The simulation of open quantum dynamics is a critical tool for understanding how the non-classical properties of matter might be functionalised in future devices. However, unlocking the enormous ...potential of molecular quantum processes is highly challenging due to the very strong and non-Markovian coupling of 'environmental' molecular vibrations to the electronic 'system' degrees of freedom. Here, we present an advanced but general computational strategy that allows tensor network methods to effectively compute the non-perturbative, real-time dynamics of exponentially large vibronic wave functions of real molecules. We demonstrate how ab initio modelling, machine learning and entanglement analysis can enable simulations which provide real-time insight and direct visualisation of dissipative photophysics, and illustrate this with an example based on the ultrafast process known as singlet fission.
A molecular movie of ultrafast singlet fission Schnedermann, Christoph; Alvertis, Antonios M; Wende, Torsten ...
Nature communications,
09/2019, Letnik:
10, Številka:
1
Journal Article
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The complex dynamics of ultrafast photoinduced reactions are governed by their evolution along vibronically coupled potential energy surfaces. It is now often possible to identify such processes, but ...a detailed depiction of the crucial nuclear degrees of freedom involved typically remains elusive. Here, combining excited-state time-domain Raman spectroscopy and tree-tensor network state simulations, we construct the full 108-atom molecular movie of ultrafast singlet fission in a pentacene dimer, explicitly treating 252 vibrational modes on 5 electronic states. We assign the tuning and coupling modes, quantifying their relative intensities and contributions, and demonstrate how these modes coherently synchronise to drive the reaction. Our combined experimental and theoretical approach reveals the atomic-scale singlet fission mechanism and can be generalized to other ultrafast photoinduced reactions in complex systems. This will enable mechanistic insight on a detailed structural level, with the ultimate aim to rationally design molecules to maximise the efficiency of photoinduced reactions.
The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine ...kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA.
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. ...Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.
Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various ...epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)
. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.
Background
Androgens function through DNA and non‐DNA binding‐dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood.
Design and methods
To ...identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA‐binding domain of the AR (ARΔZF2) with non‐aromatizable 5α‐dihydrotestosterone (5α‐DHT) or aromatizable testosterone. To distinguish direct hematopoietic and non‐hematopoietic mechanisms, we performed bone marrow reconstitution experiments.
Results
In wild‐type mice, 5α‐DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild‐type mice following 5α‐DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α‐DHT had no erythroid activity in ARΔZF2 mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α‐DHT, suppressed EPO levels in ARΔZF2 mice, suggesting testosterone following aromatization may oppose the erythroid‐stimulating effects of androgens. Female wild‐type mice reconstituted with ARΔZF2 bone marrow cells remained responsive to 5α‐DHT. In contrast, ARΔZF2 mice reconstituted with female wild‐type bone marrow cells showed no response to 5α‐DHT.
Conclusion
Erythroid promoting effects of androgens are mediated through DNA binding‐dependent actions of the AR in non‐hematopoietic cells, including stimulating EPO expression.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue tumors prevalent in neurofibromatosis type 1 (NF1) patients, posing a significant risk of metastasis and recurrence. ...Current magnetic resonance imaging (MRI) imaging lacks decisiveness in distinguishing benign peripheral nerve sheath tumors (BPNSTs) and MPNSTs, necessitating invasive biopsies. This study aims to develop a radiomics model using quantitative imaging features and machine learning to distinguish MPNSTs from BPNSTs. Clinical data and MRIs from MPNST and BPNST patients (2000–2019) were collected at a tertiary sarcoma referral center. Lesions were manually and semi-automatically segmented on MRI scans, and radiomics features were extracted using the Workflow for Optimal Radiomics Classification (WORC) algorithm, employing automated machine learning. The evaluation was conducted using a 100× random-split cross-validation. A total of 35 MPNSTs and 74 BPNSTs were included. The T1-weighted (T1w) MRI radiomics model outperformed others with an area under the curve (AUC) of 0.71. The incorporation of additional MRI scans did not enhance performance. Combining T1w MRI with clinical features achieved an AUC of 0.74. Experienced radiologists achieved AUCs of 0.75 and 0.66, respectively. Radiomics based on T1w MRI scans and clinical features show some ability to distinguish MPNSTs from BPNSTs, potentially aiding in the management of these tumors.
Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render ...cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
•Genetic loss or chemical inhibition of p38 or MK2 increases SM-induced TNF•p38 and MK2 inhibit SM-induced phosphorylation of JNK and ERK•The combination of SM and p38 inhibitor is well tolerated in vivo•p38 and MK2 inhibitors potentiate SM killing of AML in vivo
Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.
Although diffuse intrinsic pontine glioma (DIPG) carries the worst prognosis of all pediatric brain tumors, studies on prognostic factors in DIPG are sparse. To control for confounding variables in ...DIPG studies, which generally include relatively small patient numbers, a survival prediction tool is needed.
A multicenter retrospective cohort study was performed in the Netherlands, the UK, and Germany with central review of clinical data and MRI scans of children with DIPG. Cox proportional hazards with backward regression was used to select prognostic variables (P < .05) to predict the accumulated 12-month risk of death. These predictors were transformed into a practical risk score. The model's performance was validated by bootstrapping techniques.
A total of 316 patients were included. The median overall survival was 10 months. Multivariate Cox analysis yielded 5 prognostic variables of which the coefficients were included in the risk score. Age ≤3 years, longer symptom duration at diagnosis, and use of oral and intravenous chemotherapy were favorable predictors, while ring enhancement on MRI at diagnosis was an unfavorable predictor. With increasing risk score categories, overall survival decreased significantly. The model can distinguish between patients with very short, average, and increased overall survival (medians of 7.0, 9.7, and 13.7 mo, respectively). The area under the receiver operating characteristic curve was 0.68.
We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.