A sodium-dependent trehalose transporter contributes to anhydrobiosis in insect cell line, Pv11.

Pv11 is the only animal cell line that, when preconditioned with a high concentration of trehalose, can be preserved in the dry state at room temperature for more than one year while retaining the ability to resume proliferation. This extreme desiccation tolerance is referred to as anhydrobiosis. Here, we identified a transporter that contributes to the recovery of Pv11 cells from anhydrobiosis. In general, the solute carrier 5 (SLC5)-type secondary active transporters cotransport Na+ and carbohydrates including glucose. The heterologous expression systems showed that the transporter belonging to the SLC5 family, whose expression increases upon rehydration, exhibits Na+-dependent trehalose transport activity. Therefore, we named it STRT1 (sodium-ion trehalose transporter 1). We report an SLC5 family member that transports a naturally occurring disaccharide, such as trehalose. Knockout of the Strt1 gene significantly reduced the viability of Pv11 cells upon rehydration after desiccation. During rehydration, when intracellular trehalose is no longer needed, Strt1-knockout cells released the disaccharide more slowly than the parental cell line. During rehydration, Pv11 cells became roughly spherical due to osmotic pressure changes, but then returned to their original spindle shape after about 30 min. Strt1-knockout cells, however, required about 50 min to adopt their normal morphology. STRT1 probably regulates intracellular osmolality by releasing unwanted intracellular trehalose with Na+, thereby facilitating the recovery of normal cell morphology during rehydration. STRT1 likely improves the viability of dried Pv11 cells by rapidly alleviating the significant physical stresses that arise during rehydration.

Effects of nitric oxide inhalation on pulmonary arterial impedance: differences between normal and pulmonary hypertension male rats.

Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.

Short-term dynamic characteristics of diuresis during exogenous pressure perturbations with and without arterial baroreflex control.

Although body fluid volume control by the kidneys may be classified as a long-term arterial pressure (AP) control system, it does not necessarily follow that the urine flow (UF) response to changes in AP is slow. We quantified the dynamic characteristics of the UF response to short-term AP changes by changing mean AP between 60 mmHg and 100 mmHg every 10 s according to a binary white noise sequence in anesthetized rats (n = 8 animals). In a baro-on trial (the carotid sinus baroreflex was enabled), the UF response represented the combined synergistic effects of pressure diuresis (PD) and neurally mediated antidiuresis (NMA). In a baro-fix trial (the carotid sinus pressure was fixed at 100 mmHg), the UF response mainly reflected the effect of PD. The UF step response was quantified using the sum of two exponential decay functions. The fast and slow components had time constants of 6.5 ± 3.6 s and 102 ± 85 s (means ± SD), respectively, in the baro-on trial. Although the gain of the fast component did not differ between the two trials (0.49 ± 0.21 vs. 0.66 ± 0.22 µL·min-1·kg-1·mmHg-1), the gain of the slow component was greater in the baro-on than in the baro-fix trial (0.51 ± 0.14 vs. 0.09 ± 0.39 µL·min-1·kg-1·mmHg-1, P = 0.023). The magnitude of NMA relative to PD was calculated to be 32.2 ± 29.8%. In conclusion, NMA contributed to the slow component, and its magnitude was approximately one-third of that of the effect of PD.NEW & NOTEWORTHY We quantified short-term dynamic characteristics of the urine flow (UF) response to arterial pressure (AP) changes using white noise analysis. The UF step response approximated the sum of two exponential decay functions with time constants of ∼6.5 s and 102 s. The neurally mediated antidiuretic (NMA) effect contributed to the slow component of the UF step response, with the magnitude of approximately one-third of that of the pressure diuresis (PD) effect.

2'-ß-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3'-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2'-ß-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3'-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3'-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.

Multicomponent nature underlies the extraordinary mechanical properties of spider dragline silk.

Dragline silk of golden orb-weaver spiders (Nephilinae) is noted for its unsurpassed toughness, combining extraordinary extensibility and tensile strength, suggesting industrial application as a sustainable biopolymer material. To pinpoint the molecular composition of dragline silk and the roles of its constituents in achieving its mechanical properties, we report a multiomics approach, combining high-quality genome sequencing and assembly, silk gland transcriptomics, and dragline silk proteomics of four Nephilinae spiders. We observed the consistent presence of the MaSp3B spidroin unique to this subfamily as well as several nonspidroin SpiCE proteins. Artificial synthesis and the combination of these components in vitro showed that the multicomponent nature of dragline silk, including MaSp3B and SpiCE, along with MaSp1 and MaSp2, is essential to realize the mechanical properties of spider dragline silk.

The outcomes of a standardized protocol for extracorporeal mechanical circulatory support selection-left ventricular challenge protocol.

There are no criteria for surgical mechanical circulatory system (MCS) selection for acute heart failure. Since 2021, we have utilized cardiopulmonary bypass system to assess patients' heart and lung condition to inform surgical MCS selection. we aimed to retrospectively analyze the outcomes of treatments administered using our protocol. We analyzed the data of 19 patients who underwent surgical MCS implantation. We compared patients' characteristics across the biventricular-assist device (BiVAD), central Y-Y extracorporeal membrane oxygenation (ECMO), central ECMO, and left VAD (LVAD) systems. Patients' diagnoses included fulminant myocarditis (47.4%), dilated cardiomyopathy (21.1%), acute myocardial infarction (15.8%), infarction from aortic dissection (5.3%), doxorubicin-related cardiomyopathy (5.3%), and tachycardia-induced myocarditis (5.3%). Eight patients (42.1%) underwent LVAD implantation, 1 (5.2%) underwent central ECMO, 4 (21.1%) underwent BiVAD implantation, and 6 (31.6%) underwent central Y-Y ECMO. 48 h after surgery, both the pulmonary arterial and right atrial pressures were effectively controlled, with median values being 19.0 mmHg and 9.0 mmHg, respectively. No patients transitioned from LVAD to BiVAD in the delayed period. Cerebrovascular events occurred in 21.1%. Successful weaning was achieved in 11 patients (57.9%), and 5 patients (26.3%) were converted to durable LVAD. Two-year cumulative survival was 84.2%. Our protocol showed good results for device selection in patients with heart failure, and device selection according to this protocol enabled good control of the pulmonary and systemic circulations.

Verification of acromion marker cluster and scapula spinal marker cluster methods for tracking shoulder kinematics: a comparative study with upright four-dimensional computed tomography.

BACKGROUND: This study validated the accuracy of the acromion marker cluster (AMC) and scapula spinal marker cluster (SSMC) methods compared with upright four-dimensional computed tomography (4DCT) analysis. METHODS: Sixteen shoulders of eight healthy males underwent AMC and SSMC assessments. Active shoulder elevation was tracked using upright 4DCT and optical motion capture system. The scapulothoracic and glenohumeral rotation angles calculated from AMC and SSMC were compared with 4DCT. Additionally, the motion of these marker clusters on the skin with shoulder elevation was evaluated. RESULTS: The average differences between AMC and 4DCT during 10°-140° of humerothoracic elevation were - 2.2° ± 7.5° in scapulothoracic upward rotation, 14.0° ± 7.4° in internal rotation, 6.5° ± 7.5° in posterior tilting, 3.7° ± 8.1° in glenohumeral elevation, - 8.3° ± 10.7° in external rotation, and - 8.6° ± 8.9° in anterior plane of elevation. The difference between AMC and 4DCT was significant at 120° of humerothoracic elevation in scapulothoracic upward rotation, 50° in internal rotation, 90° in posterior tilting, 120° in glenohumeral elevation, 100° in external rotation, and 100° in anterior plane of elevation. However, the average differences between SSMC and 4DCT were - 7.5 ± 7.7° in scapulothoracic upward rotation, 2.0° ± 7.0° in internal rotation, 2.3° ± 7.2° in posterior tilting, 8.8° ± 7.9° in glenohumeral elevation, 2.0° ± 9.1° in external rotation, and 1.9° ± 10.1° in anterior plane of elevation. The difference between SSMC and 4DCT was significant at 50° of humerothoracic elevation in scapulothoracic upward rotation and 60° in glenohumeral elevation, with no significant differences observed in other rotations. Skin motion was significantly smaller in AMC (28.7 ± 4.0 mm) than SSMC (38.6 ± 5.8 mm). Although there was smaller skin motion in AMC, SSMC exhibited smaller differences in scapulothoracic internal rotation, posterior tilting, glenohumeral external rotation, and anterior plane of elevation compared to 4DCT. CONCLUSION: This study demonstrates that AMC is more accurate for assessing scapulothoracic upward rotation and glenohumeral elevation, while SSMC is preferable for evaluating scapulothoracic internal rotation, posterior tilting, glenohumeral external rotation, and anterior plane of elevation, with smaller differences compared to 4DCT.

Transcriptome analysis of the tardigrade Hypsibius exemplaris exposed to the DNA-damaging agent bleomycin.

Tardigrades are microscopic animals that are renowned for their capabilities of tolerating near-complete desiccation by entering an ametabolic state called anhydrobiosis. However, many species also show high tolerance against radiation in the active state as well, suggesting cross-tolerance via the anhydrobiosis mechanism. Previous studies utilized indirect DNA damaging agents to identify core components of the cross-tolerance machinery in species with high anhydrobiosis capacities. However, it was difficult to distinguish whether transcriptomic changes were specific to DNA damage or mutual with anhydrobiosis. To this end, we performed transcriptome analysis on bleomycin-exposed Hypsibius exemplaris. We observed induction of several tardigrade-specific gene families, including a previously identified novel anti-oxidative stress family, which may be a core component of the cross-tolerance mechanism. We also identified enrichment of the tryptophan metabolism pathway, for which metabolomic analysis suggested engagement of this pathway in stress tolerance. These results provide several candidates for the core component of cross-tolerance, as well as possible anhydrobiosis machinery.

The Inhibition of TREK-1 K+ Channels via Multiple Compounds Contained in the Six Kamikihito Components, Potentially Stimulating Oxytocin Neuron Pathways.

Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.

Single-pixel optical modulation analyzer based on phase retrieval for dual-polarization IQ modulators.

In-service monitoring and adaptive digital compensation of analog imperfections in optical transponders are vital in the next-generation optical coherent transmission systems employing extremely high-order, high-speed modulation formats. A notable example of such analog impairments is the imbalance of amplitude, phase, and/or timing between the in-phase (I) and quadrature (Q) tributaries in an optical IQ modulator, namely the IQ imbalance. Recently, an IQ-imbalance estimation technique based on phase retrieval without using a coherent receiver, the so-called single-pixel optical modulation analyzer (SP-OMA), has been proposed as an affordable in-service monitoring solution for the frequency-dependent IQ imbalance in a (single-polarization) IQ modulator. In this work, we extend the concept of the SP-OMA to dual-polarization IQ modulators. A novel phase retrieval algorithm with an alternating minimization procedure is proposed for identifying the frequency-dependent IQ imbalances on both polarization channels simultaneously from a single photodetector output. The validity and feasibility of the proposed SP-OMA for a dual-polarization IQ modulator are demonstrated numerically and experimentally with a 63.25-Gbaud DP-16QAM signal.

Dietary apple polyphenols enhance mitochondrial turnover and respiratory chain enzymes.

Previous studies have demonstrated the beneficial effects of apple polyphenol (AP) intake on muscle endurance. Since mitochondria are critical for muscle endurance, we investigated mitochondrial enzyme activity, biogenesis, degradation and protein quality control. Twenty-four Wistar rats were randomly fed a 5% AP diet (5% AP group, n = 8), a 0.5% AP diet (0.5% AP group, n = 8), or a control diet (control group, n = 8). After a 4-week feeding period, the expression level of peroxisome proliferator-activated receptor γ coactivator-1α, a mitochondrial biosynthetic factor, did not increase, whereas that of transcription factor EB, another regulator of mitochondrial synthesis, significantly increased. Moreover, the mitochondrial count did not differ significantly between the groups. In contrast, mitophagy-related protein levels were significantly increased. The enzymatic activities of mitochondrial respiratory chain complexes II, III and IV were significantly higher in the AP intake group than in the control group. We conclude that AP feeding increases the activity of respiratory chain complex enzymes in rat skeletal muscles. Moreover, mitochondrial biosynthesis and degradation may have increased in AP-treated rats. NEW FINDINGS: What is the central question of this study? Does the administration of apple polyphenols (AP) affect mitochondrial respiratory chain complex enzyme activity, biogenesis, degradation and protein quality control in rat skeletal muscles? What is the main finding and its importance? AP feeding increases respiratory chain complex enzyme activity in rat skeletal muscle. Moreover, AP administration increases transcription factor EB activation, and mitophagy may be enhanced to promote degradation of dysfunctional mitochondria, but mitochondrial protein quality control was not affected.

Escherichia coli-derived outer-membrane vesicles induce immune activation and progression of cirrhosis in mice and humans.

BACKGROUND AND AIMS: Decompensated cirrhosis with fibrosis progression causes portal hypertension followed by an oedematous intestinal tract. These conditions weaken the barrier function against bacteria in the intestinal tract, a condition called leaky gut, resulting in invasion by bacteria and bacterial components. Here, we investigated the role of outer-membrane vesicles (OMVs) of Escherichia coli, which is the representative pathogenic gut-derived bacteria in patients with cirrhosis in the pathogenesis of cirrhosis. METHODS: We investigated the involvement of OMVs in humans using human serum and ascites samples and also investigated the involvement of OMVs from E. coli in mice using mouse liver-derived cells and a mouse cirrhosis model. RESULTS: In vitro, OMVs induced inflammatory responses to macrophages and neutrophils, including the upregulation of C-type lectin domain family 4 member E (Clec4e), and induced the suppression of albumin production in hepatocytes but had a relatively little direct effect on hepatic stellate cells. In a mouse cirrhosis model, administration of OMVs led to increased liver inflammation, especially affecting the activation of macrophages, worsening fibrosis and decreasing albumin production. Albumin administration weakened these inflammatory changes. In addition, multiple antibodies against bacterial components were increased with a progressing Child-Pugh grade, and OMVs were detected in ascites of patients with decompensated cirrhosis. CONCLUSIONS: In conclusion, OMVs induce inflammation, fibrosis and suppression of albumin production, affecting the pathogenesis of cirrhosis. We believe that our study paves the way for the future prevention and treatment of cirrhosis.

Chronic intramuscular calcific tendinitis of the deltoid muscle.

Calcific tendinitis is a potentially symptomatic disorder characterized by calcium deposits in the substance of the tendon. Although this condition can occur in any tendinous tissue throughout the human body, calcium deposition commonly occurs at tendon insertions near the bone-tendon junction. The musculotendinous junction of the deltoid muscle has peculiarly dense intramuscular tendons to which muscle fibers attach obliquely to create muscular strength. Given that the intramuscular tendons themselves, which form the consecutive part from the insertion, are subjected to unpredictable stress load or microtrauma similar to tendon insertions, it is reasonable to assume that calcific tendinitis could also occur at the intramuscular tendons. Here we report a case of chronic symptomatic calcium deposition in the lateral part of the deltoid muscle between the origin and the insertion, which was eventually surgically removed and confirmed as intramuscular calcific tendinitis.

Time-series transcriptomic screening of factors contributing to the cross-tolerance to UV radiation and anhydrobiosis in tardigrades.

BACKGROUND: Tardigrades are microscopic animals that are capable of tolerating extreme environments by entering a desiccated state of suspended animation known as anhydrobiosis. While antioxidative stress proteins, antiapoptotic pathways and tardigrade-specific intrinsically disordered proteins have been implicated in the anhydrobiotic machinery, conservation of these mechanisms is not universal within the phylum Tardigrada, suggesting the existence of overlooked components. RESULTS: Here, we show that a novel Mn-dependent peroxidase is an important factor in tardigrade anhydrobiosis. Through time-series transcriptome analysis of Ramazzottius varieornatus specimens exposed to ultraviolet light and comparison with anhydrobiosis entry, we first identified several novel gene families without similarity to existing sequences that are induced rapidly after stress exposure. Among these, a single gene family with multiple orthologs that is highly conserved within the phylum Tardigrada and enhances oxidative stress tolerance when expressed in human cells was identified. Crystallographic study of this protein suggested Zn or Mn binding at the active site, and we further confirmed that this protein has Mn-dependent peroxidase activity in vitro. CONCLUSIONS: Our results demonstrated novel mechanisms for coping with oxidative stress that may be a fundamental mechanism of anhydrobiosis in tardigrades. Furthermore, localization of these sets of proteins mainly in the Golgi apparatus suggests an indispensable role of the Golgi stress response in desiccation tolerance.

Tracking Sub-Nano-Scale Structural Evolution in Zeolite Synthesis by In Situ High-Energy X-ray Total Scattering Measurement with Pair Distribution Function Analysis.

The crystallization mechanism of zeolites remains unclarified to date because of lack of effective techniques in characterizing the local structures of amorphous precursors under synthetic conditions. Herein, in situ high-energy X-ray total scattering measurement with pair distribution function analysis is performed throughout the hydrothermal synthesis of SSZ-13 zeolite to investigate the amorphous-to-crystalline transformation at the sub-nano level in real time. Ordered four-membered rings (4Rs) are dominantly formed during the induction period, prior to the significant increase in the number of symmetric six- and eight-membered rings (6Rs and 8Rs) in the crystal growth stage. These preformed ordered 4Rs contribute to the formation of d6r and cha composite building units containing 6Rs and 8Rs with the assistance of the organic structure-directing agent, leading to the construction of embryonic zeolite crystallites, which facilitate the crystal growth through a particle attachment pathway. This work enriches the toolbox for better understanding the crystallization pathway of zeolites.

Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non-alcoholic steatohepatitis mouse model.

AIM: Non-alcoholic steatohepatitis (NASH) with fibrosis eventually leads to cirrhosis and hepatocellular carcinoma. Thus, the development of therapies other than dietary restriction and exercise, particularly those that suppress steatosis and fibrosis of the liver and have a long-term beneficial effect, is necessary. We aimed to evaluate the therapeutic effects of the HMGB1 peptide synthesized from box A using the melanocortin-4 receptor-deficient (Mc4r-KO) NASH model mouse. METHODS: We performed short- and long-term administration of this peptide and evaluated the effects on steatosis, fibrosis, and carcinogenesis using Mc4r-KO mice. We also analyzed the direct effect of this peptide on macrophages and hepatic stellate cells in vitro and performed lipidomics and metabolomics techniques to evaluate the effect. RESULTS: Although this peptide did not show direct effects on macrophages and hepatic stellate cells in vitro, in the short-term administration model, we could confirm the reduction of liver damage, steatosis, and fibrosis progression. The results of lipidomics and metabolomics suggested that the peptide might ameliorate NASH by promoting lipolysis via the activation of fatty acid ß-oxidation and improving insulin resistance. In the long-term administration model, this peptide prevented progression to cirrhosis but retained the steatosis state, that is, the peptide prevents the progression to "burnt-out NASH." This peptide inhibited carcinogenesis by about one-third. CONCLUSION: This HMGB1 peptide can reduce liver damage, improve fibrosis and steatosis, and inhibit carcinogenesis, suggesting that the peptide would be a new treatment candidate for NASH and can contribute to the long-term prognosis for patients with NASH.

Three-Dimensional Quantitative Evaluation of the Scapular Skin Marker Movements in the Upright Posture.

Motion capture systems using skin markers are widely used to evaluate scapular kinematics. However, soft-tissue artifact (STA) is a major limitation, and there is insufficient knowledge of the marker movements from the original locations. This study explores a scapular STA, including marker movements with shoulder elevation using upright computed tomography (CT). Ten healthy males (twenty shoulders in total) had markers attached to scapular bony landmarks and underwent upright CT in the reference and elevated positions. Marker movements were calculated and compared between markers. The bone-based and marker-based scapulothoracic rotation angles were also compared in both positions. The median marker movement distances were 30.4 mm for the acromial angle, 53.1 mm for the root of the scapular spine, and 70.0 mm for the inferior angle. Marker movements were significantly smaller on the superolateral aspect of the scapula, and superior movement was largest in the directional movement. Scapulothoracic rotation angles were significantly smaller in the marker-based rotation angles than in the bone-based rotation angles of the elevated position. We noted that the markers especially did not track the inferior movement of the scapular motion with shoulder elevation, resulting in an underestimation of the marker-based rotation angles.

Upregulation of glucocorticoid receptor-mediated glucose transporter 4 in enzalutamide-resistant prostate cancer.

Enzalutamide (Enz) is a second-generation androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross-resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR-mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz-resistant prostate cancer cells, which recovered from Enz resistance and cross-resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz-resistant CRPC patients.

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.

BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

Single-pixel optical modulation analyzer: a low-complexity frequency-dependent IQ imbalance monitor based on direct detection with phase retrieval.

Tiny mismatches in timing, phase, and/or amplitude between in-phase (I) and quadrature (Q) tributaries in an electro-optic IQ modulator, namely IQ imbalance, can severely affect high baud-rate and/or high modulation-order signals in modern coherent optical communications systems. To maintain such analog impairment within the tight penalty limit over wavelength and temperature during the product lifetime, in-service in-field monitoring and calibration of the IQ imbalance, including its frequency dependence, become increasingly important. In this study, we propose a low-complexity IQ monitoring technique based on direct detection with phase retrieval called a single-pixel optical modulation analyzer (SP-OMA). By reconstructing the optical phase information lost during the detection process computationally via phase retrieval, SP-OMA facilitates the in-service in-field monitoring of the frequency-dependent imbalance profile without sending dedicated pilot tones and regardless of any receiver/monitor-side IQ imbalance. The feasibility of SP-OMA is demonstrated both numerically and experimentally with a 63.25-Gbaud 16QAM signal.