Cartilage tissues regulate systemic aging via ectonucleotide pyrophosphatase/phosphodiesterase 1 in mice.

Aging presents fundamental health concerns worldwide; however, mechanisms underlying how aging is regulated are not fully understood. Here, we show that cartilage regulates aging by controlling phosphate metabolism via ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1). We newly established an Enpp1 reporter mouse, in which an EGFP-luciferase sequence was knocked-in at the Enpp1 gene start codon (Enpp1/EGFP-luciferase), enabling detection of Enpp1 expression in cartilage tissues of resultant mice. We then established a cartilage-specific Enpp1 conditional knockout mouse (Enpp1 cKO) by generating Enpp1 flox mice and crossing them with cartilage-specific type 2 collagen Cre mice. Relative to WT controls, Enpp1 cKO mice exhibited phenotypes resembling human aging, such as short life span, ectopic calcifications, and osteoporosis, as well as significantly lower serum pyrophosphate levels. We also observed significant weight loss and worsening of osteoporosis in Enpp1 cKO mice under phosphate overload conditions, similar to global Enpp1-deficient mice. Aging phenotypes seen in Enpp1 cKO mice under phosphate overload conditions were rescued by a low vitamin D diet, even under high phosphate conditions. These findings suggest overall that cartilage tissue plays an important role in regulating systemic aging via Enpp1.

The IL-17-IL-17RA axis is required to promote osteosarcoma progression in mice.

Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.

Transthyretin amyloid deposition in ligamentum flavum (LF) is significantly correlated with LF and epidural fat hypertrophy in patients with lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) is a degenerative disease characterized by intermittent claudication and numbness in the lower extremities. These symptoms are caused by the compression of nerve tissue in the lumbar spinal canal. Ligamentum flavum (LF) hypertrophy and spinal epidural lipomatosis in the spinal canal are known to contribute to stenosis of the spinal canal: however, detailed mechanisms underlying LSS are still not fully understood. Here, we show that surgically harvested LFs from LSS patients exhibited significantly increased thickness when transthyretin (TTR), the protein responsible for amyloidosis, was deposited in LFs, compared to those without TTR deposition. Multiple regression analysis, which considered age and BMI, revealed a significant association between LF hypertrophy and TTR deposition in LFs. Moreover, TTR deposition in LF was also significantly correlated with epidural fat (EF) thickness based on multiple regression analyses. Mesenchymal cell differentiation into adipocytes was significantly stimulated by TTR in vitro. These results suggest that TTR deposition in LFs is significantly associated with increased LF hypertrophy and EF thickness, and that TTR promotes adipogenesis of mesenchymal cells. Therapeutic agents to prevent TTR deposition in tissues are currently available or under development, and targeting TTR could be a potential therapeutic approach to inhibit LSS development and progression.

Remnant tissue enhances early postoperative biomechanical strength and infiltration of Scleraxis-positive cells within the grafted tendon in a rat anterior cruciate ligament reconstruction model.

When ruptured, ligaments and tendons have limited self-repair capacity and rarely heal spontaneously. In the knee, the Anterior Cruciate Ligament (ACL) often ruptures during sports activities, causing functional impairment and requiring surgery using tendon grafts. Patients with insufficient time to recover before resuming sports risk re-injury. To develop more effective treatment, it is necessary to define mechanisms underlying ligament repair. For this, animal models can be useful, but mice are too small to create an ACL reconstruction model. Thus, we developed a transgenic rat model using control elements of Scleraxis (Scx), a transcription factor essential for ligament and tendon development, to drive GFP expression in order to localize Scx-expressing cells. As anticipated, Tg rats exhibited Scx-GFP in ACL during developmental but not adult stages. Interestingly, when we transplanted the flexor digitorum longus (FDP) tendon derived from adult Scx-GFP+ rats into WT adults, Scx-GFP was not expressed in transplanted tendons. However, tendons transplanted from adult WT rats into Scx-GFP rats showed upregulated Scx expression in tendon, suggesting that Scx-GFP+ cells are mobilized from tissues outside the tendon. Importantly, at 4 weeks post-surgery, Scx-GFP-expressing cells were more frequent within the grafted tendon when an ACL remnant was preserved (P group) relative to when it was not (R group) (P vs R groups (both n = 5), p<0.05), and by 6 weeks, biomechanical strength of the transplanted tendon was significantly increased if the remnant was preserved (P vsR groups (both n = 14), p<0.05). Scx-GFP+ cells increased in remnant tissue after surgery, suggesting remnant tissue is a source of Scx+ cells in grafted tendons. We conclude that the novel Scx-GFP Tg rat is useful to monitor emergence of Scx-positive cells, which likely contribute to increased graft strength after ACL reconstruction.

A machine learning-based scoring system and ten factors associated with hip fracture occurrence in the elderly.

Hip fractures are fragility fractures frequently seen in persons over 80-years-old. Although various factors, including decreased bone mineral density and a history of falls, are reported as hip fracture risks, few large-scale studies have confirmed their relevance to individuals older than 80, and tools to assess contributions of various risks to fracture development and the degree of risk are lacking. We recruited 1395 fresh hip fracture patients and 1075 controls without hip fractures and comprehensively evaluated various reported risk factors and their association with hip fracture development. We initially constructed a predictive model using Extreme Gradient Boosting (XGBoost), a machine learning algorithm, incorporating all 40 variables and evaluated the model's performance using the area under the receiver operating characteristic curve (AUC), yielding a value of 0.87. We also employed SHapley Additive exPlanation (SHAP) values to evaluate each feature importance and ranked the top 20. We then used a stepwise selection method to determine key factors sequentially until the AUC reached a plateau nearly equal to that of all variables and identified the top 10 sufficient to evaluate hip fracture risk. For each, we determined the cutoff value for hip fracture occurrence and calculated scores of each variable based on the respective feature importance. Individual scores were: serum 25(OH)D levels (<10 ng/ml, score 7), femoral neck T-score (<-3, score 5), Barthel index score (<100, score 3), maximal handgrip strength (<18 kg, score 3), GLFS-25 score (≥24, score 2), number of falls in previous 12 months (≥3, score 2), serum IGF-1 levels (<50 ng/ml, score 2), cups of tea/day (≥5, score -2), use of anti-osteoporosis drugs (yes, score -2), and BMI (<18.5 kg/m2, score 1). Using these scores, we performed receiver operating characteristic (ROC) analysis and the resultant optimal cutoff value was 7, with a specificity of 0.78, sensitivity of 0.75, and AUC of 0.85. These ten factors and the scoring system may represent tools useful to predict hip fracture.

The process of replication target selection in psychology: what to consider?

Increased execution of replication studies contributes to the effort to restore credibility of empirical research. However, a second generation of problems arises: the number of potential replication targets is at a serious mismatch with available resources. Given limited resources, replication target selection should be well-justified, systematic and transparently communicated. At present the discussion on what to consider when selecting a replication target is limited to theoretical discussion, self-reported justifications and a few formalized suggestions. In this Registered Report, we proposed a study involving the scientific community to create a list of considerations for consultation when selecting a replication target in psychology. We employed a modified Delphi approach. First, we constructed a preliminary list of considerations. Second, we surveyed psychologists who previously selected a replication target with regards to their considerations. Third, we incorporated the results into the preliminary list of considerations and sent the updated list to a group of individuals knowledgeable about concerns regarding replication target selection. Over the course of several rounds, we established consensus regarding what to consider when selecting a replication target. The resulting checklist can be used for transparently communicating the rationale for selecting studies for replication.

Robustness of the aging effect of smiling against vertical facial orientation.

Background: Previous studies have shown that the association between smiling and youth is a misconception; smiling faces have been estimated to be older than neutral faces. Previous studies have indicated that this aging effect of smiling (AES) is due to eye wrinkles caused by the facial action of smiling. However, whether holistic processing for facial expressions is involved in AES has not been investigated. The present study aimed to clarify these issues. Methods: Participants were recruited to participate in an online experiment that had a 3 (facial expression: smiling/neutral/surprised) × 2 (facial orientation: upright/inverted) mixed design. Participants were presented with an upright or inverted face for each expression (neutral, smiling, and surprised) and were asked to estimate the individual's age. Results: In total, 104 participants were included in the analysis. The results show that smiling faces were estimated to be older than neutral faces, whereas there was no significant difference between upright and inverted faces. Conclusions: Our findings suggest that AES is not dependent on holistic processing.

DOC-IDS: A Deep Learning-Based Method for Feature Extraction and Anomaly Detection in Network Traffic.

With the growing diversity of cyberattacks in recent years, anomaly-based intrusion detection systems that can detect unknown attacks have attracted significant attention. Furthermore, a wide range of studies on anomaly detection using machine learning and deep learning methods have been conducted. However, many machine learning and deep learning-based methods require significant effort to design the detection feature values, extract the feature values from network packets, and acquire the labeled data used for model training. To solve the aforementioned problems, this paper proposes a new model called DOC-IDS, which is an intrusion detection system based on Perera's deep one-class classification. The DOC-IDS, which comprises a pair of one-dimensional convolutional neural networks and an autoencoder, uses three different loss functions for training. Although, in general, only regular traffic from the computer network subject to detection is used for anomaly detection training, the DOC-IDS also uses multi-class labeled traffic from open datasets for feature extraction. Therefore, by streamlining the classification task on multi-class labeled traffic, we can obtain a feature representation with highly enhanced data discrimination abilities. Simultaneously, we perform variance minimization in the feature space, even on regular traffic, to further improve the model's ability to discriminate between normal and abnormal traffic. The DOC-IDS is a single deep learning model that can automatically perform feature extraction and anomaly detection. This paper also reports experiments for evaluating the anomaly detection performance of the DOC-IDS. The results suggest that the DOC-IDS offers higher anomaly detection performance while reducing the load resulting from the design and extraction of feature values.

Age of smile: a cross-cultural replication report of Ganel and Goodale (2018).

Smiling is believed to make people look younger. Ganel and Goodale (Psychon Bull Rev 25(6):612-616, 10.3758/s13423-017-1306-8, 2018) proposed that this belief is a misconception rooted in popular media, based on their findings that people actually perceive smiling faces as older. However, they did not clarify whether this misconception can be generalized across cultures. We tested the cross-cultural validity of Ganel and Goodale's findings by collecting data from Japanese and Swedish participants. Specifically, we aimed to replicate Ganel and Goodale's study using segregated sets of Japanese and Swedish facial stimuli, and including Japanese and Swedish participants in groups asked to estimate the age of either Japanese or Swedish faces (two groups of participants × two groups of stimuli; four groups total). Our multiverse analytical approach consistently showed that the participants evaluated smiling faces as older in direct evaluations, regardless of the facial stimuli culture or their nationality, although they believed that smiling makes people look younger. Further, we hypothesized that the effect of wrinkles around the eyes on the estimation of age would vary with the stimulus culture, based on previous studies. However, we found no differences in age estimates by stimulus culture in the present study. Our results showed that we successfully replicated Ganel and Goodale (2018) in a cross-cultural context. Our study thus clarified that the belief that smiling makes people look younger is a common cultural misconception.

Warning 'Don't spread' versus 'Don't be a spreader' to prevent the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) outbreak is threatening not only health but also life worldwide. It is important to encourage citizens to voluntarily practise infection-prevention (IP) behaviours such as social distancing and self-restraint. Previous research on social cognition suggested that emphasizing self-identity is key to changing a person's behaviour. The present study investigated whether reminders that highlight self-identity would be effective in changing intention and behaviour related to the COVID-19 outbreak, and hypothesized that those who read reminders highlighting self-identity (Don't be a spreader) would change IP intention and behaviour better than those who read 'Don't spread' or no reminder. We conducted a two-wave survey of the same participants with a one-week interval, during which we assigned one of three reminder conditions to the participants: 'Don't spread' (spreading condition), 'Don't be a spreader' (spreader condition) and no reminder (control condition). Participants marked their responses to IP intentions and actual behaviours each week based on the Japanese Ministry of Health, Labour and Welfare guidelines. While the results did not show significant differences between the conditions, the post hoc analyses showed significant equivalence in either IP intentions or behavioural scores. We discussed the results from the perspective of the effect size, ceiling effects and ways of manipulation checks as future methods with more effective persuasive messaging. Following in-principle acceptance, the approved Stage 1 version of this manuscript was pre-registered on the OSF at https://doi.org/10.17605/OSF.IO/KZ5Y4. This pre-registration was performed prior to data collection and analysis.

Task Difficulty Modulates the Disrupting Effects of Oral Respiration on Visual Search Performance.

Previous research has suggested that oral respiration may disturb cognitive function and health. The present study investigated whether oral respiration negatively affects visual attentional processing during a visual search task. Participants performed a visual search task in the following three breathing conditions: wearing a nasal plug, wearing surgical tape over their mouths, or no modification (oral vs. nasal vs. control). The participants searched for a target stimulus within different set sizes of distractors in three search conditions (orientation vs colour vs conjunction). Experiment 1 did not show any effect due to respiration. Experiment 2 rigorously manipulated the search efficiency and found that participants required more time to find a poorly discriminable target during oral breathing compared with other breathing styles, which was due to the heightened intercept under this condition. Because the intercept is an index of pre-search sensory processing or motor response in visual search, such cognitive processing was likely disrupted by oral respiration. These results suggest that oral respiration and attentional processing during inefficient visual search share a common cognitive resource.

Arousing emoticons edit stream/bounce perception of objects moving past each other.

When two identical objects move toward each other, overlap completely, and continue toward opposite ends of a space, observers might perceive them as streaming through or bouncing off each other. This phenomenon is known as 'stream/bounce perception'. In this study, we investigated the effect of the presentation of emoticons on stream/bounce perception in five experiments. In Experiment 1, we used emoticons representing anger ('('∧')'), a smile ('(^_^)'), and a sober face ('(°_°)', as a control), and observers were asked to judge whether two objects unrelated to the emoticon had streamed through or bounced off each other. The anger emoticon biased perception toward bouncing when compared with the smile or sober face emoticon. In Experiments 2 and 3, we controlled for the valence and arousal of emoticons, and found that arousal influenced stream/bounce perception but valence did not. Experiments 4 and 5 ruled out the possibility of attentional capture and response bias for the emoticon with higher arousal. Taken together, the findings indicate that emoticons with higher arousal evoke a mental image of a 'collision' in observers, thereby eliciting the bounce perception.