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Abstract Cockayne syndrome (CS) is a progressive multisystem disorder characterized by growth failure, microcephaly, developmental delay, and photosensitivity. The characteristic symptoms appear during early childhood in most patients with CS. Herein, we report a mild case of CS with a novel start-loss variant in ERCC8 that did not show the characteristic symptoms of CS during early childhood and exhibited sudden growth failure after the age of 10 years.

Abstract Introducing a coating layer at an active material /solid electrolyte interface is crucial for ensuring thermodynamic stability of the solid electrolyte at interfaces in solid-state batteries. To thermodynamically protect the solid electrolyte, coating layers must maintain lithium chemical potential (μ Li) at coating layer/solid electrolyte interfaces within the electrochemical window of the solid electrolyte. However, a general coating layer design principle to achieve this remains unestablished. Here we theoretically elucidate the µ Li distribution across the solid electrolyte and coating layer, examining requirements for thermodynamic protection. We show that the protective capability of coating layers is not solely determined by their intrinsic characteristics, but also by the µ Li distribution within the solid electrolyte and coating layer. We propose a quantitative approach based on µ Li distribution to determine the required characteristics and geometries of coating layers that ensure the thermodynamic stability of the solid electrolyte while minimizing ohmic resistance, providing insights for coating layer design.

Abstract Access to clean water, hygiene, and sanitation is becoming an increasingly pressing global demand, particularly owing to rapid population growth and urbanization. Phytoremediation utilizes a highly conserved phytochelatin in plants, which captures hazardous heavy metal ions from aquatic environments and sequesters them in vacuoles. Herein, we report the design of phytochelatin-inspired copolymers containing carboxylate and thiolate moieties. Titration calorimetry results indicate that the coexistence of both moieties is essential for the excellent Cd2+ ion-capturing capacity of the copolymers. The obtained dissociation constant, K D ~ 1 nM for Cd2+ ion, is four-to-five orders of magnitude higher than that for peptides mimicking the sequence of endogenous phytochelatin. Furthermore, infrared and nuclear magnetic resonance spectroscopy results unravel the mechanism underlying complex formation at the molecular level. The grafting of 0.1 g bio-inspired copolymers onto silica microparticles and cellulose membranes helps concentrate the copolymer-coated microparticles in ≈3 mL volume to remove Cd2+ ions from 0.3 L of water within 1 h to the drinking water level (

Mangroves play a vital role in the environment and contribute signific aptly to the well-being of coastal communities by providing goods and services. Unfortunately, the degradation and deforestation of mangroves has frequently occurred. Therefore, it is important to understand the vulnerability of mangroves and its impact on blue carbon storage for effective mangrove management and coastal planning. This study aims to assess the vulnerability of mangroves and its effect on blue carbon storage in the coral triangle region of Southeast Sulawesi, Indonesia. The vulnerability assessment included factors such as exposure, sensitivity, and adaptive capacity. Blue carbon storage was evaluated based on carbon stock in sediment, biomass, and total carbon stock in mangrove ecosystems in both protected and unprotected areas. The mangrove ecosystem in the protected area of Rawa Aopa Watumohai National (RAWN) Park showed lower vulnerability due to lower exposure, lower sensitivity, and higher adaptive capacity. On the other hand, mangrove ecosystems in unprotected areas such as Tinanggea (TNG), Kendari Bay (KDI), and Staring Bay (STR) exhibited moderate to high vulnerability due to higher exposure, sensitivity, and lower adaptive capacity. Mangroves in RAWN Park, which were less vulnerable, had higher blue carbon storage in sediment (381.64 tons C/ha), biomass (312.65 tons C/ha), and the entire ecosystem (706.76 tons C/ha). These values were significantly higher (p

Abstract Background Natural killer (NK) cells are effective in attacking tumor cells that escape T cell attack. Memory NK cells are believed to function as potent effector cells in cancer immunotherapy. However, knowledge of their induction, identification, and potential in vivo is limited. Herein, we report on the induction and identification of memory-like NK cells via the action of a combination of a stimulator of interferon genes (STING) agonist loaded into lipid nanoparticles (STING-LNPs) and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs), and the potential of the inducted memory-like NK cells to prevent melanoma lung metastasis. Methods The antitumor effects of either the STING-LNPs, CpG-ODNs, or the combination therapy were evaluated using a B16-F10 lung metastasis model. The effect of the combined treatment was evaluated by measuring cytokine production. The induction of memory-like NK cells was demonstrated via flow cytometry and confirmed through their preventative effect. Results The combination of STING-LNPs and CpG-ODNs tended to enhance the production of interleukin 12 (IL-12) and IL-18, and exerted a therapeutic effect against B16-F10 lung metastasis. The combination therapy increased the population of CD11bhighCD27low NK cells. Although monotherapies failed to show preventative effects, the combination therapy induced a surprisingly strong preventative effect, which indicates that CD11bhighCD27low cells could be a phenotype of memory-like NK cells. Conclusion As far as could be ascertained, this is the first report of the in vivo induction, identification, and confirmation of a phenotype of the memory-like NK cells through a prophylactic effect via the use of an immunotherapeutic drug. Our findings provide novel insights into the in vivo induction of CD11bhighCD27low memory-like NK cells thus paving the way for the development of efficient immunotherapies. Graphical Abstract

Recent studies have revealed that stony corals create their extracellular skeletons via biologically controlled calcification, in which amorphous calcium carbonate (ACC), regarded as precursors of aragonite crystals, have been observed at nanoscale using electron microscopy. However, the exact mechanism by which ACC is generated, and how it contributes to skeletal growth in coral calcifying tissue, remains enigmatic. The septal skeleton of an individual polyp is composed of radially aligned plates extending upward from the aboral calcifying tissue. This structure includes microstructure known as the centers of calcification (CoC). However, despite its importance, direct in vivo observation of septal growth has not been reported. Observations under transmitted illumination using polarized light microscopy on calcifying tissue of young Acropora digitifera revealed small crystals, a few micrometers in size, that accompany subtle movements and that emerge exclusively on the inner wall of the pocket in extracellular calcifying fluid (ECF). Crystal growth initiated from small, scattered crystals on a glass plate resembles this phenomenon observed in coral skeletons. Time-lapse photographs of 12 individuals in early primary polyp settlement revealed this process in three individuals, documenting 13 of these crystal events. This phenomenon occurred solely at the bases of subsequently formed septa. These crystals differ notably from fusiform crystals and from dumbbell-like or rod-like crystals growing individually. Upright two-photon microscopy captured movement of sub-micron-sized fluorescent calcein-accumulating particles, emphasizing their presence on the surface of the growing fronts of septa. Methodological advances that facilitate comprehensive in vivo observation of sub-micron-sized structures, calcein-accumulating particles to the skeleton, are needed to develop a more detailed understanding of coral skeletal growth.

Although biogenic carbonates, such as foraminifera and coccolithophorids, are valuable tools for reconstructing past environments, scleractinian corals also offer environmental data from tropical to subtropical regions with a higher time resolution. For example, oxygen isotopes (δ18O) and strontium-calcium (Sr/Ca) ratios have been utilized to reconstruct sea surface temperatures and salinity, primarily through the use of massive-type Porites sp. from the Pacific, as well as corals like Diploria and Montastrea from the Atlantic. While a few types of corals other than Porites have been utilized in paleoclimate studies, comprehensive evaluations of their geochemical tracers as temperature proxies have not been thoroughly conducted. Therefore, in this study, we focused on branching-type Acropora, which are found worldwide and are often present in fossil corals. We conducted a comparison of the chemical compositions (δ18O, δ13C, Sr/Ca, U/Ca, Mg/Ca, and Ba/Ca) of Acropora digitifera and Porites australiensis through temperature-controlled culture experiments. The validity of using the chemical components of A. digitifera as temperature proxies was then evaluated. Three colonies of A. digitifera and P. australiensis were collected for culture experiments on Sesoko Island, Okinawa, Japan. We reared coral samples in seawater with five different temperature settings (18, 21, 24, 27, 30°). The calcification rate and photosynthesis efficiency (Fv/Fm) of each nubbin were measured during the experimental period. After the culture experiment for 77 days, chemical components in skeletal parts grown during the experiment were then measured. Consequently, the mean growth rates and Fv/Fm throughout the experiment were higher for A. digitifera (0.22%/d and 0.63 for growth rate and Fv/Fm) compared to those for P. australiensis (0.11%/d and 0.38 for growth rate and Fv/Fm). This suggests that the higher efficiency of photosynthesis in A. digitifera would promote greater calcification compared to P. australiensis. Regarding the potential use as temperature proxies, A. digitifera exhibited a strong negative correlation, on average, between δ18O and the water temperature (r = 0.95, p< 0.001). The temperature dependency was found to be comparable to that reported in Porites corals (-0.11 and -0.17 ‰/°C for P. australiensis and A. digitifera, respectively). Thus, the δ18O of A. digitifera appeared to be a useful temperature proxy, although it was also slightly influenced by skeletal growth rate at the same temperature. A strong negative correlation was also observed between the mean Sr/Ca ratio and temperature in A. digitifera (r = 0.61, p< 0.001) as well as P. australiensis (r = 0.56, p< 0.001), without a clear influence from the skeletal growth rate. Therefore, the skeletal Sr/Ca ratio in corals may have been primarily influenced by water temperature, although large deviations in Sr/Ca were observed in A. digitifera, even at the same temperature settings. This deviation can be reduced by subsampling an apical part of a polyp including the axis of skeletal growth. The U/Ca ratio of A. digitifera appeared to be affected by internal pH variation within the corals, especially at 30°C. Similar to U/Ca ratios, metabolic and kinetic effects on corals were observed in δ13C of A. digitifera at 18 and 30°C. In addition, considering the variation pattern of both U/Ca and δ13C of A. digitifera at 30°C, it has been suggested that respirations may overwhelm photosynthesis for coral samples at 30°C. Therefore, the U/Ca and δ13C of A. digitifera could potentially be used as proxies of biomineralization processes, whereas the δ18O and Sr/Ca displayed a high possibility of acting as temperature proxies.

In cruciate-retaining total knee arthroplasty (CR-TKA), intraoperative posterior cruciate ligament (PCL) management is necessary because retention of optimum PCL tension with high reproducibility is difficult. If PCL management is not performed appropriately, problems such as postoperative pain, poor range of motion, and a feeling of instability may occur. The posterior tibial slope (PTS) has a major influence on the tension of the PCL in CR-TKA. Changes in femoral posterior condylar offset also influences PCL tension in CR-TKA. We designed a surgical procedure in which the PTS is adjusted in association with the posterior condylar offset during surgery. The postoperative clinical results of the primary total knee arthroplasty 159 knee performed by this procedure were favorable. In addition, none of the knees required management of PCL. In our procedure, PCL management, which is the main problem in CR-TKA, is not necessary, and this may be the main advantage of the new procedure.

Background: Urate-lowering drugs (ULDs) have been approved for treatment of asymptomatic hyperuricemia and gout in Japan. Although serum urate levels and rates of gout onset are known to have seasonal variations, no survey results regarding the seasonality of ULD prescriptions for asymptomatic hyperuricemia and gout have been reported.Methods: A large-scale database of medical claims in Japan filed between January 2019 and December 2022 was accessed. In addition to total size of the recorded population for each month examined, the numbers of patients every month with newly prescribed ULDs for asymptomatic hyperuricemia and gout were noted, based on the International Classification of Diseases, 10th Revision, codes E79.0 and M10.Results: The results identified 201,008 patients with newly prescribed ULDs (median age 49.0 years, male 95.6%). Of those, 64.0% were prescribed ULDs for asymptomatic hyperuricemia and 36.0% for gout. The proportion of new ULD prescriptions was seasonal, with that significantly (p < 0.001) higher in summer (June–August) [risk ratio (RR) 1.322, 95% CI 1.218 to 1.436] and autumn (September–November) (RR 1.227, 95% CI 1.129–1.335) than in winter (December–February), whereas the proportion in spring (March–May) was not significantly different from winter. There was no significant difference after stratification by drug type (uric acid production inhibitor/uricosuric agent) or size of the medical institution, nor subgrouping by age or sex (p for interaction = 0.739, 0.727, 0.886, and 0.978, respectively). On the other hand, the proportions of new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and for gout significantly higher in spring than winter, while those were similar in summer and autumn for both groups (p for interaction

Red blood cells (RBCs) are renewed in a cyclic manner. Aging RBCs are captured and degraded by phagocytic cells, and heme metabolic pigments are subsequently excreted in feces. We evaluated the effect of an organogermanium compound on RBC metabolism and found that the phagocytosis of RAW264.7 macrophage-like cells was increased by treatment with 3-(trihydroxygermyl)propanoic acid (THGP). Additionally, consumption of Ge-132 (a dehydrate polymer of THGP) changed the fecal color to bright yellow and increased the erythrocyte metabolic pigment levels and antioxidant activity in feces. These data suggest that Ge-132 may activate macrophages in the body and promote the degradation of aged RBCs. Furthermore, Ge-132 intake promoted not only increases in RBC degradation but also the induction of erythroblast differentiation in bone marrow cells. The normal hematocrit levels were maintained due to the maintenance of homeostasis, even though Ge-132 ingestion increased erythrocyte degradation. Therefore, Ge-132 enhances the degradation of senescent RBCs by macrophages. In turn, RBC production is increased to compensate for the amount of degradation, and RBC metabolism is increased.

A 52-year-old man who had received hemodialysis via a left radial–cephalic arteriovenous fistula (AVF) for 18 years presented with severe ischemic symptoms in the left upper arm 12 years after occlusion of the AVF. Diagnostic imaging revealed thrombotic occlusion from a left axillary–brachial artery aneurysm, which required distal bypass surgery. The inflow artery of an AVF can develop aneurysmal degeneration, resulting in upper limb ischemia by embolization or decreased flow, especially with a ligated or occluded AVF or immunosuppressive therapy after renal transplantation. In such cases, the AVF should be monitored, even if ligated or occluded.

Background: Xanthine oxidoreductase (XOR) inhibitor administration, known to reduce uric acid and reactive oxygen species (ROS) production, also improves vascular endothelial function (VEF). This cross-sectional study examined our hypothesis that XOR contributes to impaired VEF through ROS but not uric acid production. Methods: In 395 subjects (196 males, 199 females) without urate-lowering agent administration who underwent a health examination, plasma XOR activity was determined using our highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. For VEF evaluation, flow-mediated dilatation (FMD) in the brachial artery was determined by ultrasound, with physical and laboratory measurements also obtained. Results: The median values for plasma XOR activity, serum uric acid, and FMD were 26.6 pmol/h/mL, 5.4 mg/dL, and 6.2%, respectively. Simple regression analysis showed weak correlations of both log plasma XOR activity and serum uric acid level with FMD (r = −0.213, p

Mesophotic habitats are potential refugia for corals in the context of climate change. The seawater temperature in a mesophotic habitat is generally lower than in a shallow habitat. However, the susceptibility and threshold temperatures of mesophotic corals are not well understood. We compared 11 mesophotic and shallow species to understand their thermal stress thresholds using physiological parameters. Coral fragments were exposed to two thermal stress treatments, with temperatures set at ~30°C and ~31°C, and a low-temperature treatment set at ~28°C as the “no stress” condition for 14 days. We found that the threshold temperature of coral species at mesophotic depths is slightly lower or equal to that of corals in shallow depths. The results suggest that species in the mesophotic coral ecosystems can survive low (

This paper presents new findings on partial discharge (PD) phenomena under high-repetition nanosecond pulsed voltages, essential for the insulation design of electrical motors fed by silicon carbide (SiC) inverters with high-switching frequencies. Here, a twisted pair sample simulating the turn-to-turn insulation of a random-wound motor coil winding was subjected to high-repetition nanosecond pulsed voltages generated by a SiC inverter-based pulse generator. In this experiment, the rise time at a pulsed voltage of 1.5 kV is 23 ns, the pulse width is 500 ns, and the pulsed repetition frequency (PRF) ranges from 60 pps to 1 Mpps. In this PRF range, the partial discharge inception voltage (PDIV) was found to be almost constant. Meanwhile, the repetitive partial discharge inception voltage (RPDIV) significantly reduced when the PRF exceeded several tens of kpps. Under high PRF conditions, the high-density ions produced by the preceding PD remain in the gap space between enameled wires during the pulse-off period and contribute significantly to the initiation of subsequent PD. The resulting increase in the probability of PD occurrence reduces the RPDIV. Unlike previous reports, this study clarified the difference in the frequency characteristics between PDIV and RPDIV, providing valuable reference data for the insulation design of SiC inverter-fed motors. Based on the obtained results, we propose revising the IEC60034-18-41 standard, which verifies a PD-free system, to incorporate the effect of the pulsed voltage waveform of SiC inverters.

Study Design Prospective multicenter clinical study. Purpose To evaluate the efficacy of bioactive surface treatment for porous titanium spacers without bone graft for lateral lumbar interbody fusion (LLIF) through clinical and radiological examinations. Overview of Literature LLIF is a minimally invasive spinal fusion procedure. To achieve bony union, a substantial volume of grafted bone is typically packed into the cage; however, this is related to donor site morbidities—one of the disadvantages of LLIF. Methods For this prospective multicenter study, 40 patients were followed up through radiologic and clinical examinations for at least 1 year postoperatively. All surgical procedures were either single- or double-level LLIF using bioactive porous titanium spacers without bone grafts. Results Four patients were excluded from the study owing to aggravation from other comorbidities. Another 36 patients, including 26 and 10 with single- and double-level LLIFs, respectively, participated in the follow-up. The mean age at the time of surgery was 63.7 years. The mean operating time was 50.5 minutes per level. The mean estimated intraoperative blood loss was 11.6 mL per level. Clinical scores improved in all cases and were maintained throughout the follow-up period. The intervertebral bony union rates were 67.4% and 84.8% at 6 and 12 months, respectively. Endplate cyst signs were observed in 13.0% and 8.7% of patients at 6 and 12 months, respectively. Fused segmental angles were maintained throughout the follow-up period, indicating no cage subsidence. Conclusions Single- and double-level LLIFs using bioactive porous titanium spacers without bone grafts were found to be minimally invasive, resulting in clinical and imaging results comparable with conventional procedures. Therefore, this type of implant may be an option for minimally invasive spinal fusion surgery.

A multi-year stress experiment with broadcast spawning coral reveals that colonies exposed to a marine heatwave shift their reproductive strategy towards smaller but more numerous eggs, which, together with physiological acclimation, confers resilience to subsequent thermal stress.

BackgroundA rat model of levodopa-induced dyskinesia (LID) showed enlarged axon terminals of striatal direct pathway neurons in the internal segment of the globus pallidus (GPi) with excessive gamma-aminobutyric acid (GABA) storage in them. Massive GABA release to GPi upon levodopa administration determines the emergence of LID.ObjectivesWe examined whether LID and axon terminal hypertrophy gradually develop with repeated levodopa treatment in Parkinsonian rats to examine if the hypertrophy reflects dyskinesia priming.Methods6-hydroxydopamine-lesioned hemiparkinsonian rats were randomly allocated to receive saline injections (placebo group, 14 days; n = 4), injections of 6 mg/kg levodopa methyl ester combined with 12.5 mg/kg benserazide (levodopa-treated groups, 3-day-treatment; n = 4, 7-day-treatment; n = 4, 14-day-treatment; n = 4), or injections of 6 mg/kg levodopa methyl ester with 12.5 mg/kg benserazide and 1 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin for 14 days (8-OH-DPAT-treated group; n = 4). We evaluated abnormal involuntary movement (AIM) scores and axon terminals in the GPi.ResultsThe AIM score increased with levodopa treatment, as did the hypertrophy of axon terminals in the GPi, showing an increased number of synaptic vesicles in hypertrophied terminals.ConclusionIncreased GABA storage in axon terminals of the direct pathway neurons represents the priming process of LID.

Pineapple by-products are good sources of bromelain, a complex enzyme with commercial applications. This study evaluated the feasibility of producing bromelain powders from pineapple waste using an organic solvent-free approach. Pineapple by-products (from var. MD2), including cores, peels, crowns, stems, and basal stems, were homogenized with deionized water, and the pH of the mixture was adjusted to 4.5 and 9 (isoelectric points of fruit bromelain and stem bromelain), clarified, ultra-filtered, and freeze-dried to produce bromelain powders. The enzymatic activity of the bromelain powders was measured using the gelatin and casein digestion methods. The bromelain powders from the crowns did not show significant enzymatic activity (p < 0.05). Meanwhile, bromelain powders produced from the cores and peels had an enzymatic activity of 694 gelatin digesting units (GDU)/g and 124 casein digesting units (CDU)/mg, and 1179 GDU/g and 217 CDU/mg, respectively. Bromelain powders from the basal stems showed the highest enzymatic activity (2909 GDU/g and 717 CDU/mg). Increasing the pH of the liquid mixture before the purification and freeze drying significantly (p < 0.05) reduced the enzymatic activity of the bromelain powders. Using a practical and organic solvent-free approach, this study demonstrates the feasibility of producing bromelain powders with high enzymatic activity from pineapple waste.

Metastatic renal cell carcinoma (RCC) has a poor prognosis, and the major organ of metastasis is the lung. Immunotherapy with immune checkpoint inhibitors (ICIs) is the first-line therapy, but the response rates are low. Thus, the development of a more effective immunotherapy against metastatic RCC would be highly desirable. We previously demonstrated how a stimulator of an interferon gene (STING) agonist-loaded lipid nanoparticles (STING-LNPs) significantly activates natural killer (NK) cells and induces an antitumor effect against cases of melanoma lung metastasis that have shown ICI resistance. In this study, we evaluated the potential of using STING-LNPs in the treatment of lung metastatic RCC (Renca). An intravenous injection of STING-LNPs drastically decreased the amount of Renca tumor colonies. In contrast, monotherapies using ICIs showed no antitumor effect, and even a combination of ICI and STING-LNP therapies failed to enhance the antitumor effects. The main effector cells would be NK cells, and the activation of NK cells by the STING-LNPs may avoid the increased expression of immune checkpoint molecules. These findings provide useful insights into the development of an effective immunotherapy against metastatic RCC.

Abstract Hyperuricemia causes gout and has also been associated with metabolic syndrome and cardiovascular disease. Uric acid‐lowering drugs (ULDs) are used to reduce uric acid levels for the treatment of hyperuricemia and gout. However, there is a lack of robust and real‐world data on the history and treatment of patients with newly diagnosed hyperuricemia or gout in Japan. This retrospective, longitudinal, historical cohort study determined the characteristics of patients with hyperuricemia and/or gout, and prescription of, and adherence to, ULDs using data from the JMDC Claims Database. The primary evaluation population included 64 677 patients with newly diagnosed hyperuricemia and/or gout. Of these, only 26 501 (41.0%) had a prescription for ULDs at diagnosis. Even when ULDs were prescribed, the persistence rate of prescriptions declined over time, with a 54.4% persistence rate for ULDs at 12 months after the index diagnosis. In subgroups of patients with or without hypertension and diabetes, the rate of ULD prescription continuation was significantly higher in those with comorbidities than in those without (76.8% vs. 42.6% in those with vs. without hypertension, and 78.7% vs. 52.2% in those with vs. without diabetes). These finding suggest that therapeutic interventions to lower serum uric acid levels are under‐utilized for patients with newly diagnosed hyperuricemia and/or gout in Japan.

Abstract Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden. Physical exercise at times can be an effective remedy for frailty, but exercise therapy cannot be applied in all clinical cases. Medication is safer than exercise, but there are no drugs that reinforce both muscle and bone when administered alone. Multiple medications increase the risk of adverse events; thus, there is a need for individual drugs targeting both tissues. To this end, we established a novel sequential drug screening system and identified an aminoindazole derivative, locamidazole (LAMZ), which promotes both myogenesis and osteoblastogenesis while suppressing osteoclastogenesis. Administration of this drug enhanced locomotor function, with muscle and bone significantly strengthened. Mechanistically, LAMZ induced Mef2c and PGC-1α in a calcium signaling–dependent manner. As this signaling is activated upon physical exercise, LAMZ mimics physical exercise. Thus, LAMZ is a promising therapeutic drug for locomotor diseases, including sarcopenia and osteoporosis.

Abstract The enzyme xanthine oxidoreductase (XOR) catalyzes the synthesis of uric acid (UA) from hypoxanthine and xanthine, which are products of purine metabolism starting from ribose-5-phosphate. Several studies suggested a relationship between hyperuricemia and hepatic steatosis; however, few previous studies have directly examined the relationship between XOR activity and hepatic steatosis. A total of 223 subjects with one or more cardiovascular risk factors were enrolled. The liver-to-spleen (L/S) ratio on computed tomography and the hepatic steatosis index (HSI) were used to assess hepatic steatosis. We used a newly developed highly sensitive assay based on [13C2, 15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry to measure plasma XOR activity. Subjects with the L/S ratio of

Intramembranous and endochondral bone formation have been considered to be independent processes mediated by independent stem cells. Here the authors show that periosteal stem cells participate in both types of bone formation, supporting endochondral formation by producing Ihh.

Abstract Mesophotic coral ecosystems (MCEs, reefs between 30 and 150 m depth) have been hypothesized to contribute to shallow reef recovery through the recruitment of larvae. However, few studies have directly examined this. Here we used mesophotic colonies of Seriatopora hystrix, a depth generalist coral, to investigate the effect of light intensity on larval behavior and settlement through ex situ experiments. We also investigated juvenile survival, growth, and physiological acclimation in situ. Bleached larvae and a significant reduction in settlement rates were found when the mesophotic larvae were exposed to light conditions corresponding to shallow depths (5 and 10 m) ex situ. The in situ experiments showed that mesophotic juveniles survived well at 20 and 40 m, with juveniles in shaded areas surviving longer than three months at 3–5 m during a year of mass bleaching in 2016. Juvenile transplants at 20 m showed a sign of physiological acclimation, which was reflected by a significant decline in maximum quantum yield. These results suggest that light is a significant factor for successful recolonization of depth-generalist corals to shallow reefs. Further, recolonization of shallow reefs may only occur in shaded habitats or potentially through multigenerational recruitments with intermediate depths acting as stepping stones.

Abstract We previously found an association of insulin resistance (IR) with plasma xanthine oxidoreductase (XOR) activity in a cross-sectional study. However, whether IR induces increased XOR activity has not been elucidated. This retrospective longitudinal observational study included 347 participants (173 males, 174 females) who underwent annual health examinations and were medication naïve. Homeostasis model assessment of IR (HOMA-IR) index, and physical and laboratory measurements were determined at the baseline. At baseline and 12-month follow-up examinations, plasma XOR activity was determined using our novel assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Subjects with IR, defined as HOMA-IR index ≥ 1.7 (n = 92), exhibited significantly (p

Abstract The initial stage of fatigue failure has not been thoroughly clarified for carbon fiber reinforced plastics (CFRPs). Although the initiation of fatigue cracks has been regarded to be interfacial debonding between the carbon fiber and polymer matrix, their detection among numerous carbon fibers, whose diameter is only 7 µm, is extremely difficult. In this study, a single carbon fiber was transversely embedded in a dumbbell-shaped epoxy sample to focus on the interfacial debonding and was observed using synchrotron radiation (SR) X-ray computed tomography (CT). A tabletop fatigue testing machine driven by a piezoelectric actuator was developed to apply static and cyclic loads along the beamline. SR X-ray multiscale CT imaging was conducted by switching between an absorption-contrast projection method (micro-CT) and a phase-contrast imaging-type X-ray microscopic CT (nano-CT). The carbon fiber was entirely captured by micro-CT and then magnified at both ends on the free surfaces. Nano-CT clearly visualized the interfacial debonding under 30 MPa static tensile load and the implication of the coalescence of nano-voids along the interface under 50 MPa. Under cyclic loads, the interfacial debonding gradually progressed under a 8–40 MPa sinusoidal stress after 10,000 cycles, whereas it did not propagate under a stress below 30 MPa.

Abstract Aiming development of the fast anion conductors, we proposed a new material design using flexible molecular cation as a host cation, and demonstrated it with fluoride ion conduction in NH4MgF3 and (NH4)2MgF4 based materials. Dominant fluoride ion conduction with relatively high conductivities of 4.8 × 10–5 S cm−1 and 8.4 × 10–6 S cm−1 were achieved at 323 K in (NH4)2(Mg0.85Li0.15)F3.85 and NH4(Mg0.9Li0.1)F2.9, respectively. It is implied that the molecular cation in the host lattice can assist the anion conduction. Our findings suggest molecular cation-containing compounds can be attractive material groups for fast anion conductors.

Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132), an organogermanium, is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) in aqueous solutions, and reduces inflammation, pain and cancer, whereas the underlying mechanisms remain unknown. Sulfides including H2S, a gasotransmitter, generated from l-cysteine by some enzymes including cystathionine-γ-lyase (CSE), are pro-nociceptive, since they enhance Cav3.2 T-type Ca2+ channel activity expressed in the primary afferents, most probably by canceling the channel inhibition by Zn2+ linked via coordinate bonding to His191 of Cav3.2. Given that germanium is reactive to sulfur, we tested whether THGP would directly trap sulfide, and inhibit sulfide-induced enhancement of Cav3.2 activity and sulfide-dependent pain in mice. Using mass spectrometry and 1H NMR techniques, we demonstrated that THGP directly reacted with sulfides including Na2S and NaSH, and formed a sulfur-containing reaction product, which decreased in the presence of ZnCl2. In Cav3.2-transfected HEK293 cells, THGP inhibited the sulfide-induced enhancement of T-type Ca2+ channel-dependent membrane currents. In mice, THGP, administered systemically or locally, inhibited the mechanical allodynia caused by intraplantar Na2S. In the mice with cyclophosphamide-induced cystitis and cerulein-induced pancreatitis, which exhibited upregulation of CSE in the bladder and pancreas, respectively, systemic administration of THGP as well as a selective T-type Ca2+ channel inhibitor suppressed the cystitis-related and pancreatitis-related visceral pain. These data suggest that THGP traps sulfide and inhibits sulfide-induced enhancement of Cav3.2 activity, leading to suppression of Cav3.2-dependent pain caused by sulfide applied exogenously and generated endogenously.

Background: Topiroxostat, an inhibitor of xanthine oxidoreductase (XOR) was shown to reduce urinary albumin excretion of hyperuricemic patients with chronic kidney disease. However, its pharmacological mechanism is not well understood. In this study, we examined the effects of topiroxostat on glomerular podocytes. Podocyte is characterized by foot process and a unique cell-cell junction slit diaphragm functioning as a final barrier to prevent proteinuria. Methods: The effects of topiroxostat on the expressions of podocyte functional molecules were analysed in db/db mice, a diabetic nephropathy model, anti-nephrin antibody-induced rat podocyte injury model and cultured podocytes treated with adriamycin. Results: Topiroxostat treatment ameliorated albuminuria in db/db mice. The expression of desmin, a podocyte injury marker was increased, and nephrin and podocin, key molecules of slit diaphragm, and podoplanin, an essential molecule in maintaining foot process were downregulated in db/db mice. Topiroxostat treatment prevented the alterations in the expressions of these molecules in db/db mice. XOR activity in kidney was increased in rats with anti-nephrin antibody-induced podocyte injury. Topiroxostat treatment reduced XOR activity and restored the decreased expression of nephrin, podocin and podoplanin in the podocyte injury. Furthermore, topiroxostat enhanced the expression of podoplanin in injured human cultured podocytes. Conclusions: Podocyte injury was evident in db/db mice. Topiroxostat ameliorated albuminuria in diabetic nephropathy model by preventing podocyte injury. Increase of XOR activity in kidney contributes to development of podocyte injury caused by stimulation to slit diaphragm. Topiroxostat has an effect to stabilize slit diaphragm and foot processes by inhibiting the reduction of nephrin, podocin and podoplanin. Resumen: Antecedentes: El topiroxostat, un inhibidor de la xantina oxidorreductasa (XOR), mostró reducir la excreción de albúmina en la orina de pacientes hiperuricémicos con enfermedad renal crónica. Sin embargo, su mecanismo farmacológico no se conoce con exactitud. En este estudio examinamos los efectos del topiroxostat en los podocitos glomerulares. El podocito se caracteriza por unas prolongaciones en forma de pie y un diafragma de hendidura de unión célula-célula único que funciona como barrera final en la prevención de la proteinuria. Métodos: Se analizaron los efectos del topiroxostat en las expresiones de las moléculas funcionales de los podocitos en ratones db/db, en un modelo de nefropatía diabética, en un modelo de lesión podocitaria inducida por anticuerpos antinefrina en ratas y en podocitos cultivados tratados con adriamicina. Resultados: El tratamiento con topiroxostat mejoró la albuminuria en ratones db/db. La expresión de la desmina, un marcador de lesión podocitaria, estaba aumentada, y la nefrina y la podocina, moléculas clave del diafragma de hendidura, y la podoplanina, una molécula esencial en el mantenimiento de las prolongaciones en forma de pie, estaban atenuadas en los ratones db/db. El tratamiento con topiroxostat evitó alteraciones en las expresiones de estas moléculas en los ratones db/db. La actividad de la XOR en el riñón se incrementó en ratas con lesión podocitaria inducida por anticuerpos antinefrina. El tratamiento con topiroxostat redujo la actividad de la XOR y restauró la disminución de la expresión de nefrina, podocina y podoplanina en la lesión podocitaria. Además, el topiroxostat aumentó la expresión de podoplanina en podocitos humanos cultivados lesionados. Conclusiones: La lesión podocitaria era evidente en ratones db/db. El topiroxostat mejoró la albuminuria en el modelo de nefropatía diabética al prevenir la lesión podocitaria. El aumento de la actividad de la XOR en el riñón contribuye al desarrollo de la lesión podocitaria causada por la estimulación del diafragma de hendidura. El topiroxostat tiene un efecto de estabilización del diafragma de hendidura y de las prolongaciones en forma de pie al inhibir la reducción de nefrina, podocina y podoplanina.

Corals in the northern Red Sea exhibit high thermal tolerance despite the increasing heat stress. It is assumed that corals throughout the Red Sea have similar bleaching thresholds (32°C or higher), and hence greater bleaching tolerance of corals in the northern Red Sea region is likely due to lower ambient water temperatures (25–28°C) that remain well below the corals’ physiological maxima. Whether bleaching patterns across the Red Sea are independent of the local maximum monthly mean of seawater temperature and aligned with an assumed 32°C threshold has yet to be determined. Here, we used remotely sensed surface sea temperature data spanning 1982–2020 to model spatial distributions of Degree Heat Weeks across the Red Sea in relation to assumed coral thermal threshold values of 30, 31, and 32°C. We also used the Coupled Model Intercomparison Project Phase 5 model outputs to predict warming trends in the Red Sea under different greenhouse gas representative concentration pathways (RCPs). We show that applying 32°C thresholds dramatically reduces effective Degree Heat Weeks in the north, but not in central or southern Red Sea regions, a finding that is consistent with historical bleaching observations (1998–2020) throughout the Red Sea. Further, model predictions under the most extreme RCP8.5 scenario exhibited ~3°C warming by the end of the 21st century throughout the Red Sea with less pronounced warming for the northern Red Sea (2–2.5°C) compared to the central and southern regions (2.7–3.1°C).This warming rate will remain below the assumed thermal threshold for the northern Red Sea which should help this region to serve as refugia (i.e., maintaining favorable temperatures) for corals to persist for decades ahead. Together, our results support the notion that corals have similar thresholds throughout the Red Sea; hence, coral bleaching thresholds are independent of the local maximum monthly mean. Consequently, where regional warming projections suggest the northern Red Sea will not reach assumed bleaching thresholds (32°C) before the end of the 21st century, coral reefs in the northern region may be among the last standing against climate change.

Inner ear macrophages play a vital role in cochlear homeostasis. Recent studies have demonstrated the existence of macrophages at different sites of the cochlea, with increased cochlear infiltration as an inflammatory response mechanism to injury. However, current methods, such as conventional immunohistochemistry and flow cytometry, provide limited information about the diversity of cochlear macrophages. Recently, multiplex immunohistochemistry (mIHC) successfully identified the heterogeneity of immune cells in cancer tissue and thereby improved our understanding of the disease prognosis. In this study, we modified the mIHC technique for cochlear tissue and utilized it to investigate cochlear macrophage behavior and heterogeneity before and after exposure to ototoxic drugs such as cisplatin. Four-week-old C57BL/6N female mice were intraperitoneally injected with cisplatin at 5 mg/kg/day consecutively for 6 days. Their hearing levels were assessed before and after the injection. Their cochleae were harvested before (day 0) and on days 8 and 15 after the cisplatin injection. Paraffin-embedded sections were sequentially immunostained using macrophage surface markers to identify the different categories of macrophages. Each immunostaining cycle included incubation with primary antibody, incubation with secondary antibody, chromogenic staining, and image scanning. Thereafter, all antibodies were stripped out, and antigen retrieval was performed to prepare the tissue for the next cycle. The results revealed that activated cochlear macrophages were not entirely differentiated into M1 or M2 categories but into multi-marker M1/M2 mixed macrophages. Furthermore, the ratio of these mixed (M1/M2) macrophages to Iba1+ macrophages increased in the auditory nerve after cisplatin exposure, suggesting local auditory nerve inflammation. The increase in the population of activated macrophages in the auditory nerve region was concomitant with the temporary shift of hearing threshold on day 8 post-cisplatin injection. The findings of this study indicate the effectiveness of mIHC in identifying cochlear macrophage heterogeneity both in the resting state and after cisplatin exposure. Therefore, mIHC could be a powerful tool in cochlear immunology research. Our findings may provide new insights into the co-relation between the cochlear macrophage and cisplatin exposure.

Congenital atresia of the common and external iliac arteries is an extremely rare vascular anomaly, although often associated with limb ischemia and genitourinary malformations. We have presented a rare case of the congenital absence of the left common and external iliac arteries, with no limb ischemic symptoms or organ anomalies present.

Abstract Aims/Introduction Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short‐term glycemic control treatment. Materials and Methods We enrolled 28 Japanese patients (10 men/18 women) with type 2 diabetes mellitus who were hospitalized to undergo medical treatment for diabetes. Plasma XOR activity, quantified using triple quadrupole mass spectrometry and liquid chromatography, and other clinical parameters were examined at admission and 2 weeks after treatment during hospitalization. Changes in plasma XOR activity after treatment during hospitalization and associated clinical parameters were assessed. Results At the time of admission, the median plasma XOR activity was 83.1 pmol/h/mL, with a wide range of 14.4–1150 pmol/h/mL. Multiple regression analysis identified serum aspartate transaminase and alanine transaminase levels as significant and independent factors correlating with the baseline plasma XOR. Two weeks of treatment during hospitalization was associated with a significant decrease in plasma XOR activity. Changes in serum aspartate transaminase were also the only significant and independent factor correlating with changes in plasma XOR activity. Conclusions A close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes mellitus, cross‐sectionally, and also across treatment during hospitalization.

We experimentally evaluated the influence of stress on the Li chemical potential (μLi) and phase equilibrium in the two-phase battery electrode materials through the emf measurements while applying a mechanical load. In our measurements, we prepared an electrochemical cell by depositing a thin film of a two-phase electrode material (LiFePO4 or LiCoO2 in the two-phase region) on each of the solid electrolyte surfaces. Then we applied a mechanical load to the electrochemical cell through four-point bending, and the resulting μLi variation in the electrode material was measured as the emf between the two thin films. Our results indicated that μLi in the two-phase electrode materials immediately changed just after loading and then gradually changed while maintaining a constant mechanical load. Besides, the loading and unloading led to the μLi variation in the opposite direction. Such characteristic μLi variations could be explained by considering the change in the phase equilibrium between the two phases, which led to the Li content variation in the two phases and the stress relaxation due to the volume fraction variation of the two phases. Our results can provide valuable insights regarding the influence of stress on the performances of energy storage devices with two-phase electrode materials.

Abstract Background We evaluated malignancy according to the characteristics of pericardial fluid in symptomatic Japanese patients undergoing pericardiocentesis and computed tomography (CT). Methods This was a retrospective, single-center, observational study of 125 symptomatic patients undergoing pericardiocentesis. The patients were classified into two groups: a malignancy group and a non-malignancy group, according to the primary disease and cytology of the pericardial effusion (PE). We compared the pericardial fluid sample and CT measurements between both groups. Results All patients were diagnosed as having exudative PE by Light’s criteria. PE with malignant cells was demonstrated in 76.8% of the malignancy group patients. Pericardial to serum lactate dehydrogenase (LDH) ratio > 0.6, as one of Light’s criteria, was associated with malignancy (p = 0.017). Lower serum brain natriuretic peptide (BNP) concentration was also associated with malignancy (BNP: 126.9 ± 89.8 pg/ml vs 409.2 ± 97.7 pg/ml, malignancy vs non-malignancy groups, respectively; p = 0.037). A significant difference was observed in pericardial fluid glucose level between the malignancy and non-malignancy groups (pericardial fluid glucose: 78.24 ± 48.29 mg/dl vs 98.41 ± 44.85, respectively; p = 0.048). Moreover, CT attenuation values (Hounsfield units (HU)) tended to be higher in the malignancy group vs the non-malignancy group (22.7 [interquartile range (IQR), 17.4–26.0] vs 17.4 [IQR, 13.7–26.4], respectively; p = 0.08). The sensitivity and specificity of pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were 40.9% and 89.6%, respectively, in the malignancy group. The positive- and negative predictive values of pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were 85.7% and 50.0%, respectively, in the malignancy group. Pericardial fluid glucose level ≤ 70 mg/dl and CT attenuation values > 20 HU were cutoff values associated with malignancy (p = 0.012). Conclusions Lower pericardial fluid glucose level with higher CT attenuation values may suggest malignancy-related PE.

The purpose of this study was to introduce our patient-specific bioactive porous titanium implant manufactured using selective laser melting (SLM) and to establish the efficacy and safety of the implant for stand-alone anterior cervical discectomy and fusion (ACDF) based on a prospective clinical trial. We designed a customized ACDF implant using patient-specific data and manufactured the implant using SLM. We produced a bioactive surface through a specific chemical and thermal treatment. Using this implant, we surgically treated four patients with cervical degenerative disc disease and evaluated the clinical and radiological results. We achieved successful bony union in all but one patient without autologous bone grafting within 1 year. We observed no implant subsidence during the follow-up period, and all clinical parameters improved significantly after surgery, with no reported implant-related adverse effects. Our customized bioactive porous titanium implant is a safe and promising implant for stand-alone ACDF.

Introduction: Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. Methods: In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57–75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (13C2,15N2) xanthine and liquid chromatography/triple quadrupole mass spectrometry. Results: Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (n = 26) than in those without (n = 92) DM (62.7 [32.3–122] vs. 25.7 [13.4–45.8] pmol/h/mL, p < 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (n = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. Conclusions: These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.