Population genetic structure of the South American species Hypochaeris lutea (Asteraceae)

The genus Hypochaeris has a recent evolutionary history caused by long‐distance dispersal in conjunction with adaptive radiation in the South American continent. Hypochaeris lutea is a perennial herb that grows mostly at altitudes of around 1000 m in cold swamps of the southern regions of Brazil. We investigated the amplified fragment length polymorphism (AFLP) in 270 individuals representing 11 Brazilian populations of H. lutea to elucidate the population genetic structure of this species. The frequencies of polymorphic loci and gene diversity ranged from 83.42% to 91.66% and from 0.26 to 0.34, respectively. Analysis of molecular variance revealed that most of the genetic variability was found within (76.67%) rather than among (23.3%) populations, agreeing with the pattern of genetic distribution within and among populations observed in other allogamous species of Hypochaeris. A Mantel test showed no correlation between genetic and geographic distances when all populations were considered. Simulations performed using a Bayesian approach consistently identified two clusters with different admixture proportions of individuals, as also revealed by a UPGMA dendrogram of populations. The pattern of genetic structure observed in H. lutea is consistent with a process of successive colonization events by long‐distance dispersal resembling the rapid and recent radiation that has been proposed to explain the origin of the South American species of Hypochaeris.     

Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect

Context: Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy.

Objective: To compare the anti-tumor efficacy of different PPIs in vitro and in vivo.

Materials and methods: In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice.

Results: Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation.

Discussion: These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole.

Conclusion: The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.     

Rootstock-induced physiological and biochemical mechanisms of drought tolerance in sweet orange

The poorly understood physiological and biochemical drought responses induced in sweet orange by citrus rootstocks of contrasting drought tolerance were investigated during a drought/rewatering cycle under controlled conditions. Long-term exposure of the grafted trees to a gradually increasing water deficit and subsequent recovery revealed distinct strategies of drought acclimation that were induced by the different rootstocks. Trees grafted onto the drought-tolerant rootstock ‘Cravo’ rangpur lime were less water conservative, exhibiting an increased cell-wall elasticity that contributes to turgor maintenance and its related processes of growth and photosynthesis over a wider range of soil–water potentials. On the other hand, the drought-tolerant ‘Sunki Tropical’ mandarin and drought-sensitive ‘Flying Dragon’ trifoliate orange rootstocks induced a water conservation strategy by increasing tissue rigidity under drought. ‘Sunki Tropical’ was also able to induce osmotic adjustment, conferring thereby a more efficient water conservation strategy than ‘Flying Dragon’ by allowing for turgor maintenance at lower soil–water potentials while attenuating cell dehydration and shrinkage. In contrast to ‘Cravo’ and ‘Sunki Tropical’, trees grafted onto ‘Flying Dragon’ exhibited a significant photoinhibition of the photosystem II reaction centers, as well as an increased H₂O₂ production and lipid peroxidation under drought treatment. A significantly higher activity of the antioxidant enzyme GPX was also observed in drought stressed trees grafted onto ‘Flying Dragon’. Collectively, these results support the involvement of elastic and osmotic adjustments, as well as the control of oxidative stress, as functional leaf traits associated with the rootstock-induced drought tolerance in sweet orange.     

Decomposition and stabilisation of Norway spruce needle-derived material in Alpine soils using a <Superscript>13</Superscript>C-labelling approach in the field

Only scarce information is available on how organic C is incorporated into the soil during the decay and how (micro) climate influences this process. Therefore, we investigated the effect of exposure and elevation on the organic litter decomposition and C-stabilisation in acidic soils of an Alpine environment. An experiment with artificially ¹³C labelled Norway spruce needles was carried out at north- and south-exposed sites between 1200 and 2400 m a.s.l. in the Italian Alps using mesocosms. After 1 year, the ¹³C recoveries of the bulk soil were 18.6% at the north-facing slopes and 31.5% at the south-facing slopes. A density fractionation into a light (LF; ≤1.6 g cm^?3) and a heavy fraction (HF; >1.6 g cm^?3) of the soil helped to identify how the applied substrate was stabilised. At the northern slope, 10.5% of the substrate was recovered in the LF and 8.1% in the HF and at the south-facing slope 22.8% in the LF and 8.1% in the HF. The overall ¹³C recovery was higher at the south-facing sites due to restricted water availability. Although the climate is humid in the whole area, soil moisture availability becomes more important at south-facing sites due to higher evapotranspiration. However, at sites >1700 m a.s.l, the situation changed, as the northern slope had higher recovery rates. At such altitudes, temperature effects are more dominant. This highlights the importance of locally strongly varying edaphic factors when investigating the carbon cycle.     

The Severity of Visceral Leishmaniasis Correlates with Elevated Levels of Serum IL-6, IL-27 and sCD14

Background

Visceral leishmaniasis (VL) is a severe disease caused by infection with protozoa of the genus Leishmania. Classic VL is characterized by a systemic infection of phagocytic cells and an intense activation of the inflammatory response. It is unclear why 90% of infected individuals do not develop the disease while a minority develop the classical form. Furthermore, among those that develop disease, a small group progresses to more severe form that is unresponsive to treatment. The presence of inflammatory mediators in serum could theoretically help to control the infection. However, there is also a release of anti-inflammatory mediators that could interfere with the control of parasite multiplication. In this study, we took advantage of the spectrum of outcomes to test the hypothesis that the immune profile of individuals infected with Leishmania (L.) infantum is associated with the development and severity of disease.

Methodology/Principal Findings

Sera from patients with confirmed diagnosis of VL were evaluated for the presence of numerous molecules, and levels compared with healthy control and asymptomatic infected individuals.

Conclusions/Principal Findings

Although differences were not observed in LPS levels, higher levels of sCD14 were detected in VL patients. Our data suggest that L. infantum may activate the inflammatory response via CD14, stimulating a generalized inflammatory response with production of several cytokines and soluble molecules, including IFN-γ, IL-27, IL-10, IL-6 and sCD14. These molecules were strongly associated with hepatosplenomegaly, neutropenia and thrombocytopenia. We also observed that IL-6 levels greater than 200 pg/ml were strongly associated with death. Together our data reinforce the close relationship of IFN-γ, IL-10, IL-6, TNF-α and IL-27 in the immune dynamics of VL and suggest the direct participation of sCD14 in the activation of the immune response against L. infantum.     

Volatile Constituents of the Aerial Parts of Pulicaria sicula (L.) Moris Growing Wild in Sicily: Chemotaxonomic Volatile Markers of the Genus Pulicaria Gaertn.

The chemical composition of the essential oil isolated from the aerial parts of Pulicaria sicula (L.) Moris was characterized by GC‐FID and GC/MS analyses. The oil was particularly rich in oxygenated terpenoids. Among the oxygenated monoterpenes (content of 44.5%), the most abundant were borneol (23.7%), bornyl acetate (6.5%), and isothymol isobutyrate (6.2%). Caryophyllene oxide (10.2%), caryophylladienol I (4.3%), and caryophylla‐3,8(13)‐dien‐5β‐ol (4.4%) were identified as the main constituents among the oxygenated sesquiterpenes. Furthermore, a complete literature review on the composition of the essential oils of all the Pulicaria taxa studied so far was performed and a principal component analysis (PCA) was carried out.     

Effect of Moringa oleifera flower extract on larval trypsin and acetylcholinesterase activities in Aedes aegypti

Aedes aegypti control is crucial to reducing dengue fever. Aedes aegypti larvae have developed resistance to organophosporous insecticides and the use of natural larvicides may help manage larval resistance by increasing elements in insecticide rotation programs. Here, we report on larvicidal activity of Moringa oleifera flower extract against A. aegypti L(1), L(2), L(3), and L(4) as well as the effect of flower extract on gut trypsin and whole-larval acetylcholinesterase from L(4.) In addition, the heated flower extract was investigated for larvicidal activity against L(4) and effect on larval gut trypsin. Moringa oleifera flower extract contains a proteinaceous trypsin inhibitor (M. oleifera flower trypsin inhibitor, MoFTI), triterpene (β-amyrin), sterol (β-sitosterol) as well as flavonoids (kaempferol and quercetin). Larvicidal activity was detected against L(2), L(3), and L(4) (LC(50) of 1.72%, 1.67%, and 0.92%, respectively). Flower extract inhibited L(4) gut trypsin (MoFTI K(i) = 0.6 nM) and did not affect acetylcholinesterase activity. In vivo assay showed that gut trypsin activity from L(4) treated with M. oleifera flower extract decreased over time (0-1,440 min) and was strongly inhibited (98.6%) after 310 min incubation; acetylcholinesterase activity was not affected. Thermal treatment resulted in a loss of trypsin inhibitor and larvicidal activities, supporting the hypothesis that flower extract contains a proteinaceous trypsin inhibitor that may be responsible for the deleterious effects on larval mortality.     

Therapeutic efficacy of ipilimumab,an anti-CTLA-4 monoclonal antibody,in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases

The management of unresectable metastatic melanoma is a major clinical challenge because of the lack of reliably effective systemic therapies. Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has recently been proposed as a strategy to enhance cell-mediated immune responses to cancer, and clinical trials have demonstrated that anti-CTLA-4 therapy can produce durable outcomes with different response patterns than cytotoxic chemotherapy. We enrolled eight out of 155 patients with advanced melanoma in a multicentre phase II trial that evaluated the activity and tolerability of ipilimumab, a fully human, anti-CTLA-4 monoclonal antibody (; NCT00289627; CA184-008). Here we report our experience with three of these patients, who experienced progressive disease after a variety of previous therapies, including prior immunotherapies, and who achieved good outcomes with ipilimumab. One patient had a partial response ongoing at 17+ months on ipilimumab despite failure with four prior therapies, and the other two patients showed durable stable disease, both still ongoing at 17+ and 20+ months, respectively. The patient achieving a partial response experienced no side effects while receiving ipilimumab. The other two patients developed immune-related adverse events (irAEs) including rash (one case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the histopathology of colon biopsy samples from both was suggestive of colitis, with an abundant CD8+ T-cell infiltrate. Nausea, vomiting and acute pancreatitis were also observed in one patient. In addition, immunohistochemical findings of a dense CD8+, TIA1+ and granzyme B+ lymphoid infiltrate within a biopsied lesion provide indirect evidence of functional T-cell activation induced by treatment. These case reports highlight the potential for anti-CTLA-4-based therapy in previously treated patients with advanced melanoma. Moreover, because the patterns of response to ipilimumab differ from chemotherapy, we need to understand how and when patients may respond to treatment so that appropriate clinical decisions can be made.