A Distributed Approach for the Detection of Covert Attacks in Interconnected Systems with Stochastic Uncertainties

The design of a distributed architecture for the detection of covert attacks in interconnected Cyber-Physical Systems is addressed in this paper, in the presence of stochastic uncertainties. By exploiting communication between neighbors, the proposed scheme allows for the detection of covert attacks that are locally stealthy. The proposed methodology adopts a decentralized filter, jointly estimating the local state and the aggregate effect of the physical interconnections, and uses the communicated estimates to obtain an attack-sensitive residual. We derive some theoretical detection properties for the proposed architecture, and present numerical simulations

State Estimation Using a Network of Distributed Observers With Unknown Inputs

State estimation for a class of linear time-invariant systems with distributed output measurements (distributed sensors) and unknown inputs is addressed in this paper. The objective is to design a network of observers such that the state vector of the entire system can be estimated, while each observer has access to only local output measurements that may not be sufficient on their own to reconstruct the entire system’s state. Existing results in the literature on distributed state estimation assume either that the system does not have inputs, or that all the system’s inputs are globally known to all the observers. Accordingly, we address this gap by proposing a distributed observer capable of estimating the overall system’s state in the presence of inputs, while each observer only has limited local information on inputs and outputs. We provide a design method that guarantees convergence of the estimation errors to zero under joint detectability conditions. This design suits undirected communication graphs that may have switching topologies and also applies to strongly connected directed graphs.We also give existence conditions that are consistent with existing results on unknown input observers. Finally, simulation results verify the effectiveness of the proposed estimation scheme for various scenarios

Immunotherapeutic efficacy of retargeted ohsvs designed for propagation in an ad hoc cell line

Our laboratory has pursued the generation of cancer‐specific oncolytic herpes simplex viruses (oHSVs) which ensure high efficacy while maintaining a high safety profile. Their blueprint included retargeting to a Tumor‐Associated Antigen, e.g., HER2, coupled to detargeting from natural receptors to avoid off‐target and off‐tumor infections and preservation of the full complement of unmodified viral genes. These oHSVs are “fully virulent in their target cancer cells”. The 3rd generation retargeted oHSVs carry two distinct retargeting moieties, which enable infection of a producer cell line and of the target cancer cells, respectively. They can be propagated in an ad hoc Vero cell derivative at about tenfold higher yields than 1st generation recombinants, and more effectively replicate in human cancer cell lines. The R‐335 and R‐337 prototypes were armed with murine IL‐12. Intratumorally‐administered R‐337 conferred almost complete protection from LLC‐ 1‐HER2 primary tumors, unleashed the tumor microenvironment immunosuppression, synergized with the checkpoint blockade and conferred long‐term vaccination against distant challenge tumors. In summary, the problem intrinsic to the propagation of retargeted oHSVs—which strictly require cells positive for targeted receptors—was solved in 3rd generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen‐agnostic vaccines

Genotype of Immunologically Hot or Cold Tumors Determines the Antitumor Immune Response and Efficacy by Fully Virulent Retargeted oHSV

We report on the efficacy of the non-attenuated HER2-retargeted oHSV named R-337 against the immunologically hot CT26-HER2 tumor, and an insight into the basis of the immune protection. Preliminarily, we conducted an RNA immune profiling and immune cell content characterization of CT26-HER2 tumor in comparison to the immunologically cold LLC1-HER2 tumor. CT26-HER2 tumor was implanted into HER2-transgenic BALB/c mice. Hallmarks of R-337 effects were the protection from primary tumor, long-term adaptive vaccination directed to both HER2 and CT26-wt cell neoantigens. The latter effect differentiated R-337 from OncoVEXGM-CSF. As to the basis of the immune protection, R-337 orchestrated several changes to the tumor immune profile, which cumulatively reversed the immunosuppression typical of this tumor (graphical abstract). Thus, Ido1 (inhibitor of T cell anticancer immunity) levels and T regulatory cell infiltration were decreased; Cd40 and Cd27 co-immunostimulatory markers were increased; the IFNγ cascade was activated. Of note was the dampening of IFN-I response, which we attribute to the fact that R-337 is fully equipped with genes that contrast the host innate response. The IFN-I shut-down likely favored viral replication and the expression of the mIL-12 payload, which, in turn, boosted the antitumor response. The results call for a characterization of tumor immune markers to employ oncolytic herpesviruses more precisely

Earliest Porotic Hyperostosis on a 1.5-Million-year-old Hominin, olduvai gorge, Tanzania.

Meat-eating was an important factor affecting early hominin brain expansion, social organization and geographic movement. Stone tool butchery marks on ungulate fossils in several African archaeological assemblages demonstrate a significant level of carnivory by Pleistocene hominins, but the discovery at Olduvai Gorge of a child's pathological cranial fragments indicates that some hominins probably experienced scarcity of animal foods during various stages of their life histories. The child's parietal fragments, excavated from 1.5-million-year-old sediments, show porotic hyperostosis, a pathology associated with anemia. Nutritional deficiencies, including anemia, are most common at weaning, when children lose passive immunity received through their mothers' milk. Our results suggest, alternatively, that (1) the developmentally disruptive potential of weaning reached far beyond sedentary Holocene food-producing societies and into the early Pleistocene, or that (2) a hominin mother's meat-deficient diet negatively altered the nutritional content of her breast milk to the extent that her nursing child ultimately died from malnourishment. Either way, this discovery highlights that by at least 1.5 million years ago early human physiology was already adapted to a diet that included the regular consumption of meat

Fractal analysis of microCT images of the oviduct during the estrous cycle

It is well known that the oviduct plays a key role in several events deeply related with reproduction, such as sperm storage and capacitation, gametes interactions, fertilization and early embryo development, among others. To better understand some of the interactions and process occurring withing this organ, the study of its morphological modifications is of primordial importance. To that, we adopted a microtomografy (MicroTC) modelling system and the fractal analysis that allow to explore the 3D oviductal functional anatomy, by using eight swine oviducts at different stages of the estrous cycle. MicroCT datasets were acquired by using the high-resolution 3D-imaging system Skyscan 1172G (Bruker, Kontich – Belgium). CT images were analyzed using plugin on ImageJ software (NIH, Bethesda, MD), a box-counting method was applied to calculate the Fractal dimension of the oviduct. Focusing our attention on the utero-tubal junction (involved in sperm selection) and the isthmo-ampullar junction (the fertilization site). We found that by using PCA analysis it was possible to clearly differentiate the oviduct at different cycle stage on the basis of their values for: Db for grid, lacunarity for grid, R2 for Db, Media Db, lacunarity, σ for D for Db, Max for D, Min for D. Lacunarity, Media and Max for Db have a greater influence on the analysis. The results showed that 2 principal components were associated whit the morphological changes. This information, is obtained by a fast nondestructive method, and could be very useful because this innovative approach enables the achievement a 3D model and suggest that using fractal analysis techniques can aid to better understand the modifications of oviduct anatomy that depends on the neuroendocrine axis. This innovative approach could be a start point to design 3D cell culture systems, that could be applied in human and animal assisted reproductive techniques, improving the IVF outcomes

A surge in obsidian exploitation more than 1.2 million years ago at Simbiro III (Melka Kunture, Upper Awash, Ethiopia)

Pleistocene archaeology records the changing behaviour and capacities of early hominins. These behavioural changes, for example, to stone tools, are commonly linked to environmental constraints. It has been argued that, in earlier times, multiple activities of everyday life were all uniformly conducted at the same spot. The separation of focused activities across different localities, which indicates a degree of planning, according to this mindset characterizes later hominins since only 500,000 years ago. Simbiro III level C, in the upper Awash valley of Ethiopia, allows us to test this assumption in its assemblage of stone tools made only with obsidian, dated to more than 1.2 million years (Myr) old. Here we first reconstruct the palaeoenvironment, showing that the landscape was seasonally flooded. Following the deposition of an accumulation of obsidian cobbles by a meandering river, hominins began to exploit these in new ways, producing large tools with sharp cutting edges. We show through statistical analysis that this was a focused activity, that very standardized handaxes were produced and that this was a stone-tool workshop. We argue that at Simbiro III, hominins were doing much more than simply reacting to environmental changes; they were taking advantage of new opportunities, and developing new techniques and new skills according to them

Investigation on the Emission of Volatile Organic Compounds from Heated Vegetation and Their Potential to Cause an Accelerating Forest Fire

International audienceAn experimental study is conducted on the emission of volatile organic compounds (VOCs) emitted by Rosmarinus officinalis plants when exposed to an external radiant flux. The thermal radiation heats the plant and causes the emission of VOCs. The thermal radiation simulates the radiant flux received by vegetation in a forest fire. The results of the experiments are used in a simplified analysis to determine if the emissions of VOCs in an actual forest fire situation could produce a flammable gas mixture and potentially lead to the onset of an accelerating forest fire. The experiments consist of placing a plant in a hermetic enclosure and heating it with a radiant panel. The VOCs produced are collected and analyzed with an automatic thermal desorber coupled with a gas chromatograph/mass spectrometer (ATD-GC/MS). The effects of the fire intensity (radiant panel heat flux) and the fire retardant on the VOCs emission are then investigated. Two thresholds of the VOCs emission are observed. The first is for plant temperatures of around 120C and appears to be caused by the evaporation of the water in the plant, which carries with it a certain amount of VOCs. The second one is around 175C, which is due to the vaporization of the major parts of VOCs. The application of a fire retardant increases the emission of VOCs due to the presence of the water (80%) in the fire retardant. However, the use of the retardant results in a lower production of VOCs than using water alone. The measurements are used to estimate the concentration of VOCs potentially produced during the propagation of a specific fire and compared to the flammability limits of a-pinene. It is concluded that the quantities of VOCs emitted by Rosmarinus officinalis shrubs under certain fire conditions are capable of creating an accelerating forest fir

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye. MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively. CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes

Competences for democratic culture: An empirical study of an intercultural citizenship project in language pedagogy

This article reports on a pedagogical intervention in foreign language teaching in higher education. It analizes the competences developed by Argentinian and UK-based students as they used Skype to design a leaflet that addressed a real world issue: the Argentinian military dictatorship and its manipulation of the 1978 Football World Cup. The data consists of students’ discussions of this highly disturbing human rights issue. A first level of analysis focused on identifying evidence of competences using the Council of Europe’s conceptual model of ‘competences for democratic culture’ (2016). In a second level of analysis, the data was categorized within the framework of Article 2.2 of the United Nations Declaration on Human Rights Education and Training (2011). This research study provides an empirical test of these two frameworks in the field of language education, an aspect that has not been investigated before. It also contributes to our understanding of the potential of intercultural citizenship projects in achieving the goals of human rights education in foreign language teaching. Results indicate the development of substantial competences for democratic culture defined in the Council of Europe’s model