmission electron microscopy and dynamic light scattering, we identified two populations ranging from 50 to 100 nm and 350 to 850 nm. Two predominant seroreactive proteins (27 kDa and 37 kDa) and a group of polydispersed mannoproteins were observed in EV by immunoblotting analysis. Proteomic analysis of C. albicans EV revealed proteins related to pathogenesis, cell organization, carbohydrate and lipid metabolism, response to stress, and several other functions. The major lipids detected by thin‐layer chromatography were ergosterol, lanosterol and glucosylceramide. Short exposure of MO to EV resulted in internalization of these vesicles and production of nitric oxide, interleukin (IL)‐12, transforming growth factor‐beta (TGF‐β) and IL‐10. Similarly, EV‐treated DC produced IL‐12p40, IL‐10 and tumour necrosis factor‐alpha. In addition, EV treatment induced the up‐regulation of CD86 and major histocompatibility complex class‐II (MHC‐II). Inoculation of G. mellonella larvae with EV followed by challenge with C. albicans reduced the number of recovered viable yeasts in comparison with infected larvae control. Taken together, our results demonstrate that C. albicans EV were immunologically active and could potentially interfere with the host responses in the setting of invasive candidiasis.
This work aims to investigate the slow pyrolysis of sunflower seed residues using thermogravimetric tests carried out at five heating rates: 5, 10, 15, 20, and 25 K min
−1
. The kinetic triplet for ...global reaction, represented by activation energy (
E
a
), Arrhenius pre-exponential factor (
A
), and reaction mechanism (
f
α
)
, and the kinetic parameters for pseudo-components were determined. Thermodynamic activation parameters as enthalpy, Gibbs free energy, and entropy were calculated by using the transition state theory. The
E
a
values determined by isoconversional methods varied between 79.11 and 162.57 kJ mol
−1
, and the master plots methodology indicated the reaction mechanism of sunflower seed residues as the three-dimensional Jader equation, resulting in global parameters of 102.51 kJ mol
−1
and 8.96 × 10
5
s
−1
for
E
a
and
A
, respectively. The presence of three pseudo-components (hemicelluloses, cellulose, and lignin) was considered for the modeling of independent parallel reactions, which resulted in
E
a
values ranging from 72.4 to 170.2 kJ mol
−1
and the
A
values ranging from 1.31×10
4
mol
−2
s
−1
to 1.21×10
13
mol
−1
s
−1
, with reaction orders varying between 1 and 3. The values of thermodynamic parameters indicated that the pyrolysis of sunflower residues tends to remain continuous once the necessary energy is supplied and that the activated state presented a higher degree of organization than the reactants. This present work is the first one to investigate the kinetic triplet and the independent parallel reaction model for sunflower residue pyrolysis. The results were useful for biomass management, indicating the kinetic and thermodynamic values for pyrolysis optimization.
PYROLYSIS KINETICS FOR LIGNOCELLULOSIC SORGHUM: THERMOGRAVIMETRIC DATA ANALYSIS FOR FRIEDMAN MODEL APPLICATION. Renewable resources are alternatives to fossil fuels and pyrolysis is identified as a ...process for the generation of biofuel products. The lignocellulosic sorghum is a cereal produced in brazil and it presents several applications, such as the production of second-generation ethanol. The present work aimed to study the slow pyrolysis of lignocellulosic sorghum, the biomass was characterized by means of proximate, ultimate, composition and carbohydrate analyzes. Thermogravimetric analyzes were performed with heating rates between 5 and 25 K min-1 and with N2 atmosphere. The Friedman model allows obtaining the kinetic parameters of biomass decomposition and is widely used due to its simplicity and precision; however, since it is sensitive to experimental noise, an algorithm was developed for the calculation of kinetic parameters for the slow pyrolysis of this biomass, enabling an accurate analysis of the experimental data. The activation energy found by the proposed methodology was 122.65 ± 19.24 kJ mol-1, with determination coefficients above 0.97. The comparison between experimental and theoretical data presented deviation values of 0.934%, 3.408% and 1.101% for heating rates of 5, 10 and 15 K min-1, respectively, showing the accuracy for the determined kinetic parameters.
Dengue is a mild flu-like arboviral illness caused by dengue virus (DENV) that occurs in tropical and subtropical countries. An increasing number of reports have been indicating that dengue is also ...associated to neurological manifestations, however, little is known regarding the neuropathogenesis of the disease. Here, using BALB/c mice intravenously infected with DENV-2 strain 66985, we demonstrated that the virus is capable of invading and damaging the host's central nervous system (CNS). Brain and cerebellum of infected animals revealed histological alterations such as the presence of inflammatory infiltrates, thickening of pia matter and disorganization of white matter. Additionally, it was also seen that infection lead to altered morphology of neuroglial cells and apoptotic cell death. Such observations highlighted possible alterations that DENV may promote in the host's CNS during a natural infection, hence, helping us to better understand the neuropathological component of the disease.
Despite higher rates of sustained virologic response (SVR), important concerns remain when patients with decompensated cirrhosis due to hepatitis C virus (HCV) are treated with direct-acting ...antiviral agents (DAA). Questions include efficacy, safety, and the magnitude of liver function improvement. Here, we aimed to evaluate HCV treatment data in this specific population in Brazil.
We included 85 patients with decompensated cirrhosis submitted to HCV therapy with DAA followed at two academic tertiary centers in the southeastern region of Brazil.
Seventy-nine patients (92.9%) were Child-Pugh (CP) score B, and six (7.1%) were CP score C. The mean MELD score was 12.86. The most common treatment was sofosbuvir plus daclatasvir±ribavirin for 24 weeks. The overall intention-to-treat (ITT) SVR rate was 87.4% (74/85) and modified-ITT 96.1% (74/77). ITT SVR was associated with lower baseline INR values (p=0.029). Adverse events (AE) occurred in 57.9% (44/76) of patients. Serious AE were reported in 12.8% (10/78), and were related to the presence of hepatic encephalopathy (p=0.027). SVR was associated with improvement in CP (p<0.0001) and MELD scores (p=0.021). Among baseline CP score B patients with SVR, 46% (29/63) regressed to CP score A. Ascites was independently associated with no improvement in liver function in patients who achieved SVR (p=0.001; OR:39.285; 95% CI:4.301-258.832).
Patients with decompensated HCV cirrhosis showed a high SVR rate with interferon-free therapy. Early liver function improvement occurred after successful HCV eradication. However, long-term follow-up of these patients after SVR remains strongly advised.
Introduction
This study aimed to compare athletes practicing exercise in different environments with non-active young and elderly men and women regarding bone mineral density (BMD), hypothesizing ...that BMD values differ between athletes according to the environment of exercise practice, but those training in a low-gravitational environment have no different stimuli to BMD increasing if compared with healthy peers experiencing reduced exercise involvement, whatever the age group and sex.
Materials and methods
104 participants of both sexes were selected according to the environment of exercise practice swimmers (
N
= 26) and judo fighters (
N
= 26), and exercise level of involvement non-active young (
N
= 26) and older adults (
N
= 26). Dual-energy X-ray absorptiometry provided BMD, lean mass, and fat mass (FM) for the whole body (WB), upper (UL), and lower limbs (LL).
Results
For the BMD in WB, UL and LL no effects of group and sex were observed (
p
> 0.05). Post-hoc analyses detected higher values of BMD in UL for female swimmers compared to non-active older adults (
p <
0.05), while judo fighters showed higher BMD in WB, UL, and LL than other participants whatever the sex (
p <
0.01). Lower FM was observed for WB, UL, and LL when swimmers and judo fighters were compared to non-active young and older female peers (
p <
0.01).
Conclusion
The findings emphasized that BMD stimuli with swimming are reduced when compared to judo, and despite the stimuli in swimming is not distinguishable from that affecting BMD in WB, UL and LL of non-active young, it is effective in differing BMD in UL among non-active older for women.
PDF
