Utility of a single adjusting compartment: a novel methodology for whole body physiologically-based pharmacokinetic modelling

<p>Abstract</p> <p>Background</p> <p>There are various methods for predicting human pharmacokinetics. Among these, a whole body physiologically-based pharmacokinetic (WBPBPK) model is useful because it gives a mechanistic description. However, WBPBPK models cannot predict human pharmacokinetics with enough precision. This study was conducted to elucidate the primary reason for poor predictions by WBPBPK models, and to enable better predictions to be made without reliance on complex concepts.</p> <p>Methods</p> <p>The primary reasons for poor predictions of human pharmacokinetics were investigated using a generic WBPBPK model that incorporated a single adjusting compartment (SAC), a virtual organ compartment with physiological parameters that can be adjusted arbitrarily. The blood flow rate, organ volume, and the steady state tissue-plasma partition coefficient of a SAC were calculated to fit simulated to observed pharmacokinetics in the rat. The adjusted SAC parameters were fixed and scaled up to the human using a newly developed equation. Using the scaled-up SAC parameters, human pharmacokinetics were simulated and each pharmacokinetic parameter was calculated. These simulated parameters were compared to the observed data. Simulations were performed to confirm the relationship between the precision of prediction and the number of tissue compartments, including a SAC.</p> <p>Results</p> <p>Increasing the number of tissue compartments led to an improvement of the average-fold error (AFE) of total body clearances (CL_tot) and half-lives (T_1/2) calculated from the simulated human blood concentrations of 14 drugs. The presence of a SAC also improved the AFE values of a ten-organ model from 6.74 to 1.56 in CL_tot, and from 4.74 to 1.48 in T_1/2. Moreover, the within-2-fold errors were improved in all models; incorporating a SAC gave results from 0 to 79% in CL_tot, and from 14 to 93% in T_1/2of the ten-organ model.</p> <p>Conclusion</p> <p>By using a SAC in this study, we were able to show that poor prediction resulted mainly from such physiological factors as organ blood flow rate and organ volume, which were not satisfactorily accounted for in previous WBPBPK models. The SAC also improved precision in the prediction of human pharmacokinetics. This finding showed that the methodology of our study may be useful for functionally reinforcing a WBPBPK model.</p

MeV protons in the inner belt and slot region observed by HEP onboard the Arase satellite

The Tenth Symposium on Polar Science/Ordinary sessions: [OS] Space and upper atmospheric sciences, Wed. 4 Dec. /Entrance Hall (1st floor) at National Institute of Polar Research (NIPR

Active Hippocampal Networks Undergo Spontaneous Synaptic Modification

The brain is self-writable; as the brain voluntarily adapts itself to a changing environment, the neural circuitry rearranges its functional connectivity by referring to its own activity. How the internal activity modifies synaptic weights is largely unknown, however. Here we report that spontaneous activity causes complex reorganization of synaptic connectivity without any external (or artificial) stimuli. Under physiologically relevant ionic conditions, CA3 pyramidal cells in hippocampal slices displayed spontaneous spikes with bistable slow oscillations of membrane potential, alternating between the so-called UP and DOWN states. The generation of slow oscillations did not require fast synaptic transmission, but their patterns were coordinated by local circuit activity. In the course of generating spontaneous activity, individual neurons acquired bidirectional long-lasting synaptic modification. The spontaneous synaptic plasticity depended on a rise in intracellular calcium concentrations of postsynaptic cells, but not on NMDA receptor activity. The direction and amount of the plasticity varied depending on slow oscillation patterns and synapse locations, and thus, they were diverse in a network. Once this global synaptic refinement occurred, the same neurons now displayed different patterns of spontaneous activity, which in turn exhibited different levels of synaptic plasticity. Thus, active networks continuously update their internal states through ongoing synaptic plasticity. With computational simulations, we suggest that with this slow oscillation-induced plasticity, a recurrent network converges on a more specific state, compared to that with spike timing-dependent plasticity alone

Cryo-EM Structures of Centromeric Tri-nucleosomes Containing a Central CENP-A Nucleosome

The histone H3 variant CENP-A is a crucial epigenetic marker for centromere specification. CENP-A forms a characteristic nucleosome and dictates the higher-order configuration of centromeric chromatin. However, little is known about how the CENP-A nucleosome affects the architecture of centromeric chromatin. In this study, we reconstituted tri-nucleosomes mimicking a centromeric nucleosome arrangement containing the CENP-A nucleosome, and determined their 3D structures by cryoelectron microscopy. The H3-CENP-A-H3 tri-nucleosomes adopt an untwisted architecture, with an outward-facing linker DNA path between nucleosomes. This is distinct from the H3-H3-H3 tri-nucleosome architecture, with an inward-facing DNA path. Intriguingly, the untwisted architecture may allow the CENP-A nucleosome to be exposed to the solvent in the condensed chromatin model. These results provide a structural basis for understanding the 3D configuration of CENP-A-containing chromatin, and may explain how centromeric proteins can specifically target the CENP-A nucleosomes buried in robust amounts of H3 nucleosomes in centromeres

Exploring deep microbial life in coal-bearing sediment down to ~2.5 km below the ocean floor

Peer reviewedPostprin

Research Activities in the Department of Physical Therapy

[Introduction] It is already fifty years since the Japanese law of physical therapists and occupational therapists has been effective. The physical therapist is referred by the law as "the professionals who implements the physical therapy to persons with disabilities under the prescription of medical doctors". In fifty years, however, the target of physical therapy has been significantly expanded. The subject for physical therapy now includes the patients in acute disease just after the surgical operation in addition to those in rehabilitation stage. In other words, the physical therapy is now recognized as the indispensable intervention to the subject with acute as well as chronic disorders. On the other hand, due to a rapid transition of the society into the aged society, prevention of diseases, and decline of activity capacity due to the aging have become major issues for the physical therapy