Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip.

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient (Kp) and the apparent permeability (Papp). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems.

Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

Molecular determinants and signaling effects of PKA RIα phase separation.

Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in forming a non-canonical R:C complex, which recruits active PKA-C to RIα condensates to maintain low basal PKA activity in the cytosol. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.

Simultaneous Realization of Multilayer Interphases on a Ni-Rich NCM Cathode and a SiOx Anode by the Combination of Vinylene Carbonate with Lithium Difluoro(oxalato)borate.

Ni-rich NCM and SiOx electrode materials have garnered the most attention for advanced lithium-ion batteries (LIBs); however, severe parasitic reactions occurring at their interfaces are critical bottlenecks in their widespread application. In this study, an effective additive combination (VL) composed of vinylene carbonate (VC) and lithium difluoro(oxalato)borate (LiDFOB) is proposed for both Ni-rich NCM and SiOx electrode materials. The LiDFOB additive individually delivers inorganic-rich cathode-electrolyte interphase (CEI) and solid-electrolyte interphase (SEI) layers in anodic and cathodic polarizations before the VC additive. Subsequently, the VC additive is capable of the formation of additional CEI and SEI layers composed of relatively organic-rich components through an electrochemical reaction; thus, inorganic-organic hybridized CEI and SEI layers are simultaneously formed at the Ni-rich NCM and SiOx electrodes. Accordingly, the VL-assisted electrolyte exhibits remarkably prolonged cycling retention for the Ni-rich NCM cathode (86.5%) and SiOx anode (72.7%), whereas the standard electrolyte shows a substantial decrease in cycling retention for the Ni-rich NCM cathode (59.2%) and SiOx anode (18.1%). Further systematic analyses prove that VL-assisted electrolytes form effective interphases for Ni-rich NCM and SiOx electrodes simultaneously, thereby leading to stable and prolonged cycling behaviors of LIBs that offer high energy densities.

Microstructural characterization and inductively coupled plasma-reactive ion etching resistance of Y2O3-Y4Al2O9 composite under CF4/Ar/O2 mixed gas conditions.

In the semiconductor manufacturing process, when conducting inductively coupled plasma-reactive ion etching in challenging environments, both wafers and the ceramic components comprising the chamber's interior can be influenced by plasma attack. When ceramic components are exposed to long-term plasma environments, the eroded components must be replaced. Furthermore, non-volatile reactants can form and settle on semiconductor chips, acting as contaminants and reducing semiconductor production yield. Therefore, for semiconductor processing equipment parts to be utilized, it is necessary that they exhibit minimized generation of contaminant particles and not deviate significantly from the composition of conventionally used Al2O3 and Y2O3; part must also last long in various physicochemical etching environment. Herein, we investigate the plasma etching behavior of Y2O3-Y4Al2O9 (YAM) composites with a variety of mixing ratios under different gas fraction conditions. The investigation revealed that the etching rates and changes in surface roughness for these materials were significantly less than those of Y2O3 materials subjected to both chemical and physical etching. Microstructure analysis was conducted to demonstrate the minimization of crater formation. Mechanical properties of the composite were also analyzed. The results show that the composite can be commercialized as next-generation ceramic component in semiconductor processing equipment applications.

CT Findings of Azygos Venous System: Congenital Variants and Acquired Structural Changes.

The azygos venous system is a crucial conduit of the posterior thorax and potentially vital collateral pathway. However, it is often overlooked clinically and radiologically. This pictorial essay reviews the normal azygos venous anatomy and CT findings of congenital variations and structural changes associated with acquired pathologies.

Association of daily carbohydrate intake with intermuscular adipose tissue in Korean individuals with obesity: a cross-sectional study.

BACKGROUND/OBJECTIVES: The prevalence of obesity, a worldwide pandemic, has been increasing steadily in Korea. Reports have shown that increased intermuscular adipose tissue (IMAT) is associated with an increased risk of cardiovascular disease, independent of body mass index. However, the relationship between dietary intake and IMAT accumulation in the Korean population remains undetermined. The objective of this study was to evaluate regional fat compartments using advanced magnetic resonance imaging (MRI) techniques. We also aimed to investigate the association between IMAT amounts and dietary intake, including carbohydrate intake, among Korean individuals with obesity. SUBJECTS/METHODS: This cross-sectional study, performed at a medical center in South Korea, recruited 35 individuals with obesity (15 men and 20 women) and classified them into 2 groups according to sex. Anthropometry was performed, and body fat distribution was measured using MRI. Blood parameters, including glucose and lipid profiles, were analyzed using commercial kits. Linear regression analysis was used to test whether the IMAT was associated with daily carbohydrate intake. RESULTS: Carbohydrate intake was positively associated with IMAT in all individuals, with adjustments for age, sex, height, and weight. No significant differences in blood indicators were found between the sexes. CONCLUSIONS: Regardless of sex and age, higher carbohydrate intake was strongly correlated with greater IMAT accumulation. This suggests the need to better understand sex differences and high carbohydrate diet patterns in relation to the association between obesity and metabolic risk, which may help reduce obesity prevalence.

Daraesoon (shoot of hardy kiwi) mitigates hyperglycemia in db/db mice by alleviating insulin resistance and inflammation.

BACKGROUND/OBJECTIVES: Mitigating insulin resistance and hyperglycemia is associated with a decreased risk of diabetic complications. The effect of Daraesoon (shoot of hardy kiwi, Actinidia arguta) on hyperglycemia was investigated using a type 2 diabetes animal model. MATERIALS/METHODS: Seven-week-old db/db mice were fed either an AIN-93G diet or a diet containing 0.4% of a 70% ethanol extract of Daraesoon, whereas db/+ mice were fed the AIN-93G diet for 7 weeks. RESULTS: Consumption of Daraesoon significantly reduced serum glucose and blood glycated hemoglobin levels, along with homeostasis model assessment for insulin resistance in db/db mice. Conversely, Daraesoon elevated the serum adiponectin levels compared to the db/db control group. Furthermore, Daraesoon significantly decreased both serum and hepatic triglyceride levels, as well as serum total cholesterol levels. Additionally, consumption of Daraesoon resulted in decreased hepatic tumor necrosis factor-α and monocyte chemoattractant protein-1 expression. CONCLUSIONS: These results suggest that hypoglycemic effect of Daraesoon is mediated through the improvement of insulin resistance and the downregulation of pro-inflammatory cytokine expression in db/db mice.

Constructing the Interconnected Charge Transfer Pathways in Sulfur Composite Cathode for All-Solid-State Lithium-Sulfur Batteries.

All-solid-state lithium-sulfur batteries (ASSLSBs) have advantageous features, such as high energy, low costs, enhanced safety, and no polysulfide dissolution. However, the use of sulfur as an active material in all-solid-state batteries is difficult because of its ionic and electrical insulating properties. Herein, we introduce a flower-shaped composite material consisting of MoS2 nanoparticles and sulfur, designed to establish interconnected ionic and electrical conduction pathways at the cathode. As a host material, MoS2 nanoparticles with a large specific surface area can coconduct Li ions and electrons, possessing the potential for effectively utilizing sulfur. However, MoS2 nanoparticles are prone to physical-electrochemical isolation by being surrounded by sulfur due to their crumpling property in the process of mixing and impregnation with sulfur. This problem is addressed by mildly milling the MoS2 nanoparticles and sulfur, after which melt diffusion is applied to generate uniform MoS2/sulfur composite materials to establish an interconnected conducting pathway within the composite. A sulfide solid electrolyte (Li6PS5Cl)-based ASSLSB incorporating the proposed MoS2/sulfur composite demonstrates a stable operation over 1000 cycles with a Coulombic efficiency of nearly 100%. This study emphasizes the significance of the structural design of the sulfur composite material on top of the intrinsic properties of the material for high-performance ASSLSBs.

Robust anion exchange membranes based on ionic liquid grafted chitosan/polyvinyl alcohol/quaternary ammonium functionalized silica for polymer electrolyte membrane fuel cells.

In this study, 1-bromohexyl-1methylpiperidinium bromide (Br-6-MPRD) ionic liquid grafted quaternized chitosan (QCS) and polyvinyl alcohol (PVA) blends were composited with glycidyl trimethyl ammonium chloride (GTMAC) quaternized silica (QSiO2) at different dosages. Glutaraldehyde (GA) crosslinked the membranes and then processed into hydroxide form with an aqueous potassium hydroxide solution. The resultant IL-QCS/PVA/QSiO2 membranes exhibit significantly improved ionic conductivity, moderate water absorption and swelling ratio compared with the pristine IL-QCS/PVA anion exchange membrane (AEM). Among them, the hydroxide ion conductivity and power density of IL-QCS/PVA/QSiO2-7 membrane can reach up to 78 mS cm-1 at 80 °C and 115 mW cm-2 at 60 °C respectively. In addition, IL-QCS/PVA/QSiO2 membranes have excellent thermal, mechanical, and chemical stabilities, which can meet the application requirements of AEM for fuel cells.

Taurine supplementation alters gene expression profiles in white adipose tissue of obese C57BL/6J mice: Inflammation and lipid synthesis perspectives.

This work aimed to identify the mechanisms by which taurine exerts its anti-obesity effects in the C57BL/6J ob/ob mice model and determine if taurine supplementation increases the amelioration of inflammation and lipogenesis linked genes in the adipose and liver tissues. Three groups of C57BL/6J mice were fed a standard chow diet for a period of 10 weeks the C57BL/6J normal group, the C57BL/6J ob/ob negative control group with no taurine intake and C57BL/6J ob/ob taurine group with taurine intake. Real time PCR was used to examine the gene expression profile in the experimental groups intrascapular brown adipose tissue (BAT), inguinal white adipose tissue (WAT) and liver. TNF-alpha, Ccl2, Adgre and illb genes that are associated with inflammation were found to have varying level of expression in the three tissues. In comparison to BAT and liver these genes were expressed at a much lower level in WAT, with enhanced serum adiponectin levels.

Endothelial periostin regulates vascular remodeling by promoting endothelial dysfunction in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with extracellular matrix (ECM) deposition, vascular cell hyperproliferation, and neointima formation in the small pulmonary artery. Endothelial dysfunction is considered a key feature in the initiation of vascular remodeling. Although vasodilators have been used for the treatment of PAH, it remains a life-threatening disease. Therefore, it is necessary to identify novel therapeutic targets for PAH treatment. Periostin (POSTN) is a secretory ECM protein involved in physiological and pathological processes, such as tissue remodeling, cell adhesion, migration, and proliferation. Although POSTN has been proposed as a potential target for PAH treatment, its role in endothelial cells has not been fully elucidated. Here, we demonstrated that POSTN upregulation correlates with PAH by analyzing a public microarray conducted on the lung tissues of patients with PAH and biological experimental results from in vivo and in vitro models. Moreover, POSTN overexpression leads to ECM deposition and endothelial abnormalities such as migration. We found that PAH-associated endothelial dysfunction is mediated at least in part by the interaction between POSTN and integrin-linked protein kinase (ILK), followed by activation of nuclear factor-κB signaling. Silencing POSTN or ILK decreases PAH-related stimuli-induced ECM accumulation and attenuates endothelial abnormalities. In conclusion, our study suggests that POSTN serves as a critical regulator of PAH by regulating vascular remodeling, and targeting its role as a potential therapeutic strategy for PAH.

The Link of COVID-19-Related Beliefs and Information Sources to Ageism: Myth or Reality?

This study aimed to understand ambivalent ageism among younger adults during the pandemic by examining whether younger adults' beliefs around COVID-19 and the sources from which they received COVID-19 information were associated with the intensity of their ageism. For this aim, survey data were collected from individuals ages 18 to 44 between July and September 2021. Multiple hierarchical regression analysis revealed that benevolent ageism was more intense than hostile ageism when two subscales of ambivalent ageism-benevolent and hostile-were compared. Hispanic or Latinx respondents showed less intense ambivalent ageism than non-Hispanic and non-Latinx respondents. The respondents' beliefs about safety measures and the prioritization of medical resources were significantly associated with the intensity of their ageism. Receiving COVID-19 information via traditional media and social media was also significantly associated with more intense ageism. These findings indicate that social work advocacy should continue to combat ageism in times of crisis.

Mortality after cardiac arrest in children less than 2 years: relevant factors.

BACKGROUND: There are only scant studies of predicting outcomes of pediatric resuscitation due to lack of population-based data. This study aimed to determine variable factors that may impact the survival of resuscitated children aged under 24 months. METHODS: This is a retrospective study of 66 children under 24 months. Cardiopulmonary resuscitation (CPR) with pediatric advanced life support guideline was performed uniformly for all children. Linear regression analysis with variable factors was conducted to determine impacts on mortality. RESULT: Factors with statistically significant increases in mortality were the number of administered epinephrine (p value < 0.001), total CPR duration (p value < 0.001), in-hospital CPR duration of out-hospital cardiac arrest (p value < 0.001), and changes in cardiac rhythm (p value < 0.040). However, there is no statistically significant association between patient outcomes and remaining factors such as age, sex, underlying disease, etiology, time between last normal to CPR, initial CPR location, initial cardiac rhythm, venous access time, or inotropic usage. CONCLUSION: More than 10 times of epinephrine administration and CPR duration longer than 30 minutes were associated with a higher mortality rate, while each epinephrine administration and prolonged CPR time increased mortality. IMPACT STATEMENT: This study analyzed various factors influencing mortality after cardiac arrest in patients under 24 months. Increased number of administered epinephrine and prolonged cardiopulmonary resuscitation duration do not increase survival rate in patients under 24 months. In patients with electrocardiogram rhythm changes during CPR, mortality increased when the rhythm changed into asystole in comparison to no changes occurring in the rhythm.

Transcriptome analysis of skeletal muscle in dermatomyositis, polymyositis, and dysferlinopathy, using a bioinformatics approach.

Background: Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies. Dysferlinopathy, caused by a dysferlin gene mutation, usually presents in late adolescence with muscle weakness, degenerative muscle changes are often accompanied by inflammatory infiltrates, often resulting in a misdiagnosis as polymyositis. Objective: To identify differential biological pathways and hub genes related to polymyositis, dermatomyositis and dysferlinopathy using bioinformatics analysis for understanding the pathomechanisms and providing guidance for therapy development. Methods: We analyzed intramuscular ribonucleic acid (RNA) sequencing data from seven dermatomyositis, eight polymyositis, eight dysferlinopathy and five control subjects. Differentially expressed genes (DEGs) were identified by using DESeq2. Enrichment analyses were performed to understand the functions and enriched pathways of DEGs. A protein-protein interaction (PPI) network was constructed, and clarified the gene cluster using the molecular complex detection tool (MCODE) analysis to identify hub genes. Results: A total of 1,048, 179 and 3,807 DEGs were detected in DM, PM and dysferlinopathy, respectively. Enrichment analyses revealed that upregulated DEGs were involved in type 1 interferon (IFN1) signaling pathway in DM, antigen processing and presentation of peptide antigen in PM, and cellular response to stimuli in dysferlinopathy. The PPI network and MCODE cluster identified 23 genes related to type 1 interferon signaling pathway in DM, 4 genes (PDIA3, HLA-C, B2M, and TAP1) related to MHC class 1 formation and quality control in PM, and 7 genes (HSPA9, RPTOR, MTOR, LAMTOR1, LAMTOR5, ATP6V0D1, and ATP6V0B) related to cellular response to stress in dysferliniopathy. Conclusion: Overexpression of genes related to the IFN1 signaling pathway and major histocompatibility complex (MHC) class I formation was identified in DM and PM, respectively. In dysferlinopathy, overexpression of HSPA9 and the mTORC1 signaling pathway genes was detected.

Simple and Multiplexed Detection of Nucleic Acid Targets Based on Fluorescent Ring Patterns and Deep Learning Analysis.

Simple diagnostic tests for nucleic acid targets can provide great advantages for applications such as rapid pathogen detection. Here, we developed a membrane assay for multiplexed detection of nucleic acid targets based on the visualization of two-dimensional fluorescent ring patterns. A droplet of the assay solution is applied to a cellulose nitrate membrane, and upon radial chromatographic flow and evaporation of the solvent, fluorescent patterns appear under UV irradiation. The target nucleic acid is isothermally amplified and is immediately hybridized with fluorescent oligonucleotide probes in a one-pot reaction. We established the fluorescent ring assay integrated with isothermal amplification (iFluor-RFA = isothermal fluorescent ring-based radial flow assay), and feasibility was tested using nucleic acid targets of the receptor binding domain (RBD) and RNA-dependent RNA polymerase (RdRp) genes of SARS-CoV-2. We demonstrate that the iFluor-RFA method is capable of specific and sensitive detection in the subpicomole range, as well as multiplexed detection even in complex solutions. Furthermore, we applied deep learning analysis of the fluorescence images, showing that patterns could be classified as positive or negative and that quantitative amounts of the target could be predicted. The current technique, which is a membrane pattern-based nucleic acid assay combined with deep learning analysis, provides a novel approach in diagnostic platform development that can be versatilely applied for the rapid detection of infectious pathogens.

Acute Necrotizing Myelitis Associated with COVID-19.

Acute ascending hemorrhagic longitudinally extensive transverse myelitis is a rare inflammatory demyelinating disorder, which invades several vertebral segments and progresses rapidly and manifests severe symptoms. We present a case of acute necrotizing myelitis associated with COVID-19 infection. A 10-year-old female, with no previous medical history and no prior administration of COVID-19 vaccination, contracted COVID-19 in early April 2022. Two weeks later, she suffered from severe posterior neck pain and also presented with motor weakness and numbness in both lower extremities, making it difficult to walk independently and spontaneously void urine. Initial spinal cord MR showed longitudinally segmental extensive T2 hyperintensities. Cerebrospinal fluid (CSF) analysis revealed elevated red blood cell, normal white blood cell, and elevated protein levels and absence of oligoclonal bands. CSF culture and viral polymerase chain reaction were negative. Autoimmune work-up was negative. She was started on intravenous methylprednisolone 1g/day for 5 days and immunoglobulin (Ig) 2 g/kg for 5 days. She was also treated with six courses of therapeutic plasma exchange. Nevertheless, her pain and motor weakness persisted. She eventually developed respiratory failure. Follow-up MR presented a newly noted small hemorrhagic component. She was consequently treated with two additional courses of methylprednisolone and Ig. At 6-months follow-up, neurological examination showed improvement with normal sensory function and motor grade IV function in both upper extremities. We present the case of acute necrotizing myelitis associated with COVID-19 infection. Multiple courses of methylprednisolone and Ig showed mild improvement in motor and sensory function. However, poor prognosis was unavoidable due to rapid progression of the disease.

The Impact of Taurine on Obesity-Induced Diabetes Mellitus: Mechanisms Underlying Its Effect.

This review explores the potential benefits of taurine in ameliorating the metabolic disorders of obesity and type 2 diabetes (T2D), highlighting the factors that bridge these associations. Relevant articles and studies were reviewed to conduct a comprehensive analysis of the relationship between obesity and the development of T2D and the effect of taurine on those conditions. The loss of normal ß-cell function and development of T2D are associated with obesity-derived insulin resistance. The occurrence of diabetes has been linked to the low bioavailability of taurine, which plays critical roles in normal ß-cell function, anti-oxidation, and anti-inflammation. The relationships among obesity, insulin resistance, ß-cell dysfunction, and T2D are complex and intertwined. Taurine may play a role in ameliorating these metabolic disorders through different pathways, but further research is needed to fully understand its effects and potential as a therapeutic intervention.

A Meta-Analysis of the Effects of Comprehensive Sexuality Education Programs on Children and Adolescents.

Childhood and adolescence are crucial periods for developing one's awareness of sexuality. Comprehensive Sexuality Education (CSE) during these stages is essential for overall growth, fostering healthy self-concepts, and addressing diverse sexual issues among children and adolescents globally. A meta-analysis was conducted to analyze the effectiveness of CSE programs. A literature search was performed on EMBASE, PubMed, CINAHL, Cochrane Library, and PsycInfo for studies published before 14 June 2023, and based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used the Comprehensive Meta-Analysis (CMA, V4) software version 4.0 for the analysis and interpreted the effect sizes according to Cohen's definition. Between 2011 and 2020, 21 studies on CSE were published, with the United States having the most publications (17). Of the 34 studies reviewed, 20 were randomized controlled trials. The primary population for CSE was middle/high school students (15), with the most frequent age range being 10-19 years (26). The overall effect size of CSE was significant (effect size = 1.31, p < 0.001), with cognition (effect size = 5.76, p < 0.001) being the most significant. CSE is an effective educational tool for children and adolescents with a significant impact on variables such as cognition and abstinence. It should be incremental from childhood and adolescence to adulthood.

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.