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Abstract In our search for novel small molecules activating procaspase-3, we have designed and synthesized two series of novel (E)-N'-arylidene-2-(2-oxoindolin-1-yl)acetohydrazides (4) and (Z)-2-(5-substituted-2-oxoindolin-1-yl)-N'-(2-oxoindolin-3-ylidene)acetohydrazides (5). Cytotoxic evaluation revealed that the compounds showed notable cytotoxicity toward three human cancer cell lines: colon cancer SW620, prostate cancer PC-3, and lung cancer NCI-H23. Especially, six compounds, including 4f–h and 4n–p, exhibited cytotoxicity equal or superior to positive control PAC-1, the first procaspase-3 activating compound. The most potent compound 4o was three- to five-fold more cytotoxic than PAC-1 in three cancer cell lines tested. Analysis of compounds effects on cell cycle and apoptosis demonstrated that the representative compounds 4f, 4h, 4n, 4o and 4p (especially 4o) accumulated U937 cells in S phase and substantially induced late cellular apoptosis. The results show that compound 4o would serve as a template for further design and development of novel anticancer agents.

Abstract Background Brain metastases frequently occur in patients with non‐small cell lung cancer (NSCLC) resulting in a poor prognosis. Here, we investigated the association between PD‐L1 expression and brain metastasis in patients with NSCLC and its clinical significance. Methods A total of 270 patients diagnosed with metastatic NSCLC who underwent PD‐L1 testing on their tumor tissue between January 2017 and March 2019 were retrospectively reviewed. The VENTANA PD‐L1 (SP263) assay was used, and positive PD‐L1 expression was defined as staining in ≥1% of tumor cells. Results Positive PD‐L1 expression was observed in 181 (67.0%) patients, and 74 (27.4%) patients had brain metastasis at diagnosis. Synchronous brain metastases were more frequently observed in PD‐L1‐positive compared with PD‐L1‐negative patients (31.5% vs. 19.1%, p = 0.045). Multiple logistic regression analysis identified positive PD‐L1 expression (odds ratio [OR]: 2.24, p = 0.012) as an independent factor associated with synchronous brain metastasis, along with the histological subtype of nonsquamous cell carcinoma (OR: 2.84, p = 0.003). However, the incidence of central nervous system (CNS) progression was not associated with PD‐L1 positivity, with a two‐year cumulative CNS progression rate of 26.3% and 28.4% in PD‐L1‐positive and PD‐L1‐negative patients, respectively (log rank p = 0.944). Furthermore, positive PD‐L1 expression did not affect CNS progression or overall survival in patients with synchronous brain metastasis (long rank p = 0.513 and 0.592, respectively). Conclusions Initial brain metastases are common in NSCLC patients with positive PD‐L1 expression. Further studies are necessary to understand the relationship between early brain metastasis and cancer immunity.

Abstract Generic skills are essential because today's jobs and the future of work require flexibility, initiative, and the ability to undertake many different tasks. While higher education graduates in the Gulf Cooperation Council (GCC) countries recognize the contribution of these skills in their academics and workplace performance, generic skills development is not a consistent part of their education, which has led to socioeconomic challenges. If higher education placed a great emphasis on developing generic skills, students would expect to have pragmatic benefits, such as academic success, boosting workplace performance, positive interpersonal relationships, and better health and overall well-being. To the best of our knowledge, no systematic review has been conducted to examine generic skills development outcomes in the GCC. Hence, this systematic review aims to identify, evaluate, and summarize findings from peer-reviewed and policy-related studies that have documented generic skills development outcomes in the GCC countries, including identifying broad definitions used and areas for future research. The findings demonstrated conclusive evidence regarding the effectiveness of generic skills development at the higher education level in enhancing graduate outcomes in employability promotion skills, enhancing stakeholder engagement in curriculum and instruction, academic or workplace performance, influences on health, and effects on social dimensions.

This study investigates the application of immersive experience services to leisure facilities for the successful aging of the elderly. In the past, the social image of the elderly was that of passive beings who needed care due to physical and cognitive decline associated with biological aging. However, the concept of “successful aging” actively highlighting the positive aspects of aging and trying to promote longer and healthier life has started to acquire importance in recent years. In this context, elderly welfare centers can be described as facilities that encourage learning, leisure, and social activities of the elderly with impaired physical and cognitive functions. The use of recent immersive experience technologies such as virtual reality and mixed reality (MR), in order to mitigate physical and spatial constraints and provide an immersion into the desired environment and situation, could contribute substantially to the health of the elderly. However, the application of immersive technologies is concentrated on the provision of entertainment, education, and medical facilities. The number of previous studies on the immersion experiences of the elderly is limited, and the connection between immersion experiences and various services and programs that promote successful aging at elderly welfare centers requires further research. This study analyzes the function and space of the elderly welfare centers for successful aging through the review of previous studies and classifies immersion technology categories based on the review of the relevant literature. The study analyzes the health benefits of immersive experience technologies and related products and services and proposes an immersive experience service model for the elderly welfare center. The results of the study could provide a valuable input for the spatial application of immersive experience technologies for successful aging in the future.

Gap junctions (GJs) are intercellular channels composed of connexins. Cellular molecules smaller than 1 kDa can diffuse through GJs by a process termed gap junctional intercellular communication (GJIC), which plays essential roles in various pathological and physiological conditions. Gambogic acid (GA), a major component of a natural yellow dye, has been used as traditional medicine and has been reported to have various therapeutic effects, including an anti-cancer effect. In this study, two different GJ assay methods showed that GA and its analogs inhibited GJIC. The inhibition was rapidly reversible and was not mediated by changes in surface expression or S368 phosphorylation of Cx43, cellular calcium concentration, or redox state. We also developed an assay system to measure the intercellular communication induced by Cx40, Cx30, and Cx43. Dihydrogambogic acid (D-GA) potently inhibited GJIC by Cx40 (IC50 = 5.1 μM), whereas the IC50 value of carbenoxolone, which is known as a broad spectrum GJIC inhibitor, was 105.2 μM. Thus, D-GA can act as a pharmacological tool for the inhibition of Cx40.

Vibrio parahaemolyticus can cause gastrointestinal illness through consumption of seafood. Despite frequent food-borne outbreaks of V. parahaemolyticus, only 19 strains have subjected to complete whole-genome analysis. In this study, a novel strain of V. parahaemolyticus, designated FORC_022 (Food-borne pathogen Omics Research Center_022), was isolated from soy sauce marinated crabs, and its genome and transcriptome were analyzed to elucidate the pathogenic mechanisms. FORC_022 did not include major virulence factors of thermostable direct hemolysin (tdh) and TDH-related hemolysin (trh). However, FORC_022 showed high cytotoxicity and had several V. parahaemolyticus islands (VPaIs) and other virulence factors, such as various secretion systems (types I, II, III, IV, and VI), in comparative genome analysis with CDC_K4557 (the most similar strain) and RIMD2210633 (genome island marker strain). FORC_022 harbored additional virulence genes, including accessory cholera enterotoxin, zona occludens toxin, and tight adhesion (tad) locus, compared with CDC_K4557. In addition, O3 serotype specific gene and the marker gene of pandemic O3:K6 serotype (toxRS) were detected in FORC_022. The expressions levels of genes involved in adherence and carbohydrate transporter were high, whereas those of genes involved in motility, arginine biosynthesis, and proline metabolism were low after exposure to crabs. Moreover, the virulence factors of the type III secretion system, tad locus, and thermolabile hemolysin were overexpressed. Therefore, the risk of foodborne-illness may be high following consumption of FORC_022 contaminated crab. These results provided molecular information regarding the survival and pathogenesis of V. parahaemolyticus FORC_022 strain in contaminated crab and may have applications in food safety.

Toxigenic Vibrio cholerae strains arise upon infection and integration of the lysogenic cholera toxin phage, the CTX phage, into bacterial chromosomes. The V. cholerae serogroup O1 strains identified to date can be broadly categorized into three main groups: the classical biotype strains, which harbor CTX-cla; the prototype El Tor strains (Wave 1 strains), which harbor CTX-1; and the atypical El Tor strains, which harbor CTX-2 (Wave 2 strains) or CTX-3~6 (Wave 3 strains). The efficiencies of replication and transmission of CTX phages are similar, suggesting the possibility of existence of more diverse bacterial strains harboring various CTX phages and their arrays in nature. In this study, a set of V. cholerae strains was constructed by the chromosomal integration of CTX phages into strains that already harbored CTX phages or those that did not harbor any CTX phage or RS1 element. Strains containing repeats of the same kind of CTX phage, strains containing the same kind of CTX phage in each chromosome, strains containing alternative CTX phages in one chromosome, or containing different CTX phages in each chromosome have been constructed. Thus, strains with any CTX array can be designed and constructed. Moreover, the strains described in this study contained the toxT-139F allele, which enhances the expression of TcpA and cholera toxin. These characteristics are considered to be important for cholera vaccine development. Once their capacity to provoke immunity in human against V. cholerae infection is evaluated, some of the generated strains could be developed further to yield cholera vaccine strains.

Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB), exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy.

Collapsin response mediator protein (CRMP)-2 and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are associated with common physiological functions such as neuronal polarity, axonal outgrowth and synaptic strength, as well as various brain disorders including epilepsy. But, their regulatory and functional links are unclear. Alterations in CRMP-2 expression that lead to its functional changes are implicated in brain disorders such as epilepsy. Here, we investigate whether changes in CRMP-2 expression, possibly regulated by mTOR-related signaling, correlates with neuronal growth and viability. Inhibition of mTOR and/or phosphoinositol-3-kinase (PI3K) led to deceased p-S6K, and p-S6 signals also reduced CRMP-2 expression. These changes corresponded to inhibition of neuronal viability and proliferation in cultured hippocampal HT-22 cells under both basal serum-free and serum- or insulin-induced mTOR pathway-activated conditions. CRMP-2 expression tended to be increased by mTOR activation, indicated by an increase in p-S6/S6 level, in pentylentetrazole (PTZ)-induced epileptic rat hippocampal tissues was also significantly reduced by mTOR inhibition. Knockdown of CRMP-2 by si-RNA reduced the neuronal viability without changes in mTOR signaling, and overexpression of CRMP-2 recovered the glutamate-induced neurotoxicity and decrease of mTOR signaling in HT-22 cells. In conclusion, CRMP-2 protein expression controlled by the PI3K-mTOR-S6K signaling axis exerts its important functional roles in neuronal growth and survival.

Induction of differentiation is a therapeutic strategy in neuroblastoma, a common pediatric cancer of the sympathetic nervous system. The homeobox protein HOXC9 is a key regulator of neuroblastoma differentiation. To gain a molecular understanding of the function of HOXC9 in promoting differentiation of neuroblastoma cells, we conducted a genome-wide analysis of the HOXC9-induced differentiation program by microarray gene expression profiling and chromatin immunoprecipitation in combination with massively parallel sequencing (ChIP-seq). Here we describe in detail the experimental system, methods, and quality control for the generation of the microarray and ChIP-seq data associated with our recent publication [1].

The identification of the sex of chickens or chicken cells has biological and industrial significance. In the laboratory, molecular techniques have utilized W chromosome-specific repetitive DNA sequence fragments, such as Xho I or EcoR I family, for gender identification in chickens. The present study examined a rapid and reliable fluorescence in situ hybridization (FISH) procedure for chick sex identification using an easily obtainable sample: uncultured feather pulp cells. A chicken W chromosome-specific 416-bp partial DNA fragment of Xho I family was digoxigenin-labeled by polymerase chain reaction and used as an FISH probe for chick sex identification. In 60 newly hatched chicks, 28 of the chicks that were subsequently identified as females by the visual identification of ovaries exhibited a positive W-specific probe signal in their feather follicle cells; the others were negative for the W-specific probe signal and were identified as males by the presence of testes. Therefore, the FISH results were in perfect agreement with the anatomical analysis. We suggest that this FISH technique using feather follicle cells and the W-specific DNA probe will be useful for a fast, convenient and accurate sex diagnosis of newly hatched chicks.

The concepts of both protein glycosylation and cellular signaling have been influenced by O-linked-β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) on the hydroxyl group of serine or threonine residues. Unlike conventional protein glycosylation, O-GlcNAcylation is localized in the nucleocytoplasm and its cycling is a dynamic process that operates in a highly regulated manner in response to various cellular stimuli. These characteristics render O-GlcNAcylation similar to phosphorylation, which has long been considered a major regulatory mechanism in cellular processes. Various efficient chemical approaches and novel mass spectrometric (MS) techniques have uncovered numerous O-GlcNAcylated proteins that are involved in the regulation of many important cellular events. These discoveries imply that O-GlcNAcylation is another major regulator of cellular signaling. However, in contrast to phosphorylation, which is regulated by hundreds of kinases and phosphatases, dynamic O-GlcNAc cycling is catalyzed by only two enzymes: uridine diphospho-N-acetyl-glucosamine:polypeptide β-N-acetylglucosaminyl transferase (OGT) and β-D-N-acetylglucosaminidase (OGA). Many useful chemical tools have recently been used to greatly expand our understanding of the extensive crosstalk between O-GlcNAcylation and phosphorylation and hence of cellular signaling. This review article describes the various useful chemical tools that have been developed and discusses the considerable advances made in the O-GlcNAc field.

Secoisolariciresinol diglucoside (SDG), the most abundant lignan in flaxseed, is metabolized by the ruminal microbiota into enterolignans, which are strong antioxidants. Enterolactone (EL), the main mammalian enterolignan produced in the rumen, is transferred into physiological fluids, with potentially human health benefits with respect to menopausal symptoms, hormone-dependent cancers, cardiovascular diseases, osteoporosis and diabetes. However, no information exists to our knowledge on bacterial taxa that play a role in converting plant lignans into EL in ruminants. In order to investigate this, eight rumen cannulated cows were used in a double 4 × 4 Latin square design and fed with four treatments: control with no flax meal (FM), or 5%, 10% and 15% FM (on a dry matter basis). Concentration of EL in the rumen increased linearly with increasing FM inclusion. Total rumen bacterial 16S rRNA concentration obtained using Q-PCR did not differ among treatments. PCR-T-RFLP based dendrograms revealed no global clustering based on diet indicating between animal variation. PCR-DGGE showed a clustering by diet effect within four cows that had similar basal ruminal microbiota. DNA extracted from bands present following feeding 15% FM and absent with no FM supplementation were sequenced and it showed that many genera, in particular Prevotella spp., contributed to the metabolism of lignans. A subsequent in vitro study using selected pure cultures of ruminal bacteria incubated with SDG indicated that 11 ruminal bacteria were able to convert SDG into secoisolariciresinol (SECO), with Prevotella spp. being the main converters. These data suggest that Prevotella spp. is one genus playing an important role in the conversion of plant lignans to human health beneficial antioxidants in the rumen.

The supralittoral environment, at the transition between sea and land, is characterized by harsh conditions for life. Nonetheless, evolution of terrestrial isopods (Oniscidea), the only group of Crustacea fully adapted to live on land, appears to have involved a transitional step within the supralittoral. The two most basal oniscidean lineages (Ligiidae and Tylidae) have representatives that successfully colonized the supralittoral. One of them is the genus Tylos, which is found exclusively in supralittoral sandy beaches from tropical and subtropical coasts around the world. Comprehensive phylogenetic hypotheses for this genus are lacking, which are necessary for understanding the evolution and biogeography of a lineage that successfully diversified in the harsh sea-land interface. Herein, we studied the phylogenetic relationships among 17 of the 21 currently recognized species of the genus Tylos, based on sequences from four mitochondrial genes (Cytochrome Oxidase I, Cytochrome b, 16S rDNA, and 12S rDNA). Maximum Likelihood and Bayesian phylogenetic analyses identified several lineages with deep divergences and discrete geographic distributions. Phylogenetic and distributional patterns of Tylos provide important clues on the biogeography and evolution of this group. Large divergences among the most basal clades are consistent with ancient splits. Due to the biological characteristics of Tylos, which likely prevent dispersal of these isopods across vast oceanic scales, we argue that tectonic events rather than trans-oceanic dispersal explain the distribution of Tylos in different continents. Overwater dispersal, however, likely enabled range expansions within some basins, and explains the colonization of volcanic oceanic islands. Present-day distributions were also likely influenced by sea level and climate changes. High levels of allopatric cryptic genetic differentiation are observed in different regions of the world, implying that the dispersal abilities of Tylos isopods are more limited than previously thought. Our results indicate that a taxonomic revision of this group is necessary.

BackgroundExtensively drug-resistant Acinetobacter baumannii (XDR-Ab) has emerged as a major nosocomial pathogen, but optimal treatment regimens are unknown. Although solid organ transplant (SOT) recipients are particularly susceptible to XDR-Ab infections, studies in this population are limited. Our objectives were to determine the epidemiology, clinical characteristics and outcomes of XDR-Ab infections among SOT patients.MethodsA retrospective study of SOT recipients at our center who were colonized or infected with XDR-Ab between November 2006 and December 2011 was conducted. Among infected patients, the primary outcome was survival at 28 days. Secondary outcomes included survival at 90 days and clinical success at 28 days, and XDR-Ab infection recurrence.ResultsXDR-Ab was isolated from 69 SOT patients, of whom 41% (28) and 59% (41) were colonized and infected, respectively. Infections were significantly more common among cardiothoracic than abdominal transplant recipients (p=0.0004). Ninety-eight percent (40/41) of patients had respiratory tract infections, most commonly ventilator-associated pneumonia (VAP; 88% [36/41]). Survival rates at 28 and 90 days were 54% (22/41) and 46% (19/41), respectively. Treatment with a colistin-carbapenem regimen was an independent predictor of 28-day survival (p=0.01; odds ratio=7.88 [95% CI: 1.60-38.76]). Clinical success at 28 days was achieved in 49% (18/37) of patients who received antimicrobial therapy, but 44% (8/18) of successes were associated with infection recurrence within 3 months. Colistin resistance emerged in 18% (2/11) and 100% (3/3) of patients treated with colistin-carbapenem and colistin-tigecycline, respectively (p=0.03).ConclusionsXDR-Ab causes VAP and other respiratory infections following SOT that are associated with significant recurrence and mortality rates. Cardiothoracic transplant recipients are at greatest risk. Results from this retrospective study suggest that colistin-carbapenem combinations may result in improved clinical responses and survival compared to other regimens and may also limit the emergence of colistin resistance.

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE-which has a robust genetic linkage to AD-correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

The objective of this study is to compare two experimental approaches to characterize the ebullition pressure (or air-entry suction) of initially water-saturated organophilic clay blankets. The first is an indirect approach using the water-retention curve (WRC) and the second is a direct approach using ebullition experiments. The WRC along with the hydraulic conductivity of organophilic clay blankets in saturated and unsaturated conditions were measured using a flexible-wall permeameter with suction-saturation control. This device was also adapted to measure the ebullition pressure and the air permeability. The comparison of the experimental approaches was performed on organophilic clay blanket specimens in different initial conditions (unrinsed and rinsed to remove loose fines) under high and low effective confining stresses (20 and 5 kPa). The indirect estimates of air-entry suction from the WRC were similar to those obtained from the ebullition tests. This good agreement between the two approaches may add flexibility to the development of design specifications for capping systems. The hydraulic properties were found to be sensitive to rinsing and effective stress, with greater hydraulic conductivity and air permeability for the rinsed specimen due to the removal of fines, and greater air-entry suctions for specimens under higher effective stress.

Objectives: To investigate differences in the incidence of enteropathy or intestinal malabsorption in patients taking angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitor (ACEI), calcium channel blocker (CCB), and beta blockers (BBs) at a single center in Korea. Methods: In this retrospective study, we utilized data from the Yangsan electronic medical records to identify 129,169 patients. These individuals were prescribed olmesartan, other ARBs, ACEI, CCB, and BBs between November 2008 and February 2021. Results: Of the 44,775 patients, 51 (0.11%) were observed to have enteropathy or intestinal malabsorption. Compared with the ACEI group, the adjusted odds ratios (ORs) for enteropathy and intestinal malabsorption were OR=1.313 (95% confidence interval [CI]: [0.188-6.798], p=0.893) for olmesartan, OR=0.915 (95% CI: [0.525-1.595], p=0.754) for the other ARBs, OR=0.928 (95% CI: [0.200-4.307]; p=0.924) for the CCB, and OR=0.663 (95% CI: [0.151-2.906]; p=0.586) for the BBs group. These findings were adjusted for factors such as age, gender, duration of antihypertensive medication, and comorbidities. Conclusion: In a retrospective cohort study of patients on antihypertensive medications, no significant difference was found in the incidence of enteropathy or intestinal malabsorption when ACEI was compared to olmesartan, other ARBs, CCB, and BBs. [ABSTRACT FROM AUTHOR]

Abstract Background Kawasaki disease (KD) is a significant cause of acquired heart disease in children, particularly in developed countries. Incomplete Kawasaki disease (IKD) lacks some of the classic KD symptoms, complicating diagnosis. This study explores the potential role of anterior uveitis (AU) as a diagnostic marker for IKD and its possible association with reducing the incidence of coronary artery lesions (CALs). Methods A retrospective review of medical records was conducted on 111 pediatric patients diagnosed with IKD at two tertiary care centers between January 2018 and December 2023. The cohort consisted of 33 patients with AU and 78 without AU. The AU group had a mean age of 4.1 years, while the non-AU group had a mean age of 4.5 years. AU was present in 30% of cases. The study primarily focused on the time to diagnosis, incidence of CALs, and the independent association of AU with CALs using multivariate logistic regression analysis. Results Patients with AU were diagnosed and treated earlier, with a mean time to diagnosis of 5.1 days compared to 7.4 days in the non-AU group. Additionally, the incidence of CALs was significantly lower in the AU group (4.4%) compared to the non-AU group (31.8%, p

Abstract Background Intensive care unit‐acquired weakness (ICU‐AW) is a syndrome characterized by a long‐term muscle weakness often observed in sepsis‐surviving patients during the chronic phase. Although ICU‐AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death‐1 (PD‐1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU‐AW remains to be elucidated. Here, we study how PD‐1 deficiency affects sepsis‐induced skeletal muscle dysfunction in a preclinical sepsis model. Methods Chronic sepsis model was developed by treating wild‐type (WT) and PD‐1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL‐13) and PD‐1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow‐twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT‐qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL‐13 followed by gene expression measurements. Results WT septic mice exhibited decreased muscle weight (quadriceps, P

Abstract Aims This study evaluated how well serial pulse pressure (PP) and PP adjusted by the vasoactive inotropic score (VIS) predicted venoarterial extracorporeal membrane oxygenation (VA‐ECMO) weaning success and clinical outcomes in acute myocardial infarction complicated by cardiogenic shock (AMI‐CS) patients. Methods and results A total of 213 patients with AMI‐CS who received VA‐ECMO between January 2010 and August 2021 were enrolled in the institutional ECMO registry. Serial PP and VIS were measured immediately, 12, 24, and 48 h after VA‐ECMO insertion. PP adjusted by VIS was defined as PP/√VIS. The primary outcome was successful VA‐ECMO weaning. Successful weaning from VA‐ECMO was observed in 151 patients (70.9%). Immediately after VA‐ECMO insertion, PP [successful vs. failed weaning, 26.0 (15.5–46.0) vs. 21.0 (12.5–33.0), P = 0.386] and PP/√VIS [11.1 (5.1–25.0) vs. 6.0 (3.1–14.2), P = 0.118] did not differ between the successful and failed weaning groups. Serial PP and PP adjusted by VIS at 12, 24, and 48 h after VA‐ECMO insertion were significantly higher in patients with successful weaning than those with failed weaning [successful vs. failed weaning, 24.0 (4.0–38.0) vs. 12.5 (6.0–25.5), P = 0.007 for 12 h PP, and 10.1 (5.7–22.0) vs. 2.9 (1.7–5.9), P 7). Conclusions PP adjusted by VIS taken 12 h following VA‐ECMO initiation can predict weaning from VA‐ECMO more successfully than PP alone, and its low value was associated with a higher risk of mortality in AMI‐CS patients.

Abstract Background Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide. However, existing treatments still face numerous clinical challenges. Building on our prior research showing peripheral nerve-derived stem cell (PNSC) spheroids with Schwann cell-like phenotypes can secrete neurotrophic factors to aid in neural tissue regeneration, we hypothesized that repeated intrathecal injections of PNSC spheroids would improve the delivery of neurotrophic factors, thereby facilitating the restoration of neurological function and brain tissue repair post-TBI. Methods We generated PNSC spheroids from human peripheral nerve tissue using suspension culture techniques. These spheroids were characterized using flow cytometry, immunofluorescence, and reverse-transcription polymerase chain reaction. The conditioned media were evaluated in SH-SY5Y and RAW264.7 cell lines to assess their effects on neurogenesis and inflammation. To simulate TBI, we established a controlled cortical impact (CCI) model in rats. The animals were administered intrathecal injections of PNSC spheroids on three occasions, with each injection spaced at a 3-day interval. Recovery of sensory and motor function was assessed using the modified neurological severity score (mNSS) and rotarod tests, while histological (hematoxylin and eosin, Luxol fast blue staining) and T2-weighted magnetic resonance imaging analyses, alongside immunofluorescence, were conducted to evaluate the recovery of neural structures and pathophysiology. Results PNSC spheroids expressed high levels of Schwann cell markers and neurotrophic factors, such as neurotrophin-3 and Ephrin B3. Their conditioned medium was found to promote neurite outgrowth, reduce reactive oxygen species-mediated cell death and inflammation, and influence M1-M2 macrophage polarization. In the CCI rat model, rats receiving repeated triple intrathecal injections of PNSC spheroids showed significant improvements in sensory and motor function, with considerable neural tissue recovery in damaged areas. Notably, this treatment promoted nerve regeneration, axon regrowth, and remyelination. It also reduced glial scar formation and inflammation, while encouraging angiogenesis. Conclusion Our findings suggest that repeated intrathecal injections of PNSC spheroids can significantly enhance neural recovery after TBI. This effect is mediated by the diverse neurotrophic factors secreted by PNSC spheroids. Thus, the strategy of combining therapeutic cell delivery with multiple intrathecal injections holds promise as a novel clinical treatment for TBI recovery.

Abstract Topical eye drop approaches to treat ocular inflammation in dry eyes often face limitations such as low efficiency and short duration of drug delivery. Nanofibers serve to overcome the limitation of the short duration of action of topical eye drops used against ocular inflammation in dry eyes. Several attempts to develop suitable nanofibers have been made; however, there is no ideal solution. Here, we developed polycaprolactone (PCL) nanofibers loaded with dexamethasone acetate (DEX), prepared by electrospinning, as a potential ocular drug delivery platform for corneal injury treatment. Thirty-nine Sprague Dawley rats (7 weeks old males) were divided into four treatment groups after alkaline burns of the cornea; negative control (no treatment group); dexamethasone eyedrops (DEX group); PCL fiber (PCL group); dexamethasone loaded PCL (PCL + DEX group). We evaluated therapeutic efficacy of PCL + DEX by examining the epithelial wound healing effect, the extent of corneal opacity and neovascularization. Additionally, various inflammatory factors, including IL-1β, were investigated through immunochemistry, western blot analysis, and quantitative real-time RT-PCR (qRT-PCR). PCL + DEX group showed histologically alleviated signs of corneal inflammation compared with DEX group, which showed a decrease in IL-1β and MMP9 in the corneal stroma. The quantitative expression on day 1 after alkaline burn of pro-inflammatory markers, including IL-1β and IL-6, in the PCL + DEX group was significantly lower than that in the DEX group. Notably, PCL + DEX treatment significantly suppressed neovascularization, and enhanced the anti-inflammatory function of DEX during the acute phase of ocular inflammation. Collectively, these findings suggest that PCL + DEX may be a promising approach to effective drug delivery in corneal burn injuries.

Abstract Background/Purpose This retrospective immunohistological pilot study aimed to investigate the influence of natural killer group 2, member D (NKG2D) ligand expression on ameloblastoma recurrence after surgical resection. It also aimed to elucidate additional clinical factors that could serve as predictors of ameloblastoma recurrence. Materials and methods This study included 96 patients who were histologically diagnosed with ameloblastoma after surgical resection. The expression of NKG2D ligands, including UL16-binding proteins (ULBPs) 1–3 and major histocompatibility complex class I chain-related molecule (MIC) A/B, was evaluated in formalin-fixed paraffin-embedded tumor tissues via immunohistochemistry assays. Furthermore, the patients’ electronic medical records were reviewed. Multivariate Cox regression analysis was conducted, and data were expressed as adjusted hazard ratios [HRs] with 95% confidence intervals [95% CIs]. Results Multivariate analysis revealed that recurrent tumors (ref.: primary; adjusted HR [95% CI]: 2.780 [1.136, 6.803], p = 0.025) and positive MICA/B expression (ref.: negative; adjusted HR [95% CI]: 0.223 [0.050, 0.989], p = 0.048) independently affected recurrence-free survival in ameloblastoma. Conclusion This study identified recurrent cases and loss of MICA/B expression as independent predictors of early ameloblastoma recurrence following surgical resection. The findings suggest that decreased MICA/B expression might undermine NKG2D-mediated tumor immunosurveillance, thereby influencing early recurrence.

Abstract Background Corynebacterium glutamicum is an attractive host for secretory production of recombinant proteins, including high-value industrial enzymes and therapeutic proteins. The choice of an appropriate signaling peptide is crucial for efficient protein secretion. However, due to the limited availability of signal peptides in C. glutamicum, establishing an optimal secretion system is challenging. Result We constructed a signal peptide library for the isolation of target-specific signal peptides and developed a highly efficient secretory production system in C. glutamicum. Based on the sequence information of the signal peptides of the general secretion-dependent pathway in C. glutamicum, a synthetic signal peptide library was designed, and validated with three protein models. First, we examined endoxylanase (XynA) and one potential signal peptide (C1) was successfully isolated by library screening on xylan-containing agar plates. With this C1 signal peptide, secretory production of XynA as high as 3.2 g/L could be achieved with high purity (> 80%). Next, the signal peptide for ⍺-amylase (AmyA) was screened on a starch-containing agar plate. The production titer of the isolated signal peptide (HS06) reached 1.48 g/L which was 2-fold higher than that of the well-known Cg1514 signal peptide. Finally, we isolated the signal peptide for the M18 single-chain variable fragment (scFv). As an enzyme-independent screening tool, we developed a fluorescence-dependent screening tool using Fluorescence-Activating and Absorption-Shifting Tag (FAST) fusion, and successfully isolated the optimal signal peptide (18F11) for M18 scFv. With 18F11, secretory production as high as 228 mg/L was achieved, which was 3.4-fold higher than previous results. Conclusions By screening a fully synthetic signal peptide library, we achieved improved production of target proteins compared to previous results using well-known signal peptides. Our synthetic library provides a useful resource for the development of an optimal secretion system for various recombinant proteins in C. glutamicum, and we believe this bacterium to be a more promising workhorse for the bioindustry.

Objectives: The use of qualitative healthcare services or its discrepancy between different income levels of the type 2 diabetes (T2D) patients has seldom been studied concurrently. The present study is unique that regarding T2D patients of early stages of diagnosis. Aimed to assess the utilization of qualitative healthcare services and influence of income levels on the inequality of care among newly diagnosed patients with T2D. Methods: A retrospective cohort study of 7590 patients was conducted by the National Health Insurance Service National Sample Cohort 2.0 from 2002 to 2015. Insured employee in 2013 with no history of T2D between 2002 and 2012 were included. The standard of diabetes care includes hemoglobin A1c (HbAlc; 4 times/y), eyes (once/y) and lipid abnormalities (once/y). Multivariate logistic regression analysis was performed to examine the difference between income levels and inequality of care. Results: From years 1 to 3, rates of appropriate screening fell from 16.9% to 14.1% (HbA1c), 15.8% to 14.5% (eye), and 59.2% to 33.2% (lipid abnormalities). Relative to income class 5 (the highest-income group), HbA1 screening was significantly less common in class 2 (year 2: odds ratio [OR], 0.78; 95% confidence interval [CI], 0.61 to 0.99; year 3: OR, 0.79; 95% CI, 0.69 to 0.91). In year 1, lipid screening was less common in class 1 (OR, 0.84; 95% CI, 0.73 to 0.98) than in class 5, a trend that continued in year 2. Eye screening rates were consistently lower in class 1 than in class 5 (year 1: OR, 0.73; 95% CI, 0.60 to 0.89; year 2: OR, 0.63; 95% CI, 0.50 to 0.78; year 3: OR, 0.81; 95% CI, 0.67 to 0.99). Conclusions: Newly diagnosed T2D patients have shown low rate of HbA1c and screening for diabetic-related complications and experienced inequality in relation to receiving qualitative diabetes care by income levels.

Abstract Backrground Akkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury. Results To investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila. Conclusions A. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment. Graphical Abstract

This paper examines the use of serious games that integrate engaging gameplay with educational and therapeutic benefits with a particular focus on their application in urology. The study reviews both domestic and international cases to evaluate the current practices and implications of these digital therapies. While serious games have been widely utilized in the treatment of pediatric cancer and psychiatric disorders—areas that require long-term care and management—their application in urology, in particular pediatric urology, has been limited. Although digital therapies like serious games are still emerging in the field of urology, they hold promise as effective supplements to traditional treatments while offering new options for managing a range of urological conditions. Pediatric conditions such as bedwetting, urinary incontinence, and dysuria, which often benefit from long-term training and habit formation, are particularly well-suited to this approach. By helping pediatric patients better understand and manage their symptoms, serious games can play a supportive role in the treatment process and have shown positive medical outcomes. This paper reviews the definitions and therapeutic effects of serious games, analyzes their current use in the medical field, and argues for their increased application in treating pediatric urinary conditions.

Abstract Background The association between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been inconsistent, and the impact of hepatic fibrosis on this relationship remains uncertain. We investigated the association between NAFLD and the risk of new-onset AF across different age groups. Methods A total of 3,179,582 participants from the 2009 Korean National Health Screening Program were divided into five groups based on NAFLD status: no NAFLD (fatty liver index [FLI]

Abstract Cerebrospinal fluid (CSF) plays an important role in brain tumors, including medulloblastoma (MBL). Recent advancements in mass spectrometry systems and ‘Omics’ data analysis methods enable unbiased, high proteome depth research. We conducted proteomic profiling of the total CSF in MBL patients with the purpose of finding a potential diagnostic biomarker for MBL. We quantified 1112 proteins per CSF sample. Feature selection identified four elevated soluble proteins (SPTBN1, HSP90AA1, TKT, and NME1-NME2) in MBL CSF. Validation with ELISA confirmed that TKT was significantly elevated in MBL. Additionally, TKT-positive extracellular vesicles were significantly enriched in MBL CSF and correlated with the burden of leptomeningeal seeding. Our results provide insights into the proteomics data of the total CSF of MBL patients. Furthermore, we identified the significance of TKT within the total CSF and its presence within circulating EVs in the CSF. We suggest that TKT may serve as a biomarker for MBL.

Abstract Background Glycopeptides for ampicillin-susceptible Enterococcus faecalis/faecium bacteremia are readily prescribed depending on the severity of the condition. However, there is limited data on the outcomes of glycopeptide use compared to ampicillin-containing regimens for ampicillin-susceptible E. faecalis/faecium bacteremia. From an antibiotic stewardship perspective, it is important to determine whether the use of glycopeptides is associated with improved clinical outcomes in patients with ampicillin-susceptible E. faecalis/faecium bacteremia. Methods This retrospective cohort study was conducted at a university-affiliated hospital between January 2010 and September 2019. We collected data from patients with positive blood cultures for Enterococcus species isolates. The clinical data of patients who received ampicillin-containing regimens or glycopeptides as definitive therapy for ampicillin-susceptible E. faecalis/faecium bacteremia were reviewed. Multivariate logistic regression analysis was performed to identify risk factors for 28-day mortality. Results Ampicillin-susceptible E. faecalis/faecium accounted for 41.2% (557/1,353) of enterococcal bacteremia cases during the study period. A total of 127 patients who received ampicillin-containing regimens (N = 56) or glycopeptides (N = 71) as definitive therapy were included in the analysis. The 28-day mortality rate was higher in patients treated with glycopeptides (19.7%) than in those treated with ampicillin-containing regimens (3.6%) (p = 0.006). However, in the multivariate model, antibiotic choice was not an independent predictor of 28-day mortality (adjusted OR, 3.7; 95% CI, 0.6–23.6). Conclusions Glycopeptide use was not associated with improved mortality in patients with ampicillin-susceptible E. faecalis/faecium bacteremia. This study provides insights to reduce the inappropriate use of glycopeptides in ampicillin-susceptible E. faecalis/faecium bacteremia treatment and promote antimicrobial stewardship.

Abstract T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) exhibits unique, cell type- and context-dependent characteristics and functions. Here, we report that TIM-3 on myeloid cells plays essential roles in modulating lung inflammation. We found that myeloid cell-specific TIM-3 knock-in (FSF-TIM3/LysM-Cre+) mice have lower body weight and shorter lifespan than WT mice. Intriguingly, the lungs of FSF-TIM3/LysM-Cre+ mice display excessive inflammation and features of disease-associated pathology. We further revealed that galectin-3 levels are notably elevated in TIM-3-overexpressing lung-derived myeloid cells. Furthermore, both TIM-3 blockade and GB1107, a galectin-3 inhibitor, ameliorated lung inflammation in FSF-TIM3/LysM-Cre+/− mice. Using an LPS-induced lung inflammation model with myeloid cell-specific TIM-3 knock-out mice, we demonstrated the association of TIM-3 with both lung inflammation and galectin-3. Collectively, our findings suggest that myeloid TIM-3 is an important regulator in the lungs and that modulation of TIM-3 and galectin-3 could offer therapeutic benefits for inflammation-associated lung diseases.

Abstract Obesity is the one of the most important components of metabolic syndrome. Because obesity related hypertension accounts for two thirds of essential hypertension, managing obesity and metabolic syndrome is a crucial task in the management of hypertension. However, the current non-pharmacological therapies have limitations for achieving or maintaining ideal body weight. Recently, glucagon-like peptide-1 receptor agonists (GLP1-RAs) have demonstrated excellent weight control effects, accompanied by corresponding reductions in blood pressure. GLP1-RAs have shown cardiovascular and renal protective effects in cardiovascular outcome trials both in primary and secondary prevention. In this document, the Korean Society of Hypertension intends to remark the current clinical results of GLP1-RAs and recommend the government and health-policy makers to define obesity as a disease and to establish forward-looking policies for GLP1-RA treatment for obesity treatment, including active reimbursement policies.