Targeting viral entry as a strategy for broad-spectrum antivirals

The process of entry into a host cell is a key step in the life cycle of most viruses. In recent years, there has been a significant increase in our understanding of the routes and mechanisms of entry for a number of these viruses. This has led to the development of novel broad-spectrum antiviral approaches that target host cell proteins and pathways, in addition to strategies focused on individual viruses or virus families. Here we consider a number of these approaches and their broad-spectrum potential

On the geometric P=W conjecture

We formulate the geometric P=W conjecture for singular character varieties. We establish it for compact Riemann surfaces of genus one, and obtain partial results in arbitrary genus. To this end, we employ non-Archimedean, birational and degeneration techniques to study the topology of the dual boundary complex of certain character varieties. We also clarify the relation between the geometric and the cohomological P=W conjectures

Effectiveness of Tuned Mass Damper in Reducing Damage Caused by Strong Earthquake in a Medium-Rise Building

A case study where a tuned mass damper (TMD) was installed at the top of a five-story reinforced concrete (RC) building is presented. The aim of the study was to investigate the effectiveness of the TMD in changing the structural behavior of medium-rise existing buildings from dissipative to non-dissipative in order to eliminate reparation or demolition costs resulting from damages caused by strong earthquakes. The TMD mass is made by a RC slab lying on flat surface sliders. Horizontal stiffness and damping of the TMD are both provided by lead rubber isolators in the first proposed solution and by low-damping rubber isolators and viscous linear dampers, respectively, in the second. The improvement in the building’s structural behavior attained with the installation of the TMD was assessed by considering the flexural demand over capacity ratios of structural elements and the energy dissipated by the TMD. These results are compared with those of the same building retrofitted with a base isolation system. In both of the proposed solutions, TMD remarkably changed the modal behavior of the considered building, improved the flexural verifications, and dissipated most of the input seismic energy. It is therefore demonstrated that a TMD is a valid solution for the retrofit of medium-rise existing buildings

Pathogenesis of dengue: subversion of innate immunity

Dengue viruses (DENV) are mosquito-borne flaviviruses that cause a severe febrile illness, and sometimes a potentially lethal syndrome called dengue haemorrhagic fever (DHF). Despite decades of effort, the global resurgence of dengue is testament to the inadequacy of current control measures. Dengue has become an immense international public health concern: WHO estimates that there are 50-100 million dengue infections and 500,000 cases of DHF hospitalised each year. Thus dengue has a major economic impact in the developing world through loss of healthy life and utilisation of constrained health resources. Global dengue control is likely to require a combined approach based on the development of successful strategies for immunization and antiviral drugs, as well as vector control. Better understanding of DENV pathogenesis presents new opportunities for design of rationally attenuated vaccine candidates and antiviral therapies. This thesis focuses on understanding a critical step in DENV pathogenesis: evasion of human innate immune responses mediated by interferon. A lentiviral vector system was developed to express dengue non-structural (NS) proteins in human cells, and we used this to show that expression of dengue NS5 alone inhibited IFN-α, but not IFN-γ, signalling. The IFN-α signalling cascade is blocked downstream of Tyk2 phosphorylation: NS5 binds to the transcription factor STAT2 and inhibits its phosphorylation. The polymerase domain of NS5 is sufficient to block IFN-α induced signal transduction, and inhibition does not require NS5 nuclear translocation. We finally tested several hypotheses to explain why STAT2 degradation occurs in both DENV-infected and replicon-containing cells, but not when NS5 is expressed alone. The most important conclusion from this work is that DENV NS5 is a potent and specific type I IFN antagonist. The results of this study are an important step in defining the molecular pathogenesis of dengue, and provide clues to potential new approaches to combat this disease

The Nef Protein of the Macrophage Tropic HIV-1 Strain AD8 Counteracts Human BST-2/Tetherin

Bone Marrow Stromal Cell Antigen 2 (BST-2)/tetherin inhibits the release of numerous enveloped viruses by physically tethering nascent particles to infected cells during the process of viral budding from the cell surface. Tetherin also restricts human immunodeficiency virus (HIV), and pandemic main (M) group HIV type 1s (HIV-1s) are thought to rely exclusively on their Vpu proteins to overcome tetherin-mediated restriction of virus release. However, at least one M group HIV-1 strain, the macrophage-tropic primary AD8 isolate, is unable to express Vpu due to a mutation in its translation initiation codon. Here, using primary monocyte-derived macrophages (MDMs), we show that AD8 Nef protein can compensate for the absence of Vpu and restore virus release to wild type levels. We demonstrate that HIV-1 AD8 Nef reduces endogenous cell surface tetherin levels, physically separating it from the site of viral budding, thus preventing HIV retention. Mechanistically, AD8 Nef enhances internalisation of the long isoform of human tetherin, leading to perinuclear accumulation of the restriction factor. Finally, we show that Nef proteins from other HIV strains also display varying degrees of tetherin antagonism. Overall, we show that M group HIV-1s can use an accessory protein other than Vpu to antagonise human tetherin

Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed

Brain oscillatory patterns in mild cognitive impairment due to Alzheimer's and Parkinson's disease: An exploratory high-density EEG study

Objective: We investigated brain cortical activity alterations, using a resting-state 256-channel high-density EEG (hd-EEG), in Alzheimer's (AD) and Parkinson's (PD) disease subjects with mild cognitive impairment (MCI) and correlations between quantitative spectral EEG parameters and the global cognitive status assessed by Montreal Cognitive Assessment (MoCA) score. Methods: Fifteen AD-MCI, eleven PD-MCI and ten age-matched healthy-controls (HC) underwent hd-EEG recordings and neuropsychological assessment. Cerebrospinal fluid biomarker analysis was performed to obtain well-characterized groups. EEG spectral features were extracted and the differences between the three groups, as well as correlations with MoCA, were investigated. Results: The results showed significantly lower alpha2 power and alpha2/alpha1 ratio in both AD-MCI and PD-MCI compared to controls. The significantly higher theta and lower beta power and alpha/theta ratio were observed in PD-MCI compared to AD-MCI and HC. MoCA score correlated inversely with theta power and directly with alpha2 and beta powers, as well as with alpha2/alpha1 and alpha/theta ratios. Conclusions: This study highlighted significant differences in EEG patterns in AD-MCI and PD-MCI patients and remarked the role of EEG parameters as possible surrogate markers of cognitive status in both neurodegenerative diseases. Significance: In addition to well-established biomarkers, our findings could support early detection of cognitive dysfunction in neurodegenerative disorders and could help to monitor disease progression and therapeutic responses

Floristic composition of weeds in different winter and summer covers.

The usage of cover crops is an adopted cultural measure that shows positive effects when associated with the no-till system and weed management. During the cycle of the plants there might be competition within them for water, solar radiation and nutrients and effects of allelopathic substances released by leaching, volatilization and/or root exudation in the environment might also coexist. The study aimed to quantify the floristic composition of weed species in an cultivated area with cover crops during winter and summer, for two years, 2011/12 and 2012/13, in an experimental area of UFSM, Campus of Frederico Westphalen ? RS state, Brazil. The treatments consisted of Italian ryegrass, wild radish, black oat, vetch, wheat and uncultivated, in winter, and, sorghum, sunflower, black velvet bean, dwarf velvet bean, gray velvet bean and green velvet bean in the summer. In the first year of the experiment, a diversity of weeds in winter was observed, especially occuring Stellaria media and Bowlesia incana. In summer, the weeds of higher importance were Ipomoea spp. and Bidens spp., both of utter importance in agricultural systems. Winter cover crops of wild radish and Italian ryegrass and summer cover crops of sorghum and sunflower provided a lower weed infestatio

Evaluation of Fresh Groundwater Lens Volume and Its Possible Use in Nauru Island

A proper management of fresh groundwater lenses in small islands is required in order to avoid or at least limit uncontrolled saltwater intrusion and guarantee the availability of the resource even during drought occurrences. An accurate estimation of the freshwater volume stored in the subsoil is a key step in the water management decision process. This study focused on understanding the hydrogeological system behaviour and on assessing the sustainable use of the groundwater resource in Nauru Atoll Island (Pacific Ocean). A first phase, concerning the hydrogeological characterization of the island, highlighted the occurrence of few drought-resilient freshwater lenses along the seashore. The second part of the study focused on the characterization of a freshwater lens found in the northern coastal area and identified such area as the most suitable for the development of groundwater infrastructures for water withdrawal. The characterization activities allowed quantifying the freshwater lens thickness and volume in order to assess the capability to satisfy the population water demand. A geo-electrical tomography survey was carried out, and a 3D density-dependent numerical model was implemented in SEAWAT. The model results demonstrated that in small islands freshwater can unexpectedly accumulate underground right along the seashore and not in the centre of the island as is commonly believed. Furthermore, the model can constitute a useful tool to manage the groundwater resources and would allow the design of sustainable groundwater exploitation systems, avoiding saltwater intrusion worsening

Ethical issues associated with in-hospital emergency from the medical emergency team's perspective: a national survey

Medical Emergency Teams (METs) are frequently involved in ethical issues associated to in-hospital emergencies, like decisions about end-of-life care and intensive care unit (ICU) admission. MET involvement offers both advantages and disadvantages, especially when an immediate decision must be made. We performed a survey among Italian intensivists/anesthesiologists evaluating MET's perspective on the most relevant ethical aspects faced in daily practice