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Bacteriocins are a highly diverse group of antimicrobial peptides that have been identified in a wide range of commensal and probiotic organisms, especially those resident in host microbiomes. Rising antibiotic resistance have fueled renewed research into new drug scaffolds such as antimicrobial peptides for use in therapeutics. In this investigation, we examined mung bean seeds for endophytes possessing activity against human and plant pathogens. We isolated a novel strain of Bacillus safensis, from the contents of surface-sterilized mung bean seed, which we termed B. safensis C3. Genome sequencing of C3 identified three distinct biosynthetic systems that produce bacteriocin-based peptides. C3 exhibited antibacterial activity against Escherichia coli, Xanthomonas axonopodis, and Pseudomonas syringae. Robust antimicrobial activity of B. safensis C3 was observed when C3 was co-cultured with Bacillus subtilis. Using the cell-free supernatant of C3 and cation exchange chromatography, we enriched a product that retained antimicrobial activity against B. subtilis. The peptide was found to be approximately 3.3 kDa in size by mass spectrometry, and resistant to proteolysis by Carboxypeptidase Y and Endoproteinase GluC, suggesting that it is a modified variant of an AS-48 like bacteriocin. Our findings open new avenues into further development of novel bacteriocin-based scaffolds for therapeutic development, as well as further investigations into how our discoveries of bacteriocin-producing plant commensal microorganisms may have the potential for an immediate impact on the safety of food supplies.
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Theories of physician dominance are a foundational contribution of medical sociology to the study of health care, but must be revisited in the light of ongoing changes in medicine. As non-physician specialists like nurse practitioners grow in number and acquire more autonomy, increasing medical profession differentiation presents a challenge for traditional physician dominance theories. After evaluating potential theoretical explanations for subordinate occupations' autonomy gains, we conduct a state-level quantitative analysis of variation in nursing policies across U.S. states. We construct our dependent variable, nursing autonomy, using seven state-level advanced practice nursing policies adopted from 2001-2017. Using an ordered scale, we code nurse practitioner, nurse anaesthetist, nurse midwife and clinical-nurse-specialist practice and prescription polices according to each policy's autonomy level. We then use time-series regression to examine theory-driven propositions regarding nursing autonomy change. Nursing autonomy has increased over time, signalling a general erosion of physician dominance. However, we find differential patterns of policy adoption, indicating that erosion is not uniform. Physicians have maintained dominance in relatively prestigious specialties (e.g. anaesthesiology) while dominance declined in others (e.g. obstetrician). Factors external to the profession, such as consumer power, continue to influence within-profession dynamics. Examining ongoing professional differentiation in medicine illustrates how physician dominance depends on shifting social and professional contexts.
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Enfermeras Practicantes , Médicos , Humanos , Autonomía ProfesionalRESUMEN
Case management is a representation of managed care, cost-containment organizational practices in healthcare, where managed care and its constitutive parts are situated against physician autonomy and decision-making. As a professional field, case management has evolved considerably, with the role recently taken up increasingly by Advanced Practice Nurses in various health care settings. We look at this evolution of a relatively new work task for Advanced Practice Nurses using a countervailing powers perspective, which allows us to move beyond discussions of case management effectiveness and best practices, and draw connections to trends in the social organization of healthcare, especially hospitals. We evaluated organizational (hospital-level) and environmental (county and state-level) characteristics associated with hospitals' use of Advanced Practice Nurses as case managers, using data from U.S. community acute care hospitals for 2016-2018, collected from three data sources: American Hospital Association annual survey (AHA), Centers for Medicare and Medicaid Services (CMS), and Area Resource File. Among organizational characteristics, we found that hospitals that are a part of established Accountable Care Organizations (OR = 2.55, p = 0.009; 95% CI = 1.26-5.14) and those that serve higher acuity patients, as indicated by possessing a higher Case Mix Index (OR = 1.32, p = 0.001; 95% CI = 1.13-1.55), were more likely to use Advanced Practice Nurses as case managers. Among environmental characteristics, having higher local Advanced Practice Nurses concentrations (OR = 1.24, p < 0.001; 95% CI = 1.11-1.39) was associated with hospital Advanced Practice Nurses case management service provision. Beyond the health impacts of Covid-19, its associated recession is placing families, governments and insurers under unprecedented financial stress. Governments and insurers alike are looking to reduce costs anywhere possible. This will inevitably result in increasing amounts of managed care, and decreasing reimbursements to hospitals, likely resulting in higher demand for APRN patient navigators.
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Enfermería de Práctica Avanzada/estadística & datos numéricos , Gestores de Casos/estadística & datos numéricos , Administración Hospitalaria , Organizaciones Responsables por la Atención/organización & administración , Organizaciones Responsables por la Atención/estadística & datos numéricos , Enfermería de Práctica Avanzada/organización & administración , Gestores de Casos/organización & administración , Grupos Diagnósticos Relacionados , Fuerza Laboral en Salud/estadística & datos numéricos , Humanos , Rol de la Enfermera , Gravedad del Paciente , Factores Socioeconómicos , Estados UnidosRESUMEN
There is a critical need to develop new noninvasive therapies to treat bacteria biofilms. Previous studies have demonstrated the effectiveness of cavitation-based ultrasound histotripsy to destroy these biofilms. In this study, the dependence of biofilm destruction on multiple scan parameters was assessed by conducting exposures at different scan speeds (0.3-1.4 beamwidths/s), step sizes (0.25-0.5 beamwidths), and the number of passes of the focus across the mesh (2-6). For each of the exposure conditions, the number of colony-forming units (CFUs) remaining on the mesh was quantified. A regression analysis was then conducted, revealing that the scan speed was the most critical parameter for biofilm destruction. Reducing the number of passes and the scan speed should allow for more efficient biofilm destruction in the future, reducing the treatment time.
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Biopelículas/efectos de la radiación , Staphylococcus aureus/efectos de la radiación , Mallas Quirúrgicas/microbiología , Terapia por Ultrasonido , Recuento de Colonia Microbiana , Viabilidad Microbiana/efectos de la radiación , Modelos Biológicos , Terapia por Ultrasonido/instrumentación , Terapia por Ultrasonido/métodos , Ondas UltrasónicasRESUMEN
The use of cavitation-based ultrasound histotripsy to treat infections on surgical mesh has shown great potential. However, any impact of the therapy on the mesh must be assessed before the therapy can be applied in the clinic. The goal of this study was to determine if the cavitation-based therapy would reduce the strength of the mesh thus compromising the functionality of the mesh. First, Staphylococcus aureus biofilms were grown on the surgical mesh samples and exposed to high-intensity ultrasound pulses. For each exposure, the effectiveness of the therapy was confirmed by counting the number of colony forming units (CFUs) on the mesh. Most of the exposed meshes had no CFUs with an average reduction of 5.4-log10 relative to the sham exposures. To quantify the impact of the exposure on mesh strength, the force required to tear the mesh and the maximum mesh expansion before damage were quantified for control, sham, and exposed mesh samples. There was no statistical difference between the exposed and sham/control mesh samples in terms of ultimate tensile strength and corresponding mesh expansion. The only statistical difference was with respect to mesh orientation relative to the applied load. The tensile strength increased by 1.36 N while the expansion was reduced by 1.33 mm between different mesh orientations.
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Biopelículas/efectos de la radiación , Staphylococcus aureus/efectos de la radiación , Mallas Quirúrgicas/microbiología , Terapia por Ultrasonido , Recuento de Colonia Microbiana , Modelos BiológicosRESUMEN
Research has demonstrated a status gap between members of healthcare delivery teams. However, it is unclear which factors mitigate or exacerbate the status gap between healthcare providers. This paper examines the concept of status affirmation, the belief that others affirm the individual's social standing, as one factor that can affect the status gap between healthcare professionals. The aim of this exploratory study was to investigate two factors that affect nurses' status affirmation: nurses' educational backgrounds and clinical specializations. A close-ended survey was administered to registered nurses in Indiana, a midwestern American state 1 (N = 1262) to identify which nurses are likely to have their status affirmed by physicians, in general. Results of multinomial logistic regression analyses suggest that highly educated nurses are unlikely to receive status affirmation, and there are differences in status affirmation across clinical specialties. In addition, nurses with advanced degrees often do not work in specialties that receive status affirmation. These results suggest that conflict among nurses and doctors is as likely to exist across divisions in nurses' educational attainment as across work specializations. Status affirmation is posited as a theoretical antecedent to interprofessional collaboration.
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Éxito Académico , Actitud del Personal de Salud , Relaciones Médico-Enfermero , Médicos/psicología , Especialidades de Enfermería/educación , Adulto , Conflicto Psicológico , Conducta Cooperativa , Femenino , Humanos , Relaciones Interprofesionales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Calidad de la Atención de Salud , Lugar de Trabajo/psicologíaRESUMEN
Cavitation-based ultrasound histotripsy has shown potential for treating infections on surgical mesh. The goal of this paper was to explore a new scan strategy while assessing the impact of scan speed, scan step size, and the number of cycles in the tone burst on the destruction of S. aureus biofilms grown on surgical mesh samples using ultrasound histotripsy pulses (150 MPa/-17 MPa). For each exposure, the number of colony forming units (CFUs) on the mesh and released onto the surrounding gel was quantified. Most of the exposed mesh samples had no CFUs, and there was a statistically significant reduction in CFUs on the mesh for each of the exposures, with an average reduction of 3.8 log10 relative to the sham. Compared with the sham, there was also a statistically significant reduction in CFUs on the gel with the highest exposures.
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Biopelículas/efectos de la radiación , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Staphylococcus aureus/efectos de la radiación , Mallas Quirúrgicas/microbiología , Recuento de Colonia Microbiana , Diseño de Equipo , SonicaciónRESUMEN
Prior studies demonstrated that histotripsy generated by high-intensity tone bursts to excite a bubble cloud adjacent to a medical implant can destroy the bacteria biofilm responsible for the infection. The goal of this paper was to treat Staphylococcus aureus (S. aureus) biofilms on surgical mesh samples while varying the number of cycles in the tone burst to minimize collateral tissue damage while maximizing therapy effectiveness. S. aureus biofilms were grown on 1-cm square surgical mesh samples. The biofilms were then treated in vitro using a spherically focused transducer (1.1 MHz, 12.9-cm focal length, 12.7-cm diameter) using either a sham exposure or histotripsy pulses with tone burst durations of 3, 5, or 10 cycles (pulse repetition frequency of 333 Hz, peak compressional pressure of 150 MPa, peak rarefactional pressure of 17 MPa). After treatment, the number of colony forming units (CFUs) on the mesh and the surrounding gel was independently determined. The number of CFUs remaining on the mesh for the sham exposure (4.8 ± 0.9-log10) (sample mean ± sample standard deviation-log10 from 15 observations) was statistically significantly different from the 3-cycle (1.9 ± 1.5-log10), 5-cycle (2.2 ± 1.1-log10), and 10-cycle exposures (1 ± 1.5-log10) with an average reduction in the number of CFUs of 3.1-log10. The numbers of CFUs released into the gel for both the sham and exposure groups were the same within a bound of 0.86-log10, but this interval was too large to deduce the fate of the bacteria in the biofilm following the treatment.
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Biopelículas/efectos de la radiación , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Staphylococcus aureus/efectos de la radiación , Mallas Quirúrgicas/microbiología , Recuento de Colonia MicrobianaRESUMEN
BACKGROUND: There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. METHODS: Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. RESULTS: We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. CONCLUSIONS: Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction.
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Conducta Adictiva/fisiopatología , Dieta , Plasticidad Neuronal , Núcleo Accumbens/fisiología , Obesidad/fisiopatología , Animales , Condicionamiento Operante/fisiología , Conducta Alimentaria , Ácido Glutámico/fisiología , Depresión Sináptica a Largo Plazo , Masculino , Ratas , Ratas Sprague-Dawley , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
Immunotoxins are chimeric proteins comprising a specific cellular targeting domain linked to a cytotoxic factor. Here we describe the design and use of a novel, peptide-based immunotoxin that can initiate selective cytotoxicity on ErbB2-positive cells. ErbB2 is a receptor tyrosine kinase that is overexpressed in the tumor cells of approximately 30% of breast cancer patients. Immunotoxin candidates were designed to incorporate a targeting ligand with affinity for ErbB2 along with a membrane lysin-based toxin domain. One particular peptide candidate, NL1.1-PSA, demonstrated selective cytotoxicity towards ErbB2-overexpressing cell lines. We utilized a bioengineering strategy to show that recombinant NL1.1-PSA immunotoxin expression by Escherichia coli also conferred selective cytotoxicity towards ErbB2-overexpressing cells. Our findings hold significant promise for the use of effective immunotoxins in cancer therapeutics.
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Mucopolysaccharidosis type IIIA (MPS-IIIA, Sanfilippo syndrome) is a Lysosomal Storage Disease caused by cellular deficiency of N-sulfoglucosamine sulfohydrolase (SGSH). Given the large heterogeneity of genetic mutations responsible for the disease, a comprehensive understanding of the mechanisms by which these mutations affect enzyme function is needed to guide effective therapies. We developed a multiparametric computational algorithm to assess how patient genetic mutations in SGSH affect overall enzyme biogenesis, stability, and function. 107 patient mutations for the SGSH gene were obtained from the Human Gene Mutation Database representing all of the clinical mutations documented for Sanfilippo syndrome. We assessed each mutation individually using ten distinct parameters to give a comprehensive predictive score of the stability and misfolding capacity of the SGSH enzyme resulting from each of these mutations. The predictive score generated by our multiparametric algorithm yielded a standardized quantitative assessment of the severity of a given SGSH genetic mutation toward overall enzyme activity. Application of our algorithm has identified SGSH mutations in which enzymatic malfunction of the gene product is specifically due to impairments in protein folding. These scores provide an assessment of the degree to which a particular mutation could be treated using approaches such as chaperone therapies. Our multiparametric protein biogenesis algorithm advances a key understanding in the overall biochemical mechanism underlying Sanfilippo syndrome. Importantly, the design of our multiparametric algorithm can be tailored to many other diseases of genetic heterogeneity for which protein misfolding phenotypes may constitute a major component of disease manifestation.
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Análisis Mutacional de ADN/métodos , Mucopolisacaridosis III/genética , Mutación , Algoritmos , Humanos , FenotipoRESUMEN
Group A Streptococcus (GAS) is a leading human pathogen that causes a multitude of diseases from pharyngitis, and impetigo, to more severe outcomes such as rheumatoid arthritis and necrotizing fasciitis. GAS remains a global burden as currently no vaccine exists that is completely effective. In this review we highlight recent studies on the virulence of GAS and present several approaches that have extended those findings into aims at combating GAS disease. These and other studies such as recent genome-wide efforts into host-pathogen relationships of GAS disease will likely reveal new targets of intervention. Given the recent rise in GAS strains that have acquired resistance to several types of antibiotics, it is crucial that we continue to increase our knowledge of the mechanisms underlying GAS disease.
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Sistemas de Liberación de Medicamentos , Infecciones Estreptocócicas/terapia , Vacunas Estreptocócicas/administración & dosificación , Streptococcus pyogenes/patogenicidad , Factores de Virulencia , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/microbiología , Vacunas Estreptocócicas/inmunología , Vacunas Estreptocócicas/uso terapéutico , Streptococcus pyogenes/inmunología , Streptococcus pyogenes/aislamiento & purificación , Factores de Virulencia/inmunología , Factores de Virulencia/aislamiento & purificaciónRESUMEN
BACKGROUND: Dengue viruses are endemic across most tropical and subtropical regions. Because no proven vaccines are available, dengue prevention is primarily accomplished through controlling the mosquito vector Aedes aegypti. While dispersal distance is generally believed to be approximately 100 m, patterns of dispersion may vary in urban areas due to landscape features acting as barriers or corridors to dispersal. Anthropogenic features ultimately affect the flow of genes affecting vector competence and insecticide resistance. Therefore, a thorough understanding of what parameters impact dispersal is essential for efficient implementation of any mosquito population suppression program. Population replacement and genetic control strategies currently under consideration are also dependent upon a thorough understanding of mosquito dispersal in urban settings. METHODOLOGY AND PRINCIPAL FINDINGS: We examined the effect of a major highway on dispersal patterns over a 2 year period. A. aegypti larvae were collected on the east and west sides of Uriah Butler Highway (UBH) to examine any effect UBH may have on the observed population structure in the Charlieville neighborhood in Trinidad, West Indies. A panel of nine microsatellites, two SNPs and a 710 bp sequence of mtDNA cytochrome oxidase subunit 1 (CO1) were used for the molecular analyses of the samples. Three CO1 haplotypes were identified, one of which was only found on the east side of the road in 2006 and 2007. AMOVA using mtCO1 and nuclear markers revealed significant differentiation between the east- and west-side collections. CONCLUSION AND SIGNIFICANCE: Our results indicate that anthropogenic barriers to A. aegypti dispersal exist in urban environments and should be considered when implementing control programs during dengue outbreaks and population suppression or replacement programs.
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Aedes/clasificación , Aedes/crecimiento & desarrollo , Ciudades , Vectores de Enfermedades , Ecosistema , Aedes/genética , Animales , Análisis por Conglomerados , Complejo IV de Transporte de Electrones/genética , Haplotipos , Humanos , Proteínas de Insectos/genética , Repeticiones de Microsatélite , Proteínas Mitocondriales/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Indias OccidentalesRESUMEN
Intersubunit intraprotein electron transfer (IET) from flavin mononucleotide (FMN) to heme is essential in nitric oxide (NO) synthesis by NO synthase (NOS). Previous crystal structures and functional studies primarily concerned an enzyme conformation, which serves as the input state for reduction of FMN by electrons from NADPH and flavin adenine dinucleotide (FAD) in the reductase domain. To favor the formation of the output state for the subsequent IET from FMN to heme in the oxygenase domain, a novel truncated two-domain oxyFMN construct of rat neuronal NOS (nNOS), in which only the FMN and heme domains were present, was designed and expressed. The kinetics of IET between the FMN and heme domains in the nNOS oxyFMN construct in the presence and absence of added calmodulin (CaM) were directly determined using laser flash photolysis of CO dissociation in comparative studies on partially reduced oxyFMN and single-domain heme oxygenase constructs. The IET rate constant in the presence of CaM (262 s(-)(1)) was increased approximately 10-fold compared to that in the absence of CaM (22 s(-)(1)). The effect of CaM on interdomain interactions was further evidenced by electron paramagnetic resonance (EPR) spectra. This work provides the first direct evidence of the CaM control of electron transfer (ET) between FMN and heme domains through facilitation of the FMN/heme interactions in the output state. Therefore, CaM controls IET between heme and FMN domains by a conformational gated mechanism. This is essential in coupling ET in the reductase domain in NOS with NO synthesis in the oxygenase domain.
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Óxido Nítrico Sintasa de Tipo I/química , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico/biosíntesis , Animales , Benzoquinonas/metabolismo , Benzoquinonas/farmacología , Calmodulina/metabolismo , Calmodulina/farmacología , Transporte de Electrón/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Mononucleótido de Flavina/química , Mononucleótido de Flavina/metabolismo , Hemo/química , Hemo/metabolismo , Hemo Oxigenasa (Desciclizante)/química , Hemo Oxigenasa (Desciclizante)/metabolismo , Cinética , Rayos Láser , Modelos Biológicos , Óxido Nítrico/química , Oxidación-Reducción , Fotoquímica , Fotólisis , Estructura Terciaria de Proteína/efectos de los fármacos , Ratas , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Riboflavina/análogos & derivados , Riboflavina/metabolismo , Riboflavina/farmacologíaRESUMEN
Intersubunit intramolecular electron transfer (IET) from FMN to heme is essential in the delivery of electrons required for O2 activation in the heme domain and the subsequent nitric oxide (NO) synthesis by NO synthase (NOS). Previous crystal structures and functional studies primarily concerned an enzyme conformation that serves as the input state for reduction of FMN by electrons from NADPH and FAD in the reductase domain. To favor formation of the output state for the subsequent IET from FMN to heme in the oxygenase domain, a novel truncated two-domain oxyFMN construct murine inducible nitric oxide synthase (iNOS), in which only the FMN and heme domains were present, was designed and expressed. The kinetics of the IET between the FMN and heme domains in this construct was directly determined using laser flash photolysis of CO dissociation in comparative studies on partially reduced oxyFMN and single domain heme oxygenase constructs.
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Óxido Nítrico Sintasa de Tipo II/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Animales , Mononucleótido de Flavina/química , Mononucleótido de Flavina/metabolismo , Flavina-Adenina Dinucleótido/química , Flavina-Adenina Dinucleótido/metabolismo , Hemo/química , Hemo/metabolismo , Ratones , NADP/química , NADP/metabolismo , Oxidación-Reducción , Fotólisis , Estructura Terciaria de ProteínaRESUMEN
Mammalian nitric-oxide synthases are large modular enzymes that evolved from independently expressed ancestors. Calmodulin-controlled isoforms are signal generators; calmodulin activates electron transfer from NADPH through three reductase domains to an oxygenase domain. Structures of the reductase unit and its homologs show FMN and FAD in contact but too isolated from the protein surface to permit exit of reducing equivalents. To study states in which FMN/heme electron transfer is feasible, we designed and produced constructs including only oxygenase and FMN binding domains, eliminating strong internal reductase complex interactions. Constructs for all mammalian isoforms were expressed and purified as dimers. All synthesize NO with peroxide as the electron donor at rates comparable with corresponding oxygenase constructs. All bind cofactors nearly stoichiometrically and have native catalytic sites by spectroscopic criteria. Modest differences in electrochemistry versus independently expressed heme and FMN binding domains suggest interdomain interactions. These interactions can be convincingly demonstrated via calmodulin-induced shifts in high spin ferriheme EPR spectra and through mutual broadening of heme and FMNH. radical signals in inducible nitric-oxide synthase constructs. Blue neutral FMN semiquinone can be readily observed; potentials of one electron couple (in inducible nitric-oxide synthase oxygenase FMN, FMN oxidized/semiquinone couple = +70 mV, FMN semiquinone/hydroquinone couple = -180 mV, and heme = -180 mV) indicate that FMN is capable of serving as a one electron heme reductant. The construct will serve as the basis for future studies of the output state for NADPH derived reducing equivalents.
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Óxido Nítrico Sintasa/química , Secuencia de Aminoácidos , Animales , Espectroscopía de Resonancia por Spin del Electrón , Electrones , Humanos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Óxido Nítrico Sintasa/metabolismo , Oxidación-Reducción , Conformación Proteica , Estructura Terciaria de Proteína , Ratas , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Back pain is a universal problem that becomes persistent in 5-10% of patients following an acute episode. This makes it one of the most costly areas of health care in Australia. OBJECTIVE: This article outlines the paradigm that general practitioners should adopt to assist the patient to live with their pain experience. DISCUSSION: The development of persistent back pain is not a static process but one that is heavily influenced by the context in which it occurs. Patient characteristics, health care providers and the health system environment contribute and interact to promote the development of persistent pain. Health care providers involved in managing persistent pain should remain confidant, positive and reassuring. They should encourage activity, discourage fear avoidance behaviour, and consider rehabilitation early before illness beliefs become entrenched. Multidisciplinary rehabilitation, when used early, aims to improve function and assist in the return to work process; when used late, it aims to prevent worsening disability and increased coping for patients.