Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Cold sintering of diatomaceous earth

Diatomite, a natural silicate-based sedimentary rock, was densified by cold sintering at room temperature and 150°C under various pressures (100, 200, and 300 MPa) and using different NaOH water solutions (0–3 M). The relative density of cold sintered diatomite can be as high as 90%, a condition that can be achieved by conventional firing only at 1200–1300°C. The cold sintered materials maintain the same mineralogical composition of the starting powder (quartz, glass, and illite) and are constituted by well-deformed and flattened grains oriented orthogonally to the applied pressure. Conversely, an evident phase evolution takes place upon conventional firing with the formation of cristobalite and mullite. The bending strength of cold sintered artifacts can exceed 40 MPa and increases to ≈80 MPa after post-annealing at 800°C, such mechanical strength is much larger than that of conventionally pressed samples sintered at 800°C, which is only ≈1 MPa.     

A bacterial colony growth algorithm for mobile robot localization

Achieving robot autonomy is a fundamental objective in Mobile Robotics. However in order to realize this goal, a robot must be aware of its location within an environment. Therefore, the localization problem (i.e.,the problem of determining robot pose relative to a map of its environment) must be addressed. This paper proposes a new biology-inspired approach to this problem. It takes advantage of models of species reproduction to provide a suitable framework for maintaining the multi-hypothesis. In addition, various strategies to track robot pose are proposed and investigated through statistical comparisons. The Bacterial Colony Growth Algorithm (BCGA) provides two different levels of modeling: a background level that carries on the multi-hypothesis and a foreground level that identifies the best hypotheses according to an exchangeable strategy. Experiments, carried out on the robot ATRV-Jr manufactured by iRobot, show the effectiveness of the proposed BCGA.

Design and control of an IPMC wormlike robot.

This paper presents an innovative wormlike robot controlled by cellular neural networks (CNNs) and made of an ionic polymer-metal composite (IPMC) self-actuated skeleton. The IPMC actuators, from which it is made of, are new materials that behave similarly to biological muscles. The idea that inspired the work is the possibility of using IPMCs to design autonomous moving structures. CNNs have already demonstrated their powerfulness as new structures for bio-inspired locomotion generation and control. The control scheme for the proposed IPMC moving structure is based on CNNs. The wormlike robot is totally made of IPMCs, and each actuator has to carry its own weight. All the actuators are connected together without using any other additional part, thereby constituting the robot structure itself. Worm locomotion is performed by bending the actuators sequentially from "tail" to "head," imitating the traveling wave observed in real-world undulatory locomotion. The activation signals are generated by a CNN. In the authors' opinion, the proposed strategy represents a promising solution in the field of autonomous and light structures that are capable of reconfiguring and moving in line with spatial-temporal dynamics generated by CNNs.     

A covert attention P300-based brain-computer interface: Geospell

The Farwell and Donchin P300 speller interface is one of the most widely used brain-computer interface (BCI) paradigms for writing text. Recent studies have shown that the recognition accuracy of the P300 speller decreases significantly when eye movement is impaired. This report introduces the GeoSpell interface (Geometric Speller), which implements a stimulation framework for a P300-based BCI that has been optimised for operation in covert visual attention. We compared the Geospell with the P300 speller interface under overt attention conditions with regard to effectiveness, efficiency and user satisfaction. Ten healthy subjects participated in the study. The performance of the GeoSpell interface in covert attention was comparable with that of the P300 speller in overt attention. As expected, the effectiveness of the spelling decreased with the new interface in covert attention. The NASA task load index (TLX) for workload assessment did not differ significantly between the two modalities. PRACTITIONER SUMMARY: This study introduces and evaluates a gaze-independent, P300-based brain-computer interface, the efficacy and user satisfaction of which were comparable with those off the classical P300 speller. Despite a decrease in effectiveness due to the use of covert attention, the performance of the GeoSpell far exceeded the threshold of accuracy with regard to effective spelling.     

Diffusive Behavior of Bedform-Induced Hyporheic Exchange in Rivers

Solute transport in natural streams is a complex phenomenon that involves both in-stream dispersion and mass exchange with the porous zones surrounding the water body. Due to the complex nature of the riverine systems several models may be used to simulate and analyze the transport of solutes with different degrees of complexity. The bedform-induced hyporheic transport is a stream-subsurface exchange mechanism that can be reproduced in controlled systems, such as laboratory flumes. Application of a simple Fickian diffusion model to laboratory data obtained with passive solutes and stationary bedforms proves successful within a range of durations of the contamination process. A dimensionless form of the diffusion coefficient, scaled with dynamic, physical, and geometric properties of the system is derived by comparison with another physically based model. A prediction of the dimensionless diffusion coefficient is obtained as a function of the timescale of the exchange process and is validated with a few sets of results from laboratory tests.     

The use of EEG modifications due to motor imagery for brain-computer interfaces

The opening of a communication channel between brain and computer [brain-computer interface (BCI)] is possible by using changes in electroencephalogram (EEG) power spectra related to the imagination of movements. In this paper, we present results obtained by recording EEG during an upper limb motor imagery task in a total of 18 subjects by using low-resolution surface Laplacian, different linear and quadratic classifiers, as well as a variable number of scalp electrodes, from 2 to 26. The results (variable correct classification rate of mental imagery between 75% and 95%) suggest that it is possible to recognize quite reliably ongoing mental movement imagery for BCI applications.     

Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients

Background: Pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is still ascribed to a minority of patients. A pathway based-approach could highlight the predictive role of germline single nucleotide polymorphisms (SNPs). The primary aim of this study was to define new predictive biomarkers considering treatment specificities. Secondary aim was to determine new potential predictive biomarkers independent from radiotherapy (RT) dosage and cotreatment with oxaliplatin. Methods: Thirty germ-line SNPs in twenty-one genes were selected according to a pathway-based approach. Genetic analyses were performed on 280 LARC patients who underwent fluoropyrimidine-based CRT. The potential predictive role of these SNPs in determining pathological tumor response was tested in Group 1 (94 patients undergoing also oxaliplatin), Group 2 (73 patients treated with high RT dosage), Group 3 (113 patients treated with standard RT dosage), and in the pooled population (280 patients). Results: Nine new predictive biomarkers were identified in the three groups. The most promising one was rs3136228-MSH6 (p = 0.004) arising from Group 3. In the pooled population, rs1801133-MTHFR showed only a trend (p = 0.073). Conclusion: This exploratory study highlighted new potential predictive biomarkers of neoadjuvant CRT and underlined the importance to strictly define treatment peculiarities in pharmacogenetic analyses.     

Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation

Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using Human MicroRNA Card A followed by real-time PCR validations. In addition, to assess the discriminative power of selected miRNAs, we implemented a machine learning analysis. MiRNA profiling and validations revealed that miR-140-3p, 150-5p, 210-3p, 451a, and 487a-3p were significantly upregulated in MVP, while miR-223-3p, 323a-3p, 340-5p, and 361-5p were significantly downregulated in MVP compared to CTRL (p ≤ 0.01). Functional analysis identified several biological processes possible linked to MVP. In addition, machine learning analysis correctly classified MVP patients from CTRL with high accuracy (0.93) and an area under the receiving operator characteristic curve (AUC) of 0.97. To the best of our knowledge, this is the first study performed on human plasma, showing a strong association between miRNAs and MVP. Thus, a circulating molecular signature could be used as a first-line, fast, and cheap screening tool for MVP identification.     

Gene regulatory networks reconstruction from time series datasets using genetic programming: a comparison between tree-based and graph-based approaches

Genetic programming researchers have shown a growing interest in the study of gene regulatory networks in the last few years. Our team has also contributed to the field, by defining two systems for the automatic reverse engineering of gene regulatory networks called GRNGen and GeNet. In this paper, we revise this work by describing in detail the two approaches and empirically comparing them. The results we report, and in particular the fact that GeNet can be used on large networks while GRNGen cannot, encourage us to pursue the study of GeNet in the future. We conclude the paper by discussing the main research directions that we are planning to investigate to improve GeNet.