Diet Modification and Metformin Have a Beneficial Effect in a Fly Model of Obesity and Mucormycosis

In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients. Female Wt-type Drosophila flies were fed regular (RF) or high-fat diet (HFD; 30% coconut oil) food with or without metformin for 48 h and then injected with R. oryzae. Survival rates, glucose and triglyceride levels were compared between 1) normal-weight flies (RF), 2) obese flies (HFD), 3) obese flies fed with RF, 4) flies continuously on HFD + metformin, 5) flies fed on HFD + metformin, then transferred to RF, and 6) obese flies administered metformin after infection. Glucose levels were compared across groups of non-infected flies and across groups of infected flies. Survival was significantly decreased (P = 0.003) in obese flies, while post-infection glucose levels were significantly increased (P = 0.0001), compared to normal-weight flies. Diet and administration of metformin led to weight loss, normalized glucose levels during infection, and were associated with decreased mortality and tissue fungal burden. In conclusion, diet and metformin help control infection-associated hyperglycemia and improve survival in Drosophila flies with mucormycosis. Fly models of obesity bear intriguing similarities to the pathophysiology of insulin resistance and diabetes in humans, and can provide new insights into the pathogenesis and treatment of infections in obese and diabetic patients.     

Molecular tools that block maturation of the nuclear lamin A and decelerate cancer cell migration

Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post-translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis.     

Candidemia in Adults at a Tertiary Hospital in China: Clinical Characteristics,Species Distribution,Resistance, and Outcomes

Background

Candidemia is one of the most common nosocomial bloodstream infections. Early diagnosis and antifungal treatment improve clinical outcomes in some studies but not all, with diverse data reported from different institutions. Similarly, antifungal resistance is more common in the USA than in Europe, but there is little data regarding the microbiology and clinical course of candidemia in adult patients in Asia.

Aims

(1) To capture species distribution and drug resistance rates among Candida bloodstream isolates, (2) to describe clinical features of candidemia, and (3) to identify factors associated with all-cause mortality, with emphasis on early initiation of antifungal treatment, at a large tertiary University Hospital in China.

Methods

In this single-center retrospective study, we identified all patients with candidemia, between 2008 and 2014. Demographic and clinical characteristics, microbiological information, details of antifungal therapy and clinical outcomes were collected.

Results

We studied 166 patients. 71 (42.8%) had cancer. Candida albicans was the most frequent species (37.3%), followed by C. parapsilosis (24.1%), C. tropicalis (22.8%), and C. glabrata (14.5%). Antifungal resistance was more frequent in non-albicans strains and especially C. glabrata. Twenty patients received inappropriate treatment with all-cause mortality of 35%. The remaining 146 patients had significantly lower mortality (21.9%, P?=?0.045). Among patients who received antifungal treatment, mortality rate increased with time to appropriate antifungal therapy (AAT): 13.7%, for?<?24 h, 21.1% for 24–48 h, 23.1% for?>?48 h, and 32.4% among patients who received no AT (χ² for trend P?=?0.039). Initiating AAT more than 24 h after blood culture collection was an independent risk factor for mortality, after adjustment for other confounders (OR 7.1, 95% CI 1.3–39.4, P?=?0.024).

Conclusions

Candida albicans was the most frequent cause of candidemia at a large tertiary hospital in China, but antifungal resistance is a growing concern among non-albicans Candida species. The mortality rate of patients treated with ineffective antifungal agents based on in vitro susceptibilities was similar to that of patients who received no treatment at all, and delayed initiation of antifungal treatment was associated with increased risk of death.

     

State of art and limitations in genetic engineering to induce stable chondrogenic phenotype

Current protocols for chondrocyte expansion and chondrogenic differentiation of stem cells fail to reduce phenotypic loss and to mitigate hypertrophic tendency. To this end, cell genetic manipulation is gaining pace as a means of generating cells with stable chondrocyte phenotype. Herein, we provide an overview of candidate genes that either induce cartilage regeneration or inhibit cartilage degeneration. We further discuss in vitro, ex vivo and in vivo viral transduction and non-viral transfection strategies for targeted cells (chondrocytes, mesenchymal stem cells, induced pluripotent stem cells and synovial cells), along with the most representative results obtained in pre-clinical models and in clinical trials. We highlight current challenges and associated risks that slowdown clinical acceptance and commercialisation of gene transfer technologies.     

Using an ecosystem model linked to GCM-derived local weather scenarios to analyse effects of climate change and elevated CO2 on dry matter production and partitioning, and water use in temperate managed grasslands

Local effects of climate change (CC) and elevated CO₂ (2 × CO₂, 660 μmol mol^–1) on managed temperate grasslands were assessed by forcing a dynamic ecosystem model with weather scenarios. The aims of the study were to compare the relative importance of individual and combined effects of CC, 2 × CO₂, and photosynthetic acclimation, and to assess the importance of local site conditions. The model was driven by hourly means for temperature (T), precipitation (P), global radiation (G), vapour pressure (VP), and wind speed (U). Local climate scenarios were derived by statistical downscaling techniques from a 2 × CO₂ simulation with the General Circulation Model of the Canadian Climate Centre (CCC-GCMII). Simulations over 14 growing seasons to account for year-to-year variability of climate were carried out for a low, relatively dry site, and a high, more humid site. At both sites, shoot dry matter responded positively to 2 × CO₂ with the site at low elevation being more sensitive than the higher site. The effect of assumed changes in climate was negative at the lower, but positive at the higher site. Shoot dry matter was more sensitive to the effects of 2 × CO₂ than to CC. Both effects combined increased shoot dry matter by up to 20%. This was attributed to direct effects of 2 × CO₂ and increased T, and indirect stimulation via increased soil N availability. Biomass partitioning to roots increased with 2 × CO₂ but decreased with CC, while an intermediate response resulted from the combination. Leaf area index (LAI) increased under 2 × CO₂, but not enough to compensate fully for a decrease in leaf conductance. Under the 2 × CO₂ scenario evapotranspiration (ET) decreased, but increased under CC. Photosynthetic acclimation reduced the effect of 2 × CO₂ on shoot growth, but had little effect on ET. The seasonal water use efficiency (WUE) was improved under 2 × CO₂, and reduced under CC. With the combination of both factors, the change was small but still positive, especially at the high elevation site with more favourable soil water conditions. This reflects the stronger positive yield response in combination with a smaller increase in ET under cooler, more humid conditions. The results for the combination of factors suggest that except for shoot growth, effects of 2 × CO₂ and CC tend to offset each other. While CC determines the sign of the ET response, the sign of the biomass response is determined by 2 × CO₂. The results highlight the importance of a site-specific analysis of ecosystem responses by using a flexible approach based on a combination of state-of-the-art downscaling, spatially resolved data sets, and a mechanistic model to obtain quantitative and reproducible assessments of climate change impacts at the ecosystem level.     

Local nitric oxide levels reflect the degree of allergic airway inflammation after segmental allergen challenge in asthmatics.

Nitric oxide (NO) levels are increased in the exhaled air of asthmatics. As NO levels correlate with allergic airway inflammation, NO measurement has been suggested for disease monitoring. In patients with asthma, we previously demonstrated that intrabronchial treatment with a natural porcine surfactant enhanced airway inflammation after segmental allergen provocation. We studied whether local levels of NO reflect the degree of allergic airway inflammation following segmental allergen challenge with or without surfactant pretreatment. Segmental NO, as well as nitrite and nitrate in bronchoalveolar lavage (BAL) fluid, was measured before and after segmental challenge with either saline, saline plus allergen, or surfactant plus allergen in 16 patients with asthma and five healthy subjects. The data were compared with inflammatory BAL cells. Segmental NO levels were increased after instillation of saline (p < 0.05), or surfactant plus allergen in asthmatics (p < 0.05), and values were higher after surfactant plus allergen compared to saline challenge. Nitrate BAL levels were not altered after saline challenge but increased after allergen challenge (p < 0.05) and further raised by surfactant (p < 0.05), whereas nitrite levels were not altered by any treatment. Segmental NO and nitrate levels correlated with the degree of eosinophilic airway inflammation, and nitrate levels also correlated with neutrophil and lymphocyte numbers in BAL. In healthy subjects, NO, nitrite, and nitrate were unaffected. Thus, segmental NO and nitrate levels reflect the degree of allergic airway inflammation in patients with asthma. Measurement of both markers can be useful in studies using segmental allergen provocation, to assess local effects of potential immunomodulators.     

Oil for Fish: An Energy Return on Investment Analysis of Selected European Union Fishing Fleets

World food production has increased substantially in the past century, thanks mostly to the increase in the use of oil as input in the production processes. This growing use of fossil fuels has negative effects, both on the environment and the production costs. Fishing is a fuel consuming food production activity, and its energy efficiency performance has worsened over time. World‐wide fisheries are also suffering from overexploitation, which contributes to the poor efficiency performance, adding more pressure and criticism on this economic activity. In this paper we analyzed the energy efficiency performance of more than 20,000 European Union (EU) fishing vessels for the period 2002–2008, using the edible energy return on investment (EROI) indicator. The vessels analyzed, grouped in 49 different fleets, represented 25% of the vessels and 33% of the landings of the EU fishing sector. These EU fishing fleets’ average EROI for 2008 was 0.11, which translates to an energy content of the fuel burned that is 9 times greater than the edible energy content of the catch. Hence, the significance of this study arises from the use of time‐series data on a relevant part of the EU fleet that showed stable or even slight improvements on the EROI over time. Moreover, results showed that the energy efficiency of the different fleets varied significantly (from 0.02 to 1.12), mainly depending on the fishing gear and the vessel length. The performance of the most efficient fleets, such as large pelagic trawlers and seiners, was comparable to many agricultural production activities. The plausible drivers behind these trends are further considered.