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1.
Adv Healthc Mater ; : e2400235, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38569198

ABSTRACT

Cancer immunotherapy by immune checkpoint inhibitors (ICIs) acts on antitumor responses by stimulating the immune system to attack cancer cells. However, this powerful therapy is hampered by its high treatment cost and limited efficacy. Here, it is shown that the development of an antibody-conjugated nanogel (ANGel), consisting of N-isopropylacrylamide-co-acrylic acid and antibody-binding protein (protein A), potentiates the efficacy of two ICI monoclonal antibodies (mAbs) (cytotoxic-T-lymphocyte-associated antigen 4 and programmed death ligand-1 mAbs). Compared with mAb treatment alone, treatment with a bispecific ANGel surface-conjugated with the mAbs significantly decreases both the survival of Michigan Cancer Foundation-7 (MCF-7) and M D Anderson-Metastatic Breast-231 (MDA-MB-231) breast cancer cells in vitro and the burden of 4T1-luciferase-2-derived orthotopic syngeneic tumors in vivo. The bispecific ANGel is also more potent than the conventional treatment at prolonging survival in animals with triple-negative breast cancer. The advantage of the bispecific ANGel over other engineered bispecific antibodies arises not only from the adaptability to link multiple antibodies quickly and easily, but also from the capability to maintain the anticancer effect steadily at subcutaneously delivered tumor site. This finding has an important implication for cancer immunotherapy, opening a new paradigm to treat solid tumors.

2.
Plant Physiol Biochem ; 208: 108522, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38493663

ABSTRACT

In staple crops, such as rice (Oryza sativa L.), pollen plays a crucial role in seed production. However, the molecular mechanisms underlying rice pollen germination and tube growth remain underexplored. Notably, we recently uncovered the redundant expression and mutual interaction of two rice genes encoding cyclic nucleotide-gated channels (CNGCs), OsCNGC4 and OsCNGC5, in mature pollen. Building on these findings, the current study focused on clarifying the functional roles of these two genes in pollen germination and tube growth. To overcome functional redundancy, we produced gene-edited rice plants with mutations in both genes using the CRISPR-Cas9 system. The resulting homozygous OsCNGC4 and OsCNGC5 gene-edited mutants (oscngc4/5) exhibited significantly lower pollen germination rates than the wild type (WT), along with severely reduced fertility. Transcriptome analysis of the double oscngc4/5 mutant revealed downregulation of genes related to receptor kinases, transporters, and cell wall metabolism. To identify the direct regulators of OsCNGC4, which form a heterodimer with OsCNGC5, we screened a yeast two-hybrid library containing rice cDNAs from mature anthers. Subsequently, we identified two calmodulin isoforms (CaM1-1 and CaM1-2), NETWORKED 2 A (NET2A), and proline-rich extension-like receptor kinase 13 (PERK13) proteins as interactors of OsCNGC4, suggesting its roles in regulating Ca2+ channel activity and F-actin organization. Overall, our results suggest that OsCNGC4 and OsCNGC5 may play critical roles in pollen germination and elongation by regulating the Ca2+ gradient in growing pollen tubes.


Subject(s)
Oryza , Oryza/physiology , Cyclic Nucleotide-Gated Cation Channels/genetics , Germination/genetics , Pollen/metabolism , Pollen Tube/genetics , Calmodulin/genetics , Calmodulin/metabolism , Phosphotransferases , Nucleotides, Cyclic/metabolism
3.
Plants (Basel) ; 12(16)2023 Aug 16.
Article in English | MEDLINE | ID: mdl-37631170

ABSTRACT

The collar region plays a crucial role in leaf angle formation and plant architecture, which is important for improving crop yield given the challenges of diminishing arable land and changing environmental conditions. To determine collar region-preferential genes (CRPGs) affecting plant architecture and crop yield, we conducted genome-wide transcriptomic analysis. By integrating our RNA sequencing data with public rice anatomical expression data, we identified 657 CRPGs. Verification involved testing six randomly selected CRPGs, all of which exhibited collar-preferential expression. The functional significance of CRPGs was assessed via Gene Ontology enrichment analysis, utilizing MapMan and KEGG, and literature analysis provided additional information for characterized CRPGs. Our findings revealed links between manipulating leaf angle and phytohormone-related pathways and stress responses. Moreover, based on the CRPGs, five transcription factors downstream of the liguleless 1 (LG1) gene were identified. Overall, the identified CRPGs provide potential targets for further research and breeding applications aimed at improving crop productivity by manipulating leaf architecture.

4.
ACS Appl Polym Mater ; 5(3): 2195-2202, 2023 Mar 10.
Article in English | MEDLINE | ID: mdl-37552750

ABSTRACT

The efficacy of coronavirus disease 2019 (COVID-19) vaccination is closely related to the serum levels of SARS-CoV-2-neutralizing antibodies (NAb) that bind to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Therefore, the rapid and quantitative measurement of SARS-CoV-2 NAb in the sera of vaccinated individuals is essential to develop an effective vaccine and further achieve population immunity, that is, herd immunity. The plaque reduction neutralization test, the gold standard for NAb effectiveness in serological tests, is accurate but requires biosafety level 3 facilities because of the use of the virus, which hampers its application in common laboratories and clinical practice. Here, we developed a bioresponsive nanogel-based surface plasmon resonance (nSPR) platform that detects SARS-CoV-2 NAb in clinical samples without complicated pretreatment. We found that multivalent protein binding (MPB) between the nanogel-conjugated RBD protein and SARS-CoV-2 NAb yields significantly enhanced SPR signals compared to the nonspecific interference from serum proteins in the nSPR assay. The excellence of our nanogel-based SARS-CoV-2 NAb test is due to its selectivity for NAb, with resistance to all other proteins, allowing the rapid detection and quantification of NAbs in each individual. Importantly, this nSPR assay provides a NAb detection platform for easier and safer COVID-19 vaccination strategies.

5.
Life Sci Alliance ; 6(5)2023 05.
Article in English | MEDLINE | ID: mdl-36914268

ABSTRACT

Single-cell technologies are a method of choice to obtain vast amounts of cell-specific transcriptional information under physiological and diseased states. Myogenic cells are resistant to single-cell RNA sequencing because of their large, multinucleated nature. Here, we report a novel, reliable, and cost-effective method to analyze frozen human skeletal muscle by single-nucleus RNA sequencing. This method yields all expected cell types for human skeletal muscle and works on tissue frozen for long periods of time and with significant pathological changes. Our method is ideal for studying banked samples with the intention of studying human muscle disease.


Subject(s)
Cell Nucleus , Gene Expression Profiling , Humans , RNA-Seq/methods , Gene Expression Profiling/methods , Cell Nucleus/genetics , Cell Nucleus/metabolism , Sequence Analysis, RNA/methods , Muscle, Skeletal
6.
Plants (Basel) ; 11(22)2022 Nov 17.
Article in English | MEDLINE | ID: mdl-36432876

ABSTRACT

In the angiosperm, pollen germinates and rapidly expands the pollen tube toward the ovule. This process is important for plant double fertilization and seed setting. It is well known that the tip-focused calcium gradient is essential for pollen germination and pollen tube growth. However, little is known about the Ca2+ channels that play a role in rice pollen germination and tube growth. Here, we divided the 16 cyclic nucleotide-gated channel (CNGC) genes from rice into five subgroups and found two subgroups (clades II and III) have pollen-preferential genes. Then, we performed a meta-expression analysis of all OsCNGC genes in anatomical samples and identified three pollen-preferred OsCNGCs (OsCNGC4, OsCNGC5, and OsCNGC8). The subcellular localization of these OsCNGC proteins is matched with their roles as ion channels on the plasma membrane. Unlike other OsCNGCs, these genes have a unique cis-acting element in the promoter. OsCNGC4 can act by forming a homomeric complex or a heteromeric complex with OsCNGC5 or OsCNGC8. In addition, it was suggested that they can form a multi-complex with Mildew Resistance Locus O (MLO) protein or other types of ion transporters, and that their expression can be modulated by Ruptured Pollen tube (RUPO) encoding receptor-like kinase. These results shed light on understanding the regulatory mechanisms of pollen germination and pollen tube growth through calcium channels in rice.

7.
Oncol Lett ; 24(3): 321, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35949608

ABSTRACT

Phloretin is one of the apple polyphenols with anticancer activities. Since tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves important roles in inducing apoptosis, the present study examined the effect of phloretin on TRAIL-induced apoptosis in colon cancer cells. Treatment with both phloretin and TRAIL markedly suppressed the survival of cancer cells from several colon cancer cell lines compared with that of cells treated with either TRAIL or phloretin. Additionally, decreased numbers of colonies were observed following addition of phloretin and TRAIL. Furthermore, TRAIL- and phloretin-treated HT-29-Luc cells exhibited decreased luciferase activity. Increased apoptosis was observed in phloretin- and TRAIL-treated HT-29-Luc colon cancer cells, accompanying elevated levels of cleaved poly(ADP-ribose) polymerase, and caspase-3, -8 and -9. The expression levels of MCL1 apoptosis regulator BCL2 family member (Mcl-1) were decreased following addition of phloretin in colon cancer cells. In addition, overexpression of Mcl-1 in phloretin- and TRAIL-treated HT-29-Luc cells resulted in increased cell survival. Treatment of HT-29-Luc cells with a combination of cycloheximide (CHX) and phloretin led to a more prominent decrease in Mcl-1 expression compared with that in cells treated with CHX alone, while Mcl-1 expression was recovered by treatment with MG132. Binding of ubiquitin with Mcl-1 was verified using immunoprecipitation. Intraperitoneal injection of both TRAIL and phloretin into tumor xenografts was associated with a decreased tumor volume compared with that following injection with either TRAIL or phloretin. Overall, the present results suggest a synergistic effect of phloretin on TRAIL-induced apoptosis in colon cancer cells.

8.
PLoS One ; 17(7): e0270183, 2022.
Article in English | MEDLINE | ID: mdl-35853009

ABSTRACT

Edge computing is a novel network architecture that is in proximity to the end devices in an Internet of Things (IoT). As the IoT becoming a major factor in our daily life, provisioning a low response time of the services to IoT users through edge computing is an important problem. Caching necessary program data for the task in an edge node effectively reduces the response time of the computation task. However, due to the increase of IoT users and devices, it is noteworthy that limited-resource edge nodes would receive a number of tasks, having a heavy burden of processing the requests. Therefore, the limited resource and caching space at cloudlet need the careful design of the caching algorithm to utilize the space of multiple edge nodes and relieve the burden of computations. In this paper, we propose a cooperative program caching system that makes different edge nodes cooperatively store program data and cache the replicas of the data requested frequently to handle a number of requests from IoT users. In particular, we develop a cooperative caching algorithm that caches the appropriate number of data replicas depending on the number of requests on each cloudlet and the popularity of the data to minimize the response time. The simulation results show that the proposed cooperative caching algorithm can effectively reduce the response time for IoT users compared to other existing algorithms.


Subject(s)
Internet of Things , Algorithms , Computer Simulation , Delivery of Health Care
9.
ACS Biomater Sci Eng ; 8(7): 2878-2889, 2022 07 11.
Article in English | MEDLINE | ID: mdl-35658391

ABSTRACT

Surface plasmon resonance (SPR) phenomena have been widely studied to detect biomolecules because of their high sensitivity and ability to determine biomolecular interactions with kinetic information. However, highly selective detection in specific concentration ranges relevant to target biomolecules is still a challenging task. Recently, we developed bioresponsive nanoscale hydrogels to selectively intensify SPR signals through multivalent protein binding (MPB) events with target biomolecules, including IL-2, where we were able to demonstrate exceptional selectivity for target biomolecules with minimal responses to nonspecific and monovalent binding events. In this work, we systematically explored the relationship between the physical properties of MPB-capable nanoscale hydrogels and their SPR response induced in the presence of the programmed cell death protein 1 antibody (PD-1Ab) as a model target biomolecule. First, we developed a synthetic protocol by controlling various reaction parameters to construct a library of nanoscale poly(N-isopropylacrylamide-co-acrylic acid) hydrogels (NHs) with different sizes (from 400 nm to 1 µm) and degrees of crosslinking (from 2 to 8%). Then, by incorporating MPB-capable PD-1 receptors onto the surface of NHs to form PD-1-responsive nanoscale hydrogels (PNHs), the hydrogel size and crosslinking dependency of their SPR responses were investigated. Our results reveal the appropriate hydrogel size regime and degree of crosslinking for effective PD-1Ab detection at specific concentrations range between a few nM and 1 µM. Overall, our study demonstrates that by tuning the physical properties of the nanoscale hydrogel matrix, the sensitivity and detection range of MPB-based SPR sensors can be modulated to potentially benefit clinical applications such as monitoring diverse therapeutic biomolecules.


Subject(s)
Hydrogels , Surface Plasmon Resonance , Hydrogels/chemistry , Programmed Cell Death 1 Receptor , Protein Binding , Surface Plasmon Resonance/methods
10.
Biomed Res Int ; 2021: 2068023, 2021.
Article in English | MEDLINE | ID: mdl-34036097

ABSTRACT

Management of endometrial cancer, an adenocarcinoma of the endometrium which occupies most uterine corpus neoplasms, including uterine sarcomas, has been more relevant due to its increasing incidence. Extensive research on tumorigenesis molecular mechanisms and molecular characterization across cancers has brought paradigm shifts in the treatment of various malignant tumors. Endometrial cancer treatment has been traditionally guided according to the disease extent or histology types, while recent studies on molecular features have led to the introduction of targeted agents into clinical use, along with conventional chemotherapeutic agents in patients with recurrent or metastatic disease. Considering the proven efficacy and relatively tolerable toxicities of targeted therapies across malignant tumors, improvement of treatment outcomes is also expected in endometrial cancer by adopting an individualized therapy depending on the specific molecular features. Efficacy assessment of new biological agents is still ongoing based on previous preclinical data on endometrial cancer molecular features. Here, endometrial cancer molecular characterization will be reviewed, and then, we will introduce preclinical data, directing the adoption of new biological agents.


Subject(s)
Antineoplastic Agents/therapeutic use , Endometrial Neoplasms/drug therapy , Molecular Targeted Therapy/methods , Adenocarcinoma/drug therapy , Animals , Endometrial Neoplasms/genetics , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Endometrium/drug effects , Endometrium/pathology , Female , Humans , Poly(ADP-ribose) Polymerase Inhibitors , Sarcoma , Uterine Neoplasms/drug therapy , Uterus
11.
BMJ Open ; 11(1): e039470, 2021 01 22.
Article in English | MEDLINE | ID: mdl-33483437

ABSTRACT

OBJECTIVES: Life-sustaining treatment is any treatment that serves to prolong life without reversing the underlying medical conditions, and includes cardiopulmonary resuscitation, mechanical ventilation, haemodialysis and left ventricular assist devices. This study aimed to investigate the thoughts on life-sustaining treatment of Koreans and to assess the factors associated with deciding to not receive life-sustaining treatment if they develop a terminal disease. DESIGN: Cross-sectional study. SETTING: Guro-gu centre for dementia from 1 May 2018 to 31 December 2019. PARTICIPANTS: In total, 150 individuals participated in this study. OUTCOME MEASURES: The questionnaire consisted of self-report items with some instructions, demographic characteristics, thoughts on life-sustaining treatment and psychosocial scales. The preferences of the participants were investigated on the assumption that they develop terminal cancer. The psychosocial scales included the Generalised Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Connor-Davidson Resilience Scale and Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: We classified our participants into two groups: individuals who wanted to receive life-sustaining treatment (IRLT) and individuals who wanted to not receive life-sustaining treatment (INLT). There were twice as many participants in the INLT group than there were in the IRLT. In making this decision, the INLT group focused more on physical and mental distress. Additionally, 32.7% of participants responded that terminal status was an optimal time for this decision, but more participants want to decide it earlier. The GAD-7 and PHQ-9 scores were significantly higher in the INLT group than in the IRLT group. However, the INLT group had significantly lower MSPSS family scores. CONCLUSION: Our findings can help assess issues regarding advance directives and life-sustaining treatment, and will be a reference for designing future studies on this issue.


Subject(s)
Advance Directives , Terminal Care , Adult , Cross-Sectional Studies , Humans , Life Support Care , Republic of Korea , Resuscitation Orders
12.
Ann Surg Treat Res ; 100(1): 25-32, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33457394

ABSTRACT

PURPOSE: The prognosis of young colorectal cancer (CRC) patients has not fully been addressed. The prognostic significance of systemic inflammatory markers was examined in those patients. METHODS: A total of 965 patients with resectable CRC were divided into young (≤ 50 years, n = 101) and old groups (> 51 years, n = 864). Neutrophil-to-lymphocyte ratio (NLR) > 5, derived NLR (dNLR) > 3, lymphocyte-to-monocyte ratio (LMR) < 2, platelet-to-lymphocyte ratio (PLR) > 150, and prognostic nutritional index (PNI) < 45 were analyzed for prognosis. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test. A multivariate analysis was performed using a Cox proportional hazards regression model. RESULTS: In the young group, NLR > 5, LMR < 2, and PNI < 45 were significantly associated with OS with univariate analyses. dNLR > 3 and those markers showed significance for PFS. LMR < 2 was a significant marker for poor PFS (hazard ratio [HR], 5.81; P = 0.020) in the multivariate analysis. In the old group, all inflammatory markers were significantly associated with OS and PFS with univariate analyses. LMR < 2 (HR, 2.66; P = 0.016) and PNI < 45 (HR, 2.14; P = 0.016) were independently associated with OS in multivariate analyses. PLR > 150 (HR, 1.45; P = 0.036) and PNI < 45 (HR, 1.73; P = 0.002) were significant markers for PFS. CONCLUSION: Systemic inflammation might be one of biologic factors that influence on prognosis of young CRC.

13.
Ann Neurol ; 89(3): 444-458, 2021 03.
Article in English | MEDLINE | ID: mdl-33219556

ABSTRACT

OBJECTIVE: It is unclear if stopping treatment with dabigatran, a new oral anticoagulant (NOAC), induces a paradoxical rebound prothrombotic state. We investigated if short-term (1-3 days) dabigatran cessation is associated with a higher thrombus volume than expected from a simple reversal of the anticoagulant effect. METHODS: Ten-week-old C57Bl/6 mice (n = 338) received one of the following oral treatments: phosphate-buffered saline (PBS), dabigatran for 7 days with or without 1 to 4 day cessation, and aspirin in either a single dose or daily for 7 days. Some of the animals that ceased dabigatran for 1 to 3 days received single-dose aspirin. Thereafter, we induced FeCl3 -mediated carotid thrombosis in 130 mice, after which we performed micro computed tomography thrombus imaging. The other 208 mice underwent coagulation assays or platelet function tests. As an explorative pilot study, we reviewed the medical records of 18 consecutive patients with NOAC cessation-related cerebral infarction in a large acute stroke cohort. RESULTS: We observed a ~ 40% higher volume of carotid thrombus after dabigatran cessation at 1 to 3 days than after vehicle treatment and showed that this effect could be prevented by single-dose aspirin pretreatment. Dabigatran cessation unduly increased platelet aggregability for 2 days after drug cessation, an effect mediated through thrombin or arachidonic acid, which effect was significantly attenuated by single-dose aspirin pretreatment. In patients, short-term (≤ 3 days) cessation of NOAC therapy, compared with longer-term (≥ 5 days) cessation, tended to be associated with relatively high stroke severity. INTERPRETATION: We provide the first preclinical evidence that a rebound prothrombotic state follows short-term cessation of dabigatran therapy. ANN NEUROL 2021;89:444-458.


Subject(s)
Antithrombins/adverse effects , Carotid Artery Thrombosis/diagnostic imaging , Dabigatran/adverse effects , Deprescriptions , Platelet Aggregation/drug effects , Substance Withdrawal Syndrome/blood , Thrombophilia/blood , Aged , Aged, 80 and over , Animals , Antithrombins/pharmacology , Arachidonic Acid/blood , Aspirin/pharmacology , Carotid Artery Thrombosis/chemically induced , Carotid Artery Thrombosis/prevention & control , Cerebral Infarction/diagnostic imaging , Cerebral Infarction/etiology , Cerebral Infarction/physiopathology , Cerebral Infarction/prevention & control , Chlorides/toxicity , Computed Tomography Angiography , Dabigatran/pharmacology , Factor Xa Inhibitors/adverse effects , Female , Ferric Compounds/toxicity , Humans , Ischemic Stroke/diagnostic imaging , Ischemic Stroke/etiology , Ischemic Stroke/physiopathology , Ischemic Stroke/prevention & control , Magnetic Resonance Angiography , Male , Mean Platelet Volume , Mice , Noxae/toxicity , Pilot Projects , Platelet Aggregation Inhibitors/pharmacology , Platelet Count , Pyrazoles/adverse effects , Pyridones/adverse effects , Rivaroxaban/adverse effects , Severity of Illness Index , Substance Withdrawal Syndrome/etiology , Substance Withdrawal Syndrome/prevention & control , Thrombin/metabolism , Thrombophilia/etiology , Thrombophilia/prevention & control , X-Ray Microtomography
14.
J Affect Disord ; 274: 768-773, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32664013

ABSTRACT

BACKGROUND: Depression in adolescence is a social problem that has detrimental effects on an individual's physical and mental health and increases health care burden on families and society. This study investigates the connection between mental illness among parents and their adolescent children in Korea. METHODS: The sample included parents of 5315 adolescents (12-24 years) and data were obtained from the Korea National Health and Nutrition Survey (KNHANES) from 2007 to 2017. Family based comprehensive questionnaires were used. Multivariate logistic regression models were performed to estimate odds ratios (ORs) at 95% confidence intervals (95% CIs). RESULTS: The main findings showed that daughters with depressed mothers were 1.92 times more likely to experience depression and 1.64 times more likely to have suicidal ideations. In particular, when father was suicidal, his daughter had a 2.59 times higher risk of suicidal thoughts than father was not depressed and had no suicidal thoughts. Sons' depressive mood was rarely affected by the psychological status of mothers and fathers. LIMITATION: There are under-report issue of feelings and study design is cross-sectional. CONCLUSIONS: This study showed gender differences in the association between parents' and adolescents' experience of depression. Thus, the daughter's psychological state was found to be strongly associated with the psychological state of both parents.


Subject(s)
Depression , Suicidal Ideation , Adolescent , Child , Cross-Sectional Studies , Depression/epidemiology , Female , Humans , Male , Mental Health , Parents , Republic of Korea/epidemiology
15.
PLoS One ; 15(7): e0234415, 2020.
Article in English | MEDLINE | ID: mdl-32673322

ABSTRACT

BACKGROUND: Discrimination is associated with depressive symptoms and other negative health effects, but little is known about the mental health risks of workplace gender discrimination. We aimed to investigate the association of workplace gender discrimination and depressive symptoms among employed women in South Korea. METHODS: The 6th wave (2016) survey datasets of the Korean Longitudinal Survey of Women and Family (KLoWF) were analyzed for 2,339 respondents who are identified as wage workers. Depressive symptoms were evaluated by the short-form (10-item) Center for Epidemiological Studies-Depression scale. Association of workplace gender discrimination and depressive symptoms was assessed using multivariate logistic regression, adjusted for potential confounding variables including age, income satisfaction, education level, marital status, and currently diagnosed disease. We then measured the age effect using age stratification multivariate logistic regression model. RESULTS: Women who experienced gender discrimination at workplace had higher odds of depressive symptoms regardless of the type of the discrimination including hiring, promotion, work assignments, paid wages, and firing. These associations were consistent in younger women below 40 years of age in regard to hiring, promotion, paid wages and firing, whereas inconsistent among older women above 40 years of age. LIMITATIONS: We did not investigate the effect of workplace gender discrimination on depressive symptoms in a longitudinal manner. CONCLUSIONS: Workplace gender discrimination was found to be significantly associated with depressive symptoms after adjustment for socio-demographic factors. Further, women under 40 years of age were especially vulnerable to workplace gender discrimination.


Subject(s)
Bullying/psychology , Depression/psychology , Sexism/psychology , Adult , Cross-Sectional Studies , Depression/etiology , Employment , Female , Humans , Logistic Models , Marital Status , Middle Aged , Odds Ratio , Personal Satisfaction , Republic of Korea , Salaries and Fringe Benefits , Sexism/ethics , Surveys and Questionnaires , Workplace/psychology
16.
Cereb Cortex ; 30(9): 4964-4978, 2020 07 30.
Article in English | MEDLINE | ID: mdl-32328622

ABSTRACT

The glycoprotein Reelin maintains neuronal positioning and regulates neuronal plasticity in the adult brain. Reelin deficiency has been associated with neurological diseases. We recently showed that Reelin is depleted in mice with a targeted disruption of the Ndel1 gene in forebrain postnatal excitatory neurons (Ndel1 conditional knockout (CKO)). Ndel1 CKO mice exhibit fragmented microtubules in CA1 pyramidal neurons, profound deterioration of the CA1 hippocampus and a shortened lifespan (~10 weeks). Here we report that Ndel1 CKO mice (of both sexes) experience spatial learning and memory deficits that are associated with deregulation of neuronal cell adhesion, plasticity and neurotransmission genes, as assessed by genome-wide transcriptome analysis of the hippocampus. Importantly, a single injection of Reelin protein in the hippocampus of Ndel1 CKO mice improves spatial learning and memory function and this is correlated with reduced intrinsic hyperexcitability of CA1 pyramidal neurons, and normalized gene deregulation in the hippocampus. Strikingly, when treated with Reelin, Ndel1 CKO animals that die from an epileptic phenotype, live twice as long as nontreated, or vehicle-treated CKO animals. Thus, Reelin confers striking beneficial effects in the CA1 hippocampus, and at both behavioral and organismal levels.


Subject(s)
CA1 Region, Hippocampal/pathology , Carrier Proteins/genetics , Longevity/drug effects , Reelin Protein/pharmacology , Animals , CA1 Region, Hippocampal/drug effects , Cognition/drug effects , Female , Longevity/genetics , Male , Memory Disorders/genetics , Mice , Mice, Knockout , Mutation , Spatial Learning/drug effects
17.
Atherosclerosis ; 299: 15-23, 2020 04.
Article in English | MEDLINE | ID: mdl-32182440

ABSTRACT

BACKGROUND AND AIMS: Exercise training (ET) helps treat atherosclerosis. However, many patients stop regular ET for various reasons. The effect of detraining on atherosclerosis is not well studied. We examined the effects of ET vs. short-term detraining on atheromatous matrix-metalloproteinase (MMP) activity in preexisting plaque and circulating cytokines/lipids. METHODS AND RESULTS: Eighteen-week-old apolipoprotein-E-/- mice (n = 56) on a Western diet underwent: 1) ET for 6-weeks (ET5+1), 2) ET for 5-weeks and detraining for 1-week (ET5+0), 3) ET for the last 1-week (ET0+1), or 4) no treadmill ET at all for 6-weeks (ET0+0). Atheromatous MMP-activity was visualized using molecular imaging with an MMP-2/9-activatable near-infrared-fluorescent probe. Compared with no ET (ET0+0), regular ET (ET5+1) decreased carotid atheromatous MMP activity, but this protective effect was significantly blunted by short-term detraining (ET5+0). Short-term detraining after longer-term ET showed a reduction in MMP-activity similar to short-term ET (ET0+1). Blood levels of lipids and cytokines paralleled the molecular imaging results: exercise caused higher levels of high-density lipoprotein, adiponectin, and interleukin-10 and lower levels of vascular cell adhesion molecule, monocyte chemoattractant protein-1, interleukin-1ß, and low-density lipoprotein. However, this beneficial effect was short-lived, with the ET5+0 group being similar to the ET0+0 group, and the ET0+1 group being similar to the ET5+1 group. The effect of exercise can be modeled with an exponential-decay of the protective factor of about 15%/day. CONCLUSIONS: Even short-term detraining reduces atheroprotective effects, and tips the balance towards atherosclerosis. This suggests that ET, to be effective, needs to be prolonged and regular, and that detraining should be avoided.


Subject(s)
Carotid Artery Diseases/therapy , Carotid Artery, Common/enzymology , Exercise Therapy , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Sedentary Behavior , Animals , Carotid Artery Diseases/blood , Carotid Artery Diseases/enzymology , Carotid Artery Diseases/pathology , Carotid Artery, Common/pathology , Cytokines/blood , Disease Models, Animal , Lipids/blood , Mice, Knockout, ApoE , Plaque, Atherosclerotic , Running , Time Factors
18.
Korean J Intern Med ; 35(1): 171-184, 2020 01.
Article in English | MEDLINE | ID: mdl-30360017

ABSTRACT

BACKGROUND/AIMS: Patients with pancreatic cancer (PC) generally have poor clinical outcomes. Early determination of their prognosis is crucial for developing a therapeutic strategy. Recently, various inflammatory markers have been validated as prognostic indicators for many cancers, including PC. However, few studies have evaluated these markers together. Thus, the purpose of this study was to comprehensively evaluate the value of inflammatory markers as prognostic indicators in patients with advanced PC treated with gemcitabine-based chemotherapy as the first line regimen. METHODS: This was a single-center retrospective study evaluating 302 patients with advanced PC who began first line treatment between November 2004 and August 2016. These patients were monitored until June 2017. Survival rates were assessed with univariate and multivariate analyses. Continuous variables were separated using the normal range or ideal cut-off levels determined by receiver operating curve analyses. RESULTS: Among inflammatory markers evaluated, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and C-reactive protein (CRP) to albumin ratio (CRP-albumin ratio) were independent predictors of overall survival (hazard ratio, 1.712, 1.345, and 1.454, respectively). Difference in survival rates was significant (p < 0.001) among three groups divided by the number of marker-related risks. CONCLUSION: Baseline inflammatory markers including NLR, PLR, and CRP-albumin ratio are useful in predicting survival rates in patients with PC. Combining these three markers is proven to be valuable.


Subject(s)
Deoxycytidine , Pancreatic Neoplasms , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Humans , Lymphocytes , Neutrophils , Pancreatic Neoplasms/drug therapy , Prognosis , Retrospective Studies , Gemcitabine
19.
Sci Rep ; 9(1): 11708, 2019 08 12.
Article in English | MEDLINE | ID: mdl-31406206

ABSTRACT

We recently generated a high-resolution supratentorial vascular topographic atlas using diffusion-weighed MRI in a population of large artery infarcts. These MRI-based topographic maps are not easily applicable to CT scans, because the standard-reference-lines for axial image orientation (i.e., anterior-posterior commissure line versus orbito-meatal line, respectively) are 'not parallel' to each other. Moreover, current, widely-used CT-based vascular topographic diagrams omit demarcation of the inter-territorial border-zones. Thus, we aimed to generate a CT-specific high-resolution atlas, showing the supratentorial cerebrovascular territories and the inter-territorial border-zones in a statistically rigorous way. The diffusion-weighted MRI lesion atlas is based on 1160 patients (67.0 ± 13.3 years old, 53.7% men) with acute (<1-week) cerebral infarction due to significant (>50%) stenosis or occlusion of a single large cerebral artery: anterior, middle, or posterior cerebral artery. We developed a software package enabling the transformation of our MR-based atlas into a re-oriented CT space corresponding to the axial slice orientations used in clinical practice. Infarct volumes are individually mapped to the three vascular territories on the CT template-set, generating brain maps showing the voxelwise frequency of infarct by the affected parent vessel. We then mapped the three vascular territories collectively, generating a dataset of Certainty-Index (CI) maps to reflect the likelihood of a voxel being a member of a specific vascular territory. Border-zones could be defined by using either relative infarct frequencies or CI differences. The topographic vascular territory atlas, revised for CT, will allow for easier and more accurate delineation of arterial territories and borders on CT images.


Subject(s)
Brain Mapping/methods , Brain/diagnostic imaging , Cerebral Arteries/diagnostic imaging , Infarction, Anterior Cerebral Artery/diagnostic imaging , Infarction, Middle Cerebral Artery/diagnostic imaging , Infarction, Posterior Cerebral Artery/diagnostic imaging , Aged , Aged, 80 and over , Brain/blood supply , Brain/pathology , Brain Mapping/instrumentation , Cerebral Arteries/pathology , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Image Interpretation, Computer-Assisted , Infarction, Anterior Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/pathology , Infarction, Posterior Cerebral Artery/pathology , Male , Middle Aged , Software , Tomography, X-Ray Computed/methods
20.
Article in English | MEDLINE | ID: mdl-31274976

ABSTRACT

IEEE 802.11ay supports multi-user multiple-input-multiple-output (MU-MIMO). However, the MU-MIMO beam-forming training (BFT) is a time-consuming process for finding appropriate directional antenna patterns, and inefficient BFT results in a long training time. Thus, in this letter, we propose an algorithm that configures the transmit antenna with the aim of reducing the number of redundant transmissions during MU-MIMO BFT. Both analytic and simulation results show that our proposed algorithm can significantly reduce the training time.

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