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Abstract We have analyzed the MZ6 onshore‐offshore wide‐angle seismic profile of the MOZ3‐5 survey to investigate the crustal structure of the South Mozambique passive margin. The NNW‐SSE, 625 km‐long profile runs across the Mozambique coastal plain (MCP), the Continental Shelf and Slope, the Almirante Leite Ridge (ALR), the North Natal Valley (NNV), the Ariel Graben and the Dana Plateau of the Mozambique Ridge. Forward modeling through combined interpretation of the multichannel seismic, the main reflected and refracted phases of the wide‐angle, drill hole data and bathymetric data reveal: (a) a sedimentary cover poorly compacted up to 3 km‐thick, intruded by magmatic dykes that reach the seafloor at the ALR forming 0.5 to 5 km‐wide corrugated mounts, (b) between 2 and 7 km, thick magmatic or volcano‐clastic deposits are observed both at the MCP and NNV, forming a 40 km‐wide terrace at the center of MZ6 and southward‐dipping reflectors in the southern part interpreted as the Pre‐Neocomian Formation contemporary of the Karroo and/or Bombeni‐Movene magmatic events reached in several wells, (c) onshore, the 3‐layered crust reaches 39 km thickness, gradually thinning to ∼27 km at the southern end of MZ6. In the deepest layer, velocities exceed 7.15 km/s, reaching at its base 7.55 km/s at the vertical of the ALR. (d) the seismic Moho is marked by a strong reflection on the wide‐angle data. These results suggests that the basement is composed of slightly thinned and altered continental crust, most likely intruded by several phases of intense magmatism.

In the chapter of the book, the author describes the procedure for normative regulation of the organization and holding of assemblies in the Republic of Poland, given that the right to freedom of assembly is enshrined in the Constitution of Poland. The author identifies certain signs and types of assemblies, depending on which a particular assembly is subject to regulation or not. In particular, the issues of holding flash mobs have not been settled. There also remain questions how to determine the boundaries when the personal moral convictions of representatives of the authorities become an obstacle to the exercise of the right to freedom of assembly, or the holding of assemblies is limited with reference to the convictions of most of the society; how to draw the line between peaceful assemblies and assemblies that threaten the safety of people; how to distinguish between spontaneous and scheduled assemblies. Some of these dilemmas are being resolved at the judicial level, but some have yet to be resolved.

Coincident wide-angle and multi-channel seismic data acquired within the scope of the PAMELA Moz3-5 project allow us to reconsider the formation mechanism of East African margins offshore of southern Mozambique. This study specifically focuses on the sedimentary and deep-crustal architecture of the Limpopo margin (LM) that fringes the eastern edge of the Mozambique’s Coastal Plain (MCP) and its offshore southern prolongation the North Natal Valley (NNV). It relies primarily on the MZ3 profile that runs obliquely from the northeastern NNV towards the Mozambique basin (MB) with additional inputs from a tectonostratigraphy analysis of industrial onshore–offshore seismic lines and nearby or crossing velocity models from companion studies. Over its entire N–S extension the LM appears segmented into (1) a western domain that shows the progressive eastward crustal thinning and termination of the MCP/NNV continental crust and its overlying pre-Neocomian volcano-sedimentary basement and (2) a central corridor of anomalous crust bounded to the east by the Mozambique fracture zone (MFZ) and the oceanic crust of the MB. A prominent basement high marks the boundary between these two domains. Its development was most probably controlled by a steep and deeply rooted fault, i.e., the Limpopo fault. We infer that strike-slip or slightly transtensional rifting occurred along the LM and was accommodated along this Limpopo fault. At depth we propose that ductile shearing was responsible for the thinning of the continental crust and an oceanward flow of lower crustal material. This process was accompanied by intense magmatism that extruded to form the volcanic basement and gave the corridor its peculiar structure and mixed nature. The whole region remained at a relative high level during the rifting period and a shallow marine environment dominated the pre-Neocomian period during the early phase of continent–ocean interaction. It is only some time after break-up in the MB and the initiation of the MFZ that decoupling occurred between the MCP/NNV and the corridor, allowing for the latter to subside and become covered by deep marine sediments. A scenario for the early evolution and formation of the LM is proposed taking into account both recent kinematic and geological constraints. It implies that no or little change in extensional direction occurred between the intra-continental rifting and subsequent phase of continent–ocean interaction.

Crystal diffraction data of heart fatty acid binding protein (H-FABP) in complex with oleic acid were measured at room temperature with high-resolution X-ray and neutron protein crystallography (0.98 and 1.90 Å resolution, respectively). These data provided very detailed information about the cluster of water molecules and the bound oleic acid in the H-FABP large internal cavity. The jointly refined X-ray/neutron structure of H-FABP was complemented by a transferred multipolar electron-density distribution using the parameters of the ELMAMII library. The resulting electron density allowed a precise determination of the electrostatic potential in the fatty acid (FA) binding pocket. Bader's quantum theory of atoms in molecules was then used to study interactions involving the internal water molecules, the FA and the protein. This approach showed H...H contacts of the FA with highly conserved hydrophobic residues known to play a role in the stabilization of long-chain FAs in the binding cavity. The determination of water hydrogen (deuterium) positions allowed the analysis of the orientation and electrostatic properties of the water molecules in the very ordered cluster. As a result, a significant alignment of the permanent dipoles of the water molecules with the protein electrostatic field was observed. This can be related to the dielectric properties of hydration layers around proteins, where the shielding of electrostatic interactions depends directly on the rotational degrees of freedom of the water molecules in the interface.

Glia cell missing (GCM) transcription factors form a small family of transcriptional regulators in metazoans. The prototypical Drosophila GCM protein directs the differentiation of neuron precursor cells into glia cells, whereas mammalian GCM proteins are involved in placenta and parathyroid development. GCM proteins share a highly conserved 150 amino acid residue region responsible for DNA binding, known as the GCM domain. Here we present the crystal structure of the GCM domain from murine GCMa bound to its octameric DNA target site at 2.85 Å resolution. The GCM domain exhibits a novel fold consisting of two domains tethered together by one of two structural Zn ions. We observe the novel use of a β-sheet in DNA recognition, whereby a five- stranded β-sheet protrudes into the major groove perpendicular to the DNA axis. The structure combined with mutational analysis of the target site and of DNA-contacting residues provides insight into DNA recognition by this new type of Zn-containing DNA-binding domain. [ABSTRACT FROM AUTHOR]

Abstract Liver microphysiological systems (MPSs) are promising models for predicting hepatic drug effects. Yet, after a decade since their introduction, MPSs are not routinely used in drug development due to lack of criteria for ensuring reproducibility of results. We characterized the feasibility of a liver MPS to yield reproducible outcomes of experiments assaying drug toxicity, metabolism, and intracellular accumulation. The ability of the liver MPS to reproduce hepatotoxic effects was assessed using trovafloxacin, which increased lactate dehydrogenase (LDH) release and reduced cytochrome P450 3A4 (CYP3A4) activity. These observations were made in two test sites and with different batches of Kupffer cells. Upon culturing equivalent hepatocytes in the MPS, spheroids, and sandwich cultures, differences between culture formats were detected in CYP3A4 activity and albumin production. Cells in all culture formats exhibited different sensitivities to hepatotoxicant exposure. Hepatocytes in the MPS were more functionally stable than those of other culture platforms, as CYP3A4 activity and albumin secretion remained prominent for greater than 18 days in culture, whereas functional decline occurred earlier in spheroids (12 days) and sandwich cultures (7 days). The MPS was also demonstrated to be suitable for metabolism studies, where CYP3A4 activity, troglitazone metabolites, diclofenac clearance, and intracellular accumulation of chloroquine were quantified. To ensure reproducibility between studies with the MPS, the combined use of LDH and CYP3A4 assays were implemented as quality control metrics. Overall results indicated that the liver MPS can be used reproducibly in general drug evaluation applications. Study outcomes led to general considerations and recommendations for using liver MPSs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Microphysiological systems (MPSs) have been designed to recreate organ‐ or tissue‐specific characteristics of extracellular microenvironments that enhance the physiological relevance of cells in culture. Liver MPSs enable long‐lasting and stable culture of hepatic cells by culturing them in three‐dimensions and exposing them to fluid flow. WHAT QUESTION DID THIS STUDY ADDRESS? What is the functional performance relative to other cell culture platforms and the reproducibility of a liver MPS for assessing drug development and evaluation questions, such as toxicity, metabolism, and pharmacokinetics? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The liver MPS systematically detected the toxicity of trovafloxacin. When compared with spheroids and sandwich cultures, this system had a more stable function and different sensitivity to troglitazone, tamoxifen, and digoxin. Quantifying phase II metabolism of troglitazone and intracellular accumulation of chloroquine demonstrated the potential use of the liver MPS for studying drug metabolism and pharmacokinetics. Quality control criteria for assessing chip function were key for reliably using the liver MPS. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Due to its functional robustness and physiological relevance (3D culture, cells expose to fluid flow and co‐culture of different cell types), the liver MPS can, in a reproducible manner: (i) detect inflammatory‐induced drug toxicity, as demonstrated with trovafloxacin, (ii) detect the toxicity of other drugs, such as troglitazone, tamoxifen, and digoxin, with different effects than those detected in spheroids and sandwich cultures, (iii) enable studies of hepatic function that rely on prolonged cellular activity, and (iv) detect phase II metabolites and drug accumulation to potentially support the interpretation of clinical data. The integration of MPSs in drug development will be facilitated by careful evaluation of performance and reproducibility as performed in this study.

The purpose of this work is to identify mitochondrial optic nerve (ON) lipid alterations associated with sonication-induced traumatic optic neuropathy (TON). Briefly, a mouse model of indirect TON was generated using sound energy concentrated focally at the entrance of the optic canal using a laboratory sonifier (Branson Digital Sonifier 450, Danbury, CT, USA) with a microtip probe. We performed an analysis of a previously generated dataset from high-performance liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). We analyzed lipids from isolated mitochondria from the ON at 1 day, 7 days, and 14 days post-sonication compared to non-sonicated controls. Lipid abundance alterations in post-sonicated ON mitochondria were evaluated with 1-way ANOVA (FDR-adjusted significant p-value < 0.01), debiased sparse partial correlation (DSPC) network modeling, and partial least squares-discriminant analysis (PLS-DA). We find temporal alterations in triglyceride metabolism are observed in ON mitochondria of mice following sonication-induced optic neuropathy with notable depletions of TG(18:1/18:2/18:2), TG(18:1/18:1/18:1), and TG(16:0/16:0/18:1). Depletion of mitochondrial triglycerides may mediate ON damage in indirect traumatic optic neuropathy through loss energy substrates for neuronal metabolism.