30 research outputs found
Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity
Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.DFG [SFB740, 740/2-11, SFB618, 618/3-09, SFB/TRR43 A7]; BMBF(NGFN-Plus) [01GS08169-73, 01GS08150, 01GS08108]; HDSA Coalition for the Cure; EU (EuroSpin) [Health-F2-2009-241498, HEALTH-F2-2009-242167]; Helmholtz Association (MSBN, HelMA) [HA-215]; FCT [IF/00881/2013]info:eu-repo/semantics/publishedVersio
Self-swabbing versus assisted swabbing for viral detection by qRT-PCR: the experience from SARS-CoV-2 based on a meta-analysis of six prospectively designed evaluations conducted in a UK setting
Purpose: In April 2020, the UK Government implemented NHS Test and Trace to provide SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (qRT-PCR) testing for the public, with nose-and-throat swabbing for samples performed by trained staff. Self-swabbing (SS) would allow rapid scale-up of testing capacity and access. Six studies were undertaken to determine whether SS was as effective for detecting SARS-CoV-2 as swabbing performed by trained staff. Methods: Six prospective studies were conducted between AprilâOctober 2020, using six swab/media combinations. Differences between assisted swabbing (AS) and SS were evaluated for concordance, positivity, sensitivity, cycle threshold (Ct) values and void rates. Statistical analysis was performed using 95% confidence intervals (CIs), paired t-tests and model-based methods. Results: Overall, 3,253 individuals were recruited (median age 37 years, 49% female), with 2,933 having valid paired qRT-PCR results. Pooled concordance rate was 98% (95% CI: 96%, 99%). Positivity rate differences for SS (8.1%) and AS (8.4%) and differences in pooled sensitivities between SS (86%; 95% CI: 78%, 92%) and AS (91%; 95% CI: 78%, 96%) were nonsignificant. Both types of swabbing led to pooled void rates below 2% and strongly correlated Ct values. Age, sex and previous swabbing experience did not have a significant impact on concordance or sensitivity. Conclusion: The UK adopted a policy to promote self-testing for SARS-CoV-2 based on data demonstrating equivalence of SS versus AS. Positive outcomes with SS are likely generalisable to testing for other respiratory pathogens, and we consider self-sampling and self-testing essential for future pandemic preparedness
Tight regulation of unstructured proteins: from transcript synthesis to protein degradation
Altered abundance of several intrinsically unstructured proteins ( IUPs) has been associated with perturbed cellular signaling that may lead to pathological conditions such as cancer. Therefore, it is important to understand how cells precisely regulate the availability of IUPs. We observed that regulation of transcript clearance, proteolytic degradation, and translational rate contribute to controlling the abundance of IUPs, some of which are present in low amounts and for short periods of time. Abundant phosphorylation and low stochasticity in transcription and translation indicate that the availability of IUPs can be finely tuned. Fidelity in signaling may require that most IUPs be available in appropriate amounts and not present longer than needed.Royal Society; MRC Special Training Fellowship; Medical Research Council [MC_U105161047, MC_U105185859, G0600158]info:eu-repo/semantics/publishedVersio
Use of fractional exhaled nitric oxide to guide the treatment of asthma an official american thoracic society clinical practice guideline
Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence. </p
Large-scale assessment of olfactory preferences and learning in Drosophila melanogaster
Optimal DNA pooling for the detection of single nucleotide polymorphisms
We consider the optimal pooling of DNA to detect single nucleotide
polymorphisms (SNPs), sites along the genome at which a population shows variation.
The focus is on the detection of low frequency variants. Pooling individuals
increases the probability that a rare variant appears in the sample. However, as
the pool size increases, the mean number of reads from an individual decreases,
making it harder to distinguish reads of a rare variant from errors. A hypothesis
test for the detection of SNPs is defined. On the basis of this test, we determine
the asymptotically optimal pool size given the parameters of the genome
sequencer used, the number of lanes available and a specified significance level
Statistical tests for the detection of single nucleotide polymorphisms using DNA pooling
An important problem in genetics is detecting single nucleotide polymorphisms (SNPs),
sites along the genome at which a population shows variation. The focus is on the detection
of rare variants. Pooling individuals allows us to increase the probability that a rare variant
appears in the sample. However, as the pool size increases, the mean number of reads from an
individual decreases, making it harder to distinguish reads of a rare variant from errors. This
paper compares three statistical tests for detecting SNPs using data from pooled DNA samples