Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway.

Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes.

Uncovering risk factors for adverse events and infections in rheumatoid arthritis and rheumatoid arthritis with interstitial lung disease under treatment with biologics or targeted synthetic DMARDs: insights from the KOBIO Registry.

OBJECTIVES: This study aimed to identify the risk factors associated with overall adverse events (AEs) and infections in patients with rheumatoid arthritis (RA) and comorbid interstitial lung disease (ILD), receiving biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs), using data from the Korean College of Rheumatology Biologics registry. METHODS: We analysed data from a cohort of 2,266 adult patients with RA who received b/tsDMARDs, including 169 patients with comorbid ILD. We identified the risk factors for overall AEs and infections in both the all RA group and the subgroup of patients with RA-ILD and investigated the impact of infections on mortality in patients with RA-ILD. RESULTS: Among all patients with RA, 45.7% withdrew b/tsDMARDs, whereas among those with RA-ILD, a higher proportion of 57.4% withdrew their treatment regimen. The main reason for withdrawing b/tsDMARDs in the RA-ILD group was AEs, with infections accounting for the largest proportion of reported AEs. In multivariable analysis of the risk factors for overall AEs and infections in the RA-ILD group, older age was identified as a risk factor for overall AEs (odds ratio [OR], 3.01; p=0.014), and only a current smoking status was identified as a risk factor for infections (OR, 2.11; p=0.035). CONCLUSIONS: Patients with RA-ILD exhibited a higher rate of b/tsDMARDs withdrawal due to overall AEs and infections than those with RA without ILD. In the RA-ILD group, older age was identified as a risk factor for overall AEs, whereas a current smoking status was identified as a risk factor for infections.

GOLPH3 bridges phosphatidylinositol-4- phosphate and actomyosin to stretch and shape the Golgi to promote budding.

Golgi membranes, from yeast to humans, are uniquely enriched in phosphatidylinositol-4-phosphate (PtdIns(4)P), although the role of this lipid remains poorly understood. Using a proteomic lipid-binding screen, we identify the Golgi protein GOLPH3 (also called GPP34, GMx33, MIDAS, or yeast Vps74p) as a PtdIns(4)P-binding protein that depends on PtdIns(4)P for its Golgi localization. We further show that GOLPH3 binds the unconventional myosin MYO18A, thus connecting the Golgi to F-actin. We demonstrate that this linkage is necessary for normal Golgi trafficking and morphology. The evidence suggests that GOLPH3 binds to PtdIns(4)P-rich trans-Golgi membranes and MYO18A conveying a tensile force required for efficient tubule and vesicle formation. Consequently, this tensile force stretches the Golgi into the extended ribbon observed by fluorescence microscopy and the familiar flattened form observed by electron microscopy.

Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia.

Mycobacterium tuberculosis (Mtb) infection is difficult to treat because Mtb spends the majority of its life cycle in a nonreplicating (NR) state. Since NR Mtb is highly tolerant to antibiotic effects and can mutate to become drug resistant (DR), our conventional tuberculosis (TB) treatment is not effective. Thus, a novel strategy to kill NR Mtb is required. Accumulating evidence has shown that repetitive exposure to sublethal doses of antibiotics enhances the level of drug tolerance, implying that NR Mtb is formed by adaptive metabolic remodeling. As such, metabolic modulation strategies to block the metabolic remodeling needed to form NR Mtb have emerged as new therapeutic options. Here, we modeled in vitro NR Mtb using hypoxia, applied isotope metabolomics, and revealed that phosphoenolpyruvate (PEP) is nearly completely depleted in NR Mtb. This near loss of PEP reduces PEP-carbon flux toward multiple pathways essential for replication and drug sensitivity. Inversely, supplementing with PEP restored the carbon flux and the activities of the foregoing pathways, resulting in growth and heightened drug susceptibility of NR Mtb, which ultimately prevented the development of DR. Taken together, PEP depletion in NR Mtb is associated with the acquisition of drug tolerance and subsequent emergence of DR, demonstrating that PEP treatment is a possible metabolic modulation strategy to resensitize NR Mtb to conventional TB treatment and prevent the emergence of DR.

Glycemic Control and Oral Health Outcomes in Patients With Diabetes: Insights From a Nationwide Korean Survey.

BACKGROUND: Diabetes is recognized as a risk factor for various inflammatory conditions, including periodontitis. There exists a bidirectional relationship between glycemic control and oral health in individuals with diabetes. This study aimed to analyze the link between glycemic control and oral health status among Korean patients with diabetes. METHODS: Using data from a population-based nationwide survey conducted between 2007 and 2019, we identified 70,554 adults with diabetes-related information. The study population included 9,090 individuals diagnosed with diabetes and 61,164 healthy controls. The association between glycemic control, defined by mean glycated hemoglobin (HbA1c) values, and various oral health measures, such as tooth brushing frequency, periodontitis, denture wearing, Decayed, Missing, and Filled Teeth (DMFT) index, number of remaining teeth, and past-year dental clinic visits, was evaluated using multivariate logistic regression analyses. RESULTS: Compared to the control group, patients with diabetes exhibited a higher prevalence of periodontitis (88.6% vs. 73.3%), complete dentures (5.0% vs. 1.5%), and elevated DMFT index (33.2% vs. 26.7%) (all P < 0.001). Multivariate analyses revealed significant associations between diabetes and several oral health factors: denture status (No denture: adjusted odds ratio [aOR], 0.784; 95% confidence interval [CI], 0.627-0.979), and having fewer permanent teeth (0-19) (aOR, 1.474; 95% CI, 1.085-2.003). Additionally, a positive correlation was found between higher HbA1c levels and the risk of having fewer remaining teeth (0-19) (HbA1c < 6.5%: aOR, 1.129; 95% CI, 0.766-1.663; 6.5% ≤ HbA1c < 8.0%: aOR, 1.590; 95% CI, 1.117-2.262; HbA1c ≥ 8%: aOR, 1.910; 95% CI, 1.145-3.186) (P for trends = 0.041). CONCLUSION: We found a positive association between diabetes and poor oral health, as well as a noteworthy relationship between reduced permanent teeth (≤ 19) and glycemic control. These insights emphasize the critical role of oral health management in diabetic care and underscore the importance of maintaining effective glycemic control strategies for overall health and well-being in patients with diabetes.

Longitudinal Patterns of Strengths Among Youth with Psychiatric Disorders: A Latent Profile Transition Analysis.

A better understanding of variability in the strengths of youth with psychiatric disorders is critical as a strength-based approach can lead to recovery. This study aimed to identify subgroups of strengths among youth with mental disorders and determine whether subgroups changes were associated with mental health recovery. Youth with mental disorders (N = 2228) from a statewide database were identified in the state fiscal year of 2019. Using the latent profile analysis and latent transition analysis, we identified three strength profiles (i.e., essential, usable, and buildable). Over 90% of youth sustained or developed strengths over time. Positive transitions were associated with mental health recovery, symptom reduction, and personal recovery. Buildable strengths supported youth's personal recovery independent of improving mental health needs. The findings suggest that subgroups of strengths may be a promising source for planning and tracking youth's progress and guiding clinicians to more efficiently allocate community-based resources.

Engagement in a Preventive Intervention for Preadolescent Children in Foster Care: Considerations for Intervention Design.

Engagement in mental health-focused preventive interventions is understudied. Demographic, child, and system-level predictors of engagement were explored in a study with children in foster care (N = 222, Mage = 10.3) who participated in a 30-week intervention. Attendance and engagement in mentor visits and skills groups were rated weekly. Only 4 of 21 predictors showed bivariate associations with attendance/engagement: child sex, IQ, behavior problems, and trauma symptoms. SEM models with these three variables and a measure of adverse childhood experience (ACEs), were used to develop a model of engagement. Males had poorer mentor visit and group engagement. Group attendance was positively associated with trauma symptoms and negatively associated with ACEs. Group engagement was associated with higher IQ and fewer behavior problems. A contextually-sensitive intervention can result in high engagement for a vulnerable and diverse population, yet a few child factors still impacted engagement, and when identified could be ameliorated.Trial Registration ClinicalTrials.gov, Identifiers: NCT00809315 & NCT00810056.

Chronic Obstructive Pulmonary Disease is Associated with a More Symptomatic Burden and Severe Presentation of COVID-19: A Korean National COVID-19 Cohort Study.

Insufficient data are available on comprehensive evaluation of demographics, symptoms or signs, laboratory findings, and disease course in patients with coronavirus disease 2019 (COVID-19) and chronic obstructive pulmonary disease (COPD). We aimed to evaluate whether COPD patients are more prone to severe COVID-19 compared with those without COPD. We also investigate the clinical characteristics and disease course of COVID-19 in patients with COPD versus those without COPD. Patients were selected from a Korean nationwide cohort of 5,628 patients with confirmed COVID-19 and who had completed treatment or quarantine by April 30, 2020; 3,673 patients aged 40 years or older were included in this study. COPD was diagnosed using patient reports of physician-diagnosed COPD. During the study period, all patients with COVID-19 in Korea were hospitalized following the national health policy. Of the study participants, 38 (1.0%) had COPD. Regarding initial symptoms, COPD patients with COVID-19 showed greater sputum production (50.0% vs. 29.8%, p < 0.01) and dyspnea (36.8% vs. 14.9%, p < 0.01) than those without COPD. In addition, patients with COPD were more likely to receive oxygen therapy or non-invasive ventilation (29.0% vs. 13.7%, p = 0.01) and had a higher mortality (21.1% vs. 6.4%, p < 0.01) than those without COPD. After adjusting for age, sex, body mass index, and comorbidities, COPD patients showed increased risk of severe COVID-19 compared with those without COPD. Our nationwide study showed that COVID-19 patients with COPD have higher symptomatic burden and more severe disease course than those without COPD.

Discovery of GSK3ß Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation.

Direct inhibitors of glycogen synthase kinase 3ß (GSK3ß) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3ß enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3ß enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.

Mentoring Children in Foster Care: Examining Relationship Histories as Moderators of Intervention Impact on Children's Mental Health and Trauma Symptoms.

Mentoring-based interventions show promise among children in foster care, but previous research suggests that some benefit more than others. Because children in foster care experience relationship disruptions that could affect mentoring effectiveness, we examined whether children's relational histories at baseline (i.e., relationship quality with birth parents, relationship quality with foster parents, caregiver instability, and previous mentoring experience) moderated the impact of a mentoring intervention on children's mental health, trauma symptoms, and quality of life. Participants included 426 racially and ethnically diverse children (age: 9-11; 52% male) who participated in a randomized controlled trial of the Fostering Healthy Futures program (FHF), a 9-month one-to-one mentoring and skills group intervention. Results showed that relationship quality with foster parents and prior mentoring experience did not moderate intervention impact. Relationship quality with birth parents and caregiver instability pre-program, however, moderated the effect on some outcomes. The impact on quality of life was stronger for children with weaker birth parent relationships and fewer caregiver changes. Likewise, the impact on trauma symptoms was stronger for those with fewer caregiver changes. Overall, FHF seems to positively impact children with varied relational histories, yet some may derive more benefits - particularly those with fewer caregiver changes pre-program.

International psychological research addressing the early phase of the COVID-19 pandemic: A rapid scoping review and implications for global psychology.

In March 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. Given that keeping abreast of international perspectives and research results is of particular importance for such massive global emergencies, we employed a scoping review methodology to rapidly map the field of international psychological research addressing this important early phase of the pandemic. We included a total of 79 studies, with data mostly collected between March and June 2020. This review aimed to systematically identify and map the nature and scope of international studies examining psychological aspects of the unfolding COVID-19 pandemic. We mapped key research themes, subfields of psychology, the nature and extent of international research collaboration, data methods employed, and challenges and enablers faced by psychological researchers in the early stages of the pandemic. Among the wide range of themes covered, mental health and social behaviours were the key themes. Most studies were in clinical/health psychology and social psychology. Network analyses revealed how authors collaborated and to what extent the studies were international. Europe and the United States were often at the centre of international collaboration. The predominant study design was cross-sectional and online with quantitative analyses. We also summarised author reported critical challenges and enablers for international psychological research during the COVID pandemic, and conclude with implications for the field of psychology.

Endoplasmic Reticulum Homeostasis and Stress Responses in Caenorhabditis elegans.

The unfolded protein response (UPR) is an evolutionarily conserved adaptive regulatory pathway that alleviates protein-folding defects in the endoplasmic reticulum (ER). Physiological demands, environmental perturbations and pathological conditions can cause accumulation of unfolded proteins in the ER and the stress signal is transmitted to the nucleus to turn on a series of genes to respond the challenge. In metazoan, the UPR pathways consisted of IRE1/XBP1, PEK-1 and ATF6, which function in parallel and downstream transcriptional activation triggers the proteostasis networks consisting of molecular chaperones, protein degradation machinery and other stress response pathways ((Labbadia J, Morimoto RI, F1000Prime Rep 6:7, 2014); (Shen X, Ellis RE, Lee K, Annu Rev Biochem 28:893-903, 2014)). The integrated responses act on to resolve the ER stress by increasing protein folding capacity, attenuating ER-loading translation, activating ER-associated proteasomal degradation (ERAD), and regulating IRE1-dependent decay of mRNA (RIDD). Therefore, the effective UPR to internal and external causes is linked to the multiple pathophysiological conditions such as aging, immunity, and neurodegenerative diseases. Recent development in the research of the UPR includes cell-nonautonomous features of the UPR, interplay between the UPR and other stress response pathways, unconventional UPR inducers, and noncanonical UPR independent of the three major branches, originated from multiple cellular and molecular machineries in addition to ER. Caenorhabditis elegans model system has critically contributed to these unprecedented aspects of the ER UPR and broadens the possible therapeutic targets to treat the ER-stress associated human disorders and time-dependent physiological deterioration of aging.

Short-term therapy with anti-ICAM-1 monoclonal antibody induced long-term liver allograft survival in nonhuman primates.

Tolerance induction remains challenging following liver transplantation and the long-term use of immunosuppressants, especially calcineurin inhibitors, leads to serious complications. We aimed to test an alternative immunosuppressant, a chimeric anti-ICAM-1 monoclonal antibody, MD-3, for improving the outcomes of liver transplantation. We used a rhesus macaque liver transplantation model and monkeys were divided into three groups: no immunosuppression (n = 2), conventional immunosuppression (n = 4), and MD-3 (n = 5). Without immunosuppression, liver allografts failed within a week by acute rejection. Sixteen-week-long conventional immunosuppression that consisted of prednisolone, tacrolimus, and an mTOR inhibitor prolonged liver allograft survival; however, recipients died of acute T cell-mediated rejection (day 52), chronic rejection (days 62 and 66), or adverse effects of mTOR inhibitor (day 32). In contrast, 12-week-long MD-3 therapy with transient conventional immunosuppression in the MD-3 group significantly prolonged the survival of liver allograft recipients (5, 96, 216, 412, 730 days; p = .0483). MD-3 effectively suppressed intragraft inflammatory cell infiltration, anti-donor T cell responses, and donor-specific antibody with intact anti-cytomegalovirus antibody responses. However, this regimen ended in chronic rejection. In conclusion, short-term therapy with MD-3 markedly improved liver allograft survival to 2 years without maintenance of immunosuppressant. MD-3 is therefore a promising immune-modulating agent for liver transplantation.

Interstitial lung disease increases susceptibility to and severity of COVID-19.

BACKGROUND: There are limited data regarding the relationship between interstitial lung disease (ILD) and the natural course of COVID-19. In this study, we investigate whether patients with ILD are more susceptible to COVID-19 than those without ILD and evaluate the impact of ILD on disease severity in patients with COVID-19. METHODS: A nationwide cohort of patients with COVID-19 (n=8070) and a 1:15 age-, sex- and residential area-matched cohort (n=121 050) were constructed between 1 January 2020 and 30 May 2020 in Korea. We performed a nested case-control study to compare the proportions of patients with ILD between the COVID-19 cohort and the matched cohort. Using the COVID-19 cohort, we also evaluated the risk of severe COVID-19 in patients with ILD versus those without ILD. RESULTS: The proportion of patients with ILD was significantly higher in the COVID-19 cohort than in the matched cohort (0.8% versus 0.4%; p<0.001). The odds of having ILD was significantly higher in the COVID-19 cohort than in the matched cohort (adjusted OR 2.02, 95% CI 1.54-2.61). Among patients in the COVID-19 cohort, patients with ILD were more likely to have severe COVID-19 than patients without ILD (47.8% versus 12.6%), including mortality (13.4% versus 2.8%) (all p<0.001). The risk of severe COVID-19 was significantly higher in patients with ILD than in those without ILD (adjusted OR 2.23, 95% CI 1.24-4.01). CONCLUSION: The risks of COVID-19 and severe presentation were significantly higher in patients with ILD than in those without ILD.

Allosteric Inhibition of the Tumor-Promoting Interaction Between Exon 2-Depleted Splice Variant of Aminoacyl-Transfer RNA Synthetase-Interacting Multifunctional Protein 2 and Heat Shock Protein 70.

Although protein-protein interactions (PPIs) have emerged as an attractive therapeutic target space, the identification of chemicals that effectively inhibit PPIs remains challenging. Here, we identified through library screening a chemical probe (compound 1) that can inhibit the tumor-promoting interaction between the oncogenic factor exon 2-depleted splice variant of aminoacyl-transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2-DX2) and heat shock protein 70 (HSP70). We found that compound 1 binds to the N-terminal subdomain of glutathione S-transferase (GST-N) of AIMP2-DX2, causing a direct steric clash with HSP70 and an intramolecular interaction between the N-terminal flexible region and the GST-N of AIMP2-DX2, which induces masking of the HSP70 binding region during molecular dynamics and mutation studies. Compound 1 thus interferes with the AIMP2-DX2 and HSP70 interaction and suppresses the growth of cancer cells that express high levels of AIMP2-DX2 in vitro and in preliminary in vivo experiment. This work provides an example showing that allosteric conformational changes induced by chemicals can be a way to control pathologic PPIs. SIGNIFICANCE STATEMENT: Compound 1 is a promising protein-protein interaction inhibitor between AIMP2-DX2 and HSP70 for cancer therapy by the mechanism with allosteric modulation as well as competitive binding. It seems to induce allosteric conformational change of AIMP2-DX2 proteins and direct binding clash between AIMP2-DX2 and HSP70. The compound reduced the level of AIMP2-DX2 in ubiquitin-dependent manner via suppression of binding between AIMP2-DX2 and HSP70 and suppressed the growth of cancer cells highly expressing AIMP2-DX2 in vitro and in preliminary in vivo experiment.

Effectiveness and safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in elderly patients with rheumatoid arthritis: real-world data from the KOBIO Registry.

OBJECTIVES: We aimed to evaluate the clinical outcomes and safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and to identify predictors of treatment responses to b/tsDMARDs in elderly patients with rheumatoid arthritis (RA). METHODS: Data from the nationwide cohort of elderly (≥ 65 years) patients enrolled in the KOBIO Registry were analysed. Clinical outcomes were assessed, including changes in the Simplified Disease Activity Index, after treatment. Adverse events and reasons for drug discontinuation were assessed. Multivariable logistic regression analyses were performed to determine which baseline variables affected treatment responses and adverse events (AE). RESULTS: Elderly patients treated with b/tsDMARDs (n=355) or conventional synthetic DMARDs (csDMARDs) (n=104) were included. The median age was 70 years and 77% were female. After 1 year, 63% of patients in the b/tsDMARD group and 68% in the csDMARD group achieved remission or low disease activity (LDA). Overall, 27% of patients in the b/tsDMARDs group and 24% in the csDMARDs group experienced AE. A total of 43.4% of patients on b/tsDMARDs discontinued therapy due to lack of effectiveness (27%), AE (34%), or other reasons (35%). The estimated median retention of b/tsDMARDs was 2.5 years. Male sex and non-exposure to tobacco at baseline were independent factors associated with achieving remission or LDA after 1 year. Interstitial lung disease (ILD) was the most prominent comorbidity associated with AE. CONCLUSIONS: Treatment with b/tsDMARDs is effective and well tolerated in elderly patients with RA; nonetheless, ILD is a key comorbidity that should be monitored carefully.

A Conversion Crosswalk for the UCLA PTSD Reaction Index: Translating DSM-IV to DSM-5.

The use of patient-reported measures in assessing mental health symptoms is common in both the research and clinical fields. With regard to assessing posttraumatic stress symptoms, there are specific versions of measures designed for child and adolescent populations in accordance with the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV and DSM-5, respectively). Different clinical thresholds, numbers of items, and score ranges may present obstacles for clinicians and researchers attempting to compare self-report ratings across different versions of a measure. The current study aimed to produce a score conversion crosswalk between two child/adolescent self-report measures of posttraumatic stress disorder (PTSD): the UCLA PTSD Reaction Index for DSM-IV (RI-IV) and DSM-5 (RI-5). Using item response theory (IRT), we calibrated both measures separately to derive scaled scores. The discrimination parameters ranged from 0.57 to 2.08 (SE = 0.09-0.17) for RI-IV and from 0.73 to 2.11 for RI-5 (SE = 0.07-0.13). The scaled scores were connected with equipercentile linking. Total scores based on common items between the two measures were used as anchors to enhance the linking results. A total of 1,486 children and adolescents completed the measure: 571 respondents filled out the RI-IV and 915 respondents filled out the RI-5. The results allow linked scores to be compared to establish recommended clinical cutoffs and help elucidate the implications of changes in the diagnostic criteria for the measurement of self-reported PTSD symptoms in children and adolescents.

Granulocyte Colony-Stimulating Factor Attenuates Renal Ischemia-Reperfusion Injury by Inducing Myeloid-Derived Suppressor Cells.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) can increase populations of myeloid-derived suppressor cells, innate immune suppressors that play an immunoregulatory role in antitumor immunity. However, the roles of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury remain unclear. METHODS: We used mouse models of ischemia-reperfusion injury to investigate whether G-CSF can attenuate renal injury by increasing infiltration of myeloid-derived suppressor cells into kidney tissue. RESULTS: G-CSF treatment before ischemia-reperfusion injury subsequently attenuated acute renal dysfunction, tissue injury, and tubular apoptosis. Additionally, G-CSF treatment suppressed renal infiltration of macrophages and T cells as well as renal levels of IL-6, MCP-1, IL-12, TNF-α, and IFN-γ, but it increased levels of IL-10, arginase-1, and reactive oxygen species. Moreover, administering G-CSF after ischemia-reperfusion injury improved the recovery of renal function and attenuated renal fibrosis on day 28. G-CSF treatment increased renal infiltration of myeloid-derived suppressor cells (F4/80-CD11b+Gr-1int), especially the granulocytic myeloid-derived suppressor cell population (CD11b+Ly6GintLy6Clow); splenic F4/80-CD11b+Gr-1+ cells sorted from G-CSF-treated mice displayed higher levels of arginase-1, IL-10, and reactive oxygen species relative to those from control mice. Furthermore, these splenic cells effectively suppressed in vitro T cell activation mainly through arginase-1 and reactive oxygen species, and their adoptive transfer attenuated renal injury. Combined treatment with anti-Gr-1 and G-CSF showed better renoprotective effects than G-CSF alone, whereas preferential depletion of myeloid-derived suppressor cells by pep-G3 or gemcitabine abrogated the beneficial effects of G-CSF against renal injury. CONCLUSIONS: G-CSF induced renal myeloid-derived suppressor cells, thereby attenuating acute renal injury and chronic renal fibrosis after ischemia-reperfusion injury. These results suggest therapeutic potential of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury.

Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae, including drug-resistant strains.

New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617™ (19F), ATCC BAA-1663™ (15B), and ATCC 700904™ (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo[3,2,1-ij]quinolone and pyrido[3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d (IC50 = 0.92, 0.75, and 0.77 µM), 7d (IC50 = 0.57, 0.66, and 0.38 µM) and 12a (IC50 = 0.27, 1.03, and 0.62 µM) showed submicromolar IC50 values against 19F, 15B, and 19A, respectively, and thus serve as a starting point for further optimization. While some of compounds in this series exhibited acceptable pharmacokinetic profiles in preliminary in vivo rat experiments, the most active compound 12a showed poor solubility and high plasma protein binding. Our current research efforts are focused on optimizing compounds to improve physicochemical properties as well as potency.

Retention rate and long-term safety of biosimilar CT-P13 in patients with ankylosing spondylitis: data from the Korean College of Rheumatology Biologics registry.

OBJECTIVES: To evaluate the long-term drug retention, efficacy, and safety of the infliximab biosimilar CT-P13 in Korean patients with ankylosing spondylitis (AS) in clinical practice. The primary outcome was drug retention (i.e. time to treatment discontinuation or changing to another biologic) in Korean patients with AS. Additional outcomes included efficacy and safety. METHODS: Data were collected through the Korean College of Rheumatology Biologics (KOBIO) registry (ClinicalTrials.gov identifier: NCT01965132). CT-P13 efficacy was assessed using standard disease activity parameters, and safety was evaluated by adverse events (AEs). RESULTS: Between December 2012 and December 2017, 244 patients with AS treated with CT-P13 were enrolled. Of those, 203 (83.2%) received CT-P13 as first-line therapy. The median duration of treatment was 2.05 years. After 4 years' follow-up, the retention rate of CT-P13 in the overall patient population was 66%. Treatment changes or discontinuations occurred in 38 (15.6%) and 32 (13.1%) patients, respectively. Lack of efficacy was the most common reason for treatment changes, whereas AEs were the most common single cause of discontinuation. Disease activity decreased markedly from baseline following initiation of CT-P13 treatment, and thereafter remained stable. A total of 313 AEs occurred in 118 patients (48.4%); the majority (94.6%) were mild or moderate in severity. The most common treatment-related AEs were infusion or injection-site reactions (4.1% of patients), uveitis (3.7%), and skin rash (3.7%). CONCLUSIONS: In this real-world study, CT-P13 demonstrated encouraging drug retention rates and times, together with reasonable long-term efficacy and safety, in Korean patients with AS.