Bedload transport is a fundamental process by which coarse sediment is transferred through landscapes by river networks and may be well described stochastically by distributions of grain step length ...and rest time obtained through tracer studies. To date, none of these published tracer studies have specifically investigated the influence of large wood in the river channel on sediment transport dynamics, limiting the applicability of stochastic sediment transport models in these settings. Large wood is a major component of many forested rivers and is increasing due to anthropogenic ‘Natural Flood Management’ (NFM) practices. This study aims to investigate and model the influence of large wood on grain‐scale bedload transport.
We tagged 957 cobble to pebble sized particles (D50 = 73 mm) and 28 pieces of large wood (> 1 m in length) with radio frequency identification (RFID) tracers in an alpine mountain stream. We monitored the transport distance of tracers annually over 3 years, building distributions of tracer transport distances with which to compare with published distributions from wood free settings. We also applied linear mixed modelling (LMM), to tease out the influence of wood from other controls on likelihood of entrainment, deposition, and the transport distances of sediments.
Tracer sediments accumulated both upstream and downstream of large wood pieces, with LMM analysis confirming a reduction in the probability of entrainment of tracers closer to wood in all 3 years. Upon remobilization, tracers entrained from positions closer to large wood had shorter subsequent transport distances in each year. In 2019, large wood also had a trapping effect, significantly reducing the transport distances of tracer particles entrained from upstream, that is forcing premature deposition of tracers. This study demonstrates the role of large wood in influencing bedload transport in alpine stream environments, with implications for both natural and anthropogenic addition of wood debris in fluvial environments.
Sediment transport distances displayed expected gamma distributions with sediment transport characteristics remaining superdiffusive, although clustering around large wood temporarily flattened the power law tail of these distributions. Linear mixed modelling (LMM) analysis found large wood traps sediments and forces premature deposition and shorter step lengths. Furthermore, tracers with a closer proximity to large wood have a significantly reduced likelihood of entrainment, in addition to smaller transport distances, in comparison to tracers entrained in wood free areas.
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of ...4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
This paper contributes a rich picture of how students from refugee backgrounds navigate their way into and through undergraduate studies in a regional Australian university, paying particular ...attention to their access to and use of different forms of support. We draw on the conceptualisation of 'hot' and 'cold' knowledge, offered by Ball and Vincent (1998. "'I Heard it on the Grapevine': 'Hot' Knowledge and School Choice." British Journal of Sociology of Education 19 (3): 377-400), and the addition of 'warm' knowledge offered by Slack et al. (2014. "'Hot', 'Cold' and 'Warm' Information and Higher Education Decision Making." British Journal of Sociology of Education 35 (2): 204-223), to develop an understanding of how students from refugee backgrounds make choices about how they locate, select and access support for their studies. The findings of this paper suggest that students from refugee backgrounds do not view the 'cold' (unfamiliar-formal) institutional support on offer as 'for them'; instead they expressed a preference for the 'warm' (familiar-formal) support offered via 'trusted' people who act as literacy/sociocultural brokers or 'hot' (familiar-informal) support of their grapevine of other students (past and present) or experienced community members.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in ...individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Abstract
Background and Aims
Historical and emerging data implicate fungi in Crohn’s disease CD pathogenesis. However, a causal link between mycobiota, dysregulated immunity, and any impact of NOD2 ...variants remains elusive. This study aims to evaluate associations between NOD2 variants and faecal mycobiota in CD patients and non-CD subjects.
Methods
Faecal samples were obtained from 34 CD patients 18 NOD2 mutant, 16 NOD2 wild-type identified from the UK IBD Genetics Consortium. To avoid confounding influence of mucosal inflammation, CD patients were in clinical remission and had a faecal calprotectin <250 μg/g; 47 non-CD subjects were included as comparator groups, including 22 matched household four NOD2 mutant and 25 non-household subjects with known NOD2 genotype 14 NOD2 mutant identified by the NIHR BioResource Cambridge. Faecal mycobiota composition was determined using internal transcribed spacer 1 ITS1 sequencing and was compared with 16S rRNA gene sequences and volatile organic compounds.
Results
CD was associated with higher numbers of fungal observed taxonomic units OTUs p = 0.033. Principal coordinates analysis using Jaccard index p = 0.018 and weighted Bray‐Curtis dissimilarities p = 0.01 showed Candida spp. clustered closer to CD patients whereas Cryptococcus spp. clustered closer to non-CD. In CD, we found higher relative abundance of Ascomycota p = 0.001 and lower relative abundance Basidiomycota p = 0.019 phyla. An inverse relationship was found between bacterial and fungal Shannon diversity in NOD2 wild-type which was independent of CD r = -0.349; p = 0.029.
Conclusions
This study confirms compositional changes in the gut mycobiota in CD and provides evidence that fungi may play a role in CD pathogenesis. No NOD2 genotype-specific differences were observed in the faecal mycobiota.
Anxiety is common and problematic in dementia, yet there is a lack of effective treatments.
To develop a cognitive-behavioural therapy (CBT) manual for anxiety in dementia and determine its ...feasibility through a randomised controlled trial.
A ten-session CBT manual was developed. Participants with dementia and anxiety (and their carers) were randomly allocated to CBT plus treatment as usual (TAU) (n = 25) or TAU (n = 25). Outcome and cost measures were administered at baseline, 15 weeks and 6 months.
At 15 weeks, there was an adjusted difference in anxiety (using the Rating Anxiety in Dementia scale) of (-3.10, 95% CI -6.55 to 0.34) for CBT compared with TAU, which just fell short of statistical significance. There were significant improvements in depression at 15 weeks after adjustment (-5.37, 95% CI -9.50 to -1.25). Improvements remained significant at 6 months. CBT was cost neutral.
CBT was feasible (in terms of recruitment, acceptability and attrition) and effective. A fully powered RCT is now required.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to ...describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an
p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two
-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator,
. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance.
Some patients with severe asthma are immunologically sensitized to one or more fungi, a clinical entity categorized as severe asthma with fungal sensitization (SAFS). It is not known whether SAFS ...responds to antifungal therapy.
To evaluate the response of SAFS to oral itraconazole.
Patients with severe asthma sensitized to at least one of seven fungi by skin prick or specific IgE testing were recruited. All had total IgE less than 1,000 IU/ml and negative Aspergillus precipitins. They were treated with oral itraconazole (200 mg twice daily) or placebo for 32 weeks, with follow-up for 16 weeks.
The primary end point was change in the Asthma Quality of Life Questionnaire (AQLQ) score, with rhinitis score, total IgE, and respiratory function as secondary end points. Fifty-eight patients were enrolled, of whom 41% had been hospitalized in the previous year. Baseline mean AQLQ score was 4.13 (range, 1-7). At 32 weeks, the improvement (95% confidence interval) in AQLQ score was +0.85 (0.28, 1.41) in the antifungal group, compared with a -0.01 (-0.43, 0.42) change in the placebo group (P = 0.014). Rhinitis score improved (-0.43) in the antifungal, and deteriorated (+0.17) in the placebo group (P = 0.013). Morning peak flow improved (20.8 L/minute, P = 0.028) in the antifungal group. Total serum IgE decreased in the antifungal group (-51 IU/ml) but increased in placebo group (+30 IU/ml) (P = 0.001). No severe adverse events were observed, but seven patients developed adverse events requiring discontinuation, five in the antifungal group.
SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients.
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