The book contains 19 national reports and a comparative legal analysis of the legal regulations on the procedure of genome editing on the human germline. It is worked out which shared values the different legal systems connect and which differences exist. On this basis, it is examined whether an international regulation of the topic is possible and how it could be designed. In addition, it will be examined to what extent the regulations of other countries can serve as a model for German legislation.
Although many real-time neural decoding algorithms have been proposed for brain-machine interface (BMI) applications over the years, an optimal, consensual approach remains elusive. Recent advances in deep learning algorithms provide new opportunities for improving the design of BMI decoders, including the use of recurrent artificial neural networks to decode neuronal ensemble activity in real time. Here, we developed a long-short term memory (LSTM) decoder for extracting movement kinematics from the activity of large (N = 134-402) populations of neurons, sampled simultaneously from multiple cortical areas, in rhesus monkeys performing motor tasks. Recorded regions included primary motor, dorsal premotor, supplementary motor, and primary somatosensory cortical areas. The LSTM's capacity to retain information for extended periods of time enabled accurate decoding for tasks that required both movements and periods of immobility. Our LSTM algorithm significantly outperformed the state-of-the-art unscented Kalman filter when applied to three tasks: center-out arm reaching, bimanual reaching, and bipedal walking on a treadmill. Notably, LSTM units exhibited a variety of well-known physiological features of cortical neuronal activity, such as directional tuning and neuronal dynamics across task epochs. LSTM modeled several key physiological attributes of cortical circuits involved in motor tasks. These findings suggest that LSTM-based approaches could yield a better algorithm strategy for neuroprostheses that employ BMIs to restore movement in severely disabled patients.
The paper shows that there is a pattern in the distribution of synthetic (šēp šarrim “the king’s foot”) vs. analytical (kaspum ša awīlim “the boss’s money”) genitive constructions in Old Babylonian. The choice depends on the lexical feature of head nouns known as (in)alienability. Old Babylonian kinship and body part terms, as well as some other substantives, are “inalienable”, which means they take only the synthetic construction. All other Old Babylonian nouns are “alienable”, which means they admit both the synthetic and the analytical construction (kasap tamkārī and kaspum ša tamkārī “the merchants’ money”). In the latter case, there is no general rule to predict the choice, yet in certain cases the two constructions display a non-random frequency distribution.
Background: Chromosomal rearrangements are the typical phenomena in cancer genomes causing gene disruptions and fusions, corruption of regulatory elements, damage to chromosome integrity. Among the factors contributing to genomic instability are non-B DNA structures with stem-loops and quadruplexes being the most prevalent. We aimed at investigating the impact of specifically these two classes of non-B DNA structures on cancer breakpoint hotspots using machine learning approach.
Methods: We developed procedure for machine learning model building and evaluation as the considered data are extremely imbalanced and it was required to get a reliable estimate of the prediction power. We built logistic regression models predicting cancer breakpoint hotspots based on the densities of stem-loops and quadruplexes, jointly and separately. We also tested Random Forest models varying different resampling schemes (leave-one-out cross validation, train-test split, 3-fold cross-validation) and class balancing techniques (oversampling, stratification, synthetic minority oversampling).
Results: We performed analysis of 487,425 breakpoints from 2234 samples covering 10 cancer types available from the International Cancer Genome Consortium. We showed that distribution of breakpoint hotspots in different types of cancer are not correlated, confirming the heterogeneous nature of cancer. It appeared that stem-loop- based model best explains the blood, brain, liver, and prostate cancer breakpoint hotspot profiles while quadruplex- based model has higher performance for the bone, breast, ovary, pancreatic, and skin cancer. For the overall cancer profile and uterus cancer the joint model shows the highest performance. For particular datasets the constructed models reach high predictive power using just one predictor, and in the majority of the cases, the model built on both predictors does not increase the model performance.
Conclusion: Despite the heterogeneity in breakpoint hotspots’ distribution across different cancer types, our results demonstrate an association between cancer breakpoint hotspots and stem-loops and quadruplexes. Approximately for half of the cancer types stem-loops are the most influential factors while for the others these are quadruplexes. This fact reflects the differences in regulatory potential of stem-loops and quadruplexes at the tissue-specific level, which yet to be discovered at the genome-wide scale. The performed analysis demonstrates that influence of stem- loops and quadruplexes on breakpoint hotspots formation is tissue-specific.
A cancer cell line originating from human epithelial colorectal adenocarcinoma (Caco-2 cells) serves as a high capacity model for a preclinical screening of drugs. Recent need for incorporating barrier tissue into multi-organ chips calls for inclusion of Caco-2 cells into microperfused environment. This article describes a series of systems biology insights obtained from comparing Caco-2 models cells grown as conventional 2D layer and in a microfluidic chip. When basic electrical parameters of Caco-2 monolayers were evaluated using impedance spectrometry and MTT assays, no differences were noted. On the other hand, the microarray profiling of mRNAs and miRNAs revealed that grows on a microfluidic chip leads to the change in the production of specific miRNA, which regulate a set of genes for cell adhesion molecules (CAMs), and provide for more complete differentiation of Caco-2 monolayer. Moreover, the sets of miRNAs secreted at the apical surface of Caco-2 monolayers grown in conventional 2D culture and in microfluidic device differ. When integrated into a multi-tissue platform, Caco-2 cells may aid in generating insights into complex pathophysiological processes, not possible to dissect in conventional cultures.
Pharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population. We validated our model using local field potential data recorded from human hippocampal/subicular slices. We found that synaptic conductances and slow adaptation in the excitatory population both play essential roles for generating seizures and pre-ictal oscillations. Using bifurcation analysis, we found that transitions towards seizure and back to the resting state take place via Andronov-Hopf bifurcations. These simulations therefore suggest that single neuron adaptation as well as synaptic inhibition are responsible for orchestrating seizure dynamics and transition towards the epileptic state.
Most common drug development failures originate from either bioavailability problems, or unexpected toxic effects. The culprit is often the liver, which is responsible for biotransformation of a majority of xenobiotics. Liver may be modeled using "liver on a chip" devices, which may include established cell lines, primary human cells, and stem cell-derived hepatocyte-like cells. The choice of biological material along with its processing and maintenance greatly influence both the device performance and the resultant toxicity predictions. Impediments to the development of "liver on a chip" technology include the problems with standardization of cells, limitations imposed by culturing and the necessity to develop more complicated fluidic contours. Fortunately, recent breakthroughs in the development of cell-based reporters, including ones with fluorescent label, permits monitoring of the behavior of the cells embed into the "liver on a chip" devices. Finally, a set of computational approaches has been developed to model both particular toxic response and the homeostasis of human liver as a whole; these approaches pave a way to enhance the in silico stage of assessment for a potential toxicity.
A large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit‐level mechanisms responsible for EtOH‐dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration‐dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U‐shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH‐induced boost in the Ih and AMPA currents in the DA firing‐rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well‐established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.
Mechanical performances of titanium biomedical implants manufactured by superplastic forming are strongly related to the process parameters: the thickness distribution along the formed sheet has a key role in the evaluation of post-forming characteristics of the prosthesis. In this work, a finite element model able to reliably predict the thickness distribution after the superplastic forming operation was developed and validated in a case study. The material model was built for the investigated titanium alloy (Ti6Al4V-ELI) upon results achieved through free inflation tests in different pressure regimes. Thus, a strain and strain rate dependent material behaviour was implemented in the numerical model. It was found that, especially for relatively low strain rates, the strain rate sensitivity index of the investigated titanium alloy significantly decreases during the deformation process. Results on the case study highlighted that the strain rate has a strong influence on the thickness profile, both on its minimum value and on the position in which such a minimum is found.
The article discusses the comparative evaluation of combined treatment results in patients with DTC (differentiated thyroid cancer) at different levels of TSH-stimulated prior to RAI (radioactive iodine) treatment. The study included 197 patients (36 female, 161 male) of the age group 18-75 years with a mean age of 47 years. The data was analyzed using several statistical methods: analysis of variance (ANOVA), linear and logistic regression models. The resulting data from the analysis showed that there was no statistically significant association between serum TSH levels prior to RAI and DTC remission.