Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene ...(GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood-brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
The determinants of food choice Leng, Gareth; Adan, Roger A H; Belot, Michele ...
Proceedings of the Nutrition Society,
08/2017, Letnik:
76, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Health nudge interventions to steer people into healthier lifestyles are increasingly applied by governments worldwide, and it is natural to look to such approaches to improve health by altering what ...people choose to eat. However, to produce policy recommendations that are likely to be effective, we need to be able to make valid predictions about the consequences of proposed interventions, and for this, we need a better understanding of the determinants of food choice. These determinants include dietary components (e.g. highly palatable foods and alcohol), but also diverse cultural and social pressures, cognitive-affective factors (perceived stress, health attitude, anxiety and depression), and familial, genetic and epigenetic influences on personality characteristics. In addition, our choices are influenced by an array of physiological mechanisms, including signals to the brain from the gastrointestinal tract and adipose tissue, which affect not only our hunger and satiety but also our motivation to eat particular nutrients, and the reward we experience from eating. Thus, to develop the evidence base necessary for effective policies, we need to build bridges across different levels of knowledge and understanding. This requires experimental models that can fill in the gaps in our understanding that are needed to inform policy, translational models that connect mechanistic understanding from laboratory studies to the real life human condition, and formal models that encapsulate scientific knowledge from diverse disciplines, and which embed understanding in a way that enables policy-relevant predictions to be made. Here we review recent developments in these areas.
For the first time, we report a femtosecond mode-locked Erbium-doped fiber laser (EDFL) by using mechanically exfoliated graphite deposited onto a D-shaped optical fiber. The exfoliated graphite ...flakes were deposited onto a stacked polyvinyl alcohol/polymethyl methacrylate thick layers, and then transferred directly to the polished surface of the D-shaped optical fiber. The characterization of the exfoliated graphite sample was performed by using optical microscope and Raman spectroscopy. By measuring its polarization performance, polarization relative extinction ratio about 5.30 dB (70%) was obtained, which resulted in the broadest bandwidth of 21 nm and the shortest pulse duration of 220 fs generation as saturable absorber (SA) into an EDFL cavity. For our knowledge, these are the best mode-locking performances ever reported in the literature for all-fiber-based graphite SA in EDFL.
Acute lymphoblastic leukemia (ALL) is the first neoplasm where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has proven to be a fundamental tool to guide ...therapeutic choices. The most standardized methods to study MRD in ALL are multi-parametric flow cytometry (MFC) and polymerase chain reaction (PCR) amplification-based methods. Emerging technologies hold the promise to improve MRD detection in ALL patients. Moreover, novel therapies, such as monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T cells (CART) represent exciting advancements in the management of B-cell precursor (BCP)-ALL.
Through a review of the literature and
data, we analyze the current status of MRD assessment in ALL to better understand how some of its limitations could be overcome by emerging molecular technologies. Furthermore, we highlight the future role of MRD monitoring in the context of personalized protocols, taking into account the genetic complexity in ALL.
Molecular rearrangements (gene fusions and immunoglobulin and T-cell receptor-IG/TR gene rearrangements) are widely used as targets to detect residual leukemic cells in ALL patients. The advent of novel techniques, namely next generation flow cytometry (NGF), digital-droplet-PCR (ddPCR), and next generation sequencing (NGS) appear important tools to evaluate MRD in ALL, since they have the potential to overcome the limitations of standard approaches. It is likely that in the forthcoming future these techniques will be incorporated in clinical trials, at least at decisional time points. Finally, the advent of new powerful compounds is further increasing MRD negativity rates, with benefits in long-term survival and a potential reduction of therapy-related toxicities. However, the prognostic relevance in the setting of novel immunotherapies still needs to be evaluated.
Continuous veno-venous hemodialysis with high cut-off membranes (HCO-CVVHD) removes inflammatory mediators involved in organ dysfunction during sepsis. The aim of the present study was to assess the ...variations in SOFA score and identify early predictors of short-term mortality in a cohort of patients with septic shock, treated with HCO-CVVHD for acute kidney injury (AKI).
An observational prospective multicenter cohort study was conducted in four mixed medical-surgical ICUs. Thirty-eight patients with septic shock and AKI (KDIGO stage≥1) treated with HCO-CVVHD have been included in this study. Patients were divided into Survivors and non-Survivors according to mortality observed at 72nd hr of treatment. The variation of SOFA scores and clinical/biochemical parameters were described over time for the entire population and specifically for Survivors and non-Survivors. Similarly, circulating inflammatory mediators (as IL-6, TNF-a and IL-10) were described over time. A logistic regression analysis was used to identify the baseline clinical and biochemical parameters associated with 72 hrs-ICU mortality.
Overall, the mean SOFA score was 12±3 at baseline, 10.9±3 at 6hrs, 9.8±3 at 12hrs, 8.9±3.3 at 24 hrs, and 8±3.5 at 48 hrs after HCO-CVVHD initiation; and 6.5±2.7 at 24 hrs and 6.6±3 at 48 hrs after HCO-CVVHD discontinuation. In the multivariate regression analysis, baseline serum lactate levels and AKI stage independently correlated with short-term mortality during HCO-CVVHD. A significant reduction was observed in circulating levels of TNFα and IL-6 among Survivors.
SOFA score significantly decreased early after initiation of HCO-CVVHD in patients with septic AKI. Baseline lactate levels and the AKI stage resulted to be associated to 72 hrs-ICU-mortality.
Overfishing is one of the main impacts on the marine environment and multiple-use Marine Protected Areas (MPAs) could be a useful tool to conserve biodiversity and promote sustainable resource ...exploitation. However, ensuring a high level of protection on the ground is a difficult task. This work contributes to the analysis of the causes at the root of MPAs' ineffectiveness by examining the management of Paracentrotus lividus fishery in an Italian MPA, employing a multidisciplinary approach built on biological and socio-economic competences. This sea urchin species has a determinant ecological role in structuring infralittoral benthic assemblages and is the most exploited echinoid in Europe. From 2010 to 2018, underwater sampling was conducted over 39 monitoring sites to define P. lividus spatial and temporal trends. Declared catches and semi-structured interviews with local stakeholders were used to define the socio-economical context, underline existing conflicts among them, as well as to trace the historical evolution of sea urchin fishery. The results show that the management of sea urchin fishery is not sustainable, primarily because of the stakeholders’ non-compliance with the rules. P. lividus stock is progressively declining (−73% in 9 years), showing no difference between MPA (0.5 ± 0.15 ind./m2) and control sites (0.3 ± 0.04 ind./m2). Moreover, fishermen dominate the social arena while scientists, civil society and local press have little relevance. Additionally, the untruthfulness of catch declarations was proved, the IUU fishery is relevant and the black market is hiding the actual economic value. This work offers management solutions that may be useful in other areas that show similar compliance issues.
•Multidisciplinary research is key in examining fishery sustainability in an MPA.•Regulatory capture and coordination issues limit the institutions' effectiveness.•IUU fishing and the black market hide the real economic value of sea urchin fishery.•Stock decreased by 73% in 9 years and unreported catches compelled its management.•Short and long-term actions with feedback controls can fix compliance gaps.
Marine reserves are assumed to protect a wide range of species from deleterious effects stemming from exploitation. However, some species, due to their ecological characteristics, may not respond ...positively to protection. Very little is known about the effects of life history and ecological traits (e.g., mobility, growth, and habitat) on responses of fish species to marine reserves. Using 40 data sets from 12 European marine reserves, we show that there is significant variation in the response of different species of fish to protection and that this heterogeneity can be explained, in part, by differences in their traits. Densities of targeted size-classes of commercial species were greater in protected than unprotected areas. This effect of protection increased as the maximum body size of the targeted species increased, and it was greater for species that were not obligate schoolers. However, contrary to previous theoretical findings, even mobile species with wide home ranges benefited from protection: the effect of protection was at least as strong for mobile species as it was for sedentary ones. Noncommercial bycatch and unexploited species rarely responded to protection, and when they did (in the case of unexploited bentho-pelagic species), they exhibited the opposite response: their densities were lower inside reserves. The use of marine reserves for marine conservation and fisheries management implies that they should ensure protection for a wide range of species with different life-history and ecological traits. Our results suggest this is not the case, and instead that effects vary with economic value, body size, habitat, depth range, and schooling behavior.
•Schistosomiasis is more common in individuals with leprosy than their household contacts.•Vitamin D deficiency is more common in those with leprosy than community controls.•Children with leprosy ...have the highest burden of concomitant schistosomiasis.•Thus, comorbidities may contribute to ongoing reservoirs of infection.
Evidence suggests that biological mechanisms involved in helminth infections and vitamin deficiencies increase susceptibility to other infections. The aim of this study was to investigate the associations of helminth co-infection and select micronutrient deficiencies with leprosy using a case–control design.
From 2016 to 2018, individuals aged ≥3 years were recruited at clinics in and around Governador Valadares, Minas Gerais, Brazil in three groups: cases of leprosy, household contacts and community-matched (non-contact) controls. Helminths were diagnosed through stool Kato Katz examination and serum reactivity to anti-soluble adult worm antigen preparation IgG4. Serum ferritin, 25-OH vitamin D and retinol concentrations were measured. Multi-variate logistic regression was conducted to identify associations with active leprosy.
Seventy-nine cases of leprosy, 96 household contacts and 81 non-contact controls were recruited; 48.1% of participants were male with a median age of 40 years. Helminths were found in 7.1% of participants on Kato Katz test, all but one of which were Schistosoma mansoni, and 32.3% of participants were positive for S. mansoni serology. On multi-variate analysis, cases were more likely to be infected with helminths (diagnosed by stool) than household contacts adjusted odds ratio (aOR) 8.69, 95% confidence interval (CI) 1.50–50.51. Vitamin D deficiency was common, and was more likely in cases compared with non-contact controls (aOR 4.66, 95% CI 1.42,–15.33). Iron deficiency was not associated with leprosy, and vitamin A deficiency was not detected.
These associations suggest that the immune consequences of schistosomiasis and vitamin D deficiency may increase the risk of active leprosy. Comorbid conditions of poverty deserve further study as addressing co-infections and nutritional deficiencies could be incorporated into programmes to improve leprosy control.
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•Bedaquiline was successfully encapsulated in different nanoemulsion-based nanocarriers.•High encapsulation efficiency and in vitro activity comparable to the free drug were ...observed.•No cytotoxicity was observed at nanocarrier concentrations needed to kill the bacteria.•Preliminary microscopy results showed a close interaction of carriers with bacteria surface.•Results open the way for a future safer employment of bedaquiline against M. tuberculosis.
In the last years, the increase in antimicrobial resistance, together with a lack of new drugs for the treatment of bacterial infections resistant to classical antibiotics are of growing concern. Moreover, some of current therapies induce severe side effects and are often difficult to administer. In 2012 the FDA approved the use of bedaquiline, as the first new very effective drug against TB in the last 40 years. Despite its effectiveness, unfortunately bedaquiline side effects can be so dangerous that at present it is to be prescribed only when no other treatment options are available. The development of effective and safe nanotechnology-based methods can be particularly relevant to increase antimicrobial concentration at the site of infection, to reduce doses in the general circulation, which in turn reduces adverse effects. In this work bedaquiline was encapsulated in two types of nanocarriers, lipid nanoparticles and chitosan-based nanocapsules with high encapsulation efficiency and drug loading values. The efficacy of the drug-encapsulating nanocarriers has been demonstrated in vitro against Mycobacterium tuberculosis, together with the excellent compatibility of both carriers with animal cells. The obtained results open the way for further studies on multi-drug resistant strains of M. tuberculosis and for in vivo studies of the optimized nanocarriers. The promising behaviour of drug-loaded nanocarriers will hopefully lead to a reduction of the administered doses of a quite dangerous drug as bedaquiline, tuning its biodistribution and so decreasing its adverse effects, finally allowing its use in a higher number of patients.
In this work, we present a detailed experimental study of pulse formation mechanism in an EDFL, hybridly mode-locked by use of a CVD monolayer graphene onto a D-shaped optical fiber and nonlinear ...polarization rotation (NPR), under a large intracavity dispersion influence (up to 100 times) ranging from 12.3 to 1382 m cavity lengths. Analyzing the spectral evolution, temporal and soliton behaviors of the pulse, our results revealed the presence of four laser operating regimes with non-soliton and soliton formation from short to ultralong cavity lengths, all related to graphene/NPR nonlinearities, dispersion and soliton propagation influences.
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