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Aim:Synthetic antimicrobial peptides (SAMPs) present the potential to fight systemic fungal infections. Here, the PHO36 receptor from Candida albicanswas analyzed by in silicotools as a possible target for three anticandidal SAMPs: RcAlb-PepIII, PepGAT and PepKAA.Materials & methods:Molecular docking, dynamics and quantum biochemistry were employed to understand the individual contribution of amino acid residues in the interaction region.Results:The results revealed that SAMPs strongly interact with the PHO36 by multiple high-energy interactions. This is the first study to employ quantum biochemistry to describe the interactions between SAMPs and the PHO36 receptor.Conclusion:This work contributes to understanding and identifying new molecular targets with medical importance that could be used to discover new drugs against systemic fungal infections.

Introduction Iris prostheses are an integral tool for the management of symptoms in the setting of damaged, insufficient, or absent irides. Fixation of a custom iris prosthesis in the absence of capsular support raises similar challenges to the fixation of an intraocular lens (IOLs) without capsular support. Centration and planar orientation of these larger iris devices are perhaps even more important than with IOLs.Methods We describe two variations of a reliably reproducible suture fixation technique for securing these special devices using a modification of the tiltless, centration-adjustable suture technique for sclerally-fixated posterior chamber IOLs.Results We described a few techniques that are safe and reproductible. That have been used in more than 300 cases in our co-hort with success and follow-ups of over 10 year.Conclusion We go over the technique step-by-step, highlighting the critical steps and pitfalls to avoid complications and achieve satisfactory results and aiming to get more surgeons to use these techniques and help facilitate the steep learning curve some of the steps might have.

Purpose: Advances in the treatment of cystic fibrosis (CF) have allowed patients to reach adulthood. The forced oscillation technique (FOT) is a new method for providing an exam that is simple to perform and simultaneously provides a detailed respiratory system evaluation. The purpose of this study was to use machine learning (ML) algorithms to increase the accuracy and interpretability of FOT parameters in the investigation and diagnosis of respiratory changes in adults with CF. Methods: The database was created based on 150 measurements in 50 volunteers (23 in the control group and 27 in the test group). The following supervised ML algorithms were selected for the tests: K-nearest neighbors (KNN), random forest (RF), AdaBoost with decision trees (ADAB), and light gradient boosting (LGB). These data were also subjected to a Bayesian network synthesized by a genetic algorithm (BNGA) in an attempt to maintain good accuracy and increase the interpretability of the results. A soft vote ensemble strategy was employed to enhance the diagnostic accuracy. Results: The first part of this study showed the best FOT parameter: the reactance Xm(AUC = 0.85), indicating moderate accuracy. In the second part, the original FOT parameters were used as input in the chosen algorithms. BNGA had the best performance alone (AUC = 0.88), while the soft voting ensemble achieved AUC = 0.90. When cross-product and feature selection methods were applied, the RF and BNGA were the algorithms with the best results (AUC = 0.88), and the soft voting ensemble achieved an AUC = 0.94. Conclusion: This study provides high diagnostic accuracy with improved interpretability of the FOT parameters, which assists doctors in the medical diagnosis of respiratory changes in CF.

AbstractThe recent outbreak caused by SARS-CoV-2 continues to threat and take many lives all over the world. The lack of an efficient pharmacological treatments are serious problems to be faced by scientists and medical staffs worldwide. In this work, an in silicoapproach based on the combination of molecular docking, dynamics simulations, and quantum biochemistry revealed that the synthetic peptides RcAlb-PepI, PepGAT, and PepKAA, strongly interact with the main protease (Mpro) a pivotal protein for SARS-CoV-2 replication. Although not binding to the proteolytic site of SARS-CoV-2 Mpro, RcAlb-PepI, PepGAT, and PepKAA interact with other protein domain and allosterically altered the protease topology. Indeed, such peptide-SARS-CoV-2 Mpro complexes provoked dramatic alterations in the three-dimensional structure of Mpro leading to area and volume shrinkage of the proteolytic site, which could affect the protease activity and thus the virus replication. Based on these findings, it is suggested that RcAlb-PepI, PepGAT, and PepKAA could interfere with SARS-CoV-2 Mpro role in vivo. Also, unlike other antiviral drugs, these peptides have no toxicity to human cells. This pioneering insilico investigation opens up opportunity for further in vivoresearch on these peptides, towards discovering new drugs and entirely new perspectives to treat COVID-19.Communicated by Ramaswamy H. Sarma

Introduction:Candida kruseiand Candida albicansare biofilm-forming drug-resistant yeasts that cause bloodstream infections that can lead to death. Materials & methods:nystatin and itraconazole were combined with two synthetic peptides, PepGAT and PepKAA, to evaluate the synergistic effect against Candidabiofilms. Additionally, scanning electron and fluorescence microscopies were employed to understand the mechanism behind the synergistic activity. Results:Peptides enhanced the action of drugs to inhibit the biofilm formation of C. kruseiand C. albicansand the degradation of mature biofilms of C. krusei. In combination with antifungal drugs, peptides’ mechanism of action involved cell wall and membrane damage and overproduction of reactive oxygen species. Additionally, in combination, the peptides reduced the toxicity of drugs to red blood cells. Conclusion:These results reveal that the synthetic peptides enhanced the antibiofilm activity of drugs, in addition to reducing their toxicity. Thus, these peptides have strong potential as adjuvants and to decrease the toxicity of drugs.

AbstractVaccines could be the solution to the current SARS-CoV-2 outbreak. However, some studies have shown that the immunological memory only lasts three months. Thus, it is imperative to develop pharmacological treatments to cope with COVID-19. Here, the in silicoapproach by molecular docking, dynamic simulations and quantum biochemistry revealed that ACE2-derived peptides strongly interact with the SARS-CoV-2 RBD domain of spike glycoprotein (S-RBD). ACE2-Dev-PepI, ACE2-Dev-PepII, ACE2-Dev-PepIII and ACE2-Dev-PepIV complexed with S-RBD provoked alterations in the 3D structure of S-RBD, leading to disruption of the correct interaction with the ACE2 receptor, a pivotal step for SARS-CoV-2 infection. This wrong interaction between S-RBD and ACE2 could inhibit the entry of SARS-CoV-2 in cells, and thus virus replication and the establishment of COVID-19 disease. Therefore, we suggest that ACE2-derived peptides can interfere with recognition of ACE2 in human cells by SARS-CoV-2 in vivo. Bioinformatic prediction showed that these peptides have no toxicity or allergenic potential. By using ACE2-derived peptides against SARS-CoV-2, this study points to opportunities for further in vivoresearch on these peptides, seeking to discover new drugs and entirely new perspectives to treat COVID-19.Communicated by Ramaswamy H. Sarma

Purpose: Malignant hyperthermia (MH) is a hypermetabolic disorder that can occur in genetically susceptible individuals exposed to halogenated anesthetics and succinylcholine. Spinal cord injury (SCI) above the sixth thoracic vertebra is associated with dysfunction of the sympathetic/parasympathetic nervous pathways, including thermoregulatory dysfunction, presenting as hypothermia in cold environments because of vasodilation and heat loss. This effect could mitigate or obscure an MH episode. Here, we describe development of a fatal MH crisis in a patient with SCI. Clinical features: A 27-yr-old male patient with an SCI after fracture of the sixth cervical vertebra was admitted for spinal arthrodesis. Anesthetic medications included remifentanil, propofol, succinylcholine, rocuronium, and isoflurane. After the start of the surgery, muscular contractures resembling myoclonus were noted, which resolved with pancuronium administration. Four hours after the start of anesthesia, the patient presented with hyperthermia, hypercarbia, hypotension, muscle rigidity, arrhythmia, and cardiogenic shock, with metabolic/respiratory acidosis. Malignant hyperthermia was suspected and the treatment was started, but he developed cardiopulmonary arrest and died an hour and a half after the first cardiac arrest. Both parents were investigated and were found to have normal creatine kinase levels and positive in vitrocontracture tests. His mother carried a variant in the ryanodine receptor type 1 (RYR1) gene (c.14918C>T), which is associated with MH. Conclusion: Spinal cord injury-induced thermoregulatory dysfunction may obscure the early diagnosis of MH and lead to fatal outcome.

Abstract: Poorly soluble active pharmaceutical ingredients (APIs) create major problems in drug dosage form formulation resulting in significant delays in drug pharmaceutical screening, impairing the drug dosage form production. Aiming to minimize the use of excipients for increasing drug apparent solubility and, as a result, its bioavailability, exploration of innovative approaches is an earnest need. Microemulsion is an alternative drug delivery system that emerged as a valuable tool to achieve safe formulations for insoluble compounds and to improve their biopharmaceutical properties and pharmacokinetics. This review aims to present the state of the art of microemulsion systems, bringing an overview about their origin and how they can be properly produced and thoroughly characterized by different approaches. Furthermore, comments on regulatory issues regarding stability assessment and toxicity evaluation are discussed. The review concludes with a current opinion on microemulsion systems. The overall objective of this work was to describe all the potentialities of microemulsion systems as a drug carrier for therapeutic purposes, highlighting the unique features of this nanotechnological platform. Graphical abstract: Display Image

Press brake air bending, a process of obtaining products by sheet metal forming, can be considered at first sight a simple geometric problem. However the accuracy of the obtained geometries involves the combination of multiple parameters directly associated with the tools and the processing parameters, as well as with the sheet metal materials and dimensions. The main topic herein presented deals with the capability of predicting the punch displacement process parameter that enables the product to be accurately shaped to a desired bending angle, in press brake air bending. In our approach, it is considered separately the forming process and the elastic recovery (i.e. the springback effect). Current solutions in press brake numerical control (computer numerical control) are normally configured by analytical models developed from geometrical analysis and including correcting factors. In our approach, it is proposed to combine the use of a learning tool, artificial neural networks, with a simulation and data generation tool (finite element analysis). This combination enables modeling the complex nonlinear behavior of the forming process and springback effect, including the validation of results obtained. A developed model taking into account different process parameters and tool geometries allow extending the range of applications with practical interest in industry. The final solution is compatible with its incorporation in a computer numerical control press brake controller. It was concluded that, using this methodology, it is possible to predict efficient and accurate final geometries after bending, being also a step forward to a “first time right” solution. In addition, the developed models, methodologies and obtained results were validated by comparison with experimental tests.

Dexamethasone (DEX) causes rarefaction. In contrast, training (T) prevents rarefaction and stimulates angiogenesis. This study investigated the mechanisms responsible for the preventive role of T in DEX-induced rarefaction. Rats underwent T or were kept sedentary (8 weeks) and were treated with DEX or saline during the following 14 days. Tibialis anterior muscle was used for measurements of capillary density (CD), capillary-to-fiber ratio (C:F ratio), superoxide dismutase CuZn (SOD-1), superoxide dismutase MnSOD (SOD-2), catalase (CAT) mRNA as well as SOD-1, SOD-2, CAT, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGF-R2), cyclooxygenase-2 (COX-2), B-cell lymphoma 2 (Bcl-2), Bd-2-like protein 4 (Bax), p-Bax, and caspase-3 cleaved protein levels. DEX decreased CD (−38.1%), C:F ratio (−30.0%), VEGF (−19.0%), VEGFR-2 (−20.1%), COX-2 (−22.8%), Bcl-2 (−20.5%), Bcl-2/Bax ratio (−13.7%), p-Bax/Bax (−20.0%) and increased SOD-2 (+41.6%) and caspase-3 cleaved (+24.1%). Conversely, T prevented reductions in CD (+54.2%), C:F ratio (+32.9%), VEGF (+25.3%), VEGFR-2 (+22.2%), COX-2 (+31.5%), Bcl-2 (+35.5%), Bcl-2/Bax ratio (+19.9%), p-Bax/Bax (+32.1%), and caspase-3 cleaved increase (−7.8%). T increased CAT mRNA (+21.5%) in the DEX-treated group. In conclusion, T prevented the DEX-induced rarefaction by increasing antioxidant enzymes resulting in a better balance between apoptotic and anti-apoptotic protein levels.

Plastic is currently the most abundant form of debris in the ocean. Since the early 70's, investigators have recognized the presence of life such as pennate diatoms, bryozoans and bacteria on plastic debris, sometimes referred to as the “Plastisphere”. This review provides an overview of molecular and visualization techniques used to characterize life in the Plastisphere, presents a new data portal located on the Visual Analysis of Microbial Population Structures (VAMPS) website to illustrate how one can compare plastic debris datasets collected using different high-throughput sequencing strategies, and makes recommendations on standardized operating procedures that will facilitate future comparative studies.

Plastic marine debris is a global problem, but due to its widespread and patchy distribution, gathering sufficient samples for scientific research is challenging with limited ship time and human resources. Taking advantage of public interest in the impact of plastic on the marine environment, successful Citizen Science (CS) programs incorporate members of the public to provide repeated sampling for time series as well as synoptic collections over wide geographic regions. A key challenge with any CS program is to ensure standardized methods and quality control so that the samples and data can legitimately be compared and used in peer-reviewed research. This article describes several successful examples and outlines suggestions for projects cooperating with citizen scientists to provide reliable samples and accurate data, with benefits to science, citizen scientists, and society in general.

To evaluate the effect of low-intensity chronic exercise training (ExT) on blood pressure (BP), as well as the cardiac alterations associated with hypertension in aging hypertensive rats.

Steroid estrogens namely 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) and antibiotics including sulfamethoxazole (SMX) are pharmaceutically active compounds (PhAC) of emerging concern due to their environmental and human health impacts even at ppb range concentrations. These compounds usually flow to wastewater treatment plants (WWTP) and are released to the aquatic systems due to inefficient removal in conventional biological systems. In this work, a sequencing batch reactor (SBR) with aerobic granular sludge (AGS) was operated in the presence of E2, EE2 and SMX. SVI5, SVI30/SVI5ratio, VSS, and TSS of mature AGS (in absence of PhAC), as well as in the presence of PhAC (0.221mgL-1of E2, 0.278mgL-1of EE2 and 0.290mgL-1of SMX), were successfully predicted with multilinear regression (MLR) using morphological and structural parameters of floccular and granular fractions of AGS obtained from quantitative image analysis (QIA). Good prediction models were obtained for the SVI5(R2of 0.976), floccular VSS (R2of 0.949) and TSS (R2of 0.934), granular VSS (R2of 0.930) and TSS (R2of 0.916), SVI30/SVI5ratio (R2of 0.917) and density (R2of 0.889). These results emphasize the usefulness of this methodology for monitoring dysfunctions in AGS in the presence of the studied PhAC.

Background:Vascular endothelial growth factor (VEGF) is a macromolecule of importance in inflammation that has been implicated in periodontitis. The aims of this study were to investigate VEGF expression during the progression of periodontal disease and to evaluate the effect of a preferential cyclooxygenase (COX)‐2 inhibitor meloxicam on VEGF expression and alveolar bone loss in experimentally induced periodontitis. Methods:A total of 120 Wistar rats were randomly separated into groups 1 (control) and 2 (meloxicam, 3 mg/kg/day, intraperitoneally, for 3, 7, 14, or 30 days). Silk ligatures were placed at the gingival margin level of the lower right first molar of all rats. VEGF expression was assessed by reverse transcription‐polymerase chain reaction (RT‐PCR), Western blot (WB), and immunohistochemical (IHC) analyses. The hemiarcades were processed for histopathologic analysis. RT‐PCR and WB results were submitted to analysis of variance, the Tukey test, and Pearson correlation analysis (P<0.05). Results:A reduction in alveolar bone resorption was observed in the meloxicam‐treated group compared to the control group at all periods studied. There was a positive correlation between COX‐2 mRNA and VEGF mRNA in the gingival tissues and periodontal disease (R = 0.80; P= 0.026). Meloxicam significantly reduced the increased mRNA VEGF expression in diseased tissues after 14 days of treatment (P= 0.023). Some alterations in VEGF receptor 1 mRNA expression were observed, but these were not statistically significant. VEGF protein expression in WB experiments was significantly higher in diseased sites compared to healthy sites (P<0.05). After 14 days of treatment with meloxicam, an important decrease in VEGF protein expression was detected in diseased tissues (P= 0.08). Qualitative IHC analysis revealed that VEGF protein expression was higher in diseased tissues and decreased in tissues from rats treated with meloxicam. Conclusions:The present data suggest an important role for VEGF in the progression of periodontal disease. Systemic therapy with meloxicam can modify the progression of experimentally induced periodontitis in rats by reducing VEGF expression and alveolar bone loss.

Angiogenesis, under normal conditions, is a tightly regulated balance between pro- and antiangiogenic factors. The goal of this study was to investigate the mechanisms involved in the control of the skeletal muscle angiogenic response induced by electrical stimulation during the suppression of plasma renin activity (PRA) with a high-salt diet. Rats fed 0.4% or 4% salt diets were exposed to electrical stimulation for 7 days. The tibialis anterior (TA) muscles from stimulated and unstimulated hindlimbs were removed and prepared for gene expression analysis, CD31-terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) double-staining assay, and Bcl-2 and Bax protein expression by Western blot. Rats fed a low-salt diet showed a dramatic angiogenesis response in the stimulated limb compared with the unstimulated limb. This angiogenesis response was significantly attenuated when rats were placed on a high-salt diet. Microarray analysis showed that in the stimulated limb of rats fed a low-salt diet many genes related to angiogenesis were upregulated. In contrast, in rats fed a high-salt diet most of the genes upregulated in the stimulated limb function in apoptosis and cell cycle arrest. Endothelial cell apoptosis, as analyzed by CD31-TUNEL staining, increased by fourfold in the stimulated limb compared with the unstimulated limb. There was also a 48% decrease in the Bcl-2-to-Bax ratio in stimulated compared with unstimulated limbs of rats fed a high-salt diet, confirming severe apoptosis. This study suggests that the increase in endothelial cell apoptosis in TA muscle might contribute to the attenuation of angiogenesis response observed in rats fed a high-salt diet.

Angiogenesis, under normal conditions, is a tightly regulated balance between pro- and antiangiogenic factors. The goal of this study was to investigate the mechanisms involved in the control of the skeletal muscle angiogenic response induced by electrical stimulation during the suppression of plasma renin activity (PRA) with a high-salt diet. Rats fed 0.4% or 4% salt diets were exposed to electrical stimulation for 7 days. The tibialis anterior (TA) muscles from stimulated and unstimulated hindlimbs were removed and prepared for gene expression analysis, CD31-terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) double-staining assay, and Bcl-2 and Bax protein expression by Western blot. Rats fed a low-salt diet showed a dramatic angiogenesis response in the stimulated limb compared with the unstimulated limb. This angiogenesis response was significantly attenuated when rats were placed on a high-salt diet. Microarray analysis showed that in the stimulated limb of rats fed a low-salt diet many genes related to angiogenesis were upregulated. In contrast, in rats fed a high-salt diet most of the genes upregulated in the stimulated limb function in apoptosis and cell cycle arrest. Endothelial cell apoptosis, as analyzed by CD31-TUNEL staining, increased by fourfold in the stimulated limb compared with the unstimulated limb. There was also a 48% decrease in the Bcl-2-to-Bax ratio in stimulated compared with unstimulated limbs of rats fed a high-salt diet, confirming severe apoptosis. This study suggests that the increase in endothelial cell apoptosis in TA muscle might contribute to the attenuation of angiogenesis response observed in rats fed a high-salt diet.

Analysis of a variety of properties of supramolecular aggregates in aqueous urea supports an explanation for the urea effect that differs from traditional explanations based on the direct mechanism of urea−water solvation or the indirect mechanism via rupture of the three-dimensional (3-D) structure of water. The urea-induced effects investigated are increases in amphiphile critical micelle concentrations, ionization degrees (α), and aggregation numbers; decreases in percolation thresholds of reversed micelles; expansion of minimum areas of monolayers; increases in the radii of gyration of polyelectrolytes; changes in morphologies of sodium bis-2-ethylhexylsulfosuccinate thin films on glass substrates; and direct evidence for urea-induced reduction in ion pairing. All of these effects are attributed to an urea-induced enhancement of the hydrophilic properties of water that results in more strongly solvated polar groups and ions and a reduction in ion pair formation. The implications of this analysis for urea effects on protein 3-D structure are briefly highlighted.

To investigate whether training changes skeletal muscle venular profile and hemodynamic responses to exercise we studied spontanesouly hypertensive rats (SHR) and Wistar–Kyoto (WKY) rats submitted to training programme (T 50–60 of VO2max).

To investigate mechanisms underlying the training-induced blood pressure-lowering effect we analyzed the hemodynamic responses and morphometric changes of the skeletal muscle microcirculation of spontaneously hypertensive (SHR) and normotensive Wistar–Kyoto (WKY) rats during an exercise training program.

This work describes a comparative study of staged and non-staged anaerobic filters for treating a synthetic dairy waste. The effect of decreasing the hydraulic retention time from 2 days to 10 h at a constant substrate concentration of 9 g COD dm⁻³ by applying lateral feedings in the staged digester was evaluated with respect to overall reactor performance, in comparison with a conventional up-flow anaerobic filter. There was no advantage on the use of a multi-feed staged system under the operating conditions tested. The overall performance and the microbial activity segregation were similar for both configurations. The microbial aggregates present in both digesters, particularly in the top sections, changed significantly in biological, physical and morphological properties. The presence of aggregates larger than 4 mm equivalent diameter in those sections did not prevent a strong washout phenomenon. An effect of disintegration attributed to biogas accumulation and release was observed, when those large particles become smaller and their surface became rougher. Due to biomass accumulation, at the end of the trial period, only 40% of the total volume was occupied by the liquid phase. © 2000 Society of Chemical Industry

The properties of a novel complex between pyranine (a photoacid and an electron donor species) and methyl viologen (an efficient electron acceptor, MV⁺²) in aqueous and in micellar solutions were determined. On the basis of the electrostatic driven force for pyranine/methyl viologen (pyranine/MV²⁺) complexation, the distribution of the complexant species could be manipulated using ionic micellar aggregates. This distribution permits control over competitive photochemical and photophysical pathways and therefore allowed maximization of electron- and proton-transfer capabilities. Pyranine/MV²⁺ complexes (for the acid and conjugated base pyranine species) were characterized by UV−Vis and fluorescence titrations. Pyranine/MV²⁺ photoredox reactions were investigated by monitoring the transients (laser flash photolysis) due to the solvated electron, the reduced (PO^-•) and oxidized (PO^+•) forms of pyranine, and the semireduced methyl viologen (MV^+•). Ionic aqueous micelles (sodium dodecyl sulfate and cetyltrimethylammonium chloride) and anionic reversed micelles (sodium bis(2-ethylhexyl)sulfosuccinate) were used to disassemble the complex by attraction of one of its species by an oppositely charged micellar aggregate. Present findings demonstrate the formation of a complex and its manipulation, which may allow the development of a photocatalyst agent whose properties can be adjusted by the appropriate disposition of the complex partners in supramolecular aggregates.

It has been suggested that the chiral symmetry can be implemented only in classical Lagrangians containing higher covariant derivatives of odd order. Contrary to this belief, it is shown that one can construct an exactly soluble two-dimensional higher-derivative fermionic quantum field theory containing only derivatives of even order whose classical Lagrangian exhibits chiralgauge invariance. The original field solution is expressed in terms of usual Dirac spinors through a canonical transformation, whose generating function allows the determination of the new Hamiltonian. It is emphasized that the original and transformed Hamiltonians are different because the mapping from the old to the new canonical variables depends explicitly on time. The violation of cluster decomposition is discussed and the general Wightman functions satisfying the positive-definiteness condition are obtained.