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Abstract Physical reservoir computing is a promising solution for accelerating artificial intelligence (AI) computations. Various physical systems that exhibit nonlinear and fading-memory properties have been proposed as physical reservoirs. Highly-integrable physical reservoirs, particularly for edge AI computing, has a strong demand. However, realizing a practical physical reservoir with high performance and integrability remains challenging. Herein, we present an analogue circuit reservoir with a simple cycle architecture suitable for complementary metal-oxide-semiconductor (CMOS) chip integration. In several benchmarks and demonstrations using synthetic and real-world data, our developed hardware prototype and its simulator exhibit a high prediction performance and sufficient memory capacity for practical applications, showing promise for future applications in highly integrated AI accelerators.

Abstract Recent advancements on electrohydrodynamic (EHD) soft pumps demonstrate their applicability to various fluid-driven systems such as soft robots, wearable devices, and stretchable electronics. In particular, fiber type EHD pumps reported more recently is a promising pumping element thanks to their versatile fibrous structure. Yet existing EHD fiber pumps are less stretchable and require sophisticated, complex fabrication equipment, implying opportunity for technology advancement. This paper presents a simplified method to create highly stretchable multifunctional fiber EHD pumps. The method employs highly compliant silicone elastomers for the fiber structure that is formed by simple dipping fabrication process. The fabricated pumps (length of 100 mm, inner diameter 4 mm, and mass 5.3 g) exhibit a high stretchability (up to 40% strain) and flow rate and pressure of 167.4 ± 7.6 mL/min (31.6 mL/min/g) and 4.1 ± 0.6 kPa (0.8 kPa/g), respectively. These performances are comparable or even higher than those of previously reported EHD pumps including fiber types. The output performance of the fabricated pumps remain constant for repeated strain cycles (0–25%, up to 2000 cycles) and bending angle up to 180° (corresponding to curvature of 0–30/m). Moreover, the pumps demonstrate unprecedented functionality as a sensor to distinguish the type of fluid inside the tube and to detect strains by reading the capacitance between the electrodes. The characterization result reveals the sensing ability of the pumps as high repeatability up to 30% strain with negligible hysteresis, which is consistent for 5000 cycles.

Abstract Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.

Abstract In vivo deuterated water (2H2O) labeling leads to deuterium (2H) incorporation into biomolecules of proliferating cells and provides the basis for its use in cell kinetics research. We hypothesized that rapidly proliferating cancer cells would become preferentially labeled with 2H and, therefore, could be visualized by deuterium magnetic resonance imaging (dMRI) following a brief period of in vivo systemic 2H2O administration. We initiated systemic 2H2O administration in two xenograft mouse models harboring either human colorectal, HT-29, or pancreatic, MiaPaCa-2, tumors and 2H2O level of ~ 8% in total body water (TBW). Three schemas of 2H2O administration were tested: (1) starting at tumor seeding and continuing for 7 days of in vivo growth with imaging on day 7, (2) starting at tumor seeding and continuing for 14 days of in vivo growth with imaging on day 14, and (3) initiation of labeling following a week of in vivo tumor growth and continuing until imaging was performed on day 14. Deuterium chemical shift imaging of the tumor bearing limb and contralateral control was performed on either day 7 of 14 after tumor seeding, as described. After 14 days of in vivo tumor growth and 7 days of systemic labeling with 2H2O, a clear deuterium contrast was demonstrated between the xenografts and normal tissue. Labeling in the second week after tumor implantation afforded the highest contrast between neoplastic and healthy tissue in both models. Systemic labeling with 2H2O can be used to create imaging contrast between tumor and healthy issue, providing a non-radioactive method for in vivo cancer imaging.

Abstract In this study, the rotation of liquid crystal droplets induced by elliptically polarized laser light was investigated using optical tweezers. The rotation mechanism was analyzed based on the arrangement of liquid crystal molecules within the droplets. The change in the rotation behavior of nematic liquid crystal (NLC) droplets was evaluated by varying the droplet size. The experimental results were analyzed based on the waveplate effect and light-scattering process. The rotation behavior of cholesteric liquid crystal droplets was examined by varying the droplet size and helical pitch, which was controlled by the chiral dopant concentration. The results are discussed in terms of the selective reflection of the incident beam by the helical structure. The dependence of the rotation frequency on the ellipticity of the incident beam was also studied. The main contribution to the rotation gradually changes from light transmission to reflection with increasing chirality of the droplet. An NLC rotator system was constructed using holographic optical tweezers. Such an optically controllable rotator is a typical micro-optomechanical device. Complex flow fields, including multiple vortex and localized shear fields, were realized at the micron scale.

Abstract Resistance training (RT) progress is determined by an individual’s muscle strength, measured by one-repetition maximum (1RM). However, this evaluation is time-consuming and has some safety concerns. Bioelectrical impedance analysis (BIA) is a valid and easy-to-use method to assess skeletal muscle mass (SMM). Although BIA measurements are often correlated with muscle strength, few studies of 1RM for RT and BIA measurements are available. This observational study examined the relationship between 1RM and BIA measurements and developed BIA-based prediction models for 1RM. Thirty-five healthy young Japanese adults were included. SMM and the skeletal muscle mass index (SMI) were measured using the BIA device. In addition, dominant-leg 1RM was measured using a unilateral leg-press (LP) machine. The correlations between BIA measurements and 1RM were calculated, and simple regression analyses were performed to predict 1RM from the BIA variables. The results showed significant correlations between 1RM and dominant-leg SMM (R = 0.845, P = 0.0001) and SMI (R = 0.910, P = 0.0001). The prediction models for 1RM for LP derived from SMM of the dominant leg and SMI were Y = 8.21x + 8.77 (P = 0.0001), R2 = 0.73, and Y = 15.53x − 36.33 (P = 0.0001), R2 = 0.83, respectively. Our results indicated that BIA-based SMI might be used to predict 1RM for LP accurately.

Abstract Some asymptomatic patients with diabetes mellitus (DM) have critical coronary artery disease (CAD), although the guidelines do not recommend aggressive screening for CAD in asymptomatic patients. Chronic kidney disease (CKD) is among the serious co-morbidities of severe systemic atherosclerosis. Thus, CKD may be associated with potential myocardial ischaemia. Therefore, the present study aimed to determine the impact of CKD on the incidence of silent myocardial ischaemia (SMI) and the long-term outcomes in asymptomatic patients with DM. This study investigated 461 consecutive patients with DM. All patients who were asymptomatic and self-sufficient in daily life underwent the ergometer exercise (ERG) test. Coronary angiography was performed if the stress test was positive, or if the patient did not achieve 90% of the target heart rate. The primary end point included major adverse cardiac and cerebrovascular events (MACCE) including death, non-fatal myocardial infarction and stroke. The median follow-up duration after study enrolment was 35 months for the entire cohort of 461 patients. Eighty-one patients were diagnosed with SMI. The estimated glomerular filtration rate was significantly lower in the SMI group (70.5 ± 23.8 vs. 81.8 ± 30.0 mL/min/1.73 m2, P stage 3a in the SMI subgroup. Urinary albumin (mg/gCr) was associated with MACCE in the SMI subgroup [HR 3.37, 95%CI (1.170–9.521), P = 0.025] after adjusting for age, sex, and conventional risk factors. SMI was more prevalent in patients with CKD and the incidence was proportional to the CKD stage in asymptomatic patients with DM. Those Patients with CKD and SMI exhibited poor clinical outcomes. CKD may be a key factor for the identification and management of SMI in asymptomatic patients with DM in routine clinical practice. Trial Registration: UMIN000038340.

Abstract A cytokine storm induces acute respiratory distress syndrome, the main cause of death in coronavirus disease 2019 (COVID-19) patients. However, the detailed mechanisms of cytokine induction due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. To examine the cytokine production in COVID-19, we mimicked the disease in SARS-CoV-2-infected alveoli by adding the lysate of SARS-CoV-2-infected cells to cultured macrophages or induced pluripotent stem cell-derived myeloid cells. The cells secreted interleukin (IL)-6 after the addition of SARS-CoV-2-infected cell lysate. Screening of 25 SARS-CoV-2 protein-expressing plasmids revealed that the N protein-coding plasmid alone induced IL-6 production. The addition of anti-N antibody further enhanced IL-6 production, but the F(ab’)2 fragment did not. Sera from COVID-19 patients also enhanced IL-6 production, and sera from patients with severer disease induced higher levels of IL-6. These results suggest that anti-N antibody promotes IL-6 production in SARS-CoV-2-infected alveoli, leading to the cytokine storm of COVID-19.

Abstract In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

Abstract Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized 13C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-13C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized 13C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.

Abstract Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score–matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January–April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388–0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323–2.337; p

Abstract In recent years, non-invasive measurement of tissue stiffness (hardness) using ultrasound elastography has attracted considerable attention. It has been used to evaluate muscle stiffness in the fields of rehabilitation, sports, and orthopedics. However, ultrasonic diagnostic devices with elastography systems are expensive and clinical use of such devices has been limited. In this study, we proposed a novel estimation method for vibration-based shear wave elastography measurement of human skeletal muscle, then determined its reproducibility and reliability. The coefficient of variation and correlation coefficient were used to determine reproducibility and reliability of the method by measuring the shear wave velocities in konjac phantom gels and agar phantom gels, as well as skeletal muscle. The intra-day, day-to-day, and inter-operator reliabilities were good when measuring the shear wave velocities in phantom gels. The intra-day and day-to-day reliabilities were good when measuring the shear wave velocities in skeletal muscle. The findings confirmed adequate reproducibility and reliability of the novel estimation method for vibration-based shear wave elastography. Therefore, the proposed measurement method may be a useful tool for evaluation of muscle stiffness.

Abstract Recent progress in whole genome sequencing has revealed that animals have various kinds of opsin genes for photoreception. Among them, most opsin genes have introns in their coding regions. However, it has been known for a long time that teleost retinas express intron-less rhodopsin genes, which are presumed to have been formed by retroduplication from an ancestral intron-containing rhodopsin gene. In addition, teleosts have an intron-containing rhodopsin gene (exo-rhodopsin) exclusively for pineal photoreception. In this study, to unravel the evolutionary origin of the two teleost rhodopsin genes, we analyzed the rhodopsin genes of non-teleost fishes in the Actinopterygii. The phylogenetic analysis of full-length sequences of bichir, sturgeon and gar rhodopsins revealed that retroduplication of the rhodopsin gene occurred after branching of the bichir lineage. In addition, analysis of the tissue distribution and the molecular properties of bichir, sturgeon and gar rhodopsins showed that the abundant and exclusive expression of intron-containing rhodopsin in the pineal gland and the short lifetime of its meta II intermediate, which leads to optimization for pineal photoreception, were achieved after branching of the gar lineage. Based on these results, we propose a stepwise evolutionary model of teleost intron-containing and intron-less rhodopsin genes.

Abstract The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) system is a rapid gene-targeting technology that does not require embryonic stem cells. To demonstrate dosage effects of the Pax6 gene on eye formation, we generated Pax6-deficient mice with the CRISPR/Cas system. Eyes of founder embryos at embryonic day (E) 16.5 were examined and categorized according to macroscopic phenotype as class 1 (small eye with distinct pigmentation), class 2 (pigmentation without eye globes), or class 3 (no pigmentation and no eyes). Histologically, class 1 eyes were abnormally small in size with lens still attached to the cornea at E16.5. Class 2 eyes had no lens and distorted convoluted retinas. Class 3 eyes had only rudimentary optic vesicle-like tissues or histological anophthalmia. Genotyping of neck tissue cells from the founder embryos revealed somatic mosaicism and allelic complexity for Pax6. Relationships between eye phenotype and genotype were developed. The present results demonstrated that development of the lens from the surface ectoderm requires a higher gene dose of Pax6 than development of the retina from the optic vesicle. We further anticipate that mice with somatic mosaicism in a targeted gene generated by CRISPR/Cas-mediated genome editing will give some insights for understanding the complexity in human congenital diseases that occur in mosaic form.