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Kiyoung Lee,1,2 Ie Byung Park,1,2 Seung Hee Yu,2 Soo-Kyung Kim,3 So Hun Kim,4 Da Hea Seo,4 Seongbin Hong,4 Ja Young Jeon,5 Dae Jung Kim,5 Soo Wan Kim,6 Cheol Soo Choi,1,2 Dae Ho Lee1,21Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea; 2Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; 3Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea; 4Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea; 5Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea; 6Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of KoreaAim: We aimed to evaluate the clinical utility of blood ketone measurement and to test the performance of the diagnostic criteria for diabetic ketoacidosis (DKA) issued by the American Diabetes Association, the Joint British Diabetes Societies, and the American Association of Clinical Endocrinologists and the American College of Endocrinology.Methods: This retrospective analysis included 278 patients with suspected DKA who were hospitalized at 4 university hospitals and aged ≥16 years with a blood glucose level of >200 mg/dL and a blood ketone level of ≥1.0 mmol/L as well as other biochemical data. The patients were categorized into four subgroups (ketosis, typical DKA, atypical DKA, and DKA + lactic acidosis). Atypical DKA in each analysis was defined by our supplementary criteria if the biochemical data did not meet each set of diagnostic criteria from the aforementioned societies.Results: Blood ketone levels in patients with diabetic ketosis and those with DKA varied widely, 1.05–5.13 mmol/L and 1.02–15.9 mmol/L, respectively. Additionally, there were significant discrepancies between the guidelines in the diagnosis of DKA. Thus, the proportion of patients with atypical DKA ranged from 16.5% to 42.4%. Notably, the in-hospital mortality was comparable between patients with typical and atypical DKA, with a very high mortality in patients with DKA + lactic acidosis (blood lactate >5 mmol/L).Conclusions: Our results showed that considering variable presentations of DKA, blood ketone data need to be interpreted cautiously along with other biochemical data and suggested that a new system is required to better characterize DKA.Keywords: Diabetic ketoacidosis, ketone bodies, diagnosis, lactic acidosis, acid base imbalance

Kyu Hwan Shim,1 Kyeong-Hoon Jeong,2,3 Sun Oh Bae,1 Min O Kang,1 Eun Ho Maeng,4 Cheol Soo Choi,2,3 Yu-Ri Kim,5 John Hulme,1 Eun Kyu Lee,1 Meyoung-Kon Kim,5 Seong Soo A An1 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si, Republic of Korea; 2Korea Mouse Metabolic Phenotyping Center, Lee GilYa Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea; 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; 4Department of Analysis, Korea Testing and Research Institute (KTR), Gimpo, Republic of Korea; 5Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Republic of Korea Abstract: As increasing variants of nanoparticles (NPs) are being used in various products, it has become apparent that size alone can no longer adequately explain the variety of generated toxic profiles. Recent studies with NPs have suggested that various sizes of NPs could determine in vitro toxicity. In an attempt to address concerns regarding neurotoxicity of zinc oxide (ZnO) and silica (SiO2) NPs, these were examined after exposing them via oral, dermal, and intravenous administrations of NPs and their toxicological effects on the brain over a prescribed period of time were assessed. After 28 days of repeated oral administrations of ZnO or SiO2 independently, possibly due to damages to the blood brain barrier (BBB), neurotoxicity, were investigated by Evans blue technique. Next, in order to assess whether ZnO NPs could compromise the BBB, ZnO NPs were intravenously injected on day 0, 7, 14, 21 and 28 no further treatment was administered for 62 days. Deposition of SiO2 in brain from repeated dermal and oral administrations for 90 days were evaluated by transmission electron microscopy coupled with scanning energy-dispersive X-ray spectroscopy. Physiochemical profiles were principally determined on particle size at the beginning of the current toxicity investigations on ZnO and SiO2 NPs. The BBB was found to be intact after independent repeated oral administrations of ZnO or SiO2 NPs for 28 days, suggesting no significant damage. Neuronal death was also not observed after the intravenous administrations of ZnO NPs. After 90 days of repeated dermal and oral administration of SiO2 NPs, no deposition of NPs was observed in hippocampus, striatum, and cerebellum regions using transmission electron microscope analyses. These observations suggest that the BBB was not compromised and was able to block penetration of ZnO and SiO2 NPs, resulting in significant neurotoxic effects. Moreover, absence of SiO2 in three regions of brain after dermal and oral administrations for 90 days suggested that brain was protected from SiO2. No behavior change was observed in all studies, suggesting that 90 days may not be long enough to assess full neurotoxicity of NPs in vivo. Keywords: zinc oxide, silica, BBB, neurotoxicity, penetration, administration

Mohana Marimuthu1, Cheolsoo Park2, Sanghyo Kim1*, Cheol Soo Choi3*1College of Bionanotechnology, Kyungwon University, Seongnam-si, Gyeonggi-do, Republic of Korea; 2Department of Electrical and Electronic Engineering, Imperial College London, London, UK; 3Korea Mouse Metabolic Phenotyping Centre, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Yeonsu-gu, Incheon, Republic of Korea *These authors contributed equally to this work.Abstract: Nonexcitable cell types, fibroblasts of heart muscle or astrocytes, are well known for their spontaneous Ca2+ oscillations. On the other hand, murine fibroblast (L929) cells are known to be deficient in cell–cell adhesive proteins and therefore lack gap junctions for cellular communication. However, these cells exhibit a unique property of collectively synchronized and spontaneous oscillation, as revealed by real-time monitoring of cells cultured on a 250-µm diameter microelectrode for more than 3 days using an electrical cell-substrate impedance-sensing system (ECIS). Live-cell imaging is a widely used technique for oscillation detection, but it has limitations relating to cellular physiological environment maintenance for microscopic analysis and for prolonged periods of study. The present research emphasizes an electrical-sensing technique (ECIS) capable of overcoming the most important issues inherent in live-cell imaging systems for the detection of L929 cellular spontaneous and synchronized oscillation in real-time for longer periods. Possible mechanisms involved in L929 oscillation were elucidated to be periodic extension/contraction of lamellipodia continued as blebbing, which is produced by signals from the actomyosin complex initiated by connexin hemichannel opening and adenosine triphosphate (ATP) release. By applying the connexin hemichannel inhibitor, flufenamic acid, the hindrance of ATP release and calcium transients were analyzed to elucidate this hypothesis.Keywords: murine fibroblast, synchronization, ECIS, connexin 43, blebbing, lamellipodia

Background: a reliable assessment of mandibular invasion is crucial for treatment planning to obtain both radical tumor resection and good functional results. Purpose: to retrospectively compare the diagnostic value of three different imaging methods - computed tomography (CT), magnetic resonance (MR) imaging, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT - and their combined use for detection of mandibular invasion by squamous cell carcinoma (SCC) of the oral cavity. Material and Methods: forty-six patients (39 men and 7 women; mean age, 59.4 years) suspected of having mandibular invasion by SCC of the oral cavity underwent CT, MR, and PET/CT within 2 weeks before surgery. First, each study was reviewed separately for the presence of mandibular invasion by tumors. Then, the value of combined images was assessed based on a confidence rating score for each modality assigned by observers. These results were verified with histopathologic findings. Results: HIstopathologic examination revealed mandibular invasion in 12 of 46 SCCs. The sensitivity, specificity, and accuracy were 41.7%, 100%, and 84.8% for CT; 58.3%, 97.1%, and 87.0% for MR; and 58.3%, 97.1%, and 87.0% for PET/CT, respectively. The comparison of these modalities showed no statistically significant difference among them (P > 0.05). The combination of CT, MR, and PET/CT improved sensitivity (83.3%), without loss of specificity (100%) and accuracy (95.7%), although the difference failed to reach statistical significance (P > 0.05). Conclusion: the combined analysis of CT, MR, and PET/CT can improve sensitivity in the detection of mandibular invasion by SCC of the oral cavity. [ABSTRACT FROM AUTHOR]

Objective: White adipose tissue is a critical regulator of whole-body glucose metabolism. Preadipocyte factor-1 (Pref-1) is a secreted protein that inhibits adipocyte differentiation, both in vitro and in vivo. In this study, we have investigated the effects of Pref-1 overexpression on whole-body glucose homeostasis and its contribution to the development of insulin resistance.Research Design and Methods: To gain insight into the role of Pref-1 on the onset of insulin resistance and type 2 diabetes, we measured body composition and whole-body insulin-stimulated glucose metabolism during a hyperinsulinemic-euglycemic clamp in Pref-1 transgenic and wild-type control mice fed a high-fat diet.Results: Mice overexpressing Pref-1 were resistant to high-fat diet-induced obesity, as reflected by a marked reduction in adipose tissue mass. However, Pref-1-overexpressing mice were severely insulin resistant, mainly because of a reduction in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. The aggravated insulin resistance was associated with impaired insulin signaling and increased diacylglycerol content in skeletal muscle.Conclusions: Mice overexpressing Pref-1 are insulin resistant despite being protected from diet-induced obesity and may provide a new rodent model for the study of lipodystrophic disorders. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The aim of this study was to determine the accuracy and reproducibility of low-dose computed tomography (CT) and magnetic resonance (MR) for abdominal adipose tissue quantification on phantom and human studies. Materials and Methods: An adiposity phantom (with known internal/external oil volumes) was scanned at three different tube voltages (140, 120, and 90 kVp) using a 16-detector row CT scanner and was imaged using a T1-weighted spin echo MR sequence. For human studies, whole-volume coverage of the abdomen was obtained using CT (at 140 and 90 kVp) and T1-weighted spin echo MR imaging from five obese male volunteers (mean age, 40.6 years; mean body mass index, 30.2). The volumes of total, visceral, and subcutaneous adipose tissues (TAT, VAT, and SAT, respectively) were calculated independently by two radiologists for each CT scan and MR imaging using a computer-aided semiautomatic program. Results: The estimated radiation dose could be reduced by approximately 75% with a 90-kVp protocol as compared with the 140-kVp protocol. Phantom studies showed that there was no statistically significant difference between the four methods in estimating the percentage predicted of the true volumes (measurement errors <4% for all methods, P > .05). In human studies, we found no statistically significant difference between the three methods in TAT, VAT, and SAT volumes (P > .05). Inter- and intraobserver reproducibilities of the CT volume estimates using the 90-kVp protocol were better than those obtained from MR imaging (κ > 0.9 versus 0.4–0.5; coefficient of variation < 1% versus 15–22%). Conclusion: Low-dose CT provides accurate and reproducible measurement of abdominal adipose tissue volumes with a relevant dose reduction. [Copyright &y& Elsevier]

A growing number of nonprofit and government agencies have developed interactive databases to help their website visitors and constituents obtain information about past and recent trends in healthcare. The Office on Women's Health of the Department of Health and Human Services has joined this pursuit by launching Quick Health Data Online (QHData), an interactive database providing health statistics that specifically pertain to women. Since its inception, QHData has quickly emerged as the leader in sophisticated and user-friendly interactive databases. What is so remarkable about QHData? This database is capable of generating health statistics by race (i.e., blacks, whites, Asian and Pacific Islanders, Hispanics, and Native Americans), gender, and age. The results can also be produced across different geographic levels-the nation, by region, state, and county; the jurisdiction statuses of the counties can also be identified as a border, frontier, metropolitan, urban, or rural. Users also have the flexibility of presenting the results in tables, bar graphs, and maps or exporting results to other processing or display tools. [ABSTRACT FROM AUTHOR]

Fasting hyperglycemia, a prominent finding in diabetes, is primarily due to increased gluconeogenesis. The transcription factor Foxo1 links insulin signaling to decreased transcription of PEPCK and glucose-6-phosphatase (G6Pase) and provides a possible therapeutic target in insulin-resistant states. Synthetic, optimized antisense oligonucleotides (ASOs) specifically inhibit Foxo1 expression. Here we show the effect of such therapy on insulin resistance in mice with diet-induced obesity (DIO). Reducing Foxo1 mRNA expression with ASO therapy in mouse hepatocytes decreased levels of Foxo1 protein and mRNA expression of PEPCK by 48 +/- 4% and G6Pase by 64 +/- 3%. In mice with DIO and insulin resistance, Foxo1 ASO therapy lowered plasma glucose concentration and the rate of basal endogenous glucose production. In addition, Foxo1 ASO therapy lowered both hepatic triglyceride and diacylglycerol content and improved hepatic insulin sensitivity. Foxo1 ASO also improved adipocyte insulin action. At a tissue-specific level, this manifested as improved insulin-mediated 2-deoxyglucose uptake and suppression of lipolysis. On a whole-body level, the result was improved glucose tolerance after an intraperitoneal glucose load and increased insulin-stimulated whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp. In conclusion, Foxo1 ASO therapy improved both hepatic insulin and peripheral insulin action. Foxo1 is a potential therapeutic target for improving insulin resistance. [ABSTRACT FROM AUTHOR]

Type three secretion system (TTSS)-competent Pseudomonas aeruginosa expressing soluble promiscuous cyclase, exoenzyme Y (ExoY), generates cyclic nucleotides in pulmonary microvascular endothelial cells (PMVECs). Within cells, cyclic nucleotide signals are highly compartmentalized, but these second messengers are also released into the extracellular space. Although agonist stimulation of endogenous adenylyl cyclase (AC) or the presence of ExoY increases cyclic nucleotides, the proportion of the signal that is in the intracellular versus extracellular compartments is unresolved. Furthermore, it is unclear whether P. aeruginosa primary infection or treatment with sterile media supernatants derived from a primary infection alters beta-adrenergic agonist-induced elevations in cAMP in PMVECs. Herein, we determine that PMVECs release cAMP into the extracellular space constitutively, following beta-adrenergic stimulation of endogenous AC, and following infection with P. aeruginosa expressing ExoY. Surprisingly, in PMVECs, only a small proportion of cGMP is detected within the cell at baseline or following P. aeruginosa ExoY infection with a larger proportion of total cGMP being detected extracellularly. Thus, the ability of lung endothelium to generate cyclic nucleotides may be underestimated by examining intracellular cyclic nucleotides alone, since a large portion is delivered into the extracellular compartment. In addition, P. aeruginosa infection or treatment with sterile media supernatants from a primary infection suppresses the beta-adrenergic cAMP response, which is further attenuated by the expression of functional ExoY. These findings reveal an overabundance of extracellular cyclic nucleotides following infection with ExoY expressing TTSS-competent P. aeruginosa . NEW & NOTEWORTHY P. aeruginosa exoenzyme Y (ExoY) infection increases cyclic nucleotides intracellularly, but an overabundance of cAMP and cGMP is also detected in the extracellular space and reveals a greater capacity of pulmonary endothelial cells to generate cAMP and cGMP. P. aeruginosa infection or treatment with sterile media supernatants derived from a primary infection suppresses the β-adrenergic-induced cAMP response in pulmonary endothelial cells, which is exacerbated by the expression of functional ExoY.

Background: Loss of muscle strength and endurance with aging or in various conditions negatively affects quality of life. Resistance exercise training (RET) is the most powerful means to improve muscle mass and strength, but it does not generally lead to improvements in endurance capacity. Free essential amino acids (EAAs) act as precursors and stimuli for synthesis of both mitochondrial and myofibrillar proteins that could potentially confer endurance and strength gains. Thus, we hypothesized that daily consumption of a dietary supplement of nine free EAAs with RET improves endurance in addition to the strength gains by RET., Methods: Male C57BL6J mice (9 weeks old) were assigned to control (CON), EAA, RET (ladder climbing, 3 times a week), or combined treatment of EAA and RET (EAA + RET) groups. Physical functions focusing on strength or endurance were assessed before and after the interventions. Several analyses were performed to gain better insight into the mechanisms by which muscle function was improved. We determined cumulative rates of myofibrillar and mitochondrial protein synthesis using 2 H 2 O labelling and mass spectrometry; assessed ex vivo contractile properties and in vitro mitochondrial function, evaluated neuromuscular junction (NMJ) stability, and assessed implicated molecular singling pathways. Furthermore, whole-body and muscle insulin sensitivity along with glucose metabolism, were evaluated using a hyperinsulinaemic-euglycaemic clamp., Results: EAA + RET increased muscle mass (10%, P < 0.05) and strength (6%, P < 0.05) more than RET alone, due to an enhanced rate of integrated muscle protein synthesis (19%, P < 0.05) with concomitant activation of Akt1/mTORC1 signalling. Muscle quality (muscle strength normalized to mass) was improved by RET (i.e., RET and EAA + RET) compared with sedentary groups (10%, P < 0.05), which was associated with increased AchR cluster size and MuSK activation (P < 0.05). EAA + RET also increased endurance capacity more than RET alone (26%, P < 0.05) by increasing both mitochondrial protein synthesis (53%, P < 0.05) and DRP1 activation (P < 0.05). Maximal respiratory capacity increased (P < 0.05) through activation of the mTORC1-DRP1 signalling axis. These favourable effects were accompanied by an improvement in basal glucose metabolism (i.e., blood glucose concentrations and endogenous glucose production vs. CON, P < 0.05)., Conclusions: Combined treatment with balanced free EAAs and RET may effectively promote endurance capacity as well as muscle strength through increased muscle protein synthesis, improved NMJ stability, and enhanced mitochondrial dynamics via mTORC1-DRP1 axis activation, ultimately leading to improved basal glucose metabolism., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: In recent years, certain body composition measures, assessed by computed tomography (CT), have been found to be associated with chemotherapy toxicities. This review aims to explore available data on the relationship between skeletal muscle and adiposity, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intramuscular and intermuscular adipose tissue and their association with chemotherapy toxicity in non-metastatic colorectal cancer (CRC) patients., Methods: A systematic literature search following PRISMA guidelines was conducted in Medline, Embase, Cochrane and Web of Science, for papers published between 2011 and 2023. The search strategy combined keywords and MESH terms relevant to 'body composition', 'chemotherapy toxicities', and 'non-metastatic colorectal cancer'., Results: Out of 3868 studies identified, six retrospective studies fulfilled the inclusion criteria with 1024 eligible patients. Low skeletal muscle mass was strongly associated with increased incidence of both chemotherapy toxicities and dose-limiting toxicity (DLT). The association of VAT, intramuscular and intermuscular adiposity was heterogeneous and inconclusive. There was no association between SAT and chemotherapy intolerance. No universal definitions or cut-offs for sarcopenia and obesity were noted. All studies utilized 2-dimensional (2D) CT slices for CT body composition assessment with varied selection on the vertebral landmark and inconsistent reporting of tissue-defining Hounsfield unit (HU) measurements., Conclusion: Low skeletal muscle is associated with chemotherapy toxicities in non-metastatic CRC. However, quality evidence on the role of adiposity is limited and heterogeneous. More studies are needed to confirm these associations with an emphasis on a more coherent body composition definition and an approach to its assessment, especially regarding sarcopenia., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Purpose of Review: The transmembrane protein 16A (TMEM16A) Ca 2+ -activated Cl - channel constitutes a key depolarising mechanism in vascular smooth muscle and contractile pericytes, while in endothelial cells the channel is implicated in angiogenesis and in the response to vasoactive stimuli. Here, we offer a critical analysis of recent physiological investigations and consider the potential for targeting TMEM16A channels in vascular disease., Recent Findings: Genetic deletion or pharmacological inhibition of TMEM16A channels in vascular smooth muscle decreases artery tone and lowers systemic blood pressure in rodent models. Inhibition of TMEM16A channels in cerebral cortical pericytes protects against ischemia-induced tissue damage and improves microvascular blood flow in rodent stroke models. In endothelial cells, the TMEM16A channel plays varied roles including modulation of cell division and control of vessel tone through spread of hyperpolarisation to the smooth muscle cells. Genetic studies implicate TMEM16A channels in human disease including systemic and pulmonary hypertension, stroke and Moyamoya disease., Summary: The TMEM16A channel regulates vascular function by controlling artery tone and capillary diameter as well as vessel formation and histology. Preclinical and clinical investigations are highlighting the potential for therapeutic exploitation of the channel in a range of maladaptive states of the (micro)circulation., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Patients who recover from hospital-acquired pneumonia exhibit a high incidence of end-organ dysfunction following hospital discharge, including cognitive deficits. We have previously demonstrated that pneumonia induces the production and release of cytotoxic oligomeric tau from pulmonary endothelial cells, and these tau oligomers can enter the circulation and may be a cause of long-term morbidities. Endothelial-derived oligomeric tau is hyperphosphorylated during infection. The purpose of these studies was to determine whether Ser-214 phosphorylation of tau is a necessary stimulus for generation of cytotoxic tau variants. The results of these studies demonstrate that Ser-214 phosphorylation is critical for the cytotoxic properties of infection-induced oligomeric tau. In the lung, Ser-214 phosphorylated tau contributes to disruption of the alveolar-capillary barrier, resulting in increased permeability. However, in the brain, both the Ser-214 phosphorylated tau and the mutant Ser-214-Ala tau, which cannot be phosphorylated, disrupted hippocampal long-term potentiation suggesting that inhibition of long-term potentiation was relatively insensitive to the phosphorylation status of Ser-214. Nonetheless, phosphorylation of tau is essential to its cytotoxicity since global dephosphorylation of the infection-induced cytotoxic tau variants rescued long-term potentiation. Collectively, these data demonstrate that multiple forms of oligomeric tau are generated during infectious pneumonia, with different forms of oligomeric tau being responsible for dysfunction of distinct end-organs during pneumonia., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

A 4-year-old boy with a known diagnosis of neurofibromatosis 1 (NF1) and a diffusely infiltrative plexiform neurofibroma (PN) of the left orbit was started on selumetinib treatment for progressively worsening amblyopia. The patient first presented with new-onset left ptosis at 11 months old. He subsequently developed refractory anisometropic amblyopia of the left eye, in addition to clinically significant left proptosis and hypoglobus that interfered with glasses wear for his amblyopia treatment. The plexiform neurofibroma was not amenable to surgical resection and selumetinib treatment was initiated 3 years after the initial diagnosis. The patient showed remarkable clinical and radiographic improvement in tumor burden after treatment. Best corrected visual acuity improved from 20/50 to 20/20- in his amblyopic eye. Relative proptosis of the affected eye also improved from 4mm to 2mm on Hertel measurements, which allowed for consistent glasses wear. Adverse effects from the treatment were limited to an acneiform rash, which resolved following dose reduction according to the FDA dosing guidelines., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

In this study, a new digital technique for the analysis of the mechanical aperture and contact area of rock fractures under various normal stresses is proposed. The technique requires point cloud data of the upper and lower fracture surfaces, pressure film image data of the fracture, and normal deformation data of the fracture as input data. Three steps of algorithms were constructed using these input data: (1) a primary matching algorithm that considers the shape of the fracture surfaces; (2) a secondary matching algorithm that uses pressure film images; and (3) a translation algorithm that considers the normal deformation of a fracture. The applicability of the proposed technique was investigated using natural fracture specimens sampled at an underground research facility in Korea. In this process, the technique was validated through a comparison with the empirical equation suggested in a previous study. The proposed technique has the advantage of being able to analyze changes in the mechanical aperture and contact area under various normal stresses without multiple experiments. In addition, the change in the contact area on the fracture surface according to the normal stress can be analyzed in detail.

Atopic dermatitis (AD) is a frequently occurring skin disorder in Asia that substantially impacts the social, financial, and psychological lives of individuals. However, there is uncertainty regarding the psychological instruments for this domain. Hence, this review systematically assessed the existing measurement instruments used, developed, and/or validated for the measurement of psychological outcomes in Asian adult patients with AD as well as the scope of those assessment tools (e.g. validity and reliability). Electronic searches were performed using six databases (inception to February 2020) to identify studies. Thematic analysis of 44 included studies revealed that the commonly employed tools to assess the quality of life were the Dermatology Life Quality Index followed by the Skindex-16 questionnaire, the European Quality of Life-5 Dimensions, and the Quality of Life Hand Eczema Questionnaire. Similarly, the Patient Health Questionnaire, Self-rating depression scale (SDS), and Hospital Anxiety and Depression Scale were frequently employed to assess depressive symptoms. Additionally, symptoms of anxiety were frequently assessed through Interaction Anxiousness Scale and the Spielberger State-Trait Anxiety Inventory. Although a variety of psychological assessment measures have been used in research, data on their reliability and validity is limited. Also, information on the cultural applicability of these instruments is scantier. More research is needed to ascertain the suitability of tools for use in clinical practice.

Uncoupling protein-3 (UCP3) is a mitochondrial transmembrane protein highly expressed in the muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle-specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31 P magnetic resonance spectroscopy (MRS), and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2- 13 C]acetate incorporation into muscle [4- 13 C]-, [3- 13 C]-glutamate, and [4- 13 C]-glutamine by high-resolution 13 C/ 1 H MRS. Using this approach, we found that the overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation., (© 2022 Federation of European Biochemical Societies.)

This study monitored changes in major carotenoids (lutein, ⍺-carotene, and β-carotene), free sugars (fructose, glucose, and sucrose), ascorbic acid, vitamin E, phytosterols (campesterol, stigmasterol, and β-sitosterol), fatty acid composition, total phenol content (TPC), total flavonoid content (TFC), total anthocyanin content, and antioxidant activities (AA); ferric-reducing antioxidant power (FRAP) and 2,2'-azino-bis (3-ethylbenzothiazoline-6sulfonic acid) [ABTS] assays, in the inner and outer root tissues of nine carrot genotypes with orange, white, and purple roots. The results showed a differential accumulation of bioactive compounds and antioxidant activities depending on root tissue and color. Carotenoids, free sugars, and total phytosterol contents were higher in genotypes with orange roots than in other genotypes. Ascorbic acid, TPC, TFC, total anthocyanin, and AA were highest in purple-colored carrots while vitamin E content was higher in white/purple carrots. Root color was highly related to the accumulation of individual carotenoids, vitamin E isomers, and total anthocyanin content most prominently among the analyzed bioactive compounds and AA. Free sugar and carotenoid contents were relatively higher in outer tissues than in inner tissues. Furthermore, ascorbic acid, TPC, TFC, and AA were statistically higher or similar in outer tissues when compared to inner tissues in all genotypes. In contrast, trends in vitamin E and phytosterol content were inconsistent between the inner and outer tissues, depending on the genotype. Although fatty acid composition was affected by both root color and tissue, the results were not significant. Thus, the phytochemical profile and content were highly dependent on root color and tissue in carrot genotypes. This may be useful in the food processing and pharmaceutical industries for the extraction of targeted bioactive compounds.

A global health concern has emerged as a response to the recent SARS-CoV-2 pandemic. The identification and inhibition of drug targets of SARS-CoV-2 is a decisive obligation of scientists. In addition to the cell entry mechanism, SARS-CoV-2 expresses a complicated replication mechanism that provides excellent drug targets. Papain-like protease (PL pro ) and 3-chymotrypsin-like protease (3CL pro ) play a vital role in polyprotein processing, producing functional non-structural proteins essential for viral replication and survival in the host cell. Moreover, PL pro is employed by SARS-CoV-2 for reversing host immune responses. Therefore, if some particular compound has the potential to interfere with the proteolytic activities of 3CL pro and PL pro of SARS-CoV-2, it may be effective as a treatment or prophylaxis for COVID-19, reducing viral load, and reinstating innate immune responses. Thus, the present study aims to inhibit SARS-CoV-2 through 3CL pro and PL pro using marine natural products isolated from marine algae that contain numerous beneficial biological activities. Molecular docking analysis was utilized in the present study for the initial screening of selected natural products depending on their 3CL pro and PL pro structures. Based on this approach, Ishophloroglucin A (IPA), Dieckol, Eckmaxol, and Diphlorethohydroxycarmalol (DPHC) were isolated and used to perform in vitro evaluations. IPA presented remarkable inhibitory activity against interesting drug targets. Moreover, Dieckol, Eckmaxol, and DPHC also expressed significant potential as inhibitors. Finally, the results of the present study confirm the potential of IPA, Dieckol, Eckmaxol, and DPHC as inhibitors of SARS-CoV-2. To the best of our knowledge, this is the first study that assesses the use of marine natural products as a multifactorial approach against 3CL pro and PL pro of SARS-CoV-2.

Background: Papillorenal syndrome is an autosomal dominant disorder associated with mutations in the gene PAX2 and often presents with characteristic and specific optic disc findings, frequently with renal dysplasia. In at least half of cases, an identifiable mutation in the PAX2 gene can be detected. We report the ocular findings in a second case of papillorenal syndrome with the c.350 G > C (p.Arg117Pro) mutation detected within the PAX2 gene., Methods: A case report of papillorenal syndrome due to PAX2 mutation. Complete ophthalmologic examination was performed as well as color fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Genetic testing was performed using a next-generation sequencing with CNV calling (NGS-CNV) panel test containing 55 genes associated with nephrotic syndrome or focal segmental glomerulosclerosis., Results: An 11-year-old boy who presented with hypertension and proteinuria was found to have stage IV chronic kidney disease. Presenting visual acuity was 20/25 in the right eye and 20/20 in the left eye. The fundus exam showed bilateral centrally excavated optic discs with absent central retinal vessels and a compensatory multiplicity of cilioretinal vessels, characteristic and specific for papillorenal syndrome. OCT showed outer retinal atrophy and macular schisis. Genetic testing identified the likely pathogenic c.350 G > C (p.Arg117Pro) mutation in PAX2., Conclusions: We report the first description, to our knowledge, of the clinical presentation, ocular and systemic findings, and ophthalmic imaging in an individual with papillorenal syndrome associated with the PAX2 c.350 G > C (p.Arg117Pro) mutation. Our case adds to the current understanding of papillorenal syndrome and demonstrates that this condition is associated with a pathognomonic optic disc appearance and significant renal disease.

Sodium-hydrogen exchangers (NHEs) tightly regulate intracellular pH (pHi), proliferation, migration and cell volume. Heterogeneity exists between pulmonary endothelial cells derived from different vascular segments, yet the activity and isoform expression of NHEs between these vascular segments has not been fully examined. Utilizing the ammonium-prepulse and recovery from acidification technique in a buffer lacking bicarbonate, pulmonary microvascular and pulmonary artery endothelial cells exhibited unique recovery rates from the acid load dependent upon the concentration of the sodium transport inhibitor, amiloride; further, pulmonary artery endothelial cells required a higher dose of amiloride to inhibit sodium-dependent acid recovery compared to pulmonary microvascular endothelial cells, suggesting a unique complement of NHEs between the different endothelial cell types. While NHE1 has been described in pulmonary endothelial cells, all NHE isoforms have not been accounted for. To address NHE expression in endothelial cells, qPCR was performed. Using a two-gene normalization approach, Sdha and Ywhag were identified for qPCR normalization and analysis of NHE isoforms between pulmonary microvascular and pulmonary artery endothelial cells. NHE1 and NHE8 mRNA were equally expressed between the two cell types, but NHE5 expression was significantly higher in pulmonary microvascular versus pulmonary artery endothelial cells, which was confirmed at the protein level. Thus, pulmonary microvascular and pulmonary artery endothelial cells exhibit unique NHE isoform expression and have a unique response to acid load revealed through recovery from cellular acidification., Competing Interests: The authors have declared that no competing interests exist.

Background: Muscle regeneration includes proliferation and differentiation of muscle satellite cells, which involves the mammalian target of rapamycin (mTOR). We identified the C-terminal unique attached sequence motif (UNE) domain of leucyl-tRNA synthetase (LRS-UNE-L) as an mTORC1 (mTOR complex1)-activating domain that acts through Vps34 and phospholipase D1 (PLD1) when introduced in the form of a muscle-enhancing peptide., Methods: In vitro Vps34 lipid kinase assay, phosphatidylinositol 3-phosphate (PI(3)P) measurement, in vivo PLD1 assay, and western blot assay were performed in HEK293 cells to test the effect of the LRS-UNE-L on the Vps34-PLD1-mTOR pathway. Adeno-associated virus (AAV)-LRS-UNE-L was transduced in C2C12 cells in vitro, in BaCl 2 -injured tibialis anterior (TA) muscles, and in 18-month-old TA muscles to analyse its effect on myogenesis, muscle regeneration, and aged muscle, respectively. The muscle-specific cell-permeable peptide M12 was fused with LRS-UNE-L and tested for cell integration in C2C12 and HEK293 cells using FACS analysis and immunocytochemistry. Finally, M12-LRS-UNE-L was introduced into BaCl 2 -injured TA muscles of 15-week-old Pld1 +/+ or Pld1 -/- mice, and its effect was analysed by measurement of cross-sectional area of regenerating muscle fibres., Results: The LRS-UNE-L expression restored amino acid-induced S6K1 phosphorylation in LRS knockdown cells in a RagD GTPases-independent manner (421%, P = 0.007 vs. LRS knockdown control cells). The LRS-UNE-L domain was directly bound to Vps34; this interaction was accompanied by increases in Vps34 activity (166%, P = 0.0352), PI(3)P levels (146%, P = 0.0039), and PLD1 activity (228%, P = 0.0294) compared with amino acid-treated control cells, but it did not affect autophagic flux. AAV-delivered LRS-UNE-L domain augmented S6K1 phosphorylation (174%, P = 0.0013), mRNA levels of myosin heavy chain (MHC) (122%, P = 0.0282) and insulin-like growth factor 2 (IGF2) (146%, P = 0.008), and myogenic fusion (133%, P = 0.0479) in C2C12 myotubes. AAV-LRS-UNE-L increased the size of regenerating muscle fibres in BaCl 2 -injured TA muscles (124%, P = 0.0279) (n = 9-10), but it did not change the muscle fibre size of TA muscles in old mice. M12-LRS-UNE-L was preferentially delivered into C2C12 cells compared with HEK293 cells and augmented regeneration of BaCl 2 -injured TA muscles in a PLD1-dependent manner (116%, P = 0.0022) (n = 6)., Conclusions: Our results provide compelling evidence that M12-LRS-UNE-L could be a muscle-enhancing protein targeting mTOR., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objective: Maintaining a constant core body temperature is essential to homeothermic vertebrate survival. Adaptive thermogenesis in brown adipose tissue and skeletal muscle is the primary mechanism of adjustment to an external stimulus such as cold exposure. Recently, several reports have revealed that the liver can play a role as a metabolic hub during adaptive thermogenesis. In this study, we suggest that the liver plays a novel role in secreting thermogenic factors in adaptive thermogenesis. Bone morphogenetic protein 9 (BMP9) is a hepatokine that regulates many biological processes, including osteogenesis, chondrogenesis, hematopoiesis, and angiogenesis. Previously, BMP9 was suggested to affect preadipocyte proliferation and differentiation. However, the conditions and mechanisms underlying hepatic expression and secretion and adipose tissue browning of BMP9 remain largely unknown. In this study, we investigated the physiological conditions for secretion and the regulatory mechanism of hepatic Bmp9 expression and the molecular mechanism by which BMP9 induces thermogenic gene program activation in adipose tissue. Here, we also present the pharmacological effects of BMP9 on a high-fat-induced obese mouse model., Methods: To investigate the adaptive thermogenic role of BMP9 in vivo, we challenged mice with cold temperature exposure for 3 weeks and then examined the BMP9 plasma concentration and hepatic expression level. The cellular mechanism of hepatic Bmp9 expression under cold exposure was explored through promoter analysis. To identify the role of BMP9 in the differentiation of brown and beige adipocytes, we treated pluripotent stem cells and inguinal white adipose tissue (iWAT)-derived stromal-vascular (SV) cells with BMP9, and brown adipogenesis was monitored by examining thermogenic gene expression and signaling pathways. Furthermore, to evaluate the effect of BMP9 on diet-induced obesity, changes in body composition and glucose tolerance were analyzed in mice administered recombinant BMP9 (rBMP9) for 8 weeks., Results: Hepatic Bmp9 expression and plasma levels in mice were significantly increased after 3 weeks of cold exposure. Bmp9 mRNA expression in the liver was regulated by transcriptional activation induced by cAMP response-element binding protein (CREB) and CREB-binding protein (CBP) on the Bmp9 promoter. Treatment with BMP9 promoted the differentiation of multipotent stem cells and iWAT-derived SV cells into beige adipocytes, as indicated by the increased expression of brown adipocyte and mitochondrial biogenesis markers. Notably, activation of the mothers against decapentaplegic homolog 1 (Smad1) and p44/p42 mitogen-activated protein kinase (MAPK) pathways was required for the induction of uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) expression in BMP9-induced differentiation of SVs into beige adipocytes. The administration of rBMP9 in vivo also induced browning markers in white adipose tissue. In high-fat diet-induced obese mice, rBMP9 administration conferred protection against obesity and enhanced glucose tolerance., Conclusions: BMP9 is a hepatokine regulated by cold-activated CREB and CBP and enhances glucose and fat metabolism by promoting the activation of the thermogenic gene program in adipocytes. These data implicate BMP9 as a potential pharmacological tool for protecting against obesity and type 2 diabetes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Endothelial dysfunction is a key feature of cardiovascular disease (CVD) including atherosclerosis. Impaired endothelial signaling leads to plaque formation, vascular wall remodeling and widespread cardiovascular dysregulation. The specific changes along the vascular intima associated with atherosclerosis, including the vulnerable circulation downstream of the flow obstruction, remain poorly understood. Previous findings from animal models suggest that preservation of a distinct Ca 2+ signaling profile along the arterial endothelial network is crucial for maintaining vasculature homeostasis and preventing arterial disease. Ca 2+ signaling in the intact human artery intima has not been well characterized. Here, we employed confocal imaging and a custom analysis algorithm to assess the spatially and temporally dynamic Ca 2+ signaling profiles of human peripheral arteries isolated from the amputated legs of patients with advanced CVD (peripheral artery disease and/or diabetes) or patients who had lost limbs due to non-cardiovascular trauma. In all tibial artery branches (0.5-5 mm diameter) assessed, the intima consistently elicited a broad range of basal Ca 2+ signals ranging from isolated focal transients to broad waves. Arteries from patients with existing CVD displayed a restricted intimal Ca 2+ signaling pattern characterized by diminished event amplitude and area. Stimulation of type-4 vanilloid transient receptor potential channels (TRPV4) amplified endothelial Ca 2+ signals; however, these signals remained smaller and spatially confined in arteries from patients with CVD verses those without CVD. Our findings reveal a characteristic underlying basal Ca 2+ signaling pattern within the intima of human peripheral arteries and suggest a distinct truncation of the inherent Ca 2+ profile with CVD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Taylor, Lowery, Choi and Francis.)

The miniaturization of electrochemical energy storage (EES) systems, one of the key challenges facing the rapid expansion of the Internet-of-Things, has been limited by poor performance of the various energy-storage components at the micrometer scale. Here, the development of a unique photopatternable porous separator that overcomes the electrolyte difficulties involving resistive losses at small dimensions is reported. The separator is based on modifying the chemistry of SU-8, an epoxy-derived photoresist, through the addition of a miscible ionic liquid. The ionic liquid serves as a templating agent, which is selectively removed by solution methods, leaving the SU-8 scaffold whose interconnected porosity provides ion transport from the confined liquid electrolyte. The photopatternable separator exhibits good electrochemical, chemical, thermal, and mechanical stability during the operation of electrochemical devices in both 2D and 3D formats. For the latter, the separator demonstrates the ability to form conformal coatings over 3D structures. The development of the photopatternable separator overcomes the electrolyte issues, which have limited progress in the field of micro-EES., (© 2022 Wiley-VCH GmbH.)

Dexamethasone (DEX) induces dysregulation of protein turnover, leading to muscle atrophy and impairment of glucose metabolism. Positive protein balance, i.e., rate of protein synthesis exceeding rate of protein degradation, can be induced by dietary essential amino acids (EAAs). In this study, we investigated the roles of an EAA-enriched diet in the regulation of muscle proteostasis and its impact on glucose metabolism in the DEX-induced muscle atrophy model. Mice were fed normal chow or EAA-enriched chow and were given daily injections of DEX over 10 days. We determined muscle mass and functions using treadmill running and ladder climbing exercises, protein kinetics using the D 2 O labeling method, molecular signaling using immunoblot analysis, and glucose metabolism using a U- 13 C 6 glucose tracer during oral glucose tolerance test (OGTT). The EAA-enriched diet increased muscle mass, strength, and myofibrillar protein synthesis rate, concurrent with improved glucose metabolism (i.e., reduced plasma insulin concentrations and increased insulin sensitivity) during the OGTT. The U- 13 C 6 glucose tracing revealed that the EAA-enriched diet increased glucose uptake and subsequent glycolytic flux. In sum, our results demonstrate a vital role for the EAA-enriched diet in alleviating the DEX-induced muscle atrophy through stimulation of myofibrillar proteins synthesis, which was associated with improved glucose metabolism.

Patients who recover from nosocomial pneumonia oftentimes exhibit long-lasting cognitive impairment comparable with what is observed in Alzheimer's disease patients. We previously hypothesized that the lung endothelium contributes to infection-related neurocognitive dysfunction, because bacteria-exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long-term potentiation in the hippocampus. However, the full-length lung and endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection-induced endothelial cytotoxic tau triggers neuronal tau aggregation. Here, we demonstrate that lung endothelial cells express a big tau isoform and three additional tau isoforms that are similar to neuronal tau, each containing four microtubule-binding repeat domains, and that tau is expressed in lung capillaries in vivo. To test whether infection elicits endothelial tau capable of causing transmissible tau aggregation, the cells were infected with Pseudomonas aeruginosa. The infection-induced tau released from endothelium into the medium-induced neuronal tau aggregation in reporter cells, including reporter cells that express either the four microtubule-binding repeat domains or the full-length tau. Infection-induced release of pathological tau variant(s) from endothelium, and the ability of the endothelial-derived tau to cause neuronal tau aggregation, was abolished in tau knockout cells. After bacterial lung infection, brain homogenates from WT mice, but not from tau knockout mice, initiated tau aggregation. Thus, we conclude that bacterial pneumonia initiates the release of lung endothelial-derived cytotoxic tau, which is capable of propagating a neuronal tauopathy., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.

Rationale: Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions., Objective: Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated., Methods and Results: Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression., Conclusions: This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.

Background: Skeletal muscle as a metabolic consumer determines systemic energy homeostasis by regulating myofibre type conversion and muscle mass control. Perturbation of the skeletal muscle metabolism elevates the risk of a variety of diseases including metabolic disorders. However, the regulatory pathways and molecules are not completely understood. The discovery of relevant responsible molecules and the associated network could be an attractive strategy to overcome diseases associated with muscle problems., Methods: An initial screening using quantitative trait locus analysis enabled us to extract a set of genes including ubiquitin-specific proteases21 (USP21) (r = 0.738; P = 0.004) as potential targets associated with fasting blood glucose content. Given tight regulation of the ubiquitination status of proteins in muscle, we focused on USP21 and generated whole-body (KO) and skeletal muscle-specific USP21 knockout (MKO) mice. Transcriptomics, proteomics, and lipidomics assays in combination with various in vivo and in vitro experiments were performed to understand the functions of USP21 and underlying mechanisms. A high-fat diet (60%)-fed mouse model and diabetic patient-derived samples were utilized to assess the effects of USP21 on energy metabolism in skeletal muscle., Results: USP21 was highly expressed in both human and mouse skeletal muscle, and controlled skeletal muscle oxidative capacity and fuel consumption. USP21-KO or USP21-MKO significantly promoted oxidative fibre type changes (Δ36.6% or Δ47.2%), muscle mass increase (Δ13.8% to Δ22.8%), and energy expenditure through mitochondrial biogenesis, fatty acid oxidation, and UCP2/3 induction (P < 0.05 or P < 0.01). Consistently, cold exposure repressed USP21 expression in mouse skeletal muscle (Δ55.3%), whereas loss of USP21 increased thermogenesis (+1.37°C or +0.84°C; P < 0.01). Mechanistically, USP21 deubiquitinated DNA-PKcs and ACLY, which led to AMPK inhibition. Consequently, USP21 ablation diminished diet-induced obesity (WT vs. USP21-KO, Δ8.02 g, 17.1%, P < 0.01; litter vs. USP21-MKO, Δ3.48 g, 7.7%, P < 0.05) and insulin resistance. These findings were corroborated in a skeletal muscle-specific gene KO mouse model. USP21 was induced in skeletal muscle of a diabetic patient (1.94-fold), which was reciprocally changed to p-AMPK (0.30-fold)., Conclusions: The outcomes of this research provide novel information as to how USP21 in skeletal muscle contributes to systemic energy homeostasis, demonstrating USP21 as a key molecule in the regulation of myofibre type switch, muscle mass control, mitochondrial function, and heat generation and, thus, implicating the potential of this molecule and its downstream substrates network as targets for the treatment and/or prevention of muscle dysfunction and the associated metabolic diseases., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Fucoidans are sulfated heteropolysaccharides found in the cell walls of brown seaweeds (Phaeophyceae) and in some marine invertebrates. Generally, fucoidans are composed of significant amounts of L-fucose and sulfate groups, and lesser amounts of arabinose, galactose, glucose, glucuronic acid, mannose, rhamnose, and xylose. In recent years, fucoidans isolated from brown seaweeds have gained considerable attention owing to their promising bioactive properties such as antioxidant, immunomodulatory, anti-inflammatory, antiobesity, antidiabetic, and anticancer properties. Inflammation is a complex immune response that protects the organs from infection and tissue injury. While controlled inflammatory responses are beneficial to the host, leading to the removal of immunostimulants from the host tissues and restoration of structural and physiological functions in the host tissues, chronic inflammatory responses are often associated with the pathogenesis of tumor development, arthritis, cardiovascular diseases, diabetes, obesity, and neurodegenerative diseases. In this review, the authors mainly discuss the studies since 2016 that have reported anti-inflammatory properties of fucoidans isolated from various brown seaweeds, and their potential as a novel functional material for the treatment of inflammatory diseases.

Background: Several noninvasive tools are available for the assessment of nonalcoholic fatty liver disease (NAFLD) including clinical and blood biomarkers, transient elastography (TE), and magnetic resonance imaging (MRI) techniques, such as proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE). In the present study, we aimed to evaluate whether magnetic resonance (MR)-based examinations better discriminate the pathophysiologic features and fibrosis progression in NAFLD than other noninvasive methods., Methods: A total of 133 subjects (31 healthy volunteers and 102 patients with NAFLD) were subjected to clinical and noninvasive NAFLD evaluation, with additional liver biopsy in some patients (n=54)., Results: MRI-PDFF correlated far better with hepatic fat measured by MR spectroscopy (r=0.978, P<0.001) than with the TE controlled attenuation parameter (CAP) (r=0.727, P<0.001). In addition, MRI-PDFF showed stronger correlations with various pathophysiologic parameters for cellular injury, glucose and lipid metabolism, and inflammation, than the TE-CAP. The MRI-PDFF and TE-CAP cutoff levels associated with abnormal elevation of serum alanine aminotransferase were 9.9% and 270 dB/m, respectively. The MRE liver stiffness measurement (LSM) showed stronger correlations with liver enzymes, platelets, complement component 3, several clinical fibrosis scores, and the enhanced liver fibrosis (ELF) score than the TE-LSM. In an analysis of only biopsied patients, MRE performed better in discriminating advanced fibrosis with a cutoff value of 3.9 kPa than the TE (cutoff 8.1 kPa) and ELF test (cutoff 9.2 kPa)., Conclusion: Our results suggest that MRI-based assessment of NAFLD is the best non-invasive tool that captures the histologic, pathophysiologic and metabolic features of the disease.

Pneumonia causes short- and long-term cognitive dysfunction in a high proportion of patients, although the mechanism(s) responsible for this effect are unknown. Here, we tested the hypothesis that pneumonia-elicited cytotoxic amyloid and tau variants: (1) are present in the circulation during infection; (2) lead to impairment of long-term potentiation; and, (3) inhibit long-term potentiation dependent upon tau. Cytotoxic amyloid and tau species were recovered from the blood and the hippocampus following pneumonia, and they were present in the extracorporeal membrane oxygenation oxygenators of patients with pneumonia, especially in those who died. Introduction of immunopurified blood-borne amyloid and tau into either the airways or the blood of uninfected animals acutely and chronically impaired hippocampal information processing. In contrast, the infection did not impair long-term potentiation in tau knockout mice and the amyloid- and tau-dependent disruption in hippocampal signaling was less severe in tau knockout mice. Moreover, the infection did not elicit cytotoxic amyloid and tau variants in tau knockout mice. Therefore, pneumonia initiates a tauopathy that contributes to cognitive dysfunction., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Red, green, and blue top-emission organic light-emitting diodes (RGB TOLEDs) suffer from white color change with viewing angle due to the microcavity effect, called white angular dependence (WAD). Great efforts are devoted by applying various kinds of hazy films, but they suffer from poor mechanical stability and optical transmittance. Herein, we introduce an air-gap-embedded hazy film (AEHF) to solve these problems and suppress WAD in RGB TOLEDs. The AEHF is designed with optical simulation to realize high haze with transparency. By tuning geometries of the air gap inside the polymer, the AEHF realizes high haze of more than 90% in all RGB colors while maintaining high transparency. To experimentally demonstrate the AEHF, the O 2 plasma is treated on a polymer film with AgCl as an etching mask to fabricate microstructures with high aspect ratios. Afterward, PDMS is coated on the patterned surface; air gaps develop spontaneously in the valleys between microstructures during the coating process. Using these processes, an air gap with 1.2 μm size and 400 nm period is formed inside the film and ∼100% haze is achieved while maintaining a high transmittance of 88%; these results agree well with rigorous coupled wave analysis results. By utilizing the AEHF into TOLEDs, the WAD can be drastically suppressed by 95.2% compared with that of a device without AEHF.

The purpose of this study was to evaluate the structural performance of composite deck slabs containing macro-synthetic fibers. after a fire by proposing a deflection estimation method for non-fireproof structural decks. Therefore, this study evaluated the fire resistance performance and deflection of deck slabs mixed with macro-synthetic fibers. Afterward, the deflection estimation method considering the thermal characteristics of concrete and deck plates was proposed. A material test was first conducted to evaluate the mechanical properties of concrete mixed with macro-synthetic fibers. This test found that the compressive strength and elasticity modulus of concrete mixed with macro-synthetic fibers was greater than that of general concrete. A flexural tensile test confirmed that residual strength was maintained after the maximum strength was achieved. The fire resistance of the deck slab was adequate even when a fire-resistant coating was not applied. The internal temperature was lowest for the specimen with macro-synthetic fibers. Deflection was evaluated using previously published equations and standards. The deflection evaluation confirmed that the temperature distribution should be applied differently in the estimation method that uses the thermal load of the deck slab.

Ink-jet 3D printing technology facilitates the use of various materials of ink on each ink-jet head and simultaneous printing of multiple materials. It is suitable for manufacturing to process a complex multifunctional structure such as sensors and printed circuit boards. In this study, a complex structure of a SiO 2 insulation layer and a conductive Cu layer was fabricated with photo-curable nano SiO 2 ink and Intense Pulsed Light (IPL)-sinterable Cu nano ink using multi-material ink-jet 3D printing technology. A precise photo-cured SiO 2 insulation layer was designed by optimizing the operating conditions and the ink rheological properties, and the resistance of the insulation layer was 2.43 × 10 13 Ω·cm. On the photo-cured SiO 2 insulation layer, a Cu conductive layer was printed by controlling droplet distance. The sintering of the IPL-sinterable nano Cu ink was performed using an IPL sintering process, and electrical and mechanical properties were confirmed according to the annealing temperature and applied voltage. Then, Cu conductive layer was annealed at 100 °C to remove the solvent, and IPL sintered at 700 V. The Cu conductive layer of the complex structure had an electrical property of 29 µΩ·cm and an adhesive property with SiO 2 insulation layer of 5B.

It has been frequently reported that myostatin inhibition increases muscle mass, but decreases muscle quality (i.e., strength/muscle mass). Resistance exercise training (RT) and essential amino acids (EAAs) are potent anabolic stimuli that synergistically increase muscle mass through changes in muscle protein turnover. In addition, EAAs are known to stimulate mitochondrial biogenesis. We have investigated if RT amplifies the anabolic potential of myostatin inhibition while EAAs enhance muscle quality through stimulations of mitochondrial biogenesis and/or muscle protein turnover. Mice were assigned into ACV (myostatin inhibitor), ACV+EAA, ACV+RT, ACV+EAA +RT, or control (CON) over 4 weeks. RT, but not EAA, increased muscle mass above ACV. Despite differences in muscle mass gain, myofibrillar protein synthesis was stimulated similarly in all vs. CON, suggesting a role for changes in protein breakdown in muscle mass gains. There were increases in MyoD expression but decreases in Atrogin-1/MAFbx expression in ACV+EAA, ACV+RT, and ACV+EAA+RT vs. CON. EAA increased muscle quality (e.g., grip strength and maximal carrying load) without corresponding changes in markers of mitochondrial biogenesis and neuromuscular junction stability. In conclusion, RT amplifies muscle mass and strength through changes in muscle protein turnover in conjunction with changes in implicated signaling, while EAAs enhance muscle quality through unknown mechanisms.

TFEB, a key regulator of lysosomal biogenesis and autophagy, is induced not only by nutritional deficiency but also by organelle stress. Here, we find that Tfeb and its downstream genes are upregulated together with lipofuscin accumulation in adipose tissue macrophages (ATMs) of obese mice or humans, suggestive of obesity-associated lysosomal dysfunction/stress in ATMs. Macrophage-specific TFEB-overexpressing mice display complete abrogation of diet-induced obesity, adipose tissue inflammation and insulin resistance, which is independent of autophagy, but dependent on TFEB-induced GDF15 expression. Palmitic acid induces Gdf15 expression through lysosomal Ca 2+ -mediated TFEB nuclear translocation in response to lysosomal stress. In contrast, mice fed a high-fat diet with macrophage-specific Tfeb deletion show aggravated adipose tissue inflammation and insulin resistance, accompanied by reduced GDF15 level. Finally, we observe activation of TFEB-GDF15 in ATMs of obese humans as a consequence of lysosomal stress. These findings highlight the importance of the TFEB-GDF15 axis as a lysosomal stress response in obesity or metabolic syndrome and as a promising therapeutic target for treatment of these conditions.

Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPR mt ) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPR mt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism., Competing Interests: Declaration of interests C.L. is a consultant and shareholder of CohBar, Inc. All other authors declare no competing financial or other interests in relation to this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Type 2 diabetes mellitus may result from insulin resistance in skeletal muscle. Prokineticin receptor 1 (Prokr1) improves metabolic phenotype in adipose tissue and the cardiovascular system; however, its effects on skeletal muscle have not been investigated. We investigated the Prokr1 signaling pathways and its metabolic function in murine myoblast, satellite cells, and their differentiated myotubes. We measured the expression levels of Prokr1 in the skeletal muscle of mice as well as human skeletal muscle cell-derived myotubes. Prokineticin 2 (PROK2), a ligand of PROKR1, induced calcium mobilization in a dose-dependent manner and altered the mRNA levels of 578 genes in PROKR1-overexpressed HEK293T cells. Functional enrichment of differentially expressed genes revealed that PROKR1 activated Gq-mediated PI3K/AKT and MAPK/ERK signaling pathways in skeletal muscle cells. Prokr1 significantly activated the PI3K/AKT signaling pathway in myotubes derived from C2C12 and satellite cells, regardless of the presence or absence of insulin. Prokr1 also promoted the translocation of glucose transporter 4 (GLUT4) into the plasma membrane. In palmitate-induced insulin-resistant myotubes, Prokr1 enhanced insulin-stimulated AKT phosphorylation, GLUT4 translocation, and glucose uptake. mRNA and protein levels of Prokr1 were significantly decreased in skeletal muscle and white adipose tissue of diet-induced obese mice, and the amount of PROKR1 protein was significantly decreased in human skeletal muscle cell-derived myotubes under insulin resistance conditions. Taken together, these results demonstrate that Prokr1 plays an important role in insulin sensitivity and is a potential therapeutic target to ameliorate insulin resistance in skeletal muscle., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)