Reactive sulfur species disaggregate the SQSTM1/p62-based aggresome-like induced structures via the HSP70 induction and prevent parthanatos.

Reactive sulfur species (RSS) have emerged as key regulators of protein quality control. However, the mechanisms by which RSS contribute to cellular processes are not fully understood. In this study, we identified a novel function of RSS in preventing parthanatos, a nonapoptotic form of cell death that is induced by poly (ADP-ribose) polymerase-1 and mediated by the aggresome-like induced structures (ALIS) composed of SQSTM1/p62. We found that sodium tetrasulfide (Na2S4), a donor of RSS, strongly suppressed oxidative stress-dependent ALIS formation and subsequent parthanatos. On the other hand, the inhibitors of the RSS-producing enzymes, such as 3-mercaptopyruvate sulfurtransferase and cystathionine γ-lyase, clearly enhanced ALIS formation and parthanatos. Interestingly, we found that Na2S4 activated heat shock factor 1 by promoting its dissociation from heat shock protein 90, leading to accelerated transcription of HSP70. Considering that the genetic deletion of HSP70 allowed the enhanced ALIS formation, these findings suggest that RSS prevent parthanatos by specifically suppressing ALIS formation through induction of HSP70. Taken together, our results demonstrate a novel mechanism by which RSS prevent cell death, as well as a novel physiological role of RSS in contributing to protein quality control through HSP70 induction, which may lead to better understanding of the bioactivity of RSS.

Three-Dimensional Reconstruction Pre-Training as a Prior to Improve Robustness to Adversarial Attacks and Spurious Correlation.

Ensuring robustness of image classifiers against adversarial attacks and spurious correlation has been challenging. One of the most effective methods for adversarial robustness is a type of data augmentation that uses adversarial examples during training. Here, inspired by computational models of human vision, we explore a synthesis of this approach by leveraging a structured prior over image formation: the 3D geometry of objects and how it projects to images. We combine adversarial training with a weight initialization that implicitly encodes such a prior about 3D objects via 3D reconstruction pre-training. We evaluate our approach using two different datasets and compare it to alternative pre-training protocols that do not encode a prior about 3D shape. To systematically explore the effect of 3D pre-training, we introduce a novel dataset called Geon3D, which consists of simple shapes that nevertheless capture variation in multiple distinct dimensions of geometry. We find that while 3D reconstruction pre-training does not improve robustness for the simplest dataset setting, we consider (Geon3D on a clean background) that it improves upon adversarial training in more realistic (Geon3D with textured background and ShapeNet) conditions. We also find that 3D pre-training coupled with adversarial training improves the robustness to spurious correlations between shape and background textures. Furthermore, we show that the benefit of using 3D-based pre-training outperforms 2D-based pre-training on ShapeNet. We hope that these results encourage further investigation of the benefits of structured, 3D-based models of vision for adversarial robustness.

Relationship between the phase angle from bioelectrical impedance analysis and daily physical activity in patients with rheumatoid arthritis.

OBJECTIVES: This study aimed to examine the relationship between daily physical activity and the phase angle (PhA) obtained by bioelectrical impedance analysis in rheumatoid arthritis (RA) patients. METHODS: Data from a prospective cohort study of RA patients who were surveyed every year were analysed. The PhA was assessed by the bioelectrical impedance analysis method, and physical activity was assessed as the amount of time of exercise in metabolic equivalents (METs) per day using a triaxial accelerometer for 7 consecutive days. The association between physical activity and the PhA was evaluated using the isotemporal substitution model in multiple regression analysis. RESULTS: Seventy-six RA patients were included in the analysis (81% female and age 66.2 ± 13.1 years). On cross-sectional analysis, the isotemporal substitution model in multiple regression analysis showed that the PhA was 0.05 points higher every 10 minutes when activities with intensity of 1 ≤ METs < 2 were replaced by activities with intensity of ≥3 METs (P = .01). Over 1 year, the rate of change in the PhA was 0.69% higher every 10 minutes when activities with intensity of 1 ≤ METs < 2 were replaced by activities with intensity of ≥3 METs (P = .037). CONCLUSION: The PhA in RA patients may be related to physical activity level.

Elucidation of the Binding Mechanism of Anionic Phospholipids to Antioxidant Protein Peroxiredoxin 2.

Peroxiredoxins (Prxs) belong to a family of ubiquitously expressed peroxidases that detoxify reactive oxygen species. In addition to their enzymatic function, Prxs also function as molecular chaperones. This functional switch is related to their degree of oligomerization. We have previously revealed that Prx2 interacts with anionic phospholipids and that the anionic phospholipid-containing Prx2 oligomer forms a high molecular weight (HMW) complex in a nucleotide-dependent manner. However, the detailed mechanism of the oligomer and HMW complex formation remains unclear. In this study, we investigated the anionic phospholipid binding site in Prx2 using site-directed mutagenesis to understand the mechanism of the oligomer formation. Our findings demonstrated that six binding site residues in Prx2 are important for the binding of anionic phospholipids.

The bioimpedance phase angle may be associated with frailty in rheumatoid arthritis patients: Results from a prospective, cohort study.

OBJECTIVES: This study investigated whether the phase angle (PhA) on bioelectrical impedance analysis is related to frailty in rheumatoid arthritis (RA) patients. METHODS: Data from a prospective cohort study of RA patients were analysed. The PhA was assessed by the bioelectrical impedance analysis method, and frailty was assessed by the Kihon Check List (KCL) annually. The cut-off value of the PhA for frailty was calculated by receiver-operating characteristic analysis. The relationships between the PhA and frailty were evaluated by logistic regression analysis. The relationships between the change in PhA and frailty status and the KCL score were evaluated by analysis of covariance and multiple regression analysis. RESULTS: A total of 170 patients (81.2% female, 66.2 ± 13.1 years) were included in the analysis. A PhA of less than the cut-off for frailty was significantly associated with frailty (odds ratio: 4.75, 95% confidence interval: 1.86, 12.17). The change in the PhA was significantly associated with the change in the KCL score (ß = -0.15). In robust patients, there was a significant difference in the rate of change of the PhA between the group that became pre-frail in the next year and the group that remained robust. CONCLUSIONS: The PhA may be associated with frailty in RA patients.

3D-cultured small size adipose-derived stem cell spheroids promote bone regeneration in the critical-sized bone defect rat model.

Adipose-derived stem cells (ADSCs), due to their regenerative ability, have beneficial effects on bone and cartilage defects. In addition, spheroid formation of ADSCs obtained using three-dimensional (3D) culture accelerates the regenerative ability of ADSCs. The study investigated the regenerative effect of 3D-cultured small size ADSC spheroids without a scaffold in rats with defects in the critical-sized calvarial bone. ADSC-single cells, ADSC-spheroids, or PBS (as control) were implanted in rats, and radiological and histological assessment of bone regeneration was performed. Bone defects were significantly regenerated in the ADSC-spheroid group compared to that in the control group. ADSC-spheroids also showed the most significant bone regeneration in histological assessment. Immunohistochemistry assessment showed that ADSC-spheroids could survive 12 weeks after cell implantation. In vitro, cell apoptosis in ADSC-spheroids was significantly suppressed compared to that in ADSC-single cells. In addition, gene expression related to bone morphogenesis, angiogenesis, and stemness in ADSC-spheroids was elevated. The scaffold-free 3D-cultured small ADSC-spheroids survived in in vitro and in vivo conditions and promoted bone regeneration. Therefore, injectable small size ADSC-spheroids are a novel and less-invasive therapeutic option for treating bone defects.

Ultrasound assessment, unlike clinical assessment, reflects enthesitis in patients with psoriatic arthritis.

OBJECTIVES: Enthesitis is a major musculoskeletal manifestation of psoriatic arthritis (PsA). It is conventionally assessed clinically, by the presence of tenderness, despite its low reliability. However, ultrasound (US) provides a sensitive and feasible method for evaluating enthesitis. We investigated enthesitis as assessed clinically and by US in patients with PsA. METHODS: Forty-seven patients with PsA underwent US examination of the bilateral humeral medial epicondyles and insertions of the triceps, distal quadriceps, proximal/distal patellae, Achilles tendons, and plantar fascia. These 14 entheses were also clinically evaluated by tenderness. The correspondence between US and clinical enthesitis was evaluated, as well as their associations with inflammatory markers (C-reactive protein [CRP], matrix metalloproteinase-3 [MMP-3]), disease activity indices (Disease Activity in Psoriatic Arthritis [DAPSA], Disease Activity Score 28 joints [DAS28-CRP], Psoriatic Arthritis Screening and Evaluation [PASE], Psoriasis Area Severity Index [PASI]), radiographic damage (modified Total Sharp Score [mTSS]), and functional status (health assessment questionnaire [HAQ]), and axial involvement. RESULTS: Among 47 patients with PsA, 37 and 23 had US and clinical enthesitis, respectively. US and clinical enthesitis had very low concordance (kappa coefficient 0.04), with no correlation between enthesitis counts (r=0.15, p=0.30). The US enthesitis count correlated only with the MMP-3 level (r=0.41, p=0.007), whereas the clinical enthesitis count correlated with the DAPSA, DAS28-CRP, HAQ, and PASE (r=0.50, p<0.001; r=0.44, p=0.002; r=0.41, p=0.008; r=0.54, p<0.001, respectively). CONCLUSIONS: US and clinical enthesitis are completely different entities. US enthesitis, but not clinical enthesitis, reflects inflammatory conditions.

Associations between changes in radial peripapillary capillaries and occurrence of disc hemorrhage in normal-tension glaucoma.

PURPOSE: In order to clarify the association between peripapillary vascular changes and disc hemorrhage (DH) occurrences over time, we analyzed the density of radial peripapillary capillary (RPC) and clinical parameters during follow-up periods in patients with normal-tension glaucoma (NTG). METHODS: Seventy-seven eyes of 77 NTG patients were subjected to analysis. We selected patients who had an initial optical coherence tomography angiography (OCTA) scan in 2015 and who had another OCTA scan in 2018 with both OCTA scans showing good-quality images. We investigated the relationships between DH occurrence and each of the following parameters: RPC density, circumpapillary retinal nerve fiber layer (cpRNFL) thickness slope and total deviation (TD) slope. RESULTS: In the period between the initial and final OCTA, we categorized the patients into 53 sides with DH (DH group) and 101 sides without DH (non-DH group). The ΔRPC density of sides with DH was significantly greater than that of sides without DH (DH, - 4.42 ± 6.43%; without DH, - 2.48 ± 5.29%; p = 0.0469). The cpRNFL thickness slope of sides with DH was significantly faster than that of sides without DH (DH, - 2.85 ± 3.17; without DH, - 0.74 ± 2.46 µm/y; p < 0.0001). The TD slope of sides with DH was significantly faster than that of sides without DH (DH, - 0.50 ± 0.77; without DH, - 0.22 ± 0.53 dB/y; p = 0.0163). As DH occurrence increased, the RPC density significantly decreased (r = -0.255, p = 0.0014). Stepwise multiple regression analysis to identify factors influencing RPC changes showed that frequency of DH (ß = - 0.224, p = 0.008) and central corneal thickness (ß = - 0.220, p = 0.009) were significantly associated with RPC changes. CONCLUSIONS: DH occurrence may prompt the structural and vascular deterioration of NTG.

Systematic exploitation of thermotropic bicontinuous cubic phase families from 1,2-bis(aryloyl)hydrazine-based molecules.

Rational design of molecules that exhibit a thermotropic bicontinuous cubic (Cub) phase has been earnestly desired. In this work, we describe the suitable selection of a molecular motif that has enabled the systematic exploitation of eight new series of Cub-phase molecules with symmetric molecular cores, N-n (1), PB-n (2), S-n (3), and PEB-n (4), and unsymmetric cores, B-N-n (5), B-PB-n (6), B-S-n (7), and B-PEB-n (8). These eight series all originate from achiral chain-core-chain type rod-like molecules that exhibit two types of Cub phases, an achiral Ia3d phase, and a chiral phase. All the Ia3d phases formed were found to be isomorphous structures, with their cell dimensions being proportional to the core size, and the same was true for the latter chiral phase. We demonstrated that the formation is mainly governed by the segregation between core and alkyl moieties of the molecules, and thus, by the weight fraction of the core portion fcore. This work also demonstrates that the central dicarbonylhydrazine linkage bearing intermolecular hydrogen bonding ability exhibits a pinning effect that prevents slippage of π-stacks of molecules, which is critical for the formation of the two Cub phases that are composed of chiral networks with twisted molecular arrangements. In each series, the emergence of spontaneous chirality formation that occurred in the chiral phase was limited to between 0.36 and 0.50 in the range of fcore. An interesting insight was that the introduced unsymmetry of the molecular core strongly influenced the phase behavior, which lowered the temperature range of Cub phases to around that of the smallest core series B-n, while the high temperature limit (Tc) was roughly proportional to the core size, as determined by the strength of intermolecular π-π interactions.

Early development and neurogenesis of Temnopleurus reevesii.

Sea urchins are model non-chordate deuterostomes, and studying the nervous system of their embryos can aid in the understanding of the universal mechanisms of neurogenesis. However, despite the long history of sea urchin embryology research, the molecular mechanisms of their neurogenesis have not been well investigated, in part because neurons appear relatively late during embryogenesis. In this study, we used the species Temnopleurus reevesii as a new sea urchin model and investigated the detail of its development and neurogenesis during early embryogenesis. We found that the embryos of T. reevesii were tolerant of high temperatures and could be cultured successfully at 15-30°C during early embryogenesis. At 30°C, the embryos developed rapidly enough that the neurons appeared at just after 24 h. This is faster than the development of other model urchins, such as Hemicentrotus pulcherrimus or Strongylocentrotus purpuratus. In addition, the body of the embryo was highly transparent, allowing the details of the neural network to be easily captured by ordinary epifluorescent and confocal microscopy without any additional treatments. Because of its rapid development and high transparency during embryogenesis, T. reevesii may be a suitable sea urchin model for studying neurogenesis. Moreover, the males and females are easily distinguishable, and the style of early cleavages is intriguingly unusual, suggesting that this sea urchin might be a good candidate for addressing not only neurology but also cell and developmental biology.

Multimodal semi-supervised learning for online recognition of multi-granularity surgical workflows.

Purpose Surgical workflow recognition is a challenging task that requires understanding multiple aspects of surgery, such as gestures, phases, and steps. However, most existing methods focus on single-task or single-modal models and rely on costly annotations for training. To address these limitations, we propose a novel semi-supervised learning approach that leverages multimodal data and self-supervision to create meaningful representations for various surgical tasks. Methods Our representation learning approach conducts two processes. In the first stage, time contrastive learning is used to learn spatiotemporal visual features from video data, without any labels. In the second stage, multimodal VAE fuses the visual features with kinematic data to obtain a shared representation, which is fed into recurrent neural networks for online recognition. Results Our method is evaluated on two datasets: JIGSAWS and MISAW. We confirmed that it achieved comparable or better performance in multi-granularity workflow recognition compared to fully supervised models specialized for each task. On the JIGSAWS Suturing dataset, we achieve a gesture recognition accuracy of 83.3%. In addition, our model is more efficient in annotation usage, as it can maintain high performance with only half of the labels. On the MISAW dataset, we achieve 84.0% AD-Accuracy in phase recognition and 56.8% AD-Accuracy in step recognition. Conclusion Our multimodal representation exhibits versatility across various surgical tasks and enhances annotation efficiency. This work has significant implications for real-time decision-making systems within the operating room.

Ultrasonographic Synovitis Is Associated with the Development of Joint Destruction in Patients with Psoriatic Arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is characterized by enthesitis. As persistent inflammation around joints results in bone and cartilage destruction and physical impairment, a detailed assessment of inflammation is essential. We previously reported the difference between clinical assessment (tenderness) and ultrasound (US) assessment (inflammation) of entheses. Herein, we investigated whether clinical or US assessment of joints and entheses can predict the progression of joint destruction in Japanese patients with PsA. METHODS: Thirty joints and 14 entheses in 47 patients were assessed using US and clinical examination. The US greyscale (GS) and power Doppler (PD) scores at the ultrasonographic synovitis, the US active enthesitis count, and the clinical tender joint/entheses count were assessed. Additionally, the yearly radiographic progression of the Sharp-van der Heijde scoring method for PsA was assessed. Their correlations were investigated. RESULTS: About half of the patients with PsA experienced joint destruction during a follow-up period of 20.4 months. Progression of joint destruction in patients with PsA only correlated with joint GS and PD scores, reflecting the severity of ultrasonographic synovitis, not with the tender joint/entheses count. CONCLUSIONS: US examinations are essential for preventing joint destruction and physical impairment in patients with PsA.

Three-dimensional adipose-derived stem cell spheroids exert potent therapeutic effects on rat femur osteochondral defects.

BACKGROUND: Spheroids can allow three-dimensional (3D) cell culture without scaffolds, potentially promoting the production of growth factors from adipose-derived stem cells (ADSCs). We hypothesized that ADSC spheroids exert more favourable effects on osteochondral defects than ADSCs in two-dimensional (2D) cultures. The purpose of this study was to compare the therapeutic effects of 2D and 3D cultures of ADSCs on osteochondral defects using animal models. METHODS: Rat femoral osteochondral defects were created. When creating osteochondral defects, phosphate-buffered saline, 2D ADSCs, or ADSC spheroids as a 3D culture were administered on to the lesion. At 2, 4, 6, 8, 10 and 12 weeks post-surgery, knee tissues were harvested and evaluated via histological examination. The expression of genes related to growth factors and apoptosis were compared between 2D and 3D ADSCs. RESULTS: Histologically, the repair of osteochondral defects was significantly enhanced in 3D ADSCs than in 2D ADSCs in terms of the Wakitani score and cartilage repair rate. In 3D ADSCs, TGF-ß1, VEGF, HGF and BMP-2 were significantly upregulated, while apoptosis was suppressed in the early phase. CONCLUSION: The therapeutic effects of 3D ADSC spheroids on osteochondral defects were more potent than those of 2D ADSCs. The upregulated expression of growth factors and suppression of apoptosis could contribute to promoting these therapeutic effects. Overall, ADSC spheroids can help treat osteochondral defects.

Lifestyle and body composition changes in patients with rheumatoid arthritis during the COVID-19 pandemic: A retrospective, observational study.

Objectives: Behavioral restrictions and staying at home during the COVID-19 pandemic have affected lifestyles. It was hypothesized that patients with rheumatoid arthritis (RA) decreased their activities of daily living (ADL) and exercise during the pandemic. The aim of this study is to investigate the changes in lifestyle and body composition. Methods: Data were obtained from an observational study (CHIKARA study). Of 100 RA patients, 70 (57 women, 13 men) were followed-up with measurements of grip strength, as well as muscle mass, fat mass, and basal metabolic rate by a body composition analyzer. Changes in ADL and exercise were evaluated using a visual analog scale. The relationships between changes in ADL or exercise and body composition were investigated. Results: Muscle mass and grip strength were significantly lower after behavioral restrictions compared to the periods before restrictions (34.0 vs 34.7 kg, P < 0.001; 16.2 vs 17.2 kg, P = 0.013, respectively). Fat mass was significantly greater after behavioral restrictions compared to the periods before restrictions (16.2 vs 15.5 kg, P = 0.014). The mean decrease in ADL was 44%, whereas that of exercise was 20%.The change in muscle mass (ß = -0.335, P = 0.007) was the only independent factor for the change in exercise on multivariate analysis. Conclusions: Muscle mass and grip strength decreased and fat mass increased in RA patients with the behavioral restrictions of the COVID-19 pandemic. Muscle mass decreased in patients without exercise. Maintenance of muscle mass may be important during the COVID-19 pandemic.

Daily physical activity measured by a wearable activity monitoring device in patients with rheumatoid arthritis.

INTRODUCTION: Activities of daily living in patients with rheumatoid arthritis (RA) have been evaluated by patient-reported outcomes. However, it has been difficult to measure activity intensity quantitively. Calories expended, exercise, and steps were measured quantitively by a wearable activity meter, and their associations with patients' background characteristics were examined. METHODS: Data from a prospective, observational study (CHIKARA study) were used. Eighty-five of 100 RA patients were entered and wore a wearable activity meter for 7 days. The daily calories expended and exercise for both walking and housework and steps were evaluated. Total daily calories expended and exercise was defined as the sum of walking and housework. The relationships of DAS28-ESR, mHAQ, body composition, muscle function, and general status were analyzed. RESULTS: The median age was 66.0 years, and the disease duration was 5.3 years. DAS28-ESR was 3.11, and mHAQ was 0.125. Total daily calories expended, exercise, and number of steps were 461.7 kcal, 3.97 METs h, and 4,788, respectively. MHAQ, walking speed, power, locomotive syndrome, and frailty were independently related to exercise. Total daily exercise and steps of the moderate and high disease activity group were significantly lower than those of the remission group. When the number of steps was < 3,333 and < 2,468, the odds ratios for locomotive syndrome and frailty increased 14.4-fold and 8.7-fold, respectively, using Fisher's exact test (P < 0.001). CONCLUSIONS: Daily physical activity and number of steps were significantly decreased in RA patients with moderate and high disease activity as measured by a wearable activity meter. Key Points • Total daily calories expended and exercise for both walking and housework and steps in patients with rheumatoid arthritis were 461.7 kcal, 3.97 METs h, and 4,788, respectively, using a wearable activity meter. • Daily physical activity, especially total daily exercise and number of steps, was significantly decreased in RA patients with moderate and high disease activity. • When total daily steps were < 3,333 and < 2,468, the odds ratios for locomotive syndrome and frailty increased 14.4-fold and 8.7-fold, respectively.

The bioimpedance phase angle is more useful than sarcopenia as a predictor of falls in patients with rheumatoid arthritis: Results from a 2-y prospective cohort study.

OBJECTIVES: The phase angle (PhA) is an index derived by bioelectrical impedance analysis that reflects the fragility of cell membranes, muscle mass, muscle strength, and nutritional status, and a decrease in PhA might be associated with falls. This study aimed to investigate the relationships of the PhA with sarcopenia and falls in patients with rheumatoid arthritis (RA). METHODS: Data from a prospective cohort study of 189 patients with RA (age 66.5 ± 13.3 y; 80% women) were analyzed. PhA, muscle mass, and grip strength (GS) were evaluated. Sarcopenia was assessed using the Asian Working Group for Sarcopenia 2014 criteria. The correlation between PhA and GS was investigated, and the cutoff value of the PhA for falls during a 2-y period was estimated with a receiver operating characteristic curve analysis. The effects of the PhA and sarcopenia on falls were examined with a Cox proportional hazards model. RESULTS: Of the 189 patients, 48 (25.4%) had falls. The PhA was significantly positively correlated with GS (r = 0.58; P < 0.001). The cutoff values for the PhA for falls were 4.06° for women and 5.26° for men. In the Cox proportional hazards model adjusted for sex, age, disease activity, glucocorticoid use, and activities of daily living at baseline, the hazard ratio for falls was significantly higher when the PhA was below the cutoff value at baseline (hazard ratio: 2.29; 95% confidence interval, 1.18-4.45). Sarcopenia was not a significant risk factor for falls. CONCLUSIONS: The PhA might be a useful surrogate marker to predict falls in patients with RA.

Screening for sarcopenia and obesity by measuring thigh muscle and fat thickness by ultrasound in patients with rheumatoid arthritis.

OBJECTIVES: Sarcopenia is relatively common in rheumatoid arthritis (RA) patients. Thicknesses of the quadriceps muscle and fat are easily measured by ultrasound (US) and are known to be related to skeletal muscle mass and fat mass, respectively. METHODS: Eighty-four patients enrolled in the prospective correlation research of sarcopenia, skeletal muscle, and disease activity in rheumatoid arthritis study (UMIN000023744) underwent US examinations of anterior thigh muscle thickness (MT) and fat thickness (FT). Muscle and body fat (BF) mass were also examined by a body composition analyzer. Whether MT and FT were related to sarcopenia and obesity was examined. RESULTS: MT was significantly lower in RA patients with sarcopenia than in those without (23.8 vs 28.2 mm, P = 0.001). MT was related to sarcopenia (men: r = 0.56, P = 0.02, women: r = 0.32, P = 0.01). The cut-off value of MT for sarcopenia was 24.7 mm in men and 19.7 mm in women on receiver operating characteristic curve analyses. FT was correlated with BF percentage (%BF; men: r = 0.66, P < 0.01, women: r = 0.62, P < 0.001), which was estimated by 2.04xFT+8.53 in men and 1.2xFT+17.42 in women by a simple linear regression model. This means that FT ≥ 8.1 mm in men and FT ≥ 14.6 mm in women indicated obesity. CONCLUSIONS: US examination of the anterior thigh was useful to detect sarcopenia and obesity in RA patients.

Relationships of the stand-up time to falls and fractures in patients with rheumatoid arthritis: Results from the CHIKARA study.

AIM: Patients with rheumatoid arthritis (RA) have a higher risk of falls and fractures due to muscle weakness and painful joints of the lower extremities. Evaluation of muscle functions is important to predict falls and fractures. The aim was to investigate the relationships of muscle functions with falls and fractures in RA patients. METHODS: Stand-up muscle power, speed, and stabilizing time were evaluated by a muscle function analyzer in 90 RA patients in the CHIKARA study (UMIN000023744). The relationships of the muscle functions with falls, fractures, body composition, Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR), modified Health Assessment Questionnaire (mHAQ) scores, Steinbrocker class, stage, sarcopenia, and frailty were investigated in a cross-sectional study. RESULTS: Each parameter of muscle function was related to age, falls, frailty, and the leg muscle score. However, only stabilizing time was related with fractures (r = .217, P = .04). When stabilizing time was ≥ 1.13 and ≥1.36 seconds, the odds ratios for falls and fractures were increased 6.2-fold compared to < 1.13 seconds (95% CI: 1.2-20.1, P = .002) and 11.4-fold compared to <1.36 seconds (95% CI: 1.7-92.5, P = .071), respectively. Sarcopenia and skeletal muscle mass were not significantly related to each muscle function. There was a negative correlation between DAS28-ESR and power. Steinbrocker class and mHAQ had negative correlations with power and speed. CONCLUSIONS: Sarcopenia and skeletal muscle mass were not adequate indicators of muscle functions in RA patients. Analyzing muscle functions is helpful to predict falls and fractures. Patients with extended stabilizing times should recognize the increased risk of falls and fractures.

Osteosarcopenia synergistically increases the risk of falls in patients with rheumatoid arthritis.

OBJECTIVES: Osteosarcopenia is defined as osteoporosis with sarcopenia. The impacts of osteosarcopenia on falls and fractures in rheumatoid arthritis (RA) patients were investigated using 4 years of data from a longitudinal study (CHIKARA study). METHODS: The patients were divided into 4 groups by their baseline status: no sarcopenia and no osteoporosis (SP-OP-); only sarcopenia (SP + OP-); only osteoporosis (SP-OP+); and both sarcopenia and osteoporosis (SP + OP+). Survival rates and Cox hazard ratios were analyzed using falls and fractures as endpoints, adjusted by age, sex, and body mass index. RESULTS: A total of 100 RA patients (SP-OP-: 44%, SP + OP-: 17%, SP-OP+: 28%, and SP + OP+: 11%) were enrolled; 37 patients had falls, and 19 patients had fractures. The fall-free and fracture-free survival rates were significantly lower in SP + OP+ (36.4%, 54.5%) than in SP-OP- (75.0%, 86.4%). The hazard ratio of falls was significantly increased in SP + OP+, by 3.32-fold (95%CI: 1.01-10.9), whereas in SP + OP- and SP-OP+, there were no differences compared to SP-OP-. CONCLUSIONS: The survival rates with the endpoints of falls and fractures in RA patients with osteosarcopenia were lower during 4-year follow-up. The risk of falls increased with the synergistic effect of osteoporosis and sarcopenia.

Orthogonal Activation of Metabotropic Glutamate Receptor Using Coordination Chemogenetics.

Cell-surface receptors play a pivotal role as transducers of extracellular input. Although different cell types express the same receptor, the physiological roles of the receptor are highly dependent on cell type. To understand each role, tactics for cell-specific activation of the target receptor are in high demand. Herein, we developed an orthogonal activation method targeting metabotropic glutamate receptor 1 (mGlu1), a G-protein coupled receptor. In this method, direct activation via coordination-based chemogenetics (dA-CBC) was adopted, where activation of mGlu1 was artificially induced by a protein conformational change in response to the coordination of a metal ion or metal-ion complex. Our structure-based protein design and screening approach identified mGlu1 mutants that were directly activated by the coordination of Cu2+ or Zn2+, in addition to our previous Pd-complex-sensitive mGlu1 mutant. Notably, the activation of the mutants was mutually orthogonal, resulting in cell-type selective activation in a model system using HEK293 cells.