A novel treatment strategy to prevent Parkinson's disease: focus on iron regulatory protein 1 (IRP1).

We propose that neural damage in Parkinson's disease (PD) is due to dysregulation of iron utilization rather than to high iron levels per se. Iron deposits are associated with neuronal cell death in substantia nigra (SN) resulting in PD where high levels of iron in SNs are due to dysregulation of iron utilization. Cytosolic aconitase (ACO1) upon losing an iron-sulfur cluster becomes iron regulatory protein 1 (IRP1). Rotenone increases levels of IRP1 and induces PD in rats. An increase in iron leads to inactivation of IRP1. We propose a novel treatment strategy to prevent PD. Specifically in rats given rotenone by subcutaneous injections, iron, from iron carbonyl from which iron is slowly absorbed, given three times a day by gavage will keep iron levels constant in the gut whereby iron levels and iron utilization systematically can be tightly regulated. Rotenone adversely affects complex 1 iron-sulfur proteins. Iron supplementation will increase iron-sulfur cluster formation switching IRP1 to ACO1. With IRP1 levels kept constantly low, iron utilization will systematically be tightly regulated stopping dysregulation of complex 1 and the neural damage done by rotenone preventing PD.

Bernstein Polynomial-Based Method for Solving Optimal Trajectory Generation Problems.

This paper presents a method for the generation of trajectories for autonomous system operations. The proposed method is based on the use of Bernstein polynomial approximations to transcribe infinite dimensional optimization problems into nonlinear programming problems. These, in turn, can be solved using off-the-shelf optimization solvers. The main motivation for this approach is that Bernstein polynomials possess favorable geometric properties and yield computationally efficient algorithms that enable a trajectory planner to efficiently evaluate and enforce constraints along the vehicles' trajectories, including maximum speed and angular rates as well as minimum distance between trajectories and between the vehicles and obstacles. By virtue of these properties and algorithms, feasibility and safety constraints typically imposed on autonomous vehicle operations can be enforced and guaranteed independently of the order of the polynomials. To support the use of the proposed method we introduce BeBOT (Bernstein/Bézier Optimal Trajectories), an open-source toolbox that implements the operations and algorithms for Bernstein polynomials. We show that BeBOT can be used to efficiently generate feasible and collision-free trajectories for single and multiple vehicles, and can be deployed for real-time safety critical applications in complex environments.

Lipid Membrane Interactions of the Cationic Antimicrobial Peptide Chimeras Melimine and Cys-Melimine.

Melimine and its derivatives are synthetic chimeric antimicrobial agents based on protamine and melittin. The binding of solubilized melimine and its derivative, with a cysteine on N-terminus, (cys-melimine) on tethered bilayer lipid membranes (tBLMs) was examined using ac electrical impedance spectroscopy. The addition of melimine and cys-melimine initially increased membrane conduction, which subsequently falls over time. The results were obtained for tBLMs comprising zwitterionic phosphatidylcholine, anionic phosphatidylglycerol, or tBLMs made using purified lipids from Escherichia coli. The effect on conduction is more marked with the cysteine variant than the noncysteine variant. The variation in membrane conduction most probably arises from individual melimines inducing increased ionic permeability, which is then reduced as the melimines aggregate and phase-separate within the membrane. The actions of these antimicrobials are modeled in terms of altering the critical packing parameter (CPP) of the membranes. The variations in the peptide length of cys-melimine were compared with a truncated version of the peptide, cys-mel4. The results suggest that the smaller molecule impacts the membrane by a mechanism that increases the average CPP, reducing membrane conduction. Alternatively, an uncharged alanine-replacement version of melimine still produced an increase in membrane conduction, further supporting the CPP model of geometry-induced toroidal pore alterations. All the data were then compared to their antimicrobial effectiveness for the Gram-positive and Gram-negative strains of bacteria, and their fusogenic properties were examined using dynamic light scattering in 1-oleoyl-2-hydroxy- sn-glycero-3-phosphocholine lipid spheroids. We conclude that a degree of correlation exists between the antimicrobial effectiveness of the peptides studied here and their modulation of membrane conductivity.

Amphipathic guanidine-embedded glyoxamide-based peptidomimetics as novel antibacterial agents and biofilm disruptors.

Antimicrobial resistance in bacteria is becoming increasingly prevalent, posing a critical challenge to global health. Bacterial biofilm formation is a common resistance mechanism that reduces the effectiveness of antibiotics. Thus, the development of compounds that can disrupt bacterial biofilms is a potential strategy to combat antimicrobial resistance. We report herein the synthesis of amphipathic guanidine-embedded glyoxamide-based peptidomimetics via ring-opening reactions of N-naphthoylisatins with amines and amino acids. These compounds were investigated for their antibacterial activity by the determination of minimum inhibitory concentration (MIC) against S. aureus and E. coli. Compounds 35, 36, and 66 exhibited MIC values of 6, 8 and 10 µg mL-1 against S. aureus, respectively, while compounds 55 and 56 showed MIC values of 17 and 19 µg mL-1 against E. coli, respectively. Biofilm disruption and inhibition activities were also evaluated against various Gram-positive and Gram-negative bacteria. The most active compound 65 exhibited the greatest disruption of established biofilms by 65% in S. aureus, 61% in P. aeruginosa, and 60% in S. marcescens respectively, at 250 µM concentration, while compound 52 inhibited the formation of biofilms by 72% in S. marcescens at 250 µM. We also report here the in vitro toxicity against MRC-5 human lung fibroblast cells. Finally, the pore forming capability of the three most potent compounds were tested using tethered bilayer lipid membrane (tBLM) technology.

Evidence of the Key Role of H3O+ in Phospholipid Membrane Morphology.

This study explains the importance of the phosphate moiety and H3O+ in controlling the ionic flux through phospholipid membranes. We show that despite an increase in the H3O+ concentration when the pH is decreased, the level of ionic conduction through phospholipid bilayers is reduced. By modifying the lipid structure, we show the dominant determinant of membrane conduction is the hydrogen bonding between the phosphate oxygens on adjacent phospholipids. The modulation of conduction with pH is proposed to arise from the varying H3O+ concentrations altering the molecular area per lipid and modifying the geometry of conductive defects already present in the membrane. Given the geometrical constraints that control the lipid phase structure of membranes, these area changes predict that organisms evolving in environments with different pHs will select for different phospholipid chain lengths, as is found for organisms near highly acidic volcanic vents (short chains) or in highly alkaline salt lakes (long chains). The stabilizing effect of the hydration shells around phosphate groups also accounts for the prevalence of phospholipids across biology. Measurement of ion permeation through lipid bilayers was made tractable using sparsely tethered bilayer lipid membranes with swept frequency electrical impedance spectroscopy and ramped dc amperometry. Additional evidence of the effect of a change in pH on lipid packing density is obtained from neutron reflectometry data of tethered membranes containing perdeuterated lipids.

Synthesis and biological evaluation of N-naphthoyl-phenylglyoxamide-based small molecular antimicrobial peptide mimics as novel antimicrobial agents and biofilm inhibitors.

Antimicrobial peptides (AMPs) are a key component of the human immune system. Synthetic AMP mimics represent a novel strategy to counteract the increasing incidence of antimicrobial resistance. Here, we describe the synthesis of novel glyoxamide derivatives via ring-opening reactions of N-hexanoyl, N-benzoyl and N-naphthoylisatins with N,N-dimethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine. These were converted to both the hydrochloric acid (HCl) or quaternary ammonium iodide (MeI) salts and their antibacterial activity against Staphylococcus aureus was investigated by their zone-of-inhibition and minimum inhibitory concentration (MIC). The HCl salt 22b exhibited the lowest MIC of 16 µg mL(-1), whereas the corresponding MeI salt 22c had a MIC of 39 µg mL(-1). We also investigated the in vitro toxicity of active compounds against the MRC-5 normal human lung fibroblasts and their activity against established biofilm in S. aureus.

Effect of a functional monomer (MDP) on the enamel bond durability of single-step self-etch adhesives.

The present study aimed to determine the effect of the functional monomer, 10-methacryloxydecyl dihydrogen phosphate (MDP), on the enamel bond durability of single-step self-etch adhesives through integrating fatigue testing and long-term water storage. An MDP-containing self-etch adhesive, Clearfil Bond SE ONE (SE), and an experimental adhesive, MDP-free (MF), which comprised the same ingredients as SE apart from MDP, were used. Shear bond strength (SBS) and shear fatigue strength (SFS) were measured with or without phosphoric acid pre-etching. The specimens were stored in distilled water for 24 h, 6 months, or 1 yr. Although similar SBS and SFS values were obtained for SE with pre-etching and for MF after 24 h of storage in distilled water, SE with pre-etching showed higher SBS and SFS values than MF after storage in water for 6 months or 1 yr. Regardless of the pre-etching procedure, SE showed higher SBS and SFS values after 6 months of storage in distilled water than after 24 h or 1 yr. To conclude, MDP might play an important role in enhancing not only bond strength but also bond durability with respect to repeated subcritical loading after long-term water storage.

The Behavioral Cost of Care: Changes in Maintenance Behavior during Equine-Assisted Interventions.

This study examined human-animal symbiosis in an animal-assisted intervention through observations of animal maintenance behaviors. The rise of psychotherapy, learning, and recreation incorporating animals warrants exploration of the welfare of the animals involved in these interventions. The analysis of welfare in multispecies engagements can be discussed in terms of symbiosis. Regarding an intervention's animal provider (e.g., therapy horse) and human recipient (psychotherapy client), the balance of cost and benefit is important. Research describing human and animal interactive behavior during interventions is limited, whether focusing on client outcomes or animal welfare. The present study adapted ethological methods to study humans and animals in an equine-assisted intervention, observing equine maintenance behaviors and equid-human interactive behavior. Maintenance behaviors were recorded before, during, and after equine-assisted (psychosocial) learning sessions with youth, providing 1600 observations. Equine alertness, eating behavior, and ambulation varied significantly before, during, and after the equine-assisted sessions. Such interruptions of typical behavior are an important aspect of welfare and unit of analysis when examining symbiotic relationships. A total of 267 sequences of equid-human approach-response behavior were also recorded, indicating that human-animal interaction was predominantly from humans toward equids. Equids' dominant response to human approach was no response, followed by avoidance, while humans' dominant response to equid approach was reciprocation. The findings are discussed in terms of symbiosis and animal welfare.

Mass-gathering medicine: a descriptive analysis of a range of mass-gathering event types.

OBJECTIVE: To identify and evaluate the volume, nature, and severity of patient presentations encountered by emergency medical services (EMS) at all mass-gathering events held at or near a southeastern US university. In addition, to compare the existing literature base (single mass-gathering event held in large urban population centers) with a broader variety of events varying in crowd size and locations. METHODS: This was a retrospective review of all EMS records from mass-gathering patient presentations (individual-patient cases) between October 24, 2009, and August 27, 2011. All patrons seen by event-based EMS were included. Events categories included the following: football, concerts, public exhibitions, and nonfootball athletic events. Event volumes were defined as follows: low (<1000 patrons), medium (between 1001 and 15 000 patrons), and large (>15 000 patrons). Case presentation-management categories included the following: trauma, medical, and support (minimal medical intervention required, eg, minor dressing for abrasion, water, etc). Severity categories included the following: mild, moderate, and severe based on the following definitions using both provider assessment and the use of transport to a hospital: minor cases were considered non-life threats and did not result in a transport to a hospital; moderate cases were associated with transports to a hospital; and severe cases were life threats with transport to a hospital. RESULTS: We studied 79 events over the study period. Event volumes were 16.45% high, 79.75% medium, and 3.80% low. A total of 670 cases presented, with a mean of 8.48 cases/event. The football category had the highest mean number of cases with 37.09 cases/event, for a total of 408 cases. The nonfootball, athletic event category had the lowest mean number of cases at 1.83 cases/event. Most (81.82%) of the football events were classified as large volume. Support cases were the most common presentation (43.13%), followed closely by medical complaints (41.94%). Most cases were mild in severity (95.97%). There were 27 cases requiring transport to hospital, with 3 cases being life-threatening. The average patient age was 33 years, with 60.3% female sex. These features are similar to the published information on large event medical attendance. CONCLUSIONS: In this retrospective, descriptive study of a broad range of event type, the most common patient presentations at mass-gathering events were mild in severity, requiring minimal medical intervention. Both transports from the event to a hospital and the occurrence of life threats were uncommon. Our findings are similar to the data found in the existing medical literature.

Activation analysis and evaluation of the radionuclide inventories, decay heat for European DEMO divertor components.

This work presents neutron flux calculation results and specific decay heat and activity for the European DEMO reactor divertor structure. Two DEMO 2017 models were used in calculations; one with a homogenised WCLL breeder blanket and the other with a homogenised HCPB breeder blanket. The neutron flux calculations were performed using MCNP6 code with JEFF 3.2 nuclear data. Activation and decay heat calculations were performed using the FISPACT-II code with TENDL - 2017 nuclear data library.

Stimulated neuronal expression of brain-derived neurotrophic factor by Neurotropin.

Expression of brain-derived neurotrophic factor (BDNF) was stimulated in human neuroblastoma SH-SY5Y cells by a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin), an analgesic widely used in Japan for treatment of disorders associated with chronic pain, with the optimal dosage at 10mNU/mL. This stimulation was accompanied by activations of p42/44 MAP kinase, CREB and c-Fos expression. Inhibitors of MAP kinases or PI 3-kinase prevented the stimulatory action of Neurotropin, indicating that neuronal TrkB/CREB pathway mediates the action. Repetitive oral administration of Neurotropin (200NU/kg/day, 3months) prevented the age-dependent decline in hippocampal BDNF expression in Ts65Dn mice, a model of Down's syndrome. This effect was associated with the improvement of spatial cognition of the mice. These results open an intriguing new strategy in which Neurotropin may prove beneficial treatment for neurodegenerative disorders.

Osteoporosis and the effect of dysregulation of the transsulfuration pathway via taurine on intracellular calcium homeostasis, vitamin D absorption and vitamin K absorption.

BACKGROUND & AIMS: In this article we connect the dysregulation of the transsulfuration pathway to bone dysregulations and propose a novel treatment for osteoporosis. Current treatments for osteoporosis are very frequently inadequate. In osteoporosis, the risk of fractures increases with increased homocysteine (Hcy). METHODS: Here, we conduct a review on the relationship between osteoporosis and the dysregulation of the transsulfuration pathway. RESULTS: we show that the transsulfuration pathway metabolizes Hcy to L-cysteine. Increased Hcy levels point to the transsulfuration pathway being dysregulated. With the transsulfuration pathway dysregulated, there will be decreased levels of L-cysteine and decreased levels of taurine, which is synthesized from L-cysteine. Taurine levels are decreased in patients with osteoporosis. Taurine regulates intracellular calcium homeostasis. Taurine, also, when conjugated with bile acids assists with absorption of fats and fat-soluble vitamins such as vitamin D and vitamin K. Dysregulated calcium homeostasis, decreased calcium absorption and decreased absorption of vitamin D and vitamin K due to low levels of taurine negatively affect bone mineral density (BMD) leading to osteoporosis and fractures. CONCLUSIONS: In this article, we propose that a combination of taurine, calcium, vitamin D and vitamin K, could increase BMD reducing number of years spent in disability and reducing deaths due to fractures in patients with osteoporosis.

Tooth whitening: current status.

This article reviews the history of tooth whitening and its rapid evolution and briefly discusses tooth whitening agents and protocols. The active ingredients and mode of action during the whitening process are explained. The factors affecting the speed of whitening and its final results are discussed, as well as adverse effects and safety precautions. Protocols are explained in detail, and the predicted outcomes, including those for tetracycline-stained teeth, are covered.

A disease-modifying treatment for Alzheimer's disease: focus on the trans-sulfuration pathway.

High homocysteine levels in Alzheimer's disease (AD) result from low activity of the trans-sulfuration pathway. Glutathione levels are also low in AD. L-cysteine is required for the synthesis of glutathione. The synthesis of coenzyme A (CoA) requires L-cysteine, which is synthesized via the trans-sulfuration pathway. CoA is required for the synthesis of acetylcholine and appropriate cholinergic neurotransmission. L-cysteine is required for the synthesis of molybdenum-containing proteins. Sulfite oxidase (SUOX), which is a molybdenum-containing protein, could be dysregulated in AD. SUOX detoxifies the sulfites. Glutaminergic neurotransmission could be dysregulated in AD due to low levels of SUOX and high levels of sulfites. L-cysteine provides sulfur for iron-sulfur clusters. Oxidative phosphorylation (OXPHOS) is heavily dependent on iron-sulfur proteins. The decrease in OXPHOS seen in AD could be due to dysregulations of the trans-sulfuration pathway. There is a decrease in aconitase 1 (ACO1) in AD. ACO1 is an iron-sulfur enzyme in the citric acid cycle that upon loss of an iron-sulfur cluster converts to iron regulatory protein 1 (IRP1). With the dysregulation of iron-sulfur cluster formation ACO1 will convert to IRP1 which will decrease the 2-oxglutarate synthesis dysregulating the citric acid cycle and also dysregulating iron metabolism. Selenomethionine is also metabolized by the trans-sulfuration pathway. With the low activity of the trans-sulfuration pathway in AD selenoproteins will be dysregulated in AD. Dysregulation of selenoproteins could lead to oxidant stress in AD. In this article, we propose a novel treatment for AD that addresses dysregulations resulting from low activity of the trans-sulfuration pathway and low L-cysteine.

Treatment-resistant schizophrenia: focus on the transsulfuration pathway.

Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H2S) levels are low in schizophrenia. H2S is synthesized by cystathionine ß-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.

Predicting resource use at mass gatherings using a simplified stratification scoring model.

INTRODUCTION: Mass gathering events require varying types and amounts of medical resources to deal with patient presentations. The needs of various events have so far been difficult to predict with precision, yet likely are impacted by several factors which may be used in a predictive fashion. HYPOTHESIS: Medical needs at mass gathering events can be predicted based on a combination of weather, number in attendance, presence of alcohol, demographic of the participants in attendance, and crowd intentions. Furthermore, each of these factors can be assigned a score and events can be stratified based on that score. METHODS: Fifty-five mass gathering events of varying type occurring in proximity to a large mid-Atlantic university were analyzed retrospectively. Based on a scoring system using the factors described, the events were categorized as "minor," "intermediate," or "major." The actual medical needs at each event were then analyzed. RESULTS: Twelve events were classified a priori as "minor," 20 events were classified as "intermediate," and 23 received a classification of "major." These events had averages of 2.3, 6.3, and 71 total contacts, respectively. These trends were consistent for minor encounters, major encounters, and transports. The classification system correctly predicted the resource demand for the 3 classes of events. CONCLUSION: A classification system that stratifies events based on weather, number in attendance, presence of alcohol, demographic in attendance, and crowd intentions can effectively predict medical needs at mass gatherings. This system is most accurate in the description of minor- and intermediate-type events; major events were less well described by this classification system.

The Use of Tethered Bilayer Lipid Membranes to Identify the Mechanisms of Antimicrobial Peptide Interactions with Lipid Bilayers.

This review identifies the ways in which tethered bilayer lipid membranes (tBLMs) can be used for the identification of the actions of antimicrobials against lipid bilayers. Much of the new research in this area has originated, or included researchers from, the southern hemisphere, Australia and New Zealand in particular. More and more, tBLMs are replacing liposome release assays, black lipid membranes and patch-clamp electrophysiological techniques because they use fewer reagents, are able to obtain results far more quickly and can provide a uniformity of responses with fewer artefacts. In this work, we describe how tBLM technology can and has been used to identify the actions of numerous antimicrobial agents.

Homer proteins regulate sensitivity to cocaine.

Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.

Benefits of preheating resin composite before placement.

Resin composite can be relatively stiff, difficult to express from the compule/syringe, and challenging to place. Research has shown that heating the material prior to use not only decreases its viscosity but also improves its physical properties. This article discusses the effect of preheating composite and discusses a device designed to control the preheating process.