Change of liver metabolism of 1,2-dibromoethane during simultaneous treatment with carbon tetrachloride

The combination of carbon tetrachloride (CCl₄) and 1,2-dibromoethane (DBE) in isolated rat hepatocytes led to a significant potentiation of both lipid peroxidation and of plasma membrane damage observed after a single treatment with CCl₄. Such a synergistic effect appeared to be related to the CCl₄-induced shift of DBE metabolism from the cytosolic conjugation with glutathione towards the microsomal transformation into toxic intermediates. In fact, CCl₄ significantly inactivated hepatocyte total GSH-transferase, i.e. the DBE detoxification pathway. Furthermore, while the microsomal metabolism of CCl₄ was not affected by the simultaneous presence of DBE, the amount of DBE reactive metabolities covalently bound to hepatocyte protein was significantly enhanced in the presence of CCl₄.     

Autochthonous outer ramp sedimentation: The Alamogordo Member of the Lake Valley Formation,New Mexico

Summary Paleozoic carbonate ramp sedimentation has generally been described in terms of downlapping clinoforms composed of allochthonous sediment derived from shallower environments. However, during transgressive episodes when carbonate sediment production is low and down slope sediment transport by gravity becomes inactive, autochthonous carbonate sediment accumulates in vertical stacks of essentially in situ sediment. Autochthonous outer ramp deposition is probably a part of many Paleozoic ramp strata, but has heretofore not been recognized because of the general absence of adequate exposures. Evidence of autochthonous, in situ deposition and preservation of sediments in a starved setting is well displayed in the Alamogordo Member of the Lake Valley Formation in south central New Mexico. This evidence includes: 1) beds and bed sets that are individually continuous and traceable along ramp slope for 32 km, 2) down-ramp sequential distributions of depth-sensitive organisms and assemblages but patchy distribution of rock types, 3) lack of sedimentary structures indicative of transport, 4) well preserved, unabraded fossils, 5) the common occurrence of fossils in life position, 6) beds traceable into and through mounds 7) bed thickness trends ascribed to biotic productivity, and 8) geopetal structures in original position. Integrated paleontologic, sedimentologic, and stratigraphic data provide information about depositional processes and setting. The depositional slope was approximately 0.5^o based on the distribution of fossil algae; this is comparable to dips reported for other Mississippian homoclinal ramps. An oxygen minimum zone may have impinged on the ramp during a major flooding event. Shifts in biotic gradients from bed to bed reveal transgressive-regressive patterns that would not be resolvable without detailed paleontological evidence. The Alamogordo Member formed as a result of transgressive and early highstand starved carbonate sedimentation along a narrow, homoclinal outer ramp. The surface of maximum flooding and the boundary between the TST and HST are within the Alamogordo Member.     

Evaluation of parent and nano-encapsulated terbium(III) complex toward its photoluminescence properties,FS-DNA,BSA binding affinity,and biological applications

BackgroundThere is a crucial need for finding and developing new compounds as the anticancer and antimicrobial agents with better activity, specific target, and less toxic side effects.ObjectivesBase on the potential anticancer properties of lanthanide complexes, in the paper, the biological applications of terbium (Tb) complex, containing 2,9-dimethyl- 1,10-phenanthroline (Me₂Phen) such as anticancer, antimicrobial, DNA cleavage ability, the interaction with FS-DNA (Fish-Salmon DNA) and BSA (Bovine Serum Albumin) was examined.MethodsThe interaction of Tb-complex with BSA and DNA was studied by emission spectroscopy, absorption titration, viscosity measurement, CD spectroscopy, competitive experiments, and docking calculation. Also, the ability of this complex to cleave DNA was reported by gel electrophoresis. Tb-complex was concurrently screened for its antibacterial activities by different methods. Besides, the nanocarriers of Tb-complex (lipid nanoencapsulation (LNEP) and the starch nanoencapsulation (SNEP)), as active anticancer candidates, were prepared. MTT technique was applied to measure the antitumor properties of these compounds on human cancer cell lines.ResultsThe experimental and docking results suggest significant binding between DNA as well as BSA with terbium-complex. Besides, groove binding plays the main role in the binding of this compound with DNA and BSA. The competitive experiment with hemin demonstrated that the terbium complex was bound at site III of BSA, which was confirmed by the docking study. Also, Tb-complex was concurrently screened for its DNA cleavage, antimicrobial, and anticancer activities. The anticancer properties of LNEP and SNEP are more than the terbium compound.ConclusionsTb-complex can bond to DNA/BSA with high binding affinity. Base on biological applications of Tb-complex, it can be concluded that this complex and its nanocarriers can suggest as novel anticancer, antimicrobial candidates.     

The response of the pediatric head to impacts onto a rigid surface

The study of pediatric head injury relies heavily on the use of finite element models and child anthropomorphic test devices (ATDs). However, these tools, in the context of pediatric head injury, have yet to be validated due to a paucity of pediatric head response data. The goal of this study is to investigate the response and injury tolerance of the pediatric head to impact.Twelve pediatric heads were impacted in a series of drop tests. The heads were dropped onto five impact locations (forehead, occiput, vertex and right and left parietal) from drop heights of 15 and 30 cm. The head could freely fall without rotation onto a flat 19 mm thick platen. The impact force was measured using a 3-axis piezoelectric load cell attached to the platen.Age and drop height were found to be significant factors in the impact response of the pediatric head. The head acceleration (14%–15 cm; 103–30 cm), Head Injury Criterion (HIC) (253%–15 cm; 154%–30 cm) and impact stiffness (5800%–15 cm; 3755%–30 cm) when averaged across all impact locations increased with age from 33 weeks gestation to 16 years, while the pulse duration (66%–15 cm; 53%–30 cm) decreased with age. Increases in head acceleration, HIC and impact stiffness were also observed with increased drop height, while pulse duration decreased with increased drop height.One important observation was that three of the four cadaveric heads between the ages of 5-months and 22-months sustained fractures from the 15 cm and 30 cm drop heights. The 5-month-old sustained a right parietal linear fracture while the 11- and 22-month-old sustained diastatic linear fractures.     

Aphid Herbivory Drives Asymmetry in Carbon for Nutrient Exchange between Plants and an Arbuscular Mycorrhizal Fungus

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Optical Feedback Loop Involving Dinoflagellate Symbiont and Scleractinian Host Drives Colorful Coral Bleaching

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Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models.     

A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual,SPR and NMR screening

NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of ¹⁵N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.     

Changing water use and adaptive strategies along rainfall gradients in Mediterranean lupins

• There is growing interest in harnessing the genetic and adaptive diversity of crop wild relatives to improve drought resilience of elite cultivars. Rainfall gradients exert strong selection pressure on both natural and agricultural ecosystems. Understanding plant responses to these facilitates crop improvement.
• Wild and domesticated narrow‐leafed lupin (NLL) collected along Mediterranean terminal drought stress gradients was evaluated under contrasting reproductive phase water supply in controlled field, glasshouse and cabinet studies. Plant phenology, growth and productivity, water use and stress responses were measured over time.
• There is an integrated suite of adaptive changes along rainfall gradients in NLL. Low rainfall ecotypes flower earlier, accumulate lower seed numbers, biomass and leaf area, and have larger root:shoot ratios than high rainfall ecotypes. Water‐use is lower and stress onset slower in low compared to high rainfall ecotypes. Water‐use rates and ecotypic differences in stress response (Ψleaf decline, leaf loss) are lower in NLL than yellow lupin (YL). To mitigate the effects of profligate water use, high rainfall YL ecotypes maintain higher leaf water content over declining leaf water potential than low rainfall ecotypes. There is no evidence for such specific adaptation in NLL.
• The data suggests that appropriate phenology is the key adaptive trait to rainfall gradients in NLL because of the flow‐on effects on biomass production, fitness, transpiration and stress onset, and the lack of physiological adaptations as in YL. Accordingly, it is essential to match phenology with target environment in order to minimize risk and maximize yield potential.