Biology subjects

Fischer, S.

Publications and source records attributed to Fischer, S..

4 recordsLinked to original sources

bioRxiv2018

The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS). The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.

biochemistry↗

bioRxiv2017

Whole Genomes Define Concordance of Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 trios of matched primary tumour, PDX, and PDO. We developed a new pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Comparison of genomic events in the tumours and matched disease models displayed single-gene concordance across major PDAC driver genes, and genome-wide similarities of copy number changes. Genome-wide and chromosome-centric analysis of structural variation (SV) events revealed high variability across tumours and disease models, but also highlighted previously unrecognized concordance across chromosomes that demonstrate clustered SV events. Our approach and results demonstrate that PDX and PDO recapitulate PDAC tumourigenesis with respect to simple somatic mutations and copy number changes, and capture major SV events that are found in both resected and metastatic tumours.

bioinformatics↗

bioRxiv2017

Alterations in cortical thickness and structural connectivity are associated with symptom severity in bulimia nervosa

Bulimia nervosa (BN) is a serious psychiatric illness defined by preoccupation with weight and shape, episodic binge-eating and compensatory behaviors. Although diagnosed BN has been associated with diffuse grey matter volume reductions, characterization of brain structure alterations in women with a range of BN symptoms has yet to be made. This study examined whether changes in cortical thickness (CT) scaled with BN symptom severity in a sample of 33 adult women (n = 10 BN; n = 5 EDNOS-BN). Our second objective was to assess global structural connectivity (SC) of CT and to determine if individual differences in global SC relate to BN symptom severity. We used the validated Eating Disorder Examination Questionnaire (EDE-Q; Fairburn & Beglin, 1994) as a continuous measure of BN symptom severity. Increased EDE-Q score was negatively related to global CT and local CT in the left middle frontal gyrus, right superior frontal gyrus and bilateral orbitofrontal cortex (OFC) and temporoparietal regions. Moreover, analysis of global SC indicated that BN-related cortical thinning preferentially occurred in regions with high global connectivity. Finally, we showed that individuals contribution to global SC at the group level were significantly related to EDE-Q score, where increased EDE-Q score correlated with reduced connectivity of the left OFC and middle temporal cortex and increased connectivity of the right superior parietal lobule. Our findings offer novel insight into CT alterations in BN and further suggest that the combination of CT and structural connectivity measures may be sensitive to individual differences in BN symptom severity.

neuroscience↗

bioRxiv2016

WhatsHap: fast and accurate read-based phasing

Read-based phasing allows to reconstruct the haplotypes of a sample purely from sequencing reads. While phasing is an important step for answering questions about population genetics, compound heterozygosity, and to aid in clinical decision making, there has been a lack of accurate, usable and standards-based software.\n\nWhatsHap is a production-ready tool for highly accurate read-based phasing. It was designed from the beginning to leverage third-generation sequencing technologies, whose long reads can span many variants and are therefore ideal for phasing. WhatsHap works also well with second-generation data, is easy to use and will phase not only SNVs, but also indels and other variants. It is unique in its ability to combine read-based with pedigree-based phasing, allowing to further improve accuracy if multiple related samples are provided.

bioinformatics↗