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Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Hyung Cho1, Assumpta Madu11Department of Ophthalmology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USAAbstract: Cystoid macular edema in its various forms can be considered one of the leading causes of central vision loss in the developed world. It occurs in a wide variety of pathologic conditions and represents the final common pathway of several basic processes. Therapeutic approaches to cystoid macular edema depend on a clear understanding of its contributing pathophysiologic mechanisms. This review will discuss the mechanism of ocular inflammation in cystoid macular edema with a particular focus on the inflammatory causes: post-operative, uveitic, and after laser procedures. A variety of pharmacologic agents targeting inflammatory molecules have been shown to reduce macular edema and improve visual function. However, the long-term efficacy and safety of most new therapies have yet to be established in controlled clinical trials.Keywords: ocular inflammation, cystoid macular edema, uveitis

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes, from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys have begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here, we used a combination of approaches-including neuroimaging assays of threat anticipation and emotional-face perception and more than 10,000 momentary assessments of emotional experience-to demonstrate that individuals who showed greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experienced lower levels of stressor-dependent distress in their daily lives (ns = 202-208 university students). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world.

Photoinduced nonequilibrium phase transitions have stimulated interest in the dynamic interactions between electrons and crystalline ions, which have long been overlooked within the Born–Oppenheimer approximation. Ultrafast melting before lattice thermalization prompted researchers to revisit this issue to understand ultrafast photoinduced weakening of the crystal bonding. However, the absence of direct evidence demonstrating the role of orbital dynamics in lattice disorder leaves it elusive. By performing time-resolved resonant X-ray scattering with an X-ray free-electron laser, we directly monitored the ultrafast dynamics of bonding orbitals of Ge to drive photoinduced melting. Increased photoexcitation of bonding electrons amplifies the orbital disturbance to expedite the lattice disorder approaching the sub-picosecond scale of the nonthermal regime. The lattice disorder time shows strong nonlinear dependence on the laser fluence with a crossover behavior from thermal-driven to nonthermal-dominant kinetics, which is also verified by ab initio and two-temperature molecular dynamics simulations. This study elucidates the impact of bonding orbitals on lattice stability with a unifying interpretation on photoinduced melting.

When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.

Electrostatic discharge (ESD) testing for human body model tests is an essential part of the reliability evaluation of electronic/electrical devices and components. However, global environmental concerns have called for the need to replace the mercury-wetted relay switches, which have been used in ESD testers. Therefore, herein, we propose an ESD tester using metal oxide semiconductor-controlled thyristor (MCT) devices with a significantly higher rising rate of anode current (di/dt) characteristics. These MCTs, which have a breakdown voltage beyond 3000 V, were developed through an in-house foundry. As a replacement for the existing mercury relays, the proposed ESD tester with the developed MCT satisfies all the requirements stipulated in the JS-001 standard for conditions at or below 2000 V. Moreover, unlike traditional relays, the proposed ESD tester does not generate resonance; therefore, no additional circuitry is required for resonant removal. To the best of our knowledge, the proposed ESD tester is the first study to meet the JS-001 specification by applying a new switch instead of an existing mercury-wetted relay.

Abstract Background Certain routine medication could result in post-induction hypotension (PIH), such as angiotensin axis blockades, which are frequently administered as a first-line therapy against hypertension. Remimazolam is reportedly associated with lesser intraoperative hypotension than propofol. This study compared the overall incidence of PIH following remimazolam or propofol administration in patients managed by angiotensin axis blockades. Methods This single-blind, parallel-group, randomized control trial was conducted in a tertiary university hospital in South Korea. Patients undergoing surgery with general anesthesia were considered for enrollment if the inclusion criteria were met: administration of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, 19 to 65 years old, American Society of Anesthesiologists physical status classification ≤ III, and no involvement in other clinical trials. The primary outcome was the overall incidence of PIH, defined as a mean blood pressure (MBP)

Abstract Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract

Abstract The primary cilium, an antenna-like structure on the cell surface, acts as a mechanical and chemical sensory organelle. Primary cilia play critical roles in sensing the extracellular environment to coordinate various developmental and homeostatic signaling pathways. Here, we showed that the depletion of heat shock protein family A member 9 (HSPA9)/mortalin stimulates primary ciliogenesis in SH-SY5Y cells. The downregulation of HSPA9 enhances mitochondrial stress by increasing mitochondrial fragmentation and mitochondrial reactive oxygen species (mtROS) generation. Notably, the inhibition of either mtROS production or mitochondrial fission significantly suppressed the increase in primary ciliogenesis in HSPA9-depleted cells. In addition, enhanced primary ciliogenesis contributed to cell survival by activating AKT in SH-SY5Y cells. The abrogation of ciliogenesis through the depletion of IFT88 potentiated neurotoxicity in HSPA9-knockdown cells. Furthermore, both caspase-3 activation and cell death were increased by MK-2206, an AKT inhibitor, in HSPA9-depleted cells. Taken together, our results suggest that enhanced primary ciliogenesis plays an important role in preventing neurotoxicity caused by the loss of HSPA9 in SH-SY5Y cells.

Abstract Background Orthotopic liver transplantation is the only option for patients with end-stage liver disease and hepatocellular carcinoma. Post-transplant immunosuppressive therapy is important to prevent graft failure. We investigated the effectiveness of tacrolimus (FK506) and their mechanisms for liver transplant immune tolerance in an outbred rat LT model. Results To investigate the therapeutic effect of the FK506 on outbred rat LT model, FK506 and postoperative therapy were administered subcutaneously once or twice daily to transplanted rats. Histopathological and immunohistochemical analyses were conducted for all groups. The regulation of inflammatory cytokine signaling in the spleen was analyzed by flow cytometry. FK506 attenuated allograft rejection and increased survival in rat orthotopic liver transplantation models. The FK506-treated group had reduced serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Furthermore, FK506 decreased the expression of inflammatory cytokines and the activation of pathogenic Th1 and Th17 cells in the liver. Conclusions Taken together, we revealed that FK506 ameliorated strong allograft rejection in outbred liver transplantation model by anti-inflammatory effect and inhibitory peroperty of pathogenic T cells.

Sepsis: chemical modulation of selective autophagy alleviates systemic inflammation Sepsis is a life-threatening condition that occurs when the body’s response to infection damages its own organs. Autophagy protects the body by degrading harmful materials in the cell using the lysosome. It has been an outstanding question whether autophagy can fight systemic inflammation in sepsis. Researchers in South Korea led by Eun-Kyeong Jo at Chungnam National University and Yong Tae Kwon at Seoul National University developed small molecule chemicals that target the autophagic receptor p62/SQSTSM-1/Sequestosome-1 to induce therapeutic efficacy during septic responses. In a mouse model of septic shock, these orally administrative compounds halted the production of proinflammatory molecules and reduced oxidative stress in mitochondria by facilitating the autophagic turnover of damaged mitochondria. Chemical modulation of p62 is now emerging as a therapeutic strategy to treat sepsis responsible for 11 million deaths a year.

Abstract Background Primaquine is activated by CYP2D6 in the hepatocytes. In Korea, primaquine is the only hypnozoitocidal agent used for patients with vivax malaria. Thus, patients with poor CYP2D6 activity could have an increased risk of primaquine failure and subsequent relapse. The study sought to identify the association between CYP2D6 phenotype and recurrence of malaria in Korean patients. Methods A total of 102 patients with vivax malaria were prospectively enrolled from eight institutions in Korea. An additional 38 blood samples from patients with recurred vivax malaria were provided by the Korea Disease Control and Prevention Agency. Malaria recurrence was defined as more than one episode of vivax malaria in the same or consecutive years. CYP2D6 star alleles, phenotypes, and activity scores were examined. Results Genotyping for CYP2D6 was successful in 101 of the prospectively enrolled patients and 38 samples from the Korea Disease Control and Prevention Agency, of which 91 were included in the no-recurrence group and 48 were included in the recurrence group. Reduced CYP2D6 activity (intermediate metabolizer) phenotype was more common in the recurrence group than in the no-recurrence group (OR, 2.33 (95% CI, 1.14–4.77); p = 0.02). Patients with lower CYP2D6 activity had a higher probability of recurrence (p = 0.029). Conclusion This study suggests that CYP2D6 polymorphism may affect primaquine efficacy and thus Plasmodium vivax recurrence in Korea.

Abstract Background Osteoarthritis (OA) is the most common type of degenerative arthritis and affects the entire joint, causing pain, joint inflammation, and cartilage damage. Various risk factors are implicated in causing OA, and in recent years, a lot of research and interest have been directed toward chronic low-grade inflammation in OA. Monocyte chemoattractant protein-1 (MCP-1; also called CCL2) acts through C–C chemokine receptor type 2 (CCR2) in monocytes and is a chemotactic factor of monocytes that plays an important role in the initiation of inflammation. The targeting of CCL2–CCR2 is being studied as part of various topics including the treatment of OA. Methods In this study, we evaluated the potential therapeutic effects the sCCR2 E3 gene may exert on OA. The effects of sCCR2 E3 were investigated in animal experiments consisting of intra-articular injection of sCCR2 E3 in a monosodium iodoacetate (MIA)-induced OA rat model. The effects after intra-articular injection of sCCR2 E3 (fusion protein encoding 20 amino acids of the E3 domain of the CCL2 receptor) in a monosodium iodoacetate-induced OA rat model were compared to those in rats treated with empty vector (mock treatment) and full-length sCCR2. Results Pain improved with expression of the sCCR2 gene. Improved bone resorption upon sCCR2 E3 gene activation was confirmed via bone analyses using micro-computed tomography. Histologic analyses showed that the sCCR2 E3 gene exerted protective effects against cartilage damage and anti-inflammatory effects on joints and the intestine. Conclusions These results show that sCCR2 E3 therapy is effective in reducing pain severity, inhibiting cartilage destruction, and suppressing intestinal damage and inflammation. Thus, sCCR2 E3 may be a potential therapy for OA.

The desulfurization behavior of 316L stainless steel (STS316L) melt with the CaO-SiO2-CaF2-Al2O3-MgO slag was investigated with different CaO/SiO2 (=C/S) ratio and CaF2 content at 1873 K. As the C/S ratio increased, the sulfide capacity increased, whereas the sulfide capacity of the high C/S (=1.7) slag was not affected by CaF2 content. The overall mass transfer coefficient (kO) increased with C/S ratio, but was constant above a critical C/S value, and it was also constant across varied CaF2 content at relatively high C/S (=1.7) condition. Since the metal condition of the present study was constant, the change in kO was caused by slag phase mass transfer coefficient (ks) and sulfur distribution ratio (LS), which were affected by the physicochemical properties of the slag. Since desulfurization reaction requires consideration of both kinetic and thermodynamic factors, the ‘logCS2−−logη’ (where CS2− is sulfide capacity and η is viscosity), was proposed as a meaningful physicochemical parameter. If the slag basicity is relatively high, at which the kO is equivalent regardless of slag compositions, the desulfurization reaction is controlled by metal phase mass transfer. However, if the slag basicity becomes lower, at which the kO significantly decreases, the desulfurization reaction is assumed to be controlled by slag phase mass transfer and/or mixed controlled process.

ObjectiveThe COVID-19 pandemic has caused a decrease in the number of blood donors worldwide, posing a global problem. Therefore, this study investigates people who have continuously participated in blood donation during the COVID-19 pandemic and collects basic information as a reference for maintaining stable amounts of blood during future pandemics.MethodsThe participants of this study were selected from the population of South Korea through stratified sampling considering region and age distributions. Owing to the COVID-19 pandemic, the participants were recruited online through Embrain, an online research and survey company, from June 1 to June 28, 2021. Data were collected from a total of 1,043 participants and used in the study.ResultsThe results of this study showed that there was a difference between the donors group and non-donors group in factors such as donation attitude (F = 73.342, p < 0.001), donation knowledge (F = 6.530, p < 0.01), and preventive health behavior (F = 12.352, p < 0.001). Overall, blood donors showed favorable attitude toward and considerable knowledge of blood donation as well as a high level of preventive health behavior. The environment most preferred by people who participated in blood donation during the COVID-19 pandemic was “going with family to a blood donation center that gives out free gifts in a region far away with no confirmed cases,” which showed the highest utility (utility = 0.734).ConclusionEven during pandemics, donation attitude, donation knowledge, and preventive health behavior can serve as key factors affecting participation in blood donation. Additionally, blood donation centers that donors can visit with their families represent a favorable environment for the promotion of blood donation during pandemics.

Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

We theoretically evaluate the performance of spurious-tone suppression of a multi-loop optoelectronic oscillators (MOEO) based on closed-loop analysis. Spurious tones are unwanted oscillation signals due to the cavity effect of long-length optical fiber and the severe drawbacks of optoelectronic oscillator (OEO). The spurious tones can be suppressed using the MOEO configuration with two controllable loop parameters of length and power ratios between multiple loops. We propose the method of closed-loop analysis to accurately extract the loop parameters and to increase spurious-tone suppression ratio (SSR). We successfully evaluated the MOEO performances with various loop-power ratios and achieved an SSR of 86 dB with a phase noise of −115 dBc/Hz at 10 kHz offset for a triple-loop OEO configuration by extracting the optimum power ratio of 0.332:0.131:0.537.

This study aimed to document the functional microbiome affecting immune homeostasis in long-term post-liver transplantation (LT) patients. We compared the frequency of regulatory T (Treg) and T helper 17 (Th17) cells in the blood and fecal microbiome of 27 LT patients to matched healthy controls (n = 20) using flow cytometry and 16S rRNA sequencing. Among the 27 LT patients, 22 patients ingested immunosuppressants (long-term post-LT group) and five were tolerant patients. The changes in Treg and Th17 cell proportion after treatment with distinct microbiomes in the long-term post-LT group were also examined in vitro . Changes in the identified functional microbiome and Treg cells in tolerant patients were evaluated. The mean time after LT of the included patients was 13.2 y. The gut microbiome of the long-term post-LT group showed lower alpha-diversity (P

Osteoarthritis (OA) reduces the quality of life as a result of the pain caused by continuous joint destruction. Inactivated Lactobacillus (LA-1) ameliorated osteoarthritis and protected cartilage by modulating inflammation. In this study, we evaluated the mechanism by which live LA-1 ameliorated OA. To investigate the effect of live LA-1 on OA progression, we administered LA-1 into monosodium iodoacetate (MIA)-induced OA animals. The pain threshold, cartilage damage, and inflammation of the joint synovial membrane were improved by live LA-1. Furthermore, the analysis of intestinal tissues and feces in the disease model has been shown to affect the systems of the intestinal system and improve the microbiome environment. Interestingly, inflammation of the intestinal tissue was reduced, and the intestinal microbiome was altered by live LA-1. Live LA-1 administration led to an increase in the level of Faecalibacterium which is a short-chain fatty acid (SCFA) butyrate-producing bacteria. The daily supply of butyrate, a bacterial SCFA, showed a tendency to decrease necroptosis, a type of abnormal cell death, by inducing autophagy and reversing impaired autophagy by the inflammatory environment. These results suggest that OA is modulated by changes in the gut microbiome, suggesting that activation of autophagy can reduce aberrant cell death. In summary, live LA-1 or butyrate ameliorates OA progression by modulating the gut environment and autophagic flux. Our findings suggest the regulation of the gut microenvironment as a therapeutic target for OA.

The Elongator complex in eukaryotes has conserved tRNA modification functions and contributes to various physiological processes such as transcriptional control, DNA replication and repair, and chromatin accessibility. ARABIDOPSIS ELONGATOR PROTEIN 4 (AtELP4) is one of the six subunits (AtELP1–AtELP6) in Arabidopsis Elongator. In addition, there is an Elongator-associated protein, DEFORMED ROOTS AND LEAVES 1 (DRL1), whose homolog in yeast (Kti12) binds tRNAs. In this study, we explored the functions of AtELP4 in plant-specific aspects such as leaf morphogenesis and evolutionarily conserved ones between yeast and Arabidopsis. ELP4 comparison between yeast and Arabidopsis revealed that plant ELP4 possesses not only a highly conserved P-loop ATPase domain but also unknown plant-specific motifs. ELP4 function is partially conserved between Arabidopsis and yeast in the growth sensitivity toward caffeine and elevated cultivation temperature. Either single Atelp4 or drl1-102 mutants and double Atelp4 drl1-102 mutants exhibited a reduction in cell proliferation and changed the adaxial–abaxial polarity of leaves. In addition, the single Atelp4 and double Atelp4 drl1-102 mutants showed remarkable downward curling at the whole part of leaf blades in contrast to wild-type leaf blades. Furthermore, our genetic study revealed that AtELP4 might epistatically act on DRL1 in the regulation of cell proliferation and dorsoventral polarity in leaves. Taken together, we suggest that AtELP4 as part of the plant Elongator complex may act upstream of a regulatory pathway for adaxial–abaxial polarity and cell proliferation during leaf development.

Abstract Background Furosemide, a diuretic that acts on the loop of Henle, is commonly used to treat congestive heart failure in veterinary medicine. Some owners have difficulty in administering oral tablet medication to animal patients, which leads to noncompliance, especially during long-term administration. Oral disintegrating film (ODF) has the advantages of easy administration via a non-invasive route, rapid dissolution, and low suffocating risk. The objective of this study was to research the pharmacokinetic (PK) profiles and diuretic effect of furosemide after intravenous (IV), orally uncoated tablet (OUT), and newly developed ODF administration in healthy beagle dogs. In this study, a furosemide-loaded ODF (FS-ODF) formulation was developed and five beagle dogs were administered a single dose (2 mg/kg) of furosemide via each route using a cross-over design. Results The most suitable film-forming agent was sodium alginate; thus, this was used to develop an ODF for easy drug administration. No significant differences were detected in the PK profiles between OUT and FS-ODF. In the blood profiles, the concentration of total protein was significantly increased compared to the baseline (0 h), whereas no significant difference was detected in the concentration of creatinine and hematocrit compared to the baseline. FS-ODF resulted in a similar hourly urinary output to OUT during the initial 2 h after administration. The urine specific gravity was significantly decreased compared to the baseline in each group. The peak times of urine electrolyte (sodium and chloride) excretion per hour were 1 h (IV), 2 h (OUT), and 2 h (FS-ODF). Conclusions These results suggest that the PK/PD of furosemide after administration of newly developed FS-ODF are similar to those of OUT in healthy dogs. Therefore, the ODF formulation has the benefits of ease and convenience, which would be helpful to owners of companion animals, such as small dogs (

Summary: Background: Pseudomyxoma peritonei (PMP) is a rare disease characterized by mucinous ascites and deposits on the peritoneal surfaces. The study aimed to assess PMP patients according to the Peritoneal Surface Oncology Group International (PSOGI) classification, as a part of standardization of this rare disease. Methods: This retrospective study analyzed PMP patients who underwent surgery between January 2007 and December 2017. All histologic slides were re-evaluated and the clinical data were collected. According to the PSOGI, PMP was retrospectively classified into three categories: low-grade (LG-PMP), high-grade (HG-PMP), and signet-ring cells (SRC-PMP). The extent of peritoneal involvement was quantified by the peritoneal cancer index (PCI). The completeness of cytoreduction (CCR) was dichotomized as complete or incomplete. Results: Fifty-seven patients were included in this study, consisted of 39 patients with LG-PMP (74.0%), 14 with HG-PMP (20.8%), and 4 with SRC-PMP (5.2%). There was no operative mortality and major complications occurred in 24 patients (31.2%). The 5-year overall survival was 56.2% ± 8.1% for LG-PMP, 37.5% ± 12.1% for HG-PMP, and 25.0% ± 21.7% for SRC-PMP. Concerning CCR, the 5-year overall (complete: 59.5% ± 8.4% vs. incomplete: 12.7% ± 8.1%, p = 0.001) and disease-free survival (complete: 38.6% ± 8.9% vs. incomplete: 7.7% ± 6.8%, p = 0.001) were significantly different. In a multivariable analysis, PSOGI classification and CCR independently correlated with survival (p = 0.011 and 0.018, respectively). Conclusions: The PSOGI classification provides prognostic stratification, hopefully requiring further validation including every single case of PMP established as a standard criteria.

Background/Aims The aim of this in vivo animal study was to evaluate the effectiveness and safety of dedicated cold snare (DCS) compared with those of traditional snare (TS) for cold snare polypectomy (CSP). Methods A total of 36 diminutive (5 mm) and 36 small (9 mm) pseudolesions were made by electrocoagulation in the colons of mini-pigs. Results For the diminutive lesions, there were no significant differences in technical success rate, procedure time, or complete resection rate between the DCS and TS groups; the rate of uneven resection margin in the DCS group was significantly lower than that of the TS group. For small lesions, technical success rate and complete resection rate were significantly higher in the DCS group than in the TS group (100% [18/18] vs. 55.6% [10/18], p=0.003; 94.4% [17/18] vs. 40% [4/10], p=0.006). In addition, the procedure duration was significantly shorter, and the rate of uneven resection margin was significantly lower in the DCS group (28.5 sec vs. 66.0 sec, p=0.006; 11.1% [2/18] vs. 100% [10/10], p

The stimulation of autophagy or lysosomes has been considered therapeutic for neurodegenerative disorders because the accumulation of misfolded proteins is commonly observed in the brains of individuals with these diseases. Although zinc is known to play critical roles in the functions of lysosomes and autophagy, the mechanism behind this regulatory relationship remains unclear. Therefore, in this study, we examined which mechanism is involved in zinc-mediated activation of autophagy and lysosome. Exposure to zinc at a sub-lethal concentration activated autophagy in a concentration-dependent manner in mRFP-GFP-LC3-expressing H4 glioma cells. Zinc also rescued the blocking of autophagic flux arrested by pharmaceutical de-acidification. Co-treatment with zinc attenuated the chloroquine (CQ)-induced increase in the number and size of mRFP-GFP-LC3 puncta in H4 cells and accumulation of p62 by CQ or ammonium chloride in both H4 and mouse cerebrocortical cultures. Zinc rapidly induced the expression of cathepsin B (CTSB) and cathepsin D (CTSD), representative lysosomal proteases in neurons, which appeared likely to be mediated by transcription factor EB (TFEB). We observed the translocation of TFEB from neurite to nucleus and the dephosphorylation of TFEB by zinc. The addition of cycloheximide, a chemical inhibitor of protein synthesis, inhibited the activity of CTSB and CTSD at 8 h after zinc exposure but not at 1 h, indicating that only late lysosomal activation was dependent on the synthesis of CTSB and CTSD proteins. At the very early time point, the activation of cathepsins was mediated by an increased assembly of V-ATPase on lysosomes and resultant lysosomal acidification. Finally, considering that P301L mutation in tau protein causes frontotemporal dementia through aggressive tau accumulation, we investigated whether zinc reduces the accumulation of protein aggregates in SK-N-BE(2)-C neuroblastoma cells expressing wild-type tau or mutant P301L-tau. Zinc markedly attenuated the levels of phosphorylated tau and total tau as well as p62 in both wild-type and mutant tau-overexpressing cells. We also observed that zinc was more effective than rapamycin at inducing TFEB-dependent CTSB and CTSD expression and V-ATPase-dependent lysosomal acidification and CTSB/CTSD activation. These results suggest that the regulation of zinc homeostasis could be a new approach for developing treatments for neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes spinal inflammation and fusion. Although the cause of AS is unknown, genetic factors (e.g., HLA-B27) and environmental factors (e.g., sex, age, and infection) increase the risk of AS. Current treatments for AS are to improve symptoms and suppress disease progression. There is no way to completely cure it. High blood cholesterol and lipid levels aggravate the symptoms of autoimmune diseases. We applied hyperlipidemia drugs ezetimibe and rosuvastatin to AS mice and to PBMCs from AS patients. Ezetimibe and rosuvastatin was administered for 11 weeks to AS model mice on the SKG background. Then, the tissues and cells of mice were performed using flow cytometry, computed tomography, immunohistochemistry, and immunofluorescence. Also, the normal mouse splenocytes were cultured in Th17 differentiation conditions for in vitro analysis such as flow cytometry, ELISA and RNA sequencing. The 10 AS patients’ PBMCs were treated with ezetimibe and rosuvastatin. The patients’ PBMC were analyzed by flow cytometry and ELISA for investigation of immune cell type modification. Ezetimibe caused substantial inhibition for AS. The present study showed that ezetimibe inhibits Th17 cell function, thereby slowing the progression of AS. It is well known that statins are more effective in reducing blood lipid concentrations than ezetimibe, however, our results that ezetimibe had a better anti-inflammatory effect than rosuvastatin in AS. This data suggests that ezetimibe has an independent anti-inflammatory effect independent of blood lipid reduction. To investigate whether ezetimibe has its anti-inflammatory effect through which signaling pathway, various in vitro experiments and RNA sequencing have proceeded. Here, this study suggests that ezetimibe can be an effective treatment for AS patients by inhibiting Th17 differentiation-related genes such as IL-23R and IL-1R. Thus, this study suggests that ezetimibe has therapeutic potential for AS through inhibition of Th17 differentiation and the production of pro-inflammatory cytokines.

Abstract Background Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantation with transplanted donor T cell-mediated inflammatory response; it is characterized by a severe immune response with fibrosis in the final stage of the inflammatory process. T helper 17 cells play a critical role in the pathogenesis of GvHD. Fingolimod (FTY720), an analogue of sphingosine-1-phosphate (S1P), is an effective immunosuppressive agent in experimental transplantation models. Methods In this study, we evaluated the effects of FTY720 as a treatment for an animal GvHD model with inflammation and fibrosis. The splenocytes, lymph nodes, blood, tissues from Syngeneic mice and GvHD-induced mice treated vehicle or FTY720 were compared using flow cytometry, hematological analyses, histologic analyses. Results FTY720 reduced clinical scores based on the following five clinical parameters: weight loss, posture, activity, fur texture, and skin integrity. FACS data showed that T lymphocyte numbers increased in mesenteric lymph nodes and decreased in splenocytes of FTY720-treated mice. Tissue analysis showed that FTY720 reduced skin, intestinal inflammation, and fibrotic markers. FTY720 dramatically decreased α-smooth muscle actin, connective tissue growth factor, and fibronectin protein levels in keloid skin fibroblasts. Conclusions Thus, FTY720 suppressed migration of pathogenic T cells to target organs, reducing inflammation. FTY720 also inhibited fibrogenesis marker expression in vitro and in vivo. Together, these results suggest that FTY720 prevents GvHD progression via immunosuppression of TH17 and simultaneously acts an anti-fibrotic agent.

Purpose The purpose of this study was to find out the physical characteristics of Wushu athletes by comparing the differences on the results of physical fitness between the male athletes of the Wushu national team Taolu and the Sanda group. Methods Measurement of basic and professional fitness based on muscle function, targeting 37 men Wushu national team players (24 taolu, 13 Sanda) in the selection and evaluation contests twice in 2018 and 2019. Body composition, isometric muscle strength, flexibility and equilibrium, anaerobic power, and isokinetic muscle strength. The fitness factors were divided into two groups, Taolu and Sanda. Results First, body fat rate of the Sanda athlete group was significantly lower than that of the taolu athlete group (p

Keloid is an abnormal fibrotic disease after cutaneous injury characterized by exaggerated scar tissue formation, which often extends beyond the boundaries of the original wound. Although chronic inflammation is known to be associated with the excessive inflammation in keloid tissue, there are few studies on the role of autophagy in the pathogenesis of keloid. In this study, we evaluated the pattern of autophagy in keloid fibroblasts (KF) and normal fibroblasts (NF). Expression of HIF-1α, STAT3 and autophagic flux markers were evaluated in KF and NF. Defective autophagy caused by IL-17 was evaluated, and the relationship between defective autophagy and necroptosis was also examined. The expression of IL-17, HIF-1α and STAT3 was significantly increased in keloid tissue, and autophagosome-to autophagolysosome conversion was defective in KF. IL-17 treatment significantly elevated the expression of STAT3 and HIF-1α in NF and caused defective autophagy, which was reversed by HIF-1α inhibitor. In addition, the defective autophagy was associated with the increased necroptosis and fibrosis. In keloid tissue, the elevated necroptosis marker was confirmed, and with the HIF-1α inhibitor, the defective autophagy, necroptosis and fibrosis was decreased in KF. In conclusion, autophagy was defective in keloid tissue, which was associated with increased necroptosis and fibrosis. The IL-17-STAT3-HIF-1α axis was involved in defective autophagy in KF, and this suggests that targeting the axis could alleviate chronic inflammation in keloid disease.

Smart card data are widely used in generating the origin and destination (O-D) matrix for public transit, which contains important information for transportation planning and operation. However, the generation of the O-D matrix is limited by the smart card data information that includes the boarding (origin) information without the alighting (destination) information. To solve this problem, trip chain methods have been proposed, thereby greatly contributing in estimating the destination using the smart card data. Nevertheless, unlinked trips, that is, trips with unknown destinations, are a persisting issue. The purpose of this study is to develop a method for estimating the destination of unlinked trips, in which trip chain methods cannot be applied, using temporal travel patterns and historical boarding records of the passengers based on long-term smart card data. The passengers were clustered by k-means clustering, and the time-of-day travel patterns were estimated for each cluster using a Gaussian mixture model. The travel patterns were formulated to estimate the destination of the passengers from the smart card data. The proposed method was verified using the 2018 smart card data collected in Sejong City, South Korea. The existing trip chain method matched the destinations of 60.0% of the total trips, whereas the proposed method improved the matching to 74.9% by additionally matching the destinations of 37.2% of the unlinked trips.