50 research outputs found
Social Learning and Networking : How multiple actors can learn through joint analysis, dialogue and co-creation
We are facing complex societal problems such as climate change, human conflict, poverty and inequality, and need innovative solutions. Multi-stakeholder processes (MSPs) are more and more seen as a critical way of coming to such innovative solutions. It is thought that when multiple stakeholders are able to meet, share experiences, learn together and contribute to decisions, new and innovative ways of dealing with problems are found and turned into action. Still, much remains to be understood about the role and effectiveness of social learning in multi-stakeholder settings. This report summarizes the deliberations of the seminar âSocial learning and networking: How multiple actors can learn through joint analysis, dialogue and co-creationâ, which was held in Wageningen on 16 September 2010
Targeted Chromatin Capture (T2C): A novel high resolution high throughput method to detect genomic interactions and regulatory elements.
Background: Significant efforts have recently been put into the investigation of the spatial organization and the chromatin-interaction networks of genomes. Chromosome conformation capture (3C) technology and its derivatives are important tools used in this effort. However, many of these have limitations, such as being limited to one viewpoint, expensive with moderate to low resolution, and/or requiring a large sequencing effort. Techniques like Hi-C provide a genome-wide analysis. However, it requires massive sequencing effort with considerable costs. Here we describe a new technique termed Targeted Chromatin Capture (T2C), to interrogate large selected regions of the genome. T2C provides an unbiased view of the spatial organization of selected loci at superior resolution (single restriction fragment resolution, from 2 to 6 kbp) at much lower costs than Hi-C due to the lower sequencing effort. Results: We applied T2C on well-known model regions, the mouse ÎČ-globin locus and the human H19/IGF2 locus. In both cases we identified all known chromatin interactions. Furthermore, we compared the human H19/IGF2 locus data obtained from different chromatin conformation capturing methods with T2C data. We observed the same compartmentalization of the locus, but at a much higher resolution (single restriction fragments vs. the common 40 kbp bins) and higher coverage. Moreover, we compared the ÎČ-globin locus in two different biological samples (mouse primary erythroid cells and mouse fetal brain), where it is either actively transcribed or not, to identify possible transcriptional dependent interactions. We identified the known interactions in the ÎČ-globin locus and the same topological domains in both mouse primary erythroid cells and in mouse fetal brain with the latter having fewer interactions probably due to the inactivity of the locus. Furthermore, we show that interactions due to the important chromatin proteins, Ldb1 and Ctcf, in both tissues can be analyzed easily to reveal their role on transcriptional interactions and genome folding. Conclusions: T2C is an efficient, easy, and affordable with high (restriction fragment) resolution tool to address both genome compartmentalization and chromatin-interaction networks for specific genomic regions at high resolution for both clinical and non-clinical research
High frequency of Polio-like Enterovirus C strains with differential clustering of CVA-13 and EV-C99 subgenotypes in a cohort of Malawian children
Enteroviruses (EVs) are among the most commonly detected viruses infecting humans worldwide. Although the prevalence of EVs is widely studied, the status of EV prevalence in sub-Saharan Africa remains largely unknown. The objective of our present study was therefore to increase our knowledge on EV circulation in sub-Saharan Africa. We obtained 749 fecal samples from a cross-sectional study conducted on Malawian children aged 6 to 60 months. We tested the samples for the presence of EVs using real time PCR, and typed the positive samples based on partial viral protein 1 (VP1) sequences. A large proportion of th
Low hepatitis B surface antigen and HBV DNA levels predict response to the addition of pegylated interferon to entecavir in hepatitis B e antigen positive chronic hepatitis B
Background: Various treatment combinations of peginterferon (PEGâIFN) and
nucleos(t)ide analogues have been evaluated for chronic hepatitis B (CHB), but the
optimal regimen remains unclear.
Aims: To study whether PEGâIFN addâon increases response compared to entecavir
(ETV) monotherapy, and whether the duration of ETV pretreatment influences
response.
Methods: Response was evaluated in HBeAg positive patients previously treated in
two randomized controlled trials. Patients received ETV pretreatment for at least
24 weeks and were then allocated to 24â48 weeks of ETV+PEGâIFN addâon, or
continued ETV monotherapy. Response was defined as HBeAg loss combined with
HBV DNA <200 IU/mL 48 weeks after discontinuing PEGâIFN.
Results: Of 234 patients, 118 were assigned PEGâIFN addâon and 116 continued
ETV monotherapy. Response was observed in 38/118 (33%) patients treated with
addâon therapy and in 23/116 (20%) with monotherapy (P = 0.03). The highest
response to addâon therapy compared to monotherapy was observed in PEGâIFN
naive patients with HBsAg levels below 4000 IU/mL and HBV DNA levels below
50 IU/mL at randomization (70% vs 34%; P = 0.01). Above the cutâoff levels,
response was low and not significantly different between treatment groups. Duration of ETV pretreatment was associated with HBsAg and HBV DNA levels (both
P < 0.005), but not with response (P = 0.82).
Conclusions: PEGâIFN addâon to ETV therapy was associated with higher response
compared to ETV monotherapy in patients with HBeAg positive CHB. Response
doubled in PEGâIFN naive patients with HBsAg below 4000 IU/mL and HBV DNA
below 50 IU/mL, and therefore identifies them as the best candidates for PEGâIFN
addâon (Identifiers: NCT00877760, NCT01532843)
High frequency and diversity of parechovirus A in a cohort of Malawian children
Parechoviruses (PeVs) are highly prevalent viruses worldwide. Over the last decades, several studies have been published
on PeV epidemiology in Europe, Asia and North America, while information on other continents is lacking. The aim of this
study was to describe PeV circulation in a cohort of children in Malawi, Africa. A total of 749 stool samples obtained from
Malawian children aged 6 to 60 months were tested for the presence of PeV by real-time PCR. We performed typing by
phylogenetic and Basic Local Alignment Search Tool (BLAST) analysis. PeV was found in 57% of stool samples. Age was
signifcantly associated with PeV positivity (p = 0.01). Typing by phylogenetic analysis resulted in 15 diferent types, while
BLAST typing resulted in 14 diferent types and several indeterminate strains. In total, six strains showed inconsistencies
in typing between the two methods. One strain, P02-4058, remained untypable by all methods, but appeared to belong to
the recently reclassifed PeV-A19 genotype. PeV-A1, -A2 and -A3 were the most prevalent types (26.8%, 13.8% and 9.8%,
respectively). Both the prevalence and genetic diversity found in our study were remarkably high. Our data provide an
important contribution to the scarce data available on PeV epidemiology in Africa
Increased Mortality Among Patients With vs Without Cirrhosis and Autoimmune Hepatitis
Cellular mechanisms in basic and clinical gastroenterology and hepatolog
Tamanho de partĂcula do volumoso e freqĂŒĂȘncia de alimentação sobre o metabolismo energĂ©tico e protĂ©ico em ovinos, considerando dietas com elevada participação de concentrado
Adverse events related to low dose corticosteroids in autoimmune hepatitis
Background: Autoimmune hepatitis requires longâterm therapy, and systemic corâ
ticosteroids are the backbone of therapeutic management. Prolonged use of cortiâ
costeroids may lead to adverse events but data from longâterm studies are mainly
derived from studies in rheumatic diseases.
Aim: To assess cataract, diabetes and fractures in relation to corticosteroid doses in
the longâterm maintenance treatment of patients with autoimmune hepatitis.
Methods: We retrospectively collected data on 476 patients (77% women) with an
established diagnosis of autoimmune hepatitis. Binary logistic regression with a genâ
eralised estimating equation was used to analyse the association between current
corticosteroid use and the incidence of cataract, diabetes and fractures with onset
after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnoâ
sis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects.
Results: A total of 6634 years, with a median of 13 (range 1â40) per patient were
recorded. The median age at diagnosis was 44 years (range 2â88). Adverse events
were documented in 120 (25%) patients. Lowâdose predniso(lo)ne (0.1â5.0 mg/d) inâ
creased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds
of cataracts and diabetes. Budesonide increased the odds of cataract and fractures;
this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years.
Conclusions: Even low doses of corticosteroids frequently lead to substantial adâ
verse events refuting the assumption that adverse events are prevented by adminisâ
tering low doses
Cohesin complex-associated holoprosencephaly
Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80â90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men