The Use of Isomeric Testosterone Dimers to Explore Allosteric Effects in Substrate Binding to Cytochrome P450 CYP3A4

Abstract: Cytochrome P450 CYP3A4 is the main drug-metabolizing enzyme in the human liver, being responsible for oxidation of 50% of all pharmaceuticals metabolized by human P450 enzymes. Possessing a large substrate binding pocket, it can simultaneously bind several substrate molecules and often exhibits a complex pattern of drug–drug interactions. In order to better understand structural and functional aspects of binding of multiple substrate molecules to CYP3A4 we used resonance Raman and UV–VIS spectroscopy to document the effects of binding of synthetic testosterone dimers of different configurations, cis-TST2 and trans-TST2. We directly demonstrate that the binding of two steroid molecules, which can assume multiple possible configurations inside the substrate binding pocket of monomeric CYP3A4, can lead to active site structural changes that affect functional properties. Using resonance Raman spectroscopy, we have documented perturbations in the ferric and Fe-CO states by these substrates, and compared these results with effects caused by binding of monomeric TST. While the binding of trans-TST2 yields results similar to those obtained with monomeric TST, the binding of cis-TST2 is much tighter and results in significantly more pronounced conformational changes of the porphyrin side chains and Fe-CO unit. In addition, binding of an additional monomeric TST molecule in the remote allosteric site significantly improves binding affinity and the overall spin shift for CYP3A4 with trans-TST2 dimer bound inside the substrate binding pocket. This result provides the first direct evidence for an allosteric effect of the peripheral binding site at the protein-membrane interface on the functional properties of CYP3A4. Graphical abstract: Synthetic dimers of the steroid testosterone are used to address directly the mechanisms of multiple substrate binding at the active site of cytochrome P450 3A4 and the role of substrate binding at a distal site in the control of allostery in this central enzyme of human drug metabolism

Invariant vector fields and the prolongation method for supersymmetric quantum systems

The kinematical and dynamical symmetries of equations describing the time evolution of quantum systems like the supersymmetric harmonic oscillator in one space dimension and the interaction of a non-relativistic spin one-half particle in a constant magnetic field are reviewed from the point of view of the vector field prolongation method. Generators of supersymmetries are then introduced so that we get Lie superalgebras of symmetries and supersymmetries. This approach does not require the introduction of Grassmann valued differential equations but a specific matrix realization and the concept of dynamical symmetry. The Jaynes-Cummings model and supersymmetric generalizations are then studied. We show how it is closely related to the preceding models. Lie algebras of symmetries and supersymmetries are also obtained.Comment: 37 pages, 7 table

Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor.

The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(+/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans

Evidence of unidirectional hybridization and second‐generation adult hybrid between the two largest animals on Earth, the fin and blue whales

Biodiversity in the oceans has dramatically declined since the beginning of the industrial era, with accelerated loss of marine biodiversity impairing the ocean's capacity to maintain vital ecosystem services. A few organisms epitomize the damaging and long‐lasting effects of anthropogenic exploitation: some whale species, for instance, were brought to the brink of extinction, with their population sizes reduced to such low levels that may have cause a significant disruption to their reproductive dynamics and facilitated hybridization events. The incidence of hybridization is nevertheless believed to be rare and very little information exist on its directionality. Here, using genetic markers, we show that all but one whale hybrid sample collected in Icelandic waters originated from the successful mating of male fin whale and female blue whale, thus suggesting unidirectional hybridization. We also demonstrate for the first time the existence of a second‐generation adult (male) hybrid resulting from a backcross between a female hybrid and a pure male fin whale. The incidence of hybridization events between fin and blue whales is likely underestimated and the observed unidirectional hybridization (for F1 and F2 hybrids) is likely to induce a reproductive loss in blue whale, which may represent an additional challenge to its recovery in the Atlantic Ocean compared to other rorquals

Dietary intake and breast density in high-risk women: a cross-sectional study

Background Women with a family history of breast cancer may be at higher risk for breast cancer, but few previous studies evaluating diet and breast cancer have focused on such women. The objective of the present study was to determine whether diet, a modifiable risk factor, is related to breast density among women at high genetic risk for breast cancer. Methods Women with at least one first-degree or second-degree relative with breast cancer or ovarian cancer participating in the Fox Chase Cancer Center Family Risk Assessment Program completed health history and food frequency questionnaires and received standard screening mammograms. Cranial–caudal mammographic images were classified into the four Breast Imaging Reporting and Data System categories ranging from \u27entirely fatty\u27 to \u27extremely dense\u27. Logistic regression analysis using proportional odds models for polychotomous outcomes provided estimates of odds ratios for having a higher category versus a lower category of breast density. Results Among 157 high-risk women, breast density was inversely associated with vitamin D intake (odds ratio for third tertile versus first tertile, 0.5; 95% confidence interval, 0.2–1.0). In contrast, intakes above the median level for protein (odds ratio, 3.0; 95% confidence interval, 1.3–6.9) and above the median level for animal protein (odds ratio, 4.3; 95% confidence interval, 1.8–10.3) were associated with higher breast density, but only among women whose family history did not reflect a known familial cancer syndrome or a breast cancer predisposition gene. Conclusion For women with a strong family history that was not associated with known cancer syndromes, dietary factors may be associated with breast density, a strong predictor of breast cancer risk. Since women with strong family history are often very motivated to change their lifestyle habits, further studies are needed to confirm whether changes in diet will change the breast density and the subsequent onset of breast cancer in these women

Quantum metric nonlinear Hall effect in a topological antiferromagnetic heterostructure

Quantum geometry - the geometry of electron Bloch wavefunctions - is central to modern condensed matter physics. Due to the quantum nature, quantum geometry has two parts, the real part quantum metric and the imaginary part Berry curvature. The studies of Berry curvature have led to countless breakthroughs, ranging from the quantum Hall effect in 2DEGs to the anomalous Hall effect (AHE) in ferromagnets. However, in contrast to Berry curvature, the quantum metric has rarely been explored. Here, we report a new nonlinear Hall effect induced by quantum metric by interfacing even-layered MnBi2Te4 (a PT-symmetric antiferromagnet (AFM)) with black phosphorus. This novel nonlinear Hall effect switches direction upon reversing the AFM spins and exhibits distinct scaling that suggests a non-dissipative nature. Like the AHE brought Berry curvature under the spotlight, our results open the door to discovering quantum metric responses. Moreover, we demonstrate that the AFM can harvest wireless electromagnetic energy via the new nonlinear Hall effect, therefore enabling intriguing applications that bridges nonlinear electronics with AFM spintronics.Comment: 19 pages, 4 figures and a Supplementary Materials with 66 pages, 4 figures and 3 tables. Originally submitted to Science on Oct. 5, 202

A closer look at neuron interaction with track-etched microporous membranes

Microporous membranes support the growth of neurites into and through micro-channels, providing a different type of neural growth platform to conventional dish cultures. Microporous membranes are used to support various types of culture, however, the role of pore diameter in relation to neurite growth through the membrane has not been well characterised. In this study, the human cell line (SH-SY5Y) was differentiated into neuron-like cells and cultured on track-etched microporous membranes with pore and channel diameters selected to accommodate neurite width (0.8 µm to 5 µm). Whilst neurites extended through all pore diameters, the extent of neurite coverage on the non-seeded side of the membranes after 5 days in culture was found to be directly proportional to channel diameter. Neurite growth through membrane pores reduced significantly when neural cultures were non-confluent. Scanning electron microscopy revealed that neurites bridged pores and circumnavigated pore edges – such that the overall likelihood of a neurite entering a pore channel was decreased. These findings highlight the role of pore diameter, cell sheet confluence and contact guidance in directing neurite growth through pores and may be useful in applications that seek to use physical substrates to maintain separate neural populations whilst permitting neurite contact between cultures

Reading Ronaldo: contingent whiteness in the football media

Ever since his introduction to the first-­-team at Manchester United FC, Cristiano Ronaldo Dos Santos Aveiro has been recognised as one of the footballing world’s most stand-­-out football players. In turn, Ronaldo has drawn the attention of scholars working across a number of disciplines. While sports economists and sociologists of sport, amongst others, have contributed to a growing literature about Ronaldo and the social implications of his on and off-­-field behaviour, few critical analyses have considered the racialised aspects of Ronaldo’s representations, or how audiences make sense of his racialised or ethnic identity. Using images of Ronaldo, which we presented to and discussed with self-­-identified physically active white British men, we explore what it is representations and audience interpretations of Ronaldo reveal about the complexities of white male identity formation. We do this to understand better how white male identities can be read and interpreted through and in the context of football. Facilitated by our conception of contingent whiteness, we argue that white British men’s interpretations of Ronaldo’s whiteness are inextricably linked to discourses of ‘race’, masculinities and football

Are sciences essential and humanities elective? Disentangling competing claims for humanities research public value

[EN] Recent policy discourse suggests that arts and humanities research is seen as being less useful to society than other disciplines, notably in science, technology, engineering and mathematics. The paper explores how this assumption s construction has been built and whether it is based upon an unfair prejudice: we argue for a prima facie case to answer in assuming that arts and humanities research s lower societal value. We identify a set of claims circulating in policy circles regarding science, technology, engineering and math- ematics research and arts and humanities research s differences. We find two groups: arts and humanities research is less useful than science, technology, engineering and mathematics, and arts and humanities research is merely differently useful. We argue that empirical analysis is necessary to disentangle which ones are true to assess whether policy-making is being based on rational and evidence-based claims. We argue that debates about public research value should recognise that humanities have different (but equally valid) kinds of societal value.This work was supported by the Spanish Ministry of Education, which funded the PhD research fellowship of Julia Olmos Peñuela through the F.P.U program [AP2007- 01850]. The research fellowship took place in the framework of the HERAVALUE project, Measuring the public value of arts and humanities research, financially supported by the HERA Joint Research Programme, cofunded by AHRC, AKA, DASTI, ETF, FNR, FWF, HAZU, IRCHSS, MHEST, NWO, RANNIS, RCN, VR and The European Community FP7 2007-2013, under the Socio-economic Sciences and Humanities programme. The authors would like to thank the editors and two anonymous referees for their invaluable comments. Any errors or omissions remain the authors’ responsibilitieOlmos-Peñuela, J.; Benneworth, P.; Castro-Martínez, E. (2015). Are sciences essential and humanities elective? Disentangling competing claims for humanities research public value. Arts and Humanities in Higher Education. 14(1):61-78. https://doi.org/10.1177/1474022214534081S617814

Right-unitary transformation theory and applications

We develop a new transformation theory in quantum physics, where the transformation operators, defined in the infinite dimensional Hilbert space, have right-unitary inverses only. Through several theorems, we discuss the properties of state space of such operators. As one application of the right-unitary transformation (RUT), we show that using the RUT method, we can solve exactly various interactions of many-level atoms with quantized radiation fields, where the energy of atoms can be two levels, three levels in Lambda, V and equiv configurations, and up to higher (>3) levels. These interactions have wide applications in atomic physics, quantum optics and quantum electronics. In this paper, we focus on two typical systems: one is a two-level generalized Jaynes-Cummings model, where the cavity field varies with the external source; the other one is the interaction of three-level atom with quantized radiation fields, where the atoms have Lambda-configuration energy levels, and the radiation fields are one-mode or two-mode cavities.Comment: 51 pages, RevTeX; Figures not included but may be obtained from author by snail-mail; Accepted for publication by Phys. Rev.