Modification of single-nucleotide polymorphism in a fully humanized CYP3A mouse by genome editing technology

Abe, S., Kobayashi, K., Oji, A. et al. Modification of single-nucleotide polymorphism in a fully humanized CYP3A mouse by genome editing technology. Sci Rep 7, 15189 (2017). https://doi.org/10.1038/s41598-017-15033-

Pharmacokinetic modeling of hepatocyte growth factor in experimental animals and humans

Hepatocyte growth factor (HGF) is under development for treatment of renal failure. This study was designed to clarify changes in HGF pharmacokinetics in renal failure and to establish a pharmacokinetic model applicable to single and repeated doses. The plasma concentration profile in mice with glycerol-induced acute renal failure was similar to that in normal mice, indicating a minimal contribution of kidney to systemic clearance of HGF. Nevertheless, accumulation of fluorescein-4-isocyanate-labeled HGF in renal tubules in both cases suggests the occurrence of efficient endocytosis of HGF in kidney. A pharmacokinetic model including plasma and liver compartments was constructed, incorporating both high- and low-affinity receptors for association and subsequent endocytosis of HGF because HGF is eliminated via specific receptor c-Met and heparin-like substance. The model well explained the plasma concentration profiles at all doses examined after bolus injection in animals and humans, and those during infusion in rodents. It includes externalization of receptors, which is negatively regulated by HGF, and can explain the gradual increase in trough concentration during repeated dosing in monkeys. Overall pharmacokinetic profiles of HGF are governed by at least two receptors and are well described by this pharmacokinetic model, which should assist in safe management of clinical trials. © 2012 Wiley Periodicals, Inc

A replication-competent smallpox vaccine LC16m8Δ-based COVID-19 vaccine

金沢大学医薬保健研究域薬学系Viral vectors are a potent vaccine platform for inducing humoral and T-cell immune responses. Among the various viral vectors, replication-competent ones are less commonly used for coronavirus disease 2019 (COVID-19) vaccine development compared with replication-deficient ones. Here, we show the availability of a smallpox vaccine LC16m8Δ (m8Δ) as a replication-competent viral vector for a COVID-19 vaccine. M8Δ is a genetically stable variant of the licensed and highly effective Japanese smallpox vaccine LC16m8. Here, we generated two m8Δ recombinants: one harbouring a gene cassette encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein, named m8Δ-SARS2(P7.5-S)-HA; and one encoding the S protein with a highly polybasic motif at the S1/S2 cleavage site, named m8Δ-SARS2(P7.5-SHN)-HA. M8Δ-SARS2(P7.5-S)-HA induced S-specific antibodies in mice that persisted for at least six weeks after a homologous boost immunization. All eight analysed serum samples displayed neutralizing activity against an S-pseudotyped virus at a level similar to that of serum samples from patients with COVID-19, and more than half (5/8) also had neutralizing activity against the Delta/B.1.617.2 variant of concern. Importantly, most serum samples also neutralized the infectious SARS-CoV-2 Wuhan and Delta/B.1.617.2 strains. In contrast, immunization with m8Δ-SARS2(P7.5-SHN)-HA elicited significantly lower antibody titres, and the induced antibodies had less neutralizing activity. Regarding T-cell immunity, both m8Δ recombinants elicited S-specific multifunctional CD8+ and CD4+ T-cell responses even after just a primary immunization. Thus, m8Δ provides an alternative method for developing a novel COVID-19 vaccine

Space-Time Turbo Equalization in Frequency Selective MIMO Channels

A computationally efficient space-time turbo equalization algorithm is derived for frequency-selective multiple-input-multiple-output (MIMO) channels. The algorithm is an extension of the iterative equalization algorithm by Reynolds and Wang for frequency-selective fading channels and of iterative multiuser detection for code-division multiple-access (CDMA) systems by Wang and Poor. The proposed algorithm is implemented as a MIMO detector consisting of a soft-input-soft-output (SISO) linear MMSE detector followed by SISO channel decoders for the multiple users. The detector first forms a soft replica of each composite interfering signal using the log likelihood ratio (LLR), fed back from the SISO channel decoders, of the transmitted coded symbols and subtracts it from the received signal vector. Linear adaptive filtering then takes place to suppress the interference residuals: filter taps are adjusted based on the minimum mean square error (MMSE) criterion. The LLR is then calculated for adaptive filter output. This process is repeated in an iterative fashion to enhance signal-detection performance. This paper also discusses the performance sensitivity of the proposed algorithm to channel-estimation error. A channel-estimation scheme is introduced that works with the iterative MIMO equalization process to reduce estimation errors

Space-time turbo equalization and symbol detection in frequency selective MIMO channels

A computationally efficient space-time turbo equalization algorithm is derived for frequency selective multiple-input multiple-output (MIMO) channels. The algorithm is an extension of the iterative equalization algorithm by Reynolds and Wang (2001) for frequency selective fading channels. This paper's proposed equalizer performs MIMO channel estimation, multiple user signal detection, and decoding, jointly all in an iterative manner. The iterative channel estimator achieves high accuracy in estimating channel parameters even if only a relatively small number of unique word symbols are available. The multiple user signal detector (MUSD) consists of soft interference cancellers for the multiple users, each followed by a minimum mean square error (MMSE) filter. With this simple structure, the proposed detector achieves a drastic reduction in computational complexity compared with conventional trellis-based turbo equalizers. Simulation results show the proposed equalizer can properly separate multiple user signals in frequency selective MIMO channels

A MIMO Turbo Equalizer for Frequency Selective Channels With Unknown Interference

A new space-time turbo equalization algorithm is derived for frequency-selective multiple-input-multiple-output (MIMO) channels with unknown interference. The algorithm is an extension of our proposed MIMO equalization algorithm, which performs joint channel estimation, multiple users' signal detection, and decoding, all in an iterative manner. This paper's proposed algorithm uses estimates of the correlation matrix of composite unknown interference-plus-noise components to suppress the unknown interference while effectively separating multiple users' signals to be detected (referred to as "known user" later). The correlation matrix of the composite unknown interference-plus-noise components can be estimated by time averaging the instantaneous empirical correlation matrix over the training period. Since the iterative channel estimation yields better channel estimates as more iterations are performed, thereby the estimate of the correlation matrix of the unknown interference-plus-noise components also becomes more accurate. This results in better signal detection performances, even in the presence of unknown interferers. A series of computer simulations show that this paper's proposed algorithm can properly separate known users' signals while suppressing unknown interference

Sick sinus syndrome diagnosed after a sinus arrest during treatment for zygomatic fracture: a case report

Abstract Background Intraoperative sinus arrest is rarely seen during zygomatic fracture treatment. The patient was diagnosed with sick sinus syndrome based on repeated postoperative sinus arrest, which could have resulted in death if diagnosed late, making this case very significant to report. Case presentation Sick sinus syndrome is an arrhythmia associated with reduced automaticity of the sinoatrial node or impaired sinoatrial node conduction. We report the case of a 67-year-old man diagnosed with the syndrome after a sinus arrest that occurred during a zygomatic fracture treatment. The patient had cheek pain and mouth opening disorder, dizziness after fainting and sustaining a facial injury. Preoperative examination determined that the syncope was due to drug-induced arrhythmia, and surgery was authorized after drug withdrawal. During the operation, sinus arrest was observed due to trigeminal vagal reflex, and heart rate was restarted by stopping the operation and chest compressions. After the surgery, the patient showed symptoms of dizziness and palpitations, and sinus arrest following atrial fibrillation and supraventricular tachycardia, which was diagnosed as sick sinus syndrome, and a pacemaker was implanted. Currently, 8 years have passed since the surgery, and there are no symptoms of mouth opening disorder, dizziness, or palpitations. Conclusions In the case of maxillofacial injuries due to syncope, cardiogenic syncope is a possibility, and repeated syncope is a risk for death due to delayed diagnosis. There are no reports of maxillofacial trauma leading to a diagnosis of sick sinus syndrome. The purpose of this case report is to disseminate the importance of diagnosing the cause of syncope as well as injury treatment