Hybrid Controller Based on Numerical Methods for Chemical Processes with a Long Time Delay.

A hybrid control framework is proposed as an alternative for long time delays in chemical processes. The hybrid approach mixes the numerical methods in an internal mode control (IMC) structure, which uses the particle swarm optimization (PSO) algorithm to improve the adjustment of the controller parameters. Simulation tests are carried out on linear systems of high order and inverse response, both with dominant delay, and tests on a nonlinear process (chemical reactor). The performance of the proposed controller is stable and satisfactory despite nonlinearities in various operating conditions, set-point changes, process disturbances, and modeling errors. In addition, experimental tests were performed on a setup composed of two heaters and two temperature sensors mounted on an Arduino microcontroller-based board called the Temperature Control Laboratory (TCLab), with an additional software delay introduced. The merits and drawbacks of each scheme are analyzed using radar charts, comparing the control methods with different performance measures for set-point and disturbance changes. Furthermore, the new controller uses PSO to improve the tuning parameters.

Hybrid Approaches-Based Sliding-Mode Control for pH Process Control.

This paper presents two hybrid control topologies; the topologies are designed by combining artificial intelligence approaches and sliding-mode control methodology. The first topology mixes the learning algorithm for multivariable data analysis (LAMDA) approach with sliding-mode control. The second offers a Takagi-Sugeno multimodel approach, internal model, and sliding-mode control. The process under study is a nonlinear pH neutralization process with high nonlinearities and time-varying parameters. The pH process is simulated for multiple reference changes, disturbance rejection, and noise in the transmitter. Performance indices are used to compare the proposed approaches quantitatively. The hybrid control topologies enhance the performance and robustness of the pH process under study.

Leveraging Biological Buffers for Efficient Messenger RNA Delivery via Lipid Nanoparticles.

Lipid nanoparticles containing messenger RNA (mRNA-LNPs) have launched to the forefront of nonviral delivery systems with their realized potential during the COVID-19 pandemic. Here, we investigate the impact of commonly used biological buffers on the performance and durability of mRNA-LNPs. We tested the compatibility of three common buffers─HEPES, Tris, and phosphate-buffered saline─with a DLin-MC3-DMA mRNA-LNP formulation before and after a single controlled freeze-thaw cycle. We hypothesized that buffer composition would affect lipid-aqueous phase separation. Indeed, the buffers imposed structural changes in LNP morphology as indicated by electron microscopy, differential scanning calorimetry, and membrane fluidity assays. We employed in vitro and in vivo models to measure mRNA transfection and found that Tris or HEPES-buffered LNPs yielded better cryoprotection and transfection efficiency compared to PBS. Understanding the effects of various buffers on LNP morphology and efficacy provides valuable insights into maintaining the stability of LNPs after long-term storage.

Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery.

Lipid-based nanoparticles (LNPs) for the delivery of mRNA have jumped to the forefront of non-viral gene delivery. Despite this exciting development, poor endosomal escape after LNP cell entry remains an unsolved, rate-limiting bottleneck. Here we report the use of a galectin 8-GFP (Gal8-GFP) cell reporter system to visualize the endosomal escape capabilities of LNP-encapsulated mRNA. LNPs substituted with phytosterols in place of cholesterol exhibited various levels of Gal8 recruitment in the Gal8-GFP reporter system. In live-cell imaging, LNPs containing ß-sitosterol (LNP-Sito) showed a 10-fold increase in detectable endosomal perturbation events when compared to the standard cholesterol LNPs (LNP-Chol), suggesting the superior capability of LNP-Sito to escape from endosomal entrapment. Trafficking studies of these LNPs showed strong localization with late endosomes. This highly sensitive and robust Gal8-GFP reporter system can be a valuable tool to elucidate intricacies of LNP trafficking and ephemeral endosomal escape events, enabling advancements in gene delivery.

Quantitative Analysis of Redox-Inactive Ions by AC Voltammetry at a Polarized Interface between Two Immiscible Electrolyte Solutions.

The interface between two immiscible electrolyte solutions (ITIES) is ideally suited to detect redox-inactive ions by their ion transfer. Such electroanalysis, based on the Nernst-Donnan equation, has been predominantly performed using amperometry, cyclic voltammetry, or differential pulse voltammetry. Here, we introduce a new electroanalytical method based on alternating-current (AC) voltammetry with inherent advantages over traditional approaches such as avoidance of positive feedback iR compensation, a major issue for liquid|liquid electrochemical cells containing resistive organic media and interfacial areas in the cm2 and mm2 range. A theoretical background outlining the generation of the analytical signal is provided and based on extracting the component that depends on the Warburg impedance from the total impedance. The quantitative detection of a series of model redox-inactive tetraalkylammonium cations is demonstrated, with evidence provided of the transient adsorption of these cations at the interface during the course of ion transfer. Since ion transfer is diffusion-limited, by changing the voltage excitation frequency during AC voltammetry, the intensity of the Faradaic response can be enhanced at low frequencies (1 Hz) or made to disappear completely at higher frequencies (99 Hz). The latter produces an AC voltammogram equivalent to a "blank" measurement in the absence of analyte and is ideal for background subtraction. Therefore, major opportunities exist for the sensitive detection of ionic analyte when a "blank" measurement in the absence of analyte is impossible. This approach is particularly useful to deconvolute signals related to reversible electrochemical reactions from those due to irreversible processes, which do not give AC signals.

Brief update on endocytosis of nanomedicines.

The complexity of nanoscale interactions between biomaterials and cells has limited the realization of the ultimate vision of nanotechnology in diagnostics and therapeutics. As such, significant effort has been devoted to advancing our understanding of the biophysical interactions of the myriad nanoparticles. Endocytosis of nanomedicine has drawn tremendous interest in the last decade. Here, we highlight the ever-present barriers to efficient intracellular delivery of nanoparticles as well as the current advances and strategies deployed to breach these barriers. We also introduce new barriers that have been largely overlooked such as the glycocalyx and macromolecular crowding. Additionally, we draw attention to the potential complications arising from the disruption of the newly discovered functions of the lysosomes. Novel strategies of exploiting the inherent intracellular defects in disease states to enhance delivery and the use of exosomes for bioanalytics and drug delivery are explored. Furthermore, we discuss the advances in imaging techniques like electron microscopy, super resolution fluorescence microscopy, and single particle tracking which have been instrumental in our growing understanding of intracellular pathways and nanoparticle trafficking. Finally, we advocate for the push towards more intravital analysis of nanoparticle transport phenomena using the multitude of techniques available to us. Unraveling the underlying mechanisms governing the cellular barriers to delivery and biological interactions of nanoparticles will guide the innovations capable of breaching these barriers.

Fungal infections in pediatric neurosurgery.

INTRODUCTION: Invasive mycosis of the central nervous system represent a diverse group of diseases that have gradually emerged as not only opportunistic infections in patients with immune susceptibility due to congenital and acquired deficiency, immunomodulation, solid organ and stem cell transplantation, hematological malignancies, and chronic steroid use but also in selected risk populations such as low weight preterm infants, patients with shunted hydrocephalus and external ventricular drainages, skull base surgery, and head injury. OBJECTIVES: The purpose of this review is to familiarize the pediatric neurosurgeon with the most common mycosis and their clinical scenarios which can be encountered in the clinical practice, with special emphasis on clinical, radiological, and laboratory diagnosis beyond classical microorganism cultures as well as options in medical and surgical treatment given the high incidence of morbidity and mortality associated with these challenging entities. METHODS: We conducted an online database review (Ovid, PubMed) gathering relevant English language literature published in the last 20 years with special emphasis on recent breakthroughs in the diagnosis and treatment of invasive mycosis of the CNS as well as reported cases within the pediatric neurosurgical literature and their surgical management. RESULTS: Fungal agents capable of invading the CNS can behave as aggressive entities with rapid progression manifesting as overwhelming meningoencephalitis with vascular compromise or can lead to space-occupying lesions with abscess formation which require prompt diagnosis by either laboratory identification of the components of these biological agents and their host response or by obtaining tissue specimens for microbiological identification which may not be straightforward due to prolonged culture time. CONCLUSION: Following a high degree of suspicion with prompt initiation of antifungal agents and reversal of potential immunosuppressant therapies along with neurosurgical evacuation of intracranial collections or removal of infected hardware (CSF shunts) can lead to more optimistic outcomes of these complex clinical scenarios.

Effect of carbon tetrachloride on the luminol sonochemiluminescence reaction kinetics during multibubble cavitation.

The sonochemiluminescence (SCL) of luminol reaction was studied in alkaline medium using a dissolution of luminol, sodium carbonate, hydrogen peroxide and carbon tetrachloride. The presence of carbon tetrachloride enhances the SCL reaction up to allow the study of the reaction in real time using a cell phone video camera. This experimental setup allows the study of the cavitation dynamics in real time and through all the reactor, including homogeneous and heterogeneous cavitation zones. Finally, it was tested the effect of ethanol, the ionic strength and pH on the SCL.

SliC is a surface-displayed lipoprotein that is required for the anti-lysozyme strategy during Neisseria gonorrhoeae infection.

Lysozymes are nearly omnipresent as the first line of immune defense against microbes in animals. They exert bactericidal action through antimicrobial peptide activity and peptidoglycan hydrolysis. Gram-negative bacteria developed several weapons to battle lysozymes, including inhibitors of c-type lysozymes in the MliC/PliC family and the Neisseria adhesin complex protein (ACP). Until the recent discovery of ACP, no proteinaceous lysozyme inhibitors were reported for the genus Neisseria, including the important human pathogen N. gonorrhoeae. Here, we describe a previously unrecognized gonococcal virulence mechanism involving a protein encoded by the open reading frame ngo1063 that acts to counteract c-type Iysozyme and provides a competitive advantage in the murine model of gonorrhea. We named this protein SliC as a surface-exposed lysozyme inhibitor of c-type lysozyme. SliC displays low overall primary sequence similarity to the MliC/PliC inhibitors, but we demonstrate that it has a parallel inhibitory mechanism. Our studies provide the first evidence that bacterial proteinaceous lysozyme inhibitors protect against host lysozyme during infection based on lack of attenuation of the ΔsliC mutant in lysozyme knock-out mice, and that the conserved residues involved in lysozyme inhibition, S83 and K103, are functionally indispensable during infection in wild type mice. Recombinant SliC completely abrogated the lytic activity of human and chicken c-type lysozymes, showing a preference towards human lysozyme with an IC50 of 1.85 µM and calculated KD value of 9.2 ± 1.9 µM. In contrast, mutated SliC bearing S83A and K103A substitutions failed to protect fluorescein-labeled cell-wall from lysozyme-mediated hydrolysis. Further, we present data revealing that SliC is a surface-displayed lipoprotein released in membrane vesicles that is expressed throughout all phases of growth, in conditions relevant to different niches of the human host, and during experimental infection of the murine genital tract. SliC is also highly conserved and expressed by diverse gonococcal isolates as well as N. meningitidis, N. lactamica, and N. weaveri. This study is the first to highlight the importance of an anti-lysozyme strategy to escape the innate immune response during N. gonorrhoeae infection.

The chemistry and pharmacology of synthetic cannabinoid SDB-006 and its regioisomeric fluorinated and methoxylated analogs.

Synthetic cannabinoids are the largest and most structurally diverse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogs of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CB1 EC50 = 19 nM). All methoxy- and fluorine-substituted analogs showed reduced potency compared to SDB-006, although the 2-fluorinated analog (EC50 = 166 nM) was comparable to known synthetic cannabinoid RCS-4 (EC50 = 146 nM). Using biotelemetry in rats, SDB-006 and RCS-4 evoked comparable reduction in body temperature (~0.7°C at a dose of 10 mg/kg), suggesting lower potency than the recent synthetic cannabinoid AB-CHMINACA (>2°C, 3 mg/kg).

Chromoblastomycosis Caused by Phialophora verrucosa in a Costa Rican Child with Skin Sequelae due to Snake Bite.

Chromoblastomycosis is an implantation mycosis occurring among adults working in farms or with soil in tropical and subtropical areas worldwide. Fonsecaea pedrosoi is the most important agent in the tropical areas, while Phialophora verrucosa, although not a predominant agent, is found in the lowlands under the same conditions as the Fonsecae species. We present the case of a 10-year-old aboriginal boy, belonging to a soil worker family, with a history of extensive leg lesions and lymphedema secondary to a snake bite five years earlier. He was admitted to the National Children's Hospital (part of the Caja Costarricense del Seguro Social: the social security system in Costa Rica) with multiple verrucous confluent lesions on the ankle, some with dark coloration, and no other symptoms. Clinical suspicion of chromoblastomycosis was made and later confirmed by culture. Itraconazole was started showing clinical improvement. Chromomycosis, especially in the population with skin lesions or chronic tissue compromise, associated with the location and macroscopic findings, must be a part of our differential diagnosis. The story of an exposed pediatric patient to soil work and the history of an important leg swelling and skin disruption as sequelae of snake bite envenomation made this case unique. To our knowledge, there are no pediatric reports of Chromoblastomycosis in Latin America.

The Recent Development of α7 Nicotinic Acetylcholine Receptor (nAChR) Ligands as Therapeutic Candidates for the Treatment of Central Nervous System (CNS) Diseases.

Homomeric α7 nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation of cognitive processes such as memory and attention and have potential as therapeutic targets for the treatment of the cognitive deficits associated with schizophrenia. Though numerous α7 nAChR agonists have been developed, and several have progressed to clinical trials, these are derived from few common chemotypes. Consequently, many of these α7 nAChR clinical candidates share unfavorable side-effect profile. SEN12333 represents a novel chemotype for the development of α7 nAChR agonists, and exploration of this scaffold has produced structurally diverse ligands with promising pharmacological properties. This review will summarize structure-affinity and -activity relationships surrounding analogs of SEN12333.

The therapeutic potential of α7 nicotinic acetylcholine receptor (α7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia.

Homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple α7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical α7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other α7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of α7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology.

IR and electrochemical synthesis and characterization of thin films of PEDOT grown on platinum single crystal electrodes in [EMMIM]Tf2N ionic liquid.

Thin films of PEDOT synthesized on platinum single electrodes in contact with the ionic liquid 1-ethyl-2,3-dimethylimidazolium triflimide ([EMMIM]Tf2N) were studied by cyclic voltammetry, chronoamperometry, infrared spectroscopy and atomic force microscopy. It was found that the polymer grows faster on Pt(111) than on Pt(110) or Pt(100) and that the redox reactions associated with the PEDOT p-doping process are much more reversible in [EMMIM]Tf2N than in acetonitrile. Finally, the ion exchange and charge carriers' formation during the p-doping reaction of PEDOT were studied using in situ FTIR spectroscopy.

Molecular epidemiology of methicillin-resistant Staphylococcus aureus in Costa Rican children.

We collected all Staphylococcus aureus isolates from the National Children's Hospital in Costa Rica to evaluate the prevalence and molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA). Of 299 S. aureus isolates, 61% were MRSA. Most MRSA isolates (94.5%) carried SCCmec IV, and 45.6% carried Panton-Valentine leukocidin-encoding genes. The high prevalence of MRSA in this population highlights the need for improvement of antibiotic prescription and infection control measures.

Electrochemical and electrocatalytic properties of thin films of poly(3,4-ethylenedioxythiophene) grown on basal plane platinum electrodes.

The first part of this communication studies the electrochemical properties of thin films of poly(3,4-ethylenedioxythiophene) (PEDOT) grown on the three basal plane platinum electrodes via cyclic voltammetry, chronoamperometry, electrochemical impedance spectroscopy and in situ FTIR spectroelectrochemistry. In the second part of this work the redox reaction of 2,5-dimercapto-1,3,4-thiadiazole (DMcT) at these platinum modified electrodes is investigated via cyclic voltammetry and electrochemical impedance spectroscopy in order to elucidate the effect of some polymer properties on its electrocatalytic behavior, such as the ionic resistance, nature of the doping ion and the structure. First of all, it was found that the ionic resistance of the PEDOT films electrochemically synthesized on platinum electrodes increases in the order Pt(100) < Pt(110) < Pt(111) and the advantages of using single crystal platinum electrodes coated with PEDOT for the IR study of individual mobile species flux and the evolution of charge carriers during the reduction process of p-doped PEDOT were proven. On the other hand, it was found that compact, rigid and low resistance PEDOT films show higher standard charge transfer rates for the DMcT redox reaction than those that have a more porous structure and higher ionic resistance. Finally, PEDOT films doped with alkaline ions are more electrocatalytic for the oxidation process of the protonated form of DMcT.

Voltammetry of basal plane platinum electrodes in acetonitrile electrolytes: effect of the presence of water.

The first part of this report studies the electrochemical properties of single-crystal platinum electrodes in acetonitrile electrolytes by means of cyclic voltammetry. Potential difference infrared spectroscopy in conjunction with linear voltammetry was used to obtain a molecular-level picture of this interface. The second part of this report studies the hydrogen evolution and the hydrogen oxidation reactions on the three low-index faces of Pt electrodes in acetonitrile electrolytes. The data (CVs and IR spectra) strongly suggest that acetonitrile and CN(-) molecules are adsorbed on single-crystal platinum electrodes in the range of -1.5 to 0.3 V versus Ag/AgCl. Those species block part of the adsorption sites for hydrogen adatoms, and they decompose on the surface in the presence of water. The nature of the cation and the presence of water strongly affect the onset of acetonitrile electrolysis and the kinetics and stability of the adsorbed species on the electrode. Finally, the hydrogen evolution and the hydrogen oxidation reactions on platinum single-crystal surfaces in acetonitrile electrolytes are strongly affected by the surface-energy state of Pt electrodes.

Electrochemical properties of thin films of polythiophene polymerized on Basal plane platinum electrodes in nonaqueous media.

In this paper the electrochemical properties of polythiophene thin films synthesized on single-crystal platinum electrodes are studied. It was found that the electrochemical properties, ion transport kinetics, and morphology of the polythiophene films depend on the surface orientation of the single-crystal platinum electrode used for their electropolymerization. Different oxidation levels, regarded as neutral, polaron, bipolaron, and metallic states, are usually found in conjugated heterocyclic polymers. However, the transitions between the different oxidation levels were never clearly observed in cyclic voltammetry. Instead the voltammograms usually show broad oxidation and reduction peaks with some shoulders. With the use of single-crystal platinum electrodes, it was found that polythiophene has a well-defined redox process at low potential, not observed before, possibly related to the conversion from the neutral state to polarons. On the other hand, two well-defined consecutive steps were found during the ion exchange reaction of thin films of polymer, both characterized by nucleation kinetics. This is the first report of two consecutive nucleation processes during the ion exchange process of a conducting polymer. The results presented here could further illuminate the mechanism in which the electron is transported in organic semiconductor materials.

Polymerization of polypyrrole on single crystal platinum electrodes: a surface structure sensitive reaction.

This communication shows experimental results that clearly demonstrated the influence of the crystalline surface structure of the platinum electrode on the early stages of the electropolymerization of pyrrole in aqueous media. The platinum surface structure determines adhesion, coverage level, charge transfer properties as well as bulk properties of the synthesized film like morphology and the ion exchange kinetics during its reduction and oxidation. It is proven that the Pt(110) an Pt(111) surfaces are more suitable for obtain polypyrrole films with higher conductivity and charge-storage capacity than the Pt(100) surface.