Explore the vast range of titles available.

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.

The early events related to intracellular GA-signals in aleurone are not clearly established. We demonstrate that GA treatment induced increases in phosphatidylinositol 4P, 5-kinase (PtdInsP-k), diacylglycerol kinase (DAG-k) and phosphatidate kinase (PA-k) activities in barley aleurone within 5 min. The response to GA was also observed as a rapid and transient InsPs/InsP^sub 3^ time-dependent accumulation. U73122, a phospholipase C (PLC) inhibitor, reduced the InsPs and InsP^sub 3^ levels and amylase secretion. The G protein activator Mas7 was able to trigger the α-amylase secretion as strongly as GA did; U73122, also reduced this effect. ABA evoked only an increase in phosphatidic acid (PtdOH) and diacylglycerol pyrophosphate (DGPP) levels. This is the first time that a rapid and transient response to GA in correlation with amylase secretion, involving PLC and G protein as well as PA-k activity in the GA signalling pathway, has been demonstrated in aleurone cells.[PUBLICATION ABSTRACT]

Phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) is the rate-controlling enzyme in gluconeogenesis. In diabetic individuals, altered rates of gluconeogenesis are responsible for increased hepatic glucose output and sustained hyperglycemia. Liver-specific inhibition of PEPCK has not been assessed to date as a treatment for diabetes. We have designed a therapeutic, vector-based RNAi approach to induce posttranscriptional gene silencing of hepatic PEPCK using nonviral gene delivery. A transient reduction of PEPCK enzymatic activity (7.6 +/- 0.6 vs 9.7 +/- 1.1 mU/mg, P < 0.05) that correlated with decreased protein content of up to 50% was achieved using this strategy in diabetic mice. PEPCK partial silencing was sufficient to demonstrate lowered blood glucose (218 +/- 26 vs 364 +/- 33 mg/dl, P < 0.001) and improved glucose tolerance together with decreased circulating FFA (0.89 +/- 0.10 vs 1.44 +/- 0.11 mEq/dl, P < 0.001) and TAG (65 +/- 11 vs 102 +/- 16 mg/dl, P < 0.01), in the absence of liver steatosis or lactic acidosis. SREBP1c was down-regulated in PEPCK-silenced animals, suggesting a role for this pathway in the alterations of lipid metabolism. These data reinforce the significance of PEPCK in sustaining diabetes-induced hyperglycemia and validate liver-specific intervention at the level of PEPCK for diabetes gene therapy.

Red light, acting through the phytochromes, controls numerous aspects of plant development. Many of the signal transduction elements downstream of the phytochromes have been identified in the aerial portions of the plant; however, very few elements in red-light signalling have been identified specifically for roots. Gene profiling studies using microarrays and quantitative Real-Time PCR were performed to characterize gene expression changes in roots of Arabidopsis seedlings exposed to 1 h of red light. Several factors acting downstream of phytochromes in red-light signalling in roots were identified. Some of the genes found to be differentially expressed in this study have already been characterized in the red-light-signalling pathway for whole plants. For example, PHYTOCHROME KINASE 1 (PKS1), LONG HYPOCOTYL 5 (HY5), EARLY FLOWERING 4 (ELF4), and GIGANTEA (GI) were all significantly up-regulated in roots of seedlings exposed to 1 h of red light. The up-regulation of SUPPRESSOR OF PHYTOCHROME A RESPONSES 1 (SPA1) and CONSTITUTIVE PHOTOMORPHOGENIC 1-like (COP1-like) genes suggests that the PHYA-mediated pathway was attenuated by red light. In addition, genes involved in lateral root and root hair formation, root plastid development, phenylpropanoid metabolism, and hormone signalling were also regulated by exposure to red light. Interestingly, members of the RPT2/NPH3 (ROOT PHOTOTROPIC 2/NON PHOTOTROPIC HYPOCOTYL 3) family, which have been shown to mediate blue-light-induced phototropism, were also differentially regulated in roots in red light. Therefore, these results suggest that red and blue light pathways interact in roots of seedlings and that many elements involved in red-light-signalling found in the aerial portions of the plant are differentially expressed in roots within 1 h of red light exposure.

No n'hi ha

Background Ukrainians numbering approximately 1.2 million are the largest migrant group in Poland. Data on vaccination coverage among migrants are not collected in EU, including Poland. Therefore, this qualitative study aimed to identify vaccination practices in this migrant group, to explore facilitators and barriers to vaccination and related access to Polish healthcare services. Methods In September 2019, a qualitative study of Ukrainian migrants (UMs) living in Szczecin, Poland, and recruited through a snowball sampling method, was conducted. Using a semi-structured topic guide, four focus groups were held with 22 UMs aged 18–45. Participants were asked about their attitudes towards vaccination in general with comparison between services in Poland and Ukraine. Following transcription and translation, a thematic analysis was conducted. Results Respondents were distrustful of Ukrainian vaccination policy, medical personnel and individual vaccines, however, they often returned to Ukraine for dental and gynaecological appoint-ments. While critical with regards to registering with Polish GPs practices, UMs were confident in health professionals, as well as vaccine delivery. Vaccines were perceived as safer and of better quality than in Ukraine. Difficulties in translating vaccination records were rarely reported, verbal communi-cation was not problematic due to language similarities. All UM parents reported vaccinating their children according to the Polish schedule. However, a significant number of adult UMs have not completed mandatory vaccinations, although they may have obtained false immunization certificates; according to UMs those can be obtained by bribing. Participants reported lower acceptance of the influenza vaccine, mainly due to perceptions around its importance; none had been vaccinated against influenza. None of UMs had heard of the HPV vaccine. UMs experienced challenges in accessing credible online vaccination information in Ukrainian, no official local health authority vaccination material existed either, except for information about measles. Conclusions This study pinpointed positive UM attitudes and practices regarding child vaccination in the Polish healthcare system and identified issues for improvement, such as adult vaccination. Health communication should be more tailored within UMs information delivery systems to enable migrants to make informed choices about vaccination. Further research is needed to better assess factors affecting vaccine uptake identified in this study.

One of the largest remnants of tropical dry forest is the South American Gran Chaco. A quarter of this biome is in Paraguay, but there have been few studies in the Paraguayan Chaco. The Gran Chaco flora is diverse in structure, function, composition and phenology. Fundamental ecological questions remain in this biome, such as what bioclimatic factors shape the Chaco’s composition, structure and phenology. In this study, we integrated forest inventories from permanent plots with monthly high-resolution NDVI from PlanetScope and historical climate data from WorldClim to identify bioclimatic predictors of forest structure, composition and phenology. We found that bioclimatic variables related to precipitation were correlated with stem density and Pielou evenness index, while temperature-related variables correlated with basal area. The best predictor of forest phenology (NDVI variation) was precipitation lagged by 1 month followed by temperature lagged by 2 months. In the period with most water stress, the phenological response correlates with diversity, height and basal area, showing links with dominance and tree size. Our results indicate that even if the ecology and function of Dry Chaco Forest is characterised by water limitation, temperature has a moderating effect by limiting growth and influencing leaf flush and deciduousness.

There is a growing awareness of the need to develop professional skills among university students, which is related to connecting learning to real life. In order to foster this connection, teachers may carry out activities that involve crossing boundaries, using theory in the practice of the professional context. This study presents a teaching experience consisting of a collaborative inquiry-based learning activity mediated by a WebQuest. Students analysed real digital literacy or digital inclusion projects implemented by local organisations to propose improvements by means of creating a digital educational product (a boundary object). This involved a change in context from the university environment to the socio-educational and professional setting. The aim of this study is to examine the students’ perception of this experience. For this purpose, a case study was conducted with a group of 39 first-year students of the bachelor’s degree in Social Education of the University of Barcelona. A questionnaire was administered and the responses were analysed from the perspective of Hermans’ Dialogical Self Theory and Star’s boundary objects. The results show that the students perceive the activity as a bridge between the two contexts, that they view this transition positively—albeit with certain limitations—and that they consider digital technology to have facilitated boundary crossing. In conclusion, we consider that the examined experience is useful in respect to closing the gap between academic and professional skills and contributes to the theoretical foundations for learning between contexts.