ABSTRACT
Nitrous oxide is a potent greenhouse gas whose production is catalyzed by nitric oxide reductase (NOR) members of the heme-copper oxidoreductase (HCO) enzyme superfamily. We identified several previously uncharacterized HCO families, four of which (eNOR, sNOR, gNOR, and nNOR) appear to perform NO reduction. These families have novel active-site structures and several have conserved proton channels, suggesting that they might be able to couple NO reduction to energy conservation. We isolated and biochemically characterized a member of the eNOR family from the bacterium Rhodothermus marinus and found that it performs NO reduction. These recently identified NORs exhibited broad phylogenetic and environmental distributions, greatly expanding the diversity of microbes in nature capable of NO reduction. Phylogenetic analyses further demonstrated that NORs evolved multiple times independently from oxygen reductases, supporting the view that complete denitrification evolved after aerobic respiration.
Subject(s)
Nitric Oxide , Oxidation-Reduction , Oxidoreductases , Phylogeny , Nitric Oxide/metabolism , Oxidoreductases/metabolism , Oxidoreductases/genetics , Archaea/metabolism , Archaea/genetics , Rhodothermus/metabolism , Rhodothermus/enzymology , Rhodothermus/genetics , Evolution, Molecular , Bacteria/metabolism , Bacteria/genetics , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/chemistryABSTRACT
PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.
Subject(s)
Autonomic Nervous System Diseases , Orthostatic Intolerance , Adolescent , Humans , Child , Autonomic Nervous System Diseases/diagnosis , Autonomic Nervous System Diseases/epidemiology , Orthostatic Intolerance/diagnosis , Autonomic Nervous SystemABSTRACT
PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.
Subject(s)
Electronic Health Records , Humans , Child , ConsensusABSTRACT
Purpose: Peripheral neuropathies with autonomic nervous system involvement are a recognized cause of gastrointestinal dysmotility for a wide spectrum of diseases. Recent advances in wireless motility capsule testing allow improved sampling of regional and whole gut motility to aid in the diagnosis of gastrointestinal motility disorders and may provide additional insight into segment-specific enteric involvement of peripheral neuropathies affecting autonomic nervous system function. Methods: We utilized standardized autonomic nervous system (ANS) reflex assessment and wireless motility capsule testing to evaluate 20 individuals with idiopathic autonomic neuropathy and unexplained gastrointestinal symptoms. Additionally, we examined the relationship between quantifiable autonomic neuropathy and gastrointestinal dysmotility at specific neuroanatomical levels. Symptom profiles were evaluated using the 31-item Composite Autonomic Symptom Score questionnaire (COMPASS-31) and compared to wireless motility capsule data. Results: We found that transit times were predominately abnormal (delayed) in the foregut (10 of 20; 50%), while contractility abnormalities were far more prominent in the hindgut (17 of 20; 85%), and that motility and symptom patterns, as assessed by the COMPASS-31 GI domain items, generally corresponded. Finally, we also found that there was neuroanatomical overlap in the presence of autonomic reflex abnormalities and WMC-based transit and/or contractility abnormalities. Conclusions: We found that transit times were predominately abnormal in the foregut and midgut, while contractility abnormalities were far more prominent in the hindgut in individuals with idiopathic autonomic neuropathy. There was a high rate of agreement in segmental wireless motility capsule data with neuroanatomically corresponding standardized ANS function measures (e.g., cardiovagal, sudomotor, adrenergic). Expanded sudomotor testing, including additional neuroanatomical segments, could provide additional indirect assessment of visceral involvement in ANS dysfunction.
ABSTRACT
The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.
Subject(s)
Orthostatic Intolerance , Postural Orthostatic Tachycardia Syndrome , Autonomic Nervous System , Consensus , Humans , National Institutes of Health (U.S.) , Postural Orthostatic Tachycardia Syndrome/diagnosis , Postural Orthostatic Tachycardia Syndrome/therapy , United StatesABSTRACT
Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.
Subject(s)
Orthostatic Intolerance , Postural Orthostatic Tachycardia Syndrome , Adolescent , Consensus , Female , Heart Rate , Humans , National Institutes of Health (U.S.) , Postural Orthostatic Tachycardia Syndrome/diagnosis , Postural Orthostatic Tachycardia Syndrome/therapy , United StatesABSTRACT
The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.
Subject(s)
Mastocytosis , Consensus , Humans , Mast Cells , Mastocytosis/diagnosisABSTRACT
Mast cell activation syndrome is thought to be a common, yet under-recognized, chronic multi-system disorder caused by inappropriate mast cell activation. Gastrointestinal symptoms are frequently reported by these patients and are often mistaken by physicians as functional gastrointestinal disorders. This syndrome can be diagnosed by the medical history and measurable biomarkers. Gastroenterologists manage diseases associated with active inflammatory cells including neutrophils, lymphocytes, macrophages, and eosinophils. The mast cell has only recently been recognized as a major player in our specialty. Gastrointestinal disorders from mast cell mediators often present with apparent irritable bowel syndrome, dyspepsia, chronic or cyclical nausea, and heartburn. Individuals with mast cell activation syndrome experience significant delays in diagnosis. The gastrointestinal symptoms are often refractory to symptom-targeted prescription medications. Beyond avoiding triggers, the best therapy is directed at modulating mast cell activation and the effects of the mediators. Many of these therapies are simple over-the-counter medications. In this article, we review mast cell function and dysfunction and the gastrointestinal symptoms, comorbid conditions, diagnosis, and management of mast cell activation syndrome. Gastroenterologists who become aware of this syndrome can dramatically improve the quality of life for their patients who previously have been labeled with a functional gastrointestinal disorder.
Subject(s)
Mastocytosis , Quality of Life , Diagnosis, Differential , Disease Management , Gastrointestinal Diseases/diagnosis , Humans , Mastocytosis/diagnosis , Mastocytosis/physiopathology , Mastocytosis/psychology , Mastocytosis/therapyABSTRACT
The central nervous system (CNS) is an important regulator of the gastrointestinal tract, and CNS dysfunction can result in significant and disabling gastrointestinal symptom manifestation. For patients with neuroimmunologic and neuroinflammatory conditions, the recognition of gastrointestinal symptoms is under-appreciated, yet the gastrointestinal manifestations have a dramatic impact on quality of life. The current treatment strategies, often employed independently by the neurologist and gastroenterologist, raise the question of whether such patients are being treated optimally when siloed in one specialty. Neuroimmunogastroenterology lies at the borderlands of medical specialties, and there are few resources to guide neurologists in this area. Here, we provide an overview highlighting the potential mechanisms of crosstalk between immune-mediated neurological disorders and gastrointestinal dysfunction.
ABSTRACT
Pathogenic intestinal bacteria lead to significant disease in humans. Here we investigated the role of the multifunctional protein, Apurinic/apyrimidinic endonuclease 1 (APE1), in regulating the internalization of bacteria into the intestinal epithelium. Intestinal tumor-cell lines and primary human epithelial cells were infected with Salmonella enterica serovar Typhimurium or adherent-invasive Escherichia coli. The effects of APE1 inhibition on bacterial internalization, the regulation of Rho GTPase Rac1 as well as the epithelial cell barrier function were assessed. Increased numbers of bacteria were present in APE1-deficient colonic tumor cell lines and primary epithelial cells. Activation of Rac1 was augmented following infection but negatively regulated by APE1. Pharmacological inhibition of Rac1 reversed the increase in intracellular bacteria in APE1-deficient cells whereas overexpression of constitutively active Rac1 augmented the numbers in APE1-competent cells. Enhanced numbers of intracellular bacteria resulted in the loss of barrier function and a delay in its recovery. Our data demonstrate that APE1 inhibits the internalization of invasive bacteria into human intestinal epithelial cells through its ability to negatively regulate Rac1. This activity also protects epithelial cell barrier function.
Subject(s)
Colon , DNA-(Apurinic or Apyrimidinic Site) Lyase/immunology , Epithelial Cells , Escherichia coli Infections , Escherichia coli/immunology , Intestinal Mucosa , Salmonella Infections , Salmonella typhimurium/immunology , rac1 GTP-Binding Protein/immunology , Colon/immunology , Colon/microbiology , Colon/pathology , Epithelial Cells/immunology , Epithelial Cells/microbiology , Epithelial Cells/pathology , Escherichia coli Infections/immunology , Escherichia coli Infections/pathology , HT29 Cells , Humans , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Salmonella Infections/immunology , Salmonella Infections/pathologyABSTRACT
We report here the draft genome sequence of Hydrogenibacillus schlegelii MA48, a thermophilic facultative anaerobe that can oxidize hydrogen aerobically. H. schlegelii MA48 belongs to a deep-branching clade of the Bacilli class and provides important insight into the acquisition of aerobic respiration within the Firmicutes phylum.
ABSTRACT
The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.
Subject(s)
Biological Products/chemistry , Biological Products/classification , Data Curation/methods , Databases, Chemical , Information Dissemination/methods , Mass Spectrometry/statistics & numerical data , Database Management Systems , Information Storage and Retrieval/methods , InternationalityABSTRACT
Diet is a risk factor in several medically important disease states, including obesity, celiac disease, and functional gastrointestinal disorders. Modification of diet can prevent, treat, or alleviate some of the symptoms associated with these diseases and improve general health. It is important to provide patients with simple dietary recommendations to increase the probability of successful implementation. These recommendations include increasing vegetable, fruit, and fiber intake, consuming lean protein sources to enhance satiety, avoiding or severely limiting highly processed foods, and reducing portion sizes for overweight and obese patients.
Subject(s)
Diet , Food , Gastrointestinal Microbiome , Neoplasms/epidemiology , Obesity/epidemiology , Diet, Carbohydrate-Restricted , Diet, Fat-Restricted , Diet, Gluten-Free , Diet, Mediterranean , Diet, Paleolithic , Dietary Supplements , Food, Genetically Modified , Food, Organic , Humans , Obesity/diet therapy , ProbioticsABSTRACT
Oxygenic photosynthesis evolved from anoxygenic ancestors before the rise of oxygen ~2.32 billion years ago; however, little is known about this transition. A high redox potential reaction center is a prerequisite for the evolution of the water-oxidizing complex of photosystem II. Therefore, it is likely that high-potential phototrophy originally evolved to oxidize alternative electron donors that utilized simpler redox chemistry, such as nitrite or Mn. To determine whether nitrite could have had a role in the transition to high-potential phototrophy, we sequenced and analyzed the genome of Thiocapsa KS1, a Gammaproteobacteria capable of anoxygenic phototrophic nitrite oxidation. The genome revealed a high metabolic flexibility, which likely allows Thiocapsa KS1 to colonize a great variety of habitats and to persist under fluctuating environmental conditions. We demonstrate that Thiocapsa KS1 does not utilize a high-potential reaction center for phototrophic nitrite oxidation, which suggests that this type of phototrophic nitrite oxidation did not drive the evolution of high-potential phototrophy. In addition, phylogenetic and biochemical analyses of the nitrite oxidoreductase (NXR) from Thiocapsa KS1 illuminate a complex evolutionary history of nitrite oxidation. Our results indicate that the NXR in Thiocapsa originates from a different nitrate reductase clade than the NXRs in chemolithotrophic nitrite oxidizers, suggesting that multiple evolutionary trajectories led to modern nitrite-oxidizing bacteria.
Subject(s)
Bacteria/metabolism , Nitrites/metabolism , Photosynthesis , Bacteria/enzymology , Bacteria/genetics , Bacteria/isolation & purification , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Evolution, Molecular , Genome, Bacterial , Genomics , Nitrification , Nitrite Reductases/genetics , Nitrite Reductases/metabolism , Oxidation-Reduction , Oxidoreductases/genetics , Oxidoreductases/metabolism , Phototrophic Processes , PhylogenyABSTRACT
We report here the draft genome sequence of Ardenticatena maritima 110S, the first sequenced member of class Ardenticatenia of the phylum Chloroflexi. This thermophilic organism is capable of a range of physiologies, including aerobic respiration and iron reduction. It also encodes a complete denitrification pathway with a novel nitric oxide reductase.
ABSTRACT
We report here the draft genome sequence of Herpetosiphon geysericola GC-42, a predatory nonphototrophic member of the class Chloroflexia in the phylum Chloroflexi. This genome provides insight into the evolution of phototrophy and aerobic respiration within the Chloroflexi.
ABSTRACT
We report the draft genome sequence of Ornatilinea apprima P3M-1, a strictly anaerobic member of the Chloroflexi class Anaerolineae. This genome provides insight into the diversity of metabolism within the Anaerolineae, and the evolution of respiration within the Chloroflexi.
ABSTRACT
We present the draft genome of Thermanaerothrix daxensis GNS-1, a thermophilic member of the Chloroflexi phylum. This organism was initially characterized as a nonmotile, strictly anaerobic fermenter; however, genome analysis demonstrates that it encodes genes for a flagellum and multiple pathways for aerobic and anaerobic respiration.
ABSTRACT
We present the draft genome sequence of Leptolinea tardivitalis YMTK-2, a member of the Chloroflexi phylum. This organism was initially characterized as a strictly anaerobic nonmotile fermenter; however, genome analysis demonstrates that it encodes for a flagella and might be capable of aerobic respiration.