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Abstract Embryo implantation is crucial for successful pregnancy, requiring appropriate uterine responses to implantation-competent blastocysts. Molecular communication at the maternal–fetal junction governs this process. Leukemia inhibitory factor (Lif) plays a pivotal role in implantation across species. Lif is abundantly expressed in the glandular epithelium during blastocyst-receptive phase and is induced in the stroma surrounding attached blastocysts. While diminished Lif expression leads to infertility, its influence on peri-implantation uteri remains unclear. Therefore, we investigated the role of Lif in uterine physiology using its uterine-specific knockout (uKO) and uterine epithelial-specific KO (eKO) in mice. Lif eKO and uKO mice displayed infertility owing to failed embryo attachment. Recombinant Lif supplementation rescued the reproductive phenotype of Lif eKO mice, but not Lif uKO mice; however, recombinant Lif injection rescued embryo attachment in Lif uKO mice. RNA-seq analysis indicated that Lif governs uterine epithelial genes, but not embryonic genes, to facilitate embryo attachment via activating nuclear Stat3. Concordantly, three-dimensional imaging of the uterine epithelium revealed that luminal closure and crypt formation are regulated by the uterine Lif–Stat3 axis as well as the presence of blastocysts. Collectively, our findings shed light on previously unknown mechanism on how Lif influences uterine functions molecularly and physiologically during early pregnancy.

Abstract Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

Coronavirus disease 2019 (COVID-19) is transitioning from a pandemic to an endemic phase through recurring mutations. Initial efforts focused on developing strategies to mitigate infection of lung epithelial cells which are the primary targets of the SARS-CoV-2 virus using the affinity of the spike protein to human ACE2 receptor. SARS-CoV-2, however, infects additional cell types present in the lung such as macrophages through the alternate entry receptor Neuropilin 1 (NRP1). Developing novel therapeutic strategies to prevent SARS-CoV-2 infection of cells crucial for immunosurveillance could thus be integral to treat post-acute sequelae of COVID-19 (PASC). Since traditional drug development process takes a long time, it is imperative to establish new strategies that can be rapidly deployed to combat the dynamic nature of COVID-19 evolution and to contribute to prevention of future pandemics. We obtained the gene expression profiles of THP-1 monocytes from L1000-based Connectivity Map using CLUE, cloud- based software platform for the analysis of perturbational datasets to identify compounds that could reduce the expression level of NRP1. Out of 33,590 compounds, we analyzed the profiles of 45 compounds for their ability to reduce NRP1 expression. We selected the top five small molecule inhibitors predicted to decrease the expression of NRP1 for validation studies. All five selected compounds showed low cytotoxicity at tested doses and their ability to reduce NRP1 surface expression was evaluated in THP-1 monocytes, THP-1-derived macrophage like cells and human peripheral blood mononuclear cell (PBMC)-derived primary macrophages. Five compounds with the largest predicted reduction of NRP1 expression decreased macrophage NRP1 surface expression measured using flow cytometry and fluorescent microscopy assays in both cell line and primary macrophages. Using our computational approach, we identified 45 compounds that could potentially decrease NRP1 surface expression in macrophages based on their effect on THP-1 monocytes. Validation studies showed that such an approach can help to identify compounds for drug repositioning in target cells that are absent in the L1000 database. Our proposed approach can be applicable for the rapid compound exploration to combat novel cell types that SARS-CoV-2 targets for infection and could provide molecular bases for the development of new drugs.

Abstract Objective To evaluate the influence of environmental factors and prematurity relating to juvenile dermatomyositis (JDM), its course and refractoriness to treatment. Methods A case-control study with 35 patients followed up at a tertiary hospital and 124 healthy controls, all residents of São Paulo. Patients were classified according to monocyclic, polycyclic or chronic disease courses and refractoriness to treatment. The daily concentrations of pollutants (inhalable particulate matter-PM10, sulfur dioxide-SO2, nitrogen dioxide-NO2, ozone-O3 and carbon monoxide-CO) were provided by the Environmental Company of São Paulo. Data from the population were obtained through a questionnaire. Results Fifteen patients had monocyclic courses, and 19 polycyclic/chronic courses. Eighteen patients were refractory to treatment. Maternal occupational exposure to inhalable agents (OR = 17.88; IC 95% 2.15–148.16, p = 0.01) and exposure to O3 in the fifth year of life (third tertile > 86.28µg/m3; OR = 6.53, IC95% 1.60–26.77, p = 0.01) were risk factors for JDM in the multivariate logistic regression model. The presence of a factory/quarry at a distance farther than 200 meters from daycare/school (OR = 0.22; IC 95% 0.06–0.77; p = 0.02) was a protective factor in the same analysis. Prematurity, exposure to air pollutants/cigarette smoke/sources of inhalable pollutants in the mother’s places of residence and work during the gestational period were not associated with JDM. Prematurity, maternal exposure to occupational pollutants during pregnancy as well as patient’s exposure to ground-level pollutants up to the fifth year of life were not associated with disease course and treatment refractoriness. Conclusion Risk factors for JDM were maternal occupational exposure and exposure to O3 in the fifth year of life.

Abstract Embryo implantation failures are a major challenge in reproductive medicine, but the underlying mechanism remains poorly understood. Successful implantation requires dynamic remodeling of the endometrium through integrated proliferation and differentiation of endometrial cells including luminal epithelial, glandular epithelial, and stromal cells. Conversely, their disruption causes infertility. Spatiotemporal control of transcription is required for these processes; however, the underlying epigenetic regulation is largely unknown. In this study, we examined expression data from the human endometrium during implantation and discovered that expression of the histone lysine methyltransferase KMT2D was significantly suppressed in patients with recurrent implantation failure. Further study revealed that uterine deletion of Kmt2d in mice caused infertility due to implantation failure. Morphological analysis discovered a reduction in the number of uterine glands and aberrant differentiation of the luminal and glandular epithelium into stratified phenotypes in Kmt2d knockout uteri. Administration of leukemia inhibitory factor protein, which is expressed in uterine glands and is essential for implantation, did not rescue implantation failure in Kmt2d knockout mice, suggesting that infertility was not solely due to uterine gland dysfunction. RNA sequencing analysis revealed that Kmt2d knockout uteri displayed suppressed expression of genes involved in ion homeostasis, which may affect the uterine luminal morphology. Our study suggests that KMT2D plays an essential role in facilitating successful embryo implantation by regulating the coordinated differentiation of endometrial cells, providing valuable insights into unexplained implantation failures in women.

Abstract Video-based monitoring is essential nowadays in cattle farm management systems for automated evaluation of cow health, encompassing body condition scores, lameness detection, calving events, and other factors. In order to efficiently monitor the well-being of each individual animal, it is vital to automatically identify them in real time. Although there are various techniques available for cattle identification, a significant number of them depend on radio frequency or visible ear tags, which are prone to being lost or damaged. This can result in financial difficulties for farmers. Therefore, this paper presents a novel method for tracking and identifying the cattle with an RGB image-based camera. As a first step, to detect the cattle in the video, we employ the YOLOv8 (You Only Look Once) model. The sample data contains the raw video that was recorded with the cameras that were installed at above from the designated lane used by cattle after the milk production process and above from the rotating milking parlor. As a second step, the detected cattle are continuously tracked and assigned unique local IDs. The tracked images of each individual cattle are then stored in individual folders according to their respective IDs, facilitating the identification process. The images of each folder will be the features which are extracted using a feature extractor called VGG (Visual Geometry Group). After feature extraction task, as a final step, the SVM (Support Vector Machine) identifier for cattle identification will be used to get the identified ID of the cattle. The final ID of a cattle is determined based on the maximum identified output ID from the tracked images of that particular animal. The outcomes of this paper will act as proof of the concept for the use of combining VGG features with SVM is an effective and promising approach for an automatic cattle identification system

The interaction hypothesis of second language acquisition (Long, 1981) states that negotiated interaction is necessary for language development. In many language learning contexts, educators and stakeholders seek to provide opportunities for learners to engage in meaningful real-life interactions that help them build linguistic, semantic, and rhetorical competence. However, the opportunities provided for interaction can vary in their degree of effectiveness and may only sometimes lead to increased language ability. If these interactions are scaffolded correctly, they can be tuned to maximize their benefits (Loewen & Sato, 2018). Unfortunately, this is not always practical from a temporal and economic perspective. Artificial intelligence (AI) could be the solution for providing learners with individualized, comprehensive assistance during their learning interactions. Accordingly, the authors developed a bespoke application that employs advanced natural language processing and large language model AI technologies to support learner interactions. The application was developed to support students in two different contexts: Kanda University of International Studies in Japan, where students study English, and Massachusetts Institute of Technology in the United States, where learners study Japanese. The rationale for creating the application and selecting its major features is discussed. This is followed by a discussion of how the application functions and how it will be used. The authors will then discuss their plans for implementation into both informal and formal learning contexts at the two universities. They conclude by discussing potential limitations and plans for improving the application.

Key Clinical Message Chin augmentation by hyaluronic acid filler injection rarely causes abnormal bone resorption in the mentum. Thus, when taking the history of a patient with jaw deformity, it is imperative to check the history of treatment of the mentum. Abstract Hyaluronic acid (HA) filler injection is a common procedure in nonsurgical cosmetic chin augmentation. Due to its high biocompatibility and simple injection technique, HA filler injection is a popular procedure. However, adverse events such as allergic reactions and foreign body reactions have been reported in some cases. In this study, we report a case of skeletal Class II jaw deformity in which bone resorption was observed in the mentum after HA filler injection. The purpose of this study is to discuss the indications for HA filler injection in skeletal Class II cases that require orthognathic surgery. The patient was a 30‐year‐old woman. To improve retrusion of the mentum, she has been receiving HA filler injections in the mentum three times every 6 months in the cosmetic surgery clinic since 2015. However, the retrusion of the mentum did not improve, which prompted here to visit the orthodontic clinic. Radiographs and CT revealed bowl‐shaped bone resorption surrounding the foreign bodies in the mentum. She was diagnosed with maxillary protrusion, vertical maxillary excess, mandibular retrusion, and bilateral condylar resorption. Bimaxillary orthognathic surgery (BOGS) and removal of residual HA fillers were planned after completion of the preoperative orthodontic treatment. After BOGS, the foreign bodies were completely removed, and the resorption cavities were filled with excess bone segments from the surgical sites. X‐ray photoelectron spectroscopy analysis of the foreign bodies suggested the presence of HA. One year after the BOGS, no progression of condylar resorption occurred, and bone healing at the mentum had a good prognosis. Therefore, the patient underwent reduction and advancement genioplasty. She was satisfied with her facial profile and occlusal function. Unexpected bone resorption in the mentum caused by HA filler injection is often discovered incidentally. Although, patients may feel hesitant to confess their history of treatment of the mentum, it is important to ensure that they are carefully interviewed.

Objective This study aimed to investigate the potential of LINE, a major messaging app and social media platform in Japan, as an effective tool to enhance the health and dietary behaviors of young Japanese women who face health and dietary challenges. Methods A 6-week randomized controlled trial employing an intention-to-treat analysis was conducted on first-year female students (age range, 18–23 years) from one university and two junior colleges in Mie Prefecture. The participants were allocated to either an intervention group (n = 54) or a control (n = 55) group. The intervention group received health information focusing on proper intake and intake methods to maintain an appropriate weight and dietary balance via LINE 18 times over 6 weeks (3 times per week), whereas the control group continued their usual lifestyle without any additional intervention. Results The results revealed a significant increase in the percentage of participants in the intervention group who rated their health as “unhealthy” (from 25.9% to 40.3%). This may be attributed to increased health awareness among the participants, which led to more critical self-assessments—a phenomenon often referred to as the “health awareness paradox.” Despite this increase in perceived unhealthiness, the intervention group showed a significant increase in the intakes of iron, vitamin C, dietary fiber, and potassium, indicating improved nutritional behavior. Conclusion The provision of health information through LINE over a 6-week period demonstrated potential as a tool for health education among young Japanese women. However, the observed increase in “unhealthy” self-rated health underscores the complexity of such interventions, suggesting that while nutritional behavior may improve, increased health awareness can paradoxically lead to more negative self-assessments. Further research is needed to explore the optimal duration and content of health information delivered via social media apps to maximize their effectiveness for health interventions.

Abstract Pattern recognition of optical label is utilized not only in packet switches but also in the field of data security due to its wide range of applications. In particular, pattern recognition using waveguide devices is highly valued because it eliminates the need for encoder processing. However, existing methods suffer from the problem of degraded contrast ratio because half of the input power are emitted from non‐target waveguides. In this article, a method is proposed to improve the contrast ratio employing a 4×4 multi‐mode interference (MMI) coupler with multiple input signals. The theoretical results reveal that the proposed method improves the contrast ratio from 3.0 dB to 9.5 dB and ∞ dB for the three‐input and four‐input cases, respectively, for quadrature phase‐shift keying (QPSK)‐modulated signal. Furthermore, numerical simulation was performed through the three dimension finite‐difference time‐domain (3D‐FDTD) method, and the proposed scheme successfully discriminated each QPSK pattern. The power value |E|2 at all ports closely matches the theoretical value, and the ratios of 9.5 dB and >30.0 dB are numerically obtained.

To investigate the yet-unknown roles of prostaglandins (PGs) in the uterus, we analyzed the expression of various PG receptors in the uterus. We found that three types of Gs-coupled PG receptors, DP, EP2, and EP4, were expressed in luminal epithelial cells from the peri-implantation period to late pregnancy. DP expression was also induced in stromal cells within the mesometrial region, whereas EP4 was expressed in stromal cells within the anti-mesometrial region during the peri-implantation period. The timing of DP induction after embryo attachment correlated well with that of cyclooxygenase-2 (COX-2); however, COX-2-expressing stromal cells were located in the vicinity of the embryo, whereas DP-expressing stromal cells surrounded these cells on the mesometrial side. Specific [3H]PGD2-binding activity was detected in the decidua of uteri, with PGD2 synthesis comparable to that of PGE2 detected in the uteri during the peri-implantation period. Administration of the COX-2-specific inhibitor celecoxib caused adverse effects on decidualization, as demonstrated by the attenuated weight of the implantation sites, which was recovered by the simultaneous administration of a DP agonist. Such a rescuing effect of the DP agonist was mimicked by an EP4 agonist, but not an EP2 agonist. While the importance of DP signaling was shown pharmacologically, DP/EP2 double deficiency did not affect implantation and decidualization, suggesting the contribution of EP4 to these processes. Indeed, administration of an EP4 antagonist substantially affected decidualization in DP/EP2-deficient mice. These results suggest that COX-2-derived PGD2 and PGE2 contribute to decidualization via a coordinated pathway of DP and EP4 receptors.

Recent clinical trials demonstrated that proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors reduce cardiovascular events without affecting systemic inflammation in the patients with coronary artery disease, as determined by high sensitivity C-reactive protein (CRP) levels. However, its pro-inflammatory effects in cardiovascular disease in humans and experimental animals beyond the traditional cholesterol receptor-dependent lipid metabolism have also called attention of the scientific community. PCSK9 may target receptors associated with inflammation other than the low-density lipoprotein receptor (LDLR) and members of the LDLR family. Accumulating evidence suggests that PCSK9 promotes macrophage activation not only via lipid-dependent mechanisms, but also lipid-independent and LDLR-dependent or -independent mechanisms. In addition to dyslipidemia, PCSK9 may thus be a potential therapeutic target for various pro-inflammatory diseases.

Introduction: Carnitine O-octanoyltransferase (CROT) is a well-established peroxisomal enzyme involved in liver fatty acid oxidation, but less is known about its recently discovered role in promoting vascular calcification, and whether CROT-dependent liver metabolism contributes to the latter. To date, CROT function in the context of calcification potential has been conducted in the dyslipidemic low-density lipoprotein receptor-deficient (Ldlr−/−) mice.Objectives: To differentiate peroxisome and CROT-dependent lipid biology from that of lipoprotein-mediated lipid biology, we therefore conducted a metabolomic analysis of the liver and plasma of normolipidemic CROT-deficient (Crot−/−) mice.Methods: We performed LC-MS-based metabolomics on liver and plasma derived from Crot−/− and Crot +/− mice and sibling Crot+/+ mice, using a dual-phase metabolite extraction protocol, and multiple LC-MS acquisition strategies.Results: We identified between 79 to 453 annotated metabolites from annotated metabolites from liver samples, and 117 to 424 annotated metabolites from plasma samples. Through differential abundance analysis, we determined that omega-3 fatty acids such as EPA, DPA, and DHA were higher in the liver of Crot−/− and Crot +/− mice than Crot+/+ mice. EPA were higher in plasma of Crot−/− mice than Crot+/+ mice. We also determined that the anti-inflammatory dicarboxylic acids, tetradecanedioic acid and azelaic acid, were higher in the plasma of CROT-deficient mice.Conclusion: Our study associated genetic CROT deletion with increased levels of anti-inflammatory molecules in mouse liver and plasma. These results suggest a potential mechanism for anti-calcification effects of CROT suppression and the potential use of omega-3 fatty acids as biomarkers for future CROT inhibition therapies.

Abstract Background Suction drainages are commonly used after total knee arthroplasty (TKA) procedures; however, their use is somewhat controversial. Recently, some reports have claimed that the administration of tranexamic acid (TXA) may prevent postoperative bleeding following TKAs. Although numerous studies have reported regarding different dosages, timings of administration, or drain clamping times for intravenous and intra-articular TXA injections (IA-TXAs), few have examined whether suction drainage is necessary when TXA is administered. In this study, we compared using suction drainage without TXA administration and IA-TXA without suction drainage and aimed to examine the need for suction drainage during IA-TXA. Methods This retrospective study was conducted on 217 patients who had received TKA for osteoarthritis; 104 were placed on suction drainage after TKA without TXA (Group A), whereas the remaining 113 received IA-TXA immediately after surgery without suction drainage (Group B). Our clinical evaluation included assessments of the need for transfusion, presence of postoperative complications, incidence of deep vein thrombosis (DVT), and changes in hemoglobin (Hb), hematocrit (Hct), and D-dimer levels. Results No significant differences were observed in terms of postoperative complications and preoperative Hb, Hct, or D-dimer levels between the two groups. Although the prevalence of DVT was significantly higher in Group B (p

Abstract Recent advancements in machine learning and deep learning have revolutionized various computer vision applications, including object detection, tracking, and classification. This research investigates the application of deep learning for cattle lameness detection in dairy farming. Our study employs image processing techniques and deep learning methods for cattle detection, tracking, and lameness classification. We utilize two powerful object detection algorithms: Mask-RCNN from Detectron2 and the popular YOLOv8. Their performance is compared to identify the most effective approach for this application. Bounding boxes are drawn around detected cattle to assign unique local IDs, enabling individual tracking and isolation throughout the video sequence. Additionally, mask regions generated by the chosen detection algorithm provide valuable data for feature extraction, which is crucial for subsequent lameness classification. The extracted cattle mask region values serve as the basis for feature extraction, capturing relevant information indicative of lameness. These features, combined with the local IDs assigned during tracking, are used to compute a lameness score for each cattle. We explore the efficacy of various established machine learning algorithms, such as Support Vector Machines (SVM), AdaBoost and so on, in analyzing the extracted lameness features. Evaluation of the proposed system was conducted across three key domains: detection, tracking, and lameness classification. Notably, the detection module employing Detectron2 achieved an impressive accuracy of 98.98%. Similarly, the tracking module attained a high accuracy of 99.50%. In lameness classification, AdaBoost emerged as the most effective algorithm, yielding the highest overall average accuracy (77.9%). Other established machine learning algorithms, including Decision Trees (DT), Support Vector Machines (SVM), and Random Forests, also demonstrated promising performance (DT: 75.32%, SVM: 75.20%, Random Forest: 74.9%). The presented approach demonstrates the successful implementation for cattle lameness detection. The proposed system has the potential to revolutionize dairy farm management by enabling early lameness detection and facilitating effective monitoring of cattle health. Our findings contribute valuable insights into the application of advanced computer vision methods for livestock health management.

Abstract Aim This study aimed to verify the real‐world efficacy and safety of quetiapine fumarate extended‐release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression. Methods We performed a post‐marketing surveillance with an observation period of 12 weeks. Results In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and “longer time since the onset of the first episode” (p = 0.011) and “presence of complications” (p

Introduction Distant metastasis of T1a renal cell carcinoma is rare and whether metastasis is more probable in patients undergoing hemodialysis remains unclear. We report the autopsy case of a patient undergoing hemodialysis with multiple metastases that rapidly progressed from T1a renal cell carcinoma treated with multimodal therapy including nivolumab. Case presentation A 70‐year‐old male who underwent hemodialysis was diagnosed with clear cell carcinoma (pT1a, G2) after nephrectomy. Six months post‐surgery, bone and lung metastases appeared and treated with radiotherapy and pazopanib, respectively. Nivolumab was administered as second‐ and fourth‐line treatments for lung metastases. The patient died approximately 60 months after initial diagnosis; however, nivolumab controlled disease progression for 24 months. An autopsy revealed the lung's occupation with clear cell carcinoma tumor tissue. Conclusion Nivolumab has potential to control lung metastasis progression. Additionally, rechallenge is possible in patients with renal cell carcinoma undergoing hemodialysis.

Key Clinical Message Anti‐N‐methyl‐d‐aspartate receptor encephalitis is an autoimmune disorder characterized by various neurological symptoms with a relatively favorable prognosis. We present a case of prolonged dysphagia successfully managed with outpatient rehabilitation, including interferential current stimulation and resistance exercises. Significant improvement was observed, highlighting the efficacy of combined treatment in overcoming chronic dysphagia.