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Background/aim: The therapeutic efficacy of the paclitaxel (PTX) + cetuximab (Cmab) combination regimen was investigated in patients with recurrence or metastasis after superselective intraarterial chemoradiotherapy (SSIACRT) for oral cancer, and the safety was retrospectively examined., Patients and Methods: All enrolled patients with advanced oral cancer or who had refused surgery over 10 years from December 2012 to December 2022 underwent SSIACRT for 6 to 9 weeks [cisplatin (CDDP): total 160-630 mg/m 2  and radiotherapy: total 50-70 Gy]. Nine cases (tongue cancer, maxillary gingival cancer, and mandibular gingival cancer; three cases each) were subjected to PTX + Cmab therapy. Recurrence or metastases were observed within six months after the onset of treatment, complicating the conduct of salvage surgery. Cmab (first dose: 400 mg/m 2  and second and following doses: 250 mg/m 2 ) and PTX (80 mg/m 2 ) were administered weekly., Results: The overall response rate was 44.4% (four of nine cases), and the disease control rate was 88.9% (eight of nine cases), whereas the median progression-free survival was seven months, and the overall survival was 11 months. Grade 3-4 adverse events were neutropenia in 33.3% of the cases, leukopenia in 55.6%, anemia in 22.2%, and acneiform skin rash in 22.2%. Based on the above, PTX + Cmab therapy for recurrent and metastatic cases after SSIACRT had comparable results to other second-line modalities and enabled to cope with the side effects of myelosuppression., Conclusion: PTX + Cmab therapy may be an effective treatment mode for recurrent or metastatic head and neck cancer resistant to CDDP after SSIACRT treatment., Competing Interests: Kaname Sakuma, Tomoyuki Kii, Toko Machida, Yosuke Kikuchi, Masaki Yoda, Shuji Toya, and Akira Tanaka declare that they have no conflict of interest in relation to this study., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

Interleukin (IL) 36 is a member of the IL-1-like proinflammatory cytokine family that has a protective role in mucosal immunity. We hypothesized that mucosal delivery of IL-36γ to the intestine would be a very effective way to prevent intestinal diseases. Here, we genetically engineered a lactic acid bacterium, Lactococcus lactis, to produce recombinant mouse IL-36γ (rmIL-36γ). Western blotting and enzyme-linked immunosorbent assay results showed that the engineered strain (NZ-IL36γ) produced and hypersecreted the designed rmIL-36γ in the presence of nisin, which induces the expression of the recombinant gene. We administered NZ-IL36γ to mice via oral gavage, and collected the ruminal contents and rectal tissues. Colony PCR using primers specific for NZ-IL36γ, and enzyme-linked immunosorbent assay to measure the rmIL-36γ concentrations of the ruminal contents showed that NZ-IL36γ colonized the mouse intestines and secreted rmIL-36γ. A microbiota analysis revealed increased abundances of bacteria of the genera Acetatifactor, Eubacterium, Monoglobus, and Roseburia in the mouse intestines. Real-time quantitative PCR of the whole colon showed increased Muc2 expression. An in vitro assay using murine colorectal epithelial cells and human colonic cells showed that purified rmIL-36γ promoted Muc2 gene expression. Taken together, these data suggest that NZ-IL36γ may be an effective and attractive tool for delivering rmIL-36γ to improve the intestinal environment., (© 2024. The Author(s).)

Developing long bones alter their shape while maintaining uniform cortical thickness via coordinated activity of bone-forming osteoblasts and bone-resorbing osteoclasts at periosteal and endosteal surfaces, a process we designate trans-pairing. Two types of trans-pairing shift cortical bone in opposite orientations: peri-forming trans-pairing (peri-t-p) increases bone marrow space and endo-forming trans-pairing (endo-t-p) decreases it, via paired activity of bone resorption and formation across the cortex. Here, we focused on endo-t-p in growing bones. Analysis of endo-t-p activity in the cortex of mouse fibulae revealed osteoclasts under the periosteum compressed by muscles, and expression of RANKL in periosteal cells of the cambium layer. Furthermore, mature osteoblasts were localized on the endosteum, while preosteoblasts were at the periosteum and within cortical canals. X-ray tomographic microscopy revealed the presence of cortical canals more closely associated with endo- than with peri-t-p. Sciatic nerve transection followed by muscle atrophy and unloading induced circumferential endo-t-p with concomitant spread of cortical canals. Such canals likely supply the endosteum with preosteoblasts from the periosteum under endo-t-p, allowing bone shape to change in response to mechanical stress or nerve injury., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Canine distemper virus (CDV) belongs to morbillivirus, including measles virus (MeV) and rinderpest virus, which causes serious immunological and neurological disorders in carnivores, including dogs and rhesus monkeys, as recently reported, but their vaccines are highly effective. The attachment glycoprotein hemagglutinin (CDV-H) at the CDV surface utilizes signaling lymphocyte activation molecule (SLAM) and Nectin-4 (also called poliovirus-receptor-like-4; PVRL4) as entry receptors. Although fusion models have been proposed, the molecular mechanism of morbillivirus fusion entry is poorly understood. Here, we determined the crystal structure of the globular head domain of CDV-H vaccine strain at 3.2 Å resolution, revealing that CDV-H exhibits a highly tilted homodimeric form with a six-bladed β-propeller fold. While the predicted Nectin-4-binding site is well conserved with that of MeV-H, that of SLAM is similar but partially different, which is expected to contribute to host specificity. Five N -linked sugars covered a broad area of the CDV-H surface to expose receptor-binding sites only, supporting the effective production of neutralizing antibodies. These features are common to MeV-H, although the glycosylation sites are completely different. Furthermore, real-time observation using high-speed atomic force microscopy revealed highly mobile features of the CDV-H dimeric head via the connector region. These results suggest that sugar-shielded tilted homodimeric structure and dynamic conformational changes are common characteristics of morbilliviruses and ensure effective fusion entry and vaccination., Competing Interests: HF, KY, MS, MK, TO, MK, MY, SC, YI, ST, MM, JW, TH, JK, NM, CK, MT, KK, KM No competing interests declared, (© 2023, Fukuhara, Yumoto, Sako et al.)

Background: The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy., Methods: Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated., Results: The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice., Conclusions: Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults., (© 2024. The Author(s).)

A superconductor-insulator transition (SIT) in two dimensions is a prototypical quantum phase transition (QPT) with a clear quantum critical point (QCP) at zero temperature (T = 0). The SIT is induced by a field B and observed in disordered thin films. In some of weakly disordered or crystalline thin films, however, an anomalous metallic (AM) ground state emerges over a wide B range between the superconducting and insulating phases. It remains a fundamental open question how the QPT picture of the SIT is modified when the AM state appears. Here we present measurements of the Nernst effect N, which has great sensitivity to the fluctuations of the superconducting order parameter. From a thorough contour map of N in the B-T plane, we found a thermal-to-quantum crossover line of the superconducting fluctuations, a so-called ghost-temperature line associated with the QPT, as well as a ghost-field line associated with a thermal transition. The QCP is identified as a T = 0 intercept of the ghost-temperature line inside the AM state, which verifies that the AM state is a broadened critical state of the SIT., (© 2024. The Author(s).)

Removal of fuel debris is planned to start at Unit 2 of the Fukushima Daiichi Nuclear Power Plant. During the removal, it is desirable to distinguish fuel debris from radioactive wastes and to sort the fuel debris accordingly to the amounts of nuclear material contained. Muon scattering tomography invented at Los Alamos in the early 2000s is highly sensitivity to high-atomic-number materials such as uranium. A muon scanner to sort the debris is designed and currently in production. One of the challenges is to operate the muon scanner in the presence of high γ -ray radiations from the debris: muon-event-identification electronics and a muon-tracking algorithm in the presence of high γ -ray radiations were developed.

Objective: This study aimed to clarify nursing students' self-assessed levels of nursing skills at a nursing university at graduation and discuss how education and clinical experiences for students and post-licensure nurses should be improved, especially focusing on oncology nursing., Methods: The study population comprised fourth-year students from 2017 to 2019 at the Faculty of Health Science and Nursing, Juntendo University, who had completed all stipulated clinical placements. The Japanese government determined 141 nursing skills and their target levels. Students subjectively evaluated their achieved levels for the 141 nursing skills after the final clinical placement., Results: Of the 141 nursing skills, 81 (57%) were rated as "skills with easy-to-achieve targets" and five were rated as "skills with difficult-to-achieve targets." All nursing skills in the two subcategories of environmental adjustment skills and comfort management skills were rated as "skills with easy-to-achieve targets." Nursing skills with low target achievement rates were for patients with oral intake difficulties, unstable respiratory status, and those requiring glycemic control. These skills are also important in oncology nursing., Conclusions: It cannot be concluded that the nursing university students fully achieved the target levels of nursing skills, as determined by the Japanese government. These findings may facilitate discussions on teaching nursing skills and their target levels at the time of graduation from nursing universities or post-employment., (© 2024 The Author(s).)

Objective: During the mastication of solid food, the tongue pushes the bolus laterally to place it onto occlusal surfaces as the jaw is opened. This movement is referred to as tongue-pushing (TP). TP has an important role in efficient chewing, but its kinematic mechanisms remain unclear. The present study quantified the kinematics of TP and its coordination with masticatory jaw movements., Methods: Videofluorography (VFG) in anteroposterior projection was recorded while 14 healthy young adults ate 6 g each of cookies and meat. Small lead markers were glued to the tongue surface (left, right, and anterior) and buccal tooth surfaces (upper molars and lower canines). The position of the tongue and lower canine markers relative to the upper occlusal plane was quantified with Cartesian coordinates, using the right upper molar as the origin. Jaw motion during chewing was divided into TP and Non-TP cycles, based on the lateral movement of the food and tongue markers. The side of the jaw that compressed food particles was defined as the working side, while the other side was termed the balancing side. Horizontal and vertical displacements of tongue and jaw markers were compared between TP and Non-TP cycles, as well as between food types., Results: The mediolateral displacement of all tongue markers was significantly larger in TP than in Non-TP cycles. Vertical displacement was also significantly greater in TP than in Non-TP cycles for the anterior and working side tongue markers. TP cycles occurred more frequently with meat-chewing than with cookie-chewing., Conclusion: TP is accomplished by rotation and lateral movements of the tongue surface on the working side and the anterior tongue blade, along with medial movement on the balancing side. These movements produce lateral shift and rotation of the tongue surface toward the working side in concert with jaw opening. Designing exercises to improve the strength of the lateral motion and rotation of the tongue body may be useful for individuals with impaired tongue function for eating and swallowing., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Parents' psychological stress during the perinatal and neonatal periods continues to increase in an environment of declining birthrates, aging populations, and shrinking family sizes. The increase in child abuse and neglect cases, most likely by inexperienced and insufficiently knowledgeable parents, necessitates education on childcare and intervention techniques in nursing and midwifery training. In particular, attachment formation early in life between mother and infant is crucial. To accurately teach sensitive and comprehensive information on intervention techniques for mother-child attachment formation, realistic videos, and educational materials are necessary. Although pseudoeducational materials are available, they might be limited in explaining complex realism, particularly to support breastfeeding that involves both parents and child and that encourages interaction between the two. In a previous study in a common marmoset (Callithrix jacchus) model, we experimentally controlled infant feeding and nurturing through 24 h of constant sensing and collected 1 month of quantitative data on psychological indices that possibly translated to psychological development. Age-dependent dynamic visualization of these data by multivariate analyses inferred causal relationships between early parental feeding and psychobiological rhythm formation. In the same primate model, we identified a spontaneous case of breastfeeding failure in which the father inhibited his neonatal infant's feeding and the mother appeared to abandon nurturing, leading to clinically significant weight loss in the infant. Thus, we explored intervention techniques to promote mother-infant interaction. The mother was trained to allow the infant to spontaneously explore her breast. Initially, the mother refused to display the feeding pose potentially due to pain associated with breast engorgement. Massage was used to soften the breast and feeding was reintroduced. We hypothesize that activation of instinctive attachment formation mechanisms by encouraging spontaneity in each parent and child is the key to successful feeding intervention.

We facilely prepared a solid-state heterojunction photocatalyst in which silver vanadium oxide (Ag 2 V 4 O 11 ) and zinc rhodium oxide (ZnRh 2 O 4 ) as oxygen and hydrogen evolution photocatalysts, respectively, were directly connected to generate Ag 2 V 4 O 11 /ZnRh 2 O 4 . Ag 2 V 4 O 11 /ZnRh 2 O 4 photocatalyzed overall pure-water splitting without any electron mediator under irradiation with near-infrared light at wavelengths of up to 910 nm. The key points are that the conduction bottom potential of Ag 2 V 4 O 11 is almost the same as the valence band top potential of ZnRh 2 O 4 , and that the bandgaps of Ag 2 V 4 O 11 and ZnRh 2 O 4 are 1.4 and 1.2 eV, respectively.

Nicotinamide-N-methyltransferase (NNMT) is an enzyme that consumes S-adenosyl-methionine (SAM) and nicotinamide (NAM) to produce S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNAM). How much NNMT contributes to the quantity regulation of these four metabolites depends on whether NNMT is a major consumer or producer of these metabolites, which varies among various cellular contexts. Yet, whether NNMT critically regulates these metabolites in the AML12 hepatocyte cell line has been unexplored. To address this, we knockdown Nnmt in AML12 cells and investigate the effects of Nnmt RNAi on metabolism and gene expression. We find that Nnmt RNAi accumulates SAM and SAH, whereas it reduces MNAM with NAM being unaltered. These results indicate that NNMT is a significant consumer of SAM and critical for MNAM production in this cell line. Moreover, transcriptome analyses reveal that altered SAM and MNAM homeostasis is accompanied by various detrimental molecular phenotypes, as exemplified by the down-regulations of lipogenic genes, such as Srebf1. Consistent with this, oil-red O-staining experiments demonstrate the decrease of total neutral lipids upon Nnmt RNAi. Treating Nnmt RNAi AML12 cells with cycloleucine, an inhibitor of SAM biogenesis suppresses SAM accumulation and rescues the decrease of neutral lipids. MNAM also shows activity to elevate neutral lipids. These results suggest that NNMT contributes to lipid metabolism by maintaining proper SAM and MNAM homeostasis. This study provides an additional example where NNMT plays a critical role in regulating SAM and MNAM metabolism., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Over the past few decades, the clinical outcomes of patients with cancer have significantly improved mostly owing to the development of effective chemotherapeutic treatments. However, chronic health conditions such as bone mass loss and risk of fragility fractures caused by chemotherapy have also emerged as crucial issues in patients treated for cancer. In this study, we aimed to understand the effect of eribulin mesylate (ERI), a microtubule-targeting agent currently used to treat metastatic breast cancer and certain subtypes of advanced sarcomas, on bone metabolism in mice. The administration of ERI reduced bone mass in mice, mainly by promoting osteoclast activity. Gene expression analysis of skeletal tissues revealed no change in the expression levels of the transcripts for RANK ligand, one of the master regulators of osteoclastogenesis; however, the transcript levels of osteoprotegerin, which neutralizes RANK ligand, were significantly reduced in ERI-treated mice compared with those in vehicle-treated controls, indicating a relative increase in RANK ligand availability after ERI treatment. In line with the increased bone resorption in ERI-treated mice, we found that zoledronate administration effectively suppressed bone loss in these mice. These results reveal a previously unrecognized effect of ERI on bone metabolism and suggest the application of bisphosphonates for patients with cancer undergoing treatment with ERI., Competing Interests: All authors declare that they have no conflicts of interests., (© 2023 The Authors.)

Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause inflammation in various host organs. Despite the well-known coincidence of acute phase response and inflammation, the direct roles of SAA proteins in inflammation in the cancer context remains incompletely characterized, particularly in vivo . Here, we investigate the in vivo significance of SAA proteins in liver inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of Saa1-2 correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack Saa1-2 and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of Saa1-2 does not strongly affect 4T1-induced activation of immune cell-related genes in the liver. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. Consistently, 4T1-induced gene expression changes in bone marrow do not require Saa1-2 . This study clarifies the negligible contribution of SAA1-2 proteins in liver inflammation in the 4T1 breast cancer model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Konishi, Harata, Nakamura, Mizuno, Yoda, Toi, Kawaguchi and Kawaoka.)

Purpose: Examining the effects of an oculomotor rehabilitation program in subacute brain injury patients presenting with external ophthalmoplegia., Methods: This case-control study included 33 patients with subacute brain injury accompanied by external ophthalmoplegia (15 cases, 18 controls) from a hospital rehabilitation ward. Participants underwent comprehensive rehabilitation for 8 weeks. The patients participated in an oculomotor rehabilitation program, which involved inducing pursuit, fixation, saccade, and vergence for 20 min daily, 6 days a week for 8 weeks. We assessed improvements in the angle of strabismus; visual function index (VFI), which evaluates inconvenience in daily life; and diplopia after 8 weeks in the two groups using statistical methods., Results: The program resulted in an immediate strabismus angle improvement ( p  < 0.001). Strabismus angle change over the 8-week period was significantly higher ( p  < 0.001) in patients (22.9 ± 12.3°) than in control participants (8.3 ± 7.6°). VFI change was significantly greater ( p  = 0.003) in patients (7.1 ± 5.1 points) than in control participants (2.7 ± 2.4 points). The patients exhibited significantly higher diplopia improvement rates while looking straight ahead and in the direction of paralysis than did control participants ( p  = 0.021 and p  = 0.037, respectively)., Conclusion: This program improved external ophthalmoplegia without any specialized environmental configurations or personnel, which ensures wide clinical applications.IMPLICATIONS FOR REHABILITATIONOur oculomotor rehabilitation program improved external ophthalmoplegia in subacute brain injury patients.The program promotes pursuit, fixation, saccades, and vergence. The patients lay in the supine position and it places a little burden on them.The program can be completed within 20 min daily, requires no special environmental configurations, and can be performed by anyone.

Particles with a diameter of ∼0.5 µm in a dilute (volume fractions φ ∞  < 4 × 10 -3 ) suspension assemble into highly elongated structures called "bands" under certain conditions in combined Poiseuille and electroosmotic flows in opposite directions through microchannels at particle-based Reynolds numbers Re p  < < 1. The particles are first concentrated near, then form "bands" within ∼6 µm of, the channel wall. The experiments described here examine the near-wall dynamics of individual "tracer" particles during the initial concentration, or accumulation, of particles, and the steady-state stage when the particles have formed relatively stable bands at different near-wall shear rates and electric field magnitudes. Surprisingly, the near-wall upstream particle velocities are found to be consistently greater in magnitude than the expected values based on the particles being convected by the superposition of both flows and subject to electrophoresis, which is in the same direction as the Poiseuille flow. However, the particle velocities scale linearly with the change in electric field magnitude, suggesting that the particle dynamics are dominated by linear electrokinetic phenomena. If this discrepancy with theory is only due to changes in particle electrophoresis, electrophoresis is significantly reduced to values as small as 20%-50% of the Smoluchowski relation, or well below previous model predictions, even for high particle potentials., (© 2022 Wiley-VCH GmbH.)

Background/aim: Although paclitaxel plus cetuximab for recurrent/metastatic oral squamous cell carcinoma (OSCC) has a relatively high success rate, many cases are refractory. We investigated the change in nuclear factor-kappa B (NF-B) expression after this combination therapy using microcollagen 3D cell culture. We also investigated changes in antitumor efficacy using low doses of paclitaxel-cetuximab combined with the proteasome inhibitor bortezomib on a cell line with low sensitivity to paclitaxel plus cetuximab., Materials and Methods: Eight human OSCC cell lines were cultured in 3D and exposed to paclitaxel-cetuximab. real-time polymerase chain reaction was used to evaluate NF-B mRNA expression in OSCC cell lines in vivo and in vitro after exposure to anticancer agents. Activity at the protein level was confirmed using western blotting. Bortezomib (0.002-0.4 μg/ml) was added to paclitaxel-cetuximab and its effects assessed in OSCC cell lines with low paclitaxel-cetuximab sensitivity., Results: mRNA and protein expression of NF-B was significantly reduced after treatment with paclitaxel-cetuximab in cell lines sensitive to this combination. In contrast, both mRNA and protein expression significantly increased in the cell lines with low sensitivity to paclitaxel plus cetuximab. The addition of low concentrations of bortezomib to cell lines with low sensitivity to paclitaxel-cetuximab was found to enhance antitumor efficacy., Conclusion: Increased NF-B expression strongly contributes to resistance to paclitaxel-cetuximab, suggesting that the administration of small doses of bortezomib, which inhibits NF-B, combined with paclitaxel-cetuximab may enhance antitumor efficacy against cancer cells with low sensitivity to the combination therapy., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Predation is a major source of mortality during the early life stages of marine fishes; however, few studies have demonstrated its impact-especially that of squid predation-on survival processes. Here, we examined the feeding habits and predation impacts of swordtip squid on a major prey fish, juveniles of jack mackerel, in the East China Sea. Otoliths of the juveniles extracted from the squid stomach were used to reconstruct the age-length relationship and the growth trajectory of the consumed juveniles, and they were compared to those of juveniles collected with a net using a newly developed statistical framework. The juveniles consumed by squid had significantly shorter body lengths and smaller body sizes during the late larval and early juvenile stages than the netted juveniles, suggesting that smaller juveniles with slower growth rates have a higher probability to be selected. The body mass ratio of the predator squid to prey juveniles (predator-prey mass ratio, PPMR) ranged from 7 to 700, which was remarkably lower than the PPMR reported in various marine ecosystems based on analyses of fishes. Our findings demonstrate that squid predation can significantly impact the early life survival of fish and the trophodynamics in marine ecosystems., (© 2022. The Author(s).)

Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis., (© 2022. The Author(s).)

Purpose: The purpose of this study was to evaluate the impact of aging on muscle degeneration after rotator cuff tear (RCT) in mice., Methods: Young (12-week-old) and aged (50-to-60-week-old) female C57BL/6 mice were used (n = 29 for each group). The rotator cuff was transected, and the proximal humerus was removed to induce degeneration of the rotator cuff muscles. The mice were euthanized 4 and 12 weeks after the procedure (referred to as RCT-4wk mice and RCT-12wk mice, respectively) and compared with the sham-treated mice. The supraspinatus muscles were collected for histology, Western blot analysis, and gene expression analyses., Results: There was a significant increase in fat tissue in aged RCT-4wk mice (P = .001) and aged RCT-12wk mice (P < .001) compared with sham-treated aged mice, and aged RCT-12wk mice had a significantly increased fat area ratio compared with aged RCT-4wk mice (P < .001). The fat area was significantly larger in both the aged RCT-4wk (P = .002) and RCT-12wk mice (P < .001) than in the corresponding young mice. Muscular fibrosis was significantly increased in aged RCT-12wk mice compared with aged sham-treated mice (P = .005) and young RCT-12wk mice (P = .016). There were also significant increases in the expression of perilipin and transcripts of adipogenic and fibrogenic differentiation markers in aged RCT mice compared with young RCT mice., Conclusion: The present results show that aging is critically involved in the pathology of muscular fatty infiltration and fibrosis after RCT, and muscular degeneration progresses over time in aged mice., Clinical Relevance: Aging promotes the progression of muscle degeneration in a mouse RCT model. Furthermore, this study shows that muscle degeneration occurs in aged mice even without denervation and that the model described in the present study is a useful tool for studying the pathology of muscle degeneration., (Copyright © 2021 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Watabe T, Abe M, Sako R, Suzuki H, Yoda M, Kawate N. Association between external ophthalmoplegia with diplopia due to brain injury and FIM motor items: a case-control study. Jpn J Compr Rehabil Sci 2021; 12: 58-63., Objectives: This study aimed to determine the association between the presence of external ophthalmoplegia with diplopia due to brain injury and Functional Independence Measure (FIM) motor items in a case-control study., Methods: The subjects were patients with brain injury, admitted to a convalescent rehabilitation ward, who were able to walk under supervision and had preserved intellectual function. The correlation between the strabismus angle of the external ophthalmoplegia group and the total points of FIM motor items were examined. In addition, the total points and sub-items were compared between the external ophthalmoplegia group and control group using statistical processing., Results: There were 78 subjects: 34 in the external ophthalmoplegia group and 44 in the control group. Strabismus angle and the total points of FIM motor items of the external ophthalmoplegia group were significantly negatively correlated. Compared with the control group, the external ophthalmoplegia group had significantly lower levels of independence in bathing, dressing (lower body), toileting, transfer to the chair, transfer to the toilet, transfer to the bathroom, and locomotion (walking)., Conclusions: External ophthalmoplegia with diplopia is associated with FIM motor items., Competing Interests: Conflict of Interest: The authors declare no conflicts of interest., (©Kaifukuki Rehabilitation Ward Association 2021.)

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene ( Adam10 ) flox/flox /Lyz2-Cre ( Adam10 ΔLyz2 ) and control Adam10 flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10 ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-α, IL-1β, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10 ΔLyz2 mice following infection. CD11b + Ly6G - F4/80 + myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10 ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10 ΔLyz2 mice. Seven days after infection, CD11b + Ly6G - F4/80 + lung cells exhibited significantly higher arginase-1 expression levels in Adam10 ΔLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10 ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

On the basis of previous studies, the particles in a dilute (volume fractions φ ∞ < 4 × 10 -3 ) suspension in combined Poiseuille and electroosmotic "counterflow" at flow Reynolds numbers Re ≤ 1 accumulate, then assemble into structures called "bands," within ∼6 μm of the channel wall. The experimental studies presented here use a small fraction of tracer particles labeled with a different fluorophore from the majority "bulk" particles to visualize the dynamics of individual particles in a φ ∞ = 1.7 × 10 -3  suspension. The results at two different near-wall shear rates and three electric field magnitudes E show that the near-wall particles are concentrated about 150-fold when the bands start to form, and are then concentrated about 200-fold to a maximum near-wall volume fraction of ∼0.34. The growth in the near-wall particles during this accumulation stage appears to be exponential. This near-wall particle accumulation is presumably driven by a wall-normal "lift" force. The observations of how the particles accumulate near the wall are compared with recent analyses that predict that suspended particles subject to shear flow and a dc electric field at small particle Reynolds numbers experience such a lift force. A simple model that assumes that the particles are subject to this lift force and Stokes drag suggests that the force driving particles toward the wall, of O(10 -17 N), is consistent with the time scales for particle accumulation observed in the experiments., (© 2021 Wiley-VCH GmbH.)

Introduction: We identified a novel heterozygous AαE11del variant in a patient with congenital dysfibrinogenemia. This mutation is located in fibrinopeptide A (FpA). We analyzed the effect of AαE11del on the catalyzation of thrombin and batroxobin and simulated the stability of the complex structure between the FpA fragment (AαG6-V20) peptide and thrombin., Materials and Methods: We performed fibrin polymerization and examined the kinetics of FpA release catalyzed by thrombin and batroxobin using purified plasma fibrinogen. To clarify the association between the AαE11 residue and thrombin, we calculated binding free energy using molecular dynamics simulation trajectories., Results: Increasing the thrombin concentration improved release of FpA from the patient's fibrinogen to approximately 90%, compared to the previous 50% of that of normal fibrinogen. Fibrin polymerization of variant fibrinogen also improved. In addition, greater impairment of variant FpA release from the patient's fibrinogen was observed with thrombin than with batroxobin. Moreover, the calculated binding free energy showed that the FpA fragment-thrombin complex became unstable due to the missing AαE11 residue., Conclusions: Our findings indicate that the AαE11 residue is involved in FpA release in thrombin catalyzation more than in batroxobin catalyzation, and that the AαE11 residue stabilizes FpA fragment-thrombin complex formation., (© 2021. Japanese Society of Hematology.)