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An effective method to understand cloud processes and to assess the fidelity with which they are represented in climate models is the cloud controlling factor framework, in which cloud properties are linked with variations in large-scale dynamical and thermodynamical variables. This study examines how midlatitude cloud radiative effects (CRE) over oceans co-vary with four cloud controlling factors: mid-tropospheric vertical velocity, estimated inversion strength (EIS), near-surface temperature advection, and sea surface temperature (SST), and assesses their representation in CMIP6 models with respect to observations and CMIP5 models.CMIP5 and CMIP6 models overestimate the sensitivity of midlatitude CRE to perturbations in vertical velocity, and underestimate the sensitivity of midlatitude shortwave CRE to perturbations in EIS and temperature advection. The largest improvement in CMIP6 models is a reduced sensitivity of CRE to vertical velocity perturbations. As in CMIP5 models, many CMIP6 models simulate a shortwave cloud radiative warming effect associated with a poleward shift in the Southern Hemisphere (SH) midlatitude jet stream, an effect not present in observations. This bias arises because most models’ shortwave CRE are too sensitive to vertical velocity perturbations and not sensitive enough to EIS perturbations, and because most models overestimate the SST anomalies associated with SH jet shifts. The presence of this bias directly impacts the transient surface temperature response to increasing greenhouse gases over the Southern Ocean, but not the global-mean surface temperature. Instead, the models’ climate sensitivity is correlated with their shortwave CRE sensitivity to surface temperature advection perturbations near 40°S, with models with more realistic values of temperature advection sensitivity generally having higher climate sensitivity.

SummaryThe use of isotopic tracers and metabolic flux analysis (MFA) has unveiled a number of metabolic pathways differentially activated in cancer cells. To support efforts to design effective metabolic therapies for cancer, we sought to distinguish metabolic behavior in cancer versus normal cells growing at the same rate. To this end, we performed13C-isotope tracing and MFA in human mammary epithelial cells (HMECs) harboring different combinations of oncogenes. By introducing a new quantity termed metabolic flux intensity, defined as pathway flux divided by specific growth rate, we showed that metabolism is dually controlled by proliferation and oncogenotypes.13C-MFA further revealed that oxidative pentose phosphate pathway (oxPPP), malate dehydrogenase (MDH) and isocitrate dehydrogenase (IDH) were most enhanced in cancerous HMECs. Drug targeting of these pathways selectively reduced growth in the tumorigenic HMEC line. Our study provides direct evidence that metabolism of cancer cells is different than that of normal proliferating cells.

Changes in midlatitude clouds as a result of shifts in general circulation patterns are widely thought to be a potential source of radiative feedbacks onto the climate system. Previous work has suggested that two general circulation shifts anticipated to occur in a warming climate, poleward shifts in the midlatitude jet streams and a poleward expansion of the Hadley circulation, are associated with differing effects on midlatitude clouds. This study examines two dynamical cloud‐controlling factors, mid‐tropospheric vertical velocity, and the estimated inversion strength (EIS) of the marine boundary layer temperature inversion, to explain why poleward shifts in the Southern Hemisphere midlatitude jet and Hadley cell edge have varying shortwave cloud‐radiative responses at midlatitudes. Changes in vertical velocity and EIS occur further equatorward for poleward shifts in the Hadley cell edge than they do for poleward shifts of the midlatitude jet. Because the sensitivity of shortwave cloud radiative effects (SWCRE) to variations in vertical velocity and EIS is a function of latitude, the SWCRE anomalies associated with jet and Hadley cell shifts differ. The dynamical changes associated with a poleward jet shift occur further poleward in a regime where the sensitivities of SWCRE to changes in vertical velocity and EIS balance, leading to a near‐net zero change in SWCRE in midlatitudes with a poleward jet shift. Conversely, the dynamical changes associated with Hadley cell expansion occur further equatorward at a latitude where the sensitivity of SWCRE is more strongly associated with changes in mid‐tropospheric vertical velocity, leading to a net shortwave cloud radiative warming effect in midlatitudes.

Isotopic tracers have been widely used to probe specific pathways within metabolic networks. Tracers are metabolized through various metabolic routes, generating differential labeling patterns. Cor...

Clouds and their associated radiative effects are a large source of uncertainty in global climate models. One region with particularly large model biases in shortwave cloud radiative effects (CRE) is the Southern Ocean. Previous research has shown that many dynamical “cloud controlling factors” influence shortwave CRE on monthly time scales and that two important cloud controlling factors over the Southern Ocean are midtropospheric vertical velocity and estimated inversion strength (EIS). Model errors may thus arise from biases in representing cloud controlling factors (atmospheric dynamics) or in representing how clouds respond to those cloud controlling factors (cloud parameterizations), or some combination thereof. This study extends previous work by examining cloud controlling factors over the Southern Ocean on daily time scales in both observations and global climate models. This allows the cloud controlling factors to be examined in the context of transient weather systems. Composites of EIS and midtropospheric vertical velocity are constructed around extratropical cyclones and anticyclones to examine how the different dynamical cloud controlling factors influence shortwave CRE around midlatitude weather systems and to assess how models compare to observations. On average, models tend to produce a realistic cyclone and anticyclone, when compared to observations, in terms of the dynamical cloud controlling factors. The difference between observations and models instead lies in how the models’ shortwave CRE respond to the dynamics. In particular, the models’ shortwave CRE are too sensitive to perturbations in midtropospheric vertical velocity and, thus, they tend to produce clouds that excessively brighten in the frontal region of the cyclone and excessively dim in the center of the anticyclone.

© 2017 Taylor & Francis. The scoring scheme for the functional movement screen implicitly assumes that the factor structure is consistent, stable, and congruent across different populations. To determine if this is the case, we compared principal components analyses of three samples: a healthy, general population (n = 100), a group of varsity athletes (n = 101), and a group of firefighters (n = 397). The congruence of the principal components derived through these analyses were evaluated across all of the samples, using Tucker’s congruence coefficient. Factor extraction was guided by parallel analyses, and interpretation was facilitated by Varimax rotation. We observed factor instability, low factor congruence, and inconsistent factor structure. Additionally, we observed a two-factor structure of the functional movement screen in all of our sample groups. These analyses suggest that, although the independent elements of the functional movement screen may continue to be used, use of the composite score is not supported by the factor structure of the measure.

Background: The Functional Movement Screen (FMS) is used to evaluate key movement patterns, functional symmetry, and identify individuals that are at elevated risk of injury. The purpose of this study was to assess whether dynamic postural control is a significant component of the composite FMS score by comparing it with Y-Balance Test (YBT) reach distances. Methods: Seventy-eight participants (including 40 males) performed the standardized FMS protocol followed by the YBT. The YBT reach distances were normalized to leg length and averaged between sides and trials. The individual reach directions were evaluated, and were also summed to form an aggregate YBT distance (TotalY). Results: We observed weak correlations between the composite FMS score and normalized posterolateral reach, normalized posteromedial reach, and the TotalY (r=0.36, 0.37, and 0.36, respectively; all p< 0.05). There was no correlation between the composite FMS score and normalized anterior reach (r=0.22; p=0.053). Together these findings demonstrate partial correspondence between the two tests. Conclusion: This indicates that dynamic postural control is a small component of the aggregate FMS score.

Intercomparison results of Radon (Rn-222) measurements using two phase liquid scintillation counting (LSC) technique was performed. The results obtained are in good agreement with the assigned levels. Several water samples from different Portuguese underground catchments were also analyzed. In general, the waters showed acceptable Rn-222 levels, however, 20% presented concentrations between 500 and 1000 Bq L−1 and 5% higher than 1000 Bq L−1. In Finland, the mean Rn-222 concentration obtained in drilled wells was 460 Bq L−1 and in wells dug in soil 50 Bq L−1. Approximately 10% of drilled wells exceeded a radon concentration of 1000 Bq L−1.

In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using13C-metabolic flux analysis (13C-MFA) aided by multiple tracer experiments and integrated data analysis. Using13C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different13C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of13C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems.

We investigated the compartmentation of the catabolism of dodecanedioate (DODA), azelate, and glutarate in perfused rat livers, using a combination of metabolomics and mass isotopomer analyses. Livers were perfused with recirculating or nonrecirculating buffer containing one fully 13C-labeled dicarboxylate. Information on the peroxisomal versus mitochondrial catabolism was gathered from the labeling patterns of acetyl-CoA proxies, i.e. total acetyl-CoA, the acetyl moiety of citrate, C-1 + 2 of β-hydroxybutyrate, malonyl-CoA, and acetylcarnitine. Additional information was obtained from the labeling patterns of citric acid cycle intermediates and related compounds. The data characterize the partial oxidation of DODA and azelate in peroxisomes, with terminal oxidation in mitochondria. We did not find evidence of peroxisomal oxidation of glutarate. Unexpectedly, DODA contributes a substantial fraction to anaplerosis of the citric acid cycle. This opens the possibility to use water-soluble DODA in nutritional or pharmacological anaplerotic therapy when other anaplerotic substrates are impractical or contraindicated, e.g. in propionic acidemia and methylmalonic acidemia.

Concerns about healthcare-associated infections and the global crisis in antimicrobial resistance has combined to accentuate the fears around so-called "superbugs". In Ireland there is no single agreed indicator regarded as a true measure of the level of methicillin resistant Staphylococcus aureus (MRSA) in hospitals. The objective of this study was to compare two crude measures of MRSA - the percentage of bacteraemia caused by MRSA and the incidence rate (per 1000 bed days used) of MRSA bacteraemia in six acute hospitals. We examined all blood cultures positive for S. aureus (methicillin sensitive and resistant) from 2002 to 2004 in the Health Service Executive (HSE) Mid-Western Area of Ireland. Hospital In-Patient Enquiry (HIPE) data was used to determine monthly in-patient bed days used. Of 245 patient episodes of bacteraemia, 119 were MRSA. The trends in the percentage of isolates that were MRSA and the incidence rate calculated were compared. The incidence rate appears to be a more reliable and robust indicator of MRSA in hospitals than the percentage. Despite many difficulties in interpreting indicators of MRSA they should not preclude the regular publication of data at least at regional level in Ireland.

The effects of water-filtered infrared-A (wIRA) and of convective heat on viability, inflammation, inducible free radicals and antioxidative power were investigated in natural and viable skin using the ex vivo Bovine Udder System (BUS) model. Therefore, skin samples from differently treated parts of the udder of a healthy cow were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, by prostaglandin E2 (PGE2) measurement and by electron spin resonance (ESR) spectroscopy. Neither cell viability, the inflammation status, the radical status or the antioxidative defence systems of the skin were significantly affected by wIRA applied within 30 min by using an irradiance of 1900 W m(-2) which is of relevance for clinical use, but which exceeded the maximum solar IR-A irradiance at the Earth's surface more than 5 times and which resulted in a skin surface temperature of about 45 °C without cooling and of about 37 °C with convective cooling by air ventilation. No significant effects on viability and on inflammation were detected when convective heat was applied alone under equivalent conditions in terms of the resulting skin surface temperatures and exposure time. As compared with untreated skin, free radical formation was almost doubled, whereas the antioxidative power was reduced to about 50% after convective heating to about 45 °C.

The most recent Cassini RADAR images of Titan show widespread regions (up to 1500 kilometers by 200 kilometers) of near-parallel radar-dark linear features that appear to be seas of longitudinal dunes similar to those seen in the Namib desert on Earth. The Ku-band (2.17-centimeter wavelength) images show approximately 100-meter ridges consistent with duneforms and reveal flow interactions with underlying hills. The distribution and orientation of the dunes support a model of fluctuating surface winds of approximately 0.5 meter per second resulting from the combination of an eastward flow with a variable tidal wind. The existence of dunes also requires geological processes that create sand-sized (100- to 300-micrometer) particulates and a lack of persistent equatorial surface liquids to act as sand traps.

Performing arts biomechanics is concerned with quantifying the musculoskeletal demands of artistic tasks. The growing body of related research has prompted this scoping study, solely focused on quantitative research, to summarize the state of the science, identify knowledge gaps, and identify opportunities for future research. OBJECTIVES: To identify, summarize, and categorize quantitative research on the biomechanics of violin, viola, cello, and double bass players, using scoping study methodology. METHODS: Established scoping study methodology was used to identify and categorize existing research. We identified 74 articles for review. Of these, 34 met our scoping study criteria and were included in this study. RESULTS: Twenty-one of the 34 articles that met the scoping criteria were published since 2000. Investigations using electromyography (16 studies) and kinematics (15 studies) comprise the bulk of the research. Two studies employed force transducers for data collection. Violinists were the most frequently studied musicians (22 studies) and double bass players were the least (1 study). Fewer than half of the studies used solely professional musicians as their subjects (13 studies). CONCLUSIONS: This scoping study confirmed that quantitative biomechanical research into bowed string musicians has been performed with increasing frequency and that there are voids in the research, particularly in investigating mechanisms of injury and protective strategies. Currently, arts biomechanics research is largely descriptive in nature. There are few studies that investigate protective strategies, although it is expected that the field will progress to incorporate this type of research.

We present well-calibrated, high-resolution maps of Saturn’s thermal emission at 2.2-cm wavelength obtained by the Cassini RADAR radiometer through the Prime and Equinox Cassini missions, a period covering approximately 6 years. The absolute brightness temperature calibration of 2% achieved is more than twice better than for all previous microwave observations reported for Saturn, and the spatial resolution and sensitivity achieved each represent nearly an order of magnitude improvement. The brightness temperature of Saturn in the microwave region depends on the distribution of ammonia, which our radiative transfer modeling shows is the only significant source of absorption in Saturn’s atmosphere at 2.2-cm wavelength. At this wavelength the thermal emission comes from just below and within the ammonia cloud-forming region, and yields information about atmospheric circulations and ammonia cloud-forming processes. The maps are presented as residuals compared to a fully saturated model atmosphere in hydrostatic equilibrium. Bright regions in these maps are readily interpreted as due to depletion of ammonia vapor in, and, for very bright regions, below the ammonia saturation region. Features seen include the following: a narrow equatorial band near full saturation surrounded by bands out to about 10° planetographic latitude that demonstrate highly variable ammonia depletion in longitude; narrow bands of depletion at −35° latitude; occasional large oval features with depleted ammonia around −45° latitude; and the 2010–2011 storm, with extensive saturated and depleted areas as it stretched halfway around the planet in the northern hemisphere. Comparison of the maps over time indicates a high degree of stability outside a few latitudes that contain active regions.

Cancer and proliferating cells exhibit an increased demand for glutamine-derived carbons to support anabolic processes. In addition, reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) was recently shown to be a major source of citrate synthesis from glutamine. The role of NAD(P)H/NAD(P)(+) cofactors in coordinating glucose and glutamine utilization in the tricarboxylic acid (TCA) cycle is not well understood, with the source(s) of NADPH for the reductive carboxylation reaction remaining unexplored. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial enzyme that transfers reducing equivalents from NADH to NADPH. Here, we show that knockdown of NNT inhibits the contribution of glutamine to the TCA cycle and activates glucose catabolism in SkMel5 melanoma cells. The increase in glucose oxidation partially occurred through pyruvate carboxylase and rendered NNT knockdown cells more sensitive to glucose deprivation. Importantly, knocking down NNT inhibits reductive carboxylation in SkMel5 and 786-O renal carcinoma cells. Overexpression of NNT is sufficient to stimulate glutamine oxidation and reductive carboxylation, whereas it inhibits glucose catabolism in the TCA cycle. These observations are supported by an impairment of the NAD(P)H/NAD(P)(+) ratios. Our findings underscore the role of NNT in regulating central carbon metabolism via redox balance, calling for other mechanisms that coordinate substrate preference to maintain a functional TCA cycle.

article i nfo Tetrapyrroles are multisided natural products which are of relevance in clinical medicine. Owing to their specific accumulation in tumour tissue, porphyrins, metalloporphyrins and chlorins have been used as in photodynamic therapy and optical imaging. Moreover, their specific uptake into inflammatory atheromatous plaques via LDL endocytosis has been reported. The present study is concerned with the synthesis of 68 Ga labelled porphyrin derivatives and an in vitro assessment of the utility of radiotracers in positron emission tomography. A set of five porphyrin derivatives were labelled using 68 Ga from a commercially obtained radionuclide generator. Dedicated post-processing of the generator eluate was conducted to allow for labelling in aqueous media and also under anhydrous conditions. Challenge studies and incubation in human serum confirmed the stability of the tracers. Plasma protein binding was investigated in order to confirm the presence of freely diffusible radioligand in plasma. A preliminary microPET study in a tumour-bearing rat resulted in a clear visualisation of the tumour.

Background: The study of cancer metabolism has been largely dedicated to exploring the hypothesis that oncogenic transformation rewires cellular metabolism to sustain elevated rates of growth and division. Intense examination of tumors and cancer cell lines has confirmed that many cancer-associated metabolic phenotypes allow robust growth and survival; however, little attention has been given to explicitly identifying the biochemical requirements for cell proliferation in a rigorous manner in the context of cancer metabolism. Results: Using a well-studied hybridoma line as a model, we comprehensively and quantitatively enumerate the metabolic requirements for generating new biomass in mammalian cells; this indicated a large biosynthetic requirement for ATP, NADPH, NAD+, acetyl-CoA, and amino acids. Extension of this approach to serine/glycine and glutamine metabolic pathways suggested lower limits on serine and glycine catabolism to supply one-carbon unit synthesis and significant availability of glutamine-derived carbon for biosynthesis resulting from nitrogen demands alone, respectively. We integrated our biomass composition results into a flux balance analysis model, placing upper bounds on mitochondrial NADH oxidation to simulate metformin treatment; these simulations reproduced several empirically observed metabolic phenotypes, including increased reductive isocitrate dehydrogenase flux. Conclusions: Our analysis clarifies the differential needs for central carbon metabolism precursors, glutamine-derived nitrogen, and cofactors such as ATP, NADPH, and NAD+, while also providing justification for various extracellular nutrient uptake behaviors observed in tumors. Collectively, these results demonstrate how stoichiometric considerations alone can successfully predict empirically observed phenotypes and provide insight into biochemical dynamics that underlie responses to metabolic perturbations., National Institutes of Health (U.S.) (Grant 1R01DK075850-01), National Institutes of Health (U.S.) (Grant 1R01CA160458-01A1)

A review of patient notification exercises (PNEs) carried out in Ireland between 1997 and 2011 to investigate potential exposure to blood-borne viruses (BBVs) in healthcare settings was undertaken to inform future policy and practice. A questionnaire was sent to key informants in the health services to identify all relevant PNEs. Structured interviews were conducted with key investigators, and available documentation was examined. Ten BBV-related PNEs were identified. Despite testing over 2000 patients, only one case of transmission was found. However, in-depth local investigations before undertaking the PNEs identified six cases of healthcare-associated transmission.

Members of the public are exposed to radiation because of where they live and their habits bring them into contact with sources of radiation. They may be exposed directly by the source, by direct irradiation or inhalation of released activity or indirectly by exposure to contaminated environmental materials such as food. Consequently habit data are an essential part of dose assessment for members of the public [1]. Previously no detailed surveys had been undertaken in Ireland of habit data relevant to the assessment of doses to the population from radioactivity in the marine environment. Instead RPII dose assessments were made on the basis of assumed or notional data inferred from habit surveys undertaken elsewhere and from national average consumption figures. Following a tender process the Centre for Environment, Fisheries & Aquaculture Science, Cefas, UK, were commissioned to undertake a Habits Survey. Its report [2] provides an assessment of aquatic radiation exposure pathways in Ireland relating to anthropogenic radioactivity in the Irish Sea.

Systems level tools for the quantitative analysis of metabolic networks are required to engineer metabolism for biomedical and industrial applications. While current metabolomics techniques enable high-throughput quantification of metabolites, these methods provide minimal information on the rates and connectivity of metabolic pathways. Here we present a new method, nontargeted tracer fate detection (NTFD), that expands upon the concept of metabolomics to solve the above problems. Through the combined use of stable isotope tracers and chromatography coupled to mass spectrometry, our computational analysis enables the quantitative detection of all measurable metabolites derived from a specific labeled compound. Without a priori knowledge of a reaction network or compound library, NTFD provides information about relative flux magnitudes into each metabolite pool by determining the mass isotopomer distribution for all labeled compounds. This novel method adds a new dimension to the metabolomics tool box and provides a framework for global analysis of metabolic fluxes.

Cassini radar tracks on Saturn’s icy satellites through the end of the Prime Mission in 2008 have increased the number of radar albedo estimates from 10 ( Ostro et al., 2006 ) to 73. The measurements sample diverse subradar locations (and for Dione, Rhea, and Iapetus almost always use beamwidths less than half the target angular diameters), thereby constraining the satellites’ global radar albedo distributions. The echoes result predominantly from volume scattering, and their strength is thus strongly sensitive to ice purity and regolith maturity. The combination of the Cassini data set and Arecibo 13-cm observations of Enceladus, Tethys, Dione, Rhea ( Black et al., 2007 ), and Iapetus ( Black et al., 2004 ) discloses an unexpectedly complex pattern of 13-to-2-cm wavelength dependence. The 13-cm albedos are generally smaller than 2-cm albedos and lack the correlation seen between 2-cm and optical geometric albedos. Enceladus and Iapetus are the most interesting cases. We infer from hemispheric albedo variations that the E-ring has a prominent effect on the 13-cm radar “lightcurve”. The uppermost trailing-side regolith is too fresh for meteoroid bombardment to have developed larger-scale heterogeneities that would be necessary to elevate the 13-cm radar albedo, whereas all of Enceladus is clean and mature enough for the 2-cm albedo to be uniformly high. For, Iapetus, the 2-cm albedo is strongly correlated with optical albedo: low for the optically dark, leading-side material and high for the optically bright, trailing-side material. However, Iapetus’ 13-cm albedo values show no significant albedo dichotomy and are several times lower than 2-cm values, being indistinguishable from the weighted mean of 13-cm albedos for main-belt asteroids, 0.15 ± 0.10. The leading side’s optically dark contaminant must be present to depths of at least one to several decimeters, so 2-cm albedos can mimic the optical dichotomy; however, it does not have to extend any deeper than that. The fact that both hemispheres of Iapetus look Asteroid-like at 13 cm means that coherent backscattering itself is not nearly as effective as it is at 2 cm. Since Iapetus’ entire surface is mature regolith, the wavelength dependence must involve composition, not structure. Either the composition is a function of depth everywhere (with electrical loss much greater at depths greater than a decimeter or two), or the intrinsic electrical loss of some pervasive constituent is much higher at 13 cm than at 2 cm. Ammonia is a candidate for such a contaminant. If ammonia’s electrical properties do not depend on frequency, and if ammonia is globally much less abundant within the upper one or two decimeters than at greater depths, then coherent backscattering would effectively be shut down at 13 cm, explaining the Asteroid-like 13-cm albedo.

Skin exposure to infrared (IR) radiation should be limited in terms of irradiance, exposure time and frequency in order to avoid acute or chronic damage. Recommendations aimed at protecting humans from the risks of skin exposure to IR (e.g. ICNIRP, ACGIH) are only defined in terms of acute effects (e.g. heat pain and cardiovascular collapse), whereas the actual exposure conditions (e.g. spectral distribution, exposure geometry, frequency and number of exposures, thermal exchange with the environment, metabolic energy production and regulatory responses) are not taken into consideration. Since the IR component of solar radiation reaching the Earth's surface is mainly IR-A, and considering the increased use of devices emitting artificially generated IR-A radiation, this radiation band is of special interest. A number of in vitro and/or in vivo investigations assessing cellular or tissue damage caused by IR-A radiation have been undertaken. While such studies are necessary for the development of safety recommendations, the results of measurements undertaken to examine the interaction between skin and IR radiation emitted from different sources presented in this study, together with the detailed examination of the literature reveals a wide spectrum of contradictory findings, which in some instances may be related to methodological shortcomings or fundamental errors in the application of physical and photobiological laws, thus highlighting the need for physically and photobiologically appropriate experiments.

Tumour blood flow before and during clinically relevant mild hyperthermia exhibits pronounced heterogeneity. Flow changes upon heating are not predictable and are both spatially and temporally highly variable. Flow increases may result in improved heat dissipation to the extent that therapeutically relevant tissue temperatures may not be achieved. This holds especially true for tumours or tumour regions in which flow rates are substantially higher than in the surrounding normal tissues. Changes in tumour oxygenation tend to reflect alterations in blood flow upon hyperthermia. An initial improvement in the oxygenation status, followed by a return to baseline levels (or even a drop to below baseline at high thermal doses) has been reported for some tumours, whereas a predictable and universal occurrence of sustained increases in O(2) tensions upon mild hyperthermia is questionable and still needs to be verified in the clinical setting. Clarification of the pathogenetic mechanisms behind possible sustained increases is mandatory. High-dose hyperthermia leads to a decrease in the extracellular and intracellular pH and a deterioration of the energy status, both of which are known to be parameters capable of acting as direct sensitisers and thus pivotal factors in hyperthermia treatment. The role of the tumour microcirculatory function, hypoxia, acidosis and energy status is complex and is further complicated by a pronounced heterogeneity. These latter aspects require additional critical evaluation in clinically relevant tumour models in order for their impact on the response to heat to be clarified.

To identify metabolic pathways involved in hepatic lipoapoptosis, metabolic flux analysis using [U-(13)C(5)]glutamine as an isotopic tracer was applied to quantify phenotypic changes in H4IIEC3 hepatoma cells treated with either palmitate alone (PA-cells) or both palmitate and oleate in combination (PA/OA-cells). Our results indicate that palmitate inhibited glycolysis and lactate dehydrogenase fluxes while activating citric acid cycle (CAC) flux and glutamine uptake. This decoupling of glycolysis and CAC fluxes occurred during the period following palmitate exposure but preceding the onset of apoptosis. Oleate co-treatment restored most fluxes to their control levels, resulting in steatotic lipid accumulation while preventing apoptosis. In addition, palmitate strongly increased the cytosolic NAD(+)/NADH ratio, whereas oleate co-treatment had the opposite effect on cellular redox. We next examined the influence of amino acids on these free fatty acid-induced phenotypic changes. Increased medium amino acids enhanced reactive oxygen species (ROS) generation and apoptosis in PA-cells but not in PA/OA-cells. Overloading the medium with non-essential amino acids induced apoptosis, but essential amino acid overloading partially ameliorated apoptosis. Glutamate was the most effective single amino acid in promoting ROS. Amino acid overloading also increased cellular palmitoyl-ceramide; however, ceramide synthesis inhibitors had no effect on measurable indicators of apoptosis. Our results indicate that free fatty acid-induced ROS generation and apoptosis are accompanied by the decoupling of glycolysis and CAC fluxes leading to abnormal cytosolic redox states. Amino acids play a modulatory role in these processes via a mechanism that does not involve ceramide accumulation.

The first comprehensive calibration and mapping of the thermal microwave emission from Titan's surface is reported based on radiometric data obtained at 2.2-cm wavelength by the passive radiometer included in the Cassini Radar instrument. The data reported were accumulated from 69 separate observational segments in Titan passes from Ta (October 2004) through T30 (May 2007) and include emission from 94% of Titan's surface. They are diverse in the key observing parameters of emission angle, polarization, and spatial resolution, and their reduction into calibrated global mosaic maps involved several steps. Analysis of the polarimetry obtained at low to moderate resolution (50+ km) enabled integration of the radiometry into a single mosaic of the equivalent brightness temperature at normal incidence with a relative precision of about 1 K. The Huygens probe measurement of Titan's surface temperature and radiometry obtained on Titan's dune fields allowed us to infer an absolute calibration estimated to be accurate to a level approaching 1 K. The results provide evidence for a surface that is complex and varied on large scales. The radiometry primarily constrains physical properties of the surface, where we see strong evidence for subsurface (volume) scattering as a dominant mechanism that determines the emissivity, with the possibility of a fluffy or graded-density surface layer in many regions. The results are consistent with, but not necessarily definitive of a surface composition resulting from the slow deposition and processing of organic compounds from the atmosphere.

The paper deals with a specific aspect of a general survey, that is being carried out during last ten years in several regions of Serbia (former Yugoslavia, former Serbia and Montenegro) to assess population exposure to natural radioactivity based on geochemical and integrative pattern research approach. The originality regarding this work is related to the facts such as follows: the first identification and assessment of high areas of natural radiation in Serbia which provides insight into its regional characteristics, the interpretation of the results in terms of geological aspects, building types and human habits, the first introduction and field applicability of both (surface and volume trap) retro techniques in Serbia and assessment of doses and risks to the population in investigated high natural radiation rural communities.

In this second of two companion articles, we compare the mass isotopomer distribution of metabolites of liver gluconeogenesis and citric acid cycle labeled from NaH(13)CO(3) or dimethyl [1,4-(13)C(2)]succinate. The mass isotopomer distribution of intermediates reveals the reversibility of the isocitrate dehydrogenase + aconitase reactions, even in the absence of a source of alpha-ketoglutarate. In addition, in many cases, a number of labeling incompatibilities were found as follows: (i) glucose versus triose phosphates and phosphoenolpyruvate; (ii) differences in the labeling ratios C-4/C-3 of glucose versus (glyceraldehyde 3-phosphate)/(dihydroxyacetone phosphate); and (iii) labeling of citric acid cycle intermediates in tissue versus effluent perfusate. Overall, our data show that gluconeogenic and citric acid cycle intermediates cannot be considered as sets of homogeneously labeled pools. This probably results from the zonation of hepatic metabolism and, in some cases, from differences in the labeling pattern of mitochondrial versus extramitochondrial metabolites. Our data have implications for the use of labeling patterns for the calculation of metabolic rates or fractional syntheses in liver, as well as for modeling liver intermediary metabolism.

We previously reported that glutamine was a major source of carbon for de novo fatty acid synthesis in a brown adipocyte cell line. The pathway for fatty acid synthesis from glutamine may follow either of two distinct pathways after it enters the citric acid cycle. The glutaminolysis pathway follows the citric acid cycle, whereas the reductive carboxylation pathway travels in reverse of the citric acid cycle from α-ketoglutarate to citrate. To quantify fluxes in these pathways we incubated brown adipocyte cells in [U-13C]glutamine or [5-13C]glutamine and analyzed the mass isotopomer distribution of key metabolites using models that fit the isotopomer distribution to fluxes. We also investigated inhibitors of NADP-dependent isocitrate dehydrogenase and mitochondrial citrate export. The results indicated that one third of glutamine entering the citric acid cycle travels to citrate via reductive carboxylation while the remainder is oxidized through succinate. The reductive carboxylation flux accounted for 90% of all flux of glutamine to lipid. The inhibitor studies were compatible with reductive carboxylation flux through mitochondrial isocitrate dehydrogenase. Total cell citrate and α-ketoglutarate were near isotopic equilibrium as expected if rapid cycling exists between these compounds involving the mitochondrial membrane NAD/NADP transhydrogenase. Taken together, these studies demonstrate a new role for glutamine as a lipogenic precursor and propose an alternative to the glutaminolysis pathway where flux of glutamine to lipogenic acetyl-CoA occurs via reductive carboxylation. These findings were enabled by a new modeling tool and software implementation (Metran) for global flux estimation.

International audience; The Cassini Titan Radar Mapper obtained Synthetic Aperture Radar images of Titan's surface during four fly-bys during the mission's first year. These images show that Titan's surface is very complex geologically, showing evidence of major planetary geologic processes, including cryovolcanism. This paper discusses the variety of cryovolcanic features identified from SAR images, their possible origin, and their geologic context. The features which we identify as cryovolcanic in origin include a large (180 km diameter) volcanic construct (dome or shield), several extensive flows, and three calderas which appear to be the source of flows. The composition of the cryomagma on Titan is still unknown, but constraints on rheological properties can be estimated using flow thickness. Rheological properties of one flow were estimated and appear inconsistent with ammonia-water slurries, and possibly more consistent with ammonia-water-methanol slurries. The extent of cryovolcanism on Titan is still not known, as only a small fraction of the surface has been imaged at sufficient resolution. Energetic considerations suggest that cryovolcanism may have been a dominant process in the resurfacing of Titan.

The nucleoredoxin-like gene Nxnl1 (Txnl6) and its paralogue Nxnl2 encode the rod-derived cone viability factors (RdCVF and RdCVF2), which increase the resistance to photooxidative damage and have therapeutic potential for the survival of cones in retinitis pigmentosa. In this study, the transcription of Nxnl genes was investigated as a function of the day/night cycle in rats. The transcript levels of Nxnl1 and Nxnl2 were seen to display daily rhythms with steadily increasing values during the light phase and peak expression around dark onset in preparations of whole retina, photoreceptor cells and—but only in regard to Nxnl1—in photoreceptor-related pinealocytes. The cycling of Nxnl1 but not that of Nxnl2 persisted in constant darkness in the retina. This suggests that daily regulation of Nxnl1 is driven by a circadian clock, whereas that of Nxnl2 is promoted by environmental light. The present data indicate clock- and light-dependent regulations of nucleoredoxin-like genes that may be part of a protective shield against photooxidative damage.

Background: The butterfly save technique is commonly used by ice hockey goaltenders and has recently been identified as a potential mechanism for hip joint injuries due to the extreme body positions involved. Unfortunately, commonly used kinematic marker sets that determine these body positions are heavily influenced by skin motion artifact and are obscured by protective equipment, making it difficult to obtain reliable measures of hip motion. Purpose: To create a new kinematic protocol that could be used when protective equipment prevents typical marker placements and to use this protocol to quantify hip kinematics and butterfly performance in 4 different goalie pad conditions. Study Design: Controlled laboratory study. Methods: A new marker set consisting of marker clusters attached to the lateral thigh and posterior leg was developed. This marker set was verified by evaluating the root mean square (RMS) difference between the developed testing marker set and the calibrated anatomic systems technique marker set during passive range of motion (ROM) tests. The testing marker set was then used in a repeated-measures study in which 12 junior goaltenders performed 5 butterfly movements on synthetic ice, in 4 different goalie pad conditions (control, flexible-wide leg channel, flexible-tight leg channel, and stiff-wide leg channel). Results: The grouped RMS differences and SDs calculated during verification were 1.43° ± 0.41°, 1.0° ± 0.39°, and 3.32° ± 1.32° for hip flexion-extension, abduction-adduction, and internal-external rotation, respectively. There was no significant main effect of goal pad condition on the peak amount of hip internal rotation; however, there was a significant main effect of goal pad condition on the butterfly width ( P = .022). Post hoc comparisons revealed that the butterfly width was significantly smaller in the control pad condition compared with the flexible-tight pad condition ( P = .03). Conclusion: The new marker set enabled measurements of hip joint kinematics while subjects are wearing protective equipment that are not possible with other marker sets. Interindividual variations in performance of the butterfly technique influenced the amount of hip internal rotation achieved; however, on average, goaltenders exceeded their active internal ROM during butterfly movements. Clinical Relevance: Exceeding internal rotation range of hip motion may make goaltenders susceptible to hip injuries such as femoral acetabular impingement.

The marine atmosphere, coastal ocean, estuary, harbor and river water systems constitute a physically coupled system. While these systems have always been heavily impacted by coastal storms, increases in population density, infrastructure, and personal and business merchandise have exacerbated the economic and personal impacts of these events over the past half century. As such there has been increased focus on the need for more timely and accurate forecasts of impending events. Traditionally model forecast architectures for coastal storm surge, flooding and inundation of coastal and inland areas have taken the approach of dealing with each system separately: rivers, estuaries, harbors and offshore facing areas. However, given advances in coupled modeling and the availability of real-time data, the ability to accurately predict and project coastal, estuary and inland flooding related to the passage of high energy and wet atmospheric events is rapidly emerging and requires a new paradigm in system architecture. No longer do monthly averaged winds or river discharge or water levels have to be invoked in developing hindcasts for planning purposes or for real-time forecasts. In 1999 a hurricane associated flood on the North Carolina coast took 56 lives and caused more than $6 billion in economic impacts. None of the models existing at that time were able to properly forecast the massive flooding and clearly called for a new model paradigm. Here we propose a model system that couples atmospheric information to fully three dimensional, non-linear time dependent ocean basin, coastal and estuary hydrodynamic models coupled to interactive river models with input of real or modeled winds, observed or modeled precipitation, measured and modeled water levels, and streamflow. The river and estuarine components must both be capable of going into modes of storage or accelerated discharge. Spatial scales must downscale in the horizontal from thousands to tens meters and in the vertical from hundreds to several centimeters. Topography and elevation data should be of the highest resolution available, necessary for highly accurate predictions of the timing and location of the inundation and retreat of flood waters. Precipitation information must be derived from the optimal mix of direct radar, satellite and ground-based observations. Creating the capability described above will advance the modernization of hydrologic services provided by the National Oceanic & Atmospheric Administration and provide more accurate and timely forecasts and climatologies of coastal and estuary flooding. The goal of these climatologies and improved forecasts is to provide better information to local and regional planners, emergency managers, highway patrols and to improve the capacity of coastal communities to mitigate against the impacts of coastal flooding.

Metabolic fluxes, estimated from stable isotope studies, provide a key to quantifying physiology in fields ranging from metabolic engineering to the analysis of human metabolic diseases. A serious drawback of the flux estimation method in current use is that it does not produce confidence limits for the estimated fluxes. Without this information it is difficult to interpret flux results and expand the physiological significance of flux studies. To address this shortcoming we derived analytical expressions of flux sensitivities with respect to isotope measurements and measurement errors. These tools allow the determination of local statistical properties of fluxes and relative importance of measurements. Furthermore, we developed an efficient algorithm to determine accurate flux confidence intervals and demonstrated that confidence intervals obtained with this method closely approximate true flux uncertainty. In contrast, confidence intervals approximated from local estimates of standard deviations are inappropriate due to inherent system nonlinearities. We applied these methods to analyze the statistical significance and confidence of estimated gluconeogenesis fluxes from human studies with [U–13C]glucose as tracer and found true limits for flux estimation in specific human isotopic protocols.

We developed gas chromatography-mass spectrometry assays for the relative concentration and for the mass isotopomer distribution of gluconeogenic and citric acid cycle intermediates in tissues. The assay involves (i) spiking the sample with one or more internal standards, (ii) chloroform–methanol extraction at −25 °C, (iii) Folch wash of the extract, (iv) treatment of the water-methanol phase with methoxylamine, (v) evaporation and trimethylsilyl derivatization, and (vi) ammonia positive chemical ionization gas chromatography-mass spectrometry. For metabolomic computations, indices of concentrations for all compounds assayed are calculated as (Area of analyte)/(Area of reference compound). The assay was applied to a study of the effect of mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, on the profile of gluconeogenic intermediates in rat livers perfused with pyruvate. Crossover analysis of concentrations indices, compared to a control group, yielded very similar profiles as previous enzymatic assays, and correctly identified the site of action of mercaptopicolinate. Principal component analysis distinguished between control and drug treated samples. A loadings plot was used to identify the site of action of the drug in the metabolic pathway. Since metabolite concentrations do not address the flux through a pathway, perfusions with [1,4-13C2] succinate dimethylester were conducted to assess fluxes around PEPCK. This allowed a dynamic metabolomics analysis which indicated that considerable flux through the pathway remained in the presence of mercaptopicolinate. This study illustrates the power of dynamic metabolomics to complement concentration based metabolomic studies.

Background Protein-energy malnutrition is common among infants with congenital heart disease. We hypothesized that infants with hypoplastic left heart syndrome (HLHS) are at risk for malnutrition. Objective To determine the prevalence of and risk factors for malnutrition in infants undergoing palliative surgery for HLHS. Methods Retrospective chart review of 50 infants with HLHS who underwent both stage 1 Norwood and bidirectional Glenn (BDG) procedures over 4.5 y. Results After a median hospital stay of 21 d, median discharge weight was 3.4 kg, unchanged from admission. Adjusting for weight on admission, children with longer length of hospital stay, longer intensive care unit stay, shorter duration of parental nutrition therapy, and higher diuretic dosage at discharge had a lower weight-for-age Z score at discharge ( R 2 = 0.85). On admission for BDG, median weight-for-age Z score was −2.0. After adjusting for weight on discharge from the initial hospitalization, children with fewer calories/ounce of their enteral nutrition at discharge, worse right ventricular function, more frequent readmissions, and higher oxygen saturation at discharge had a lower weight-for-age Z score at BDG ( R 2 = 0.49). Conclusions Malnutrition is common in infants with HLHS after stage 1 palliation. Variables associated with more complex postoperative course and imbalance between systemic and pulmonary blood flow were all associated with poorer nutritional status. When adjusting for these factors, the use of parenteral nutrition and high calorie enteral feeds were associated with improved nutritional status. Aggressive parenteral and enteral nutritional therapy might help reduce the prevalence of growth faltering in infants who have HLHS.

The expression and activity of P-glycoprotein (pGP) play a role in the multidrug resistance of tumors. Because solid-growing tumors often show pronounced hypoxia or extracellular acidosis, this study attempted to analyze the impact of an acidic environment on the expression and activity of pGP and on the cytotoxicity of chemotherapeutic agents. For this, prostate carcinoma cells were exposed to an acidic extracellular environment (pH 6.6) for up to 24 hours. pGP activity was more than doubled after 3 to 6 hours of incubation in acidic medium, whereas cellular pGP expression remained constant, indicating that increased transport rate is the result of functional modulation. In parallel, the cytotoxic efficacy of daunorubicin showed pronounced reduction at low pH, an effect that was reversible on coincubation with a pGP inhibitor. A reduction of intracellular Ca2+ concentration by 35% under acidic conditions induced a higher transport rate of pGP, an effect comparable to that found on inhibition of protein kinase C (PKC). These data indicate that pGP activity is increased by acidic pH presumably as a result of lowered intracellular calcium levels and inhibition of PKC. These findings may explain the reduced cytotoxicity of chemotherapeutic agents in hypoxic/acidic tumors.

Measurement of fractional lipogenesis by condensation polymerization methods assumes constant enrichment of lipogenic acetyl-CoA in all hepatocytes. mass isotopomer distribution analysis (MIDA) and isotopomer spectral analysis (ISA) represent such methods and are based on the combinatorial analyses of mass isotopomer distributions (MIDs) of fatty acids and sterols. We previously showed that the concentration and enrichment of [13C]acetate decrease markedly across the dog liver because of the simultaneous uptake and production of acetate. To test for zonation of the enrichment of lipogenic acetyl-CoA, conscious dogs, prefitted with transhepatic catheters, were infused with glucose and [1,2-13C2]acetate in a branch of the portal vein. Analyses of MIDs of fatty acids and sterols isolated from liver, bile, and plasma very low density lipoprotein by a variant of ISA designed to detect gradients in precursor enrichment revealed marked zonation of enrichment of lipogenic acetyl-CoA. As control experiments where no zonation of acetyl-CoA enrichment would be expected, isolated rat livers were perfused with 10 mm [1,2-13C2]acetate. The ISA analyses of MIDs of fatty acids and sterols from liver and bile still revealed a zonation of acetyl-CoA enrichment. We conclude that zonation of hepatic acetyl-CoA enrichment occurs under a variety of animal models and physiological conditions. Failure to consider gradients of precursor enrichment can lead to underestimations of fractional lipogenesis calculated from the mass isotopomer distributions. The degree of such underestimation was modeled in vitro, and the data are reported in the companion paper (Bederman, I. R., Kasumov, T., Reszko, A. E., David, F., Brunengraber, H., and Kelleher, J. K. (2004) J. Biol. Chem. 279, 43217-43226).

This study investigated long-term microenvironmental responses (oxygenation, perfusion, metabolic status, proliferation, vascular endothelial growth factor (VEGF) expression and vascularisation) to chronic hypoxia in experimental tumours. Experiments were performed using s.c.-implanted DS-sarcomas in rats. In order to induce more pronounced tumour hypoxia, one group of animals was housed in a hypoxic atmosphere (8% O(2)) for the whole period of tumour growth (chronic hypoxia). A second group was acutely exposed to inspiratory hypoxia for only 20 min prior to the measurements (acute hypoxia), whereas animals housed under normal atmospheric conditions served as controls. Acute hypoxia reduced the median oxygen partial pressure (pO(2)) dramatically (1 vs 10 mmHg in controls), whereas in chronically hypoxic tumours the pO(2) was significantly improved (median pO(2)=4 mmHg), however not reaching the control level. These findings reflect the changes in tumour perfusion where acutely hypoxic tumours show a dramatic reduction of perfused tumour vessels (maybe the result of a simultaneous reduction in arterial blood pressure). In animals under chronic inspiratory hypoxia, the number of perfused vessels increased (compared to acute hypoxia), although the perfusion pattern found in control tumours was not reached. In the chronically hypoxic animals, tumour cell proliferation and tumour growth were significantly reduced, whereas no differences in VEGF expression and vascular density between these groups were observed. These results suggest that long-term adaptation of tumours to chronic hypoxia in vivo, while not affecting vascularity, does influence the functional status of the microvessels in favour of a more homogeneous perfusion.

Objective . To evaluate the impact of treatment for genital cancer on quality of life and body image to determine patients' therapy-related needs for quality improvement of medical care before and after surgery. Methods . We started to evaluate women with cervical cancer planned for pelvic exenteration in 1993 and integrated women planned for a Wertheim–Meigs surgery in 1995 before surgery, 4 and 12 months after surgery. Thanks to funding since 1999, more than 400 patients with a diagnosis of genital ( n = 185) or breast ( n = 217) cancer participated in this prospective study until July 2003. In this paper, we will focus on n = 129 women with cervical cancer. The assessment protocol included objective questionnaires for quality of life and body image (CARES; EORTC; Body image by Strauss and Appelt). The evaluation of quality of life incorporated five dimensions: physical and psychosocial health, marital and sexual status, and medical interaction. Results . Before surgery, women with a Wertheim's procedure indicated significantly less problems concerning the quality of life global score ( P = 0.002) and several subscales compared to women with a pelvic exenteration. After surgery, both groups indicated their sexual problems to be the greatest restriction in terms of quality of life, especially in women with non-reconstructive surgery as well as in women with adjuvant radio and/or chemotherapy. Concerning body image, attractiveness or self-confidence was significantly reduced postoperatively compared to the preoperative status for both groups ( P = 0.000), and also worsened with the extent of treatment. Worries about the patient's family persisted over time and represented the most important item about all questions concerning quality of life as well as the fear of recurrence. Conclusion . This on-going study demonstrates the interferences between the treatment modality and the patient's quality of life, especially about sexuality and body image. Our results suggest not only to provide reconstructive surgery if possible, but also to integrate psychosocial information aspects on future quality of life outcome before surgery as well as to offer psychosocial support related to the extent of treatment modality after surgery.

The effects of combined and simultaneously applied localised 43 degrees C hyperthermia (HT) and an antivascular bacteriochlorophyll-serine-based photodynamic therapy (Bchl-ser-PDT) on tumour growth and several microenvironmental parameters were examined. Rats bearing DS-sarcomas were allocated to treatment groups: (i) sham-treatment (control), (ii) Bchl-ser-PDT (20 mg kg(-1) i.v.), (iii) localised HT, (iv) Bchl-ser-PDT+HT. The light source used was an infrared-A irradiator, which, by use of appropriate filters, delivered the different ranges of wavelengths required. Following treatment, tumour volume was monitored. The greatest tumour growth inhibition was seen with Bchl-ser-PDT+HT, and subsequent experiments identified the pathophysiological basis for this effect. Red blood cell flux in tumour microvessels declined rapidly upon Bchl-ser-PDT+HT, reaching approximately 10% of initial values by the end of treatment. Similarly, tumour oxygenation worsened, reaching almost anoxic levels by the end of the treatment period. Assessment of metabolic parameters showed a pronounced increase in lactate levels and a decrease in ATP concentrations after combined treatment. The results presented suggest that vascular collapse and flow stasis resulting in a deterioration of tumour oxygenation and a switch from oxidative to glycolytic glucose turnover are key elements in the tumour eradication seen with this novel approach in which an antivascular PDT and HT are combined and simultaneously applied.

We present the principles underlying the isotopomer spectral analysis (ISA) method for evaluating biosynthesis using stable isotopes. ISA addresses a classic conundrum encountered in the use of radioisotopes to estimate biosynthesis rates whereby the information available is insufficient to estimate biosynthesis. ISA overcomes this difficulty capitalizing on the additional information available from the mass isotopomer labeling profile of a polymer. ISA utilizes nonlinear regression to estimate the two unknown parameters of the model. A key parameter estimated by ISA represents the fractional contribution of the tracer to the precursor pool for the biosynthesis, D. By estimating D in cells synthesizing lipids, ISA quantifies the relative importance of two distinct pathways for flux of glutamine to lipid, reductive carboxylation, and glutaminolysis. ISA can also evaluate the competition between different metabolites, such as glucose and acetoacetate, as precursors for lipogenesis and thereby reveal regulatory properties of the biosynthesis pathway. The model is flexible and may be expanded to quantify sterol biosynthesis allowing tracer to enter the pathway at three different positions, acetyl CoA, acetoacetyl CoA, and mevalonate. The nonlinear properties of ISA provide a method of testing for the presence of gradients of precursor enrichment illustrated by in vivo sterol synthesis. A second ISA parameter provides the fraction of the polymer that is newly synthesized over the time course of the experiment. In summary, ISA is a flexible framework for developing models of polymerization biosynthesis providing insight into pools and pathway that are not easily quantified by other techniques.

This study was undertaken to explore the metabolic fate of acetyl-L-carnitine in rat brain. To measure the flux of carbon atoms into anabolic processes occurring at regional levels, we have injected [1-(14)C]acetyl-L-carnitine into the lateral brain ventricle of conscious rats. After injection of [1-(14)C]acetyl-L-carnitine, the majority of radioactivity was recovered as 14CO2 expired (60% of that injected). The percentage of radioactivity recovered in brain was 1.95, 1.60, 1.30, and 0.93% at 1, 3, 6, and 22 h, respectively. Radioactivity distribution in various lipid components indicated that the fatty acid moiety of phospholipid contained the majority of radioactivity. The radioactive profile of these fatty acids showed that the acetyl moiety of acetyl-L-carnitine was incorporated into saturated (60%), monounsaturated (15%), and polyunsaturated (25%) fatty acids [mainly present in 20:4 (5.2%) and 22:6 (7.8%)]. Injection in the brain ventricle of radioactive glucose, the major source of acetyl-CoA in the CNS, revealed that glucose was a precursor of saturated (85%) and monounsaturated (15%) but not of polyunsaturated fatty acids. Thus, this study demonstrated distinct fates of glucose and acetyl-L-carnitine following intracerebroventricular injection. In summary, these data implicate acetyl-L-carnitine as an important member of a complex acetate trafficking system in brain lipid metabolism.