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Abstract Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

Abstract This retrospective observational study aimed to investigate the difference in 4-year outcomes of ranibizumab or aflibercept therapy for macular neovascularization (MNV) with high myopia between pathologic myopia (PM) and non-PM. This study was conducted at Kyoto University Hospital and included consecutive treatment-naïve eyes with active myopic MNV, in which a single intravitreal ranibizumab or aflibercept injection was administered, followed by a pro re nata (PRN) regimen for 4 years. Based on the META-PM study classification, eyes were assigned to the non-PM and PM groups. This study analyzed 118 eyes of 118 patients (non-PM group, 19 eyes; PM group, 99 eyes). Baseline, 1-year, and 2-year best-corrected visual acuity (BCVA) were significantly better in the non-PM group (P = 0.02, 0.01, and 0.02, respectively); however, the 3-year and 4-year BCVA were not. The 4-year BCVA course was similar in both groups. However, the total number of injections over 4 years was significantly higher in the non-PM than in the PM group (4.6 ± 2.6 vs. 2.9 ± 2.6, P = 0.001). Four-year BCVA significantly correlated only with baseline BCVA in both non-PM (P = 0.047, β = 0.46) and PM groups (P

Abstract During the pandemic, digital communication became paramount. Due to the discrepancy between the placement of the camera and the screen in typical smartphones, tablets and laptops, mutual eye contact cannot be made in standard video communication. Although the positive effect of eye contact in traditional communication has been well-documented, its role in virtual contexts remains less explored. In this study, we conducted experiments to gauge the impact of gaze direction during a simulated online job interview. Twelve university students were recruited as interviewees. The interview consisted of two recording sessions where they delivered the same prepared speech: in the first session, they faced the camera, and in the second, they directed their gaze towards the screen. Based on the recorded videos, we created three stimuli: one where the interviewee’s gaze was directed at the camera (CAM), one where the interviewee’s gaze was skewed downward (SKW), and a voice-only stimulus without camera recordings (VO). Thirty-eight full-time workers participated in the study and evaluated the stimuli. The results revealed that the SKW condition garnered significantly less favorable evaluations than the CAM condition and the VO condition. Moreover, a secondary analysis indicated a potential gender bias in evaluations: the female evaluators evaluated the interviewees of SKW condition more harshly than the male evaluators did, and the difference in some evaluation criteria between the CAM and SKW conditions was larger for the female interviewees than for the male interviewees. Our findings emphasize the significance of gaze direction and potential gender biases in online interactions.

Objectives The condition of air bubbles in the large intestine is an influential factor for good quality of colonoscopy. However, the correlative factors of severity of air bubbles during colonoscopy in the large intestine are not established. Therefore, this study aimed to elucidate the correlative factors influencing the severity of air bubbles in the large intestine.

Abstract Glymphatic transport is vital for the physiological homeostasis of the retina and optic nerve. Pathological alterations of ocular glymphatic fluid transport and enlarged perivascular spaces have been described in glaucomatous mice. It remains to be established how diabetic retinopathy, which impairs vision in about 50% of diabetes patients, impacts ocular glymphatic fluid transport. Here, we examined ocular glymphatic transport in chronic hyperglycemic diabetic mice as well as in healthy mice experiencing a daily transient increase in blood glucose. Mice suffering from severe diabetes for two and four months, induced by streptozotocin, exhibited no alterations in ocular glymphatic fluid transport in the optic nerve compared to age-matched, non-diabetic controls. In contrast, transient increases in blood glucose induced by repeated daily glucose injections in healthy, awake, non-diabetic mice accelerated antero- and retrograde ocular glymphatic transport. Structural analysis showed enlarged perivascular spaces in the optic nerves of glucose-treated mice, which were absent in diabetic mice. Thus, transient repeated hyperglycemic events, but not constant hyperglycemia, ultimately enlarge perivascular spaces in the murine optic nerve. These findings indicate that fluid transport in the mouse eye is vulnerable to fluctuating glycemic levels rather than constant hyperglycemia, suggesting that poor glycemic control drives glymphatic malfunction and perivascular enlargement in the optic nerve.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival. Methods We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan–Meier method and the log-rank test. Results Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at − 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs. Conclusions In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

Abstract Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1–3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations.

Abstract Background Pleomorphic liposarcoma is the rarest subtype of liposarcoma. Pleomorphic liposarcomas are generally unresponsive to chemotherapy and radiotherapy. Moreover, metastasis in the liver, as the first and sole site, from a primary extremity soft tissue sarcoma, including pleomorphic liposarcoma, is extremely rare. Information regarding the appropriate management of these lesions is limited. Case presentation A 50-year-old Japanese woman presented with a mass in the left thigh. Imaging examination revealed a soft tissue sarcoma on the left posterior thigh. The tumor was histologically diagnosed as pleomorphic liposarcoma. Computed tomography examination for assessment of metastases incidentally detected a huge liver mass. Wide excision of sarcoma was performed prior to chemotherapy. Right trisectionectomy was necessary to achieve hepatic clearance; however, the future liver remnant volume was insufficient. Therefore, we decided to administer anthracycline-based chemotheraphy to shrink the tumor. After seven courses of adriamycin-based chemotherapy, the liver tumor size was reduced from 211 mm × 106 mm × 180 mm to 105 mm × 66 mm × 90 mm. Finally, a right hemihepatectomy was performed. The patient was continuously monitored and was metastasis or local recurrence free within 5 months after liver surgery. Conclusion Chemotherapy is effective in some cases for the treatment of unresectable liver metastases of pleomorphic liposarcoma, and complete resection is possible with conversion surgery. If the patient’s general condition permits, anthracycline-based chemotherapy can be used for the treatment of stage 4 pleomorphic liposarcoma.

Purpose: To elucidate the clinical characteristics and progression rates of pachychoroid and conventional geographic atrophy (GA). Design: Retrospective, multicenter, observational study. Participants: A total of 173 eyes from 173 patients (38 eyes with pachychoroid GA and 135 with conventional GA) from 6 university hospitals in Japan were included. All patients were Japanese, aged ≥50 years and with fundus autofluorescence images having analyzable image quality. A total of 101 eyes (22 with pachychoroid GA and 79 with conventional GA) were included in the follow-up group. Methods: The studied eyes were classified as having pachychoroid or conventional GA; the former was diagnosed if the eye had features of pachychoroid and no drusen. The GA area was semiautomatically measured on fundus autofluorescence images, and the GA progression rate was calculated for the follow-up group. Multivariable linear regression analysis was used to determine whether the rate of GA progression was associated with GA subtype. Main Outcome Measures: Clinical characteristics and progression rates of pachychoroid and conventional GA. Results: The pachychoroid GA group was significantly younger (70.3 vs. 78.7 years; P < 0.001), more male-dominant (89.5 vs. 55.6%; P < 0.001), and had better best-corrected visual acuity (0.15 vs. 0.40 in logarithm of the minimum angle of resolution; P = 0.002), thicker choroid (312.4 vs. 161.6 μm; P < 0.001), higher rate of unifocal GA type (94.7 vs. 49.6%; P < 0.001), and smaller GA area (0.59 vs. 3.76 mm2; P < 0.001) than the conventional GA group. In the follow-up group, the mean GA progression rate (square-root transformation) was significantly lower in the pachychoroid GA group than in the conventional GA group (0.11 vs. 0.27 mm/year; P < 0.001). Conclusions: Demographic and ocular characteristics differed between GA subtypes. The progression rate of pachychoroid GA, adjusted for age and baseline GA area, was significantly lower than that of conventional GA. Japanese patients with conventional GA showed characteristics and progression rates similar to those in White populations. Some characteristics of GA in Japanese population differ from those in Waucasian populations, which may be due to the inclusion of pachychoroid GA. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Objectives To investigate the effectiveness of BMAX, a deep learning-based computer-aided detection system for detecting fibrosing interstitial lung disease (ILD) on chest radiographs among non-expert and expert physicians in the real-world clinical setting.Design Retrospective, observational study.Setting This study used chest radiograph images consecutively taken in three medical facilities with various degrees of referral. Three expert ILD physicians interpreted each image and determined whether it was a fibrosing ILD-suspected image (fibrosing ILD positive) or not (fibrosing ILD negative). Interpreters, including non-experts and experts, classified each of 120 images extracted from the pooled data for the reading test into positive or negative for fibrosing ILD without and with the assistance of BMAX.Participants Chest radiographs of patients aged 20 years or older with two or more visits that were taken during consecutive periods were accumulated. 1251 chest radiograph images were collected, from which 120 images (24 positive and 96 negative images) were randomly extracted for the reading test. The interpreters for the reading test were 20 non-expert physicians and 5 expert physicians (3 pulmonologists and 2 radiologists).Primary and secondary outcome measures The primary outcome was the comparison of area under the receiver-operating characteristic curve (ROC-AUC) for identifying fibrosing ILD-positive images by non-experts without versus with BMAX. The secondary outcome was the comparison of sensitivity, specificity and accuracy by non-experts and experts without versus with BMAX.Results The mean ROC-AUC of non-expert interpreters was 0.795 (95% CI; 0.765 to 0.825) without BMAX and 0.825 (95% CI; 0.799 to 0.850) with BMAX (p=0.005). After using BMAX, sensitivity was improved from 0.744 (95% CI; 0.697 to 0.791) to 0.802 (95% CI; 0.754 to 0.850) among non-experts (p=0.003), but not among experts (p=0.285). Specificity and accuracy were not changed after using BMAX among either non-expert or expert interpreters.Conclusion BMAX was useful for detecting fibrosing ILD-suspected chest radiographs for non-expert physicians.Trial registration number jRCT1032220090.

This paper proposes a novel path planning algorithm designed for efficient lunar water exploration. The proposed algorithm leverages a Bayesian network-based sensor model in combination with the RRT* algorithm. It is well-known that water is highly likely to be present in permanently shadowed regions (PSRs). However, during exploration within these regions, the rover must escape to illuminated areas within a limited time to recharge its battery. Therefore, it is crucial to develop a path planning algorithm that ensures both timely battery recharging and efficient water exploration. To address this challenge, we first introduce a sensor model based on a Bayesian network for the neutron spectrometer. Subsequently, we propose an algorithm that utilizes this sensor model and the RRT* algorithm to effectively explore water on the lunar surface. The paper provides a numerical simulation, using real data about time-variant illumination areas and time-invariant PSRs on the lunar surface, to illustrate the effectiveness of the proposed algorithm. The results reveal that the algorithm accurately and efficiently detects water under realistic illumination conditions.

Abstract Bridgmanite formation and amorphization in shocked meteorites constrain the pressure and temperature conditions during planetary impact. However, the effect of the bridgmanite grain size on its amorphization kinetics is still unclear. Here, the amorphization mechanism and kinetics of fine-grained polycrystalline bridgmanite were studied at high temperatures up to 1080 K. High-temperature time-resolved synchrotron X-ray diffraction measurements showed that significant volume expansion due to temperature-induced amorphization caused static stress, which then hindered amorphization progress. Further, the temperature required for the amorphization of fine-grained bridgmanite (~ 1 μm) was found to be approximately 100 K higher than that required for the amorphization of coarse-grained samples (> 10 μm). We also noted that amorphization preferentially commenced at the twin planes and subgrain boundaries of bridgmanite grains, resulting in lower amorphization temperatures for the coarse-grained samples. The limited number of such specific locations in fine-grained natural bridgmanite suggested that grain boundary amorphization may be the dominant mechanism for bridgmanite amorphization in shocked meteorites. This unique amorphization kinetics would support the preservation of bridgmanite during the post-shock annealing in the shocked meteorite. Although bridgmanite amorphization starts easily at temperatures above ~ 420 K, a small amount of bridgmanite grains can survive at temperatures above 800 K by the effect of amorphization-induced stress.

Abstract Background In robot-assisted thoracic surgery (RATS) lobectomy using a robotic stapler, stapling is difficult when the stapler port place is close to the resection target vessel. We examined whether three-dimensional computed tomography (3D-CT) software enables stapler port place determination for stapling. Methods Seventy-three patients who underwent RATS lobectomy were enrolled. The SureForm 45 Curved-Tip stapler (136 mm from the remote center to the anvil tip) was used. The virtual distance between the resection target vessel and stapler port place (VD) was preoperatively measured with 3D-CT software. The stapler port place was the most cranial intercostal space with a VD ≥ 136 mm. The actual distance between the resection target vessel and anvil tip (AD) was measured intraoperatively. We examined the associations of the difficulty in stapling with VD, AD, chest wall damage, and clinical features. Results Stapling was easier with a larger anteroposterior thoracic diameter and AD. The cut-off VD and AD for smooth stapling were 142 mm and 6 mm. Chest wall damage was frequently observed at the caudal and dorsal side ports. Conclusions As the stapler port place is located more caudally, stapling becomes easier. However, chest wall damage increases. If the stapler port place is positioned at a site ensuring VD ≥ 142 mm by 3D-CT software, smooth stapling may be possible with a decreased incidence of chest wall damage.

Abstract Obesity affects millions of people worldwide and is associated with an increased risk of cognitive decline. The glymphatic system is a brain-wide metabolic waste clearance system, dysfunction of which is linked to dementia. We herein examined glymphatic transport in mice with long-term obesity induced by a high-fat diet for 10 months. The obese mice developed hypertension and elevated heart rate, neuroinflammation and gliosis, but not apparent systemic inflammation. Surprisingly, glymphatic inflow was globally unaffected by the high-fat diet except for the hypothalamus, which displayed increased influx and elevated AQP4 vascular polarization compared to the normal weight control group. We propose that a long-term high-fat diet induced metabolic alteration of hypothalamic neurons and neuroinflammation, which in turn enhanced glymphatic clearance in the effected brain region.

Scientists write research articles, process ethics reviews, evaluate proposals and research, and seek funding. Several strategies have been proposed to optimize these operations and to decentralize access to research resources and opportunities. For instance, we previously proposed the trinity review method, combining registered reports with financing and research ethics assessments. However, previously proposed systems have a number of shortcomings, including how to implement them, e.g., who manages them, how incentives for reviewers are paid, etc. Various solutions have been proposed to address these issues, employing methods based on blockchain technologies, called “decentralized science (DeSci)”. Decentralized approaches that exploit these developments offer potentially profound improvements to the troubled scientific ecosystem. Here, we propose a system that integrates ethics reviews, peer reviews, and funding in a decentralized manner, based on Web3 technology. This new method, named ABCDEF publishing, would enhance the speed, fairness, and transparency of scientific research and publishing.

We studied the optical variability of 241 BL Lacertae (BL Lacs) and 83 flat-spectrum radio quasars (FSRQs) from the 4LAC catalog using data from the Tomo-e Gozen Northern Sky Transient Survey, with ∼50 epochs per blazar on average. We excluded blazars whose optical variability may be underestimated due to the influence of their host galaxy based on their optical luminosity ( L _O ). FSRQs with γ -ray photon index greater than 2.6 exhibit very low optical variability, and their distribution of standard deviation of repeated photometry is significantly different from that of the other FSRQs (Kolmogorov–Smirnov test p -value equal to 5 × 10 ^−6 ). Among a sample of blazars at any particular cosmological epoch, those with lower γ -ray luminosity ( L _γ ) tend to have lower optical variability, and those FSRQs with a γ -ray photon index greater than 2.6 tend to have low L _γ . We also measured the structure function of optical variability and found that the amplitude of the structure function for FSRQs is higher than previously measured and higher than that of BL Lacs at multiple time lags. Additionally, the amplitude of the structure function of FSRQs with high γ -ray photon index is significantly lower than that of FSRQs with low γ -ray photon index. The structure function of FSRQs of high γ -ray photon index shows a characteristic timescale of more than 10 days, which may be the variability timescale of the accretion disk. In summary, we infer that the optical component of FSRQs with high γ -ray photon index may be dominated by the accretion disk.

IntroductionPreterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation would improve brain development in preterm pigs, used as a model for preterm infants.MethodsPreterm pigs delivered by cesarean section received recombinant human IGF-1/IGF binding protein-3 complex (rhIGF-1/rhIGFBP-3, 2.25 mg/kg/day) or vehicle from birth to postnatal day 19. Motor function and cognition were assessed by monitoring of in-cage and open field activities, balance beam test, gait parameters, novel object recognition and operant conditioning tests. Collected brains were subject to magnetic resonance imaging (MRI), immunohistochemistry, gene expression analyses and protein synthesis measurements.ResultsThe IGF-1 treatment increased cerebellar protein synthesis rates (both in vivo and ex vivo). Performance in the balance beam test was improved by IGF-1 but not in other neurofunctional tests. The treatment decreased total and relative caudate nucleus weights, without any effects to total brain weight or grey/white matter volumes. Supplementation with IGF-1 reduced myelination in caudate nucleus, cerebellum, and white matter regions and decreased hilar synapse formation, without effects to oligodendrocyte maturation or neuron differentiation. Gene expression analyses indicated enhanced maturation of the GABAergic system in the caudate nucleus (decreased NKCC1:KCC2 ratio) with limited effects in cerebellum or hippocampus.ConclusionSupplemental IGF-1 during the first three weeks after preterm birth may support motor function by enhancing GABAergic maturation in the caudate nucleus, despite reduced myelination. Supplemental IGF-1 may support postnatal brain development in preterm infants, but more studies are required to identify optimal treatment regimens for subgroups of very or extremely preterm infants.

Abstract Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease characterized by the accumulation of aggregated amyloid beta (Aβ) and hyperphosphorylated tau along with a slow decline in cognitive functions. Unlike advanced AD, the initial steps of AD pathophysiology have been poorly investigated, partially due to limited availability of animal models focused on the early, plaque-free stages of the disease. The aim of this study was to evaluate the early behavioral, anatomical and molecular alterations in wild-type rats following intracerebroventricular injections of human Aβ oligomers (AβOs). Bioactive human AD and nondemented control brain tissue extracts were characterized using ELISA and proteomics approaches. Following a bilateral infusion, rats underwent behavioral testing, including the elevated plus maze, social recognition test, Morris water maze and Y-maze within 6 weeks postinjection. An analysis of brain structure was performed with manganese-enhanced MRI. Collected brain tissues were analyzed using stereology, immunohistochemistry, ELISA and qPCR. No sensorimotor deficits affecting motor performance on different maze tasks were observed, nor was spatial memory disturbed in AD rats. In contrast, a significant impairment of social memory became evident at 21 days postinjection. This deficit was associated with a significantly decreased volume of the lateral entorhinal cortex and a tendency toward a decrease in the total brain volume. Significant increase of cleaved caspase-3-positive cells, microglial activation and proinflammatory responses accompanied by altered expression of synaptic markers were observed in the hippocampus of AD rats with immunohistochemical and qPCR approaches at 6 weeks postinjection. Our data suggest that the social memory impairment observed in AβO-injected rats might be determined by neuroinflammatory responses and synaptopathy. An infusion of native oligomeric Aβ in the rat brain represents a feasible tool to model early plaque-free events associated with AD.

Abstract Background Mesenchymal stem cells (MSCs) have shown promising results in stimulating cartilage repair and in the treatment of osteoarthritis (OA). However, the fate of the MSCs after intra-articular injection and their role in cartilage regeneration is not clear. To address these questions, this study investigated (1) homing of labeled human adipose tissue derived integrin α10β1-selected MSCs (integrin α10-MSCs) to a cartilage defect in a rabbit model and (2) the ability of the integrin α10-MSCs to differentiate to chondrocytes and to produce cartilage matrix molecules in vivo. Design Integrin α10-MSCs were labeled with superparamagnetic iron oxide nanoparticles (SPIONs) co-conjugated with Rhodamine B to allow visualization by both MRI and fluorescence microscopy. A cartilage defect was created in the articular cartilage of the intertrochlear groove of the femur of rabbits. Seven days post-surgery, labeled integrin α10-MSCs or vehicle were injected into the joint. Migration and distribution of the SPION-labeled integrin α10-MSCs was evaluated by high-field 9.4 T MRI up to 10 days after injection. Tissue sections from the repair tissue in the defects were examined by fluorescence microscopy. Results In vitro characterization of the labeled integrin α10-MSCs demonstrated maintained viability, proliferation rate and trilineage differentiation capacity compared to unlabeled MSCs. In vivo MRI analysis detected the labeled integrin α10-MSCs in the cartilage defects at all time points from 12 h after injection until day 10 with a peak concentration between day 1 and 4 after injection. The labeled MSCs were also detected lining the synovial membrane at the early time points. Fluorescence analysis confirmed the presence of the labeled integrin α10-MSCs in all layers of the cartilage repair tissue and showed co-localization between the labeled cells and the specific cartilage molecules aggrecan and collagen type II indicating in vivo differentiation of the MSCs to chondrocyte-like cells. No adverse effects of the α10-MSC treatment were detected during the study period. Conclusion Our results demonstrated migration and homing of human integrin α10β1-selected MSCs to cartilage defects in the rabbit knee after intra-articular administration as well as chondrogenic differentiation of the MSCs in the regenerated cartilage tissue.

Abstract One major source of exhaustion for researchers is the redundant paperwork of three different documents—research papers, ethics review applications, and research grant applications—for the same research plan. This is a wasteful and redundant process for researchers, and it has a more direct impact on the career development of early-career researchers. Here, we propose a trinity review system based on Registered Reports that integrates scientific, ethics, and research funding reviews. In our proposed trinity review system, scientific and ethics reviews are undertaken concurrently for a research protocol before running the study. After the protocol is approved in principle through these review processes, a funding review will take place, and the researchers will begin their research. Following the experiments or surveys, the scientific review will be conducted on a completed version of the paper again, including the results and discussions (i.e., the full paper), and the full paper will be published once it has passed the second review. This paper provides the brief process of the trinity review system and discusses the need for and benefits of the proposed system. Although the trinity review system only applies to a few appropriate disciplines, it helps improve reproducibility and integrity.

Abstract The dopamine D1 receptor (D1R) is associated with schizophrenia, Parkinson's disease, and attention deficit hyperactivity disorder. Although the receptor is considered a therapeutic target for these diseases, its neurophysiological function has not been fully elucidated. Pharmacological functional MRI (phfMRI) has been used to evaluate regional brain hemodynamic changes induced by neurovascular coupling resulting from pharmacological interventions, thus phfMRI studies can be used to help understand the neurophysiological function of specific receptors. Herein, the blood oxygenation level‐dependent (BOLD) signal changes associated with D1R action in anesthetized rats was investigated by using a preclinical ultra‐high‐field 11.7‐T MRI scanner. PhfMRI was performed before and after administration of the D1‐like receptor agonist (SKF82958), antagonist (SCH39166), or physiological saline subcutaneously. Compared to saline, the D1‐agonist induced a BOLD signal increase in the striatum, thalamus, prefrontal cortex, and cerebellum. At the same time, the D1‐antagonist reduced the BOLD signal in the striatum, thalamus, and cerebellum by evaluating temporal profiles. PhfMRI detected D1R‐related BOLD signal changes in the brain regions associated with high expression of D1R. We also measured the early expression of c‐fos at the mRNA level to evaluate the effects of SKF82958 and isoflurane anesthesia on neuronal activity. Regardless of the presence of isoflurane anesthesia, c‐fos expression level was increased in the region where positive BOLD responses were observed with administration of SKF82958. These findings demonstrated that phfMRI could be used to identify the effects of direct D1 blockade on physiological brain functions and also for neurophysiological assessment of dopamine receptor functions in living animals.

Purpose: To investigate the distribution of clinically significant nonperfusion areas (NPAs) on widefield OCT angiography (OCTA) images in patients with diabetes. Design: Prospective, cross-sectional, observational study. Participants: One hundred and forty-four eyes of 114 patients with diabetes. Methods: Nominal 20 × 23 mm OCTA images were obtained using a swept-source OCTA device (Xephilio OCT-S1), followed by the creation of en face images 20-mm (1614 pixels) in diameter centering on the fovea. The nonperfusion squares (NPSs) were defined as the 10 × 10 pixel squares without retinal vessels, and the ratio of eyes with the NPSs to all eyes in each square was referred to as the NPS ratio. The areas with probabilistic differences (APD) for proliferative diabetic retinopathy (PDR) and nonproliferative diabetic retinopathy (NPDR) (APD[PDR] and APD[NPDR]) were defined as sets of squares with higher NPS ratios in eyes with PDR and NPDR, respectively. The P ratio (NPSs within APD[PDR] but not APD[NPDR]/all NPSs) was also calculated. Main Outcome Measures: The probabilistic distribution of the NPSs and the association with diabetic retinopathy (DR) severity. Results: The NPSs developed randomly in eyes with mild and moderate NPDR and were more prevalent in the extramacular areas and the temporal quadrant in eyes with severe NPDR and PDR. The APD(PDR) was distributed mainly in the extramacular areas, sparing the areas around the vascular arcades and radially peripapillary capillaries. The APD(PDR) contained retinal neovascularization more frequently than the non-APD(PDR) (P = 0.023). The P ratio was higher in eyes with PDR than in those with NPDR (P < 0.001). The multivariate analysis designated the P ratio (odds ratio, 8.293 × 107; 95% confidence interval, 6.529 × 102–1.053 × 1013; P = 0.002) and the total NPSs (odds ratio, 1.002; 95% confidence interval, 1.001–1.003; P < 0.001) as independent risk factors of PDR. Most eyes with NPDR and 4-2-1 rule findings of DR severity had higher P ratios but not necessarily greater NPS numbers. Conclusions: The APD(PDR) is uniquely distributed on widefield OCTA images, and the NPA location patterns are associated with DR severity, independent of the entire area of NPAs. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular endfeet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport. Yet, no studies have systematically examined how these abnormalities in structure and water transport correlate with glymphatic function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) along with intravoxel-incoherent motion (IVIM) DWI, while evaluating glymphatic function using a standard dynamic contrast-enhanced MR imaging to better understand how water transport and glymphatic function is disrupted after genetic deletion of AQP4. AQP4 KO mice had larger interstitial spaces and total brain volumes resulting in higher water content and reduced CSF space volumes, despite similar CSF production rates and vascular density compared to wildtype mice. The larger interstitial fluid volume likely resulted in increased slow but not fast MR diffusion measures and coincided with reduced glymphatic influx. This markedly altered brain fluid transport in AQP4 KO mice may result from a reduction in glymphatic clearance, leading to enlargement and stagnation of fluid in the interstitial space. Overall, diffusion MR is a useful tool to evaluate glymphatic function and may serve as valuable translational biomarker to study glymphatics in human disease.

Abstract Breast milk has neurodevelopmental advantages compared to infant formula, especially in low-birth-weight infants, which may in part relate to the fat source. This study compared neurodevelopmental outcomes in three-day-old normal birth weight (NBW) and intrauterine growth restricted (IUGR) piglets fed a formula diet with either vegetable oil (VEG) or bovine milk fat sources (MILK) for three weeks in a 2 × 2 factorial design. Behavioural tests, lipidomics, MRI and RNA sequencing analyses of plasma and brain tissue were conducted. The absolute levels of 82% and 11% of lipid molecules were different between dietary groups in plasma and hippocampus, respectively. Of the lipid molecules with differential abundance in the hippocampus, the majority were upregulated in MILK versus VEG, and they mainly belonged to the group of glycerophospholipids. Lower absolute brain weights, absolute grey and white matter volumes and behaviour and motor function scores, and higher relative total brain weights were present in IUGR compared to NBW with minor influence of diet. Cognitive function and cerebellar gene expression profiles were similar for dietary and weight groups, and overall only minor interactive effects between diet and birth weight were observed. Overall, we show that the dietary fat source influences the plasma and to a lesser degree the hippocampal lipidome and is unable to improve on IUGR-induced brain structural and functional impairments.

Purpose: To investigate the natural course of pachychoroid pigment epitheliopathy (PPE). Design: A retrospective cohort study. Subjects: From the Kyoto central serous chorioretinopathy (CSC) cohort consisting of 548 patients with CSC as of September 2020, we included consecutive unilateral patients with acute or chronic CSC between January 2013 and December 2016. Methods: All patients underwent complete ophthalmic examination, including multimodal imaging such as fundus autofluorescence, spectral-domain optical coherence tomography, and fluorescein angiography/indocyanine green angiography and/or optimal coherence tomography angiography. The fellow eyes of eyes diagnosed with CSC were screened for PPE, and their natural course was evaluated. We also evaluated the association of ARMS2 rs10490924, CFH rs800292, TNFRSF10A rs13278062, and GATA5 rs6061548 genotypes with the natural course. Main Outcome Measures: Incidence of CSC, pachychoroid neovasculopathy, and pachychoroid geographic atrophy (GA). Results: In total, 165 patients with unilateral CSC (mean age, 55.7 ± 12.6 years; female, 22.4%) were included from the Kyoto CSC cohort. Among them, 148 (89.7%) were diagnosed as having PPE in their non-CSC eye. Survival analysis revealed that 16.8% of PPE eyes developed CSC during the 6-year follow up, whereas non-PPE eyes did not. Although genetic factors did not have significant association with CSC development (P > 0.05, log-rank test), choroidal vascular hyperpermeability (CVH) and subfoveal choroidal thickness (SFCT) were significantly associated with CSC incidence (P = 0.001, log-rank test). Survival analysis showed that eyes without CVH and eyes with SFCT < 300 μm did not develop CSC during the 6-year follow-up. Pachychoroid neovasculopathy developed in only 1 eye with PPE during a follow-up of 46.4 months. Pachychoroid GA did not develop in any of the studied eyes. Conclusions: This study revealed a natural history of PPE in a relatively large Japanese cohort. Choroidal vascular hyperpermeability and SFCT were significant risk factors for the development of CSC in PPE eyes. Although the current results cannot be generalized for all eyes with PPE, these findings present an important clinical implication.

Summary: We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid and interstitial fluid around the brain, facilitating solute transport. Models enable hypothesis development and predictions of transport, with clinical applications including drug delivery, stroke, cardiac arrest, and neurodegenerative disorders like Alzheimer’s disease. We sort existing models into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, and links to neuronal activity. Needs and opportunities for future work are highlighted wherever possible; new models, expanded models, and novel experiments to inform models could all have tremendous value for advancing the field.

Abstract Background and Aim Colonic diverticular bleeding is a common cause of acute lower gastrointestinal bleeding. Endoscopic hemostasis is generally selected as the first‐line treatment; however, a considerable number of patients experience early rebleeding after endoscopic treatment. We investigated the risk factors for early rebleeding after endoscopic treatment. Methods We retrospectively evaluated the data of 142 consecutive patients who underwent endoscopic treatment (endoscopic clipping or endoscopic band ligation) for colonic diverticular bleeding with stigmata of recent hemorrhage between April 2012 and April 2020. Multivariate logistic regression analysis was conducted to evaluate the statistical relationship between patient characteristics and the incidence of early rebleeding occurring within 30 days after endoscopic treatment. Results Of 142 patients, early rebleeding was detected in 34 (23.9%) patients. According to univariate analysis, platelet count of

Purpose: To investigate the 2-year effectiveness of reduced-fluence photodynamic therapy (rf-PDT) for chronic central serous chorioretinopathy (cCSC). Design: Retrospective cohort study. Participants: A total of 223 consecutive patients with newly diagnosed cCSC with active serous retinal detachment (SRD) were included from May 2007 to June 2017 and followed up for at least 2 years. Patients who underwent ocular treatment other than cataract surgery before the beginning of recruitment and those who had macular neovascularization at baseline were excluded. Methods: All patients underwent a comprehensive ophthalmic evaluation, including measurements of best-corrected visual acuity (BCVA), slit-lamp examination, dilated fundus examination, color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and spectral-domain OCT. An inverse probability of treatment weighting (IPTW) methodology was applied to balance 18 baseline characteristics between patients who received rf-PDT (rf-PDT group) and those who did not receive treatment (controls). Inverse probability of treatment weighting survival analysis and regression were performed. Main Outcome Measures: The proportion of patients whose BCVA at 24 months was the same or improved compared with the baseline visual acuity (VA) (VA maintenance rate). Results: A total of 155 eyes (rf-PDT group: 74; controls: 81) were analyzed. The patients’ backgrounds were well balanced after IPTW with standardized differences of < 0.10. An IPTW regression analysis revealed that the VA maintenance rate was significantly higher in the rf-PDT group than in the controls (93.6% vs. 70.9%, P

Behçet’s disease (BD) is a multisystem inflammatory disease of unknown origin. Rarely, BD occurs together with myelodysplastic syndrome (MDS). Interestingly, it is speculated that these are not simple coexistence but that the etiology of intestinal BD is at least partly derived from MDS itself. Furthermore, there is a relationship between MDS in patients with intestinal BD and trisomy 8. Immunosuppressive agents alone are insufficient to control MDS-associated BD, and many of these patients die of infection or hemorrhage. Surgery is considered for intestinal BD patients who are unresponsive to medical treatment or those with bowel complications such as perforation or persistent bleeding. We report a case of intestinal BD associated with MDS and trisomy 8. The patient was unresponsive to oral steroids and immunosuppressive treatment; the patient improved by surgical repair of a bowel perforation. Five years after the surgery, the patient is free of recurrence and not on medication. Our experience suggests that surgery may provide an effective therapeutic option for the treatment of MDS-related BD.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. Methods We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group. Results Forty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months − 6.0% vs 16.7%, 6 months − 10.2% vs 20.2%, KL-6: 3 months − 9.2% vs 6.7%, 6 months − 15.0% vs 12.1%, p

The discrete element method (DEM) and the moving particle semi-implicit (MPS) method are the most popular mesh-free particle methods in the discontinuum and continuum. This paper describes a state-of-the-art modeling on multi-phase flows using these mesh-free particle methods. Herein, a combinational model of the signed distance function (SDF) and immersed boundary method (IBM) is introduced for an arbitrary-shaped wall boundary in the DEM simulation. Practically, this model uses a simple operation to create the wall boundary. Although the SDF is a scalar field for the wall boundary of the DEM, it is useful for the wall boundary of the CFD through combination with the IBM. Validation tests are carried out to demonstrate the adequacy of the SDF/IBM wall boundary model. Regarding the mesh-free particle method for continuum, the phase change problem is one of the challenging topics, as the solid state is usually modeled by extremely high viscous fluid in the phase change simulation. The phase change simulation is shown to be efficiently performed through an implicit algorithm and a heat flux model in the MPS method. The adequacy of these models is verified by the numerical examples.

Purpose: To report fundamental epidemiologic data for choroidal parameters such as choroidal thickness and index of choroidal vascularity in Japanese individuals and to evaluate their correlations with age, sex, systemic parameters, and other ocular parameters. Design: Population-based cohort study. Participants: A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Methods: All participants underwent standardized ophthalmic examinations, including OCT with enhanced depth imaging (EDI; RS-3000 Advance; Nidek). We manually segmented the choroidoscleral interface to measure subfoveal choroidal thickness (SFCT) and calculated the normalized choroidal intensity obtained with EDI (NCIEDI) and choroidal vascularity index (CVI). These are indices of choroidal brightness in OCT and reportedly represent the dilation of choroidal vessels. After summarizing the age-sex stratified distributions of SFCT, NCIEDI, and CVI, their associations with age, sex, axial length (AL), and spherical equivalent (SE) were evaluated using linear regression analysis with adjustments for possible confounders. Main Outcome Measures: Distribution of SFCT, NCIEDI, and CVI in the healthy Japanese population and their characteristics. Results: Age-sex standardized SFCT, NCIEDI, and CVI were 291.2 μm, 0.653, and 66.88%, respectively. In both men and women, SFCT was associated negatively with age (P < 0.001) and NCIEDI was associated positively with age (P < 0.001). Although both SFCT and NCIEDI did not differ significantly between men and women overall (P = 0.87 and P = 0.21, respectively), among younger participants (35–50 years of age), men showed significantly greater SFCT than women (P < 0.001). Only in men was CVI associated positively with age (P < 0.001). In the multivariable analysis, SFCT was associated significantly with age, sex, AL, SE, and the interaction term of age and sex (P < 0.001). Independent of SFCT, NCIEDI and CVI were associated significantly with age (P < 0.001). Conclusions: We report normative Japanese SFCT, NCIEDI, and CVI data using a large general Japanese cohort. The association analysis of SFCT with NCIEDI and CVI suggested that younger individuals have a more lumen-rich choroid for their choroidal thickness than older individuals.

The entorhinal cortex (EC) is the spatial processing center of the brain and structurally is an interface between the three layered paleocortex and six layered neocortex, known as the periarchicortex. Limited studies indicate peculiarities in the formation of the EC such as early emergence of cells in layers (L) II and late deposition of LIII, as well as divergence in the timing of maturation of cell types in the superficial layers. In this study, we examine developmental events in the entorhinal cortex using an understudied model in neuroanatomy and development, the pig and supplement the research with BrdU labeling in the developing mouse EC. We determine the pig serves as an excellent anatomical model for studying human neurogenesis, given its long gestational length, presence of a moderate sized outer subventricular zone and early cessation of neurogenesis during gestation. Immunohistochemistry identified prominent clusters of OLIG2+ oligoprogenitor-like cells in the superficial layers of the lateral EC (LEC) that are sparser in the medial EC (MEC). These are first detected in the subplate during the early second trimester. MRI analyses reveal an acceleration of EC growth at the end of the second trimester. BrdU labeling of the developing MEC, shows the deeper layers form first and prior to the superficial layers, but the LV/VI emerges in parallel and the LII/III emerges later, but also in parallel. We coin this lamination pattern parallel lamination. The early born Reln+ stellate cells in the superficial layers express the classic LV marker, Bcl11b (Ctip2) and arise from a common progenitor that forms the late deep layer LV neurons. In summary, we characterize the developing EC in a novel animal model and outline in detail the formation of the EC. We further provide insight into how the periarchicortex forms in the brain, which differs remarkably to the inside-out lamination of the neocortex.

Endoscopic submucosal dissection (ESD) is a safe and minimally invasive method for the treatment of early gastric cancer (EGC). However, whether ESD for EGC is also safe and feasible in patients aged ≥85 years is unclear. The patients enrolled in this study were divided into three groups: age ≥85 years (44 patients, 49 lesions), age 65–84 years (624 patients, 687 lesions), and age ≤64 years (162 patients, 174 lesions). We evaluated the incidence of adverse events (AEs) and overall survival (OS) and disease-specific survival (DSS). We analyzed the factors that had a significant impact on the prognosis of patients aged ≥85 years. No significant differences were found in the incidence of AEs among the three groups (p = 0.612). The OS was significantly lower in patients aged ≥85 years (p < 0.001). Conversely, DSS was not significantly worse in patients aged ≥85 years (p = 0.100). The poor Geriatric Nutritional Risk Index correlated with poor prognosis in patients aged ≥85 years (p < 0.001). ESD is a safe and valid treatment for EGC in patients aged ≥85 years. However, the indications should be carefully decided because it is difficult to estimate the survival contribution of ESD for EGC in patients aged ≥85 years, especially in those with poor nutritional status.

Summary: Intravenously injected ONO-1301–containing nanoparticles (ONO-1301NPs), unlike an ONO-1301 solution, selectively accumulated in the ischemia/reperfusion (I/R)-injured myocardium of rats and contributed to the prolonged retention of ONO-1301 in the targeted myocardial tissue. In the ischemic area, proangiogenic cytokines were up-regulated and inflammatory cytokines were down-regulated upon ONO-1301NP administration. Consequently, ONO-1301NP–injected rats exhibited a smaller infarct size, better-preserved capillary networks, and a better-preserved myocardial blood flow at 24 h after I/R injury, compared with those in vehicle-injected or ONO-1301 solution–injected rats. ONO-1301NPs attenuate the myocardial I/R injury via proangiogenic and anti-inflammatory effects of the drug. Key Words: ischemia/reperfusion injury, nanoparticles, ONO-1301, prostacyclin

Summary: Candida albicans infection can cause skin, vulvar, or oral pain. Despite the obvious algesic activity of C. albicans, the molecular mechanisms of fungal nociception remain largely unknown. Here we show that the C. albicans-specific signaling pathway led to severe mechanical allodynia. We discovered that C. albicans-derived β-glucan stimulated nociceptors depending on Dectin-1, and two pathways in inflammatory pain. The major pathway operates via the Dectin-1-mediated ATP-P2X3/P2X2/3 axis through intercellular relationships between keratinocytes and primary sensory neurons, which depends on the ATP transporter vesicular nucleotide transporter (VNUT). The other pathway operates via the Dectin-1-mediated PLC-TRPV1/TRPA1 axis in primary sensory neurons. Intriguingly, C. albicans-derived β-glucan has the ability to enhance histamine-independent pruritus, and VNUT inhibitor clodronate can be used to treat unpleasant feelings induced by β-glucan. Collectively, this is the first report to indicate that Dectin-1 and VNUT mediated innate sensory mechanisms that detect fungal infection. : Molecular Mechanism of Behavior; Molecular Neuroscience; Medical Microbiology Subject Areas: Molecular Mechanism of Behavior, Molecular Neuroscience, Medical Microbiology

Background: Langerhans cells (LCs) polarize the immune milieu towards a T helper type (Th) 1 or Th2 immune response. We investigated the effects of selected tetracyclines on Th cells development mediated by LCs, and their implications for the treatment of atopic dermatitis (AD). Methods: Mice were primed with ovalbumin (OVA) peptide-pulsed LCs, which had been treated with each antibiotic, via the hind footpad. After 5 days, the Th1/Th2 cytokine response in the popliteal lymph nodes was investigated by enzyme-linked immunosorbent assay. The expression of cell surface molecules on LCs was investigated using reverse transcriptase polymerase chain reaction. The therapeutic effects of a selected antibiotic on AD-like skin lesions of NC/Nga mice were assessed in terms of the skin severity score, histological changes in the lesioned skin, the serum level of total IgE, and expression of Th1/Th2 cytokines in lymph nodes and skin lesions. Results: Antibiotic-treated, OVA peptide-pulsed LCs inhibited development of Th2 cells but not Th1 cells. This was accompanied by suppression of T-cell immunoglobulin and mucin domain-containing protein (TIM)-4 expression in LCs. Doxycycline had the greatest activity against Staphylococcus aureus strains isolated from skin lesions of patients with AD, and a strong inhibitory effect on Th2 cell development. Doxycycline suppressed the increase in the skin severity score during the acute phase in NC/Nga mice similar to betamethasone. This suppressive effect was associated with a decrease in the serum IgE level and production of Th2 cytokines in auricular lymph node cells and skin lesions. Conclusion: Topical application of doxycycline to AD lesions would act on both superficial S. aureus colonization and epidermal LCs, thus possibly inhibiting the development of Th2 cells in vivo, with benefits for control of acute inflammation in AD.

Ovarian cancer (OC) is the most aggressive gynecological cancer. Even with the advances in detection and therapeutics, it still remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in OC. In this study, we found the MTDH is overexpressed in OC tissues. Through in vitro assays with overexpression cells, we characterized the role of MTDH. We confirmed MTDH stable overexpression significantly increased the expression of TNF-α, IL-6, IL-8, IL-10, and IL-1β. Interestingly, NF-kappa-B (NF-κB) and MTDH were found in a feed-forward loop motif. Thus, our findings support the notion that the MTDH and NF-κB signaling network contributes to OC traits. MTDH represents a new OC-associated gene that can contribute to insights of OC biology and suggests other treatment strategies.

Abstract Background Chondroid lipoma, first described in 1993 by Meis and Enzinger, is a very rare lipomatous tumor. Because it is a benign tumor, it does not require radiotherapy, chemotherapy, or extensive resection. However, histologically, it is often confused with a sarcoma. It is crucial to differentiate chondroid lipoma from sarcoma to avoid choosing an inappropriate treatment strategy. Although MRI, radiography, and ultrasound have been used to evaluate chondroid lipomas, imaging cannot accurately differentiate chondroid lipoma from sarcoma. Case presentation A 39-year-old man presented to a local clinic with a 1-month history of a painless mass in his left neck. Results of a needle biopsy suggested an atypical lipomatous tumor, and the patient was referred to our hospital. Physical examination revealed a hard and mobile mass in the left neck. Plain X-ray radiographs showed an absence of calcification in the soft tissue mass. MRI revealed a well-defined and lobulated mass, and on T1-weighted images, the lesion showed heterogeneity, with higher signal intensity than that of muscle. On T2-weighted images, the septum had low-signal intensity. On T2-weighted fat-suppressed images, the signal of the mass was completely suppressed. The SUVmax of the mass on FDG PET was 1.84. An additional needle biopsy was performed, and on the basis of the results, we arrived at a diagnosis of well-differentiated liposarcoma. The mass was resected marginally. Macroscopically, the mass was encapsulated and markedly harder than well-differentiated liposarcoma. Histologically, the tumor was composed of myxoid and cartilaginous matrix, and mature fat cells and lipoblast-like cells were present. The final diagnosis was chondroid lipoma, and no recurrence was observed 1 year after surgery. Conclusions Chondroid lipoma is an extremely rare benign soft tissue tumor that is often confused with sarcoma. It is very important to differentiate chondroid lipoma from sarcoma when the SUVmax value of the mass is low, even when biopsy results suggest that it is a sarcoma.

We reported previously that EGAM1 homeoproteins (EGAM1 and EGAM1N), transcribed from the Crxos gene as splicing variants, are expressed in preimplantation mouse embryos and mouse embryonic stem (ES) cells. Exogenous expression of these proteins affects the maintenance of an undifferentiated state and the progression of differentiation in mouse ES cells. Human tetrapeptide-repeat homeobox 1 (TPRX1), a member of the eutherian totipotent cell homeobox (ETCHbox) genes, is an ortholog of Crxos. However, the roles of TPRX1 in the differentiation of human pluripotent cells are still unknown. Because the TPRX1 transcripts were undetectable in an undifferentiated state and during the progression of differentiation in wild-type human embryonal carcinoma NT2/D1 cells, it would be advantageous to clarify the relationship between the exogenous expression of TPRX1 and the induction of genes encoding lineage-specific transcription factors in pluripotent cells. The expression of GATA6 and FOXA2, crucial transcription factors for the formation of the primitive endoderm, was upregulated, whereas that of CDX2, a crucial transcription factor for the formation of the trophectoderm, was downregulated by enforced expression of TPRX1. Overall, we suggest that TPRX1 is capable of modulating the expression of lineage-specific transcription factors in pluripotent cells derived from humans.

Abstract Background Ewing’s sarcoma is a primary malignant tumor of bone occurring mostly in childhood. Few effective reconstruction techniques are available after wide resection of Ewing’s sarcoma at the distal end of the tibia. Reconstruction after wide resection is especially difficult in children, as it is necessary to consider the growth and activity of the lower limbs. Case presentation A 12-year-old Japanese boy had presented with right lower leg pain at age 8 years. Imaging examination showed a bone tumor accompanied by a large extra-skeletal mass in the distal part of his tibia. The tumor was histologically diagnosed as Ewing’s sarcoma. The patient received chemotherapy, followed by wide resection. Reconstruction consisted of a bone transport method involving external fixation of Taylor Spatial Frame. To prevent infection after surgery, the external fixation pin was coated with iodine. One year after surgery, the patient showed poor consolidation of bone, so iliac bone transplantation was performed on the extended bones and docking site of the distal tibia. After 20 months, tibia formation was good. Three years after surgery, there was no evidence of tumor recurrence or metastases; bone fusion was good, and he was able to run. Conclusions The bone transport method is an effective surgical method of reconstruction after wide resection of a bone tumor at the distal end of the tibia, if a pin can be inserted into the distal bone fragment. Coating external fixation pins with iodine may prevent postoperative infection.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients. Methods Using quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre- and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1β production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1β production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes. Results Extracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1β from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1β production depends on specific innate immune pathways. Conclusion Extracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.

Purpose: To report a case of macular hole (MH) secondary to a retinal arterial macroaneurysm (RAMA) which was successfully treated with an autologous transplantation of internal limiting membrane (ILM). Case Report: An 87-year-old female presented with a sudden decrease in central vision in the right eye. A fundus examination revealed a RAMA in the superonasal macular region, a subretinal hemorrhage (SRH), involving the macula, and a sub-ILM hemorrhage. A pars plana vitrectomy (PPV) was performed. Intraoperatively, an MH filled with coagulum was detected. We tried to blow off and drain the SRH with a current of BSS and a gentle suction with a 27-gauge vitreous cutter from the MH, but some amount of SRH at the bottom of the MH remained. The ILM was peeled off for 2 disc diameters around the MH. The vitreous cavity was filled with air at the end of the operation. Two weeks after the surgery, the MH was not closed. One month following the initial PPV, a second PPV was performed to achieve closure of the MH. Results: An autologous transplantation of ILM was performed as second PPV. Six months after the final surgery, the MH was successfully closed and the best-corrected decimal visual acuity was 0.6. Conclusions: Autologous ILM transplantation can be an effective treatment option for MH closure following RAMA rupture.

Due to the heterogeneous pathology of traumatic brain injury (TBI), the exact mechanism of how initial brain damage leads to chronic inflammation and its effects on the whole brain remain unclear. Here, we report on long-term neuroinflammation, remote from the initial injury site, even after subsiding of the original inflammatory response, in a focal TBI mouse model. The use of translocator protein-positron emission tomography in conjunction with specialised magnetic resonance imaging modalities enabled us to visualize “previously undetected areas” of spreading inflammation after focal cortical injury. These clinically available modalities further revealed the pathophysiology of thalamic neuronal degeneration occurring as resident microglia sense damage to corticothalamic neuronal tracts and become activated. The resulting microglial activation plays a major role in prolonged inflammatory processes, which are deleterious to the thalamic network. In light of the association of this mechanism with neuronal tracts, we propose it can be termed “brain injury related inflammatory projection”. Our findings on multiple spatial and temporal scales provide insight into the chronic inflammation present in neurodegenerative diseases after TBI. Keywords: Translocator protein-positron emission tomography, Traumatic brain injury, Neurodegeneration, Neuroinflammation

Abstract The purpose of this study was to longitudinally assess left ventricular function and wall thickness in a hamster model of cardiomyopathy using 11.7-T magnetic resonance imaging (MRI). MRI were performed for six cardiomyopathic J2N-k hamsters and six J2N-n hamsters at 5, 10, 15, and 20 weeks of age. Echocardiography was also performed at 20 weeks. The ejection fraction (EF) at 15 and 20 weeks of age in J2N-k hamsters showed a significant decrease compared with those in controls. Conversely, the end-systolic and end-diastolic volumes in cardiomyopathic hamsters showed a significant increase compared with those in controls. Moreover, the heart walls of J2N-k hamsters at 15 and 20 weeks were thicker than those of controls at end-systole; however, there were no significant differences at end-diastole. Optical microscopy with Masson’s trichrome staining depicted no fibrosis in the control myocardium, although it showed interstitial fibrosis in the 20-week-old J2N-k cardiomyopathic myocardium. There were no differences in EF and the wall thickness observed on MRI and those observed on echocardiography. These results indicate the presence of systolic dysfunction in cardiomyopathic hamsters. Self-gated cine imaging based on 11.7-T MRI can be used for serial measurements of cardiac function and wall thickness in a cardiomyopathic model.

Abstract Renal cysts are detected in one third of acromegaly patients, especially in uncontrolled cases. Clinicians should pay attention to unexpected infection of enlarged renal cysts in acromegaly patients.

Following publication of the original article [1], the authors have flagged that there is an error in Fig. 3.

A no-backlash drive control technique which used two motors for forward rotation and reverse rotation to drive one load so as to cancel backlash has been using the same motor so far. However, there is a water gradient on an actual road surface, and we need to turn a steering wheel a little to the right in order to drive the car straight ahead. Therefore, it may be considered to make the right steering motor larger than the left one. In this paper, the effect of the two motor inertia difference on the control system is examined. We evaluate the effect by the analysis and experiment:1) the motor equivalent inertia of the two motors is the geometric mean of the respective inertia, when back calculated from the 1st natural frequency, 2) the damping of the 1st natural frequency increases with an increase in the inertia difference, when the position control gain, the rate control gain, and the reduction ratio are set high, 3) the smaller these set values, the larger the change in the damping characteristic with the inertia difference becomes, 4) the rate control gain has remarkable influence on the change of the damping characteristic , 5) the damping characteristic decreases when the motor inertia is equal and both the forward and the reverse motor inertia increase, on the other hand, the damping characteristic increases when the motor inertia difference increases.

Sulfur (S) assimilation, which is initiated by sulfate uptake, generates cysteine, the substrate for glutathione (GSH) and phytochelatin (PC) synthesis. GSH and PC contribute to cadmium (Cd) detoxification by capturing it for sequestration. Although Cd exposure is known to induce the expression of S-assimilating enzyme genes, including sulfate transporters (SULTRs), mechanisms of their transcriptional regulation are not well understood. Transcription factor SLIM1 controls transcriptional changes during S deficiency (−S) in Arabidopsis thaliana. We examined the potential involvement of SLIM1 in inducing the S assimilation pathway and PC accumulation. Cd treatment reduced the shoot fresh weight in the sulfur limitation1 (slim1) mutant but not in the parental line (1;2PGN). Cd-induced increases of sulfate uptake and SULTR1;2 expressions were diminished in the slim1 mutant, suggesting that SLIM1 is involved in inducing sulfate uptake during Cd exposure. The GSH and PC levels were lower in slim1 than in the parental line, indicating that SLIM1 was required for increasing PC during Cd treatment. Hence, SLIM1 indirectly contributes to Cd tolerance of plants by inducing −S responses in the cell caused by depleting the GSH pool, which is consumed by enhanced PC synthesis and sequestration to the vacuole.