Publications by authors named "C Richter"

1,357 Publications

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Biologically informed deep neural network for prostate cancer discovery.

Nature 2021 Sep 22. Epub 2021 Sep 22.

Dana-Farber Cancer Institute, Boston, MA, USA.

The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge. Recent advances in interpretability of machine learning models as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics. Here we developed P-NET-a biologically informed deep learning model-to stratify patients with prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
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http://dx.doi.org/10.1038/s41586-021-03922-4DOI Listing
September 2021

Advanced Cardiac Rhythm Management by Applying Optogenetic Multi-Site Photostimulation in Murine Hearts.

J Vis Exp 2021 Aug 26(174). Epub 2021 Aug 26.

Research Group Biomedical Physics, Max Planck Institute for Dynamics and Self-Organization; Department of Cardiology and Pneumology, University Medical Center Goettingen; German Center for Cardiovascular Research, DZHK e.V., partner site Goettingen; Laboratory Animal Science Unit, German Primate Center Leibniz Institute for Primate Research;

Ventricular tachyarrhythmias are a major cause of mortality and morbidity worldwide. Electrical defibrillation using high-energy electric shocks is currently the only treatment for life-threatening ventricular fibrillation. However, defibrillation may have side-effects, including intolerable pain, tissue damage, and worsening of prognosis, indicating a significant medical need for the development of more gentle cardiac rhythm management strategies. Besides energy-reducing electrical approaches, cardiac optogenetics was introduced as a powerful tool to influence cardiac activity using light-sensitive membrane ion channels and light pulses. In the present study, a robust and valid method for successful photostimulation of Langendorff perfused intact murine hearts will be described based on multi-site pacing applying a 3 x 3 array of micro light-emitting diodes (micro-LED). Simultaneous optical mapping of epicardial membrane voltage waves allows the investigation of the effects of region-specific stimulation and evaluates the newly induced cardiac activity directly on-site. The obtained results show that the efficacy of defibrillation is strongly dependent on the parameters chosen for photostimulation during a cardiac arrhythmia. It will be demonstrated that the illuminated area of the heart plays a crucial role for termination success as well as how the targeted control of cardiac activity during illumination for modifying arrhythmia patterns can be achieved. In summary, this technique provides a possibility to optimize the on-site mechanism manipulation on the way to real-time feedback control of cardiac rhythm and, regarding the region specificity, new approaches in reducing the potential harm to the cardiac system compared to the usage of non-specific electrical shock applications.
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http://dx.doi.org/10.3791/62335DOI Listing
August 2021

Fatal and Non-Fatal Heroin-Related Overdoses: Circumstances and Patterns.

Subst Use Misuse 2021 Sep 1:1-10. Epub 2021 Sep 1.

Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Mannheim, Germany.

Introduction: Heroin overdose is a leading cause of mortality among drug users. This paper aims to identify individual and contextual factors associated with lethal and non-lethal heroin-related overdoses on the basis of case reports and semi-structured proxy interviews. Typical patterns within these cases are determined by means of cluster analysis.

Methods: Within the CaRe (Case Reports of heroin-related overdoses) study, case reports (100 proxy reports of overdose events from 36 different facilities) were gathered and evaluated as part of a nationwide survey of experts conducted in Germany in 2019. Following initial descriptive analyses a two-step cluster analysis with the four binary variables of gender, age, time and place was conducted to identify patterns within the reported cases.

Results: The case reports grouped into five clusters: 1) Younger male drug users, found in a public space during the daytime; 2) Female drug users; 3) Older male drug users, found in a public space during the daytime; 4) Drug users found at home at night; 5) Drug users found outside at night. Overdoses by female drug users and those which occurred at home and/or at night were significantly more likely to have a fatal outcome.

Conclusion: Future prevention and intervention measures should aim to consider the context, i.e. typical constellations of risk, and attempt to inhibit this through appropriate counter measures.
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http://dx.doi.org/10.1080/10826084.2021.1963986DOI Listing
September 2021

H, C and N assignment of stem-loop SL1 from the 5'-UTR of SARS-CoV-2.

Biomol NMR Assign 2021 Aug 28. Epub 2021 Aug 28.

Institute for Organic Chemistry and Chemical Biology, Goethe-University Frankfurt, Max-von-Laue- Straße 7, 60438, Frankfurt, Germany.

The stem-loop (SL1) is the 5'-terminal structural element within the single-stranded SARS-CoV-2 RNA genome. It is formed by nucleotides 7-33 and consists of two short helical segments interrupted by an asymmetric internal loop. This architecture is conserved among Betacoronaviruses. SL1 is present in genomic SARS-CoV-2 RNA as well as in all subgenomic mRNA species produced by the virus during replication, thus representing a ubiquitous cis-regulatory RNA with potential functions at all stages of the viral life cycle. We present here the H, C and N chemical shift assignment of the 29 nucleotides-RNA construct 5_SL1, which denotes the native 27mer SL1 stabilized by an additional terminal G-C base-pair.
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http://dx.doi.org/10.1007/s12104-021-10047-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401371PMC
August 2021

Effects of Cranberry Juice Supplementation on Cardiovascular Disease Risk Factors in Adults with Elevated Blood Pressure: A Randomized Controlled Trial.

Nutrients 2021 Jul 29;13(8). Epub 2021 Jul 29.

Department of Nutritional Sciences, Pennsylvania State University, University Park, PA 16802, USA.

Emerging cardiovascular disease (CVD) risk factors, including central vascular function and HDL efflux, may be modifiable with food-based interventions such as cranberry juice. A randomized, placebo-controlled, crossover trial was conducted in middle-aged adults with overweight/obesity ( = 40; mean BMI: 28.7 ± 0.8 kg/m; mean age: 47 ± 2 years) and elevated brachial blood pressure (mean systolic/diastolic BP: 124 ± 2/81 ± 1 mm Hg). Study participants consumed 500 mL/d of cranberry juice (~16 fl oz; 27% cranberry juice) or a matched placebo juice in a randomized order (8-week supplementation periods; 8-week compliance break), with blood samples and vascular measurements obtained at study entry and following each supplementation period. There was no significant treatment effect of cranberry juice supplementation on the primary endpoint of central systolic blood pressure or central or brachial diastolic pressure. Cranberry juice significantly reduced 24-h diastolic ambulatory BP by ~2 mm Hg compared to the placebo ( = 0.05) during daytime hours. Cranberry juice supplementation did not alter LDL-C but significantly changed the composition of the lipoprotein profile compared to the placebo, increasing the concentration of large LDL-C particles (+29.5 vs. -6.7 nmol/L; = 0.02) and LDL size (+0.073 vs. -0.068 nm; = 0.001). There was no effect of treatment on ex vivo HDL efflux in the total population, but exploratory subgroup analyses identified an interaction between BMI and global HDL efflux ( = 0.02), with greater effect of cranberry juice in participants who were overweight. Exploratory analyses indicate that baseline C-reactive protein (CRP) values may moderate treatment effects. In this population of adults with elevated blood pressure, cranberry juice supplementation had no significant effect on central systolic blood pressure but did have modest effects on 24-h diastolic ambulatory BP and the lipoprotein profile. Future studies are needed to verify these findings and the results of our exploratory analyses related to baseline health moderators.
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http://dx.doi.org/10.3390/nu13082618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398037PMC
July 2021
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