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Phenylalanine hydroxylase (PAH) is the key enzyme in phenylalanine metabolism, deficiency of which is associated with the most common metabolic phenotype of phenylketonuria (PKU) and hyperphenylalaninemia (HPA). A bulk of PKU disease-associated missense mutations in the PAH gene have been studied, and the consequence of each PAH variant vary immensely. Prior research established that PKU-associated variants possess defects in protein folding with reduced cellular stability leading to rapid degradation. However, recent evidence revealed that PAH tetramers exist as a mixture of resting state and activated state whose transition depends upon the phenylalanine concentration and certain PAH variants that fail to modulate the structural equilibrium are associated with PKU disease. Collectively, these findings framed our understanding of the complex genotype-phenotype correlation in PKU. In the current study, we substantiate a link between PAH protein stability and its degradation by the ubiquitin-mediated proteasomal degradation system. Here, we provide an evidence that PAH protein undergoes ubiquitination and proteasomal degradation, which can be reversed by deubiquitinating enzymes (DUBs). We identified USP19 as a novel DUB that regulates PAH protein stability. We found that ectopic expression of USP19 increased PAH protein level, whereas depletion of USP19 promoted PAH protein degradation. Our study indicates that USP19 interacts with PAH and prevents polyubiquitination of PAH subsequently extending the half-life of PAH protein. Finally, the increase in the level of PAH protein by the deubiquitinating activity of USP19 resulted in enhanced metabolic function of PAH. In summary, our study identifies the role of USP19 in regulating PAH protein stability and promotes its metabolic activity. Graphical highlights 1. E3 ligase Cdh1 promotes PAH protein degradation leading to insufficient cellular amount of PAH causing PKU. 2. A balance between E3 ligase and DUB is important to regulate the proteostasis of PAH. 3. USP19 deubiquitinates and stabilizes PAH further protecting it from rapid degradation. 4. USP19 increases the enzymatic activity of PAH, thus maintaining normal Phe levels., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Adolescents make up roughly a quarter of the population in Zambia; however, most nutrition-related programming is targeted at the under-five population. Understanding the scale of undernutrition in older children and adolescents is fundamental to alleviating food insecurity and addressing undernutrition across all age groups., Methods: A cross-sectional survey was performed in four low-income, peri-urban compounds in Chilanga District which included anthropometric measurements of children between ages 6 months-19 years and a household-level diet diversity and food security questionnaire. Wasting was used for children under 5 and thinness for children 5-19 years. Descriptive analysis and multivariate logistic regression were conducted to quantify the prevalence and distribution of malnutrition and understand the impact of food security., Results: We surveyed 393 households and 1,004 children between the ages of 6 months and 19 years. Children aged 6-9 years had the highest prevalence of severe thinness (5.2%) and adolescents (10-19 years) had the highest rates of moderate thinness (6.5%). Across all age groups, more than 75% of children were in households that worried about running out of food in the previous month. 24.9% of adolescents and 28.4% of older children were in households were more likely to go a whole day without eating compared to 16.9% of children under 5., Conclusion: Our survey indicated that malnutrition in adolescents and older children living in Chilanga district was comparable to those under 5. Interventions to address undernutrition must be targeted at older children and adolescents in order to ameliorate this burden., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sridhar, Kang, Madzorera, Zulu, Makasa, Cross and Hamer.)

Eight rifamycin-related polyketides were isolated from the culture broth of a marine-derived bacterium Salinispora arenicola , including five known ( 2 - 5 and 8 ) and three new derivatives ( 1 , 6 , and 7 ). The structures of the new compounds were determined by means of spectroscopic methods (HRESIMS and 1D, 2D NMR) and a comparison of their experimental data with those previously reported in the literature. The isolated compounds were evaluated for their cytotoxicity against one normal, six solid, and seven blood cancer cell lines and 1 showed moderate activity against all the tested cell lines with GI 50 values ranging from 2.36 to 9.96 µM.

Skeletal muscle wasting related to aging or pathological conditions is critically associated with the increased incidence and prevalence of secondary diseases including cardiovascular diseases, metabolic syndromes, and chronic inflammations. Much effort is made to develop agents to enhance muscle metabolism and function. Inonotus obliquus ( I . obliquus ; IO) is a mushroom popularly called chaga and has been widely employed as a folk medicine for inflammation, cardiovascular diseases, diabetes, and cancer in Eastern Europe and Asia. However, its effect on muscle health has not been explored. Here, we aimed to investigate the beneficial effect of IO extract in muscle regeneration and metabolism. The treatment of IO in C2C12 myoblasts led to increased myogenic differentiation and alleviation of dexamethasone-induced myotube atrophy. Network pharmacological analysis using the identified specific chemical constituents of IO extracts predicted protein kinase B (AKT)-dependent mechanisms to promote myogenesis and muscle regeneration. Consistently, IO treatment resulted in the activation of AKT, which suppressed muscle-specific ubiquitin E3 ligases induced by dexamethasone. IO treatment in mice improved the regeneration of cardiotoxin-injured muscles accompanied by elevated proliferation and differentiation of muscle stem cells. Furthermore, it elevated the mitochondrial content and muscle oxidative metabolism accompanied by the induction of peroxisome proliferator-activated receptor γ coactivator α (PGC-1α). Our current data suggest that IO is a promising natural agent in enhancing muscle regenerative capacity and oxidative metabolism thereby preventing muscle wasting., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The loss of vitamin D 3 upregulated protein 1 (VDUP1) has been implicated in the pathogenesis of various inflammation-related diseases. Notably, reduced expression of VDUP1 has been observed in clinical specimens of ulcerative colitis (UC). However, the role of VDUP1 deficiency in colitis remains unclear. In this study, we investigated the role of VDUP1 in dextran sulfate sodium (DSS)-induced experimental colitis in mice. VDUP1-deficient mice were more susceptible to DSS-induced colitis than their wild-type (WT) littermates after 2% DSS administration. VDUP1-deficient mice exhibited an increased disease activity index (DAI) and histological scores, as well as significant colonic goblet cell loss and an increase in apoptotic cells. These changes were accompanied by a significant decrease in MUC2 mRNA expression and a marked increase in proinflammatory cytokines and chemokines within damaged tissues. Furthermore, phosphorylated NF-κB p65 expression was significantly upregulated in damaged tissues in the context of VDUP1 deficiency. VDUP1 deficiency also led to significant infiltration of macrophages into the site of ulceration. An in vitro chemotaxis assay confirmed that VDUP1 deficiency enhanced bone marrow-derived macrophage (BMDM) chemotaxis induced by CCL2. Overall, this study highlights VDUP1 as a regulator of UC pathogenesis and a potential target for the future development of therapeutic strategies.

Objective: Surgical site infection is the most detrimental complication following cranioplasty. In other surgical fields, intrawound vancomycin powder application has been introduced to prevent surgical site infection and is widely used based on results in multiple studies. This study evaluated the effect of intrawound vancomycin powder in cranioplasty compared with the conventional method without topical antibiotics., Methods: This retrospective study included 580 patients with skull defects who underwent cranioplasty between August 1, 1998 and December 31, 2021. The conventional method was used in 475 (81.9%; conventional group) and vancomycin powder (1 g) was applied on the dura mater and bone flap in 105 patients (18.1%; vancomycin powder group). Surgical site infection was defined as infection of the incision, organ, or space that occurred after cranioplasty. Surgical site infection within 1-year surveillance period was compared between the conventional and vancomycin powder groups with logistic regression analysis. Penalized likelihood estimation method was used in logistic regression to deal with zero events. All local and systemic adverse events associated with topical vancomycin application were also evaluated., Results: Surgical site infection occurred in 31 patients (5.3%) and all were observed in the conventional group. The median time between cranioplasty and detection of surgical site infection was 13 days (range, 4-333). Staphylococci were the most common organisms and identified in 25 (80.6%) of 31 cases with surgical site infections. The surgical site infection rate in the vancomycin powder group (0/105, 0.0%) was significantly lower than that in the conventional group (31/475, 6.5%; crude odds ratio [OR], 0.067; 95% confidence interval [CI], 0.006-0.762; adjusted OR, 0.068; 95% CI, 0.006-0.731; p=0.026). No adverse events associated with intrawound vancomycin powder were observed during the follow-up., Conclusion: Intrawound vancomycin powder effectively prevented surgical site infections following cranioplasty without local or systemic adverse events. Our results suggest that intrawound vancomycin powder is an effective and safe strategy for patients undergoing cranioplasty.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions, such as neurodegenerative diseases and diabetes; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here, we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farnesol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/ Zfp746 ), a transcriptional repressor of PGC-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS expression in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.

Plant-based bioactive substances have long been used to treat inflammatory ailments, owing to their low toxicity and cost-effectiveness. To enhance plant treatment by eliminating undesirable isomers, optimizing the chiral separation techniques in pharmaceutical and clinical studies is important. This study reported a simple and effective method for chiral separation of decursinol and its derivatives, which are pyranocoumarin compounds with anti-cancer and anti-inflammatory properties. Baseline separation (Rs >1.5) was achieved using five different polysaccharide-based chiral stationary phases (CSPs) that differed in chiral origin, chiral selector chemistry, and preparation technique. To separate all six enantiomers simultaneously, n-hexane and three alcohol modifiers (ethanol, isopropanol, and n-butanol) were used as mobile phases in the normal-phase mode. The chiral separation ability of each column with various mobile phase compositions was compared and discussed. As a result, amylose-based CSPs with linear alcohol modifiers demonstrated superior resolution. Three cases of elution order reversal caused by modifications of CSPs and alcohol modifiers were observed and thoroughly analyzed. To elucidate the chiral recognition mechanism and enantiomeric elution order (EEO) reversal phenomenon, detailed molecular docking simulations were conducted. The R- and S-enantiomers of decursinol, epoxide, and CGK012 exhibited binding energies of -6.6, -6.3, -6.2, -6.3, -7.3, and -7.5 kcal/mol, respectively. The magnitude of the difference in binding energies was consistent with the elution order and enantioselectivity (α) of the analytes. The molecular simulation results demonstrated that hydrogen bonds, π-π interactions, and hydrophobic interactions have a significant impact on chiral recognition mechanisms. Overall, this study presented a novel and logical approach of optimizing chiral separation techniques in the pharmaceutical and clinical industries. Our findings could be further applied for screening and optimizing enantiomeric separation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

HCC is a major contributor to cancer-related mortality worldwide. Curative treatments are available for a minority of patients diagnosed at early stages; however, only a few multikinase inhibitors are available and are marginally effective in advanced cases, highlighting the need for novel therapeutic targets. One potential target is the protein arginine methyltransferase, which catalyzes various forms of arginine methylation and is often overexpressed in various cancers. However, the diverse expression patterns and clinical values of PRMTs in HCC remain unclear. In the present study, we evaluated the transcriptional expression of PRMTs in HCC cohorts using publicly available datasets. Our results revealed a significant association between PRMTs and prognosis in HCC patients with diverse clinical characteristics and backgrounds. This highlights the promising potential of PRMTs as prognostic biomarkers in patients with HCC. In particular, single-cell RNA (scRNA) sequencing analysis coupled with another human cohort study highlighted the pivotal role of PRMT1 in HCC progression, particularly in the context of Tex. Translating these findings into specific therapeutic decisions may address the unmet therapeutic needs of patients with HCC.

While the world is rapidly transforming into a superaging society, pharmaceutical approaches to treat sarcopenia have hitherto not been successful due to their insufficient efficacy and failure to specifically target skeletal muscle cells (skMCs). Although electrical stimulation (ES) is emerging as an alternative intervention, its efficacy toward treating sarcopenia remains unexplored. In this study, we demonstrate a silver electroceutical technology with the potential to treat sarcopenia. First, we developed a high-throughput ES screening platform that can simultaneously stimulate 15 independent conditions, while utilizing only a small number of human-derived primary aged/young skMCs (hAskMC/hYskMC). The in vitro screening showed that specific ES conditions induced hypertrophy and rejuvenation in hAskMCs, and the optimal ES frequency in hAskMCs was different from that in hYskMCs. When applied to aged mice in vivo, specific ES conditions improved the prevalence and thickness of Type IIA fibers, along with biomechanical attributes, toward a younger skMC phenotype. This study is expected to pave the way toward an electroceutical treatment for sarcopenia with minimal side effects and help realize personalized bioelectronic medicine.

Aralia elata , a renowned medicinal plant with a rich history in traditional medicine, has gained attention for its potential therapeutic applications. However, the leaves of this plant have been largely overlooked and discarded due to limited knowledge of their biological activity and chemical composition. To bridge this gap, a comprehensive study was conducted to explore the therapeutic potential of the 70% ethanol extract derived from Aralia elata leaves (LAE) for the treatment of cardiovascular disease (CVD). Initially, the cytotoxic effects of LAE on human umbilical vein endothelial cells (HUVECs) were assessed, revealing no toxicity within concentrations up to 5 μg/mL. This suggests that LAE could serve as a safe raw material for the development of health supplements and drugs aimed at promoting cardiovascular well-being. Furthermore, the study found that LAE extract demonstrated anti-inflammatory properties in HUVECs by modulating the PI3K/Akt and MAPK signaling pathways. These findings are particularly significant as inflammation plays a crucial role in the progression of CVD. Moreover, LAE extract exhibited the ability to suppress the expression of adhesion molecules VCAM-1 and ICAM-1, which are pivotal in leukocyte migration to inflamed blood vessels observed in various pathological conditions. In conjunction with the investigation on therapeutic potential, the study also established an optimal HPLC-PDA-ESI-MS/MS method to identify and confirm the chemical constituents present in 24 samples collected from distinct regions in South Korea. Tentative identification revealed the presence of 14 saponins and nine phenolic compounds, while further analysis using PCA and PLS-DA allowed for the differentiation of samples based on their geographical origins. Notably, specific compounds such as chlorogenic acid, isochlorogenic acid A, and quercitrin emerged as marker compounds responsible for distinguishing samples from different regions. Overall, by unraveling its endothelial protective activity and identifying key chemical constituents, this research not only offers valuable insights for the development of novel treatments but also underscores the importance of utilizing and preserving natural resources efficiently.

Amplification and specificity of polymerase chain reaction (PCR) are affected by the position and type of primer-template mismatches (MMs) as well as various conditions of reaction. In this study, multiple linear regression (MLR) models and artificial neural network (ANN) models were developed for the prediction of the effects of primer-template mismatches on the primer extension efficiency in primer-template duplex. In MLR models, the independent variable P i representing the position effect of i -th mismatch from 3' end of primers was normalized to values between 0 and 1 according to the size of ΔΔG i , the difference of Gibbs free energy changes between the mismatch and its corresponding perfect-match, and other independent variables P j representing the position effect of the j -th perfect-match from 3' end of primer were coded 1. A dependent variable of MLR model was relative extension efficiencies of primers. In ANN models, an input layer has neurons equal to the number of independent variables of corresponding MLR models and a hidden layer and an output layer have four and one neurons, respectively. Our MLR models and ANN models outperform the previous polynomial regression model for the prediction of the single base extension (SBE) efficiencies of single-MM primers. Especially, ANN model 6 which has 32 neurons representing the position effect of mismatch, the type of mismatch and the annealing temperature on primer-template duplex in the input layer can predict the SBE efficiencies of single-MM primers with a high accuracy, since its correlation coefficients R in training set, testing set and all data are 0.9870, 0.9782 and 0.9857, respectively. These results will have a good prospect applicable to the design of primer and testing the primer specificity in genome database., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

In vitro investigation of a glomerular filtration barrier (GFB) remains difficult because of the inability to mimic its specialized structure, although various kidney diseases are characterized by GFB dysfunction. Here, the development of a microfluidic model that replicates the physiology of the GFB has been achieved by tunable glomerular basement membrane (gBM) deposition and 3D co-culture of podocytes with glomerular endothelial cells (gECs). By precisely controlling the thickness of the gBM, our model successfully reproduced the biphasic response of the GFB, where variations in gBM thickness influence barrier properties. Moreover, this microscale proximity of gECs and podocytes facilitated their dynamic crosstalk, which is essential for maintaining the integrity and function of the GFB. We observed that addition of gBM and podocytes enhanced barrier function of gECs by inducing up-regulation of gEC's tight junctions synergistically, and moreover, found an ultrastructure of gECs-gBM-podocytes' foot process contacting each other by confocal and TEM imaging. The dynamic interaction of gECs and podocytes played a significant role in the response to drug-induced injury and the regulation of barrier properties. Nephrotoxic injury simulated in our model helped to elucidate that the over-production of vascular endothelial growth factor A from the injured podocytes mediates GFB impairment. We believe that our GFB model can provide a valuable tool for mechanistic studies such as investigating GFB biology, comprehending disease mechanisms, and evaluating potential therapeutic approaches in a controlled and physiologically relevant environment.

During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Both AP-1 and PRMT1 are vital molecules in variety of cellular progresssion, but the interaction between these proteins in the context of cellular functions is less clear. Gastric cancer (GC) is one of the pernicious diseases worldwide. An in-depth understanding of the molecular mode of action underlying gastric tumorigenesis is still elusive. In this study, we found that PRMT1 directly interacts with c-Fos and enhances AP-1 activation. PRMT1-mediated arginine methylation (mono- and dimethylation) of c-Fos synergistically enhances c-Fos-mediated AP-1 liveliness and consequently increases c-Fos protein stabilization. Consistent with this finding, PRMT1 knockdown decreases the protein level of c-Fos. We discovered that the c-Fos protein undergoes autophagic degradation and found that PRMT1-mediated methylation at R287 protects c-Fos from autophagosomal degradation and is linked to clinicopathologic variables as well as prognosis in stomach tumor. Together, our data demonstrate that PRMT1-mediated c-Fos protein stabilization promotes gastric tumorigenesis. We contend that targeting this modification could constitute a new therapeutic strategy in gastric cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The efficient generation of high-quality random numbers is essential in the operation of cryptographic modules. The quality of a random number generator is evaluated by the min-entropy of its entropy source. The typical method used to achieve high min-entropy of the output sequence is an entropy accumulation based on a hash function. This is grounded in the famous Leftover Hash Lemma, which guarantees a lower bound on the min-entropy of the output sequence. However, the hash function-based entropy accumulation has slow speed in general. For a practical perspective, we need a new efficient entropy accumulation with the theoretical background for the min-entropy of the output sequence. In this work, we obtain the theoretical bound for the min-entropy of the output random sequence through the very efficient entropy accumulation using only bitwise XOR operations, where the input sequences from the entropy source are independent. Moreover, we examine our theoretical results by applying them to the quantum random number generator that uses dark shot noise arising from image sensor pixels as its entropy source.

Altered lipid patterns in Caenorhabditis elegans (C. elegans) resulting from exposure to harmane remain to be explored. In this study, untargeted lipidomics was carried out to elucidate the effects of acute exposure to harmane on the lipidome of C. elegans. Exposure to the compound was evaluated based on the reproduction ability of the worms at 0.1 and 1 μg/mL. No significant effects of harmane were observed at these concentrations. Furthermore, we found that the modulatory effects of harmane on the lipidome of C. elegans at 1 μg/mL were lipid class dependent. In particular, harmane-treated worms were enriched in triglycerides and fatty acids, regardless of the degree of saturation. Glycerophospholipids were generally down-regulated. Furthermore, functional analyses suggested that there was a reduction in lipid membrane bilayer-related terms, and in some related to the mitochondria, and endoplasmic reticulum of C. elegans when treated with harmane. Lipid droplets and storage appeared to be up-regulated. In conclusion, our findings suggest that harmane exposure affects the lipidome of C. elegans in a sophisticated manner. Further investigations are required to elucidate the molecular mechanisms underlying these lipid pattern changes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background/purpose: The efficacy of neoadjuvant treatment (NAT) for resectable pancreatic cancer remains debatable, particularly in patients with portal vein (PV)/superior mesenteric vein (SMV) contact and elevated serum carbohydrate antigen (CA) 19-9. This study investigated the clinical significance of PV/SMV contact and CA19-9 levels, and the role of NAT in resectable pancreatic cancer., Methods: A total of 775 patients who underwent surgery for resectable pancreatic cancer between 2007 and 2018 were included. Propensity score-matched (PSM) analysis (1:3) was performed based on tumor size, lymph node enlargement, and PV/SMV contact. Subgroup analyses were performed according to PV/SMV contact and CA19-9 level., Results: Among the patients, 52 underwent NAT and 723 underwent upfront surgery. After PSM, NAT group showed better survival than upfront surgery group (median 30.0 vs 22.0 months, P = .047). In patients with PV/SMV contact, NAT tended to have better survival (30.0 vs 22.0 months, P = .069). CA19-9 >150 U/mL was a poor prognostic factor, with NAT showing a significant survival difference compared with upfront surgery (34.0 vs 18.0 months, P = .004)., Conclusions: Neoadjuvant treatment showed better survival than upfront surgery in resectable pancreatic cancer. In patients with PV/SMV contact or CA19-9 >150 U/mL, NAT showed a survival difference compared to upfront surgery; therefore, NAT could be considered in these patients., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

We present measurements of the cross section and double-helicity asymmetry A&#95;{LL} of direct-photon production in p[over →]+p[over →] collisions at sqrt[s]=510  GeV. The measurements have been performed at midrapidity (|η|<0.25) with the PHENIX detector at the Relativistic Heavy Ion Collider. At relativistic energies, direct photons are dominantly produced from the initial quark-gluon hard scattering and do not interact via the strong force at leading order. Therefore, at sqrt[s]=510  GeV, where leading-order-effects dominate, these measurements provide clean and direct access to the gluon helicity in the polarized proton in the gluon-momentum-fraction range 0.02

It was recently found that glutamine (Gln) supplementation activates glutamatergic neurotransmission and prevents chronic-stress-induced mild cognitive impairment (MCI). In this study, we evaluated the effects of Gln on glutamatergic activity in the medial prefrontal cortex and the onset of cognitive impairment in a triple-transgenic Alzheimer's disease mouse model (3×Tg-AD). Female 3×Tg-AD mice were fed a normal diet (3×Tg) or a Gln-supplemented diet (3×Tg+Gln) from 2 to 6 months of age. Glutamatergic neuronal activity was analyzed at 6 months, and cognitive function was examined at 2, 4, and 6 months. 3×Tg mice exhibited a decrease in glutamatergic neurotransmission in the infralimbic cortex, but 3×Tg+Gln mice did not. The 3×Tg group showed MCI at 6 months of age, but the 3×Tg+Gln group did not. The expressions of amyloid peptide, inducible nitric oxide synthase, and IBA-1 were not elevated in the infralimbic cortex in the 3×Tg+Gln group. Therefore, a Gln-supplemented diet could delay the onset of MCI even in a mouse model predisposed to cognitive impairment and dementia through genetic modification.

Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases. However, the molecular mechanisms underlying neuromuscular dysfunction are currently unclear. Recent studies have proposed important roles of Protein arginine methyltransferase 1 (Prmt1) in muscle stem cell function and muscle maintenance. In the current study, we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1 (mnKO) using Hb9-Cre. mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality. Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury. The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation, cell death, oxidative stress, and mitochondria. Consistently, mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor neurons. Furthermore, Prmt1 inhibition in motor neurons elicited mitochondrial dysfunction. Our findings demonstrate that Prmt1 ablation in motor neurons causes age-related motor neuron degeneration attributing to muscle loss. Thus, Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging., (Copyright © 2023 Hyun-Kyung So et al.)

Nine sesquiterpenes, including eight pentalenenes ( 1 - 8 ) and one bolinane derivative ( 9 ), were isolated from the culture broth of a marine-derived actinobacterium Streptomyces qinglanensis 213DD-006. Among them, 1 , 4 , 7 , and 9 were new compounds. Their planar structures were determined by spectroscopic methods (HRMS, 1D, and 2D NMR), and the absolute configuration was established by biosynthesis consideration and electronic-circular-dichroism (ECD) calculations. All the isolated compounds were screened for their cytotoxicity against six solid and seven blood cancer cell lines. Compounds 4 - 6 and 8 showed a moderate activity against all of the tested solid cell lines, with GI 50 values ranging from 1.97 to 3.46 µM.

Exercise and caloric restriction (CR) significantly increase longevity across a range of species and delay aging-related losses in organ function. Although both interventions enhance skeletal muscle function, the molecular mechanisms underlying these associations are unknown. We sought to identify genes regulated by CR and exercise in muscle, and investigate their relationship with muscle function. To do this, expression profiles of Gene Expression Omnibus datasets obtained from the muscle tissue of calorie-restricted male primates and young men post-exercise were analyzed. There were seven transcripts ( ADAMTS1 , CPEB4 , EGR2, IRS2 , NR4A1 , PYGO1 , and ZBTB43 ) that were consistently upregulated by both CR and exercise training. We used C2C12 murine myoblasts to investigate the effect of silencing these genes on myogenesis, mitochondrial respiration, autophagy, and insulin signaling, all of which are processes affected by CR and exercise. Our results show that in C2C12 cells, Irs2 and Nr4a1 expression were critical for myogenesis, and five genes ( Egr2 , Irs2 , Nr4a1 , Pygo1 , and ZBTB43 ) regulated mitochondrial respiration while having no effect on autophagy. Cpeb4 knockdown increased the expression of genes involved in muscle atrophy and induced myotube atrophy. These findings suggest new resources for studying the mechanisms underlying the beneficial effects of exercise and calorie restriction on skeletal muscle function and lifespan extension.

Fungal superinfections have been reported in patients with coronavirus disease 2019 (COVID-19). We analyzed the incidence and clinical characteristics of Pneumocystis jirovecii pneumonia (PCP) in non-human immunodeficiency virus patients at a tertiary hospital between 2016 and 2022 to evaluate the impact of the COVID-19 pandemic on PCP. The study period was divided into pre-COVID-19 and COVID-19 eras based on the pandemic declaration by the World Health Organization. Among the 113 patients included, the incidence of PCP in the COVID-19 era (37/1000 patient-years) was significantly higher than that in the pre-COVID-19 era (13.1/1000 patient-years) ( p < 0.001). Co-infection with invasive pulmonary aspergillosis (IPA) also increased (2.4% vs. 18.3%, p = 0.013). Independent risk factors for PCP-related mortality were previous glucocorticoid use, hypoxemia, acute kidney injury, and IPA co-infection. Risk factors for IPA in patients with PCP included previous use of tyrosine kinase inhibitors, COVID-19 infection within 30 days, leukopenia, and intensive care unit admission. In the COVID-19 era, 12 (16.9%) patients with PCP had a history of COVID-19 infection within 90 days; however, infection was not associated with mortality. Active evaluation of patients with suspected PCP and assessment of IPA co-infection risk may help improve the outcomes of patients with PCP.

Dentin regeneration is the preferred method used to preserve dental pulp vitality after pulp exposure due to caries. Red light-emitting diode irradiation (LEDI), which is based on photobiomodulation (PBM), has been used to promote hard-tissue regeneration. However, the underlying mechanism still needs elucidation. This study aimed to explore the mechanism involved in red LEDI affecting dentin regeneration. Alizarin red S (ARS) staining revealed that red LEDI induced mineralization of human dental pulp cells (HDPCs) in vitro. We further distinguished the cell proliferation (0-6 d), differentiation (6-12 d), and mineralization (12-18 d) of HDPCs in vitro and treated cells either with or without red LEDI in each stage. The results showed that red LEDI treatment in the mineralization stage, but not the proliferation or differentiation stages, increased mineralized nodule formation around HDPCs. Western blot also indicated that red LEDI treatment in the mineralization stage, but not the proliferation or differentiation stages, upregulated the expression of dentin matrix marker proteins (dentin sialophosphoprotein, DSPP; dentin matrix protein 1, DMP1; osteopontin, OPN) and an intracellular secretory vesicle marker protein (lysosomal-associated membrane protein 1, LAMP1). Therefore, the red LEDI might enhance the matrix vesicle secretion of HDPCs. On the molecular level, red LEDI enhanced mineralization by activating the mitogen-activated protein kinase (MAPK) signaling pathways (ERK and P38). ERK and P38 inhibition reduced mineralized nodule formation and the expression of relevant marker proteins. In summary, red LEDI enhanced the mineralization of HDPCs by functioning to produce a positive effect in the mineralization stage in vitro.

Aims: To determine whether the blood-brain barrier (BBB) opens to enhance drug delivery during the acute stage of unsaturated fat embolism., Methods: We infused oleic, linoleic, and linolenic acid emulsions through the right common carotid artery of rats, followed by trypan blue for gross and lanthanum for electron microscopic (EM) examination. Doxorubicin and temozolomide were also administered, and then the rats were euthanized at 30 min, 1 h, and 2 h. Trypan blue hue was analyzed to semiquantitatively measure BBB opening. Desorption electrospray ionization-mass spectrometry (DESI-MS) imaging was used to evaluate drug delivery., Results: Trypan blue staining observed in each group 30 min after emulsion infusion increased at 1 h and decreased after 2 h in the oleic acid group. The linoleic and linolenic acid groups showed weak staining over time. The hue and trypan blue analysis results were corroborative. EM showed tight junction opening, whereas DESI-MS imaging showed increased doxorubicin and temozolomide signal intensities in ipsilateral hemispheres of all three groups., Conclusion: We demonstrated that oleic, linoleic, and linolenic acid emulsions opened the BBB, promoting drug delivery to the brain. Hue analysis and DESI-MS imaging are appropriate for analysis of doxorubicin and temozolomide concentrations in brain tissue., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Long-term follow-up data on cancer incidence and spectrum among human immunodeficiency virus (HIV)-infected individuals in Korea have been scarce., Material and Methods: This retrospective cohort study included HIV-infected individuals visiting a tertiary care hospital in Busan, South Korea between 1990 and 2021. The observation was divided into 4 periods. The incidence rate was calculated using direct standardization on age and sex, stratified by calendar period., Results: Of the 1,297 patients, 92 patients (7.1%) were diagnosed with 97 cancers. Excluding 37 patients with prevalent cancer, 1,260 patients were followed for a total of 8,803.7 person-years (PYs), and 55 patients developed 60 incident cancers including 5 second primary incident cancers. In men, the AIDS-defining cancer (ADC) incidence decreased from 294.7 per 100,000 PYs in 1990-1997 to 124.8 per 100,000 PYs in 2014-2021, while the non-AIDS-defining cancer (NADC) incidence increased from 0 per 100,000 PYs to 316.5 per 100,000 PYs during the same period. The proportion of virus-unrelated NADCs (VU-NADCs) increased from 33.3% in 1998-2005 to 49% in 2014-2021. The proportion of human papillomavirus-associated cancers (HPVACs) has recently increased in both ADCs and NADCs. The median time from HIV diagnosis to their first cancer was 1.48 years for ADCs, 6.11 years for VR-NADCs, 8.3 years for VU-NADCs, and 11.5 years for HPVACs., Conclusion: The incidence of NADCs is increasing with the aging of HIV-infected patients, and thus, it is necessary to promote cancer screening and prevention programs., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to disclose., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Context: Telomerase reverse transcriptase is a key factor responsible for structural and cellular alterations in aged oocytes and changes in the structure of the zona pellucida and mitochondria. Telomerase expression is reduced in aged cumulus oocyte complexes, and its activation or enhanced expression would be beneficial for in vitro oocyte maturation and in vitro embryo development., Aims: This study aimed to investigate telomerase activation by cycloastragenol and its effect on bovine oocyte in vitro maturation, fertilisation, and early embryo development., Methods: We used qPCR, Western blot, immunofluorescence, reactive oxygen species (ROS) assay,TUNEL assay, JC-1 assay, and invasion assay to analyse the affect of cycloastragenol (CAG) on bovine oocyte maturation, embryo development, embryo quality and implantation potential., Key Results: Cycloastragenol treatment of oocytes in in vitro maturation (IVM) media significantly (P <0.05) improved oocyte IVM (90.87%), embryo cleavage (90.78%), blastocyst hatching (27.04%), and embryo implantation potential. Telomerase also interacts with mitochondria, and JC-1 staining results showed significantly (P <0.05) higher mitochondrial membrane potential (ΔΨ m) in the CAG-treated group. Furthermore, the inner cell mass (OCT4 and SOX2) and trophoblasts (CDX2) of the control and CAG groups were examined. Moreover, CAG treatment to primary cultured bovine cumulus cells substantially enhanced telomerase activity., Conclusions: Telomerase activation via cycloastragenol is beneficial for bovine oocyte IVM and for the production of high-quality bovine embryos., Implications: Cycloastragenol is a natural telomerase activator, and could be useful as a permanent component of oocyte maturation media.

Osteoblasts must acquire a considerable capacity for folding unfolded and misfolded proteins (MPs) to produce large amounts of extracellular matrix proteins and maintain bone homeostasis. MP accumulation contributes to cellular apoptosis and bone disorders. Photobiomodulation therapy has been used to treat bone diseases, but the effects of decreasing MPs with photobiomodulation remain unclear. In this study, we explored the efficacy of 625 nm light-emitting diode irradiation (LEDI) to reduce MPs in tunicamycin (TM) induced-MC3T3-E1 cells. Binding immunoglobulin protein (BiP), an adenosine triphosphate (ATP)-dependent chaperone, is used to evaluate the capacity of folding MPs. The results revealed that pretreatment with 625 nm LEDI (Pre-IR) induced reactive oxygen species (ROS) production, leading to the increased chaperone BiP through the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1s (XBP-1s) pathway, and then restoration of collagen type I (COL-I) and osteopontin (OPN) expression relieving cell apoptosis. Furthermore, the translocation of BiP into the endoplasmic reticulum (ER) lumen might be followed by a high level of ATP production. Taken together, these results suggest that Pre-IR could be beneficial to prevent MP accumulation through ROS and ATP in TM-induced MC3T3-E1cells.

Although chimeric antigen receptor T cell (CAR-T) is a promising immunotherapy in hematological malignancies, there remain many obstacles to CAR-T cell therapy for solid tumors. Identifying appropriate tumor-associated antigens (TAAs) is especially critical for success. Using a bioinformatics approach, we identified common potential TAAs for CAR-T cell immunotherapy in solid tumors. We used the GEO database as a training dataset to find differentially expressed genes (DEGs) and verified candidates using the TCGA database, obtaining seven common DEGs (HM13, SDC1, MST1R, HMMR, MIF, CD24, and PDIA4). Then, we used MERAV to analyze the expression of six genes in normal tissues to determine the ideal target genes. Finally, we analyzed tumor microenvironment factors. The results of major microenvironment factor analyses showed that MDSCs, CXCL1, CXCL12, CXCL5, CCL2, CCL5, TGF-β, CTLA-4, and IFN-γ were significantly overexpressed in breast cancer. The expression of MST1R was positively correlated with TGF-β, CTLA-4, and IFN-γ. In lung adenocarcinoma, MDSCs, Tregs, CXCL12, CXCL5, CCL2, PD-L1, CTLA-4, and IFN-γ were significantly overexpressed in tumor tissues. The expression of MST1R was positively correlated with TGF-β, CTLA-4, and IFN-γ. In bladder cancer, CXCL12, CCL2, and CXCL5 were significantly overexpressed in tumor tissues. MST1R expression was positively correlated with TGF-β. Our results demonstrate that MST1R has the potential as a new target antigen for treating breast cancer, lung adenocarcinoma, and bladder cancer and may be used as a progression indicator for bladder cancer.

Background: Bacterial infection is common in acute cholecystitis (AC). To identify appropriate empirical antibiotics, we investigated AC-associated microorganisms and their susceptibilities to antibiotics. We also compared preoperative clinical findings of patients grouped according to specific microorganisms., Methods: Patients who underwent laparoscopic cholecystectomy for AC between 2018 and 2019 were enrolled. Bile cultures and antibiotic susceptibility tests were performed, and clinical findings of patients were noted., Results: A total of 282 patients were enrolled (147 culture-positive and 135 culture-negative). The most frequent microorganisms were Escherichia (n = 53, 32.7%), Enterococcus (n = 37, 22.8%), Klebsiella (n = 28, 17.3%), and Enterobacter (n = 18, 11.1%). For Gram-negative microorganisms, second-generation cephalosporin (cefotetan: 96.2%) was more effective than third-generation cephalosporin (cefotaxime: 69.8%). Vancomycin and teicoplanin (83.8%) were the most effective antibiotics for Enterococcus. Patients with Enterococcus had higher rates of CBD stones (51.4%, p = 0.001) and biliary drainage (81.1%, p = 0.002), as well as higher levels of liver enzymes, than patients with other microorganisms. Patients with ESBL-producing bacteria had higher rates of CBD stones (36.0% vs. 6.8%, p = 0.001) and biliary drainage (64.0% vs. 32.4%, p = 0.005) than those without., Discussion: Preoperative clinical findings of AC are related to microorganisms in bile samples. Periodic antibiotic susceptibility tests should be conducted to select appropriate empirical antibiotics., Competing Interests: Conflicts of interest None declare., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Bis(2-ethylhexyl) phthalate (DEHP) is the most used member of the phthalate class of compounds. Extensive use of this plasticizer allows daily exposure to humans via various routes. A positive relationship between DEHP exposure and neurobehavioral disorders is suspected. But, there are insufficient data on the harmfulness of neurobehavioral disorders caused by DEHP exposure, particularly at daily exposure levels. In this study, we assessed the consequences of daily DEHP ingestion (2 and 20 mg/kg diets) in male mice for at least 100 days and examined its effects on neuronal functions associated with neurobehavioral disorders, such as depression and cognitive decline. We found the marked depressive behaviors and reduced learning and memory function in the DEHP-ingestion groups, and that biomarkers related to chronic stress were increased in plasma and brain tissues. Long-term DEHP ingestion induced collapse of glutamate (Glu) and glutamine (Gln) homeostasis as a result of disruption of the Glu-Gln cycle in the medial prefrontal cortex and hippocampus. The reduced glutamatergic neurotransmission activity caused by DEHP ingestion was demonstrated using an electrophysiological method. This study revealed that long-term exposure to DEHP is hazardous and can cause neurobehavioral disorders, even at daily exposure levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Heparan sulfate (HS) is a heterogeneous, cell-surface polysaccharide critical for transducing signals essential for mammalian development. Imaging of signaling proteins has revealed how their localization influences their information transfer. In contrast, the contribution of the spatial distribution and nanostructure of information-rich, signaling polysaccharides like HS is not known. Using expansion microscopy (ExM), we found striking changes in HS nanostructure occur as human pluripotent stem (hPS) cells differentiate, and these changes correlate with growth factor signaling. Our imaging studies show that undifferentiated hPS cells are densely coated with HS displayed as hair-like protrusions. This ultrastructure can recruit fibroblast growth factor for signaling. When the hPS cells differentiate into the ectoderm lineage, HS is localized into dispersed puncta. This striking change in HS distribution coincides with a decrease in fibroblast growth factor binding to neural cells. While developmental variations in HS sequence were thought to be the primary driver of alterations in HS-mediated growth factor signaling, our high-resolution images indicate a role for the HS nanostructure. Our study highlights the utility of high-resolution glycan imaging using ExM. In the case of HS, we found that changes in how the polysaccharide is displayed link to profound differences in growth factor binding.

While inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, due to compliance, drug safety, and resistance issues, new medications to replace ICSs are in high demand. Inotodiol, a fungal triterpenoid, showed a unique immunosuppressive property with a preference for mast cells. It exerted a mast cell-stabilizing activity equally potent to dexamethasone in mouse anaphylaxis models when orally administered in a lipid-based formulation, upgrading bioavailability. However, it was four to over ten times less effective in suppressing other immune cell subsets, depending on the subsets, than dexamethasone showing invariably potent inhibition. Accordingly, inotodiol affected the membrane-proximal signaling for activating mast cell functions more profoundly than other subsets. Inotodiol also effectively prevented asthma exacerbation. Importantly, considering the no-observed-adverse-effect level of inotodiol was over 15 times higher than dexamethasone, its therapeutic index would be at least eight times better,implying that inotodiol is a viable option for replacing CSs in treating asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Two new alkaloids, streptopyrroles B and C ( 1 and 2 ), were discovered through a chemical investigation of the ethyl acetate (EtOAc) extract from a marine-derived actinomycete, Streptomyces zhaozhouensis , along with four known analogs ( 3 - 6 ). The structures of the new compounds were elucidated by spectroscopic analysis (HR-ESIMS, 1D, and 2D NMR) and a comparison of their experimental data with literature values. The new compounds were evaluated for their antimicrobial activity by standard broth dilution assay, and the tested compounds showed significant activity against Gram-positive bacteria with minimum inhibitory concentration (MIC) values ranging from 0.7 to 2.9 µM, and kanamycin was used as a positive control with MIC values ranging from <0.5 to 4.1 µM. Additionally, 1 , 3 , and 5 were evaluated for their cytotoxicity against six tumor cell lines by sulforhodamine B (SRB) assay, and these compounds displayed cytotoxic activities against all the tested cell lines, with concentration causing 50% cell growth inhibition (GI 50 ) values ranging from 4.9 to 10.8 µM, while a positive control, adriamycin, showed GI 50 values of 0.13-0.17 µM.

Recycling lithium-ion batteries has recently become a major concern. Ammonia leaching is commonly employed in such battery recycling methods since it has various advantages such as low toxicity and excellent selectivity toward precious metals. In this study, an electrochemical system with intercalation-type electrodes was used to investigate the selective recovery of lithium and ammonium from ammonia battery leachate. Using an activated carbon electrode as a counter electrode, the selectivity of lithium from the lithium manganese oxide (LMO) electrode and the selectivity of ammonium from the nickel hexacyanoferrate (NiHCF) electrode were examined within the system. The LMO//NiHCF system was next evaluated for lithium and ammonium recovery using a synthetic solution as well as real ammonia battery leachate. When compared to previous ammonium recovery methods, the results revealed good selectivity of lithium and ammonium from each LMO and NiHCF electrode with relatively low energy consumption for ammonium recovery (2.43 Wh g-N -1 ). The average recovery capacity of lithium was 1.39 mmol g -1 with a purity of up to 96.8% and the recovery capacity of ammonium was 1.09 mmol g -1 with 97.8% purity from the pre-treated leachate. This electrochemical method together with ammonia leaching can be a promising method for selective resource recovery from spent lithium-ion batteries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The unfavorable effects of environmental pollutants are becoming increasingly evident. In recent years, Caenorhabditis elegans (C. elegans) has been used as a powerful terrestrial model organism for environmental toxicity studies owing to its various advantages, including ease of culture, short lifespan, small size, transparent body, and well-characterized genome. In vivo bioassays and field studies can analyze and evaluate various toxic effects of the toxicants on the model organism, while emerging technologies allow profound insights into molecular disturbances underlying the observed phenotypes. In this review, we discuss the applications of C. elegans as a model organism in environmental toxicity studies and delineate apical assays such as lifespan, growth rate, reproduction, and locomotion, which are widely used in toxicity evaluation. In addition to phenotype assays, a comprehensive understanding of the toxic mode of action and mechanism can be achieved through a highly sensitive multi-omics approach, including the expression levels of genes and endogenous metabolites. Recent studies on environmental toxicity using these approaches have been summarized. This review highlights the practicality and advantages of C. elegans in evaluating the toxicity of environmental pollutants and presents the findings of recent toxicity studies performed using this model organism. Finally, we propose crucial technical considerations to escalate the appropriate use of C. elegans in examining the toxic effects of environmental pollutants., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Outer membrane vesicles (OMVs) are spherical bilayered nanoparticles derived from the outer layer of Gram-negative bacteria. Bacteria communicate with nearby bacteria, their environment, and the cells of their host by secreting OMVs, which are essential for their survival. OMVs also play a critical role in bacterial pathogenesis since they are loaded with virulence factors, toxins, and enzymes. OMVs may modulate the immune response of the host by initiating inflammation through cytokine production and activating the innate immune response. OMVs also contribute to the resistance of bacteria to antibiotics by carrying antibiotic-degrading enzymes and acting as natural protection barriers. Concerns have also been raised regarding OMVs mediating the transfer of antibiotic resistance. Due to their advantageous properties, OMVs are attractive platforms for vaccine discovery and drug delivery research. In this review, we discuss the fundamental structure and biogenesis mechanisms of OMVs as well as their multifaceted roles in bacterial infection pathogenesis and host immune responses. We also discuss application examples of OMVs., Competing Interests: No conflict of interest., (Copyright © 2023 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Background and Objectives: mRNA-based protein expression technology has been used to express functional proteins. We have previously generated dopamine neurons from rat-embryo derived neural precursor cells (NPCs) through repeated transfection of synthetic transcription factor mRNA encoding dopamine-inducible genes. However, NPCs began to die approximately 10 d post-transfection. In this study, we examined a long-term transfection protocol that did not affect cell viability., Methods and Results: Experiments were performed in eight groups sorted according to the start date of mRNA transfection. mRNA was transfected into NPCs daily for 21 d and live cell images of each group were recorded. NPCs which were differentiated for more than five days showed sustained gene expression and appreciable viability despite daily mRNA transfection for 21 d., Conclusions: Repeated mRNA transfection requires cells with a sufficient differentiation period.

We aimed to evaluate various aspects of antibiotic therapy as factors associated with candidemia in non-neutropenic patients. A retrospective, matched, case-control study was conducted in two teaching hospitals. Patients with candidemia (cases) were compared to patients without candidemia (controls), matched by age, intensive care unit admission, duration of hospitalization, and type of surgery. Logistic regression analyses were performed to identify factors associated with candidemia. A total of 246 patients were included in the study. Of 123 candidemia patients, 36% had catheter-related bloodstream infections (CRBSIs). Independent factors in the whole population included immunosuppression (adjusted odds ratio [aOR] = 2.195; p = 0.036), total parenteral nutrition (aOR = 3.642; p < 0.001), and anti-methicillin-resistant S. aureus (MRSA) therapy for ≥11 days (aOR = 5.151; p = 0.004). The antibiotic factor in the non-CRBSI population was anti-pseudomonal beta-lactam treatment duration of ≥3 days (aOR = 5.260; p = 0.008). The antibiotic factors in the CRBSI population included anti-MRSA therapy for ≥11 days (aOR = 10.031; p = 0.019). Antimicrobial stewardship that reduces exposure to these antibacterial spectra could help prevent the development of candidemia.

This article shows experimentally that an external electric field affects the velocity of the longitudinal acoustic phonons ( v LA ), thermal conductivity (κ), and diffusivity ( D ) in a bulk lead zirconium titanate-based ferroelectric. Phonon conduction dominates κ, and the observations are due to changes in the phonon dispersion, not in the phonon scattering. This gives insight into the nature of the thermal fluctuations in ferroelectrics, namely, phonons labeled ferrons that carry heat and polarization. It also opens the way for phonon-based electrically driven all-solid-state heat switches, an enabling technology for solid-state heat engines. A quantitative theoretical model combining piezoelectric strain and phonon anharmonicity explains the field dependence of v LA , κ, and D without any adjustable parameters, thus connecting thermodynamic equilibrium properties with transport properties. The effect is four times larger than previously reported effects, which were ascribed to field-dependent scattering of phonons.

In recent years, deep learning (DL) has been widely studied using various methods across the globe, especially with respect to training methods and network structures, proving highly effective in a wide range of tasks and applications, including image, speech, and text recognition. One important aspect of this advancement is involved in the effort of designing and upgrading neural architectures, which has been consistently attempted thus far. However, designing such architectures requires the combined knowledge and know-how of experts from each relevant discipline and a series of trial-and-error steps. In this light, automated neural architecture search (NAS) methods are increasingly at the center of attention; this paper aimed at summarizing the basic concepts of NAS while providing an overview of recent studies on the applications of NAS. It is worth noting that most previous survey studies on NAS have been focused on perspectives of hardware or search strategies. To the best knowledge of the present authors, this study is the first to look at NAS from a computer vision perspective. In the present study, computer vision areas were categorized by task, and recent trends found in each study on NAS were analyzed in detail.

The characterization of soft tissues remains a vital need for various bioengineering and medical fields. Developing areas such as regenerative medicine, robot-aided surgery, and surgical simulations all require accurate knowledge about the mechanical properties of soft tissues to replicate their mechanics. Mechanical properties can be characterized through several different characterization techniques such as atomic force microscopy, compression testing, and tensile testing. However, many of these methods contain considerable differences in ability to accurately characterize the mechanical properties of soft tissues. As a result of these variations, there are often discrepancies in the reported values for numerous studies. This paper reviews common characterization methods that have been applied to obtain the mechanical properties of soft tissues and highlights their advantages as well as disadvantages. The limitations, accuracies, repeatability, in-vivo testing capability, and types of properties measurable for each method are also discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Obtaining the mechanical properties of soft tissues is critical in many medical fields, such as regenerative medicine and surgical simulation training. Although various tissue-characterization methods have been developed, such as AFM, indentation, and elastography, there remain some limitations on their accuracy and validity for measuring small and fragile soft tissues. This paper presents a tensile testing technique to measure the mechanical properties of soft tissues directly and accurately. Tensile testing was chosen as the primary method because of its simple procedure and ability to derive mechanical properties without requiring many assumptions or complicated models. However, tensile testing on soft tissues presents challenges related to gripping the tissue sample without affecting its inherent properties, applying minuscule forces to the sample, and measuring the cross-section area and strain of the sample. To solve these issues, this study presents a sub-micro scale tensile testing system that uses a flexure mechanism and a novel 3D-printed sample holder for gripping the tissue samples. The system also measures tested samples' cross-section area and strain using two high-resolution cameras. The system was validated by testing standard materials and used to characterize the elastic modulus, yield stress, and yield strain of lung tissue slices from six different mice. The results from the validation tests showed a less than 2.5% error for elastic modulus values measured using the tensile tester. At the same time, results from the mice lung tissue measurements revealed qualitative findings that closely matched those seen in the literature and displayed low coefficient of variation values, demonstrating the high repeatability of the system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study was conducted to determine the optimal boiling time to reduce ptaquiloside (PTA) and to carry out a risk assessment for PTA, a representative toxic substance found in bracken fern (BF; Pteridium aquilinum ), which is frequently consumed as food in East Asian countries. High-performance liquid chromatography showed that the concentration of PTA in BF was reduced by up to 99% after boiling for 20 min. Risk assessment results showed that the cancer margin of exposure (MOE; ≥ 25,000 = safe) to PTA for an average daily exposure scenario after boiling BF for 20 min was considered safe. In addition, the non-cancer MOE (≥ 300 = safe) to PTA under an average daily exposure scenario after BF boiling for 20 min was considered safe. However, human exposure to PTA was considered unsafe under the non-boiled BF exposure and maximum daily exposure scenarios. Therefore, boiling BF for at least 20 min is recommended before consumption, to reduce exposure to PTA as much as possible., Competing Interests: The authors declare no conflicts of interest.

Background/purpose: The current study aimed to develop a prediction model using a multi-marker panel as a diagnostic screening tool for pancreatic ductal adenocarcinoma., Methods: Multi-center cohort of 1991 blood samples were collected from January 2011 to September 2019, of which 609 were normal, 145 were other cancer (colorectal, thyroid, and breast cancer), 314 were pancreatic benign disease, and 923 were pancreatic ductal adenocarcinoma. The automated multi-biomarker Enzyme-Linked Immunosorbent Assay kit was developed using three potential biomarkers: LRG1, TTR, and CA 19-9. Using a logistic regression model on a training data set, the predicted values for pancreatic ductal adenocarcinoma were obtained, and the result was classification into one of the three risk groups: low, intermediate, and high. The five covariates used to create the model were sex, age, and three biomarkers., Results: Participants were categorized into four groups as normal (n = 609), other cancer (n = 145), pancreatic benign disease (n = 314), and pancreatic ductal adenocarcinoma (n = 923). The normal, other cancer, and pancreatic benign disease groups were clubbed into the non-pancreatic ductal adenocarcinoma group (n = 1068). The positive and negative predictive value, sensitivity, and specificity were 94.12, 90.40, 93.81, and 90.86, respectively., Conclusions: This study demonstrates a significant diagnostic performance of the multi-marker panel in distinguishing pancreatic ductal adenocarcinoma from normal and benign pancreatic disease states, as well as patients with other cancers., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) is a risk factor associated with vascular diseases. Wnt signaling is one of the major mechanisms implicated in the osteogenic conversion of VSMCs. Since Cdon has a negative effect on Wnt signaling in distinct cellular processes, we sought to investigate the role of Cdon in vascular calcification. The expression of Cdon was significantly downregulated in VSMCs of the aortas of patients with atherosclerosis and aortic stenosis. Consistently, calcification models, including vitamin D3 (VD3)-injected mice and VSMCs cultured with calcifying media, exhibited reduced Cdon expression. Cdon ablation mice (cKO) exhibited exacerbated aortic stiffness and calcification in response to VD3 compared to the controls. Cdon depletion induced the osteogenic conversion of VSMCs accompanied by cellular senescence. The Cdon-deficient aortas showed a significant alteration in gene expression related to cell proliferation and differentiation together with Wnt signaling regulators. Consistently, Cdon depletion or overexpression in VSMCs elevated or attenuated Wnt-reporter activities, respectively. The deletion mutant of the second immunoglobulin domain (Ig2) in the Cdon ectodomain failed to suppress Wnt signaling and osteogenic conversion of VSMCs. Furthermore, treatment with purified recombinant proteins of the entire ectodomain or Ig2 domain of Cdon displayed suppressive effects on Wnt signaling and VSMC calcification. Our results demonstrate a protective role of Cdon in VSMC calcification by suppressing Wnt signaling. The Ig2 domain of Cdon has the potential as a therapeutic tool to prevent vascular calcification., (© 2023. The Author(s).)

Background: Locally advanced (unresectable) pancreatic cancer (LAPC) is surgically unresectable and often treated with chemotherapy. Most previous studies, that have evaluated conversion surgery after chemotherapy, included heterogeneous patients and chemotherapy regimens, making it challenging to determine the impact of FOLFIRINOX. The present study evaluated the survival benefit of conversion surgery in patients with LAPC who received FOLFIRINOX chemotherapy, and analyzed the prognostic factors., Methods: Patients with LAPC who received FOLFIRINOX as first-line therapy for at least four cycles were included. During chemotherapy, surgical eligibility was determined based on radiologic and metabolic response to the treatment. Clinicopathologic characteristics were compared between the curative-intent surgery and non-resection groups, and the prognostic factors were analyzed., Results: A total of 279 patients were included. The rates of partial response (PR) and stable disease (SD) were 34.1% and 51.4%, respectively, and 16.8% patients underwent curative-intent surgery. The median survival was significantly longer in the resection group than in the non-resection group (56 vs 21 months, P < .001). In a multivariate analysis, curative-intent surgery (HR 0.260; P < .001) was the most important factor., Conclusions: Conversion surgery after FOLFIRINOX chemotherapy effectively rescues patients with LAPC. Patients without progression after FOLFIRINOX could be considered as potential candidates for conversion surgery., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objectives: Deep brain stimulation (DBS) is a safe and effective treatment option for patients with movement disorders as Parkinson's disease, essential tremor and dystonia[1]. For many of these patients the need for imaging may arise in the following years after implantation. The study's aim was to get an overview of the amount of patients with a DBS system who needed an MRI after successful implantation, and if they did, whether the imaging led to a surgical consequence., Materials and Methods: In this retrospective descriptive work patients were included if they had their DBS implantation for at least 12 months at the time of analysis. Data were collected by retrospective analysis of the electronic patient files as well as a telephone interview. The reason of each imaging performed was assessed, if patients got MRI after the implantation, it was additionally recorded whether imaging led to a consequence (conservative treatment or surgery). An independent neurologist assessed if an MRI would have been better than a CT for the particular indication., Results: From 54 included patients, 28 patients received imaging after implantation, either CT or MRI. 7 patients underwent MRIs, of whom 3 patients received cranial MRIs and 4 patients received lumbar spine MRIs. All cranial MRIs led to conservative therapy, in 2 lumbar MRIs the diagnosis led to surgery. Nearly 13 % of the imaging performed in our study population occurred because of fall events, 9 of the included patients developed or have had a tumor diagnosis., Conclusions: Safety of MRI for patients with implanted DBS-systems is and remains an important consideration. Since it can be assumed that patients at a younger age are more likely to get an MRI in the course of their disease, we suggest paying particular attention to the MRI's suitability of the DBS device by patients age. In the end it remains always an individual decision for the surgeon or the consulting physician, which system to use., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: In general, bile is normally sterile. However, there are reports bactibilia may occur in certain instances, though the causal factors are unclear. We analyzed possible preoperative predictors of bactibilia upon cholecystectomy., Methods: Bile samples were collected during cholecystectomies from November 2018 to November 2019. A total of 428 open or laparoscopic cholecystectomies were performed. Preoperative, intraoperative, and postoperative variables were compared between the culture-positive and culture-negative groups., Results: One hundred fifty-seven patients (36.7%) were culture-positive. Gram-negative bacteria (95 [61.0%]) were more common. Escherichia coli (38 [40.0%]) and Enterobacter (22 [23.2%]) were the most common species. In univariate analysis, age of ≥70 years (P < 0.001), male sex (P < 0.001), high American Society of Anesthesiologists physical status grades (P = 0.001), diabetes mellitus (P = 0.002), jaundice (P = 0.007), high Tokyo Guideline grades (P = 0.008), percutaneous transhepatic gallbladder drainage (PTGBD; P < 0.001), endoscopic retrograde cholangiopancreatography (ERCP; P < 0.001) were identified as a risk factors for bactibilia. In multivariate analysis, age of ≥70 years (hazard ratio [HR], 2.874; 95% confidence interval [CI], 1.769-4.670; P = 0.001), ERCP (HR, 9.001; 95% CI, 4.833-16.75; P < 0.001), and PTGBD (HR, 2.866; 95% CI, 1.440-4.901; P = 0.002) were independent risk factors for bactibilia., Conclusion: Among patients who underwent cholecystectomy, those who were elderly, symptomatic, and underwent preoperative drainage were more likely to have bactibilia. In such cases, surgeons should take care to prevent bile leakage during surgery and consider administering appropriate antibiotics., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2023, the Korean Surgical Society.)