Relationship between Very Early Enteral Nutrition and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome in cardiovascular surgery patients: A propensity score-matched study.

BACKGROUND: Early enteral nutrition (EN) is recommended for patients with critical illness to maintain intestinal immunity. However, the optimal timing of the commencement of EN remains unclear, particularly after cardiovascular surgery. OBJECTIVE: We herein focused on Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) as a predisposing immunodeficiency, and investigated its association with very early EN (<24 hours) in patients who underwent cardiovascular surgery. DESIGN: In this retrospective study, we used an administrative claims database with laboratory examinations between 2008 and 2021 to identify adult patients admitted to the intensive care unit after cardiovascular surgery. Patients who received EN the day after surgery were assigned to the EN <24 h group, while those who received EN on day 2 or 3 were assigned to the control group. The primary outcome was a composite of the incidence of PICS and mortality on day 14 after surgery. We defined PICS as patients hospitalized for >14 days and meeting at least two of the following conditions: a lymphocyte count <800/µL, albumin <3.0 g/dL, and CRP >2.0 mg/dL. We compared the two groups using a propensity score analysis. RESULTS: Propensity score matching generated 2,082 pairs. The primary outcome was significantly lower in the EN <24 h group than in the control group on days 14 (risk difference [95% CI], -3.1% [-5.9%, -0.3%]) and 28 (risk difference [95% CI], -2.1% [-3.7%, -0.4%]). Mortality did not significantly differ between the two groups. The length of hospital stay was significantly shorter in the EN <24 h group: the difference (95% CI) was -2.2 (-3.7, -0.7) days. CONCLUSIONS: Among patients who underwent cardiovascular surgery, very early EN provided on the day after surgery was associated with a lower incidence of PICS and a shorter length of hospital stay than EN provided two or three days after surgery.

Association Between Osteoporosis Self-Assessment Tool for Asians and Airflow Limitation in Japanese Post-Menopausal Women.

Purpose: This study aimed to reveal the association between the osteoporosis self-assessment tool for Asians (OSTA) and airflow limitation (AL) in post-menopausal Japanese women. Participants and Methods: This cross-sectional study included 1580 participants undergoing a comprehensive health examination using spirometry and dual-energy X-ray absorptiometry. The OSTA was calculated by subtracting the age in years from the body weight (BW) in kilograms, and the result was multiplied by 0.2. The OSTA risk level was defined as low (>-1), moderate (-4 to -1), or high (<-4). AL was defined as forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.7. The association between the OSTA and AL was assessed using logistic regression analysis. Results: The prevalence of AL was significantly higher in the high OSTA group (15.3%) than in the low OSTA group (3.1%) (p<0.001). In multiple linear regression analysis, the OSTA was independently associated with FEV1/FVC. In logistic regression models adjusted for smoking status, alcohol consumption, current use of medication for diabetes, hyperglycemia, rheumatoid arthritis, second-hand smoke, and ovary removal showed a significantly higher risk of AL (odds ratio: 5.48; 95% confidence interval: 2.90-10.37; p<0.001) in participants with OSTA high risk than in those with OSTA low risk. Conclusion: These results suggest that the OSTA high risk indicates reduced BMD at the femoral neck and presence of AL in Japanese post-menopausal women aged ≥45 years.

Catalytic Aerobic Carbooxygenation for the Construction of Vicinal Tetrasubstituted Centers: Application to the Synthesis of Hexasubstituted γ-Lactones.

Strategic design for the construction of contiguous tetrasubstituted carbon centers represents a daunting challenge in synthetic organic chemistry. Herein, we report a combined experimental and computational investigation aimed at developing catalytic aerobic carbooxygenation, involving the intramolecular addition of tertiary radicals to geminally disubstituted alkenes, followed by aerobic oxygenation. This reaction provides a straightforward route to various α,α,ß,ß-tetrasubstituted γ-lactones, which can be readily transformed into hexasubstituted γ-lactones through allylation/translactonization. Computational analysis reveals that the key mechanistic foundation for achieving the developed aerobic carbooxygenation involves the design of endothermic (energetically uphill) C-C bond formation followed by exothermic (energetically downhill) oxygenation. Furthermore, we highlight a unique fluorine-induced stereoelectronic effect that stabilizes the endothermic stereodetermining transition state.

Differences in code status practice patterns among emergency clinicians working in Japan and the United States.

OBJECTIVE: This study aimed to examine self-reported code-status practice patterns among emergency clinicians from Japan and the U.S. METHODS: A cross-sectional questionnaire was distributed to emergency clinicians from one academic medical center and four general hospitals in Japan and two academic medical centers in the U.S. The questionnaire was based on a hypothetical case involving a critically ill patient with end-stage lung cancer. The questionnaire items assessed whether respondent clinicians would be likely to pose questions to patients about their preferences for medical procedures and their values and goals. RESULTS: A total of 176 emergency clinicians from Japan and the U.S participated. After adjusting for participants' backgrounds, emergency clinicians in Japan were less likely to pose procedure-based questions than those in the U.S. Conversely, emergency clinicians in Japan showed a statistically higher likelihood of asking 10 out of 12 value-based questions. CONCLUSION: Significant differences were found between emergency clinicians in Japan and the U.S. in their reported practices on posing procedure-based and patient value-based questions. PRACTICE IMPLICATIONS: Serious illness communication training based in the U.S. must be adapted to the Japanese context, considering the cultural characteristics and practical responsibilities of Japanese emergency clinicians.

An Exploratory Study of the Potential of Online Counseling for University Students by a Human-Operated Avatar Counselor.

Recently, the use of digital technologies, such as avatars and virtual reality, has been increasingly explored to address university students' mental health issues. However, there is limited research on the advantages and disadvantages of counselors using avatars in online video counseling. Herein, 25 university students were enrolled in a pilot online counseling session with a human counselor-controlled avatar, and asked about their emotional experiences and impressions of the avatar and to provide qualitative feedback on their communication experience. Positive emotions during the session were associated with impressions of the avatar's intelligence and likeability. The anthropomorphism, animacy, likeability, and intelligent impressions of the avatar were interrelated, indicating that the avatar's smile and the counselor's expertise in empathy and approval may have contributed to these impressions. However, no associations were observed between participant experiences and their prior communication with avatars, or between participant experiences and their gender or the perceived gender of the avatar. Accordingly, recommendations for future practice and research are provided. Accumulating practical and empirical findings on the effectiveness of human-operated avatar counselors is crucial for addressing university students' mental health issues.

Effects of early enteral nutrition on persistent inflammation, immunosuppression, and catabolism syndrome in critically ill patients: A claims database study using a propensity score analysis.

BACKGROUND & AIMS: Early enteral nutrition (EEN) potentially improves immune-related outcomes via the maintenance of intestinal immunity; however, the effects of EEN on clinical outcomes, including infectious complications, are controversial. Therefore, we herein investigated whether EEN affected persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which represents the immunocompromised state after critical illness. METHODS: This retrospective cohort study utilized the administrative claims database of inpatients and laboratory findings. Patients admitted to and treated in the intensive care unit (ICU) for more than 3 consecutive days were included. The primary outcome, a composite of PICS or mortality on day 14 after admission, was compared between the EEN group, which received enteral nutrition (EN) on the first 3 days (day 0, 1, or 2), and the late enteral nutrition (LEN) group, which did not receive EN on the first 3 days, but then received EN on days 3 through 7, using a propensity score-matched analysis. Secondary outcomes included the composite outcome on day 28, in-hospital mortality, the Barthel index, and laboratory data. Patients who met at least two of the following conditions were diagnosed with PICS: CRP >2.0 mg/dL, albumin <3.0 g/dL, and a lymphocyte count <800/µL. RESULTS: A total of 7530 matched pairs were generated after propensity score matching. The primary outcome was significantly lower in the EEN group (risk difference -3.0%, 95% confidence interval (CI) -4.5 to -1.4%), whereas mortality did not significantly differ. The 28-day composite outcome was similar in the 2 groups (risk difference -1.5%, 95% CI -2.8% to -0.2%, no significant difference in mortality). There was no significant difference in in-hospital mortality between the EEN and LEN groups; however, the Barthel index at discharge was higher in the EEN group (the medians, 50 vs 45, P = 0.001). Laboratory data showed lower Albumin and CRP on day 14 in the EEN group, but no other significant differences. CONCLUSIONS: In patients admitted to the ICU, EEN was associated with a lower incidence of PICS on days 14 and 28, but was not associated with mortality. This positive association was not observed in sepsis, cardiac diseases, or gastrointestinal diseases.

Structure-activity relationship study of nitrogen signaling factors.

We have synthesized 10 analogs of oxylipins, which are nitrogen signaling factors (NSFs) that mediate cell-to-cell communication in the fission yeast Schizosaccharomyces pombe, and evaluated their structure-activity relationships with the aim of developing molecular probes for NSFs. We found that the OH or OAc group at C10 could be replaced with a compact amide (17) or carbamate (19). Introducing an alkyne as a detection tag at C10 led to decreased, though still sufficient, activity. Introducing an alkyne at the C18 position showed a similar trend, suggesting tolerance is relatively low even for compact functional groups such as alkynes. Although introduction of a diazirine moiety as a photoreactive group at the C5 position decreased the activity, we found that introducing diazirine at the C13 position was acceptable, and compound 38 exhibited potent NSF activity. These findings will be helpful in the development of molecular probes for NSFs.

Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 µM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.

Reduction of H3K9 methylation by G9a inhibitors improves the development of mouse SCNT embryos.

Removal of somatic histone H3 lysine 9 trimethylation (H3K9me3) from the embryonic genome can improve the efficiency of mammalian cloning using somatic cell nuclear transfer (SCNT). However, this strategy involves the injection of histone demethylase mRNA into embryos, which is limiting because of its invasive and labor-consuming nature. Here, we report that treatment with an inhibitor of G9a (G9ai), the major histone methyltransferase that introduces H3K9me1/2 in mammals, greatly improved the development of mouse SCNT embryos. Intriguingly, G9ai caused an immediate reduction of H3K9me1/2, a secondary loss of H3K9me3 in SCNT embryos, and increased the birth rate of cloned pups about 5-fold (up to 3.9%). G9ai combined with the histone deacetylase inhibitor trichostatin A further improved this rate to 14.5%. Mechanistically, G9ai and TSA synergistically enhanced H3K9me3 demethylation and boosted zygotic genome activation. Thus, we established an easy, highly effective SCNT protocol that would enhance future cloning research and applications.

The Association of the Cholesterol Efflux Capacity with the Paraoxonase 1 Q192R Genotype and the Paraoxonase Activity.

AIMS: Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism, which is associated with the hydrolysis of paraoxon (POXase activity) and atherosclerotic cardiovascular disease (ASCVD), remains controversial. As the effect of PON1 Q192R polymorphism on the HDL function is unclear, we investigated the relationship between this polymorphism and the cholesterol efflux capacity (CEC), one of the biological functions of HDL, in association with the PON1 activity. METHODS: The relationship between PON1 Q192R polymorphisms and CEC was investigated retrospectively in 150 subjects without ASCVD (50 with the PON1 Q/Q genotype, 50 with the Q/R genotype, and 50 with the R/R genotype) who participated in a health screening program. The POXase and arylesterase (AREase: hydrolysis of aromatic esters) activities were used as measures of the PON1 activity. RESULTS: The AREase activity was positively correlated with CEC independent of the HDL cholesterol levels. When stratified by the PON1 Q192R genotype, the POXase activity was also positively correlated with CEC independent of HDL cholesterol. PON1 Q192R R/R genotype carriers had a lower CEC than Q/Q or Q/R genotype carriers, despite having a higher POXase activity. Moreover, in a multiple regression analysis, the PON1 Q192R genotype was associated with the degree of CEC, independent of the HDL cholesterol and POXase activity. CONCLUSIONS: The PON1 Q192R R allele is associated with reduced CEC in Japanese people without ASCVD. Further studies on the impact of this association on the severity of atherosclerosis and ASCVD development are thus called for.

Impaired Cholesterol Efflux Capacity rather than Low HDL-C Reflects Oxidative Stress under Acute Myocardial Infarction.

AIMS: Acute myocardial infarction (AMI) causes irreversible damage to cardiomyocytes due to the discontinuation of oxygen supply and leads to systemic oxidative stress. It has been reported that high-density lipoprotein (HDL) particles have antioxidant capacity, and reduced antioxidant capacity is associated with decreased cholesterol efflux capacity (CEC). The purpose of this study was to clarify the usefulness of CEC measurement in patients with AMI. METHODS: We investigated the association between CEC and oxidative stress status in a case-control study. This study included 193 AMI cases and 445 age- and sex-matched controls. We examined the associations of CEC with HDL-cholesterol (HDL-C) and oxidized human serum albumin (HSA), an index of systemic oxidative stress status, and the effect of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which has been reported to affect HDL-C level and risk for MI, on these associations. RESULTS: Both bivariable and multivariable analyses showed that CEC was positively correlated with HDL-C levels in both AMI cases and controls, with a weaker correlation in AMI cases than in controls. In AMI cases, oxidized HSA levels were associated with CEC in both bivariable and multivariable analyses, but not with HDL-C. These associations did not differ among the ALDH2 genotypes. CONCLUSIONS: CEC, but not HDL-C level, reflects systemic oxidative stress status in patients with AMI. CEC measurement for patients with AMI may be useful in that it provides information on systemic oxidative stress status as well as atherosclerosis risk.

Post-intensive care syndrome follow-up system after hospital discharge: a narrative review.

BACKGROUND: Post-intensive care syndrome (PICS) is the long-lasting impairment of physical functions, cognitive functions, and mental health after intensive care. Although a long-term follow-up is essential for the successful management of PICS, few reviews have summarized evidence for the efficacy and management of the PICS follow-up system. MAIN TEXT: The PICS follow-up system includes a PICS follow-up clinic, home visitations, telephone or mail follow-ups, and telemedicine. The first PICS follow-up clinic was established in the U.K. in 1993 and its use spread thereafter. There are currently no consistent findings on the efficacy of PICS follow-up clinics. Under recent evidence and recommendations, attendance at a PICS follow-up clinic needs to start within three months after hospital discharge. A multidisciplinary team approach is important for the treatment of PICS from various aspects of impairments, including the nutritional status. We classified face-to-face and telephone-based assessments for a PICS follow-up from recent recommendations. Recent findings on medications, rehabilitation, and nutrition for the treatment of PICS were summarized. CONCLUSIONS: This narrative review aimed to summarize the PICS follow-up system after hospital discharge and provide a comprehensive approach for the prevention and treatment of PICS.

Neurobehavioral effects of the exposure to mercury vapor and methylmercury during postnatal period on mice.

In this study, we investigated the neurobehavioral alterations and modifications of gene expression in the brains of female mice exposed to low-level mercury vapor and/or methylmercury during postnatal development. The mice were exposed to low-level mercury vapor at a mean concentration of 0.094 mg/m3 and supplied with tap water containing 5 ppm methylmercury from postnatal day 11 to 12 weeks of age. Behavioral analyses were performed at 17 weeks of age. Total locomotor activity in the open field test and the retention trial performance in the passive avoidance test were significantly reduced in the combined exposure group compared with those in the control group. The differences in locomotor activity and performance in the retention trial at 17 weeks were no longer detected at 45 weeks. These results suggest that the effect of aging on the behavioral abnormalities resulting from postnatal exposure to mercury complexes are not significant. In the microarray analysis of brains in the combined exposure group, the gene expression levels of Ano2 and Sgk1 were decreased. Real-time RT-PCR analysis confirmed these changes caused by combined mercury exposure, showing significant downregulation of Ano2 and Sgk1 in the cerebrum. These genes play key roles in the brain as a calcium-activated chloride channel and as a kinase that responds to cellular stress, respectively. Our findings provide insight into the neurobehavioral changes caused by combined mercury exposure.

Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator.

PURPOSE: We investigated whether twice-daily administration of a bilayer tablet formulation of tramadol (35% immediate-release [IR] and 65% sustained-release) is as effective as four-times-daily IR tramadol capsules for managing cancer pain. METHODS: This randomized, double-blind, double-dummy, active-comparator, non-inferiority study enrolled opioid-naïve patients using non-steroidal anti-inflammatory drugs or acetaminophen (paracetamol) to manage cancer pain and self-reported pain (mean value over 3 days ≥ 25 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to either bilayer tablets or IR capsules for 14 days. The starting dose was 100 mg/day and could be escalated to 300 mg/day. The primary endpoint was the change in VAS (averaged over 3 days) for pain at rest from baseline to end of treatment/discontinuation. RESULTS: Overall, 251 patients were randomized. The baseline mean VAS at rest was 47.67 mm (range: 25.6-82.7 mm). In the full analysis set, the adjusted mean change in VAS was - 22.07 and - 19.08 mm in the bilayer tablet (n = 124) and IR capsule (n = 120) groups, respectively. The adjusted mean difference was - 2.99 mm (95% confidence interval [CI] - 7.96 to 1.99 mm). The upper 95% CI was less than the predefined non-inferiority margin of 7.5 mm. Other efficacy outcomes were similar in both groups. Adverse events were reported for 97/126 (77.0%) and 101/125 (80.8%) patients in the bilayer tablet and IR capsule groups, respectively. CONCLUSION: Twice-daily administration of bilayer tramadol tablets was as effective as four-times-daily administration of IR capsules regarding the improvement in pain VAS, with comparable safety outcomes. CLINICAL TRIAL REGISTRATION: JapicCTI-184143/jRCT2080224082 (October 5, 2018).

Protocol for detecting threonine deaminase activity in fission yeast cell lysates.

Threonine deaminase catalyzes the first step of isoleucine biosynthesis from threonine. In this protocol, we describe the process of measuring the enzymatic activity of threonine deaminase in the fission yeast cell lysate, which is catalyzed by Tda1. First, we describe the process of preparing cell lysates from fission yeast cell cultures. Subsequently, we explain how to measure the threonine deaminase activity using threonine or serine as a substrate. For complete details on the use and execution of this protocol, please refer to Sasaki et al. (2022).1.

Acidic extracellular pH drives accumulation of N1-acetylspermidine and recruitment of protumor neutrophils.

An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a protumor metabolite, through up-regulation of the expression of spermidine/spermine acetyltransferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to protumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that antineutrophil-neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of protumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a metabolic target for antitumor immune therapy.

UBL3 Interaction with α-Synuclein Is Downregulated by Silencing MGST3.

Ubiquitin-like 3 (UBL3) is a membrane-anchored protein that plays a crucial role in sorting proteins into small extracellular vesicles. Aggregations of alpha-synuclein (α-syn) are associated with the pathology of neurodegenerative diseases such as Parkinson's disease. Recently, the interaction between UBL3 and α-syn was discovered, with potential implications in clearing excess α-syn from neurons and its role in disease spread. However, the regulator that can mediate the interaction between UBL3 and α-syn remains unclear. In this study, using the split gaussian luciferase complementation assay and RNA interference technology, we identified that QSOX2, HTATIP2, UBE3C, MGST3, NSF, HECTD1, SAE1, and ATG3 were involved in downregulating the interaction between UBL3 and α-syn. Notably, silencing MGST3 had the most significant impact. Immunocytochemistry staining confirmed the impact of MGST3 silencing on the co-localization of UBL3 and α-syn in cells. MGST3 is a part of the antioxidant system, and silencing MGST3 is believed to contribute to oxidative stress. We induced oxidative stress with hydrogen peroxide, observing its effect on the UBL3-α-syn interaction, and showing that 800 µM of H2O2 downregulated this interaction. In conclusion, silencing MGST3 downregulates the interaction between UBL3 and α-syn.

Identification of small-molecule inhibitors against the interaction of RNA-binding protein PSF and its target RNA for cancer treatment.

Diverse cellular activities are modulated through a variety of RNAs, including long noncoding RNAs (lncRNAs), by binding to certain proteins. The inhibition of oncogenic proteins or RNAs is expected to suppress cancer cell proliferation. We have previously demonstrated that PSF interaction with its target RNAs, such as androgen-induced lncRNA CTBP1-AS, is critical for hormone therapy resistance in prostate and breast cancers. However, the action of protein-RNA interactions remains almost undruggable to date. High-throughput screening (HTS) has facilitated the discovery of drugs for protein-protein interactions. In the present study, we developed an in vitro alpha assay using Flag peptide-conjugated lncRNA, CTBP1-AS, and PSF. We then constructed an effective HTS screening system to explore small compounds that inhibit PSF-RNA interactions. Thirty-six compounds were identified and dose-dependently inhibited PSF-RNA interaction in vitro. Moreover, chemical optimization of these lead compounds and evaluation of cancer cell proliferation revealed two promising compounds, N-3 and C-65. These compounds induced apoptosis and inhibited cell growth in prostate and breast cancer cells. By inhibiting PSF-RNA interaction, N-3 and C-65 up-regulated signals that are repressed by PSF, such as the cell cycle signals by p53 and p27. Furthermore, using a mouse xenograft model for hormone therapy-resistant prostate cancer, we revealed that N-3 and C-65 can significantly suppress tumor growth and downstream target gene expression, such as the androgen receptor (AR). Thus, our findings highlight a therapeutic strategy through the development of inhibitors for RNA-binding events in advanced cancers.

High accuracy distinction of shockable and non-shockable arrhythmias in abnormal classes through wavelet transform with pseudo differential like operators.

Arrhythmia is an abnormal rhythm of the heart which leads to sudden death. Among these arrhythmias, some are shockable, and some are non-shockable arrhythmias with external defibrillation. The automated external defibrillator (AED) is used as the automated arrhythmia diagnosis system and requires an accurate and rapid decision to increase the survival rate. Therefore, a precise and quick decision by the AED has become essential in improving the survival rate. This paper presents an arrhythmia diagnosis system for the AED by engineering methods and generalized function theories. In the arrhythmia diagnosis system, the proposed wavelet transform with pseudo-differential like operators-based method effectively generates a distinguishable scalogram for the shockable and non-shockable arrhythmia in the abnormal class signals, which leads to the decision algorithm getting the best distinction. Then, a new quality parameter is introduced to get more details by quantizing the statistical features on the scalogram. Finally, design a simple AED shock and non-shock advice method by following this information to improve the precision and rapid decision. Here, an adequate topology (metric function) is adopted to the space of the scatter plot, where we can give different scales to select the best area of the scatter plot for the test sample. As a consequence, the proposed decision method gives the highest accuracy and rapid decision between shockable and non-shockable arrhythmias. The proposed arrhythmia diagnosis system increases the accuracy to 97.98%, with a gain of 11.75% compared to the conventional approach in the abnormal class signals. Therefore, the proposed method contributes an additional 11.75% possibility for increasing the survival rate. The proposed arrhythmia diagnosis system is general and could be applied to distinguish different arrhythmia-based applications. Also, each contribution could be used independently in various applications.

UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib.

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future.