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To predict the health effects of accidental or therapeutic radiation exposure, one must estimate the radiation dose that person received. A well-known ionising radiation biomarker, phosphorylated [Formula: see text]-H2AX protein, is used to evaluate cell damage and is thus suitable for the dose estimation process. In this paper, we present new Bayesian methods that, in contrast to approaches where estimation is carried out at predetermined post-irradiation times, allow for uncertainty regarding the time since radiation exposure and, as a result, produce more precise results. We also use the Laplace approximation method, which drastically cuts down on the time needed to get results. Real data are used to illustrate the methods, and analyses indicate that the models might be a practical choice for the [Formula: see text]-H2AX biomarker dose estimation process.

The glycocalyx regulates the interaction of mammalian cells with extracellular molecules, such as cytokines. However, it is unknown to which extend the glycocalyx of distinct cancer cells control the binding and uptake of nanoparticles. In the present study, exome sequencing data of cancer patients and analysis of distinct melanoma and bladder cancer cell lines suggested differences in cancer cell-exposed glycocalyx components such as heparan sulphate. Our data indicate that glycocalyx differences affected the binding of cationic chitosan nanocapsules (Chi-NCs). The pronounced glycocalyx of bladder cancer cells enhanced the internalisation of nanoencapsulated capsaicin. Consequently, capsaicin induced apoptosis in the cancer cells, but not in the less glycosylated benign urothelial cells. Moreover, we measured counterion condensation on highly negatively charged heparan sulphate chains. Counterion condensation triggered a cooperative binding of Chi-NCs, characterised by a weak binding rate at low Chi-NC doses and a strongly increased binding rate at high Chi-NC concentrations. Our results indicate that the glycocalyx of tumour cells controls the binding and biological activity of nanoparticles. This has to be considered for the design of tumour cell directed nanocarriers to improve the delivery of cytotoxic drugs. Differential nanoparticle binding may also be useful to discriminate tumour cells from healthy cells.

Extreme wildfires have recently caused disastrous impacts in Australia and other regions of the world, including events with strong convective processes in their plumes (i.e., strong pyroconvection). Dangerous wildfire events such as these could potentially be influenced by anthropogenic climate change, however, there are large knowledge gaps on how these events might change in the future. The McArthur Forest Fire Danger Index (FFDI) is used to represent near-surface weather conditions and the Continuous Haines index (CH) is used here to represent lower to mid-tropospheric vertical atmospheric stability and humidity measures relevant to dangerous wildfires and pyroconvective processes. Projected changes in extreme measures of CH and FFDI are examined using a multi-method approach, including an ensemble of global climate models together with two ensembles of regional climate models. The projections show a clear trend towards more dangerous near-surface fire weather conditions for Australia based on the FFDI, as well as increased pyroconvection risk factors for some regions of southern Australia based on the CH. These results have implications for fields such as disaster risk reduction, climate adaptation, ecology, policy and planning, noting that improved knowledge on how climate change can influence extreme wildfires can help reduce future impacts of these events.

Vessel and perfusion densities may decrease before diabetic retinopathy appears; it is unknown whether these changes affect the contribution of vessel density to perfusion density. This was a non-experimental, comparative, prospective, cross-sectional study in non-diabetic subjects (group 1) and diabetics without retinopathy (group 2). Vessel and perfusion densities in the superficial capillary plexus were compared between groups at the center, inner, and full regions and by field (superior, temporal, inferior, nasal) using optical coherence tomography angiography. Coefficients of determination (R2) between vessel and perfusion densities were calculated to find the contribution of larger retinal vessels to perfusion density. Percent differences were used to evaluate the contribution of these vessels to perfusion density in a regression model. There were 62 participants, 31 eyes by group; vessel and perfusion densities as well as the coefficients of determination between them were lower in group 2, especially in the nasal field (R2 0.85 vs. 0.71), which showed a higher contribution of larger retinal vessels to perfusion density. The regression model adjusted to a quadratic equation. In diabetics without retinopathy the contribution of vessel density to perfusion density may decrease; a low vessel density may increase the contribution of larger retinal vessels to perfusion density.

Beyond the regulation of cardiovascular function, baroreceptor afferents play polymodal roles in health and disease. Sepsis is a life-threatening condition characterized by systemic inflammation (SI) and hemodynamic dysfunction. We hypothesized that baroreceptor denervation worsens lipopolysaccharide (LPS) induced-hemodynamic collapse and SI in conscious rats. We combined: (a) hemodynamic and thermoregulatory recordings after LPS administration at a septic-like non-lethal dose (b) analysis of the cardiovascular complexity, (c) evaluation of vascular function in mesenteric resistance vessels, and (d) measurements of inflammatory cytokines (plasma and spleen). LPS-induced drop in blood pressure was higher in sino-aortic denervated (SAD) rats. LPS-induced hemodynamic collapse was associated with SAD-dependent autonomic disbalance. LPS-induced vascular dysfunction was not affected by SAD. Surprisingly, SAD blunted LPS-induced surges of plasma and spleen cytokines. These data indicate that baroreceptor afferents are key to alleviate LPS-induced hemodynamic collapse, affecting the autonomic control of cardiovascular function, without affecting resistance blood vessels. Moreover, baroreflex modulation of the LPS-induced SI and hemodynamic collapse are not dependent of each other given that baroreceptor denervation worsened hypotension and reduced SI.

In this paper, we report our investigations on analogues of the anti-human immunodeficiency virus type 1 (HIV-1) integrase (IN) aptamer T30175 in which the individual thymidines forming the loops were replaced by 5-hydroxymethyl-2′-deoxyuridine residues (H). Circular dichroism, nuclear magnetic resonance and gel electrophoresis investigations clearly indicated that all the modified aptamers preserve the ability to form the original 5′-5′ end-stacked head-to-head dimeric G-quadruplex structure, in which each G-quadruplex adopts a parallel arrangement and is characterized by three G-tetrads, three propeller loops and one bulge-loop. All the modified aptamers were tested in an IN inhibition LEDGF-independent assay. While the modified aptamers INTB-H13 and INTB-H17 showed IC50 values comparable with that of the parent aptamer (INTB-nat), analogues INTB-H2, INTB-H5 and, to a lesser extent, INTB-H9 showed a higher ability to inhibit the HIV IN than the unmodified aptamer. Molecular modelling studies evaluating the aptamer/HIV IN interaction highlighted the ability of the modified thymidines to establish several contacts with the target protein. All the data point to the importance of loops in the aptamer/target interaction and suggest that the site-specific replacement of loop residues with commercially available analogues can be considered a straightforward strategy to improve the biological activities of several G-quadruplex aptamers.

In the last decades the EU has made substantial efforts implementing conservation strategies to halt biodiversity loss. However, little improvement has been reported. Given the proximity of the 2020 landmark set by the EU Biodiversity Strategy and the Convention for Biological Diversity, alternatives to reduce this conservation gap and prospect future strategies must be assessed urgently. Here, we explore how the current Natura 2000 could be used to enhance management of terrestrial and freshwater threatened vertebrates. We identified Natura 2000 sites to increase the coverage of threatened species as target species under two alternative scenarios: a policy-driven approach including only threatened vertebrates listed in the Directives; and a conservation-driven approach, including all the remaining threatened vertebrates. We show that representation of threatened vertebrates in Natura 2000 could be improved by updating lists of target species in less than 1% and 3% of sites in the policy-driven and conservation-driven scenarios, respectively. We highlight the strength of Natura 2000, with sites that complement each other and could contribute to achieving more ambitious conservation targets under future strategies. Prioritisation exercises like this could help realise the potential of this network and enhance the management of threatened species and improve current gaps.

Photocoagulation may still be a therapeutic choice for center-sparing diabetic macular edema. We compared the visual evolution after photocoagulation, in eyes with focal diabetic macular edema, stratified per the location of thickening with optical coherence tomography. We evaluated people with type 2 diabetes and focal diabetic macular edema, before and three weeks after focal photocoagulation. We divided the sample by edema location: central (group1); paracentral (group 2) and pericentral (group 3) and compared the proportions of eyes with baseline visual impairment, visual improvement, and visual deterioration between groups; central edema was evaluated with logistic regression, as an explaining variable of baseline visual impairment and visual improvement. The study included 160 eyes: 77 in group 1, 20 in group 2, 63 in group 3; baseline visual impairment was more frequent in groups 1 and 2 (52.6%) than in group 3 (28.6%, p = 0.002, OR 2.77) and as common in groups 1 (51.9%) and 2 (55.0%, p = 0.8). The proportions of visual improvement and visual deterioration did not differ between groups (p > 0.05). The outcome after focal photocoagulation was similar in paracentral (considered center-sparing) and central macular edema; the definition of center involvement, which needs intravitreal antiangiogenics, should expand to include paracentral thickening.

Spectral analysis of heart rate (HR) has been widely used to assess the autonomic cardiovascular control. A nonlinear approach, known as symbolic analysis, has been reported to be very useful to assess the autonomic control of cardiovascular system in humans, but very few studies reported on the differences between these two approaches on experimental models. Two distinct approaches were used to elicit autonomic changes in conscious Wistar rats: (1) pharmacological blockade of cardiac autonomic receptors with atenolol (ATE, N = 9) or methylatropine (ATR, N = 9) and (2) mild changes in arterial pressure (AP) induced by phenylephrine (PHE, N = 9) or sodium nitroprusside (NPS, N = 9). Series of cardiac interval (CI) and systolic AP (SAP) were assessed using spectral analysis and symbolic dynamics. Results show that, for spectral analysis, the power in high frequency band of CI and the power in low frequency band of SAP are the most reliable indices of vagal and sympathetic modulation, respectively. For symbolic analysis, results point 0V% and 1V% to be related to sympathetic and 2UV% to vagal modulation. Interestingly, the incidence of 1V patterns, hitherto with unknown meaning, was revealed the best index of sympathetic modulation in the rat and should be accounted for in the future studies.

Cancer cell motility is one of the major events involved in metastatic process. Tumor cells that disseminate from a primary tumor can migrate into the vascular system and, being carried by the bloodstream, transmigrate across the endothelium, giving rise to a new tumor site. However, during the invasive process, tumor cells must pass through the extracellular matrix, whose structural and mechanical properties define the parameters of the migration process. Here, we propose 3D-complex cage-like microstructures, realized by two-photon (TP) direct laser writing (DLW), to analyze cell migration through pores significantly smaller than the cell nucleus. We found that the ability to traverse differently sized pores depends on the metastatic potential and on the invasiveness of the cell lines, allowing to establish a pore-area threshold value able to discriminate between non-tumorigenic and tumorigenic human breast cells.

We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.

We examined the local adaptation patterns in a system comprising several interconnected heterogeneous plant populations from which populations of two phylogenetically closely related pathogens were also sampled. The host is Hordeum vulgare (cultivated barley); the pathogens are Pyrenophora teres f. teres (net form) and Pyrenophora teres f. maculata (spot form), the causal agents of barley net blotch. We integrated two approaches, the comparison between the population structures of the host and the pathogens and a cross-inoculation test. We demonstrated that two closely related pathogens with very similar niche specialisation and life-styles can give rise to different co-evolutionary outcomes on the same host. Indeed, we detected local adaptation for the net form of the pathogen but not for the spot form. We also provided evidence that an a-priori well-known resistance quantitative-trait-locus on barley chromosome 6H is involved in the co-evolutionary ‘arms race’ between the plant and the net-form pathogen. Moreover, data suggested latitudinal clines of host resistance and that different ecological conditions can result in differential selective pressures at different sites. Our data are of interest for on-farm conservation of plant genetic resources, as also in establishing efficient breeding programs and strategies for deployment of resistance genes of P. teres.

Altered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi-drug resistant phenotype. Changes in three major pathways were involved in this transition to a multidrug resistance phenotype: ER, Death Receptor and epithelial to mesenchymal transition (EMT). Resistant cells exhibited altered ER signaling, resulting in decreased ER target gene expression. The death receptor pathway was significantly altered, blocking extrinsic apoptosis and increasing NF-kappaB survival signaling. TNF resistance promoted EMT changes, resulting in a more aggressive phenotype. This first report identifying specific mechanisms underlying acquired resistance to TNF could lead to a better understanding of the progression of breast cancer in response to chemotherapy treatment.