ClusPro (http://nrc.bu.edu/cluster) represents the first fully automated, web-based program for the computational docking of protein structures. Users may upload the coordinate files of two protein ...structures through ClusPro's web interface, or enter the PDB codes of the respective structures, which ClusPro will then download from the PDB server (http://www.rcsb.org/pdb/). The docking algorithms evaluate billions of putative complexes, retaining a preset number with favorable surface complementarities. A filtering method is then applied to this set of structures, selecting those with good electrostatic and desolvation free energies for further clustering. The program output is a short list of putative complexes ranked according to their clustering properties, which is automatically sent back to the user via email.
Background and Objective
Photodynamic therapy (PDT) and antiresorptive drugs, such as alendronate (ALN), have been shown to reduce alveolar bone loss. The aim of this study was to evaluate the ...possible synergic effects of combining PDT and ALN on bone loss in periodontitis in rats.
Material and Methods
Periodontitis was induced by ligature in 60 Wistar rats randomized into the following groups: control (Group 1); PDT (Group 2); ALN 0.01 mg/kg (Group 3); ALN 0.25 mg/kg (Group 4); PDT + ALN 0.01 mg/kg (Group 5); and PDT + ALN 0.25 mg/kg (Group 6). The rats were killed on day 12 and the mandibles were processed for macroscopic morphometric analysis, micro‐computed tomography to analyze bone mineral density (BMD) and histological analysis. Gingival samples were collected to evaluate myeloperoxidase (MPO) and malonaldehyde (MDA) levels.
Results
Bone loss and inflammatory activity in histological studies, from the greatest to least was: control > ALN 0.01 mg/kg > PDT > ALN 0.25 mg/kg > PDT + ALN 0.01 mg/kg > PDT + ALN 0.25 mg/kg, while the order from least to greatest BMD was: control < ALN 0.01 mg/kg < PDT < ALN 0.25 mg/kg < PDT + ALN 0.01 mg/kg < PDT + ALN 0.25 mg/kg. The order of MPO and MDA activity from greatest to least was: control > ALN 0.01 mg/kg > PDT > ALN 0.25 mg/kg > PDT + ALN 0.01 mg/kg > PDT + ALN 0.25 mg/kg. The positive results obtained in the group treated with PDT + ALN 0.25 mg/kg showed statistically significant differences (P ≤ .05) compared with the other 5 groups for BMD, MPO and MDA.
Conclusion
Combined approach therapy of PDT + ALN 0.25 mg/kg demonstrated a protective effect on alveolar bone loss.
Health and lifestyle factors are associated with variations in serum testosterone levels in ageing men. However, it remains unclear how age-related changes in testosterone may be attenuated by ...lifestyle modifications. The objective was to investigate the longitudinal relationships between changes in health and lifestyle factors with changes in hormones of the reproductive endocrine axis in ageing men.
A longitudinal survey of 2736 community-dwelling men aged 40-79 years at baseline recruited from eight centres across Europe. Follow-up assessment occurred mean (±S.D.) 4.4±0.3 years later.
Paired testosterone results were available for 2395 men. Mean (±S.D.) annualised hormone changes were as follows: testosterone -0.1±0.95 nmol/l; free testosterone (FT) -3.83±16.8 pmol/l; sex hormone-binding globulin (SHBG) 0.56±2.5 nmol/l and LH 0.08±0.57 U/l. Weight loss was associated with a proportional increase, and weight gain a proportional decrease, in testosterone and SHBG. FT showed a curvilinear relationship to weight change; only those who gained or lost ≥15% of weight showed a significant change (in the same direction as testosterone). Smoking cessation was associated with a greater decline in testosterone than being a non-smoker, which was unrelated to weight change. Changes in number of comorbid conditions or physical activity were not associated with significant alterations in hypothalamic-pituitary-testicular (HPT) axis function.
Body weight and lifestyle factors influence HPT axis function in ageing. Weight loss was associated with a rise, and weight gain a fall, in testosterone, FT and SHBG. Weight management appears to be important in maintaining circulating testosterone in ageing men, and obesity-associated changes in HPT axis hormones are reversible following weight reduction.
There has been very limited use of computer assisted semen analysis (CASA) to evaluate reptile sperm. The aim of this study was to examine sperm kinematic variables in American crocodile (Crocodylus ...acutus) semen samples and to assess whether sperm subpopulations could be characterized. Eight ejaculates (two ejaculates/male) from four sexually mature captive crocodiles were obtained. An ISAS®v1 CASA-Mot system, with an image acquisition rate of 50 Hz, and ISAS®D4C20 counting chambers were used for sperm analyses. The percentages of motile and progressively motile spermatozoa did not differ among animals (P > 0.05) but there was a significant animal effect with regards to kinematic variables (P < 0.05). Principal component (PC) analysis revealed that kinematic variables grouped into three components: PC1, related to velocity; PC2 to progressiveness and PC3 to oscillation. Subpopulation structure analysis identified four groups (P < 0.05), which represented, on average, 9.8%, 32.1%, 26.8%, and 31.3% of the total sperm population. Males differed in the proportion of sperm in each of the kinematic subpopulations. This new approach for the analysis of reptile sperm kinematic subpopulations, reflecting quantifiable parameters generated by CASA system technology, opens up possibilities for future assessments of crocodile sperm and will be useful in the future development of assisted reproduction for these species.
Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed ...data from the Parkinson's Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n = 313, 67.3%), minor (n = 97, 20.9%) and major (n = 55, 11.8%). Clinical progression to all three outcomes was more rapid in those with more severe constipation at baseline (Kaplan-Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology.
•Kaurane diterpenoids, fatty acids and sterols are the major lipophilic families.•Kaurenoic acid is the most abundant compound (554–1350mgkg−1 of dry mesocarp).•Cherimoya mesocarp shows several ...galloylated and non-galloylated flavan-3-ols.•‘Mateus I’ and ‘Mateus III’ cultivars have the highest phenolic contents.•Cherimoya fruit is a rich source of valuable phytochemicals in human diet and health.
The lipophilic and phenolic extractives of the ripe mesocarp of four cherimoya cultivars (‘Perry Vidal’, ‘Mateus I’, ‘Mateus III’ and ‘Funchal’) from Madeira Island, were studied for the first time. The predominant lipophilic compounds are kaurene diterpenes (42.2–59.6%), fatty acids (18.0–35.6%) and sterols (9.6–23.7%). Kaur-16-en-19-oic acid is the major lipophilic component of all cultivars accounting between 554 and 1350mgkg−1 of dry material.
The studied fruits also contain a high variety of flavan-3-ols, including galloylated and non-galloylated compounds. Five phenolic compounds were identified for the first time: catechin, (epi)catechin-(epi)gallocatechin, (epi)gallocatechin, (epi)afzelechin-(epi)catechin and procyanidin tetramer. ‘Mateus I’ and ‘Mateus III’ cultivars present the highest content of phenolic compounds (6299 and 9603mgkg−1 of dry weight, respectively). These results support the use of this fruit as a rich source of health-promoting components, with the capacity to prevent or delay the progress of oxidative-stress related disorders.
Cryptococcus neoformans causes lethal meningitis and accounts for approximately 10%–15% of AIDS-associated deaths worldwide. There are major gaps in our understanding of how this fungus invades the ...mammalian brain. To investigate the dynamics of C. neoformans tissue invasion, we mapped fungal localization and host cell interactions in infected brain, lung, and upper airways using mouse models of systemic and airway infection. To enable this, we developed an in situ imaging pipeline capable of measuring large volumes of tissue while preserving anatomical and cellular information by combining thick tissue sections, tissue clarification, and confocal imaging. We confirm high fungal burden in mouse upper airway after nasal inoculation. Yeast in turbinates were frequently titan cells, with faster kinetics than reported in mouse lungs. Importantly, we observed one instance of fungal cells enmeshed in lamina propria of the upper airways, suggesting penetration of airway mucosa as a possible route of tissue invasion and dissemination to the bloodstream. We extend previous literature positing bloodstream dissemination of C. neoformans, by finding viable fungi in the bloodstream of mice a few days after intranasal infection. As early as 24 h post systemic infection, the majority of C. neoformans cells traversed the blood-brain barrier, and were engulfed or in close proximity to microglia. Our work presents a new method for investigating microbial invasion, establishes that C. neoformans can breach multiple tissue barriers within the first days of infection, and demonstrates microglia as the first cells responding to C. neoformans invasion of the brain.IMPORTANCECryptococcal meningitis causes 10%–15% of AIDS-associated deaths globally. Still, brain-specific immunity to cryptococci is a conundrum. By employing innovative imaging, this study reveals what occurs during the first days of infection in brain and in airways. We found that titan cells predominate in upper airways and that cryptococci breach the upper airway mucosa, which implies that, at least in mice, the upper airways are a site for fungal dissemination. This would signify that mucosal immunity of the upper airway needs to be better understood. Importantly, we also show that microglia, the brain-resident macrophages, are the first responders to infection, and microglia clusters are formed surrounding cryptococci. This study opens the field to detailed molecular investigations on airway immune response, how fungus traverses the blood-brain barrier, how microglia respond to infection, and ultimately how microglia monitor the blood-brain barrier to preserve brain function.
Meningococcal disease by serogroup B has been a public health problem in Brazil in the last decades. The Brazilian Oswaldo Cruz Foundation has been working to develop a vaccine with detergent-treated ...outer membrane vesicles (OMV) and detoxified endotoxin (dLOS) from Neisseria meningitidis serogroup B prevalent strains. A phase I study, enrolling 26 adults (18–44 years of age) was performed using experimental vaccines combining B components and aluminum hydroxide as adjuvant. It was a dose escalation study testing vaccines made of 25, 50, and 100 µg OMV protein/mL (sum of both strains) and dLOS in half amount of total protein concentration, with three doses given two months apart. Adverse events were mild/moderate with frequency increasing with the amount of antigens. Pain in the site of injection was the most frequent reaction in all doses, reported in more than the 85% across vaccine groups. Considering all injections, cephalea was the most common systemic adverse event, detected in 11.1%, 17.2% and 32.1%, respectively with doses of 12.5 μg, 25 μg and 50 μg. High titers of total IgG (ELISA) were observed for the vaccine components before vaccination. Protective levels of bactericidal antibodies (titer ≥1:4) for both vaccine strains were also present. Considering a 4-fold increase of IgG titers compared to pre-immune values (seroconversion), 50%-70% of those who received intermediate and highest doses of antigens presented satisfactory response for OMV of N44/89 strain. The lowest dose vaccine induced no seroconversion for strain N44/89, and 11% for strain N603/95. For the three vaccines doses, 25% of seroconversion, in total IgG against LOS, was observed. Increased antibody bactericidal activity was observed for both strains in higher antigen concentrations. For IgG against LOS, all vaccine formulations showed 25% of seroconversion. In conclusion, MenB-Bio experimental vaccines were well tolerated and immunogenic, thus allowing phase II studies.
Summary
Background Patients are commonly nonadherent to medication regimens. In dermatology, there has been little study of the effect of nonadherence on outcomes.
Objectives To test the ...association between adherence behaviour and changes in severity of psoriasis.
Methods Twenty‐four subjects with psoriasis were enrolled in an 8‐week, left/right, controlled trial of salicylic acid plus topical tacrolimus ointment vs. salicylic acid plus placebo. Subjects were given salicylic acid to apply to all lesions. The salicylic acid was supplied in a bottle with a medication event monitoring system cap in order to assess adherence to the salicylic acid. The primary outcome for this study was the relationship between the change in the disease severity (change in sum score of erythema, scale and thickness scores for a target plaque) and medication adherence.
Results The mean initial disease severity was 5·8 on a nine‐point sum score scale. For the topical tacrolimus‐treated side, a decrease in adherence rate of 10% was associated with a 1‐point increase in severity (P < 0·05). For the placebo‐treated side, adherence was not significantly correlated with changes in severity.
Conclusions Nonadherence may have a significant role in altering clinical trial data, skewing it towards ineffectiveness. Improved outcomes in psoriasis may be achievable through interventions that improve patients' adherence to treatment.
The existence of multiple subclasses of Type Ia supernovae (SNe Ia) has been the subject of great debate in the last decade. One major challenge inevitably met when trying to infer the existence of ...one or more subclasses is the time consuming, and subjective, process of subclass definition. In this work, we show how machine learning tools facilitate identification of subtypes of SNe Ia through the establishment of a hierarchical group structure in the continuous space of spectral diversity formed by these objects. Using deep learning, we were capable of performing such identification in a four-dimensional feature space (+1 for time evolution), while the standard principal component analysis barely achieves similar results using 15 principal components. This is evidence that the progenitor system and the explosion mechanism can be described by a small number of initial physical parameters. As a proof of concept, we show that our results are in close agreement with a previously suggested classification scheme and that our proposed method can grasp the main spectral features behind the definition of such subtypes. This allows the confirmation of the velocity of lines as a first-order effect in the determination of SN Ia subtypes, followed by 91bg-like events. Given the expected data deluge in the forthcoming years, our proposed approach is essential to allow a quick and statistically coherent identification of SNe Ia subtypes (and outliers). All tools used in this work were made publicly available in the python package Dimensionality Reduction And Clustering for Unsupervised Learning in Astronomy (dracula) and can be found within COINtoolbox (https://github.com/COINtoolbox/DRACULA).
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