Reconstruction of Caspian Sea level changes using magnetic susceptibility during the last millennium

1452-1459Magnetic susceptibility is one of the most important methods for monitoring sediment composition during environmental studies. In this research, to reconstruct the Caspian Sea level changes, magnetic susceptibility variations were used during studies of five sedimentary cores (K1,K3,K5,K7,N1), collected from bottom sediments of Gorgan Bay. Samples were analyzed for grain size, total organic matter, carbonate content and magnetic susceptibility (MS). The results showed a close relationship between particle size distribution and MS magnitude due to variation in terrestrial influx, which is caused by sea-level fluctuations in different times. This process increases with particle size and magnitude of MS simultaneously with sea level fall and decreases during sea level rise. Moreover, no relationship between magnitude of MS and carbonate content was observed. Using magnetic susceptibility curves with other data, such as geological and historical, it can be concluded that these data are suitable for the reconstruction of marine environments, especially in the near shore coastal area

Study of Corrosion and Scaling of Water Resources and Wastewater of Shahid Hashemi Nezhad Gas Refinery

In this study, 18 surface and groundwater samples and 5 wastewater samples were analyzed to assess water recourses and wastewater quality at Shahid Hashemi Nezhad Gas Refinery region in terms of corrosion and scaling. The parameters measured were pH, EC, temperature, and concentration of major ions, including K+, Na +, Ca2+, Mg2+, SO42, Cl, HCO3- and CO32,. Majority of the water samples showed Na+- SO42- and Na+-Cl- type and face by Piper diagram. To assess corrosion and scaling of the samples, various indices were calculated including LSI, RSI, PSI, AI and S&DSI for CaCO3 deposition, and L&SI and Skillman for sulfates deposition especially CaSO4. The results showed most of the water samples had scale forming due to high hardness and alkalinity, and the wastewater samples were often corrosive and therefore, all of the samples did not have favorable quality for industrial uses. The results of hydrogeochemical studies indicated evaporation, evaporative minerals such as gypsum and anhydrite in the water flow path, carbonate formations and their dissolution were the most important parameters in controlling ionic content of the water resources

The biochemically defined Super Relaxed state of myosin – a paradox

The biochemical SRX (super relaxed) state of myosin has been defined as a low ATPase activity state. This state can conserve energy when the myosin is not recruited for muscle contraction. The SRX state has been correlated with a structurally defined ordered (verses disordered) state of muscle thick filaments. The two states may be linked via a common interacting head motif (IHM) where the two heads of heavy meromyosin (HMM), or myosin, fold back onto each other and form additional contacts with S2 and the thick filament. Experimental observations of the SRX, IHM, and the ordered form of thick filaments, however, do not always agree, and result in a series of unresolved paradoxes. To address these paradoxes, we have reexamined the biochemical measurements of the SRX state for porcine cardiac HMM. In our hands, the commonly employed mantATP displacement assay was unable to quantify the population of the SRX state with all data fitting very well by a single exponential. We further show that Mavacamten inhibits the basal ATPases of both porcine ventricle HMM and S1 (Ki, 0.32 and 1.76 μM respectively) while dATP activates HMM cooperatively without any evidence of a SRX state. A combination of our experimental observations and theories suggests that the displacement of mantATP in purified proteins is not a reliable assay to quantify the SRX population. This means that while the structurally defined IHM and ordered thick filaments clearly exist, great care must be employed when using the mantATP displacement assay

Elucidating the mechanism of Danicamtiv on force, kinetics, and myosin structure and function

Myosin modulators are a novel class of small molecules that alter cardiac contractility. Omecamtiv mecarbil, the first identified myosin activator, showed only modest clinical benefits in systolic heart failure patients. Thus, there is an urgency to develop alternative myosin activators. Danicamtiv (Dani) has emerged as a potential candidate; however, a detailed mechanism is not known. Here, we aim to elucidate the mechanism of Dani on contractile function in pig cardiac muscle. Demembranated ventricular tissues show a significant 0.1 pCa unit increase in calcium sensitivity and 10% increase in maximal force after incubation in 1 µM Dani. The most potent effects occur in submaximal calcium concentrations, leading to a flattening of the force-calcium relationship, suggesting decreased cooperativity. Maximal rates of tension redevelopment are decreased by approximately 60% with Dani. Isolated cardiac myofibrils provide details about contractile kinetics. Experiments with 1 µM Dani show a 49% decrease in fast-phase relaxation kinetics. Slow-phase isometric relaxation exhibits 47% slower crossbridge detachment rate and 34% longer thin filament deactivation. Next, we assess ATP utilization in the crossbridge cycle. Filament sliding velocity slows 55% on addition of 0.5 µM Dani, similar to the effect of ADP on velocity. The effects of Dani and ADP are not additive suggesting a similar mode of action. ATP binding is unaltered up to 10 µM Dani using stopped flow spectroscopy. Results of X-ray diffraction studies of porcine myocardium at rest show an increase in equatorial intensity ratio (I1,1/I1,0) in response to 50 µM Dani, reflecting an increased proximity of myosin heads to the thin filament. In conclusion, we hypothesize that Dani primes the thick filament for activation and alters relaxation through inhibited ATP hydrolysis product release. Future studies will test these hypotheses

Petrographical and geochemical evidences for paragenetic sequence interpretation of diagenesis in mixed siliciclastic–carbonate sediments: Mozduran Formation (Upper Jurassic), south of Agh-Darband, NE Iran

The Upper Jurassic Mozduran Formation with a thickness of 420 m at the type locality is the most important gas-bearing reservoir in NE Iran. It is mainly composed of limestone, dolostone with shale and gypsum interbeds that grade into coarser siliciclastics in the easternmost part of the basin. Eight stratigraphic sections were studied in detail in south of the Agh-Darband area. These analyses suggest that four carbonate facies associations and three siliciclastic lithofacies were deposited in shallow marine to shoreline environments, respectively. Cementation, compaction, dissolution, micritization, neomorphism, hematitization, dolomitization and fracturing are diagenetic processes that affected these sediments.Stable isotope variations of δ18O and δ13C in carbonate rocks show two different trends. High depletion of δ18O and low variation of δ13C probably reflect increasing temperatures during burial diagenesis, while the higher depletion in carbon isotope values with low variations in oxygen isotopes are related to fresh water flushing during meteoric diagenesis. Negative values of carbon isotopes may have also resulted from organic matter alteration during penetration of meteoric water. Fe and Mn enrichment with depletion of δ18O also supports the contention that alteration associated with higher depletion in carbon isotope values with low variations in oxygen isotopes took place during meteoric diagenesis. The presence of bright luminescence indicates redox conditions during precipitation of calcite cement

Development and characterization of a microfluidic model of the tumour microenvironment

The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening

ADAM8 signaling drives neutrophil migration and ARDS severity

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain

Danicamtiv increases myosin recruitment and alters cross-bridge cycling in cardiac muscle

Background: Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking. Methods: Permeabilized porcine cardiac tissue and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse model of genetic dilated cardiomyopathy was used to evaluate the ability of danicamtiv to correct the contractile deficient. Results: Danicamtiv increased force and calcium sensitivity via increasing the number of myosins in the on state and slowing cross-bridge turnover. Our detailed analysis showed that inhibition of ADP release results in decreased cross-bridge turnover with cross bridges staying attached longer and prolonging myofibril relaxation. Danicamtiv corrected decreased calcium sensitivity in demembranated tissue, abnormal twitch magnitude and kinetics in intact cardiac tissue, and reduced ejection fraction in the whole organ. Conclusions: As demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering crossbridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopath