Electron Release via Internal Polarization Fields for Optimal S-H Bonding States.

Transition metal dichalcogenides (TMDs) have received considerable attention as promising electrocatalysts for the hydrogen evolution reaction (HER), yet their potential is often constrained by the inertness of the basal planes arising from their poor hydrogen adsorption ability. Here, the relationship between the electronic structure of the WS2 basal plane and HER activity is systemically analyzed to establish a clear insight. The valance state of the sulfur atoms on the basal plane has been tuned to enhance hydrogen adsorption through sequential engineering processes, including direct phase transition and heterostructure that induces work function-difference-induced unidirectional electron transfer. Additionally, an innovative synthetic approach, harnessing the built-in internal polarization field at the W-graphene heterointerface, triggers the in-situ formation of sulfur vacancies in the bottom WSx (x < 2) layers. The resultant modulation of the valance state of the sulfur atom stabilizes the W-S bond, while destabilizing the S-H bond. The electronic structural changes are further amplified by the release and transfer of surplus electrons via sulfur vacancies, filling the valance state of W and S atoms. Consequently, this work provides a comprehensive understanding of the interplay between the electronic structure of the WS2 basal plane and the HER activity, focusing on optimizing S-H bonding state.

Multifunctional Natural and Synthetic Melanin for Bioelectronic Applications: A Review.

Emerging material interest in bioelectronic applications has highlighted natural melanin and its derivatives as promising alternatives to conventional synthetic conductors. These materials, traditionally noted for their adhesive, antioxidant, biocompatible, and biodegradable properties, have barely been used as conductors due to their extremely low electrical activities. However, recent studies have demonstrated good conductive properties in melanin materials that promote electronic-ionic hybrid charge transfer, attributed to the formation of an extended conjugated backbone. This review examines the multifunctional properties of melanin materials, focusing on their chemical and electrochemical synthesis and their resulting structure-property-function relationship. The wide range of bioelectronic applications will also be presented to highlight their importance and potential to expand into new design concepts for high-performance electronic functional materials. The review concludes by addressing the current challenges in utilizing melanin for biodegradable bioelectronics, providing a perspective on future developments.

Comprehensive immune cell spectral library for large-scale human primary T, B, and NK cell proteomics.

Although proteomics is extensively used in immune research, there is currently no publicly accessible spectral assay library for the comprehensive proteome of immune cells. This study generated spectral assay libraries for five human immune cell lines and four primary immune cells: CD4 T, CD8 T, natural killer (NK) cells, and B cells. This was achieved by utilizing data-dependent acquisition (DDA) and employing fractionated samples from over 100 µg of proteins, which was applied to acquire the highest-quality MS/MS spectral data. In addition, Data-indedendent acquisition (DIA) was used to obtain sufficient data points for analyzing proteins from 10,000 primary CD4 T, CD8 T, NK, and B cells. The immune cell spectral assay library generated included 10,544 protein groups and 127,106 peptides. The proteomic profiles of 10,000 primary human immune cells obtained from 15 healthy volunteers analyzed using DIA revealed the highest heterogeneity of B cells among other immune cell types and the similarity between CD4 T and CD8 T cells. All data and spectral library are deposited in ProteomeXchange (PXD047742).

Coexistence of double seropositivity for MPO antibody and anti-GBM antibody in ANCA-associated vasculitis concurrent with multiple myeloma: A case report.

RATIONALE: Immune-mediated vasculitis with 2 or more autoantibodies, for example, anti-proteinase-3, combined with anti-myeloperoxidase (MPO) or anti-glomerular basement membrane (GBM) antibodies, is extremely unusual. Furthermore, the coexistence of autoimmune vasculitis and hematological malignancies is uncommon. Herein, we describe a case of double-seropositive anti-neutrophil cytoplasmic antibody (ANCA) vasculitis with multiple myeloma. PATIENT CONCERNS: A 79-year-old Asian man presented with persistent leg edema and kidney dysfunction. His kidney function rapidly decreased, and serologic test results showed higher titers of the anti-MPO antibody (54.7 IU/mL) and anti-GBM antibodies (>200 IU/mL). Additionally, the clinical features showed the possibility of monoclonal gammopathy with anemia and hyperglobulinemia. We performed kidney and bone marrow biopsy. Serum protein electrophoresis and immunofixation revealed no significant differences, but the results of the bone marrow smear were compatible with those of myeloma with 15% plasmacytosis. However, kidney biopsy showed diffuse crescentic glomerulonephritis without deposition of the immune complex or kappa/lambda chain. DIAGNOSES AND INTERVENTIONS: Finally, the patient was diagnosed with double-seropositive ANCA-associated glomerulonephritis and multiple myeloma. Given the patient's performance status, we initiated low-dose steroid pulse therapy, followed by conservative management. OUTCOMES: While the pulmonary lesions showed improvement, the kidney function did not regain its previous state, prompting the initiation of kidney replacement therapy by hemodialysis. There has been a decrease in the levels of anti-GBM and anti-MPO antibodies since the initial diagnosis. LESSONS: This case elucidates the complex interplay between ANCA-associated glomerulonephritis and hematologic malignancy and emphasizes the need for a nuanced treatment strategy considering its multifaceted clinical presentation.

Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells.

In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.

Joint-specific regulation of homeobox D10 expression in rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by joint inflammation and destruction. The disease typically affects small joints in the hands and feet, later progressing to involve larger joints such as the knees, shoulders, and hips. While the reasons for these joint-specific differences are unclear, distinct epigenetic patterns associated with joint location have been reported. In this study, we evaluated the unique epigenetic landscapes of fibroblast-like synoviocytes (FLS) from hip and knee synovium in RA patients, focusing on the expression and regulation of Homeobox (HOX) transcription factors. These highly conserved genes play a critical role in embryonic development and are known to maintain distinct expression patterns in various adult tissues. We found that several HOX genes, especially HOXD10, were differentially expressed in knee FLS compared with hip FLS. Epigenetic differences in chromatin accessibility and histone marks were observed in HOXD10 promoter between knee and hip FLS. Histone modification, particularly histone acetylation, was identified as an important regulator of HOXD10 expression. To understand the mechanism of differential HOXD10 expression, we inhibited histone deacetylases (HDACs) with small molecules and siRNA. We found that HDAC1 blockade or deficiency normalized the joint-specific HOXD10 expression patterns. These observations suggest that epigenetic differences, specifically histone acetylation related to increased HDAC1 expression, play a crucial role in joint-specific HOXD10 expression. Understanding these mechanisms could provide insights into the regional aspects of RA and potentially lead to therapeutic strategies targeting specific patterns of joint involvement during the course of disease.

Preoperative echocardiography as a predictor of spinal anesthesia-induced hypotension in older patients with mild left ventricular diastolic dysfunction: a retrospective observational study.

BACKGROUND: Spinal anesthesia-induced hypotension (SAH) frequently occurs in older patients, many of whom have mild left ventricular (LV) diastolic dysfunction, often asymptomatic at rest. This study investigated the association between preoperative echocardiographic measurements and SAH in older patients with mild LV diastolic dysfunction. METHODS: We conducted a retrospective observational study using data from electronic medical records. The patients ≥ 65 years old who underwent spinal anesthesia for urologic surgery between January 2016 and December 2017 and whose preoperative echocardiography within 6 months before surgery revealed grade I LV diastolic dysfunction were recruited. SAH was investigated using the anesthesia records. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: A total of 163 patients were analyzed. SAH and significant SAH developed in 55 (33.7%) patients. The mitral inflow E velocity was an independent risk factor for SAH (odds ratio [OR], 0.886; 95% confidence interval [CI], 0.845-0.929; P < 0.001). The area under the ROC curve for mitral inflow E velocity to predict SAH was 0.819 (95% CI, 0.752-0.875; P < 0.001). If mitral inflow E velocity was ≤ 60 cm/s, SAH was predicted with a sensitivity of 83.6% and specificity of 70.4%. CONCLUSIONS: The preoperative mitral inflow E velocity demonstrated the greatest predictability of SAH in older patients with mild LV diastolic dysfunction. This may assist in identifying patients at high risk of SAH and guiding preventive strategies in the future.

Safety evaluation of vitamin K2 (menaquinone-7) via toxicological tests.

This study aims to evaluate the safety of MK-7 produced by fermentation process using a Bacillus subtilis var. natto strain for human ingestion via acute oral toxicity, repeated dose 90-day oral toxicity, 28-day recovery test, and genotoxicity tests. The acute oral toxicity test results indicated that all subjects survived at the dose of 5000 mg/kg with no toxic effects. For the repeated dose 90-day oral toxicity test, MK-7 was administered to rats at 500, 1500, and 4500 mg/kg for 90 d. No abnormal findings were detected in clinical observations or in clinical pathological and histopathological examinations. The no-observed-adverse-effect level(NOAEL) was determined to be 4500 mg/kg/d, the maximum dose tested. For the evaluation of genotoxicity, reverse mutation, chromosomal aberration, and micronucleus tests were performed. In the reversion mutation test, vitamin K2 did not induce reversion in bacterial strains, and no chromosomal abnormality was observed in the chromosomal abnormality test using Chinese hamster lung cells. In the micronucleus test, micronuclei were not induced using ICR mouse bone marrow cells. All the toxicity test results suggest that vitamin K2 produced by fermentation processes using Bacillus subtilis var. natto induced no toxicological changes under the experimental conditions.

Development of an Ephedrine In-House Matrix Reference Material and Its Application to Doping Analysis.

Biomatrix-based reference materials (RMs) improve the quality of laboratory test results by better representing actual samples. However, a matrix RM of ephedrine (EP) for threshold substances that require accurate analysis results has not yet been developed. Therefore, this study aimed to develop an in-house matrix RM for EP and subsequently apply it to analytical procedures. During the development of the in-house matrix EP RM, the system underwent homogeneity and stability studies. Additionally, it was subjected to interlaboratory comparison study in 11 laboratories, including 10 World Anti-Doping Agency (WADA)-accredited laboratories and our laboratory. Stability testing revealed no significant changes in the RM characteristics. For homogeneity, 10 random batches out of 200 were analyzed to confirm the uniformity within and between bottles. These results, combined with data from 11 laboratories, ensured retroactive validation. The traceability value of the in-house matrix EP RM was assigned as 9.83 ± 0.57 µg/mL (k = 2) by interlaboratory comparison studies and traceable uncertain evaluation. The feasibility of this method as a single calibration standard was confirmed in two laboratories. This substance is reliable and consistent for quality control during EP quantification, ensuring accurate and trustworthy outcomes. Consequently, this study establishes a framework and guidelines for producing in-house matrix RMs and serves as a reference for generating similar matrix RMs in other contexts.

Impaired Capillary Recruitment Capacity in Obesity: A Subgroup Analysis of Prospective Observational Study on Anesthesia Effects.

BACKGROUND This subgroup analysis of prospective observational research, involving 71 participants, compared the effects of anesthesia on microvascular reactivity in obese vs lean individuals using near-infrared spectroscopy and vascular occlusion tests. The correlation between the body mass index (BMI) and microvascular reactivity under general anesthesia was also investigated. MATERIAL AND METHODS This study enrolled adult patients classified as American Society of Anesthesiologists physical status I or II, undergoing elective surgery under general anesthesia. The microcirculatory variables measured before (Tpre) and 30 min following the induction of anesthesia (Tpost) were as follows: baseline tissue oxygen saturation (StO2), occlusion slope (∇occl), and recovery slope (∇recov). The patients were grouped according to their BMI (lean [BMI <25 kg/m²] vs obese [BMI ≥25 kg/m²]). Data are presented as medians and interquartile ranges. RESULTS There were 43 patients in the lean group and 28 in the obese group. At Tpre, baseline StO2, ∇occl, and ∇recov were not different between the 2 groups (P=0.860, 0.659, and 0.518, respectively). At Tpost, the baseline StO2 and ∇occl were not different between the 2 groups (P=0.343 and 0.791); however, the ∇recov was lower in the obese group than in the lean group (3.245 [2.737, 3.977] vs 4.131 [3.491, 4.843], P=0.003). At Tpost, BMI showed a moderate correlation with ∇recov (correlation coefficient: -0.319, P=0.007). CONCLUSIONS In obese patients, capillary recruitment capacity during general anesthesia is compromised compared to lean patients.

Cost-effectiveness of the anti-vascular endothelial growth factor intravitreal injection and panretinal photocoagulation for patients with proliferative diabetic retinopathy in South Korea.

BACKGROUND: We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea. METHODS: We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first. RESULTS: In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratio was $95,456 per quality-adjusted life-year (QALY) for PRP first, $34,375 per QALY for anti-VEGF injection first, and $33,405 per QALY for anti-VEGF injection only from a healthcare perspective. From the societal and payer perspective, strategy (2) was more cost-saving and effective than (1). In the probabilistic sensitivity analysis, only-PRP was cost-effective up to the willingness-to-pay (WTP) of about $42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy. CONCLUSION: In our study, the anti-VEGF injection for PDR was cost-effective from the payer and societal perspectives.

Application of Skyline software for detecting prohibited substances in doping control analysis.

As the number of prohibited drugs has been progressively increasing and analytical methods for detecting such substances are renewed continuously for doping control, the need for more sensitive and accurate doping analysis has increased. To address the urgent need for high throughput and accurate analysis, liquid chromatography with tandem mass spectrometry is actively utilized in case of most of the newly designated prohibited substances. However, because all mass spectrometer vendors provide data processing software that is incapable of handling other instrumental data, it is difficult to cover all doping analysis procedures, from method development to result reporting, on one platform. Skyline is an open-source and vendor-neutral software program invented for the method development and data processing of targeted proteomics. Recently, the utilization of Skyline has been expanding for the quantitative analysis of small molecules and lipids. Herein, we demonstrated Skyline as a simple platform for unifying overall doping control, including the optimization of analytical methods, monitoring of data quality, discovery of suspected doping samples, and validation of analytical methods for detecting newly prohibited substances. For method optimization, we selected the optimal collision energies for 339 prohibited substances. Notably, 195 substances exhibited a signal intensity increase of >110% compared with the signal intensity of the original collision energy. All data related to method validation and quantitative analysis were efficiently visualized, extracted, or calculated using Skyline. Moreover, a comparison of the time consumed and the number of suspicious samples screened in the initial test procedure highlighted the advantages of using Skyline over the commercially available software TraceFinder in doping control.

Glial cell proteome using targeted quantitative methods for potential multi-diagnostic biomarkers.

Glioblastoma is one of the most malignant primary brain cancer. Despite surgical resection with modern technology followed by chemo-radiation therapy with temozolomide, resistance to the treatment and recurrence is common due to its aggressive and infiltrating nature of the tumor with high proliferation index. The median survival time of the patients with glioblastomas is less than 15 months. Till now there has been no report of molecular target specific for glioblastomas. Early diagnosis and development of molecular target specific for glioblastomas are essential for longer survival of the patients with glioblastomas. Development of biomarkers specific for glioblastomas is most important for early diagnosis, estimation of the prognosis, and molecular target therapy of glioblastomas. To that end, in this study, we have conducted a comprehensive proteome study using primary cells and tissues from patients with glioblastoma. In the discovery stage, we have identified 7429 glioblastoma-specific proteins, where 476 proteins were quantitated using Tandem Mass Tag (TMT) method; 228 and 248 proteins showed up and down-regulated pattern, respectively. In the validation stage (20 selected target proteins), we developed quantitative targeted method (MRM: Multiple reaction monitoring) using stable isotope standards (SIS) peptide. In this study, five proteins (CCT3, PCMT1, TKT, TOMM34, UBA1) showed the significantly different protein levels (t-test: p value ≤ 0.05, AUC ≥ 0.7) between control and cancer groups and the result of multiplex assay using logistic regression showed the 5-marker panel showed better sensitivity (0.80 and 0.90), specificity (0.92 and 1.00), error rate (10 and 2%), and AUC value (0.94 and 0.98) than the best single marker (TOMM34) in primary cells and tissues, respectively. Although we acknowledge that the model requires further validation in a large sample size, the 5 protein marker panel can be used as baseline data for the discovery of novel biomarkers of the glioblastoma.

Untargeted Metabolomics Analysis Reveals Toxicity Based on the Sex and Sexual Maturity of Single Low-Dose DEHP Exposure.

Di-(2-Ethylhexyl) phthalate (DEHP) is a prevalent environmental endocrine disruptor that affects homeostasis, reproduction, and developmental processes. The effects of DEHP have been shown to differ based on sex and sexual maturity. This study examines the metabolic profiles of mature adult rats from both sexes, aged 10 weeks, and adolescent female rats, aged 6 weeks, following a single 5 mg/kg of body weight DEHP oral administration. An untargeted metabolomic analysis was conducted on urine samples collected at multiple times to discern potential sex- and maturity-specific DEHP toxicities. Various multivariate statistical analyses were employed to identify the relevant metabolites. The findings revealed disruptions to the steroid hormone and primary bile acid biosynthesis. Notably, DEHP exposure increased hyocholic, muricholic, and ketodeoxycholic acids in male rats. Moreover, DEHP exposure was linked to heart, liver, and kidney damage, as indicated by increased plasma GOT1 levels when compared to the levels before DEHP exposure. This study provides detailed insights into the unique mechanisms triggered by DEHP exposure concerning sex and sexual maturity, emphasizing significant distinctions in lipid metabolic profiles across the different groups. This study results deepens our understanding of the health risks linked to DEHP, informing future risk assessments and policy decisions.

Image Clarity Affects Tip-of-the-Tongue Rates for Faces.

Tip-of-the-tongue states are subjective experiences that unrecalled target words will be remembered. This study investigates if the visual fluency of familiar faces affects the likelihood of tip-of-the-tongue experiences (TOTs) as well as name recall and name recognition. To manipulate visual fluency, three levels of clarity for 396 celebrity faces were set: high, medium, and low clarity. Four hundred and twenty-nine participants were asked to recall the last names of the celebrities for all clarity levels, and, if they did not recall, to indicate if they experienced a TOT. Following the TOT question, they performed a name recognition test. Results showed that higher-clarity faces resulted in higher TOT rates than lower-clarity faces for unrecalled faces. Name recall was also higher for clearer faces. However, clarity level did not affect the correct answer rate on the name recognition test. These results support the view that perceptual cue-based factors influence TOT experiences.

Perioperative considerations of pyruvate dehydrogenase complex deficiency: a case report of two consecutive anesthesia.

BACKGROUND: Pyruvate dehydrogenase complex (PDHC) deficiency is a rare mitochondrial disorder caused by a genetic mutation affecting the activity of the PDHC enzyme, which plays a major role in the tricarboxylic cycle. Few cases of surgery or anesthesia have been reported. Moreover, there is no recommended anesthetic method. CASE: A 24-month-old child with a PDHC deficiency presented to the emergency room with respiratory failure, mental decline, systemic cyanosis, and lactic acidosis. During hospitalization period, the patient presented with pneumothorax, pneumoperitoneum, and multiple air pockets in the heart. Two surgeries were performed under general anesthesia using an inhalational anesthetic agent. The patient was discharged with home ventilation. CONCLUSIONS: Anesthesiologists should be wary of multiple factors when administering anesthesia to patients with PDHC deficiency, including airway abnormalities, acid-base imbalance, intraoperative fluid management, selection of appropriate anesthetics, and monitoring of lactic acid levels.

Comparison of safety and efficacy between therapeutic or intermediate versus prophylactic anticoagulation for thrombosis in COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) infections often have macrovascular or microvascular thrombosis and inflammation, which are known to be associated with a poor prognosis. Heparin has been hypothesized that administration of heparin with treatment dose rather than prophylactic dose for prevention of deep vein thrombosis in COVID-19 patients. METHODS: Studies comparing therapeutic or intermediate anticoagulation with prophylactic anticoagulation in COVID-19 patients were eligible. Mortality, thromboembolic events, and bleeding were the primary outcomes. PubMed, Embase, the Cochrane Library, and KMbase were searched up to July 2021. A meta-analysis was performed using random-effect model. Subgroup analysis was conducted according to disease severity. RESULTS: Six randomized controlled trials (RCTs) with 4,678 patients and four cohort studies with 1,080 patients were included in this review. In the RCTs, the therapeutic or intermediate anticoagulation was associated with significant reductions in the occurrence of thromboembolic events (5 studies, n=4,664; relative risk [RR], 0.72; P=0.01), and a significant increase in bleeding events (5 studies, n=4,667; RR, 1.88; P=0.004). In the moderate patients, therapeutic or intermediate anticoagulation was more beneficial than prophylactic anticoagulation in terms of thromboembolic events, but showed significantly higher bleeding events. In the severe patients, the incidence of thromboembolic and bleeding events in the therapeutic or intermediate. CONCLUSIONS: The study findings suggest that prophylactic anticoagulant treatment should be used in patients with moderate and severe COVID-19 infection groups. Further studies are needed to determine more individualized anticoagulation guidance for all COVID-19 patients.

Two Years of Experience and Methodology of Korean COVID-19 Living Clinical Practice Guideline Development.

BACKGROUND: In Korea, during the early phase of the coronavirus disease 2019 (COVID-19) pandemic, we responded to the uncertainty of treatments under various conditions, consistently playing catch up with the speed of evidence updates. Therefore, there was high demand for national-level evidence-based clinical practice guidelines for clinicians in a timely manner. We developed evidence-based and updated living recommendations for clinicians through a transparent development process and multidisciplinary expert collaboration. METHODS: The National Evidence-based Healthcare Collaborating Agency (NECA) and the Korean Academy of Medical Sciences (KAMS) collaborated to develop trustworthy Korean living guidelines. The NECA-supported methodological sections and 8 professional medical societies of the KAMS worked with clinical experts, and 31 clinicians were involved annually. We developed a total of 35 clinical questions, including medications, respiratory/critical care, pediatric care, emergency care, diagnostic tests, and radiological examinations. RESULTS: An evidence-based search for treatments began in March 2021 and monthly updates were performed. It was expanded to other areas, and the search interval was organized by a steering committee owing to priority changes. Evidence synthesis and recommendation review was performed by researchers, and living recommendations were updated within 3-4 months. CONCLUSION: We provided timely recommendations on living schemes and disseminated them to the public, policymakers and various stakeholders using webpages and social media. Although the output was successful, there were some limitations. The rigor of development issues, urgent timelines for public dissemination, education for new developers, and spread of several new COVID-19 variants have worked as barriers. Therefore, we must prepare systematic processes and funding for future pandemics.