Search

Abstract Mental disorders have become one of the most burdensome health concerns. We have previously demonstrated that whey-derived β-lactolin (glycine–thereonine–tryptophan–tyrosine tetrapeptide) activates dopaminergic systems and improves psychiatric function in rodents. However, the effects of β-lactolin on human mood states have not been investigated. This randomized, double-blind, placebo-controlled study aimed to evaluate the effects of supplementation with β-lactolin–rich whey peptide on human mood states. Sixty healthy adults (aged 45–64 years) with relatively low psychological health were randomly allocated to receive either whey peptide (containing β-lactolin 1.6 mg/day) or placebo for 6 weeks. Mood states (primary outcomes) were evaluated using self-reporting questionnaires. Health-related quality of life (QOL), salivary stress marker and lipid mediator levels were evaluated as secondary outcomes. Compared with placebo, supplementation with β-lactolin improved changes in trait anxiety (p = 0.046), as assessed using the state–trait anxiety inventory, and in subjective stress (p = 0.043), as assessed using the Perceived Stress Scale. In the assessment of QOL, changes in the vitality subscale and mental health summary score of the 36-Item Short-Form Health Survey were improved in the β-lactolin group. The levels of salivary immunoglobulin A were significantly higher in the β-lactolin group. In a subgroup analysis by median age (54.5 years), subjective stress and salivary prostaglandin levels were significantly decreased by β-lactolin supplementation in the 45–54 -year-old subgroup. In conclusion, supplementation with β-lactolin improves trait anxiety, subjective stress, and psychological QOL, which may be associated with immunologic responses detected via salivary analysis.

Abstract Possible local influence of an extreme marine heatwave is investigated on unprecedentedly hot summer around northern Japan in 2023. Sea-surface temperatures (SSTs) and subsurface ocean temperatures around northern Japan were also unprecedentedly high in the summer. This was especially the case off the east coast of Japan, where cool Oyashio water was replaced with much warmer water due to a striking poleward meander of the Kuroshio Extension persistent from the spring. Particularly amplified near-surface air temperature anomalies and even stronger warm anomalies in the subsurface ocean suggest that the marine heatwave acted to sustain the atmospheric heatwave. Anomalous upward of latent and sensible heat fluxes from the warmed sea surface are indicative of local oceanic impact. The warm SST anomalies reduced the lower-tropospheric stratification to maintain unfavourable condition for low-level cloud formation, which in turn led to increased surface insolation for further SST warming as positive feedback. The increased moisture in the warmed lower troposphere contributed to the enhanced surface downward longwave radiation. This enhanced greenhouse effect acted not only as positive feedback on the warm SST anomalies that increased evaporation but also as a contributor for the extreme warmth over northern Japan landmass.

Abstract Steatotic liver disease (SLD) is a burgeoning health problem predominantly associated with excessive alcohol consumption, which causes alcohol-related liver disease (ALD), and high caloric intake, which results in metabolic dysfunction-associated SLD (MASLD). The pathogenesis of ALD and MASLD, which can progress from steatohepatitis to more severe conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma, is complicated by several factors. Recently, extracellular ATP and adenosine (Ado), as damage-associated molecular patterns, were reported to promote inflammation and liver fibrosis, contributing to SLD pathogenesis. Here, we explored the in vivo dynamics of hepatic extracellular ATP and Ado during the progression of steatohepatitis using a genetically encoded GPCR-activation-based sensor (GRAB) in zebrafish models. We established hepatocyte-specific GRABATP and GRABAdo in zebrafish and investigated the changes in in vivo hepatic extracellular ATP and Ado levels under ALD or MASLD conditions. Disease-specific changes in hepatocyte extracellular ATP and Ado levels were observed, clearly indicating a correlation between hepatocyte extracellular ATP/Ado dynamics and disease progression. Furthermore, clodronate, a vesicular nucleotide transporter inhibitor, alleviated the MASLD phenotype by reducing the hepatic extracellular ATP and Ado content. These findings provide deep insights into extracellular ATP/Ado dynamics in disease progression, suggesting therapeutic potential for ALD and MASLD.

Abstract While obesity is a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC, "long-COVID"), the mechanism(s) underlying this phenomenon remains poorly understood. To address this gap in knowledge, we performed a 6-week longitudinal study to examine immune activity and gut microbiome dysbiosis in post-acute stage patients recovering from SARS-CoV-2 infection. Self-reported symptom frequencies and blood samples were collected weekly, with plasma assessed by ELISA and Luminex for multiple biomarkers and immune cell profiling. DNA from stool samples were collected at the early stage of recovery for baseline assessments of gut microbial composition and diversity using 16S-based metagenomic sequencing. Multiple regression analyses revealed obesity-related PASC linked to a sustained proinflammatory immune profile and reduced adaptive immunity, corresponding with reduced gut microbial diversity. In particular, enhanced signaling of the high mobility group box 1 (HMGB1) protein was found to associate with this dysregulation, with its upregulated levels in plasma associated with significantly impaired viral neutralization that was exacerbated with obesity. These findings implicate HMGB1 as a candidate biomarker of PASC, with potential applications for risk assessment and targeted therapies.

Abstract Photodynamic therapy is a treatment that combines a light source with a photosensitizer. LEDs have attracted considerable attention in clinical dentistry because they are inexpensive and safe to use. Although the interaction between photosensitizers and LEDs in dental practice is effective for treating periodontal disease by killing periodontopathic bacteria, little is known about the effects of LEDs on human gingival fibroblasts (HGnFs), which play an important role in gingival wound healing. In this study, we investigated the effects of high-intensity red LED irradiation on HGnFs after the addition of methylene blue (MB), one of the least harmful photosensitizers, on wound healing and reactive oxygen species (ROS) production induced by photodynamic reactions. We found that irradiation of MB with high-intensity red LED at controlled energy levels promoted cell proliferation, migration, and production of wound healing factors. Furthermore, ROS production by a photodynamic reaction enabled the translocation of phosphorylated Grb2-associated binder-1, activating Extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase signals. Our findings suggest that proper control of ROS production has a beneficial effect on gingival fibroblasts, which constitute periodontal tissue, from the perspective of gingival wound healing.

Abstract Our thought states shift from one state to another from moment to moment. The relationship between the thought shifting and bodily responses is yet to be directly examined. This exploratory study examined the influence of cardiovascular reactivity and interoception—sensing an internal bodily state—on the shifting of thought states. Participants (N = 100, 70 women) completed two tasks: the heartbeat counting task (HCT) and the vigilance task (VT). We assessed their interoceptive accuracy through their performance on the HCT. The VT was a simple sustained attention task in which participants pressed a key when the target stimulus appeared and were asked to report their thoughts. We presented subliminal vibration stimuli to induce alterations in heart rate (i.e., vibration block). Results showed that participants with higher interoceptive accuracy reported more continuation of self-referential thought (about past episodes and future plans regarding themselves) during the vibration block than did those with lower interoceptive accuracy. These results suggest that individuals with higher interoceptive accuracy are more likely to be influenced by their subliminal bodily response, resulting in divergent attention from the task and intermittent self-referential thought.

Abstract There is a need for serum diagnostic biomarkers to improve the prognosis of solid malignant tumors. Here, we conducted a single-institutional study to evaluate the diagnostic performance of serum stromal cell-derived factor 4 (SDF4) levels in cancer patients. Serum samples were collected from a total of 582 patients with solid cancers including gastric cancer (GC) and 80 healthy volunteers. SDF4 protein levels in sera, and conditioned media or lysates of human GC cell lines were measured by enzyme-linked immunosorbent assay, and those in GC tissue by immunohistochemistry. Serum SDF4 levels were higher in patients with cancer than the healthy control in all cancer type. Regarding GC, serum SDF4 levels distinguished healthy controls from GC patients with the area under the curve value of 0.973, sensitivity of 89%, and specificity of 99%. Serum SDF4 levels were significantly elevated in patient with early stage GC. In immunohistochemistry, the frequency of SDF4-positive GC tumors did not vary significantly between GC stages. The ability of human GC cell lines to both produce and secrete SDF4 was confirmed in vitro. In conclusion, serum SDF4 levels could be a promising candidate for a novel diagnostic biomarker for GC and other malignancies.

Abstract Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy.

Abstract Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability–high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p

Abstract 2-Bromopropane (2-BP) is a colorless liquid at room temperature and is used in closed systems in factories, mainly as an intermediate for medicines, pesticides, and other chemicals. However, the carcinogenicity of 2-BP is still unknown. The CByB6F1-Tg(HRAS)2Jic (rasH2) transgenic mouse model has been established as an alternative to long-term studies (1.5 years—lifetime) to detect carcinogenicity in as short a time as six months. We performed a 26-week inhalation exposure study of 2-BP using the rasH2 mouse model. Male and female rasH2 mice were exposed to 0, 67, 200, or 600 ppm of 2-BP for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. The results showed a concentration-dependent increase in lung tumor development in male and female rasH2 mice exposed by inhalation to 2-BP, which was significant by Peto’s and Poly-3 trend tests. Furthermore, in male rasH2 mice, 2-BP was found to be a testicular toxin. This study is the first to demonstrate that 2-BP is carcinogenic in male and female mice and a testicular toxin in male mice using the rasH2 mouse model.

Abstract Some studies have asked participants about attentional state on a scale from on-task to off-task, which set the middle option as attention focused on both, including the possibility of the coexistence of thoughts. In addition, studies using multidimensional probes explicitly assumed coexistence within spontaneous thoughts and task-focus dimensions. Although several studies have assumed the coexistence of some thought dimensions, none has explored whether these are different types of thoughts (task-focus, mind-wandering, task-related, external stimuli-related). To examine whether this coexistence of thought types occurred, we used thought probes to determine the degree of immersion in each. The participants responded to probes presented at random during a sustained attention task. The results revealed a mixture of thought types in many self-reports. In addition, the state of attentional allocation behind self-reports was estimated using the hidden Markov model. We observed the following attentional states: task-focused, task-unrelated, task-related, external stimuli-focused, and task-focused—but also focused on other thoughts. These results suggest that individuals can simultaneously allocate attention to thought types and discriminate between reporting. In some cases, probe options should also be considered for this coexistence. We also examined the relationship between self-reports and behavioral indexes, and discussed the necessity of separately measuring the degree of immersion for each thought type.

Abstract Cytokinin, a plant hormone, plays essential roles in organ growth and development. The type-B response regulator-mediated cytokinin signaling is repressed by type-A response regulators and is conserved in the liverwort Marchantia polymorpha. Its signal coordinates the development of diverse organs on the thallus body, such as the gemma cup, rhizoid, and air pores. Here we report that the type-B response regulator MpRRB upregulates the expression of the R2R3-MYB transcription factor GEMMA CUP-ASSOCIATED MYB1 (MpGCAM1) in M. polymorpha. Whereas both Mpgcam1 and Mprrb knockout mutants exhibited defects in gemma cup formation, the Mpgcam1 Mprra double mutant, in which cytokinin signaling is activated due to the lack of type-A response regulator, also formed no gemma cups. This suggests that MpGCAM1 functions downstream of cytokinin signaling. Inducible overexpression of MpGCAM1 produced undifferentiated cell clumps on the thalli of both wild-type and Mprrb. However, smaller thalli were formed in Mprrb compared to the wild-type after the cessation of overexpression. These results suggest that cytokinin signaling promotes gemma cup formation and cellular reprogramming through MpGCAM1, while cytokinin signals also participate in activating cell division during thallus development.

Abstract With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. We performed a 26-week inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) mice model for detecting carcinogenicity. Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. TiO2 NPs exposure induced deposition of particles in lungs in a dose-dependent manner in each exposure group. Exposure to TiO2 NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of alveolar epithelial type 2 cells was examined, and it was not increased by exposure to TiO2 NPs. This is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO2 NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m3, which is considered to be a high concentration.

Abstract The nuclear receptors liver X receptor α (LXRα) and LXRβ are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/β in hepatic NKT cells remains unknown. In this study, we examined the role of LXRα and LXRβ in NKT cells using mice deficient for LXRα and/or LXRβ, and found that hepatic invariant NKT (iNKT) cells are drastically decreased in LXRα/β-KO mice. Cytokine production stimulated by the iNKT cell activator α-galactosylceramide was impaired in LXRα/β-KO hepatic mononuclear cells and in LXRα/β-KO mice. iNKT cell-mediated antitumor effect was also disturbed in LXRα/β-KO mice. LXRα/β-KO mice transplanted with wild-type bone marrow showed decreased iNKT cells in the liver and spleen. The thymus of LXRα/β-KO mice showed a decreased population of iNKT cells. In conclusion, LXRα and LXRβ are essential for NKT cell-mediated immunity, such as cytokine production and hepatic antitumor activity, and are involved in NKT cell development in immune tissues, such as the thymus.

Abstract This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR

Abstract Endoscopic submucosal dissection (ESD) is a minimally invasive treatment option for superficial esophageal cancer (SEC) with high rates of complete resection. However, limited research exists on the efficacy of ESD for SEC in gastrectomized patients. This study aimed to evaluate the efficacy of ESD for SEC in gastrectomized patients. We included 318 patients of SEC treated at our institution between April 2005 and October 2021. To minimize bias between the gastrectomized and non-gastrectomized groups, we conducted a propensity-score matched analysis and compared the ESD outcomes for SEC of the two groups. Of the 318 patients included in the study, 48 and 270 patients were in the gastrectomized and non-gastrectomized groups, respectively. After 1:2 propensity-score matching, we matched 44 patients in the gastrectomized group to 88 patients in the non-gastrectomized group, and found no significant differences in the baseline clinicopathological characteristics. Regarding the ESD outcomes, there were no significant differences in the complete resection rate, procedure time, hospitalized period, and recurrence rates between the two groups. Multivariate analysis also cofirmed that the history of gastrectomy was not a risk factor of the difficult case of esophageal ESD. In conclusion, history of gastrectomy might not negatively affect the ESD outcomes of SECs.

Abstract A drug holiday of 3 months does not promote separation of sequestra and is not correlated with treatment outcomes after surgical therapy in osteoporosis patients who receive antiresorptive agents and who have medication-related osteonecrosis of the jaw. Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive agents alone or in combination with immune modulators or antiangiogenic medications, in the absence of radiation exposure to the head and neck region. The effectiveness of surgical treatment for MRONJ has been reported, but the timing of the operation remains controversial. The purpose of this study was to clarify whether preoperative drug holidays of antiresorptive agents promote sequestrum separation and improve treatment outcomes in patients who receive low doses of antiresorptive agents. This retrospective study included 173 patients who received low-dose antiresorptive agents and underwent surgical therapy. The effects of a drug holiday on the separation of sequestra and treatment outcomes were analyzed using logistic and Cox regression analyses. Multivariate analysis revealed that administration of an antiresorptive agent for more than 4 years, a high number of lymphocytes, and an extensive osteolytic area were significantly correlated with separation of sequestra, but drug holiday did not promote sequestrum separation. Furthermore, a drug holiday of 90, 120 or 180 days did not show any improvement in treatment outcomes. The drug holiday of the antiresorptive agents for the treatment of MRONJ is unnecessary, and surgical therapy should be performed early.

Abstract Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

Abstract Elevated numbers of candida in the oral cavity often lead to oral candidiasis development in patients undergoing radiotherapy for oral or oropharyngeal cancer. This study aimed to verify the effect of miconazole mucoadhesive tablets on suppression of oral candida infection during radiotherapy. For this preliminary interventional study, miconazole mucoadhesive tablets were attached to the oral mucosa for 14 days from when grade 2 oral mucositis appeared in patients with oral or oropharyngeal cancer receiving radiotherapy, and the incidence of oral candidiasis was investigated. Various clinical factors were examined; univariate and multivariate Cox regression analyses were performed to investigate and compare the efficacy of this drug in preventing oral candidiasis with results of our previous study as historical control. Miconazole mucoadhesive tablets were administered to 18 patients, and oral candidiasis was observed in one patient (5.6%) after treatment completion. Among 144 historical control patients, 43 (29.9%) developed oral candidiasis. Multivariate Cox regression showed that miconazole mucoadhesive tablets significantly reduced oral candidiasis development during radiotherapy (p = 0.049, Hazard ratio 0.136, 95% confidence interval 0.019–0.994). This preliminary study suggests the efficacy of miconazole mucoadhesive tablets in preventing oral candidiasis in oral or oropharyngeal cancer patients treated with radiotherapy. Trial registration: Japan Registry of Clinical Trials (jRCT), jRCTs071190023. Registered 3 September, 2019.

Abstract Early regression—the regression in tumor volume during the initial phase of radiotherapy (approximately 2 weeks after treatment initiation)—is a common occurrence during radiotherapy. This rapid radiation-induced tumor regression may alter target coordinates, necessitating adaptive radiotherapy (ART). We developed a deep learning-based radiomics (DLR) approach to predict early head and neck tumor regression and thereby facilitate ART. Primary gross tumor volume (GTVp) was monitored in 96 patients and nodal GTV (GTVn) in 79 patients during treatment. All patients underwent two computed tomography (CT) scans: one before the start of radiotherapy for initial planning and one during radiotherapy for boost planning. Patients were assigned to regression and nonregression groups according to their median tumor regression rate (ΔGTV/treatment day from initial to boost CT scan). We input a GTV image into the convolutional neural network model, which was pretrained using natural image datasets, via transfer learning. The deep features were extracted from the last fully connected layer. To clarify the prognostic power of the deep features, machine learning models were trained. The models then predicted the regression and nonregression of GTVp and GTVn and evaluated the predictive performance by 0.632 + bootstrap area under the curve (AUC). Predictive performance for GTVp regression was highest using the InceptionResNetv2 model (mean AUC = 0.75) and that for GTVn was highest using NASNetLarge (mean AUC = 0.73). Both models outperformed the handcrafted radiomics features (mean AUC = 0.63 for GTVp and 0.61 for GTVn) or clinical factors (0.64 and 0.67, respectively). DLR may facilitate ART for improved radiation side-effects and target coverage.

Abstract Triphenylamine derivatives are superior hole-transport materials. For their application to high-functional organic semiconductor devices, efficient hole injection at the electrode/triphenylamine derivative interface is required. Herein, we report the design and evaluation of a Au/fullerene-doped α-phenyl-4′-[(4-methoxyphenyl)phenylamino]stilbene (TPA) buffer layer/TPA/Au layered device. It exhibits rectification conductivity, indicating that hole injection occurs more easily at the Au/fullerene-doped TPA interface than at the Au/TPA interface. The Richardson-Schottky analysis of the device reveals that the hole injection barrier (Φ B) at the Au/fullerene-doped TPA interface decreases to 0.021 eV upon using C70 as a dopant, and Φ B of Au/TPA is as large as 0.37 eV. The reduced Φ B of 0.021 eV satisfies the condition for ohmic contact at room temperature (Φ B $$\le $$ ≤ 0.025 eV). Notably, C70 doping has a higher barrier-reduction effect than C60 doping. Furthermore, a noteworthy hole-injection mechanism, in which the ion–dipole interaction between TPA and fullerenes plays an important role in reducing the barrier height, is considered based on cyclic voltammetry. These results should facilitate the design of an electrode/organic semiconductor interface for realizing low-voltage driven organic devices.

Abstract Human gingival fibroblasts (HGnFs) maintain periodontal tissue homeostasis through active proliferation and migration. Clinically, it is considered that the wound-healing ability of the gingival tissue is maintained even in environments with insufficient supply of nutrients, such as glucose, immediately after periodontal surgery. However, the effects of such glucose-deficient environments on HGnFs remain unclear. This study aimed to investigate the effects of low-glucose environment on HGnFs homeostasis. We evaluated gingival wound healing by examining cell proliferation and migration and collagen synthesis in HGnFs cultured in 100, 50, 25, and 0 mg/dL glucose in vitro. The cellular stress levels were determined by measuring the lactate dehydrogenase (LDH) and reactive oxygen species (ROS) levels. The glucose metabolism of HGnFs in the low-glucose concentrations was studied by measuring glucose transporter type 1 (GLUT1) mRNA expression, glucose uptake assays, lactate and ATP productions. Molecular effects were examined with a focus on the LKB1-AMPK signaling pathway. Autophagy activity in glucose-deprived HGnFs was evaluated by measuring the levels of autophagy-related proteins. Low glucose levels increased cellular stress levels, autophagy activity, and enhanced glucose metabolism through the LKB1-AMPK signaling pathway, providing more ATPs to promote wound healing. Our results regarding glucose transfer suggest the rapid healing of gingival wounds.

Abstract Cardiovascular disease is the leading cause of death in women during pregnancy and the postpartum period. Obesity is an independent risk factor for cardiovascular diseases. Nearly 60% of women of reproductive age are considered overweight or obese, cardiovascular disease morbidity and mortality continue to be pervasive. The objective of this study was to determine the effects of an obesogenic diet on the cardiometabolic health of dams during pregnancy and postpartum. Female mice were fed either a high-fat, high-sucrose diet (HFHS) or a refined control diet (CON) for 8 weeks before initiation of pregnancy and throughout the study period. Mice in the HFHS showed two distinct phenotypes, obesity-prone (HFHS/OP) and obesity resistance (HFHS/OR). Pre-pregnancy obesity (HFHS/OP) induced glucose intolerance before pregnancy and during postpartum. Systolic function indicated by the percent fractional shortening (%FS) was significantly decreased in the HFHS/OP at late pregnancy (vs. HFHS/OR) and weaning (vs. CON), but no differences were found at 6 weeks of postpartum among groups. No induction of pathological cardiac hypertrophy markers was found during postpartum. Plasma adiponectin was decreased while total cholesterol was increased in the HFHS/OP. Our results suggested that obesity, not the diet alone, negatively affected cardiac adaptation during pregnancy and postpartum.

Abstract Tooth extraction has been avoided since it has been considered a major risk factor for medication-related osteonecrosis of the jaw (MRONJ). However, MRONJ may also develop from tooth that is an infection source. This study aimed to clarify whether tooth extraction is a risk factor for the development of MRONJ in cancer patients receiving bone-modifying agents (BMAs). This retrospective observational study included 189 patients (361 jaws) from two hospitals. The risk factors of MRONJ were identified by comparing patient characteristics between those who did and did not develop MRONJ. Furthermore, the effect of tooth extraction during BMA therapy was analyzed after adjusting for confounding factors using the propensity score matching method. MRONJ occurred in 33 patients jaws. A longer duration of BMA administration, fewer number of teeth, presence of symptoms of local infection, and infected teeth were independent risk factors of MRONJ. However, tooth extraction during BMA therapy did not increase the risk. Propensity score matching analysis showed that tooth extraction significantly lowered the risk of MRONJ development. Teeth that can be an infection source increases the risk of MRONJ, and thus, they need to be extracted even during BMA administration.

Abstract High-speed atomic force microscopy (HS-AFM) is a powerful tool for visualizing the dynamics of individual biomolecules. However, in single-molecule HS-AFM imaging applications, x,y-scanner ranges are typically restricted to a few hundred nanometers, preventing overview observation of larger molecular assemblies, such as 2-dimensional protein crystal growth or fibrillar aggregation. Previous advances in scanner design using mechanical amplification of the piezo-driven x,y-positioning system have extended the size of HS-AFM image frames to several tens of micrometer, but these large scanners may suffer from mechanical instabilities at high scan speeds and only record images with limited pixel numbers and comparatively low lateral resolutions (> 20–100 nm/pixel), complicating single-molecule analysis. Thus, AFM systems able to image large sample areas at high speeds and with nanometer resolution have still been missing. Here, we describe a HS-AFM sample-scanner system able to record large topographic images (≤ 36 × 36 µm2) containing up to 16 megapixels, providing molecular resolution throughout the image frame. Despite its large size, the flexure-based scanner features a high resonance frequency (> 2 kHz) and delivers stable operation even at high scans speeds of up to 7.2 mm/s, minimizing the time required for recording megapixel scans. We furthermore demonstrate that operating this high-speed scanner in time-lapse mode can simultaneously identify areas of spontaneous 2-dimensional Annexin A5 crystal growth, resolve the angular orientation of large crystalline domains, and even detect rare crystal lattice defects, all without changing scan frame size or resolution. Dynamic processes first identified from overview scans can then be further imaged at increased frame rates in reduced scan areas after switching to conventional HS-AFM scanning. The added ability to collect large-area, high-resolution images of complex samples within biological-relevant time frames extends the capabilities of HS-AFM from single-molecule imaging to the study of large dynamic molecular arrays. Moreover, large-area HS-AFM scanning can generate detailed structural data sets from a single scan, aiding the quantitative analysis of structurally heterogenous samples, including cellular surfaces.