bioRxiv Science⌕ Search

Biology subjects

Yamada, K.

Publications and source records attributed to Yamada, K..

85 records · Page 5Linked to original sources

A machine learning model that emulates experts decision making in vancomycin initial dose planning

Vancomycin is a glycopeptide antibiotic that has been used primarily in the treatment of methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended. Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinicians experience and expertise. In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. The target trough concentration was attained at comparable rates with the model- and expert-recommended dosing regimens, suggesting that the ML model successfully incorporated the experts knowledge. The predictive model developed here will contribute to improved decision making for initial vancomycin dosing and early attainment of therapeutic windows.

pharmacology and toxicology↗

Habit formation viewed as structural change in the behavioral network

Habit formation is a process in which an action becomes involuntary. While goal-directed behavior is driven by its consequences, habits are elicited by a situation rather than its consequences. Existing theories have proposed that actions are controlled by corresponding two distinct systems. Although canonical theories based on such distinctions are starting to be challenged, a few theoretical frameworks that implement goal-directed behavior and habits within a single system. Here, we propose a novel theoretical framework by hypothesizing that behavior is a network composed of several responses. With this framework, we have shown that the transition of goal-directed actions to habits is caused by a change in a single network structure. Furthermore, we confirmed that the proposed network model behaves in a manner consistent with the existing experimental results reported in animal behavioral studies. Our results revealed that habit could be formed under the control of a single system rather than two distinct systems. By capturing the behavior as a single network change, this framework provides a new perspective on studying the structure of the behavior for experimental and theoretical research. Author summaryTo obtain the desired consequences, organisms need to respond based on the knowledge of the consequences obtained by the response and the change in the environment caused by it. Such a process is called goal-directed behavior, which is flexible, but requires high computational cost. Once the same response is repeatedly performed under the same environment, the response becomes automatic, and transforms into a habit. In the canonical views, such a change from goal-directed response to habit was explained by the associative structures between the corresponding systems, goal-directed, and habit systems. However, the dichotomy in the mechanisms of behavior between goal-directed responses and habits has recently been challenged. Here, we show that, instead of assuming two explicitly distinguished mechanisms as in the canonical views, behavior is regarded as a network consisting of multiple responses, and that changes in the structure of the network cause two behavioral features, goal-directed behavior and habit. The transition from goal-directed behavior to habit has been operationally defined by sensitivity to the reward obtained by the response. We replicate such an experimental paradigm in the simulation and show that the behavioral network model can reproduce the empirical results on habit formation obtained from animal experiments. Our results demonstrate that habit formation can be explained in terms of changes in the network structure of behavior without assuming explicitly distinct systems and thus, provide a new theoretical framework to study the psychological, biological, and computational mechanisms of the behavior.

animal behavior and cognition↗

Prediction of RNA-protein interactions using a nucleotide language model

MotivationThe accumulation of sequencing data has enabled researchers to predict the interactions between RNA sequences and RNA-binding proteins (RBPs) using novel machine learning techniques. However, existing models are often difficult to interpret and require additional information to sequences. Bidirectional encoder representations from Transformer (BERT) is a language-based deep learning model that is highly interpretable. Therefore, a model based on BERT architecture can potentially overcome such limitations. ResultsHere, we propose BERT-RBP as a model to predict RNA-RBP interactions by adapting the BERT architecture pre-trained on a human reference genome. Our model outperformed state-of-the-art prediction models using the eCLIP-seq data of 154 RBPs. The detailed analysis further revealed that BERT-RBP could recognize both the transcript region type and RNA secondary structure only from sequence information. Overall, the results provide insights into the fine-tuning mechanism of BERT in biological contexts and provide evidence of the applicability of the model to other RNA-related problems. AvailabilityPython source codes are freely available at https://github.com/kkyamada/bert-rbp. Contactmhamada@waseda.jp

bioinformatics↗

Representation learning applications in biological sequence analysis

Remarkable advances in high-throughput sequencing have resulted in rapid data accumulation, and analyzing biological (DNA/RNA/protein) sequences to discover new insights in biology has become more critical and challenging. To tackle this issue, the application of natural language processing (NLP) to biological sequence analysis has received increased attention, because biological sequences are regarded as sentences and k-mers in these sequences as words. Embedding is an essential step in NLP, which converts words into vectors. This transformation is called representation learning and can be applied to biological sequences. Vectorized biological sequences can be used for function and structure estimation, or as inputs for other probabilistic models. Given the importance and growing trend in the application of representation learning in biology, here, we review the existing knowledge in representation learning for biological sequence analysis.

bioinformatics↗

The endosomal TbTpr86/TbUsp7/SkpZ (TUS) complex controls surface protein abundance in trypanosomes

In trypanosomes the orthologs of human USP7 and VDU1 control abundance of a cohort of surface proteins, including invariant surface glycoproteins (ISGs) by functioning as deubiquitinases (DUBs) Silencing TbUsp7 partially inhibits endocytosis and invariant surface glycoprotein turnover. As a component of cullin E3 ubiquitin ligases, S-phase kinase-associated protein 1 (Skp1) has crucial roles in cell cycle progression, transcriptional regulation, signal transduction and other processes in animals and fungi. Unexpectedly, trypanosomes possess multiple Skp1 paralogs, including a divergent paralog designated SkpZ. SkpZ is implicated in suramin-sensitivity and endocytosis and decreases in abundance following TbUsp7 knockdown and physically interacts with TbUsp7 and TbTpr86. The latter is a tetratricopeptide-repeat protein also implicated in suramin sensitivity and located close to the flagellar pocket/endosomes, consistent with a role in endocytosis. Further, silencing SkpZ reduced abundance of TbUsp7 and TbTpr86 and many trans-membrane domain surface proteins. Our data indicate that TbTpr86, TbUsp7 and SkpZ form the TUS complex that regulates abundance of a significant cohort of trypanosome surface proteins.

cell biology↗

Pattern recognition receptors confer plant salt tolerance via WRKY18/WRKY40 transcription factors

Pattern recognition receptors (PRRs) bind microbe- and damage-associated molecular patterns (MAMPs/DAMPs, respectively) to enhance host immunity in animals and plants. Here, we report that PRRs also confer salt tolerance in the model plant Arabidopsis thaliana following recognition of cognate ligands, such as bacterial flagellin and EF-Tu and the endogenous Pep peptides. Pattern-triggered salt tolerance (PTST) requires the PRR-associated kinases BAK1 and BIK1, and the NADPH oxidase RBOHD. Transcriptome profiling reveals an inventory of PTST target genes, which increase or acquire salt responsiveness following an exposure to immunogenic patterns. In their regulatory DNA sequences, specific binding sites for a subset of WRKY transcription factors are over-represented. Accordingly, PTST requires WRKY40 and WRKY18, which activate salt tolerance-related genes but attenuate pathogen defense-related genes, including the EDS1 immunity activator. PRR signaling leads to sustained WRKY40/WRKY18 accumulation under salt stress and utilizes both WRKYs for salt tolerance. The PRR-WRKY40/WRKY18 module also confers salt tolerance after challenge with non-pathogenic bacteria. Our findings give molecular insight into signaling plasticity underlying biotic-abiotic stress cross-tolerance in plants conferred by PRRs.

plant biology↗

AUTS2 regulation of synapses for proper synaptic inputs and social communication.

Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.

neuroscience↗

Long-term associative memory in rats: effects of familiarization period in object-place-context recognition test

Spontaneous recognition tests, which utilize rodents innate tendency to explore novelty, can evaluate not only simple non-associative recognition memory but also more complex associative memory in animals. In the present study, we investigated whether the length of the object familiarization period (sample phase) improved subsequent novelty discrimination in the spontaneous object, place, and object-place-context (OPC) recognition tests in rats. In the OPC test, rats showed a significant novelty preference only when the familiarization period was 30 min but not when it was 5 min or 15 min. However, the rats exhibited a successful discrimination between the stayed and replaced objects under 15 min and 30 min familiarization period conditions in the place recognition test and between the novel and familiar objects under all conditions of 5, 15 and 30 min in the object recognition test. Our results suggest that the extension of the familiarization period improves performance in the spontaneous recognition paradigms, and a longer familiarization period is necessary for long-term associative recognition memory than for non-associative memory.

animal behavior and cognition↗

Simulating bout-and-pause patterns with reinforcement learning

Animal responses occur according to a specific temporal structure composed of two states, where a bout is followed by a long pause until the next bout. Such about-and-pause pattern has three components: the bout length, the within-bout response rate, and the bout initiation rate. Previous studies have investigated how these three components are affected by experimental manipulations. However, it remains unknown what underlying mechanisms cause bout-and-pause patterns. In this article, we propose two mechanisms and examine computational models developed based on reinforcement learning. The model is characterized by two mechanisms. The first mechanism is choice—an agent makes a choice between operant and other behaviors. The second mechanism is cost—a cost is associated with the changeover of behaviors. These two mechanisms are extracted from past experimental findings. Simulation results suggested that both the choice and cost mechanisms are required to generate bout-and-pause patterns and if either of them is knocked out, the model does not generate bout-and-pause patterns. We further analyzed the proposed model and found that it reproduced the relationships between experimental manipulations and the three components that have been reported by previous studies. In addition, we showed alternative models can generate bout-and-pause patterns as long as they implement the two mechanisms.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

Basement membrane regulates fibronectin organization using sliding focal adhesions driven by a contractile winch

We have discovered that basement membrane and its major components can induce rapid, strikingly robust fibronectin organization. In this new matrix assembly mechanism, 5{beta}1 integrin-based focal adhesions slide actively on the underlying matrix towards the ventral cell center through the dynamic shortening of myosin IIA-associated actin stress fibers to drive rapid fibronectin fibrillogenesis distal to the adhesion. This mechanism contrasts with classical fibronectin assembly based on stable/fixed-position focal adhesions containing V{beta}3 integrins plus 5{beta}1 integrin translocation into proximal fibrillar adhesions. On basement membrane components, these sliding focal adhesions contain standard focal adhesion constituents but completely lack classical V{beta}3 integrins. Instead, peripheral 3{beta}1 or 2{beta}1 adhesions mediate initial cell attachment, but over time are switched to 5{beta}1 integrin-based sliding focal adhesions to assemble fibronectin matrix. This basement membrane-triggered mechanism produces rapid fibronectin fibrillogenesis, providing a mechanistic explanation for the well-known widespread accumulation of fibronectin at many organ basement membranes.

cell biology↗

Titer estimation for quality control (TEQC) method: a practical approach for optimal production of protein complexes using the baculovirus expression vector system

The baculovirus expression vector system (BEVS) is becoming the method of choice for expression of many eukaryotic proteins and protein complexes for biochemical, structural and pharmaceutical studies. Significant technological advancement has made generation of recombinant baculoviruses easy, efficient and user-friendly. However, there is a tremendous variability in the amount of proteins made using the BEVS, including different batches of virus made to express the same proteins. Yet, what influences the overall production of proteins or protein complexes remains largely unclear. Many downstream applications, particularly protein structure determination, require purification of large quantities of proteins in a repetitive manner, calling for a reliable experimental set-up to obtain the protein or protein complexes of interest consistently. During our investigation of optimizing the expression of the Mediator Head module, we discovered that the initial infectivity was an excellent indicator of overall production of protein complexes. Further, we show that this initial infectivity can be mathematically described as a function of multiplicity of infection (MOI), correlating recombinant protein yield and virus titer. All these findings led us to develop the Titer Estimation for Quality Control (TEQC) method, which enables researchers to estimate initial infectivity, titer/MOI values in a simple and affordable way, and to use these values to quantitatively optimize protein expressions utilizing BEVS in a highly reproducible fashion.

molecular biology↗

Evaluation of variability in human protein X-ray structures

Systematic analysis of statistical and dynamical properties of proteins is critical to understanding cellular events. Extraction of biologically relevant information from a set of high-resolution structures is important because it can provide mechanistic details behind the functional properties of protein families, enabling rational comparison between families. Most of the current structure comparisons are pairwise-based, which hampers the global analysis of increasing contents in the Protein Data Bank. Additionally, pairing of protein structures introduces uncertainty with respect to reproducibility because it frequently accompanies other settings for superimposition. This study introduces intramolecular distance scoring, for the analysis of human proteins, for each of which at least several high-resolution are available. We show that the results are comprehensively used to overview advances at the atomic level exploration of each protein and protein family. This method, and the interpretation based on model calculations, provide new criteria for understanding specific and non-specific structure variation in a protein, enabling global comparison of the dynamics among a vast variety of proteins from different species.

biophysics↗

Dynamic Current Clamp Experiments Define The Functional Roles Of IK1 And Ito,f In Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

The transient outward potassium current (Ito) plays a key, albeit incompletely defined, role in cardiomyocyte physiology and pathophysiology. In light of the technical challenges of studying adult human cardiomyocytes, this study examines the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a system which potentially preserves the native cellular milieu of human cardiomyocytes. ISPC-CMs express a robust Ito with slow recovery kinetics and fail to express the rapidly recovering Ito,f which is implicated in human disease. Overexpression of the accessory subunit KChIP2 (which is not expressed in iPSC-CMs) resulted in restoration of a rapid component of recovery. To define the functional role of Ito, dynamic current clamp was used to introduce computationally modeled currents into iPSC-CMs while recording action potentials. However, iPSC-CMs exhibit action potentials with multiple immature physiological properties, including slow upstroke velocity, heterogeneous action potential waveforms, and the absence of a phase 1 notch, thus potentially limiting the utility of these cells as a model of adult cardiomyocytes. Importantly, the introduction of modeled inwardly rectified current (IK1) ameliorated these immature properties by restoring a hyperpolarized resting membrane potential. In this context of normalized action potential morphologies, dynamic current clamp experiments introducing Ito,f demonstrated that there is significant cell-to-cell heterogeneity and that the functional effect of Ito,f is highly sensitive to the action potential plateau voltage in each cell.

cell biology↗