Biology subjects

Frank, D.

Publications and source records attributed to Frank, D..

43 records · Page 3Linked to original sources

bioRxiv2020

Expectation violation dynamically engages a bottom-up encoding state

To efficiently process information, the brain shifts between encoding and retrieval states, prioritising bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected similar events also triggered occipital engagement, however, this did not enhance memory performance. Taken together, our findings suggest that when the goal is to retrieve, encountering surprising events engages an encoding mechanism, supported by bottom-up processing, that may enhance memory for future related events. Significance statementOptimising the balance between new learning and the retrieval of existing knowledge is an ongoing process, at the core of human cognition. Previous research into memory encoding suggests experiencing surprise leads to the prioritisation of the leaning of new memories, forming an adaptive encoding mechanism. We examined whether this mechanism is also engaged when the current goal is to retrieve information. Our results demonstrate that an expectation-driven shift towards an encoding state, supported by enhanced perceptual processing, is beneficial for the correct identification of subsequent expected similar events. These findings have important implications for our understanding of the temporal dynamics of the adaptive encoding of information into memory.

neuroscience↗

bioRxiv2020

A JAK/STAT-Mediated Inflammatory Signaling Cascade Drives Oncogenesis In AF10-Rearranged AML

Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of AML driven by the most common AF10 fusion proteins, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a comprehensive map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent anti-oncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias. STATEMENT OF SIGNIFICANCEGene fusions of AF10/MLLT10 are recurrent in acute myeloid and lymphoid leukemia and are associated with extremely poor survival outcomes. We show that the JAK1 kinase is required for activation of the AF10 fusion oncotranscriptome and for leukemogenesis. Since a number of JAK/STAT pathways inhibitors are in clinical development or approved for use, our studies may help develop a therapeutic strategy for AF10-rearranged leukemias.

cancer biology↗

bioRxiv2019

Dose-dependent role of Gfi1 in murine hematopoietic stem cell self-renewal and differentiation

Gfi1 (Growth factor independence 1) is a transcription factor that influences the stem cell capacity of hematopoietic stem cells (HSCs) as well as their differentiation into the myeloid and lymphoid lineage. Loss of Gfi1 impedes the repopulation capacity of HSCs and leads to a block in granulocyte generation causing severe neutropenia and monocytosis. Competitive transplantation assays showed that Gfi1-deficient cells were not able to reconstitute myeloid and lymphoid hematopoiesis in competition with Gfi1-wildtype (GFI1-36S) cells. Low Gfi1 levels (GFI1-knockdown = GFI1-KD) in blasts of myelodysplastic neoplasms, acute and chronic myeloid leukemia patients are associated with poor patient survival. To understand how reduced levels or loss of Gfi1 contribute to hematopoiesis, we analyzed the effect of GFI1-KD and Gfi1-KO on HSCs and more mature cell types in mice. GFI1-KD and Gfi1-KO led to strong decrease in HSC numbers, while the numbers of early progenitors (Lin- Sca1+cKit+ cells) were slightly increased. Competitive transplantation assays showed that GFI1-KD and Gfi1-KO HSCs can still engraft and expand, but they cannot contribute to myeloid and lymphoid differentiation.

molecular biology↗

bioRxiv2019

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

cancer biology↗

bioRxiv2019

Computational modelling of hippocampal sensitivity to expectation violation

Pattern separation and completion are fundamental hippocampal computations supporting memory encoding and retrieval. However, despite extensive exploration of these processes, it remains unclear whether they are modulated by top-down processes. We used a neural network model to examine how unexpected information is represented by the hippocampus. During training the network learned a contingency between a cue and a category, which the target object belongs to. At test, we presented the network with congruous and incongruous cues, as well as perceptually similar foils. We used representational similarity analysis to examine how the top-down expectation modulation interacts with bottom-up perceptual input, in each layer. All subfields showed an interaction between the two, with DG and CA3 being more sensitive to expectation violation than CA1. A further multivariate analysis revealed that representational differences between expected and unexpected inputs were prominent for moderate to high levels of perceptual overlap in DG/CA3. This effect diminished when inputs from DG and CA3 into CA1 were lesioned. Overall, our findings suggest pattern separation in DG and CA3 underlies the effect that violation of expectation exerts on memory.

neuroscience↗

bioRxiv2019

Pattern separation is the key driver of expectation-modulated memory

The hippocampus uses pattern separation and pattern completion in a continuous manner to successfully encode and retrieve memories1,2. However, whether and how cognitive factors might modulate the dynamics between these types of computation is not well understood. Here we examine the role of expectation in shifting the hippocampus to perform pattern separation. Expectation can be built up through multiple contextual exposures leading to prediction (as in a learnt contingency) or through logical deduction based on a previous mnemonic response. Participants first learned a contingency between a cue and an objects category (man-made or natural). Then, at encoding, one third of the cues that preceded the to-be-memorised objects violated the studied rule. At test, participants performed an old/new recognition task with old items (targets) and a set of parametrically manipulated (very similar to dissimilar) new foils for each object. We explored the effects of both contextual expectation, manipulated at initial encoding, and mnemonic-attribution expectation, driven by the mnemonic decisions taken on previous retrieval trials. For example, a target would be unexpected if in a previous trial a similar foil had been erroneously accepted as old. Memory was found to be better for foils of high and mid similarity to contextually unexpected targets at encoding, compared to expected ones. Additionally, violations of mnemonic-attribution expectation also yielded improved memory performance when the level of foil similarity was high. These results suggest that violations of both contextual expectation and mnemonic-attribution expectation engage pattern separation, resulting in better discrimination performance for these items. Importantly, this mechanism is engaged when input differentiation is required in order to make a correct recognition decision.

neuroscience↗

bioRxiv2017

Mutations in C11ORF70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to outer and inner dynein arm defects

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility and randomization of the left/right body axis caused by defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open reading frame C11ORF70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11ORF70 cause immotility of respiratory cilia and sperm flagella, respectively, due to loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11ORF70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11ORF70 showed that C11ORF70 is expressed in ciliated respiratory cells and that the expression of C11ORF70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein arm assembly factors. Furthermore, C11ORF70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11ORF70 is a novel preassembly factor involved in the pathogenesis of PCD. The identification of a novel genetic defect that causes PCD and male infertility is of great clinical importance as well as for genetic counselling.

molecular biology↗