Rationale: An imbalance between activin and BMP signaling pathways is thought to drive the development of pulmonary arterial hypertension (PAH).Encouraging pharmacodynamic effects of sotatercept-an activin receptor type IIA-Fc fusion protein that traps activins and growth differentiation factors-have been reported in PAH patients treated with standard-of-care therapies in recent phase 2 clinical studies (PULSAR and SPECTRA).We found previously that a rodent sotatercept analog, RAP-011, reverses cardiopulmonary remodeling and inflammation in an induced model of idiopathic PAH.Here, we hypothesized that RAP-011 would also suppress cardiopulmonary remodeling and macrophage infiltration in a genetic model of heritable PAH arising from Bmpr2 haploinsufficiency.Methods: We generated Bmpr2 haploinsufficient (Bmpr2 +/R899X ) mice and confirmed the heterozygous nucleotide substitution by sequence analysis of genomic DNA.Experimental PAH was then triggered in Bmpr2 +/R899X mice by exposure to hypoxic conditions, a necessary second hit for disease development, during preventive treatment with RAP-011 (10 mg/kg) or vehicle twice weekly for 5 weeks.Cardiopulmonary parameters including pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE), right ventricular wall thickness (RVWT) and right ventricular systolic pressure (RVSP) were evaluated by echocardiography and right heart catheterization at the end of week 5. Macrophage infiltration was evaluated by immunostaining lung sections with an antibody directed against F4/80, a macrophage marker in mice.Results: In comparison with Bmpr2 +/R899X mice under normoxic control conditions, exposure of Bmpr2 +/R899X mice to hypoxia significantly elevated RVSP (P < 0.0001), induced right ventricular hypertrophy (P < 0.0001), increased RVWT (P<0.0001),reduced PAAT (P < 0.001) and reduced TAPSE (P < 0.0001).Importantly, preventive treatment with RAP-011, but not vehicle, significantly restored each of these cardiopulmonary parameters (P < 0.001 in all cases).In addition, RAP-011 fully prevented macrophage infiltration into the lungs of Bmpr2 +/R899X mice under hypoxic conditions (P < 0.01).Conclusions: These results indicate that treatment with RAP-011 suppresses macrophage infiltration and improves cardiopulmonary structure and function in a mouse model of heritable PAH arising from Bmpr2 haploinsufficiency.Together with our previous studies of induced experimental PAH, these findings suggest that therapeutic benefits of RAP-011 are robust and observed across multiple causative mechanisms in experimental PAH, including genetic and environmental factors, thus supporting evaluation of sotatercept broadly in heritable and idiopathic forms of human PAH.

Gas lift is the process of injecting gas into the tubing at a predetermined depth in order to lift the crude oil to the surface. Gas lift is applied to a well when the reservoir pressure falls to such a level that it does not produce without application of external energy. There are mainly two types of gas lift which are Continuous and Intermittent gas lift. This paper deals with the theoretical determination of relationship between liquid accumulation and gas injection duration in an intermittent gas lift well and how this knowledge can be combined with the experience of Engineers to maximize the production of a well. In order to find the relationship between the given durations, a simple mathematical approach with the assumption that the gas injection time is independent of liquid accumulation time is followed. We, then apply various tools of mathematics such as the principles of maxima and minima, Leibnitz theorem, definition of the slope of a line etc. to finally prove the interdependence of liquid accumulation and gas injection time at which the well can produce at its maximum capacity. This interdependence is plotted on a separate graph with the given times on two axis. This curve represents the values at which the reservoir inflow is maximised and hence another curve representing the tubing outflow is drawn on the same graph to intersect the former curve at the optimum value of liquid accumulation and gas injection time. The paper also discusses the physical significance of the cases in which the two curves do not intersect and its possible solutions which vary in accordance with the experience of engineers and conditions of well. Our mathematical calculation led to an astonishing result that the interdependence between the two given durations is elegant and can be easily found without the use of computer in a very short interval of time. The result indicated that if a tangent is drawn from a point representing gas injection time to the graph of accumulation height versus time, it touches the graph at the value of liquid accumulation time at which the production of well is maximized. This novel approach to determine the value of time in an intermitter or time cycle controller in an intermittent well can be proved to be a boon for gas lift optimizers who would otherwise spend a large part of the time in setting the value on hit and trial basis. The graphical method can determine the optimum value in a shorter interval of time and with greater accuracy saving companies from extra man-hours and unscientific approach to optimizing any intermittent gas lift well.

A novel and general protocol towards the synthesis of highly functionalized ortho-amido oxobenzoxazine frameworks via ruthenium catalyzed intermolecular C–H amidation using sulfonyl azides as amidation components has been developed for the first time.

An efficient protocol for the introduction of acetoxy and hydroxy functionalities on unactivated aryl sp2 carbons of oxobenzoxazine derivatives via an ortho-C-H activation reaction using a palladium catalyst has been developed for the first time. Interestingly, this intermolecular C-H functionalization reaction takes place in a facile and simple manner with high chemo- and site selectivity.

Acknowledements Paul B. Yu, M.D., Ph.D. Research Support: Acceleron ActRIIA-Fc reverses pulmonary vascular remodeling, improves pulmonary hemodynamics, and improves RV function by reducing Smad2/3 overactivation and rebalancing activin/BMP signaling in pulmonary arteries and RV. These changes could potentially translate to distinct clinical benefit over currently available therapies for PAH. Right Ventricular Systolic Pressure

Keeping in view the successive attributes of benzodiazepines on the central nervous system, we have synthesized a novel series of benzodiazepine derivatives as antioxidant and anxiolytic agents. All the compounds were obtained in good yield by facile synthesis. To check their antioxidant potential, DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay was performed. Among all the synthetics seven derivatives (SD-3, SD-5, SD-7, SD-14, SD-18, SD-19, and SD-20) exhibited IC50 values ranging from 76 to 489nM. These seven compounds were further evaluated to check their binding abilities towards the benzodiazepine binding site on GABA(A) receptors. Three best-fit ligands (SD-3, SD-14 and SD-20) were further evaluated for their anxiolytic effect by using three in vivo mice models i.e. Elevated Plus Maze, Light & Dark box, and Mirror Chamber model. The study revealed that compounds SD-3 and SD-20 showed the best anxiolytic effect as compared to standard drug diazepam even at an oral dose of 1.0mg/kg.

Keeping in view various pharmacological attributes of curcumin, coumarin, and isatin derivatives, triazole-tethered monocarbonyl curcumin-coumarin and curcumin-isatin molecular hybrids have been synthesized and evaluated for their antibacterial potential against Gram-positive (Enterococcus faecalis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) human pathogenic bacterial strains. Among all hybrid molecules, A-4 and B-38 showed the most potent antibacterial activity with inhibition zones of 29 and 31 mm along with MIC values of 12.50 and 6.25 μg/mL, respectively. Structure-activity relationship that emerged from biological data revealed that the two-carbon alkyl chain between triazole and coumarin/isatin moiety is well tolerable for the activity. Bromo substitution at the fifth position of isatin, para-cholo substitution in the case of curcumin-isatin, and para-methoxy in the case of curcumin-coumarin hybrids on ring A of curcumin are most suitable groups for the antibacterial activity. Various types of binding interactions of A-4 and B-38 within the active site of dihydrofolate reductase (DHFR) of S. aureus are also streamlined by molecular modeling studies, suggesting their capability in completely blocking DHFR.

The present study was conducted to assess the effectiveness of e-Content strategy as compared with conventional strategy of teaching Mathematics to the students of class seventh. The experimental procedure was executed. One experimental and one control group was formed. The e-Content group as experimental group was taught Mathematics with the supplement of e-Content, the control group was taught Mathematics through Conventional method. A sample of 80 pupils from VII grade was taken and to measure the achievement in Mathematics, self developed Mathematics Achievement Test was used as research tool. After the Pre-test, 2 months treatment and post test, descriptive statistics namely mean, standard deviation and inferential statistics namely t-test and analysis of covariance was used. Analyzing the data with the help of correlated t-test, it was concluded that teaching Mathematics through e-Content significantly enhanced Mathematics achievement of students. With the help of one way ANCOVA, it was also concluded that e-Content improve Mathematics achievement significantly higher in comparison to Conventional method when groups were matched on Pre-Mathematics achievement.

This article focuses on how thigmotropic stigmas play a role in limiting fruit set of plants in their non-native environment. Their pollination success requires optimum pollen transfer in terms of its quality as well as quantity and is dependent on efficient pollinator visitation. This study is particularly valuable both for horticultural purposes and general botanical research. This in turn can improve our ability to understand the behavioural response of exotic plants in non-native environments.

Abstract Knowledge of the in-situ stress state and how it varies with reservoir depletion is important for the design and execution of in-fill drilling. This paper highlights the key geomechanical aspects and their usage in planning of wells through severely depleted (up to 25 MPa) and overpressured zones within a very short depth interval (few 10s of m), in an onshore gas field in Brunei. With focus shifting from oil to deep-gas development, drilling complications include risks of wellbore instability, excessive mud loss and internal blowouts, as well as differential sticking in the depleted reservoirs. Moreover, fracturing of the depleted sands while drilling infill wells carries the risk of jeopardizing production at nearby producing wells because of locally altered flow paths. The risks were evaluated by application of empirical and analytical geomechanical models of stress changes with depletion, and by elasto-plastic finite element models of borehole instability (collapse) due to shear failure. Our results show that for an average depletion rate of 1 MPa/year, the drilling window (difference between maximum allowable mud weight controlled by fracture pressure and minimum mud weight controlled by formation pore pressure or borehole collapse pressure, whichever is greater) is likely to remain open for the coming 12 years. Minifrac or extended leak-off tests at different stages of field development should be taken to monitor stress changes within the reservoirs and provide updates for calibration of the geomechanical model. Next to showing the geomechanical model results and their application to drilling, we demonstrate the refinement of pore pressure/fracture pressure predictions (i.e. narrowing down the uncertainty in the drilling window) for mature fields where producing "from the bottom up" has not been feasible. We also indicate how risks associated with drilling through depleted/undepleted reservoir sequences in a single hole section can be managed to as low as reasonably practicable with the help of geomechanical input. These results "open the door" for accessing deeper potential pay zones by drilling through severely depleted formations.

AbstractThere are many cases when operators are forced to deviate from the conventional bottom-up approach for the development of multiple stacked reservoirs, thereby being exposed to the challenges of drilling through depleted reservoirs. The field under study, called Field X in this paper, presents similar challenges with shallow, fault-bounded depleted reservoirs (depletion of several MPa) underlain by (overpressured) reservoirs at virgin pressure.Reservoir pressure changes (ΔPp) are accompanied by changes in the total principal stresses (Sv = vertical stress, Shmin = lesser compressive horizontal stress, Shmax = greater compressive horizontal stress), characterized by the three stress path coefficients (γv = ΔSv / ΔPp, γshmax= ΔShmax / ΔPp and γshmin= ΔShmin / ΔPp). From drilling perspective, the two horizontal stress path coefficients (γshmax and γshmin) are the key for accurate borehole collapse pressure and fracture pressure prediction in the depleted reservoirs. However, field measurements and theoretical descriptions have focused only on the change in the minimum horizontal stress. Constrained by opportunities for direct measurement and calibration, the changes in the total stresses in the horizontal plane are often assumed symmetric, i.e. γshmax = γshmin. This paper explores the stress path computed for the depleted reservoirs in Field X from full-field numerical simulations and its implications on future drilling activity. The major findings are:The numerical model suggests significant anisotropy in the two horizontal stress path coefficients.The model also predicts variations in the two horizontal stress path coefficients with time at different stages of depletion despite a linear-elastic reservoir constitutive model.The onset of production is defined by a relatively higher γshmin compared to γshmax. This is seen to reverse with a higher γshmax compared to γshmin at the later stages of reservoir development.These insights on the evolution of horizontal stresses in Field X favorably affect future development options in Field X. The paper discusses the causes and implications of the temporal variations in the horizontal stress path coefficients in Field X, which are also applicable to other small fault bounded reservoirs.

In this paper, Energy Dispersive X-ray Fluorescence (EDXRF) analysis of eight fungi species, namely, Aspergillus niger, Aspergillus terreus, Trichoderma longibrachiatum, Trichoderma fasciculatum, Penicillin Janthinellum, Aspergillus awamori, Phanerochaete chrysosporium, and Rhizopus arrhizus for the uptake capacity of 28Ni, 48Cd, and 82Pb metals ions from aqueous solution have been reported. Fungal samples having superior ion removal capacity through bioaccumulation and biosorption were obtained from sites contaminated with heavy metals. The detection limit in EDXRF set up was improved considerably using selective absorbers in the path of incident photons from the X-ray tube to reduce the background in the desired energy region. It has been observed that all fungi species under present study have greater affinity for 82Pb ions as compared to 28Ni and 48Cd metal ions. The Trichoderma longibrachiatum and Trichoderma fasciculatum fungi species were identified to be more efficient for removal of heavy metal ions from waste water. The measured uptake capacity of Trichoderma longibrachiatumfor 28Ni, 48Cd, and 82Pb ions from aqueous solution is 0.52 mg/g, 0.97 mg/g, and 6.4 mg/g, respectively, and for Trichoderma fasciculatum it is 0.43 mg/g, 0.79 mg/g, and 3.5 mg/g, respectively. This indicated the potential of these identified fungi species as biosorbent for removal of high metal ions from waste water and industrial effluents.

Abstract The use of smart completion with downhole fluid control through Inflow Control Valves (ICVs) has been extensively described in the literature for balancing the water injection profile and improving the sweep efficiency in commingled water injection. This paper describes the limitations of such a system in ensuring zonal distribution of water in stacked, highly heterogeneous reservoir systems. Voidage replacement and pressure maintenance requirements necessitate waterflood under fracturing conditions in the four stacked reservoirs (Zone 1 to Zone 4) in Piltun field, offshore Sakhalin Island, Russia. These reservoirs are heterogeneous with differences in their permeability and fracture gradient. Consequently, smart injectors with four ICVs were planned to maintain the desired injection allocation in these reservoirs. The initial injectivity of these wells was extremely low with all of the injected water going to the deepest zone (Zone 4). An expensive pump upgrade improved the overall injectivity, with drastic changes in the distribution of the injected water amongst the reservoir layers. Contrary to performance prior to pump upgrade, the shallowest zone (Zone 1) emerged as the dominant receiver of injected water. Overall, the zonal distribution of water remained a problem with little success in injecting water in the remaining two zones (Zone 2 and Zone 3). Very limited improvement in the water distribution was obtained by manipulating the ICV valves. Sector modeling was taken up for the injection wells to understand the injection behavior. Modelling results show that after the pump upgrade, fracturing was initially achieved in all zones, although sustained fracture opening and propagation was only possible in Zone 1, the reservoir with better flow properties and reasonably low fracture gradient. The other zones gradually reverted back to injection under matrix conditions with time. The additional pressure drop created by the flow control device is not sufficient to choke back the major zones and achieve sustained fracture growth and water injection in the minor zones in Piltun field. The results demonstrate that the use of intelligent completion for waterflood conformance can be limited by large stress and permeability contrast.

Two checkpointing approaches i.e., coordinated checkpointing and times based checkpointing are widely used in the literature of MDSs. Coordinated checkpointing protocols uses the less checkpoints and domino free but have large coordinated message overheads as processes synchronize by exchanging coordinated message. However, time based protocol requires every process to take checkpoint during checkpointing. Some of the time based protocols defines the timeout period tp. When this timeouts occur, processes take their checkpoint. If the checkpointing interval is too small then multiple checkpoints are transferred from MHs to MSS through wireless link and also checkpointing takes some time to save the application state. This approach increases the checkpointing overheads. On the other hand, if checkpointing interval is too large this may leads to large amount of computational loss during rollback and recovery. As a result time based approach has minimum coordinated messages overheads cost but has high checkpointing cost as it requires large number checkpoints than minimum but coordinated checkpointing approach have minimum checkpointing cost than time based approach but higher coordinated message overheads cost. In this paper, we design an efficient coordinated checkpointing protocol which uses time to indirectly coordinate to minimize the number of coordinated message transmitted through the wireless link and reduces the number of checkpoints nearest to the minimum. The algorithm is non-blocking and minimum process.

ABRAXAS is an integral member of BRCA1-complex, which helps in its recruitment to the DNA damage site. It interacts with BRCA1 via its C-terminal phospho-peptide binding motif while the N-terminal associates with RAP80, and thereby recruits the BRCA1-complex at the site of DNA damage. Nonetheless, how ABRAXAS helps in the structural integrity of BRCA1-complex, and its DNA repair mechanism remains elusive. To elucidate the role of ABRAXAS in the DNA repair process, we characterized the ABRAXAS wild type and Arg361Gln mutant using in silico and in vitro approach. It has been observed that ABRAXAS Arg361Gln mutant is responsible for defective nuclear localization of BRCA1-complex, and hence important for DNA repair function. We found conformational changes in ABRAXAS mutant, which impaired binding to RAP80 and further disturb BRCA1-complex localization. The results presented in this paper will help to understand the cause of BRCA1 mislocalization, and various DNA repair defects that occur due to substitution. Comparative study of ABRAXAS wild type and mutant will provide helpful perspective for inhibitor designing that can potentially recompense the deleterious effect(s) of Arg361Gln mutation, and have therapeutic application.

Abstract Drilling overpressured and deep reservoirs is a challenge in itself, but can be complicated by the need to drill through depleted (depressurized) shallower reservoirs. The field under study consists of multiple stacked clastic reservoirs bounded by steeply dipping sealing faults. The deeper reservoirs fall in the high pressure high temperature (HPHT) category and account for one third of the in-place volumes. Ideally, field development for such stacked reservoirs is recommended through the "bottom-up" strategy to prevent late-in-life drilling through depleted zones with reduced drilling window and increased risk of fluid losses and well failure. Here, this would imply drilling and developing the deeper HPHT reservoirs before the shallow, normally pressured reservoirs. From a technical and financial perspective, it is tempting to develop and produce the shallow, normally pressured reservoirs (that contain 70% of the volumes and also have better flow properties) first, and bring the deeper HPHT reservoirs on-stream later. But, is such phased development of the reservoirs possible? Or would producing from the shallower reservoirs first permanently damage our ability to drill and produce the deeper HPHT reservoirs at a later stage in field life? These were the questions we tried to answer in this work. We built a full-field finite element model to simulate the geomechanical response of the reservoirs to pressure depletion i.e. quantify the displacement, strains and total stress changes in and around the reservoirs as a function of production. Such geomechanical models can serve as a predictive tool to help answer the questions above. In this paper, we show the construction and application of such a geomechanical model in field development planning. Our paper highlights how our geomechanical model results were applied, together with other work, to develop this field safely and efficiently, emphasizing field life cycle value.

MERIT40 (MEdiator of RAP80 Interaction and Targeting 40) is a novel associate of the BRCA1-complex and plays an essential role in DNA damage repair. It is the least characterized protein of BRCA1-complex and mainly responsible for maintaining the complex integrity. However, its structural and functional aspects of regulating the complex stability still remain elusive. Here, we carried out a comprehensive examination of MERIT40 biophysical properties and identified its novel interacting partner which would help to understand its role in BRCA1-complex. The recombinant protein was purified by affinity chromatography and unfolding pathway was determined using spectroscopic and calorimetric methods. Molecular model was generated using combinatorial approaches of modeling, and monomer–monomer docking was carried out to identify dimeric interface. Disordered region of MERIT40 was hatchet using trypsin and chymotrypsin to illustrate the existence of stable domain whose function was speculated through DALI search. Our findings suggest that MERIT40 forms a dimer in a concentration-independent manner. Its central region shows remarkable stability towards the protease digestion and has structural similarity with vWA-like region, a domain mainly present in complement activation factors. MERIT40 undergoes a three-state unfolding transition pathway with a dimeric intermediate. It interacts with adaptor molecule of BRCA1-complex, called ABRAXAS, thus help in extending the bridging interaction among various members which further stabilizes the whole complex. The results presented in this paper provide first-hand information on structural and folding behavior of MERIT40. These findings will help in elucidating the role of protein–protein interactions in stabilization of BRCA1-complex.