Towards de novo RNA 3D Structure Prediction

RNA is a fundamental class of biomolecules that mediate a large variety of molecular processes within the cell. Computational algorithms can be of great help in the understanding of RNA structure-function relationship. One of the main challenges in this field is the development of structure-prediction algorithms, which aim at the prediction of the three-dimensional (3D) native fold from the sole knowledge of the sequence. In a recent paper, we have introduced a scoring function for RNA structure prediction. Here, we analyze in detail the performance of the method, we underline strengths and shortcomings, and we discuss the results with respect to state-of-the-art techniques. These observations provide a starting point for improving current methodologies, thus paving the way to the advances of more accurate approaches for RNA 3D structure prediction

Kissing loop interaction in adenine riboswitch: insights from umbrella sampling simulations

Introduction: Riboswitches are cis-acting regulatory RNA elements prevalently located in the leader sequences of bacterial mRNA. An adenine sensing riboswitch cis-regulates adeninosine deaminase gene (add) in Vibrio vulnificus. The structural mechanism regulating its conformational changes upon ligand binding mostly remains to be elucidated. In this open framework it has been suggested that the ligand stabilizes the interaction of the distal "kissing loop" complex. Using accurate full-atom molecular dynamics with explicit solvent in combination with enhanced sampling techniques and advanced analysis methods it could be possible to provide a more detailed perspective on the formation of these tertiary contacts. Methods In this work, we used umbrella sampling simulations to study the thermodynamics of the kissing loop complex in the presence and in the absence of the cognate ligand. We enforced the breaking/formation of the loop-loop interaction restraining the distance between the two loops. We also assessed the convergence of the results by using two alternative initialization protocols. A structural analysis was performed using a novel approach to analyze base contacts. Results Contacts between the two loops were progressively lost when larger inter-loop distances were enforced. Inter-loop Watson-Crick contacts survived at larger separation when compared with non-canonical pairing and stacking interactions. Intra-loop stacking contacts remained formed upon loop undocking. Our simulations qualitatively indicated that the ligand could stabilize the kissing loop complex. We also compared with previously published simulation studies. Discussion and Conclusions Kissing complex stabilization given by the ligand was compatible with available experimental data. However, the dependence of its value on the initialization protocol of the umbrella sampling simulations posed some questions on the quantitative interpretation of the results and called for better converged enhanced sampling simulations

The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea.

PurposeDiarrhea is recognized as a common adverse event associated with tyrosine kinase inhibitors (TKIs), with those targeting the ErbB family of receptors being associated with the highest rate of diarrhea.MethodsThis paper reviews data on the incidence, timing, and duration of diarrhea associated with US Food and Drug Administration-approved ErbB family-targeted TKIs from the published literature, and sets forth recommendations for management.ResultsIn the absence of anti-diarrheal prophylaxis the incidence of any-grade diarrhea varies and typically occurs early during the course of treatment. Although it is difficult to determine if the incidence and severity of diarrhea is related to inhibition of a particular kinase target because of the multi-targeted and overlapping activity of many agents, evidence suggests that second-generation TKIs with broader target profiles (i.e., afatinib, lapatinib, neratinib) result in a higher incidence of diarrhea compared with highly specific first- (erlotinib, gefitinib) or third- (osimertinib) generation agents. The mechanisms responsible for TKI-associated diarrhea are not fully understood and are likely multi-factorial, involving dysregulated ion transport, inflammation, and mucosal injury. Management strategies have been developed-and continue to be refined-to prevent and reduce the severity and duration of TKI-associated diarrhea. For agents associated with more significant symptoms, anti-diarrheal prophylaxis reduces the incidence and severity of diarrhea, and ongoing studies are evaluating specific strategies to further reduce incidence and duration of TKI-associated diarrhea.ConclusionsContinued investigations into risk factors and pharmacogenomic markers for diarrhea may further improve management of this common toxicity

Free electron laser high gain equation and harmonic generation

The FEL integral equation is reviewed here and is studied under different contexts, accounting for diverse physical regimes. We include higher order harmonics and saturation effects, and explain the origin of scaling relations, widely exploited to describe either FEL dynamics or nonnlinear harmonic generation

Information-flux approach to multiple-spin dynamics

We introduce and formalize the concept of information flux in a many-body register as the influence that the dynamics of a specific element receive from any other element of the register. By quantifying the information flux in a protocol, we can design the most appropriate initial state of the system and, noticeably, the distribution of coupling strengths among the parts of the register itself. The intuitive nature of this tool and its flexibility, which allow for easily manageable numerical approaches when analytic expressions are not straightforward, are greatly useful in interacting many-body systems such as quantum spin chains. We illustrate the use of this concept in quantum cloning and quantum state transfer and we also sketch its extension to non-unitary dynamics.Comment: 7 pages, 4 figures, RevTeX

Quasi Exact Solution of the Fisher Equation

We propose an accurate non numerical solution of the Fisher Equation (FE), capable of reproducing the known analy- tical solutions and those obtained from a numerical analysis. The form we propose is based on educated guesses con- cerning the possibility of merging diffusive and logistic behavior into a single formul

Generalized bessel functions and their use in bremsstrahlung and multi-photon processes

The theory of Generalized Bessel Functions is reviewed and their application to various problems in the study of electro-magnetic processes is presented. We consider the cases of emission of bremsstrahlung radiation by ultra-relativistic electrons in linearly polarized undulators, including also exotic configurations, aimed at enhancing the harmonic content of the emitted radiation. The analysis is eventually extended to the generalization of the FEL pendulum equation to treat Free Electron Laser operating with multi-harmonic undulators. The paper aims at picking out those elements supporting the usefulness of the Generalized Bessel Functions in the elaboration of the theory underlying the study of the spectral properties of the bremsstrahlung radiation emitted by relativistic charges, along with the relevant flexibility in accounting for a large variety of apparently uncorrelated phenomenolgies, like multi-photon processes, including non linear Compton scattering

Pathway to a Compact SASE FEL Device

Newly developed high peak power lasers have opened the possibilities of driving coherent light sources operating with laser plasma accelerated beams and wave undulators. We speculate on the combination of these two concepts and show that the merging of the underlying technologies could lead to new and interesting possibilities to achieve truly compact, coherent radiator devices

Fluorescence Spectroscopy for the Diagnosis of Endometritis in the Mare

By exploiting the PMN property to produce high quantities of oxygen peroxide to neutralize pathogens, the oxygen peroxide content of uterine cells was measured to diagnose endometritis. After preliminary in vitro studies in which endometrial cells from slaughtered mares were mixed with leukocytes from peripheral blood, endometrial samples were collected by uterine flushing from mares before insemination. Staining endometrial cells with H2DCF-DA was combined with hydroethidine to normalize the fluorescence intensity with the cellular content of the sample. Stained cell smears were assumed as the gold standard of endometritis, and based on this assay, the samples were considered positive (C+) and negative (C-) for endometritis. The amount and the turbidity of fluid recovered by uterine flushing were significantly (p < 0.01) higher in C+ than in C-. Moreover, the oxygen peroxide content of the endometrial cells was significantly higher in the C+ than in the C- group (6.31 ± 1.92 vs. 3.12 ± 1.26, p = 0.001). Using the value of 4.4 as the cutoff level of this fluorescence cytology assay, it was found that only one C- sample exceeded the cutoff level (false positives = 7.7%) while three C+ samples showed values below the cutoff level (false negative = 11.5%)

Concordance of c-kit mutational status in matched primary and metastatic cutaneous canine mast cell tumors at baseline

BackgroundMutation analysis of proto-oncogene c-kit (c-kit) is advisable before starting treatment with tyrosine kinase inhibitors in dogs with mast cell tumor (MCT), including those with metastatic disease. Testing is usually performed on primary tumors, assuming that c-kit mutation status does not change in metastasis.Hypothesis/ObjectivesTo give an insight into the mutational processes and to make a recommendation on the use of c-kit mutational analysis in the clinical setting.AnimalsTwenty-one client-owned dogs with metastatic MCT.MethodsDogs undergoing resection or biopsy for both primary and matched metastatic MCT were prospectively enrolled. Total RNA or DNA was extracted from primary MCT and corresponding metastases. Exons 8, 9, and 11 were amplified by PCR and sequenced. Genetic features between primary MCT and metastases were compared. Their correlation with clinicopathologic features was investigated.ResultsConcordance (mutated or wild-type) of mutational status, evaluable in 21 primary and matched metastatic (20 nodal and 1 splenic) MCTs, was 100%. Three new c-kit mutations were identified. No significant correlation was detected between c-kit mutation and clinicopathologic features.Conclusions and Clinical ImportanceProto-oncogene c-kit mutational status is conserved between any primary and its matched secondary tumor, suggesting that both can be used for c-kit mutational testing. Targeted therapies might be also used to treat metastatic disease