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AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that p -Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA's actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.

The organ allocation system should be fair and efficient to predict the prognosis of patients with end-stage organ failure. The liver allocation system in Korea was changed to the model for end-stage liver disease (MELD) score system from Child-Turcotte-Pugh score-based status system in 2016. Since then, there have been some changes in matching liver graft to recipients in deceased liver transplantation. The severity of sickness of the end-stage liver failure patients has been increased in the MELD era than before. Since 2013, liver transplantation for alcoholic liver disease has been gradually increasing in Korea. We should take proper evaluation into consideration when we decide early liver transplantation particularly for patients with severe alcoholic hepatitis, who have a high MELD score. Above all, overcoming organ shortage, it is necessary for us to try to increase the number of deceased donors to meet the need for liver transplantation for end-stage liver disease patients.

Background: Some studies reported the correlations between renal parenchymal stiffness measured by transient elastography or acoustic radiation force impulse (ARFI) and the extent of interstitial fibrosis. This study was prospectively designed to evaluate the correlation between clinical, histological findings and the kidney shear wave velocity (SWV, m/s) assessed by ARFI elastography to identify factors affecting the kidney SWV in normal patients., Methods: Seventy-three adult living kidney transplantation donors were enrolled in our center between September 2010 and January 2013. Before transplantation, all donors were evaluated by ARFI elastography to identify the range of SWV in kidneys. Time-zero biopsies were performed on all graft kidneys before implantation., Results: Mean age of donors was 42.0 ± 11.3 years. The mean SWV and depth were 2.21 ± 0.58 m/s and 5.37 ± 1.06 cm. All histological findings showed mild degree of the Banff score, only grade I. In univariate analyses, the SWV was not associated with all histological parameters. Age (r = -0.274, P = .019) diastolic blood pressure (DBP, r = -0.255, P = .030) and depth for SWV measurement (r = -0.345, P = .003) were significantly correlated with the SWV. In multivariate linear regression analysis, age, gender, body mass index (BMI), and depth for SWV measurement were significantly correlated with the SWV (P = .003, .005, .002, and .004, respectively)., Conclusions: We demonstrated that all histological findings are not correlated with the SWV of donor kidney. Otherwise, factors influencing the kidney SWV assessed by ARFI elastography are age, gender, BMI, and depth for the SWV measurement in donors for kidney transplantation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-KOSF-1) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-KOSF-1 and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.

Background: Curly toe deformity is a relatively common deformity that generally occurs at the 4th and 5th proximal and/or middle phalanges but rarely presents with symptoms. Although numerous open operative techniques have been introduced, there is no established treatment yet. We report the results of minimally invasive correction for symptomatic, fixed curly toe deformity., Methods: Between 2016 and 2018, 25 consecutive percutaneous dorsolateral closing wedge-shaped osteotomies with Shannon burrs at the proximal and/or middle phalanx were performed. We assessed the postoperative clinical and radiological changes at a mean of 22.51 months of follow-up., Results: The locations of osteotomy were at the middle phalanx in 10 cases, proximal phalanx in 13 cases, and both in one case. The mean amount of corrections of varus inclination and shortening were 16.54° and 2.24 mm, respectively. The Foot and Ankle Ability Measure Activities of Daily Living scores significantly improved from 59.09 preoperatively to 74.55 at the last follow-up. There was one case of pin site infection and one case of incision site numbness due to digital nerve injury., Conclusions: Minimally invasive dorsolateral closing wedge-shape osteotomy is a simple, safe, and effective correction for symptomatic, fixed curly toe deformity., (Copyright © 2020 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Background: Surgical defects of the distal nose can pose significant reconstructive challenges. Free cartilage batten graft (FCBG) with secondary intention healing is an underreported yet effective repair option with cosmetically and functionally satisfying outcomes., Objective: To share the authors' experience using FCBG with secondary intention healing on multiple nasal subunits, including a detailed evaluation of wound/graft characteristics and design modifications to optimize success with this single-stage approach., Methods: A retrospective study of 129 patients who underwent FCBG with secondary intention healing after Mohs surgery from 2011 to 2018, using statistical analysis of numerous outcome measures graded independently by 2 fellowship-trained Mohs surgeons., Results: Overall, healed wounds were graded aesthetically as follows: excellent (24%), very good (31%), good (31%), or poor (14%). Excellent/very good outcomes were seen for superficial (p < .001), small-to-medium sized wounds (p < .0001) repaired with cartilage that closely approximated the defect size (p < .05). Consistently optimal outcomes were seen in the 19 repairs involving the alar lobule (mid-ala) alone, graded excellent (47%), very good (32%), and good (21%). A majority of patients (86%) experienced mild to no alar retraction. Although 67% of all patients had some skin surface contour irregularity, only 8% of patients sought dermabrasion. Neither hematoma, infection, ear deformity, chondritis, nor graft desiccation were reported., Conclusion: A modified approach to FCBG with secondary intention healing provides a reliable, minimalistic, low-risk reconstructive option for mid-alar defects., (Copyright © 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: The future of artificial intelligence (AI) heralds unprecedented change for the field of radiation oncology. Commercial vendors and academic institutions have created AI tools for radiation oncology, but such tools have not yet been widely adopted into clinical practice. In addition, numerous discussions have prompted careful thoughts about AI's impact upon the future landscape of radiation oncology: How can we preserve innovation, creativity, and patient safety? When will AI-based tools be widely adopted into the clinic? Will the need for clinical staff be reduced? How will these devices and tools be developed and regulated?, Summary: In this work, we examine how deep learning, a rapidly emerging subset of AI, fits into the broader historical context of advancements made in radiation oncology and medical physics. In addition, we examine a representative set of deep learning-based tools that are being made available for use in external beam radiotherapy treatment planning and how these deep learning-based tools and other AI-based tools will impact members of the radiation treatment planning team. Key Messages: Compared to past transformative innovations explored in this article, such as the Monte Carlo method or intensity-modulated radiotherapy, the development and adoption of deep learning-based tools is occurring at faster rates and promises to transform practices of the radiation treatment planning team. However, accessibility to these tools will be determined by each clinic's access to the internet, web-based solutions, or high-performance computing hardware. As seen by the trends exhibited by many technologies, high dependence on new technology can result in harm should the product fail in an unexpected manner, be misused by the operator, or if the mitigation to an expected failure is not adequate. Thus, the need for developers and researchers to rigorously validate deep learning-based tools, for users to understand how to operate tools appropriately, and for professional bodies to develop guidelines for their use and maintenance is essential. Given that members of the radiation treatment planning team perform many tasks that are automatable, the use of deep learning-based tools, in combination with other automated treatment planning tools, may refocus tasks performed by the treatment planning team and may potentially reduce resource-related burdens for clinics with limited resources., (© 2020 S. Karger AG, Basel.)

Background: The coronavirus disease 2019 (COVID-19) has forced healthcare systems to reduce transplant activities in order to preserve resources and minimize the risk of nosocomial transmission. Although transplantation societies around the world have proposed interim recommendations, little is known about the safety of transplant surgery under pandemic conditions and how transplant medicine should move forward after the peak of the pandemic., Methods: We describe our experiences regarding the continuation of living and deceased donor transplantation under infection control measures during the COVID-19 outbreak in South Korea. We reviewed consecutive liver and kidney transplantations at Severance Hospital and analyzed national transplantation activities in South Korea., Results: Transplantation activities with living and deceased donors remained stable during the COVID-19 outbreak compared to the same period in 2019. We performed 94 transplantations (58 kidney, 35 liver, and 1 simultaneous liver-kidney) during the COVID-19 outbreak. Twenty-five patients underwent desensitization therapy prior to transplant (nine ABO-incompatible kidney, eight human leukocyte antigen-incompatible kidney, and eight ABO-incompatible liver). No transplant recipients in our center contracted COVID-19. In South Korea, national transplant activities with living and deceased donors remained stable in 2020 compared to 2019., Conclusions: Organ transplantation during pandemics appears to be feasible with appropriate infection prevention measures., Competing Interests: Conflict of Interest No potential conflict of interest relevant to this article was reported., (Copyright © 2020 The Korean Society for Transplantation.)

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene., Competing Interests: Competing interest statement: J.K. and K.D.M. are listed as inventors on patent applications filed by Indiana University related to targeting progesterone signaling.

Objectives: The purpose of the present study was to investigate which peri-transplant dental treatments were deemed necessary, and to determine retrospectively how often these treatments were actually performed, in patients who had received organ transplants., Materials and Methods: Medical records of the Department of Advanced General Dentistry at Yonsei University Dental Hospital were searched to identify liver or kidney transplant recipients who attended from 1st March 2014 to 31st December 2017. A total of 418 patients were identified, and their medical charts were reviewed. Sex, underlying systemic disease, oral hygiene status, dental treatment deemed necessary, dental treatment actually performed and durations of follow-up were tabulated., Results: More than half (53.8%) of the liver transplant recipients had poor oral hygiene, and poor oral hygiene was statistically significantly more prevalent in the liver transplant group than in the kidney transplant group (40.3%). In liver recipients in whom scaling was deemed to be required pre-transplant, the rate of it actually being performed pre-transplant was high (83.2%). By contrast, the rates of tooth extraction and prosthetic treatment actually being performed pre-transplant were low (12.8% and 0%, respectively). In kidney recipients, the rates of scaling, tooth extraction and prosthetic treatment actually performed pre-transplant, when deemed to be required, were 93.5%, 10.0% and 0.0%, respectively., Conclusions: We recommend that patients scheduled to receive an organ transplant be referred to a dental clinic as soon as possible beforehand, to remove any potential sources of oral infection. Educating physicians, as well as their patients, about the importance of early dental screening and pre-transplant dental treatment is essential., (© 2020 FDI World Dental Federation.)

Purpose: The purpose of this work was to evaluate the performance of X-Net, a multiview deep learning architecture, to automatically label vertebral levels (S2-C1) in palliative radiotherapy simulation CT scans., Methods: For each patient CT scan, our automated approach 1) segmented spinal canal using a convolutional-neural network (CNN), 2) formed sagittal and coronal intensity projection pairs, 3) labeled vertebral levels with X-Net, and 4) detected irregular intervertebral spacing using an analytic methodology. The spinal canal CNN was trained via fivefold cross validation using 1,966 simulation CT scans and evaluated on 330 CT scans. After labeling vertebral levels (S2-C1) in 897 palliative radiotherapy simulation CT scans, a volume of interest surrounding the spinal canal in each patient's CT scan was converted into sagittal and coronal intensity projection image pairs. Then, intensity projection image pairs were augmented and used to train X-Net to automatically label vertebral levels using fivefold cross validation (n = 803). Prior to testing upon the final test set (n = 94), CT scans of patients with anatomical abnormalities, surgical implants, or other atypical features from the final test set were placed in an outlier group (n = 20), whereas those without these features were placed in a normative group (n = 74). The performance of X-Net, X-Net Ensemble, and another leading vertebral labeling architecture (Btrfly Net) was evaluated on both groups using identification rate, localization error, and other metrics. The performance of our approach was also evaluated on the MICCAI 2014 test dataset (n = 60). Finally, a method to detect irregular intervertebral spacing was created based on the rate of change in spacing between predicted vertebral body locations and was also evaluated using the final test set. Receiver operating characteristic analysis was used to investigate the performance of the method to detect irregular intervertebral spacing., Results: The spinal canal architecture yielded centroid coordinates spanning S2-C1 with submillimeter accuracy (mean ± standard deviation, 0.399 ± 0.299 mm; n = 330 patients) and was robust in the localization of spinal canal centroid to surgical implants and widespread metastases. Cross-validation testing of X-Net for vertebral labeling revealed that the deep learning model performance (F 1 score, precision, and sensitivity) improved with CT scan length. The X-Net, X-Net Ensemble, and Btrfly Net mean identification rates and localization errors were 92.4% and 2.3 mm, 94.2% and 2.2 mm, and 90.5% and 3.4 mm, respectively, in the final test set and 96.7% and 2.2 mm, 96.9% and 2.0 mm, and 94.8% and 3.3 mm, respectively, within the normative group of the final test set. The X-Net Ensemble yielded the highest percentage of patients (94%) having all vertebral bodies identified correctly in the final test set when the three most inferior and superior vertebral bodies were excluded from the CT scan. The method used to detect labeling failures had 67% sensitivity and 95% specificity when combined with the X-Net Ensemble and flagged five of six patients with atypical vertebral counts (additional thoracic (T13), additional lumbar (L6) or only four lumbar vertebrae). Mean identification rate on the MICCAI 2014 dataset using an X-Net Ensemble was increased from 86.8% to 91.3% through the use of transfer learning and obtained state-of-the-art results for various regions of the spine., Conclusions: We trained X-Net, our unique convolutional neural network, to automatically label vertebral levels from S2 to C1 on palliative radiotherapy CT images and found that an ensemble of X-Net models had high vertebral body identification rate (94.2%) and small localization errors (2.2 ± 1.8 mm). In addition, our transfer learning approach achieved state-of-the-art results on a well-known benchmark dataset with high identification rate (91.3%) and low localization error (3.3 mm ± 2.7 mm). When we pre-screened radiotherapy CT images for the presence of hardware, surgical implants, or other anatomic abnormalities prior to the use of X-Net, it labeled the spine correctly in more than 97% of patients and 94% of patients when scans were not prescreened. Automatically generated labels are robust to widespread vertebral metastases and surgical implants and our method to detect labeling failures based on neighborhood intervertebral spacing can reliably identify patients with an additional lumbar or thoracic vertebral body., (© 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: To develop a tool for the automatic contouring of clinical treatment volumes (CTVs) and normal tissues for radiotherapy treatment planning in cervical cancer patients., Methods: An auto-contouring tool based on convolutional neural networks (CNN) was developed to delineate three cervical CTVs and 11 normal structures (seven OARs, four bony structures) in cervical cancer treatment for use with the Radiation Planning Assistant, a web-based automatic plan generation system. A total of 2254 retrospective clinical computed tomography (CT) scans from a single cancer center and 210 CT scans from a segmentation challenge were used to train and validate the CNN-based auto-contouring tool. The accuracy of the tool was evaluated by calculating the Sørensen-dice similarity coefficient (DSC) and mean surface and Hausdorff distances between the automatically generated contours and physician-drawn contours on 140 internal CT scans. A radiation oncologist scored the automatically generated contours on 30 external CT scans from three South African hospitals., Results: The average DSC, mean surface distance, and Hausdorff distance of our CNN-based tool were 0.86/0.19 cm/2.02 cm for the primary CTV, 0.81/0.21 cm/2.09 cm for the nodal CTV, 0.76/0.27 cm/2.00 cm for the PAN CTV, 0.89/0.11 cm/1.07 cm for the bladder, 0.81/0.18 cm/1.66 cm for the rectum, 0.90/0.06 cm/0.65 cm for the spinal cord, 0.94/0.06 cm/0.60 cm for the left femur, 0.93/0.07 cm/0.66 cm for the right femur, 0.94/0.08 cm/0.76 cm for the left kidney, 0.95/0.07 cm/0.84 cm for the right kidney, 0.93/0.05 cm/1.06 cm for the pelvic bone, 0.91/0.07 cm/1.25 cm for the sacrum, 0.91/0.07 cm/0.53 cm for the L4 vertebral body, and 0.90/0.08 cm/0.68 cm for the L5 vertebral bodies. On average, 80% of the CTVs, 97% of the organ at risk, and 98% of the bony structure contours in the external test dataset were clinically acceptable based on physician review., Conclusions: Our CNN-based auto-contouring tool performed well on both internal and external datasets and had a high rate of clinical acceptability., (© 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Layer 2/3 pyramidal neurons (L2/3 PyNs) of the cortex extend their basal dendrites near the soma and as apical dendritic tufts in layer 1, which mainly receive feedforward and feedback inputs, respectively. It is suggested that neuromodulators such as serotonin and acetylcholine may regulate the information flow between brain structures depending on the brain state. However, little is known about the dendritic compartment-specific induction of synaptic transmission in single PyNs. Here, we studied layer-specific serotonergic and cholinergic induction of long-term synaptic plasticity in L2/3 PyNs of the agranular insular cortex, a lateral component of the orbitofrontal cortex. Using FM1-43 dye unloading, we verified that local electrical stimulation to layers 1 (L1) and 3 (L3) activated axon terminals mostly located in L1 and perisomatic area (L2/3). Independent and AMPA receptor-mediated excitatory postsynaptic potential was evoked by local electrical stimulation of either L1 or L3. Application of serotonin (5-HT, 10 µM) induced activity-dependent longterm depression (LTD) in L2/3 but not in L1 inputs. LTD induced by 5-HT was blocked by the 5-HT 2 receptor antagonist ketanserin, an NMDA receptor antagonist and by intracellular Ca 2+ chelation. The 5-HT 2 receptor agonist α-me-5-HT mimicked the LTD induced by 5-HT. However, the application of carbachol induced muscarinic receptor- dependent LTD in both inputs. The differential layer-specific induction of LTD by neuromodulators might play an important role in information processing mechanism of the prefrontal cortex.

Background and Purpose: Liver-directed combined radiotherapy (LDCRT) can provide substantial tumor control, which may be an effective bridge to curative surgery for selected patients. We aimed to investigate the outcomes of LDCRT for locally advanced hepatocellular carcinoma (LAHCC) beyond the Milan criteria., Materials and Methods: We identified 1078 patients diagnosed with LAHCC who received LDCRT and compared the outcomes based on no surgery, conversion to surgical resection, and liver transplantation (LT). Predictive factors for conversion to curative surgery were identified using logistic regression analysis., Results: The most frequently used LDCRT strategies were concurrent chemoradiation (CCRT) (497 patients, 46.1%) and transarterial chemoembolization (TACE) plus radiotherapy (251 patients 23.3%). After LDCRT, 96 (8.9%) and 42 patients (3.9%) received surgical resection and LT, respectively. After a median follow-up of 14.4 months, the 5-year overall survival (OS) rate was 16.5% for all patients. Conversion to curative surgery group had higher 5-year OS (surgical resection vs. LT vs. no surgery: 58.1% vs. 54.3% vs. 10.2%, p < 0.001). Patients aged < 60 years with a single tumor, no treatment history, pre-treatment Child class A, lower pre-treatment tumor marker levels, and radiologic complete or partial response (all p < 0.050) had a higher chance of conversion to surgery., Conclusion: LDCRT could convert tumors to within the Milan criteria as a bridge to curative surgery, and improved long-term survival for the selected patients. Clinicians should consider LDCRT followed by curative surgery for young patients who are treatment-naïve and have good liver function with favorable tumor characteristics showing radiologic response to LDCRT., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Sarcopenia is associated with fibrotic burden in patients with chronic hepatitis B. We investigated the dynamic association between fibrosis changes and appendicular skeletal muscle mass during antiviral therapy in patients with chronic hepatitis B., Methods: Between 2015 and 2018, chronic hepatitis B patients who received paired transient elastography to assess fibrotic burden in the liver and bioelectrical impedance analysis to assess appendicular skeletal muscle mass were recruited retrospectively. The sarcopenia index was calculated as total appendicular skeletal muscle mass/body mass index. Significant liver fibrosis was defined as a liver stiffness value≥8 kPa., Results: In total, 223 (53.7%) received antiviral therapy, whereas 192 (46.3%) did not. Appendicular skeletal muscle mass decreased significantly in the antiviral therapy group (mean 21.16→21.00 kg, P = 0.01), but not in the non-antiviral therapy group (mean 20.77→20.64 kg, P = 0.134). In a subgroup with significant liver fibrosis, similar findings were observed (mean 20.73→20.54 kg in antiviral therapy group, P = 0.037; mean 21.39→21.07 kg in the non-antiviral therapy group, P = 0.097). Older age, male gender, higher body mass index, and higher aspartate aminotransferase were significantly associated with the increased risk of appendicular skeletal muscle mass reduction (≥5% from the baseline)., Conclusions: Appendicular skeletal muscle mass significantly decreased during antiviral therapy in patients with chronic hepatitis B patients., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aripiprazole is a quinolinone derivative approved as an atypical antipsychotic drug for the treatment of schizophrenia and bipolar disorder. It acts as with partial agonist activities at the dopamine D2 receptors. Although it is known to be relatively safe for patients with cardiac ailments, less is known about the effect of aripiprazole on voltage-gated ion channels such as transient A-type K + channels, which are important for the repolarization of cardiac and neuronal action potentials. Here, we investigated the effects of aripiprazole on Kv1.4 currents expressed in HEK293 cells using a whole-cell patch-clamp technique. Aripiprazole blocked Kv1.4 channels in a concentration-dependent manner with an IC 50 value of 4.4 µM and a Hill coefficient of 2.5. Aripiprazole also accelerated the activation (time-to-peak) and inactivation kinetics. Aripiprazole induced a voltage-dependent (δ = 0.17) inhibition, which was use-dependent with successive pulses on Kv1.4 currents without altering the time course of recovery from inactivation. Dehydroaripiprazole, an active metabolite of aripiprazole, inhibited Kv1.4 with an IC 50 value of 6.3 µM (p < 0.05 compared with aripiprazole) with a Hill coefficient of 2.0. Furthermore, aripiprazole inhibited Kv4.3 currents to a similar extent in a concentration-dependent manner with an IC 50 value of 4.9 µM and a Hill coefficient of 2.3. Thus, our results indicate that aripiprazole blocked Kv1.4 by preferentially binding to the open state of the channels.

The skin is the largest and a remarkably plastic organ that serves as a protective barrier against environmental stimuli and injuries throughout life. Skin injuries are serious health problems, and wound healing is a critical process to replace devitalized cellular and tissue structures. Although some endogenous opioids are known to be involved in the modulation of wound healing, it remains to be determined whether the β-neoendorphin (β-NEP), an endogenous opioid, has beneficial effects on wound repair in human keratinocyte. In this study, we found that β-NEP accelerated wound repair through activation of mitogen-activated protein kinase (MAPK)/Erk1/2 signaling pathways in human keratinocytes. Moreover, the wound healing effect of β-NEP is mainly through the acceleration of keratinocyte migration without affecting cell proliferation. Therefore, our studies reveal that β-NEP plays an important role in the regulation of wound repair and suggest a therapeutic strategy to promote wound healing using β-NEP.

Monocyte-derived macrophages play a role in the repair of the injured brain. We previously reported that a deficiency of the Parkinson's disease (PD)-associated gene DJ-1 delays repair of brain injury produced by stereotaxic injection of ATP, a component of damage-associated molecular patterns. Here, we show that a DJ-1 deficiency attenuates monocyte infiltration into the damaged brain owing to a decrease in C-C motif chemokine ligand 2 (CCL2) expression in astrocytes. Like DJ-1-knockout (KO) mice, CCL2 receptor (CCR2)-KO mice showed defects in monocyte infiltration and delayed recovery of brain injury, as determined by 9.4 T magnetic resonance imaging analysis and immunostaining for tyrosine hydroxylase and glial fibrillary acid protein. Notably, transcriptome analyses showed that genes related to regeneration and synapse formation were similarly downregulated in injured brains of DJ-1-KO and CCR2-KO mice compared with the injured wild-type brain. These results indicate that defective astrogliosis in DJ-1-KO mice is associated with decreased CCL2 expression and attenuated monocyte infiltration, resulting in delayed repair of brain injury. Thus, delayed repair of brain injury could contribute to the development of PD. MAIN POINTS: A DJ-1 deficiency attenuates infiltration of monocytes owing to a decrease in CCL2 expression in astrocytes, which in turn led to delay in repair of brain injury., (© 2020 Wiley Periodicals, Inc.)

The radiation treatment-planning process includes contouring, planning, and reviewing the final plan, and each component requires substantial time and effort from multiple experts. Automation of treatment planning can save time and reduce the cost of radiation treatment, and potentially provides more consistent and better quality plans. With the recent breakthroughs in computer hardware and artificial intelligence technology, automation methods for radiation treatment planning have achieved a clinically acceptable level of performance in general. At the same time, the automation process should be developed and evaluated independently for different disease sites and treatment techniques as they are unique from each other. In this article, we will discuss the current status of automated radiation treatment planning for cervical cancer for simple and complex plans and corresponding automated quality assurance methods. Furthermore, we will introduce Radiation Planning Assistant, a web-based system designed to fully automate treatment planning for cervical cancer and other treatment sites., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nontumoral portal vein thrombosis (PVT) is present at liver transplantation (LT) in 5-26% of cirrhotic patients, and is known to affect post LT outcomes. Up to 31% of patients who are found to have PVT at the time of LT, would have had PVT at the time of initial listing, but others develop PVT during the waiting period. Adequate screening and treatment of the PVT on the waiting list for LT is thus essential so that a portoportal anastomoses can be performed at the time of LT. Early PVT (Yerdel Grade I/II) can be usually managed by thrombectomy, whereas Grade III PVT may require a jump graft from the superior mesenteric vein to the graft PV. Complete portomesenteric thrombosis is a huge challenge, and sometimes a cause for denying a LT in these patients, with multivisceral transplant being the only alternative. The presence of spontaneous, or previously surgically created portosytemic shunts like the leinorenal shunt, may serve as a good inflow option (renoportal anastomosis) in these patients to establish a physiological reconstruction. Although challenging, good outcomes are possible in patients with complex PVT if the appropriate surgical technique is chosen to ensure portal inflow and resolution of PHT post LT., (Copyright © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

With the increasing demand for organ transplantation, organ procurement from a deceased donor is an essential step for deceased donor organ transplantation. A proper surgical technique for the procurement of an organ graft from a deceased donor must be carried out to avoid any damage to it. Moreover, how to manage deceased donors until they enter the operating room in a stable condition is a critical point to be considered. The establishment of a surgical technique and preoperative management for organ procurement is encouraged to achieve a nationwide standard and consistency for organ graft sharing among the transplant units., (Copyright © 2020 The Korean Society for Transplantation.)

In this study, recycled waste fishing net (WFN) short fibers were proposed to be used as short fiber reinforcements. The pullout resistance of WFN short fibers embedded in cement mortar was investigated by conducting fiber pullout tests. Three types of WFN short fibers and two types of commercial polypropylene (CP) fibers were investigated. To quantitatively compare the pullout resistance of WFN short fibers and CP fibers, pullout parameters, including peak pullout load (peak bond strength), peak fiber stress, slip at peak load, and pullout energy (equivalent bond strength) of the pullout specimens, were analyzed. In addition, the analysis of fiber images, captured by using a stereoscopic digital microscope, before and after pullout tests, elucidated the different mechanisms of fiber pullout corresponding to the type of fibers. The bundled structures of the WFN fibers generated mechanical interaction between fiber and matrix during fiber pullout; consequently, they produced higher bond resistance and more damage on the surface of fibers after the pullout. Therefore, the bundled WFN fibers showed comparable pullout resistance with CP fibers., Competing Interests: The authors declare no conflict of interest.

Background & Aims: Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in the human liver, can be activated by cytokines during viral infection without TCR stimulation. Here, we examined the mechanisms underlying TCR/MR1-independent innate-like cytotoxicity of cytokine-activated liver MAIT cells. We also examined the phenotype and function of MAIT cells from patients with acute viral hepatitis., Methods: We obtained liver sinusoidal mononuclear cells from donor liver perfusate during liver transplantation and examined the effect of various cytokines on liver MAIT cells using flow cytometry and in vitro cytotoxicity assays. We also obtained peripheral blood and liver-infiltrating T cells from patients with acute hepatitis A (AHA) and examined the phenotype and function of MAIT cells using flow cytometry., Results: IL-15-stimulated MAIT cells exerted granzyme B-dependent innate-like cytotoxicity in the absence of TCR/MR1 interaction. PI3K-mTOR signaling, NKG2D ligation, and CD2-mediated conjugate formation were critically required for this IL-15-induced innate-like cytotoxicity. MAIT cells from patients with AHA exhibited activated and cytotoxic phenotypes with higher NKG2D expression. The innate-like cytotoxicity of MAIT cells was significantly increased in patients with AHA and correlated with serum alanine aminotransferase levels., Conclusions: Taken together, the results demonstrate that liver MAIT cells activated by IL-15 exert NKG2D-dependent innate-like cytotoxicity in the absence of TCR/MR1 engagement. Furthermore, the innate-like cytotoxicity of MAIT cells is associated with liver injury in patients with AHA, suggesting that MAIT cells contribute to immune-mediated liver injury., Lay Summary: Immune-mediated liver injury commonly occurs during viral infections of the liver. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the human liver. Herein, we have identified a mechanism by which MAIT cells circumvent conventional T cell receptor interactions to exert cytotoxicity. We show that this innate-like cytotoxicity is increased during acute hepatitis A virus infection and correlates with the degree of hepatocyte injury., Competing Interests: Conflict of interest The authors have no conflicting financial interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Although potent P2Y12 inhibitor-based dual antiplatelet therapy (DAPT) has replaced clopidogrel-based therapy as the standard treatment in patients with acute myocardial infarction (AMI), there is a concern about the risk of bleeding in East Asian patients. We compared the efficacy and safety of cilostazol-based triple antiplatelet therapy (TAT) with potent P2Y12 inhibitor-based DAPT in Korean patients. A total of 4152 AMI patients who underwent percutaneous coronary intervention (PCI) in the Korea Acute Myocardial Infarction Registry were analyzed retrospectively. Patients were divided into two groups: the TAT group (aspirin + clopidogrel + cilostazol, n = 3161) and the potent DAPT group (aspirin + potent P2Y12 inhibitors [ticagrelor or prasugrel], n = 991). Major clinical outcomes at 30 days and 2 years were compared between the two groups using propensity score matching (PSM) analysis. After PSM (869 pairs), there were no significant differences between the two groups in the incidence of total death, cardiac death, myocardial infarction (MI), target vessel revascularization, stent thrombosis, and stroke at 30 days and 2 years. However, the Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding rates were significantly lower in the TAT group compared with the potent DAPT group at 2 years (6.4% vs. 3.6%, p = 0.006). In Korean AMI patients undergoing PCI, TAT with cilostazol was associated with lower bleeding than the potent P2Y12 inhibitor-based DAPT without increased ischemic risk. These results could provide a rationale for the use of TAT in East Asian AMI patients.

Clear cell sarcoma of the Achilles tendon is an extremely rare condition, with a handful of cases reported in the literature over the past 3 decades. Patients usually present late because of the slow progress of the disease and seemingly benign nature of its presentation. Clinical and radiological findings are not enough to make a diagnosis; hence, a high index of suspicion is required. A firm diagnosis is made only after histopathologic studies. We present a rare case of this tumor in a young female, the management plan, and prognostic outlook, with subsequent review of the literature., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.

C57BL/6NKorl mice are a novel mouse stock recently developed by the National Institute of Food and Drug Safety Evaluation in Korea. Extensive research into the nature of C57BL/6NKorl mice is being conducted. However, there is no scientific evidence for the phenotypic response to restraint stress (RST), a stress paradigm for modeling depressive disorders, in rodents. In this study, we investigated the repeated RST-induced depressive-like phenotypes in C57BL/6 N mouse substrains (viz., C57BL/6NKorl mice from Korea, C57BL/6NA mice from the United States, and C57BL/6NB mice from Japan) obtained from different sources. The results showed that C57BL/6 N mice derived from various sources exposed to repeated RST resulted in depressive-like phenotypes reflected by a similar degree of behavioral modification and susceptibility to oxidative stress in a duration-dependent manner, except for the distinctive features (increased body weight (BW) and tolerance to the suppression of BW gain by exposure to repeated RST) in C57BL/6NKorl mice. Taken together, the duration-dependent alteration in depressive-like phenotypes by repeated exposure to RST observed in this study may provide valuable insights into the nature of C57BL/6NKorl mice as an alternative animal resource for better understanding of the etiology of depressive disorders and the mechanisms of antidepressant actions., Competing Interests: Competing interestsThe authors declare that there is no financial conflict of interests to publish these results., (© The Author(s) 2020.)

In lithium metal batteries, electrolytes containing a high concentration of salts have demonstrated promising cyclability, but their practicality with respect to the cost of materials is yet to be proved. Here we report a fluorinated aromatic compound, namely 1,2-difluorobenzene, for use as a diluent solvent in the electrolyte to realize the "high-concentration effect". The low energy level of the lowest unoccupied molecular orbital (LUMO), weak binding affinity for lithium ions, and high fluorine-donating power of 1,2-difluorobenzene jointly give rise to the high-concentration effect at a bulk salt concentration near 2 m, while modifying the composition of the solid-electrolyte-interphase (SEI) layer to be rich in lithium fluoride (LiF). The employment of triple salts to prevent corrosion of the aluminum current collector further improves cycling performance. This study offers a design principle for achieving a local high-concentration effect with reasonably low bulk concentrations of salts., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This study aimed to investigate the prevalence of foodborne viruses in reservoirs (an important resource of irrigation water) and its correlation with environmental and weather factors. From May 2017 to November 2018, we visited ten reservoirs and a river in the Anseong region of South Korea and collected a total of 192 samples in accordance with the environment protection agency guidelines. We recorded the weather factors (temperature, humidity, and accumulated precipitation) and investigated the surrounding environment factors (livestock, fishing site, the catchment area of reservoirs, etc.). Our research results show that from the river and reservoirs, the detection rates of human norovirus GII, adenovirus, rotavirus, human norovirus GI, and astrovirus were 27.1, 10.4, 10.4, 4.16, and 3.1%, respectively. Their viral load ranged from -1.48 to 1.55 log 10 genome copies/l. However, hepatitis A virus was not detected in any irrigation water sample. Although no sampling was performed in winter, foodborne viruses and male-specific coliphages were frequently found during spring (40.78%) and autumn (39.47%). Interestingly, the significant correlation between the accumulative precipitation and the number of detected norovirus and adenovirus was confirmed by linear regression analysis. Furthermore, when the accumulative precipitation ranged from 20 to 60 mm, it significantly affected the viral load and prevalence. Among the environmental factors, recreational facilities such as fishing sites and bungalow fishing spots were identified as contamination sources by correlation analysis. Our research results confirmed the correlations between environmental contamination factors in the reservoir and weather factors with the prevalence of foodborne viruses in the reservoir. These facilitates the assessment of potential foodborne virus contamination during crop irrigation. In addition, predictive models including environmental and weather factors should be developed for monitoring and controlling the safety of irrigation waters in reservoirs.

Potent nucleos(t)ide analogues and hepatitis B immunoglobulin combinations are recommended after liver transplantation to prevent the recurrence of hepatitis B virus (HBV). Despite its proven efficacy, the renal safety of tenofovir disoproxil fumarate (TDF) has not been well established in liver transplant recipients. We aimed to assess the impacts of TDF and entecavir (ETV) on tubular and glomerular functions. We analysed 206 liver transplant patients treated with TDF (n = 102) or ETV (n = 104) plus hepatitis B immunoglobulin. Serum creatinine, phosphate and uric acid levels were measured. Proximal tubular dysfunction was defined as the presence of hypophosphatemia (<2 mg/dL) and hypouricemia (<2 mg/dL). Glomerular dysfunction was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m 2 accompanied by a ≥25% eGFR decline from baseline. During a median follow-up of 42.5 months, 48 patients developed proximal tubular dysfunction (30.4% and 16.3% in the TDF and ETV groups; P = .017). Serum levels of phosphate and uric acid were significantly lower in the TDF group post-LT. TDF (OR, 2.34; 95% CI, 1.16-4.69; P = .017) and low body mass index (OR, 2.11; 95% CI, 1.06-4.21; P = .034) were independent risk factors for proximal tubular dysfunction. The prevalence of glomerular dysfunction was not significantly different between the two groups (TDF 51.0% and ETV 54.8%; P = .582). TDF significantly increased the risk of proximal tubular dysfunction. Although the effect of TDF on glomerular function was comparable to that of ETV, glomerular dysfunction was common after liver transplant., (© 2020 John Wiley & Sons Ltd.)

Expression of the homeodomain transcription factor HOXB13 has been demonstrated in several malignancies but its role in tumorigenesis remains elusive. We observed high levels of HOXB13 in poorly differentiated pediatric tumors including a highly aggressive childhood neoplasm - malignant rhabdoid tumor. In a xenograft model of rhabdoid tumor, knockout of HOXB13 diminished tumor growth while partial knockdown of HOXB13 promoted differentiation of tumor cells into bone. These results suggest that HOXB13 enhances rhabdoid malignancy by interfering with mesenchymal stem cell differentiation. Consistent with this hypothesis, overexpression of HOXB13 in mesenchymal progenitor cells inhibited adipogenic, myogenic, and osteogenic differentiation. Mechanistically, we demonstrated that HOXB13 binds to super-enhancer regions regulating genes involved in differentiation and tumorigenesis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Regulatory T (Treg) cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non-rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pretransplant, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy-proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL-2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first-week peripheral blood Treg frequency correlates with AR after LT under tacrolimus-based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Aromatic organic compounds can be used as electrode materials in rechargeable batteries and are expected to advance the development of both anode and cathode materials for sodium-ion batteries (SIBs). However, most aromatic organic compounds assessed as anode materials in SIBs to date exhibit significant degradation issues under fast-charge/discharge conditions and unsatisfying long-term cycling performance. Now, a molecular design concept is presented for improving the stability of organic compounds for battery electrodes. The molecular design of the investigated compound, [2.2.2.2]paracyclophane-1,9,17,25-tetraene (PCT), can stabilize the neutral state by local aromaticity and the doubly reduced state by global aromaticity, resulting in an anode material with extraordinarily stable cycling performance and outstanding performance under fast-charge/discharge conditions, demonstrating an exciting new path for the development of electrode materials for SIBs and other types of batteries., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Infection by hepatitis E virus (HEV) via the oral route causes acute hepatitis. Extra-hepatic manifestations of HEV infection may stem from various causes; however, its distribution in organs such as the liver, as well as the mechanisms underlying HEV-induced cell injury, remain unclear. The objective of this study was to determine the chronological distribution of HEV in various tissues of HEV-challenged miniature pigs and to investigate the mechanisms underlying HEV-induced cell death in the pancreas and liver. Virological and serological analyses were performed on blood and faecal samples. Histopathology of the liver and extra-hepatic tissues was analysed. Cell death pathways and immune cell characterisation in inflammatory lesions were analysed using immunohistochemistry. The liver and pancreas displayed inflammation and cellular injury, and a large amount of HEV was observed in the lesions. The liver was infiltrated by T and natural killer cells. HEV was identified in all organs except the heart, and was associated with immune cells. Although the liver and the pancreas strongly expressed TNF-α and TRAIL, TUNEL assay results were negative. RIP3 and pMLKL were expressed in the pancreas. RIP3, but not pMLKL, was expressed in the liver. Pancreatitis induced in HEV-infected miniature pigs is associated with necroptosis.

Background: Living donors are the major source of kidneys in countries with a shortage of deceased donors. Kidney donation after careful donor selection is generally accepted as a safe procedure, but the physiologic consequences after donor nephrectomy are not fully verified. In this study we retrospectively reviewed the renal function of the residual kidney in living donors., Methods: Post-nephrectomy laboratory data of 1,175 living donors (60.7%) from 1,933 living donors who received uninephrectomy from January 1999 to December 2017 at Yonsei University, Severance Hospital, Korea were retrospectively collected. Post-nephrectomy renal function was monitored by the relative ratio of estimated glomerular filtration rate (e-GFR; pre-nephrectomy e-GFR ratio vs. post-nephrectomy e-GFR) that was calculated by the Modification of Diet in Renal Disease formula., Results: During 36.3±37.6 months of mean follow-up, two cases (0.17%, 2/1,175) of renal failure developed. The mean e-GFR decreased to 64.3±14.2 mL/min/1.73 m 2 immediately after nephrectomy from 99.2±19.9 mL/min/1.73 m 2 of the pre-nephrectomy e-GFR. Early decrement of e-GFR was prominent in male and obese donors (body mass index >25 kg/m 2 , P<0.05). The e-GFR ratio increased according to post-nephrectomy duration, and the mean increment degree of e-GFR ratio after nephrectomy calculated by linear regression analysis was 1.94% per year. Unlike the early decrement of e-GFR ratio after nephrectomy, donor factors such as degree of obesity and donor sex did not affect the late increment of e-GFR ratio after nephrectomy (P>0.05)., Conclusions: Our data showed that long-term compensation of the renal function after nephrectomy occurs independently of preoperative donor characteristics., (© 2020 The Korean Society for Transplantation.)

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Human liver CD69 + CD8 + T cells are ~95% CD103 - and ~5% CD103 + . Although CD69 + CD103 + CD8 + T cells show tissue residency and robustly respond to antigens, CD69 + CD103 - CD8 + T cells are not yet well understood., Methods: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α., Results: Human liver CD69 + CD103 - CD8 + T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103 - cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103 + cells exhibited only hepatotropic virus specificity. Although CD103 - cells were weaker effectors on a per cell basis than CD103 + cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69 + CD8 + effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69 + CD103 - CD8 + T cells. In addition, HIF-2α expression in liver CD69 + CD103 - CD8 + T cells was significantly increased in patients with acute hepatitis A or cirrhosis., Conclusions: Liver CD69 + CD103 - CD8 + T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69 + CD103 - CD8 + T cells with HIF-2α upregulation is observed during liver pathology., Lay Summary: The immunologic characteristics and the role of CD69 + CD103 - CD8 + T cells, which are a major population of human liver CD8 + T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease., Competing Interests: Conflict of interest The authors have no conflicting financial interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Several conservative treatment methods, from intrinsic muscle exercises to orthoses, including insoles or specially designed shoes, have been introduced for pediatric flexible flat foot (PFFF). However, the structural effects of a long-term use of medial arch support insole remain unclear because the normal physiological maturation of the medial longitudinal arch cannot be ruled out., Methods: From January 2005 to June 2015, 18 patients (34 feet) in group 1 (continuously insole applied group) and 13 patients (26 feet) in group 2 (untreated group) were enrolled. Medial arch support insole was applied from the age 10-11years to radiographic physeal closure., Results: In group 1, talonavicular coverage angle, lateral talo-1st metatarsal angle, calcaneal pitch angle and medial cuneiform height were significantly changed at final follow-up, although all values were still within the abnormal range. Further, no significant differences were found in any of the increments of the radiographic parameters between group 1 and 2., Conclusions: Radiographic improvements were found in both of medial arch support insole treated or untreated group despite all radiographic values were still within the abnormal range. It was meaningful that the PFFF could be improved somewhat until the physes were closed. And the hindfoot alignment remained unchanged regardless of medial arch support insole application., (Copyright © 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Background: As the practice of dermatology becomes increasingly procedurally based, there is a concordant rise in musculoskeletal injury (MSI) risk. Dermatologic surgeons are most susceptible and, although the majority suffer from MSI, few have received any formal ergonomics training. This stems from a lack of awareness of this troubling trend and a paucity of research and education on the ergonomics of dermatologic surgery., Objective: To highlight pertinent ergonomics principles and strategies from other specialties that could be translated into dermatology, and to synthesize general recommendations aimed at reducing MSI among dermatologic surgeons., Materials and Methods: A comprehensive search of the PubMed and Cochrane Reviews databases from 1975 to 2019 was conducted, using a combination of ergonomics-related search terms, generating 6 publications from the dermatology literature and 58 from the fields of dentistry, medicine, and select surgical subspecialties., Results: This multidisciplinary approach yielded multiple interventions that could be applied directly (i.e., adequate lighting, adjustable operating tables, and surgical seat heights) or indirectly pending further investigation into their feasibility (i.e., video displays of the surgical field to allow neutral head and neck postures)., Conclusion: Although much can be learned from decades of prior ergonomics research from other specialties, considerations that are unique to dermatology remain and must be addressed with specialty-specific research.

The mellitic triimide (MTI) bearing three imide groups on a benzene core with C3 symmetry is proposed as a new building block for organic electrode materials in lithium-ion batteries. MTI was anticipated to deliver a higher theoretical specific capacity of up to 282 mAh g -1 with increased reduction potentials compared with the well-known pyromellitic diimide building block bearing two imide groups because the additional imide group can accept one more electron and provide an electron-withdrawing effect. A model compound, ethyl-substituted mellitic triimide (ETTI), shows three well distinguished and reversible one-electron redox reactions at -0.97, -1.62, and -2.34 V versus Ag/Ag + in 0.1 m tetrabutylammonium hexafluorophosphate electrolyte, but the redox potentials were increased in 2 m lithium bis(trifluoromethanesulfonyl)imide electrolyte: -0.60 V, -0.86 V, and -1.42 V vs. Ag/Ag + . The DFT calculations revealed that the unique C3 symmetric structural design leads to the higher reduction potential of MTI in the Li-based electrolyte by formation of a stable 7-membered ring with a Li ion and the two carbonyl oxygen atoms from the adjacent imide groups. In a Li-ion coin cell, the ETTI electrode delivered a specific capacity of 176 mAh g -1 , corresponding to 81 % of capacity utilization, with three clear voltage plateaus. The higher average discharge voltage (2.41 V vs. Li/Li + ) of ETTI allows it to deliver one of the highest specific energies (421 Wh kg -1 ) among reported diimide-based electrode materials. Finally, its redox mechanism was investigated by ex situ FTIR measurements and DFT calculations., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Brain-machine interfaces (BMIs) can be used to decode brain activity into commands to control external devices. This paper presents the decoding of intuitive upper extremity imagery for multi-directional arm reaching tasks in three-dimensional (3D) environments. We designed and implemented an experimental environment in which electroencephalogram (EEG) signals can be acquired for movement execution and imagery. Fifteen subjects participated in our experiments. We proposed a multi-directional convolution neural network-bidirectional long short-term memory network (MDCBN)-based deep learning framework. The decoding performances for six directions in 3D space were measured by the correlation coefficient (CC) and the normalized root mean square error (NRMSE) between predicted and baseline velocity profiles. The grand-averaged CCs of multi-direction were 0.47 and 0.45 for the execution and imagery sessions, respectively, across all subjects. The NRMSE values were below 0.2 for both sessions. Furthermore, in this study, the proposed MDCBN was evaluated by two online experiments for real-time robotic arm control, and the grand-averaged success rates were approximately 0.60 (±0.14) and 0.43 (±0.09), respectively. Hence, we demonstrate the feasibility of intuitive robotic arm control based on EEG signals for real-world environments.

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.

Implanted bioengineered livers have not exceeded three days of continuous perfusion. Here we show that decellularized whole porcine livers revascularized with human umbilical vein endothelial cells and implanted heterotopically into immunosuppressed pigs whose spleens had been removed can sustain perfusion for up to 15 days. We identified peak glucose consumption rate as a main predictor of the patency of the revascularized bioengineered livers (rBELs). Heterotopic implantation of rBELs into pigs in the absence of anticoagulation therapy led to sustained perfusion for three days, followed by a pronounced immune responses directed against the human endothelial cells. A 10 day steroid-based immunosuppression protocol and a splenectomy at the time of rBEL implantation reduced the immune responses and resulted in continuous perfusion of the rBELs for over two weeks. We also show that the human endothelial cells in the perfused rBELs colonize the liver sinusoids and express sinusoidal endothelial markers similar to those in normal liver tissue. Revascularized liver scaffolds that can maintain blood perfusion at physiological pressures might eventually help to overcome the chronic shortage of transplantable human livers.

Alcoholic liver disease is the most prevalent chronic liver disease. Melatonin is known to control many vital processes. Here, we explored a novel molecular mechanism by which melatonin-induced SIRT1 signaling protects against alcohol-mediated oxidative stress and liver injury. Gene expression profiles and metabolic changes were measured in liver specimens of mice and human subjects. Expression levels of Cb1r, Crbn, Btg2, Yy1, pro-inflammatory cytokines, and Cyp2e1 were significantly enhanced in chronic alcohol-challenged mice and human subjects. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic CYP2E1 protein, and reactive oxygen species (ROS) were elevated in alcohol-fed WT mice but not in Cb1r antagonist-treated, Crbn null, or Yy1-silenced mice. Importantly, alcohol-induced Yy1 and Cyp2e1 expression, ROS amount, and liver injury were markedly diminished by melatonin treatment and the transduction of Sirt1 in mice, whereas this phenomenon was prominently ablated by silencing of Sirt1. Notably, SIRT1 physically interacted with YY1 and attenuated YY1 occupancy on the Cyp2e1 gene promoter. Melatonin-SIRT1 signaling ameliorates alcohol-induced oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway. The manipulation of CRBN-YY1-CYP2E1 signaling network by the melatonin-SIRT1 pathway highlights a novel entry point for treating alcoholic liver disease., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Graft-versus-host disease (GVHD) is rare complication after simultaneous pancreas-kidney transplantation (SPK). Here, we present a rare case of GVHD that developed in a SPK recipient. A 38-year-old female patient with end-stage renal disease due to type 1 diabetes mellitus underwent SPK from a deceased female donor. Four months after transplantation, she was readmitted with fever and abdominal pain and computed tomography revealed a retroperitoneal abscess. While being treated for the retroperitoneal abscess by percutaneous drainage and antibiotics, the patient developed skin rash and diarrhea. A skin biopsy performed at the time showed vacuolization and peri-venular lymphocytic infiltration compatible with GVHD. High-dose steroids resulted in complete remission of GVHD, and the patient was discharged after 2 weeks of treatment. This case demonstrates that early diagnosis of GVHD followed by timely treatment may led to a favorable outcome, and cautions that GVHD can occur in SPK patients., (Copyright: © 2020 The Korean Society for Transplantation.)

Aluminum batteries are of great interest in "beyond-lithium" battery research because of their remarkably high performance in terms of rate capability and cycle life, in addition to the intrinsic advantages of aluminum metal such as its natural abundance and high theoretical capacity of 8056 mAh cm -3 . The electrochemical performance that has been achieved thus far is unusual, as cells usually adopted viscous ionic liquid (IL) electrolytes with bulky complex carrier ions. Herein, we not only demonstrate the excellent rate and cycling performance of phenanthrenequinone (PQ) but also elucidate the origin of this extraordinary performance. Density functional theory (DFT) calculations and experimental analyses jointly revealed that the long-term cyclability of PQ arises from PQ-AlCl 2 complexation, which lessens the effective charge of PQ to mitigate its dissolution into the electrolyte. Moreover, the formation of AlCl 2 + without a separate desolvation step allows fast charge transfer, accelerating the AlCl 2 + insertion process. This work unveils the importance of aluminum coordination chemistry in determining the key electrochemical properties of aluminum batteries and forms the basis of a new research direction for the development of battery systems based on complex ions.

Background: We aimed to evaluate the structural effects of the long-term use of orthoses for pediatric flexible flat foot (PFFF) using an algorithmic approach and a structured critical framework to assess the methodological quality of reported studies., Methods: A comprehensive literature search using five databases, namely MEDLINE, the Cochrane Library, Scopus, the Web of Science, and EMBASE, was performed for pertinent articles published before March 30, 2018. Studies with quantitative data on the effects of the long-term use of orthoses for PFFF were included. The search strategy was adapted as appropriate for all other databases searched considering the differences in indexing terms and search syntax for each database., Results: Randomized controlled trials and prospective cohort studies could not prove the estimated effects of orthoses on the medial longitudinal arch. They revealed that flexible flat feet in young children slowly improved with growth, regardless of the type of footwear used. However, three of four case series studies revealed that positive long-term effects could be achieved using orthoses., Conclusion: There is no strong evidence that the long-term use of orthoses improved the structural problem of PFFF., (Copyright © 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Ischemic white matter injuries underlie cognitive decline in the elderly and vascular dementia. Ischemia in the subcortical white matter is caused by chronic reduction of blood flow due to narrowing of small arterioles. However, it remains unclear how chronic ischemia leads to white matter pathology. We aimed to develop an in vitro model of ischemic white matter injury using organotypic slice cultures. Cultured cerebellar slices preserved fully myelinated white matter tracts that were amenable to chronic hypoxic insult. Prolonged hypoxia caused progressive morphological evidence of axonal degeneration with focal constrictions and swellings. In contrast, myelin sheaths and oligodendrocytes exhibited remarkable resilience to hypoxia. The cytoskeletal degradation of axons was accompanied by mitochondrial shortening and lysosomal activation. Multiple pharmacological manipulations revealed that the AMPA glutamate receptor, calpain proteolysis, and lysosomal proteases were independently implicated in hypoxia-induced axonal degeneration in our model. Thus, our in vitro model would be a novel experimental system to explore molecular mechanisms of ischemic white matter injury. Furthermore, we verified that the in vitro assay could be successfully utilized to screen for molecules that can ameliorate hypoxia/ischemia-induced axonal degeneration., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Biliary complications (strictures and leaks) represent major limitations in living donor liver transplantation. Mesenchymal stem cells (MSCs) are a promising modality to prevent biliary complications because of immunosuppressive and angiogenic properties. Our goal was to evaluate the safety of adipose-derived MSC delivery to biliary anastomoses in a porcine model. Secondary objectives were defining the optimal method of delivery (intraluminal versus extraluminal) and to investigate MSC engraftment, angiogenesis, and fibrosis. Pigs were divided into 3 groups. Animals underwent adipose collection, MSC isolation, and expansion. Two weeks later, animals underwent bile duct transection, reanastomosis, and stent insertion. Group 1 received plastic stents wrapped in unseeded Vicryl mesh. Group 2 received stents wrapped in MSC-seeded mesh. Group 3 received unwrapped stents with the anastomosis immersed in an MSC suspension. Animals were killed 1 month after stent insertion when cholangiograms and biliary tissue were obtained. Serum was collected for liver biochemistries. Tissue was used for hematoxylin-eosin and trichrome staining and immunohistochemistry for MSC markers (CD44 and CD34) and for a marker of neoangiogenesis (CD31). There were no intraoperative complications. One pig died on postoperative day 3 due to acute cholangitis. All others recovered without complications. Cholangiography demonstrated no biliary leaks and minimal luminal narrowing. Surviving animals exhibited no symptoms, abnormal liver biochemistries, or clinically significant biliary stricturing. Group 3 showed significantly greater CD44 and CD34 staining, indicating MSC engraftment. Fibrosis was reduced at the anastomotic site in group 3 based on trichrome stain. CD31 staining of group 3 was more pronounced, supporting enhanced neoangiogenesis. In conclusion, adipose-derived MSCs were safely applied to biliary anastomoses. MSCs were locally engrafted within the bile duct and may have beneficial effects in terms of fibrosis and angiogenesis., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)