The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and ...iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell iron-processing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial iron-processing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.
Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses ...and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD.
Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations.
PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks.
We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.
To harmonize the collection of nonsurgical clinical and epidemiologic data relevant to endometriosis research, allowing large-scale collaboration.
An international collaboration involving 34 ...clinical/academic centers and three industry collaborators from 16 countries on five continents.
In 2013, two workshops followed by global consultation, bringing together 54 leaders in endometriosis research.
None.
Development of a self-administered endometriosis patient questionnaire (EPQ), based on 1 systematic comparison of questionnaires from eight centers that collect data from endometriosis cases (and controls/comparison women) on a medium to large scale (publication on >100 cases); 2 literature evidence; and 3 several global consultation rounds.
Standard recommended and minimum required questionnaires to capture detailed clinical and covariate data.
The standard recommended (EPHect EPQ-S) and minimum required (EPHect EPQ-M) questionnaires contain questions on pelvic pain, subfertility and menstrual/reproductive history, hormone/medication use, medical history, and personal information.
The EPQ captures the basic set of patient characteristics and exposures considered by the WERF EPHect Working Group to be most critical for the advancement of endometriosis research, but is also relevant to other female conditions with similar risk factors and/or symptomatology. The instruments will be reviewed based on feedback from investigators, and—after a first review after 1 year—triannually through systematic follow-up surveys. Updated versions will be made available through http://endometriosisfoundation.org/ephect.
Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive ...therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro
C-glucose and in vivo hyperpolarized
C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition.
A key factor for flavoenzyme activity is the reduction potential of the bound flavin. The reduction potentials of protein-bound flavins span approximately a 500-mV range consistent with flavoenzymes ...having critical roles in metabolism and a variety of biological processes. Redox potentials of flavoenzymes have traditionally been determined using an electrode-based system with either direct or indirect electrochemical coupling between the protein and the working electrode. An electrode independent method, however, is also now commonly used and involves calculating the unknown flavin reduction potential of the protein from the known reduction potential of a reference or indicator dye. Here, the "classic" potentiometric method and the xanthine/xanthine oxidase methods are described. Both methods rely on equilibrium between protein-bound flavin and redox dyes. The potentiometric method measures the equilibrated redox potential of the protein-dye mixture whereas the xanthine/xanthine oxidase technique relies on slow continuous enzymatic reduction to maintain a constant equilibrium between the protein and the dyes. Because electrochemical equipment is not required, the xanthine/xanthine oxidase method is more accessible and convenient for researchers seeking to determine reduction potentials of flavoproteins or other biological redox centers such as hemes. The xanthine/xanthine oxidase method has been used to determine flavin reduction potentials from +132 to -417mV, demonstrating it is suitable for characterizing the redox properties of most flavoproteins.
We present results from a study of the eclipsing, colliding-wind binary V444 Cyg that uses a combination of X-ray and optical spectropolarimetric methods to describe the 3D nature of the shock and ...wind structure within the system. We have created the most complete X-ray light curve of V444 Cyg to date using 40 ks of new data from Swift, and 200 ks of new and archived XMM-Newton observations. In addition, we have characterized the intrinsic, polarimetric phase-dependent behavior of the strongest optical emission lines using data obtained with the University of Wisconsin’s Half-Wave Spectropolarimeter. We have detected evidence of the Coriolis distortion of the wind-wind collision in the X-ray regime, which manifests itself through asymmetric behavior around the eclipses in the system’s X-ray light curves. The large opening angle of the X-ray emitting region, as well as its location (i.e. the WN wind does not collide with the O star, but rather its wind) are evidence of radiative braking/inhibition occurring within the system. Additionally, the polarimetric results show evidence of the cavity the wind-wind collision region carves out of the Wolf-Rayet star’s wind.
Activity recognition modelling using smartphone Inertial Measurement Units (IMUs) is an underutilized resource defining and assessing work efficiency for a wide range of natural resource management ...tasks. This study focused on the initial development and validation of a smartphone-based activity recognition system for excavator-based mastication equipment working in Ponderosa pine (Pinus ponderosa) plantations in North Idaho, USA. During mastication treatments, sensor data from smartphone gyroscopes, accelerometers, and sound pressure meters (decibel meters) were collected at three sampling frequencies (10, 20, and 50 hertz (Hz)). These data were then separated into 9 time domain features using 4 sliding window widths (1, 5, 7.5 and 10 seconds) and two levels of window overlap (50% and 90%). Random forest machine learning algorithms were trained and evaluated for 40 combinations of model parameters to determine the best combination of parameters. 5 work elements (masticate, clear, move, travel, and delay) were classified with the performance metrics for individual elements of the best model (50 Hz, 10 second window, 90% window overlap) falling within the following ranges: area under the curve (AUC) (95.0% - 99.9%); sensitivity (74.9% - 95.6%); specificity (90.8% - 99.9%); precision (81.1% - 98.3%); F1-score (81.9% - 96.9%); balanced accuracy (87.4% - 97.7%). Smartphone sensors effectively characterized individual work elements of mechanical fuel treatments. This study is the first example of developing a smartphone-based activity recognition model for ground-based forest equipment. The continued development and dissemination of smartphone-based activity recognition models may assist land managers and operators with ubiquitous, manufacturer-independent systems for continuous and automated time study and production analysis for mechanized forest operations.
Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between ...peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis.
We conducted a systematic search using several databases (PubMed, MEDLINE, EMBASE and CINAHL) of publications from January 1977 to October 2013 to evaluate the possible roles of the peripheral nervous system in endometriosis pathophysiology and how it can contribute to endometriosis-associated pain.
Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins. In women suffering from deep infiltrating endometriosis and bowel endometriosis, in which the anatomical distribution of lesions is generally more closely related to pelvic pain symptoms, endometriotic lesions and surrounding tissues present higher nerve fibre densities compared with peritoneal lesions and endometriomas. More data are needed to fully confirm a direct correlation between fibre density in these locations and the amount of perceived pain. A better correlation between the presence of nerve fibres and pain symptoms seems to exist for eutopic endometrium. However, this appears not to be exclusive to endometriosis. No correlation between elevated neurotrophin levels and pain severity appears to exist, suggesting the involvement of other mediators in the modulation of pain.
The increased expression of neurotrophic factors and nerve fibres in endometriotic lesions, eutopic endometrium and the peritoneum imply a role of such peripheral changes in the pathogenesis of endometriosis-associated pain. However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated.
Recent studies indicate differential involvement of the centromedial amygdala (CM) and the bed nucleus of the stria terminalis (BNST) during processing (anticipation and confrontation) of threat ...stimuli. Here, temporal predictability was shown to be a relevant factor. In this study, we want to investigate the relevance of these effects, which were found in healthy subjects, for anxiety disorders. Therefore, we investigated the differential involvement of CM and BNST in the anticipation and confrontation of phobic stimuli under variation of temporal predictability in spider phobia. 21 patients with spider phobia and 21 healthy controls underwent a temporally predictable/unpredictable phobic and neutral anticipation and confrontation paradigm using functional magnetic resonance imaging (fMRI) and ROI analyses. During the anticipation phase, healthy controls showed higher CM and BNST activity during the predictable compared with the unpredictable condition compared with the anxiety patients. During a confrontation phase that followed the anticipation phase, CM was more activated than BNST during the phobic compared with the neutral confrontation. While this effect was independent of threat predictability in patients, healthy controls showed higher activation in the CM compared with the BNST only during the predictable spider confrontation compared with the predictable bird confrontation. The results contribute to a better understanding of the separate roles of the CM and BNST during phobic processes. The CM was found to be more relevant to phobic confrontation in patients with spider phobia compared with the BNST.
Estimating reflector heights at stationary GNSS sites with interferometric reflectometry (IR) is a well-established technique in ocean remote sensing. Additionally, IR offers the possibility to ...estimate the significant wave height (SWH) with a linear model using the damping coefficient from an inverse modelling applied to GNSS signal-to-noise ratio (SNR) observations. Such a linear model serves as a benchmark in the present study, where an alternative approach for the estimation of both SWH and reflector height is presented that is based on kernel regression and clustering techniques. In this alternative approach, the reflector height is estimated by analyzing local extrema occurring in the interference pattern that is present in GNSS SNR observations. Various predictors are derived from clustering statistics and the estimated reflector heights. These predictors are used for the SWH determination with supervised machine learning. Linear models, bagged regression trees, and artificial neural networks are applied and respective results are compared for various predictor sets. In a second step, damping coefficients obtained from the inverse modelling mentioned above are additionally taken into account as predictors. The usability of the alternative approach is demonstrated. Compared to the benchmark, a significant improvement in terms of accuracy is found for an artificial neural network with predictors from both the alternative and the inverse modelling approach.
PDF
