Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors

Necroptosis has emerged as an exciting target in oncological, inflammatory, neurodegenerative, and autoimmune diseases, in addition to acute ischemic injuries. It is known to play a role in innate immune response, as well as in antiviral cellular response. Here we devised a concerted in silico and experimental framework to identify novel RIPK1 inhibitors, a key necroptosis factor. We propose the first in silico model for the prediction of new RIPK1 inhibitor scaffolds by combining docking and machine learning methodologies. Through the data analysis of patterns in docking results, we derived two rules, where rule #1 consisted of a four-residue signature filter, and rule #2 consisted of a six-residue similarity filter based on docking calculations. These were used in consensus with a machine learning QSAR model from data collated from ChEMBL, the literature, in patents, and from PubChem data. The models allowed for good prediction of actives of >90, 92, and 96.4% precision, respectively. As a proof-of-concept, we selected 50 compounds from the ChemBridge database, using a consensus of both molecular docking and machine learning methods, and tested them in a phenotypic necroptosis assay and a biochemical RIPK1 inhibition assay. A total of 7 of the 47 tested compounds demonstrated around 20–25% inhibition of RIPK1’s kinase activity but, more importantly, these compounds were discovered to occupy new areas of chemical space. Although no strong actives were found, they could be candidates for further optimization, particularly because they have new scaffolds. In conclusion, this screening method may prove valuable for future screening efforts as it allows for the exploration of new areas of the chemical space in a very fast and inexpensive manner, therefore providing efficient starting points amenable to further hit-optimization campaigns.     

Probing Structural Compositions of Porous Media with Two-dimensional Nuclear Magnetic Resonance

Combination of two-dimensional nuclear magnetic resonance (2-D NMR) correlation maps and a simple three-component model are proposed here to identify the structural composition of porous media. Homogeneous magnetic field and field with constant gradient of a novel Halbach sensor are employed for respective relaxation and diffusion measurements. NMR results are compared and confirmed with independent measurements on a scanning electron microscope and by energy dispersive spectrometer methods.     

Genetics of Vocal Quality Characteristics in Monozygotic Twins: A Multiparameter Approach

The main purpose of this study was to determine the vocal quality characteristics among the 45 monozygotic cotwins (MT). As the performance of the voice is related to several genetically determined anatomical and physiological factors, the authors hypothesized that the vocal characteristics and the overall vocal quality by means of the Dysphonia Severity Index (DSI) will be identical in MT. An additional objective of this study was to determine whether sex and age influence vocal similarities in MT and to compare the voice characteristics of MT with the normative data of unrelated peers. As more environmental factors influence the aging of the voice, age-related differences were expected. No sex-related differences were expected. Subjective and objective assessment techniques determined the vocal quality. No significant differences were obtained, and most comparisons resulted in significant correlation coefficients. For the acoustic parameters jitter and shimmer only, no significant correlation coefficients could be obtained. It is clear that the perceptual voice characteristics, the laryngeal aerodynamic measurements of maximum phonation time (MPT), the vocal performances, and the overall vocal quality by means of the DSI are similar in MT. These vocal characteristics are not influenced either by the subjects' age or sex and are situated within the normative range of unrelated peers. To what extent other aspects (environment, anxiety, tension, etc) might play a role in the acoustical dimensions regarding frequency and amplitude perturbation, which were in the normal range, is a subject of further research.     

On the cube problem of Las Vergnas

We prove a conjecture of Las Vergnas in dimensions d7: The matroid of the d-dimensional cube C ^d has a unique reorientation class. This extends a result of Las Vergnas, Roudneff and Salaün in dimension 4. Moreover, we determine the automorphism group G ^d of the matroid of the d-cube C ^d for arbitrary dimension d, and we discuss its relation to the Coxeter group of C ^d . We introduce matroid facets of the matroid of the d-cube in order to evaluate the order of G ^d . These matroid facets turn out to be arbitrary pairs of parallel subfacets of the cube. We show that the Euclidean automorphism group W ^d is a proper subgroup of the group G ^d of all matroid symmetries of the d-cube by describing genuine matroid symmetries for each Euclidean facet. A main theorem asserts that any one of these matroid symmetries together with the Euclidean Coxeter symmetries generate the full automorphism group G ^d . For the proof of Las Vergnas' conjecture we use essentially these symmetry results together with the fact that the reorientation class of an oriented matroid is determined by the labeled lower rank contractions of the oriented matroid. We also describe the Folkman-Lawrence representation of the vertex figure of the d-cube and a contraction of it. Finally, we apply our method of proof to show a result of Las Vergnas, Roudneff, and Salaün that the matroid of the 24-cell has a unique reorientation class, too.     

Developmental changes of poly(ADP-ribose) polymerase expression in Sarcophaga peregrina

To elucidate the physiological role of poly(ADP-ribose) polymerase (PARP), we studied the levels of PARP mRNA and protein during the developmental stages of Sarcophaga peregrina. PARP mRNA expression changed remarkably throughout the developmental stages. The level of PARP mRNA (the molecular ratio of PARP mRNA to the total RNA) was highest in unfertilized eggs and that of PARP protein (the molecular ratio of PARP protein to the total protein of the crude extract) was high in unfertilized and fertilized eggs and in 1st instar larvae. During the embryogenesis period, the levels of PARP mRNA and protein gradually decreased. The levels of PARP mRNA during larval and pupal periods became less than about 5% of that in unfertilized eggs. After the emergence of adult flies, the levels of PARP mRNA and protein increased both in female and male flies. PARP activity normalized with the total amount of protein in the crude extract changed in parallel to the level of PARP protein throughout the developmental stages. The biological significance of the drastic change of mRNA and protein levels of PARP still remains to be clarified.     

Effects of neutron skin on the excitation of isovector modes of neutron-rich nuclei

The existence of a neutron skin in neutron-rich nuclei is discussed in connection with the excitation of isovector dipole and quadrupole giant modes via isoscalar nuclear probes. In the case of large neutron excess, important contributions are obtained from the nuclear excitation, which may even become predominant according to proper kinematical conditions. At variance with the usual situation encountered in inelastic processes, constructive interference can be found between nuclear and Coulomb contributions.     

An improved mixed numerical-experimental method for stress field calculation

In this work a numerical-experimental method is used to study the dynamic behavior of an aluminum plate subjected to a small mass impact. The out-of-plane displacements, due to transient bending wave propagation, were assessed for successive time instants, using double pulse TV-holography, also known as pulsed ESPI. The experimental setup and the image processing methods were improved to allow the calculation of the plate transient stress field. Integral transforms are used to obtain the strain fields from spatial derivatives of displacements noisy data. A numerical simulation of the plate transient response was carried out with FEM Ansys^®. For this purpose a PZT transducer was used to record the impact force history, which was inputted in the numerical model. Finally, the comparisons between numerical and experimental results are presented in order to validate the present methodology.     

Fission-track dating of Macusanite glasses with plateau and size correction methods

Two Macusanite pebbles (MB1 and MB2) were dated with the fission-track method. Six irradiations were carried out in different nuclear reactors: Pavia (Italy), IPEN-CNEN (Brazil) and IPEN-Lima (Peru). Measurements of the thorium and uranium induced-fission per target nucleus using natural thorium thin films and natural U-doped glasses calibrated against natural uranium thin films, together with a λ_F of 8.46×10⁻¹⁷ a⁻¹ were used to determine the ages. The apparent ages were corrected using the plateau and size correction methods. Track measurements were performed by different analysts, using different counting criteria. In addition, tracks were measured on samples which had been submitted to thermal treatment as well as on samples which had not been heated. Thermal treatments were carried out to erase the fossil tracks before neutron irradiation. No significant differences have been found in individual results, using the two Macusanite pebbles and the different nuclear reactors, age correction techniques, analysts, track-counting criteria, and thermal treatments before neutron irradiation. The great majority of the results (14/17) is compatible with the Ar–Ar ages of 5.12±0.11 and 5.10±0.11 Ma, Macusanite MB1 and MB2, respectively. However, the fission-track ages are systematically less (8%) than the Ar–Ar ages of the two Macusanite samples studied.     

Ferroelectric switching behavior of pulsed laser deposited Ba0.8Sr0.2TiO3 thin films

The effect of pulse amplitude on the ferroelectric and switching properties of pulsed laser deposited Ba_0.8Sr_0.2TiO₃ thin films has been studied. The structural and morphological analysis revealed that the films had a well crystallized perovskite phase and grain size of about 30–40 nm. A well saturated P–E hysteresis loop was observed with a remnant polarization (P_r) ≈ 4.8 μC/cm² and a coercive field ≈ 100 kV/cm at a frequency of 1 kHz. The P_r has been found to be decreased only 4.3% after passing 8.0 × 10⁸ cycles. The analysis of switching response with nucleation limited switching model reveals that characteristic switching time (t₀) variance is due to the random distribution of the local electric fields. The peak value of polarization current and t₀ exhibits exponential dependence on reciprocal of pulse amplitude.