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The world's spoken languages are universally composed of vowels and consonants, but the primate prototypical call repertoire is almost exclusively composed of vowel-like calls. What was the origin of consonant-like calls? Their prevalence across great apes suggests that an arboreal lifestyle and extractive foraging were ecological preconditions for speech evolution. [ABSTRACT FROM AUTHOR]

• Extract from Phyllanthus brasiliensis has antiviral activity against Zika virus. • Lignans from Phyllanthus brasiliensis reduce the Zika virus load. • Promising use of Phyllanthus brasiliensis in the treatment of Zika disease. Zika virus (ZIKV) is an emerging arbovirus that in recent years has been associated with cases of severe neurological disorders, such as microcephaly in newborns and Guillain-Barré syndrome in adults. As there is no vaccine or treatment, the search for new therapeutic targets is of great relevance. In this sense, plants are extremely rich sources for the discovery of new bioactive compounds and the species Phyllanthus brasiliensis (native to the Amazon region) remains unexplored. To investigate the potential antiviral activity of compounds isolated from P. brasiliensis leaves against ZIKV infection. In vitro antiviral assays were performed with justicidin B (a lignan) and four glycosylated lignans (tuberculatin, phyllanthostatin A, 5-O-β-d-glucopyranosyljusticidin B, and cleistanthin B) against ZIKV in Vero cells. MTT colorimetric assay was used to assess cell viability and plaque forming unit assay to quantify viral load. In addition, for justicidin B, tests were performed to investigate the mechanism of action (virucidal, adsorption, internalization, post-infection). The isolated compounds showed potent anti-ZIKV activities and high selectivity indexes. Moreover, justicidin B, tuberculatin, and phyllanthostatin A completely reduced the viral load in at least one of the concentrations evaluated. Among them, justicidin B stood out as the main active, and further investigation revealed that justicidin B exerts its antiviral effect during post-infection stages, resulting in a remarkable 99.9 % reduction in viral load when treatment was initiated 24 h after infection. Our findings suggest that justicidin B inhibits endosomal internalization and acidification, effectively interrupting the viral multiplication cycle. Therefore, the findings shed light on the promising potential of isolated compounds isolated from P. brasiliensis , especially justicidin B, which could contribute to the drug development and treatments for Zika virus infections. [Display omitted] [ABSTRACT FROM AUTHOR]

Yellow fever (YF) presents a wide spectrum of severity, with clinical manifestations in humans ranging from febrile and self-limited to fatal cases. Although YF is an old disease for which an effective and safe vaccine exists, little is known about the viral- and host-specific mechanisms that contribute to liver pathology. Several studies have demonstrated that oxidative stress triggered by viral infections contributes to pathogenesis. We evaluated whether yellow fever virus (YFV), when infecting human hepatocytes cells, could trigger an imbalance in redox homeostasis, culminating in oxidative stress. YFV infection resulted in a significant increase in reactive oxygen species (ROS) levels from 2 to 4 days post infection (dpi). When measuring oxidative parameters at 4 dpi, YFV infection caused oxidative damage to lipids, proteins, and DNA, evidenced by an increase in lipid peroxidation/8-isoprostane, carbonyl protein, and 8-hydroxy-2′-deoxyguanosine, respectively. Furthermore, there was a significant reduction in the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), in addition to a reduction in the ratio of reduced to oxidized glutathione (GSH/GSSG), indicating a pro-oxidant environment. However, no changes were observed in the enzymatic activity of the enzyme catalase (CAT) or in the gene expression of SOD isoforms (1/2/3), CAT, or GPx. Therefore, our results show that YFV infection generates an imbalance in redox homeostasis, with the overproduction of ROS and depletion of antioxidant enzymes, which induces oxidative damage to cellular constituents. Moreover, as it has been demonstrated that oxidative stress is a conspicuous event in YFV infection, therapeutic strategies based on antioxidant biopharmaceuticals may be new targets for the treatment of YF. [Display omitted] • Yellow fever virus induces increase in reactive oxygen species (ROS). • Yellow fever virus triggers oxidative stress cellular response. • Yellow fever virus reduces the activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). • Oxidative stress may be an important factor in the hepatic pathogenesis of Yellow fever. [ABSTRACT FROM AUTHOR]

Speech evolution seems to defy scientific explanation. Progress on this front has been jammed in an entrenched orthodoxy about what great apes can and (mostly) cannot do vocally, an idea epitomized by the Kuypers/Jürgens hypothesis. Findings by great ape researchers paint, however, starkly different and more optimistic landscapes for speech evolution. Over twenty studies qualify as positive evidence for primate vocal (production) learning following accepted terminology. Additionally, the Kuypers/Jürgens hypothesis shows low etymological, empirical, and theoretical soundness. Great apes can produce novel voiced calls and voluntarily control their modification – observations supposedly impossible. Furthermore, no valid pretext justifies dismissing heuristically the production of new voiceless consonant-like calls by great apes. To underscore this point, new evidence is provided for a novel supra-genera voiceless call across all great ape species. Their vocal invention and vocal learning faculties are real and sufficiently potent to, at times, uphold vocal traditions. These data overpower conventional predicaments in speech evolution theory and will help to make new strides explaining why, among hominids, only humans developed speech. [ABSTRACT FROM AUTHOR]

Transshipment operations around the world are in high demand, notably so in the Amazon. Usually, this type of operation occurs with mooring buoys. In Brazil, transshipment operations are handled with temporary use contracts of a maximum of 4 years. An adaptation of a method for fatigue analysis of this type of structure is proposed. This method uses computational modeling and simulation via the FEM, focusing on the points of greatest cyclical loading of the padeye, to estimate the useful life of this structural component through S–N curves and internationally recognized regulations. Thereunto, the main tensions in the buoy are obtained from the application of calculated forces for traction on a mooring cable at the bitt of the buoy, whose magnitudes satisfy ranges validated by means of instrumentation on board. The limitations of the method are based on environmental conditions corresponding to a river region with no tidal influence, a fact that allows simplification regarding the influence of waves. The results indicate that regular loads acting on the padeye can ensure a useful life as if the component were a medium-term anchored system since the minimum fatigue life for an applied load of 30 tf is 7.66 years. • Direct transshipment to Largo is an alternative for handling solid bulk. • Mooring buoys will be increasingly used for offshore transshipment operations. • An adaptation of a method for fatigue analysis via FEM was proposed. • Hot-spot stresses and S–N curves allowed estimating the fatigue life of the padeye. • This can indicate specific laws and regulations for offshore transshipment. [ABSTRACT FROM AUTHOR]

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Summary Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis ( M. tuberculosis ), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB. [ABSTRACT FROM AUTHOR]

• Taxonomic families have high potential as surrogates of stream fish diversity. • Cichlidae and Lebiasinidae are potential diversity surrogates in six Amazon basins. • Crenuchidae and Hypopomidae were good diversity surrogates in floodplain basins. • Characidae, Gymnotidae, Rivulidae were good diversity surrogates in upland basins. The reliable identification of the fish species found in Amazonian streams requires a considerable investment of both time and resources, which often hampers the biodiversity pattern mapping and conservation planning. This problem can be overcome using biological surrogates such taxonomic families, this would reduce the number of fish to be identified and thus facilitate the development of studies. The present study analyzes the potential of families as surrogates of the fish diversity of Amazonian streams. For this, we verified the degree of congruence between the distribution of species organized by family and the composition of the assemblage in two different spatial scenarios. At the biome scale, we verified the degree of congruence in the fish faunas of 54 streams located within six drainage basins in Brazilian Amazonia. At the regional scale, we compared the data from the basins located on the lowland floodplain and those at higher altitudes. The Cichlidae and Lebiasinidae were identified as potential biological surrogates at both spatial scenarios, demonstrating more than 80% similarity with species matrix in all the analytical approaches. The families Crenuchidae and Hypopomidae were the most congruent with the fish from the floodplain basins, both were more than 80% congruent with the species matrix. In upland basins, Characidae, Gymnotidae and Rivulidae were highly similar to the species matrix, in particular Gymnotidae and Rivulidae with more than 90% similarity. Overall, we can conclude that the biological surrogacy approach is a potentially valuable alternative for species diversity evaluation of Amazonian streams ecosystems, considering the accelerated loss of the diversity of these systems. [ABSTRACT FROM AUTHOR]

Abstract: The human footprint is increasing across the world’s natural habitats, causing large negative impacts on the survival of many species. In order to successfully mitigate the negative effects on species’ survival, it is crucial to understand their responses to human-induced changes. This paper examines the effect of one such disturbance, logging, on Sumatran orangutans – a critically endangered great ape. Orangutan population densities may decrease or remain stable after logging, but data on the effects of logging on the behavior of individuals is scant. Here, we provide individual-level behavioral data based on direct observations in 2003–2008 at the Ketambe (Sumatra, Indonesia) research area (partly subject to intense selective logging) in order to assess responses of Sumatran orangutans to logging. Logging significantly negatively affected forest structure and orangutan food resources, specifically important fallback and liana-derived foods. Individual orangutans behaved differently between logged and pristine forest; they moved more and rested less in logged forest. With the exception of figs, diet composition remained overall similar. Altogether, life after logging seems energetically more expensive for orangutans. Based on the results of this study, we provide recommendations for conservation research and guidelines for reduced-impact logging. [Copyright &y& Elsevier]

Abstract: Introduction: While in developed countries prenatal diagnosis is currently used to detect Congenital Heart Disease before (CHD) before birth, in developing countries only a minority of children with CHD is detected and few benefit from surgical treatment. Having created a referral unit for diagnosis and treatment of cardiovascular diseases in a resource-deprived country we designed a study aiming at describing the spectrum and characteristics of CHD and discuss the challenges of its management. Population and methods: We studied retrospectively all patients assisted at a referral unit between 2001 and 2007, collecting epidemiological, clinical, echocardiographic and surgical data from hospital files. Results: We studied 534 patients with median age at diagnosis of 4years (range 0–79); 296 were females (55.4%). Only 282 (52.8%) patients were diagnosed under the age of two years, and complications were present in 155 (29.0%) at time of diagnosis. We operated 196 patients with mean age of 8±10years. Only 29 of the 111 complex defects were considered for surgery. The 30-days post-operative mortality was 8/196 (4.0%). The most important post-surgical complications were post pericardectomy syndrome (22). Discussion: A pattern of late presentation accompanied by high rate of complications was found. In resource-deprived settings the approach to the management of CHD emphasizes the treatment of “curable” malformations. Surgery for CHD in these settings must be linked to early detection and a referral system in which general practitioners, pediatricians, obstetricians and cardiologists interact in the design and implementation protocols for diagnosis, management and follow-up of patients. [Copyright &y& Elsevier]

Objective: Recognition of body parts activates specific somatosensory representations in a way that similar to motor imagery. These representations are implicitly activated to compare the body with the stimulus. In the present study, we investigate the influence of proprioceptive information relating to body posture on the recognition of body parts (hands). It proposes that this task could be used for rehabilitation of neurological patients. Methods: Ten right-handed volunteers participated in this experiment. The task was to recognize the handedness of drawings of a hand that were presented in different perspectives and several orientations. For drawings of a right hand, the volunteers pressed the right key, and for drawings of a left hand, they pressed the left key. The volunteers underwent two sessions: one with their hands in a prone posture and the other with their hands in a supine posture. Results: The manual reaction time was longer for perspectives and orientations for which the real movement was difficult to achieve. This showed that, during the task, motor representations were activated to compare the body with the stimulus. Furthermore, the subject's posture had an influence in relation to specific perspectives and orientations, Conclusions: These results showed that motor representations are activated to compare the body with the stimulus, and that the position of the hand influences this resonance between the stimulus and the body part. [ABSTRACT FROM AUTHOR]

Objective: Recognition of body parts activates specific somatosensory representations in a way that is similar to motor imagery. These representations are implicitly activated to compare the body with the stimulus. In the present study, we investigate the influence of proprioceptive information relating to body posture on the recognition of body parts (hands). It proposes that this task could be used for rehabilitation of neurological patients. Methods: Ten right-handed volunteers participated in this experiment. The task was to recognize the handedness of drawings of a hand that were presented in different perspectives and several orientations. For drawings of a right hand, the volunteers pressed the right key, and for drawings of a left hand, they pressed the left key. The volunteers underwent two sessions: one with their hands in a prone posture and the other with their hands in a supine posture. Results: The manual reaction time was longer for perspectives and orientations for which the real movement was difficult to achieve. This showed that, during the task, motor representations were activated to compare the body with the stimulus. Furthermore, the subject's posture had an influence in relation to specific perspectives and orientations. Conclusions: These results showed that motor representations are activated to compare the body with the stimulus, and that the position of the hand influences this resonance between the stimulus and the body part. [ABSTRACT FROM AUTHOR]

Abstract: Human immunodeficiency virus type-1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Flavone compounds have been very much studied due to their activity during the inhibition process of HIV-1 IN. In this study, we employed density functional theory (DFT) using the B3LYP hybrid functional to calculate a set of molecular properties for 32 flavonoid compounds with anti-HIV-1 IN activity. The stepwise discriminant analysis (SDA), principal component analysis (PCA) and hierarchical cluster analysis (HCA) methods were employed to reduce dimensionality and investigate possible relationship between the calculated properties and the anti-HIV-1 IN activity. These analyses showed that the molecular hydrophobicity (Clog P), charge on atom 11 and electrophilic index (ω) are responsible for the separation between anti-HIV-1 IN active and inactive compounds. [Copyright &y& Elsevier]

Abstract: Quantum chemical calculations at the DFT/B3LYP theory level, with the 6-31G* basis set, was employed to calculate a set of molecular properties of 26 flavonoid compounds with anti-HIV activity. The correlation between biological activity and structural properties was obtained by using the multiple linear regression method. The model obtained showed not only statistical significance but also predictive ability. We demonstrate in this paper that the anti-HIV activity of compounds can be related with the molecular hydrophobicity (ClogP), the electronegativity (χ) and the charges on some key atoms, while that the toxicity can be related with the electronic affinities (EA), ClogP and charge on atom 8. [Copyright &y& Elsevier]

• Critically ill patients are more vulnerable to corneal injury. • Lagophthalmos and chemosis contribute to the development of corneal injury. • An eye care protocol is an essential component of critically ill patients' care. To identify the incidence and risk factors for corneal injury amongst critically ill patients. A prospective cohort study with adult patients from one intensive care unit in Northern Brazil. Logistic regression was performed to predict the risk factors associated with corneal injury. Data from 149 patients revealed 18.8% (28/149) corneal injuries. Factors independently associated with corneal injury were patients with eyeball exposure (OR: 27.31; 95% CI: 3.50–212.78); lagophthalmos (OR: 17.15; 95% CI: 5.78–50.85); chemosis (OR: 7.39; 95% CI: 2.28–23.97), periorbital oedema (OR: 7.99; 95% CI: 2.19–29.13) and hospitalisation >7-days (OR: 11.96; 95% CI: 3.27–43.66) had a significantly higher risk of developing corneal injury in this ICU. Corneal injury was a common complication amongst critically ill patients and was associated with altered physiological function of the eyes such as exposure, lagophthalmos, chemosis and periorbital oedema. This study suggests introduction of a corneal injury prevention protocol for nursing and adding lagophthalmos and chemosis to the NANDA-I Taxonomy, thus contributing to the assessment and monitoring for the risk for corneal injury in critically ill patients. [ABSTRACT FROM AUTHOR]

The evolution of speech remains an elusive scientific problem. A widespread notion is that vocal learning, underlined by vocal-fold control, is a key prerequisite for speech evolution. Although present in birds and non-primate mammals, vocal learning is ostensibly absent in non-human primates. Here we argue that the main road to speech evolution has been through controlling the supralaryngeal vocal tract, for which we find evidence for evolutionary continuity within the great apes. [Copyright &y& Elsevier]

Abstract: The ameloblastic fibro-odontoma is defined as a tumour with the general features of the ameloblastic fibroma but that also contains enamel and dentine. AFO normally presents as a painless swelling in the posterior portion of the maxilla or mandible. Radiographs show a well-defined radiolucent area containing various amounts of radiopaque material of irregular size and form. The most appropriate treatment for a large AFO has not been completely determined. This paper reports four large AFO cases and reviews the relevant literature regarding the clinical and surgical features of this lesion. [Copyright &y& Elsevier]

Researching disinfection strategies is pivotal because effectively eliminating bacteria and their byproducts during root canal treatment (RCT) remains a challenge. This study investigated the antimicrobial efficacy of natural antimicrobial compounds, propolis (PRO) and copaiba oil-resin (COR), compared to conventional agents in Endodontics. Antimicrobials were tested against endodontic pathogens via macrodilution with standardized inoculums to determine the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). Biofilm killing efficacy were performed using two dual-species biofilms: Enterococcus faecalis (ATCC 29212) and Streptococcus mutans (ATCC 20523) and Streptococcus oralis (J22) and Actinomyces naeslundii (T14V-J1) grown on dentine discs. At the intratubular level (dentine cylinders), dentine tubule contamination was performed with E. faecalis and S. mutans. The specimens were exposed to antimicrobials to simulate their use at different sets of RCT and bacterial viability was quantified using Live/Dead staining via confocal laser scanning microscopy (CLSM). Biofilm characteristics and immediate removal of S. oralis and A. naeslundii biofilm model were evaluated employing optical coherence tomography (OCT) and CFU/mL counting. Statistical tests were applied according to data distribution for each analysis (α =0.05). Macrodilutions showed different effects against endodontic pathogens. Direct contact and intratubular analysis showed that PRO and COR promoted disinfection like conventional agents (p > 0.05). According to OCT analysis, PRO and COR showed similar biofilm reduction after immediate contact (p < 0.05). CFU/mL counting showed decontamination (p < 0.05) after using natural and conventional agents. PRO and COR showed antimicrobial effects, indicating their suitability as complementary approaches in RCT to eliminate as much microbial load as possible. [Display omitted] • Propolis and copaiba oil-resin are effective against endodontic pathogens. • Disinfection levels are comparable to conventional endodontic agents. • The antimicrobial action occurs in both direct contact and intratubular settings. • The natural compounds reduce biofilm thickness and achieve bacterial reduction. [ABSTRACT FROM AUTHOR]

[Display omitted] • Rigidification of P2 leucine fragment to create new proline-based inhibitors. • High affinity CatK inhibitor inactive for cathepsins B, L, and S. • Novelty employing fragments not yet used in other CatK inhibitors. Human cathepsin K (CatK) stands out as a promising target for the treatment of osteoporosis, considering its role in degrading the bone matrix. Given the small and shallow S2 subsite of CatK and considering its preference for proline or hydroxyproline, we now propose the rigidification of the leucine fragment found at the P2 position in a dipeptidyl-based inhibitor, generating rigid proline-based analogs. Accordingly, with these new proline-based peptidomimetics inhibitors, we selectively inhibited CatK against other human cathepsins (B, L and S). Among these new ligands, the most active one exhibited a high affinity (p K i = 7.3 – 50.1 nM) for CatK and no inhibition over the other cathepsins. This specific inhibitor harbors two novel substituents never employed in other CatK inhibitors: the trifluoromethylpyrazole and the 4-methylproline at P3 and P2 positions. These results broaden and advance the path toward new potent and selective inhibitors for CatK. [ABSTRACT FROM AUTHOR]

Abstract: Quantum chemical calculations at the DFT/B3LYP, HF, and AM1 and PM3 semiempirical levels were employed to calculate a set of molecular properties for 41 phenol compounds with antioxidant activity. The significant molecular descriptors related to the compounds were the vertical ionization potentials (IPvs) and the charge on oxygen atom 7. The IPv has been calculated using Koopman''s theorem IPv=−ɛ HOMO(DFT), IPv=−ɛ HOMO(HF) and as the difference of energy calculations for the corresponding cation and for the neutral form IPv(E cation − E neutral) obtained with the DFT/B3LYP method. The best model obtained showed not only the statistical significance but also predictive ability. [Copyright &y& Elsevier]

Root canal treatment addresses infectious processes that require control. Occasionally, the radicular pulp is vital and inflamed, presenting a superficial infection. To preserve pulpal remnants, conservative procedures have gained favor, employing anti-inflammatory medications. This study investigated the effects of propolis (PRO), and copaiba oil-resin (COR) associated with hydrocortisone (H) and compared their impact to that of Otosporin® concerning cytotoxic and genotoxic activity, cytokine detection, and toxicity in the Galleria mellonella model. Human periodontal ligament fibroblasts (PDLFs) were exposed to drug concentrations and evaluated by the MTT assay. Associations were tested from concentrations that did not compromise cell density. Genotoxicity was evaluated through micronucleus counting, while cytokines IL-6 and TGF-β1 were detected in the cell supernatant using ELISA. Molecular docking simulations were conducted, considering the major compounds identified in PRO, COR, and H. Increasing concentrations of PRO and COR were assessed for acute toxicity in Galleria mellonella model. Cellular assays were analyzed using one-way ANOVA followed by Tukey tests, while larval survivals were evaluated using the Log-rank (Mantel-Cox) test (α = 0.05). PRO and COR promoted PDLFs proliferation, even in conjunction with H. No changes in cell metabolism were observed concerning cytokine levels. The tested materials induce the release of AT 1 R, proliferating the PDFLs through interactions. PRO and COR had low toxicity in larvae, suggesting safety at tested levels. These findings endorse the potential of PRO and COR in endodontics and present promising applications across medical domains, such as preventive strategies in inflammation, shedding light on their potential development into commercially available drugs. [Display omitted] • Propolis and copaiba oil-resin can promote a proliferative action on human cells. • Cytokine levels do not change after the application of natural antimicrobial compounds. • Natural antimicrobial compounds and associations with hydrocortisone induce AngII. • AT 1 R liberation suggests effects on inflammatory reactions and cell proliferation. • Propolis and copaiba oil-resin are not toxic to Galleria mellonella. [ABSTRACT FROM AUTHOR]

In Plasmodium falciparum the bifunctional enzyme glucose-6-phosphate dehydrogenase‒6-phosphogluconolactonase ( Pf G6PD‒6PGL) is involved in the catalysis of the first reaction of the pentose phosphate pathway. Since this enzyme has a key role in parasite development, its unique structure represents a potential target for the discovery of antimalarial drugs. Here we describe the first 3D structural model of the G6PD domain of Pf G6PD‒6PGL. Compared to the human enzyme (hG6PD), the 3D model has enabled the identification of a key difference in the substrate-binding site, which involves the replacement of Arg365 in hG6PD by Asp750 in Pf G6PD. In a prospective validation of the model, this critical change has been exploited to rationally design a novel family of substrate analog-based inhibitors that can display the necessary selectivity towards Pf G6PD. A series of glucose derivatives featuring an α-methoxy group at the anomeric position and different side chains at position 6 bearing distinct basic functionalities has been synthesized, and their Pf G6PD and hG6PD inhibitory activities and their toxicity against parasite and mammalian cells have been assessed. Several compounds displayed micromolar affinity ( K i up to 23 μM), favorable selectivity (up to > 26-fold), and low cytotoxicity. Phenotypic assays with P. falciparum cultures revealed high micromolar IC 50 values, likely as a result of poor internalization of the compounds in the parasite cell. Overall, these results endorse confidence to the 3D model of Pf G6PD, paving the way for the use of target-based drug design approaches in antimalarial drug discovery studies around this promising target. [ABSTRACT FROM AUTHOR]

Calpain-10 (CAPN10) is a cysteine protease that is activated by intracellular calcium (Ca2+) and known to be involved in diseases such as cancer, heart attack, and stroke. A role for the CAPNI0 gene in diabetes mellitus type II was recently identified. Hyper activation of the enzyme initiates a series of destructive cycles that can cause irreversible damage to cells. The development of inhibitors may be useful as therapeutic agents for a number of calpainopathies. In this paper, we have used the homology modelling technique to determine the 3D structure of calpain-10 from Homo sapiens. The model of calpain-10 obtained by homology modelling suggests that its active site is conserved among family members and the main interactions are similar to those observed for μ-calpain. Structural analysis revealed that there are small differences in the charge distribution and molecular surface of the enzyme. These differences are probably less dependent on calcium for calpain-10 than they are for -calpain. In addition, the ion pair Cys-/His+ formation was observed using of Molecular Dynamics (MD) simulations that were based upon hybrid quantum mechanical/molecular mechanical (QM/MM) approaches. Finally, the binding of the SNJ-1715 inhibitor to calpain-10 was investigated in order to further understand the mechanism of inhibition of calpain-10 by this inhibitor at the molecular level. [ABSTRACT FROM AUTHOR]

Abstract: This paper deals with the possibility of using beef tallow and beef tallow biodiesel in energy generation. The environmental, energetic and social–economic aspects are discussed. The steps for obtaining biodiesel from beef tallow are presented as well as the characterization of beef tallow and beef tallow biodiesel. Results for performance and emissions of using beef tallow and beef tallow biodiesel in a stationary engine are also shown. Beef tallow can be successfully applied in compression ignition engine blending with diesel up to 15% of beef tallow. Beef tallow can also be converted in biodiesel and applied in compression ignition engines neat or blended with diesel in any proportion. In the case of neat beef tallow biodiesel, it is not recommended to be used in cold weather conditions, due to its relatively low pour point. The possibility of using beef tallow in power generation, leads to the concepts of sustainability and cleaner production, by the use of a material usually discarded in butcheries. [Copyright &y& Elsevier]

Abstract: Metalloendopeptidases are zinc-dependent hydrolases enzymes with many different roles in biological systems, ranging from remodeling conjunctive tissue to removing signaling sequences from nascent proteins. Here, we describe the three-dimensional structure of the metalloendopeptidase from Corynebacterium pseudotuberculosis generated by homology modeling and molecular dynamics. Analysis of key distances shows that His-132, Asp-136, His-211, Leu-212 and one molecule of water play an important role in the protein–Zn2+ ion interaction. The model obtained may provide structural insights into this enzyme and can be useful for the design of new caseous lymphadenitis vaccines based on genetic attenuation from key point mutation. [Copyright &y& Elsevier]

Abstract: The oleoresin of the copaiba tree (Copaifera sp., Fabaceae) is traditionally used in Brazilian herbal medicine to treat a variety of illnesses and symptoms. This study, conducted according to the OECD Guideline 414, provides data on the developmental toxicity of oleoresin from C. reticulata (COPA-R) in rats. Pregnant Wistar rats (25 per dose group) were treated by gavage with COPA-R (0, 500, 1000 and 1250mg/kgbw/day) on gestation days (GD) 6–19 and Caesarean sections performed on GD20. Implantations, living and dead fetuses and resorptions were recorded. Half of the fetuses from each litter were examined for visceral abnormalities and the remaining were cleared and stained for skeleton evaluation. COPA-R was maternally toxic (reduced food intake and weight gain) and embryotoxic (lower fetal body weight and increased occurrence of fetal skeleton variations) at the two highest doses, but did not cause embryo deaths or fetal malformations at any dose level. The study derived an oral no-observed-adverse-effect-level (NOAEL) for maternal and developmental toxicity induced by COPA-R of 500mg/kgbw/day. The results suggest that copaiba oleoresin does not pose a health risk to pregnant women when used according to the recommended doses (up to five drops, three times a day). [Copyright &y& Elsevier]

Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h , 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P 3, halogenated phenylalanine in P 2 and Thr-O-Bz group at P 1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one 7e → 6b , where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure–activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins. [ABSTRACT FROM AUTHOR]

Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 Å X ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases. [ABSTRACT FROM AUTHOR]

• The predicted natural products with anticancer activity are widely distributed in 46 families and have at least 19 different molecular targets involved in cancer development and progression. • The analysis of predicted target inhibition showed that some compounds were stable during MD simulations and exhibited similar interactions with the reference inhibitors. • Some chemical classes revealed interesting chemotypes that could be further tested as cancer agents. Cancer is one of the leading causes of death worldwide, and the number of patients has only increased each year, despite the considerable efforts and investments in scientific research. Since natural products (NPs) may serve as suitable sources for drug development, the cytotoxicity against cancer cells of 2221 compounds from the Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBE DB) was predicted using CDRUG algorithm. Molecular modeling, chemoinformatics, and chemometric tools were then used to analyze the structural and physicochemical properties of these compounds. We compared the positive NPs with FDA-approved anticancer drugs and predicted the molecular targets involved in the anticancer activity. In the present study, 46 families comprising potential anticancer compounds and at least 19 molecular targets involved in oncogenesis. To the best of our knowledge, this is the first large-scale study conducted to evaluate the potentiality of NPs sourced from Brazilian biodiversity as anticancer agents, using in silico approaches. Our results provided interesting insights about the mechanism of action of these compounds, and also suggested that their structural diversity may aid structure-based optimization strategies for developing novel drugs for cancer therapy. [ABSTRACT FROM AUTHOR]